Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:6](=[O:31])[N:5]([CH3:32])[C:4]=2[N:3]=1.C([Li])CCC.[CH:38](=[O:40])[CH3:39]>C1COCC1.O>[Si:24]([O:23][CH2:22][CH2:21][CH2:20][N:7]1[C:8](=[O:19])[C:9]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:2]([CH:38]([OH:40])[CH3:39])=[N:3][C:4]=2[N:5]([CH3:32])[C:6]1=[O:31])([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26]
Reactant: CC=O
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 22.3 %

Procedure:
Step 1 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, intermediate 77) was dissolved in THF (5 mL) and cooled to −78° C. To the clear solution was added 2.5 M n-butyllithium in hexanes (0.20 mL, 0.51 mmol) dropwise. The reaction was stirred in the cold for 5 min and acetaldehyde (0.13 mL, 2.31 mmol) was added. The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to leave a golden oil. The oil was purified using two 1000 microns preparative TLC plates eluted with 50% ethyl acetate/hexanes. Target band was extracted with ethyl acetate and the solvent was removed under reduced pressure to give 1-(3-((tert-butyldimethysilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.052 g, 30% yield) as a clear oil. LCMS retention time=4.490 min and 97% purity, LCMS MH+ 507.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([OH:22])=O)=[O:14])[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2].CN(C(ON1N=[N:44][C:39]2[CH:40]=[CH:41][CH:42]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CCC1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:22])[NH:44][CH:39]2[CH2:40][CH2:41][CH2:42]2)=[O:14])[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)O)n(-c2ccccc2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1

Procedure:
To a solution of 4.5 g 5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 105 ml DMF were added 4.4 g HATU and 1.9 ml DIPEA. After 10 minutes 1.0 ml cyclobutylamine was added and after 30 minutes the reaction mixture was concentrated. The residue was taken up in dichloromethane and extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using ethyl acetate/heptane 4:1 as eluent. Yield: 3.2 g colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])C=C.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:10]1[CH:9]=[CH:8][C:7]([Cl:11])=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]=1[OH:4])[CH:19]=[CH2:20]
Reactant: C=CCOc1cccc(Cl)c1-c1ccccc1Cl
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1ccc(Cl)c(-c2ccccc2Cl)c1O
Yield: 77 %

Procedure:
A solution of 2-allyloxy-2′,6-dichlorobiphenyl (11.6 g, 41.8 mmol) in mesitylene (100 mL) was refluxed for 24 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 9.0 g (77%) of 3-allyl-2′,6-dichlorobiphenyl-2-ol as a light yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][N:7]=[C:6]([S:13][CH3:14])[N:5]=1)[CH3:2].C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[CH2:1]([NH:3][C:4]1[C:9]([C:10]([F:24])=[O:11])=[CH:8][N:7]=[C:6]([S:13][CH3:14])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(SC)ncc1C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNc1nc(SC)ncc1C(=O)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution containing 3.0 g (14.0 mmol) of 4-ethylamino-2-methylthio-5-pyrimidinecarboxylic acid and 2.1 mL (15.0 mmol) of triethylamine in 50 mL of CH2Cl2 are added 2.3 mL (28.0 mmol) of cyanuric fluoride. The mixture is stirred for 3 hours and the solution is diluted with 250 mL of CH2Cl2 and 75 mL of ice-cold water. After separation of the phases by settling, the organic phase is washed with 75 mL of ice-cold water and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 3.0 g of expected product are obtained in the form of a greenish gum. The yield is quantitative.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]=[C:37]=[O:38])=[CH:31][CH:30]=1>CN(C=O)C.Cl>[ClH:28].[NH2:3][C:4]([CH:15]1[CH2:16][CH2:17][N:18]([C:37](=[O:38])[NH:36][CH2:35][C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:19][CH2:20]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6]
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Reactant: O=C=NCc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(C(=O)NCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
A stirred solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (Example 26-A, Step 1, 0.240 g, 0.594 mmol) in dry DMF (12 mL) under nitrogen was treated with triethylamine (0.662 mL, 4.75 mmol) to give a white slurry. 1-chloro-4-(isocyanatomethyl)benzene (0.177 mL, 1.34 mmol) was added dropwise, and the resulting opaque mixture was stirred at room temperature for 1 h. The mixture was diluted with 1 N HCl (15 mL) and washed with ethyl acetate (2×20 mL), and the aqueous layer was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 5% to 50% A over 24 min, then 50% to 100% A over 1 min]. Product fractions were pooled and concentrated, and the residue was taken up in 0.5N HCl (5 mL)/acetonitrile (8 mL) and concentrated. The residue was once again treated with 0.5N HCl (5 mL)/acetonitrile (8 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-{1-[(4-chlorobenzyl)carbamoyl]-piperidin-4-yl}hexanoic acid hydrochloride (92 mg, 34%) as an off-white solid. 1H NMR (D2O, 400 MHz) δ 7.26 (m, 2H), 7.15 (m, 2H), 4.19 (s, 2H), 3.95 (bt, J=14.6 Hz, 2H), 2.75 (bt, J=12.8 Hz, 2H), 2.06 (bt, J=12.4 Hz, 1H), 1.81 (m, 3H), 1.53 (bd, J=12.8 Hz, 1H), 1.32 (m, 4H), 1.11 (m, 2H), 0.69 (t, J=7.6 Hz, 2H). ESI+ MS found for C19H29BClN3O5 m/z 408.4 (M−18+H); ESI− MS m/z 424.4 (M−H), 406.4 (M−18−H).
Reaction SMILES: Br.[F:2][C:3]([F:33])([F:32])[C:4]1[CH:5]=[C:6](O)[N:7]=[N:8][C:9]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[N:11]=1.O=P(Cl)(Cl)[Cl:36]>>[Cl:36][C:6]1[N:7]=[N:8][C:9]([C:10]2[N:11]=[C:12]3[C:17]([C:16]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)=[CH:15][CH:14]=[N:13]3)=[CH:18][CH:19]=2)=[C:4]([C:3]([F:33])([F:32])[F:2])[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C(F)(F)F)c(-c2ccc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)nn1
Agent: Br
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4nnc(Cl)cc4C(F)(F)F)ccc23)nc1

