Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(C=CC=1)CSC1OC(C2C=CN=C(N)C=2)=NN=1.C(N(CC)CC)C.C(Cl)(=O)C=C.[C:34]([N:38]([C:43]1[CH:48]=[C:47]([C:49]2[O:50][C:51]([S:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[CH:57]=3)=[N:52][N:53]=2)[CH:46]=[CH:45][N:44]=1)C(=O)C=C)(=[O:37])[CH:35]=[CH2:36]>O1CCCC1.C(OCC)(=O)C>[F:62][C:58]1[CH:57]=[C:56]([CH:61]=[CH:60][CH:59]=1)[CH2:55][S:54][C:51]1[O:50][C:49]([C:47]2[CH:46]=[CH:45][N:44]=[C:43]([NH:38][C:34](=[O:37])[CH:35]=[CH2:36])[CH:48]=2)=[N:53][N:52]=1
Reactant: C=CC(=O)N(C(=O)C=C)c1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Agent: C=CC(=O)Cl
Agent: Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 4-[5-[(3-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]pyridin-2-amine (1.35 g, 4.75 mmol) and triethylamine (1.98 mL, 14.25 mmol) in tetrahydrofuran (100 mL) was added acryloyl chloride (0.97 mL, 11.88 mmol) at 0° C., and the resulting mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) to give a mixture (1/1, 1.08 g, yield 61%) of N-[4-[5-[(3-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]-2-pyridyl]acrylamide and N-acryloyl-N-[4-[5-[(3-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]-2-pyridyl]acrylamide as pale-yellow crystals.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][N:10]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:11](=[O:22])[NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].I[CH:49]([CH3:51])[CH3:50]>CC(C)=O>[CH:49]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([NH:12][C:11]([N:10]([CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:22])[CH:14]=1)([CH3:51])[CH3:50]
Reactant: O=C(O)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)OC(=O)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Yield: 99 %

Procedure:
200 mg (0.41 mmol, 1 eq.) of product of Example 45 are dissolved in 2 mL of acetone and 2 mL of dry DMF under argon. 283 mg (2.05 mmol, 5 eq.) of K2CO3 and 328 μL (3.28 mmol, 8 eq.) of 2-iodopropane, the mixture is heated under reflux for 2 hours. The medium is then concentrated and taken up in water and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water then brine, dried over MgSO4, filtered and concentrated. The oil obtained is freed from DMF by entraining the DMF to the rotary evaporator with ethyl acetate, then dried with a vane pump. The product is obtained in the form of white crystals (m=214 mg, yield=99%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([NH:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:19]([CH:24]=2)[C:20]([O:22]C)=O)=[O:14])[N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.Cl>CO.O>[Br:3][C:4]1[N:5]=[C:6]([C:13]([C:15]2[CH:24]=[C:19]3[C:18](=[CH:17][CH:16]=2)[NH:25][C:26](=[O:38])[N:27]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:20]3=[O:22])=[O:14])[N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12
Reactant: COC(=O)c1cc(C(=O)c2nc(Br)c3ccccn23)ccc1NC(=O)NCCOc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(c1ccc2[nH]c(=O)n(CCOc3ccc(F)cc3)c(=O)c2c1)c1nc(Br)c2ccccn12
Yield: 92.8 %

