Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12]C2)C=CC=1N.F[C:16]1[CH:17]=[CH:18][C:19]([N+:26]([O-])=O)=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.CC1CCCNC1.CC#N>O>[CH3:12][CH:13]1[CH2:3][CH2:9][CH2:8][N:10]([C:16]2[CH:17]=[CH:18][C:19]([NH2:26])=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: COc1cc(N2CCCC2)ccc1N
Agent: CC1CCCNC1
Solvent: CC#N
Solvent: O
Product: CC1CCCN(c2ccc(N)c(C(F)(F)F)c2)C1

Procedure:
2-Methoxy-4-(pyrrolidin-1-yl)aniline can be synthesized following the general scheme above starting from 5-fluoro-2-nitrobenzotrifluoride and 3-methylpiperidine. 1H NMR (400 MHz, CDCl3) δ 7.05-6.93 (m, 2H), 6.69 (d, J=8.7 Hz, 1H), 3.85 (s, 2H), 3.42-3.29 (m, 2H), 2.52 (td, J=11.5, 3.1 Hz, 1H), 2.25-2.15 (m, 1H), 1.86-1.62 (m, 5H), 0.94 (d, J=6.4 Hz, 3H). LC/MS: m/z 259.0 (M+H)+ at 0.79 min (10%99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(OCC)(=O)C.Cl.[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:28][C:29]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@H]1COc2ccccc2NC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@H]1COc2ccccc2NC1=O)OCc1ccccc1

Procedure:
To a mixture of 100 ml of ethyl acetate and 50 ml of water is added 1.5 of 3(S)-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride, and 1.5 ml of benzyloxycarbonyl chloride is added dropwise to the mixture at ice bath temperature with stirring. After stirring for 1 hour, the ethyl acetate layer separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue is added ethyl ether and the deposited crystals are collected by filtration to give 2 g of 3(S)-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one. This product is recrystallized from a mixture of ethyl acetate and ether to give colorless needles melting at 157°-159° C.
Reaction SMILES: [O:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](Cl)([Cl:11])=[O:10].C(Cl)Cl>CN(C)C=O>[Cl:11][C:9]([O:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(Cl)Cl
Reactant: OOc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)OOc1ccccc1

Procedure:
The intermediate phenoxy chloroformates are prepared by reaction of the appropriate phenoxyalcohol with excess phosgene in an inert solvent such as methylene chloride in the presence of a catalytic quantity of dimethyl formamide. The reaction is carried out at 20°-80° C. The solvent and excess phosgene is then removed under vacuo to give the desired intermediate phenoxy chloroformate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16]Br)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.C(O)(=O)C(O)=O.S1C2C=CC=CC=2C(N2CCN(CCCC(C3SC4SCCNC(=O)C=4C=3)=O)CC2)=N1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCc1sc2c(c1CCBr)CCN(C(C)=O)C2
Agent: Cl
Agent: O=C(CCCN1CCN(c2nsc3ccccc23)CC1)c1cc2c(s1)SCCNC2=O
Agent: O=C(O)C(=O)O
Product: CCc1sc2c(c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCN(C(C)=O)C2
Yield: 62 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.5 g of 6-acetyl-3-(2-bromoethyl)-2-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 2.2 g of 6-acetyl-2-ethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 191°-201° C. as oxalate 1/2 hydrate thereof.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[Cl:38])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[Cl:38])[C:18]([CH:11]1[C:10](=[O:21])[C@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)cc1Cl
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Triethylamine (3.9 mL; 28 mmol) was added over a period of 2-3 min to a cooled (0° C.) solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 2.2 g, 10.2 mmol) in dichloromethane (25 mL), resulting in a heavy precipitate. Dichloromethane (10 mL) was added, followed by N′-(2-chloro-4-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 33; 1.87 g, 7.2 mmol). The reaction mixture was stirred at 0° C. for 5 min, and then at 50° C. (oil-bath temperature) over the weekend. Dichloromethane was added and the solution was washed with water (3×50 mL) and brine (50 mL), dried (magnesium sulfate, filtered, evaporated, and dried under high vacuum to give N′-(2-chloro-4-fluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (3.8 g, 120% of the expected amount). This was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=C[C:45]([O:49]C)=CC=3)CC2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][C:23]([O:49][CH3:45])=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCc3cc(OC)ccc32)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCc2cc(OC)ccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ) 1.28, 1.95, 2.51, 2.65, 2.80, 2.95, 3.02, 3.85, 4.14, 4.65, 5.73, 6.82, 6.87, 7.28-7.35, 7.5; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1450.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:39])[C:31]=1[C:32](=O)[C:33]([O:35]CC)=O.CC(O)=O>COCCO>[Cl:39][C:30]1[CH:29]=[N:28][CH:27]=[C:26]([Cl:25])[C:31]=1[C:32]1[C:33](=[O:35])[N:23]([CH3:24])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCN(CC)CCOc1ccc(Nc2ncc(N)c(NC)n2)cc1
Reactant: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: CCN(CC)CCOc1ccc(Nc2ncc3nc(-c4c(Cl)cncc4Cl)c(=O)n(C)c3n2)cc1
Yield: 15.3 %