Procedure:
Dissolve 5-(trifluoromethyl)-6-(5-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1,8-naphthyridin-2-yl)pyridazin-3-ol hydrobromide in neat POCl3 (20 mL). Heat the mixture at reflux for 4 hours. Cool and evaporate to dryness. Add toluene (25 mL) and remove the solvent under reduced pressure. Dissolve the residue in CH2Cl2 (30 mL) and sat. NaHCO3 (aq) (30 mL). Extract the aqueous phase with CH2Cl2 (3×30 mL). Combine, dry and evaporate the organic extracts to yield the title compound. LC/MS (MH+) 472.04.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][OH:17])=[NH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:18][C:19](=[O:24])[O:20][CH:21]([CH3:23])[CH3:22])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].N1C=CC=[CH:28][CH:27]=1.C(Cl)(=O)C>C1(C)C=CC=CC=1>[CH3:23][CH:21]([O:20][C:19](=[O:24])[NH:18][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[C:27]([CH3:28])[O:17][N:16]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:25])[CH2:6]1)[CH3:22]
Reactant: CC(=O)N1c2ccc(C(=N)NO)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Product: CC(=O)N1c2ccc(-c3noc(C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 1-methylethyl {(2S,4R)-1-acetyl-6-[(hydroxyamino)(imino)methyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation, see Intermediate 56) (130 mg, 0.373 mmol) in toluene (2 mL) and pyridine (2 mL) was added acetyl chloride (a solution 0.34 mL of acetyl chloride in 5 mL of toluene was made and 0.52 mL was used, 0.485 mmol) dropwise and the resulting mixture was stirred at room temperature under nitrogen for 30 min. The mixture was then warmed to 110° C. and stirred at this temperature for 16 h then cooled to room temperature. Most of the solvents were removed in vacuo and the residue was partitioned between AcOEt and water (acidified to pH 1 with a 2N HCl aqueous solution). The two layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed with a saturated NaHCO3 aqueous solution then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient: 13 to 63% AcOEt in hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (120 mg, 0.322 mmol, 86% yield) as a white foam. LCMS (method A): Retention time 0.94 min, [M+H]+=373.05
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH2:28][CH:25]4[CH2:27][CH2:26]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CC1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 49 %