Procedure:
60.1 ml (60.1 mmol) of a 1N aqueous solution of sodium hydroxide are added to 6.67 g (12 mmol) of methyl 5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-({[2-(4-fluorophenoxy)ethyl]carbamoyl}amino)benzoate dissolved in 600 ml of methanol. After refluxing for 2 hours, the reaction medium is acidified with 120 ml of a 1N aqueous solution of hydrochloric acid and then diluted with 2000 ml of water. The precipitate obtained is filtered off, and dried under reduced pressure at 40° C. overnight. 5.83 g of a yellow solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH2:8][NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:25]([O:27][CH3:28])=[O:26]>C(OCC)C>[CH:10]1([N:9]([CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[C:25](=[O:26])[O:27][CH3:28])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(CCNC2CCCC2)cc1
Reactant: COC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)N(CCc1ccc(OC)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of N-(4-methoxyphenethyl)cyclopentanamine (0.827 g, 3.77 mmol) in diethyl ether was added triethylamine (0.83 mL, 5.66 mmol) and methyl chloroformate (0.44 mL, 5.66 mmol) at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 30 min. Filtration and concentration of mixture under reduced pressure gave the crude product which was purified by silica gel column chromatography using hexanes/ethyl acetate to provide the product (0.898 g, 86%) as light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.10 (d, 2H, J=8.6 Hz), 6.81 (d, 211, J=8.6 Hz), 4.32-4.12 (m, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.24 (t, 2H, J=7.9 Hz), 2.76 (t, 2H, J=7.9 Hz), 1.79-1.76 (m, 2H), 1.67-1.66 (m, 2H), 1.54-1.47 (m, 4H). LC-MS (ESI) Calcd for C16H23NO3 [M+H]+: 278.17. Found: 278.00.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:13][CH:12]([OH:14])[CH:11]([OH:15])[CH2:10]1.CCN(C(C)C)C(C)C.[N:25]1([C:31]([NH:33][C@@H:34]([CH2:38][S:39]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)(=[O:41])=[O:40])[C:35](O)=[O:36])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:15][CH:11]1[CH:12]([OH:14])[CH2:13][CH:9]([NH:8][C:35]([C@@H:34]([NH:33][C:31]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:32])[CH2:38][S:39]([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)(=[O:41])=[O:40])=[O:36])[CH2:10]1
Reactant: NC1CC(O)C(O)C1
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NC1CC(O)C(O)C1)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
A solution of 4-amino-cyclopentane-1,2-diol; compound with trifluoroacetic acid (745 mg, 3.23 mmol) in DMF (15 ml) was treated with DIPEA (1.12 ml, 6.4 mmol) and the mixture was stirred for 5 minutes at room temperature. Then (R)-2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (1.15 g, 3.23 mmol) was added followed by HATU (1.23 g, 3.24 mmol). This mixture was stirred at room temperature overnight and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate and then with a mixture of ethyl acetate and methanol to give morpholine-4-carboxylic acid [(R)-1-(3,4-dihydroxy-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide as a brown solid (680 mg). LC/MS: RT=2.64 min. (215 and 254 nM), MH+=456.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C@:14]2([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:15]([O:32]2)[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC=C(Cc2ccccc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC[C@@]2(Cc3ccccc3)O[C@H]2C1
Reaction time: 2 h

Procedure:
To a solution of 36.0 g (117 mmol) of 4-benzyl-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester in 250 ml CH2Cl2 were added 40.9 g (166 mmol, ˜70%) MCPBA. The reaction mixture was stirred for 2 hours and a 1N NaOH-solution was added. The aqueous phase was extracted twice with CH2Cl2 and the combined organic layers were washed with 1 N NaOH, dried over MgSO4 and the solvent was removed under reduced pressure to give 37.6 g (116 mmol, 99%) of (1R,6S) and (1S,6R)-6-benzyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([Cl:16])=[CH:14][NH:13][C:12](=[O:17])[CH:11]=2)[CH:3]=1.Br[CH:19]([CH3:23])[C:20]([OH:22])=[O:21]>>[Cl:16][C:15]1[C:10]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])=[CH:11][C:12](=[O:17])[N:13]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:14]=1.[ClH:1]
Reactant: CC(Br)C(=O)O
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1Cl
Product: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: Cl
Reaction time: 2.5 h

Procedure:
910 mg (purity 57%, 1.96 mmol) of 4-chloro-2-(5-chloro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A, initially at RT for 2.5 h and then at 45° C. overnight. The desired product was obtained by precipitation with hydrochloric acid. Yield: 1.06 g (purity 78%, quant.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:11][C:12](=[O:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Br[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CC(CC(C)=O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:11][C:12](=[O:14])[CH3:13])([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:10]
Reactant: CC(C)=CCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCOC(=O)C(CCC=C(C)C)(NC(C)=O)C(=O)OCC

Procedure:
27.1 g of acetamidomalonic acid diethyl ester are heated for 14 hours with 19.6 g of 5-bromo-2-methyl-2-pentene and 16.6 g of potassium carbonate in 100 ml of MIBK in a water separator. The reaction solution was extracted with 100 ml of water, and the organic phase was concentrated in vacuo. LC-MS analysis of the residue shows that it is a mixture of N-acetyl-D,L-2-amino-6-methyl-5-heptenoic acid ethyl ester (M+H+=228) and acetamido-(4-methyl-3-pentenyl)-malonic acid diethyl ester (M+H+=300) in a ratio of 3:2.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7](=[O:20])[C:8](=[CH:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[S:9][C:4]=2[CH:3]=1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[O:20]=[C:7]1[NH:6][C:5]2[CH:21]=[CH:22][C:2]([NH:1][C:28]([NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[CH:3][C:4]=2[S:9][C:8]1=[CH:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ccc2c(c1)SC(=Cc1c[nH]c3ccccc13)C(=O)N2
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Nc1ccc2c(c1)SC(=Cc1c[nH]c3ccccc13)C(=O)N2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 7-amino-2-[(indol-3-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (see Example 38) (0.17 g, 0.55 mmol) and tert-butyl isocyanate (0.17 g, 1.75 mmol) in dry DMF (1 ml) was stirred at room temperature for 4 days. The reaction was poured into water (25 ml) and the precipitated solid was collected by filtration. The precipitate was purified by silica gel chromatography using a gradient of (9:1) to (4:6) toluene:ethyl acetate as the mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[C:13]2[C:16]([F:19])([F:18])[CH3:17])[CH:11]=[CH:10][CH:9]=[N:8]3)=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:20]#[N:21])([C:16]([F:19])([F:18])[CH3:17])[C:14]=2[CH:15]=1
Reactant: CC(F)(F)c1c2cc(Cl)ccc2nc2ncccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(F)(F)C1(C#N)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 15 h
Yield: 70 %