Procedure:
A mixture of 0.465 g (1.4 mmol) of 5-amino-2-[[4-[2-(diethylamino)-ethoxy]-phenyl]amino]-4-(methylamino)pyrimidine, 0.69 g (2.8 mmol) of ethyl 2-(3,5-dichloropyridin-4-yl)-2-oxoacetate, and 0.5 mL of HOAc in 15 mL of 2-methoxyethanol is heated under reflux for 18 hours, and the reaction is worked up as above in 6 to give 0.11 g (15%) of the title compound (Compound 20): mp (MeOH) 179–180.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1)c1ccccc1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 4-chlorophenol (0.774 g) and phenacyl bromide (1 g) in N,N-dimethyl formamide (10 ml) potassium carbonate (3.5 g) was added. The mixture was refluxed with stirring for 2 h. After cooling the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (MgSO4), and evaporated. The crude was purified by flash chromatography on silica gel (petrol ether/ethyl acetate 10:1) to give 2-(4-chlorophenoxy)-1-phenylethanone (1.22 g) as pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:7]([OH:9])=[O:8])[CH3:2].C(O)C>[Pd].CN(C=O)C>[NH2:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)O)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-ethoxy-4-nitrobenzoic acid (Intermediate 165; 1.0 g, 4.74 mmol) ethanol:DMF (50 mL:5 mL) over 5% Pd/C catalyst (100 mg) was hydrogenated with stirring at ambient temperature for 4 hours. The mixture was filtered and the catalyst washed with ethanol and the solvent evaporated and the residue that on trituration with diethyl ether yielded the title compound as an off white solid (688 mg, 81%)
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[CH2:17]([N:1]([CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:4]=1)[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1c(-c2ccccc2)sc2ccccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)c2c(-c3ccccc3)sc3ccccc23)cc1
Reaction time: 20 h

Procedure:
A mixture of 2.25 g (10 mmol) of 3-amino-2-phenyl benzo(b)thiophene, 3.8 g (22 mmol) of benzyl bromide, 3.6 g (26 mmol) of K2CO3 and 0.5 g (3.3 mmol) of NAI in 25 ml of absolute CHCl3 is refluxed with stirring for 20 hours. After cooling, it is mixed with water, the organic phase is dried and washed with water. After drying over calcium carbonate and elimination of the solvent, there remains 3-dibenzylamino-2-phenyl-benzo(b)thiophene in the form of a crude oily product which crystallises in ethanol: 2.3 g (57% of theory), colourless crystals, mp 97°-101° (ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([C:27](=[O:28])[C:26]5[CH:30]=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(Cl)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 67 was synthesized using 9-chlorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. (81 mg, 95%); M.p.=125-130° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, J=8.4 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.63 (dd, J=1.2 and 8.4 Hz, 1H), 7.55-7.48 (m, 3H), 7.42 (d, J=7.2 Hz, 1H), 4.4-4.2 (m, 1H), 3.84 (brs, 2H), 3.34-3.24 (m, 1H), 3.12 (s, 2H), 2.19-2.08 (m, 1H), 2.02-1.8 (m, 3H); LCMS: 474 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 500 mL round-bottomed flask was charged with 2-(3-nitrophenyl)ethanol (1.0235 g, 6.12 mmol), 4-dimethylaminopyridine (0.075 g, 0.612 mmol) and p-toluenesulfonyl chloride (1.401 g, 7.35 mmol) in CH2Cl2 (61.2 ml). Triethylamine (1.707 ml, 12.25 mmol) was added, and the mixture stirred at ambient temperature for 3 hours. The reaction mixture was washed with water and brine, dried (MgSO4), filtered and concentrated onto silica gel. The crude product was purified by flash chromatography using an Argonaut Flashmaster Solo 25 g column (100% hexanes to 30% ethyl acetate:hexanes over 25 minutes, then to 100% ethyl acetate over 10 minutes) to provide the title compound. MS (ESI(+)) m/e 338.9 (M+NH4)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.Cl.Cl.[C:17]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:44])[O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]([C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH3:35])[CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)CCC>[C:17]1([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]([CH3:35])[C:36](=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:2]2[S:3][C:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)[CH2:28][CH2:27]1)=[O:44]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN
Reactant: Cc1nc(Br)sc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cc1nc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)OC(C)(C)C
Yield: 28.6 %

Procedure:
tert-Butyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (247 mg, 0.739 mmol), the compound (199 mg, 0.369 mmol) obtained in Example 11c, triethylamine (180 μL) and 4.0 mL of n-butanol were used to give the title compound (70 mg; yield, 29%) as a colorless oily substance according to the same procedure as in Example 104b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc(N)cc1F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Yield: 73.3 %