Procedure:
As described for example 98b, 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) was converted, using cyclopropanemethylamine instead of 2,2,2-trifluoroethylamine, to the title compound (39 mg, 49%) which was obtained as a white solid. MS: m/e=398.0 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12](Cl)=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][OH:21])=[S:17])[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C(=O)C>O>[OH:21][CH2:20][CH2:19][NH:18][C:16]1[S:17][C:12]2[CH:11]=[CH:10][C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])=[CH:14][C:13]=2[N:15]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c(NC(=S)NCCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc2sc(NCCO)nc2c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 6 parts of N-(5-benzoyl-2-chlorophenyl)N'-(2-hydroxyethyl)thiourea, 2.5 parts of sodium hydride dispersion 75% and 90 parts of N,N-dimethylacetamide is stirred and heated quickly to 130° C. The reaction mixture is cooled, water is added and the whole is allowed to stand overnight. The precipitated product is filtered off, washed with water and crystallized from ethanol, yielding 2.8 parts of {2-[(2-hydroxyethyl)amino]-5-benzothiazolyl}phenylmethanone; mp. 159° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.O.[NH3:26]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH2:26])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: N
Solvent: CC(=O)CC(C)C
Solvent: O
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 100 ml of methylisobutylketone, and 200 ml of 28% ammonia water, a reaction similar to that conducted in Example 107 was carried out. The crystal procipitated was filtered out, yielding 0.9 g of N-(trans-4-methylcyclohexyl)-4-(2-aminoethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].CN1CCOCC1.CN(C(O[N:48]1N=[N:55][C:50]2C=CC=N[C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:49]([CH2:50][NH:55][C:3](=[O:4])[C:2]([OH:1])([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)[CH3:6])#[N:48]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(O)(C(=O)O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(O)(C(=O)NCC#N)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 20.16 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (Int-XV, (30 mg, 0.067 mmol), 4-methylmorpholine (27.3 mg, 0.269 mmol), and HATU (33.3 mg, 0.088 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.21 min) to provide (R/S)-N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide (7 mg, 0.014 mmol, 20.16% yield): LCMS=484.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.81 (1 H, t, J=5.83 Hz), 8.11-8.23 (2 H, m), 7.51-7.92 (7 H, m), 4.04-4.23 (2 H, m), 1.81 (3 H, s); HPLC peak RT=10.0 min (Method A).
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>CCOC(C)=O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCC(c2nccnc2F)CC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(N)cc2)CC1
Temperature: 80 °C

Procedure:
1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (0.153 g, 0.685 mmol), 4-aminophenol (0.079 g, 0.720 mmol), cesium carbonate (0.246 g, 0.754 mmol), and 1-methyl-2-pyrrolidinone (0.685 mL, 0.685 mmol) were combined in a sealed tube and heated at 80° C. for 20 h. The cooled reaction mixture was diluted with EtOAc and washed with water; the aqueous layer was back-extracted with EtOAc (1×). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification (20% to 80% EtOAc/Hexanes) afforded 1-(4-(3-(4-aminophenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as a light brown oil. MS (ESI, pos. ion) m/z: 313.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31].Cl>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:29]([O:30][CH3:31])=[O:32])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(CCc2ccc(F)cc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(CCc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
Methyl 2-(4-fluorophenethyl)piperidine-4-carboxylate (3.89 g, 14.65 mmol) was dissolved in dichloromethane (150 mL). DIPEA (3.06 mL, 17.58 mmol) was added, followed by methyl carbonochloridate (1.615 mL, 20.51 mmol). The mixture was stirred at room temperature for 2 h. 0.1 HCl and DCM were added. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with satd NaHCO3, filtered through a phase separator and evaporated. Dimethyl 2-(4-fluorophenethyl)piperidine-1,4-dicarboxylate (3.19 g, 67%) was isolated. MS m/z 324 (M+H)+
Reaction SMILES: N[C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=2[N:13]=1.N(OCCC(C)C)=O.[ClH:30].O>CS(C)=O.[Cu](Cl)Cl>[Cl:30][C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=2[N:13]=1
Reactant: N#Cc1c(N)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccccc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1c(Cl)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.0 g (3.04 mmol) of 7-amino-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile [Assy, M. G. et al., J. Indian Chem. Soc. 1996, 73 (11), 623-624] was dissolved in 8 ml of DMSO, 0.82 ml (713 mg, 6.09 mmol) of isopentyl nitrite and 818 mg (6.09 mmol) of copper(II) chloride were added and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled, and 6 ml of 1 N hydrochloric acid solution followed by 100 ml of water were then added. The precipitate formed was filtered off and dried under high vacuum. The product was not purified any further (purity according to LC-MS: about 82%).
Reaction SMILES: [C:1](=[O:11])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:2].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15]>CCOCC>[OH:15][CH:14]([C:13]([OH:17])=[O:16])[NH:2][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:11]
Reactant: NC(=O)OCc1ccccc1
Reactant: O=CC(=O)O
Solvent: CCOCC
Solvent: O
Product: O=C(NC(O)C(=O)O)OCc1ccccc1
Yield: 69.4 %