Procedure:
Method NN: To a stirred solution of 7-chloro-9-(1,1-difluoroethyl)-4-azaacridine (47) (1.440 g, 5.167 mmol) in anhydrous DMF (25 mL) at room temperature was added NaCN (533 mg, 10.334 mmol). After 15 h at room temperature, the reaction was quenched with 1:1 saturated aqueous NaHCO3/H2O (50 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (20%-40% EtOAc-hexane, gradient elution) furnished 49 (1.106 g, 70% yield) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cccnc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2c(c1)NCCC2
Reaction time: 18 h
Yield: 45.5 %

Procedure:
A solution of 7-bromoquinoline (J. Amer. Chem. Soc., 1947, 69, 705) (362 mg, 1.74 mmol) in glacial acetic acid (10 ml) was treated portion-wise with sodium cyanoborohydride (437 mg, 7.0 mmol) under argon at room temperature. After 18 h at this temperature, the mixture was cooled in an ice bath and to it was added water (35 ml) and 50% aq. sodium hydroxide until pH 14 was attained. The mixture was extracted with dichloromethane and the organic phase washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated in vacuo to a residue which was purified by column chromatography over silica gel eluting with a gradient of methanol/dichloromethane to give the title compound (D15) (168 mg, 46%). MH+ 212/214.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[CH3:19][S:20]([N:23]1[CH2:28][C@@H:27]([CH3:29])[NH:26][C@@H:25]([CH3:30])[CH2:24]1)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:26]3[C@H:25]([CH3:30])[CH2:24][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:28][C@@H:27]3[CH3:29])=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 80 °C

Procedure:
To a mixture of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (380 mg) and (3S,5R)-1-methanesulfonyl-3,5-dimethyl-piperazine (314 mg) in acetonitrile (10 mL) was added potassium carbonate (620 mg). The reaction mixture was heated at 80° C. for 16 h and then allowed to cool to room temperature. The reaction mixture was then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 2-chloro-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 46.4 %

Procedure:
4-Chloro-2-fluoro-5-isopropoxyaniline (1.3 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.12 g) were dissolved in acetic acid (10 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain 1.0 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (Compound No. 1). M.P., 81°-82° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)([CH3:22])[CH3:21].ClCCl>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:28][N:27]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1ccc(N)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (241 mg, 0.800 mmol) in pyridine (5 mL), stirred under nitrogen at room temperature, was added 5-isopropylpyridin-2-amine (54.5 mg, 0.4 mmol). The mixture was then stirred at room temperature overnight. Dichloromethane (25 mL) was added to the mixture and the organic phase washed with water (25 mL) and brine (25 mL) then dried using a hydrophobic frit. Solvent was removed in vacuo to give the crude product. This was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient), to provide the title compound (39 mg) as an off-white solid. LCMS (2 min, formic) Rt 0.96 min, m/z (ES+) 402 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[N:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][C:18](C#N)=[CH:17]3)[C:10](=[O:12])[N:11]=1.C(O[Na])(C)=O.[CH:35]([O:38]C1C=CN=C2C=1N=C(C=C1SC(NC3CC3C3C=CC=CC=3)=NC1=O)C=C2)([CH3:37])[CH3:36]>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[C:17]([O:38][CH:35]([CH3:37])[CH3:36])[CH:18]=[CH:19][N:20]=3)[N:15]=2)[C:10](=[O:12])[N:11]=1
Reactant: CC(C)Oc1ccnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Reactant: N#Cc1cnc2ccc(C=C3SC(NCc4ccc(F)c(Cl)c4)=NC3=O)nc2c1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1ccnc2ccc(C=C3SC(NCc4ccc(F)c(Cl)c4)=NC3=O)nc12
Temperature: 100 °C
Yield: 86.9 %