Procedure:
A mixture of 3-fluoro-4-methylaniline (12.5 g), phthalic anhydride (17.8 g), triethylamine (27.9 ml) and chloroform (100 ml) was heated under reflux for 6 days and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. Subsequently, chloroform was added to the resulting residue and the insoluble matter was filtered off whereas the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=98:2) to give 18.7 g of the titled compound (yield, 73%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29](O)=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:32][N:33]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29]([NH:33][OH:32])=[O:30])[CH2:16][CH2:17][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:19][CH2:20]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccnc3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)c3cccnc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidinecarboxylic acid (195 mg, 0.44 mmol) in dimethylformamide (4 ml), 1-hydroxybenzotriazole(72 mg, 0.53 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(119 mg, 0.62 mmol), N-methylmorpholine (0.072 ml, 0.66 mmol), and hydroxylamine (0.135 ml, 2.2 mmol), 65 mg (32%) of the product was isolated as a solid. HR-MS: m/z Calculated for C22H23N3O6S 458.1380; Found 458.1373.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]COC(C)=O.CCCCCCC>CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:20])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: CO
Product: COC(=O)c1ccc(Br)c2ccccc12
Yield: 91 %

Procedure:
To a solution of 4-bromo naphthoic acid (4.0 g, 15.9 mmol) in MeOH (75 mL) was added sulfuric acid (0.5 mL) and the reaction was heated to reflux for 18 hours. TLC 50:50 EtOAc:heptane showed consumption of starting material. The reaction was cooled and concentrated under vacuum to remove MeOH. The residue was diluted with EtOAc (150 mL), washed with water (100 mL), diluted with saturated NaHCO3 (100 mL), dried over Na2SO4 and concentrated under vacuum to afford a solid (3.85 g, 91%). 1H NMR (CDCl3) δ ppm: 8.96 (1H), 8.36 (1H), 8.02 (1H), 7.85 (1H), 7.70-7.66 (2H), 4.03 (3H).
Reaction SMILES: [Na].[CH2:2]1[CH:4]([C:5]([NH2:7])=[NH:6])[CH2:3]1.Cl.O=[C:10]1[CH2:15][CH2:14][CH2:13][S:12][CH:11]1[C:16](OCC)=[O:17].C(O)(=O)C>CO>[CH:4]1([C:5]2[N:6]=[C:16]([OH:17])[C:11]3[S:12][CH2:13][CH2:14][CH2:15][C:10]=3[N:7]=2)[CH2:3][CH2:2]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)C1SCCCC1=O
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: Oc1nc(C2CC2)nc2c1SCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Sodium metal (3.94 g, 0.17 g atom) was dissolved in methanol (150 ml) and cyclopropylcarboxamidine hydrochloride (21.0 g, 0.174 mol) was added followed after 1/4 hour stirring by the addition of ethyl 3-oxotetrahydrothiopyran-2-carboxylate (27.2 g, 0.145 mol). The reaction mixture was stirred at 25° C. for 18 hours then treated with ice water (200 ml) and neutralized with acetic acid to give 24.6 g of the title compound which melted at 249°-250° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([OH:23])=O)[NH:6]2.[N:24]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:24])=[O:23])[NH:6]2
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A mixture of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (2.2 g), 1H-1,2,3-benzotriazol-1-ol (1.2 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.5 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 1 hr, and then at 60° C. for 1 hr. 28% Aqueous ammonia (2.0 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (1.84 g, yield 84%) as colorless prism crystals. melting point 221-222° C.
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:9][CH2:10][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][CH2:13]3)[N:7]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Reactant: Nc1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(Nc2nc(N3CCN(c4ccccc4)CC3)nc3c2SCC3)c1

Procedure:
0.320 g (0.96 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V), 1.0 mL (9.5 mmol) of 3-chlorophenylamine, and 0.33 mL (1.92 mmol) of diisopropylethylamine are combined and the mixture is reacted for 0.5 hours at 130° C. in the microwave. Then the reaction mixture is combined with ethyl acetate and acidically extracted. The organic phase is dried and evaporated to dryness. The residue is combined with acetonitrile, water, and trifluoroacetic acid. The phase containing the product I is purified by chromatography through an RP column by HPLC (column: Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid (A), water+0.13% formic acid (B)).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Br)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].Cl.[F:28][C:29]1([F:33])[CH2:32][NH:31][CH2:30]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([N:31]2[CH2:32][C:29]([F:33])([F:28])[CH2:30]2)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: FC1(F)CNC1
Reactant: Cc1nc(C(C)(C)NC(=O)c2cnc(Br)c(-c3cccc(Cl)c3)n2)no1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(N3CC(F)(F)C3)c(-c3cccc(Cl)c3)n2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.4 %

Procedure:
5-Bromo-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 1e, 0.075 g, 172 μmol) was added to a solution containing 3,3-difluoroazetidine hydrochloride (77.9 mg, 601 μmol) and DBU (91.5 mg, 89.8 μl, 601 μmol) in DMSO (1 mL). The reaction mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate and 10% citric acid. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase chromatography to give the desired product (8 mg, 10%) as colorless oil; MS (ESI): 449.1 (M+H).