Procedure:
Benzyl carbamate (63 g, 0.05 mol) was stirred with glyoxylic acid monohydrate (5.09 g, 0.055 mol) in dry ether (50 mL). The crystalline product 22A (7.81 g, 73%) formed was filtered and washed with ether.
Reaction SMILES: CS[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH2:10]([CH2:12][NH2:13])[OH:11].C(OC(=O)C)C>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:5]([CH:4]=[C:3]1[NH:13][CH2:12][CH2:10][O:11]1)([O-:7])=[O:6]
Reactant: NCCO
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=[N+]([O-])C=C1NCCO1
Temperature: 25 °C
Yield: 259.8 %

Procedure:
p-Toluene sulfonic acid (0.5 g) was added to a boiling solution of 1,1-bis-methylsulfanyl-2-nitro-ethene (I-1b: 20 g, 12.13 mol) in ethanol (200 mL). This was followed by the addition of ethanolamine (7.4 g, 12.13 mmol) and the resulting mixture was heated to reflux for 12 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated, 300 mL of water added and resultant filtered. The filtrate was further concentrated and was followed by the addition of acetone. The reaction mixture was refluxed for 1 hour, cooled to room temperature, and filtered. The acetone layer was concentrated to afford 4.1 g of the crude product which was used in the next step without further purification.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:17]2[CH:16]=[C:15]3[C:11]([O:12][CH2:13][O:14]3)=[CH:10][C:9]=2[S:8][C:7]=1[CH2:18]O>CCOCC>[Br:2][CH2:18][C:7]1[S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][C:17]=2[C:6]=1[Cl:5])[O:14][CH2:13][O:12]3
Reactant: OCc1sc2cc3c(cc2c1Cl)OCO3
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Clc1c(CBr)sc2cc3c(cc12)OCO3
Temperature: 25 °C
Yield: 95 %

Procedure:
Add a solution of phosphorous tribromide (1.5 equivalents) in ether (10 mL/g) to a solution of (7-chloro-1,3-dioxa-5-thia-s-indacen-6-yl)-methanol (1.64 g, 6.8 mmol) in ether (20 mL/g) at 0° C. Stir to room temp for an hour. Pour onto ice water, wash with water, saturated sodium bicarbonate, brine, dry, and concentrate to afford the title compound as a white powder (1.96 g, 95%): 1H NMR (CDCl3) δ 7.17 (s, 1H), 7.13 (s, 1H), 6.05 (s, 2H), 4.72 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:17])[CH:10]=3.Br[CH2:30][CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:17][CH2:30][CH2:31][CH2:32][OH:33])[CH:10]=3
Reactant: OCCCBr
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c(=O)c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c(=O)c3cc(OCCCO)cc1c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
The compound (47 mg) obtained in Example 33 was suspended in DMF (2 mL) and to the suspension was added 3-bromopropanol (11 μL) and potassium carbonate(19 mg) The mixture was stirred at room temperature overnight. After addition of water, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride:methanol=100:0˜10:1) to obtain the title compound (27 mg; 51%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][S:18]([CH2:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])(=[O:20])=[O:19]>>[F:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:6]1[C:5]([F:16])=[CH:4][N:3]=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([CH2:21][S:18]([CH3:17])(=[O:20])=[O:19])[CH:23]=2)[N:7]=1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(F)c1
Reactant: CS(=O)(=O)Cc1cccc(N)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3F)n2)c1

Procedure:
Example 16.2 was prepared under similar conditions as described in the preparation of Example 3. using 2-chloro-4-(2,4-difluorophenyl)-5-fluoropyrimidine (Intermediate 16.1) and 3-[(methylsulfonyl)methyl]aniline (Intermediate 1.3). The batch was purified by preparative HPLC.