Procedure:
To a mixture of 2-(3-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol) (see Example 19), AcONa (160 mg, 1.95 mmol), and 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde (38.9 mg, 0.18 mmol) (see Example 20) in a sealed tube was added AcOH(0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 2 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, acetone and ether to give 2-(3-chloro-4-fluoro-benzylamino)-5-(8-isopropoxy-[1,5]naphthyridin-2-ylmethylene)-thiazol-4-one as a light brown solid (63.5 mg, 86.9%). HR-ES (+) m/e calcd for C22H18FClN4O2S (M+H)+ 457.0896. found 457.0897.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.C1(C2C=CC(O)=CC=2)CCCCC1.C([O:41][C:42](=O)[C:43]([S:46][CH3:47])=[CH:44]O)C>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:42](=[O:41])[C:43]([S:46][CH3:47])=[CH:44][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C(=CO)SC
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CSc1cn2c(nc1=O)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 80 °C
Yield: 35.4 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.91 g, 3.34 mmol) (prepared in accordance with the procedures set forth in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol) in toluene (50 mL) was added 3-hydroxy-2-methylsulfanyl-acrylic acid ethyl ester (1.08 g, 6.68 mmol) prepared in accordance with the procedures in Step 1 of Example 87 The reaction mixture was heated at 80° C. for 18 hours. The reaction mixture was concentrated and loaded onto a silica gel column and eluted with 0-5% 2-propanol/CH2Cl2 to afford 0.44 g of the title compound. [α]D25 +18.24 (c 0.537, CHCl3)
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[CH3:23][S:24]([CH2:27][CH2:28][NH2:29])(=[O:26])=[O:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:29][CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:15])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)NCCS(C)(=O)=O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 39.6 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol) under nitrogen. DMF (0.5 mL), 2-(methylsulfonyl)ethanamine hydrochloride (8.2 mg, 0.051 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (8 mg, 39.2%). 1H NMR (400 MHz, CD3OD) δ 0.91 (d, J=6.82 Hz, 3 H) 1.05 (d, J=6.32 Hz, 3 H) 2.50 (dq, J=17.94, 6.57 Hz, 1 H) 2.92 (s, 3 H) 3.22-3.28 (m, 1 H) 3.33-3.38 (m, 1 H) 3.61 (dt, J=14.40, 6.57 Hz, 1 H) 3.73 (dt, J=14.40, 6.57 Hz, 1 H) 4.94-5.13 (m, 2 H) 5.19-5.40 (m, 1 H) 7.85 (s, 1 H) 8.17 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C17H21FN4O4S, 398; found, 398.3.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].S(=O)(=O)(O)O.O[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([NH:21][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[O:23])([CH2:14]3)[CH2:12]1)[CH2:18]2.[OH-:30].[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:4][C:15]12[CH2:20][CH:11]3[CH2:18][CH:17]([CH2:19][C:13]([NH:21][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[O:23])([CH2:12]3)[CH2:14]1)[CH2:16]2)=[O:30]
Reactant: N#CCCl
Reactant: O=C(NC12CC3CC(CC(O)(C3)C1)C2)c1ccccn1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)NC12CC3CC(C1)CC(NC(=O)c1ccccn1)(C3)C2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
Chloroacetonitrile (2.0 mL, 32 mmol) was cooled to 0° C. Sulfuric acid (1.0 mL, 19 mmol) was added slowly at 0° C. After addition completed, the mixture was stirred at 0° C. for 5 minutes. Pyridine-2-carboxylic acid (3-hydroxy-adamantan-1-yl)-amide (0.42 g, 1.56 mmol, from step 1) was added in one portion and the mixture was stirred at rt overnight. The thick solution was poured into ice-water (10 mL). DCM (10 mL) was added. While the mixture was cooled with an ice-bath, the pH of the aqueous phase (top) was adjusted to 10-13 with 10 N aq. NaOH. The aqueous layer was extracted with DCM. The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford 0.53 g (96.9%) of crude title compound, pyridine-2-carboxylic acid [3-(2-chloro-acetylamino)-adamantan-1-yl]-amide, as an oil, which became a colorless solid upon standing at room temperature. LC-MS (Gradient: acetonitrile in water, 20-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column: Inertsil® ODS, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time: 1.08 min; purity (UV254): 100%; ESI-MS m/z: 348 (M+H)+. It was used in the next step without further purification.