Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.O.[CH3:16]O>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: NCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCCCCN

Procedure:
To a suspension of 6-aminohexanoic acid (10.0 g, 76.2 mmol) in methanol (300 mL), was added 5.51 g of concentrated sulfuric acid. The mixture was heated and reacted for 8 hours, while the water formed along with the progress of esterification distilled off with methanol and 60 mL of methanol was added four times on cue. The reaction mixture was cooled, and the pH of the mixture was adjusted to 6.2 by adding 28% methanol solution of sodium methoxide. The solvent was distilled off, the residue was added to 500 mL of water, and the pH of the mixture was adjusted to 10.3 by adding sodium carbonate. After extraction with 350 mL of dichloromethane for three times, the extract was dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off, thereby to yield methyl 6-aminohexanoate.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[N:21]([CH3:32])[C:22]4[C:27]([C:28]=3[C:29]#[N:30])=[CH:26][CH:25]=[C:24]([Cl:31])[CH:23]=4)[CH:19]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[N:21]([CH3:32])[C:22]4[C:27]([C:28]=3[C:29]#[N:30])=[CH:26][CH:25]=[C:24]([Cl:31])[CH:23]=4)[CH:17]=[N:16][CH:15]=2)[CH2:9]1
Reactant: Cn1c(-c2cncc(CN3CC[C@@H](NC(=O)OC(C)(C)C)C3)c2)c(C#N)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(-c2cncc(CN3CC[C@@H](N)C3)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {(R)-1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (140 mg, 0.3 mmol) in dichloromethane (5 mL) is added TFA (2 mL) and the mixture is stirred at room temperature for 2 h. The solvents are then removed in vacuo and the residue is purified by Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to give 2-[5-((R)-3-amino-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.43 (m, 1H), 1.64 (br. s., 2H), 1.97-2.08 (m, 1H), 2.21 (dd, J=9.0, 4.9 Hz, 1H), 2.59-2.68 (m, 1H), 2.71 (dd, J=9.1, 6.6 Hz, 1H), 3.32-3.39 (m, 1H), 3.72 (q, J=13.6 Hz, 2H), 3.79 (s, 3H), 7.36 (dd, J=8.3, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 8.05 (t, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 366.1483 [(M+H)+ Calcd for C20H21ClN5: 366.1485].
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[CH2:30]([NH2:36])[C:31]1[O:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:35]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:30][NH:36][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH3:7])=[C:9]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:19]=2)[CH:10]=1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Reactant: NCc1ccco1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCc2ccco2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), furfurylamine (Aldrich, Buchs, Switzerland; 61.8 μL, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is crystallised from dichloromethane to give the title compound as a crystalline solid.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])#[N:2].FC(F)(F)C(O)=[O:30]>C(Cl)Cl>[C:1]([CH2:3][NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])(=[O:30])[NH2:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NCC#N)c2nc(C3CC3)cnc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)CNC(=O)c1c[nH]c2ncc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyanomethyl-amide (0.19 g, 0.50 mmol) in CH2Cl2 (6 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was dissolved in MeOH (10 mL) and H2O (2 mL) and Et3N (2 mL) were added. The reaction mixture was stirred at room temperature overnight then concentrated. The residue was triturated with EtOH to afford 0.093 g (77%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid carbamoylmethyl-amide as a light yellow solid. MS: (M+H)+=260; mp=215.0-220.0.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[NH:3])[CH3:2].Br[CH2:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1)=O.C(N(CC)C(C)C)(C)C>COCCOC>[C:9]([O:8][C:6](=[O:7])[NH:5][N:4]1[CH:14]=[C:15]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)[N:3]=[C:1]1[CH3:2])([CH3:12])([CH3:11])[CH3:10]
Reactant: Cn1cc(C(=O)CBr)cn1
Reactant: CC(=N)NNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: Cc1nc(-c2cnn(C)c2)cn1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 2-ethanimidoylhydrazinecarboxylate (17.3 g, 99.9 mmol), 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethanone (16.89 g, 83.18 mmol) and N,N-diisopropylethylamine (31.9 mL, 183 mmol) were combined in ice-cold 2-methyltetrahydrofuran (400 mL) and 1,2-dimethoxyethane (100 mL), and the reaction mixture was heated to reflux. After 2.5 hours, the reaction was cooled and washed with 50% saturated aqueous sodium chloride solution (75 mL). The aqueous layer was extracted with 2-methyltetrahydrofuran (100 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in warm ethyl acetate (60 mL), allowed to cool to room temperature, then cooled to 5° C. for 30 minutes. The resulting solid was collected by filtration and washed with a small quantity of cold ethyl acetate, then washed with diethyl ether, to provide the product as a very pale yellow solid. Yield: 16.0 g, 57.7 mmol, 69%. LCMS m/z 278.5 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.49 (br s, 9H), 2.23 (s, 3H), 3.84 (s, 3H), 6.87 (s, 1H), 7.51 (s, 1H), 7.60 (s, 1H), 8.67 (br s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=[C:5]([F:20])[CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([Cl:24])=[O:12])=[C:5]([F:20])[CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(OCc2ccccc2C(=O)O)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 2-(4-cyano-2-fluoro-phenoxymethyl)-benzoic acid (1.0 g, 3.68 mmol) in dichloromethane (15 ml) was added oxalyl chloride (0.45 ml, 4.79 mmol), followed by a drop of N,N-dimethylformamide, and stirred for 12 h at 25° C. The resulting clear solution was evaporated in vacuo and the crude product was used in the next step without any further purification (99%). MS (Turbo Spray): m/z=290.1 (M+H).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:23])[C@H:8]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([F:21])=[C:16]([CH3:22])[CH:15]=1)[CH2:9][CH2:10][CH2:11][CH3:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:5][NH:6][C:7](=[O:23])[CH:8]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([F:21])=[C:16]([CH3:22])[CH:15]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@@H](Nc1cc(C)c(F)c(C)c1)C(=O)NOC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC(Nc1cc(C)c(F)c(C)c1)C(=O)NO
Temperature: 25 °C
Reaction time: 87 h
Yield: 29.8 %

Procedure:
To a solution of (R)-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid tert-butoxy-amide (0.737 g, 2.273 mmol) in 1 mL of dichloromethane, was added trifluoroacetic acid (9 mL). After stirring at room temperature for 87 h, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 0-10% methanol/dichoromethane to give the title compound as a white solid (0.182 g, 30% yield). Pure analytical sample was obtained by RP-HPLC purification. LC-MS: tR=6.8 min; m/z 269 (M+H)+;)+; 1H NMR (500 MHz, CD3OD) δ 0.92 (t, J=7.05 Hz, 3H), 1.33-1.45 (m, 4H), 1.71-1.79 (m, 2H), 2.13 (d, J=2.02 Hz, 6H), 3.65 (t, J=7.05 Hz, 1H), 6.36 (d, J=5.88 Hz, 2H); 13C NMR (125.75 MHz, CD3OD) δ 14.24, 14.80, 23.50, 29.18, 33.99, 58.94, 115.65 (d, J=3.14 Hz), 125.69 (d, J=18.74 Hz), 143.30, 155.19 (d, J=233.14 Hz), 172.75; 19F NMR (470.58 MHz, CD3OD) δ −135.79.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:9]1[C:20](=[O:44])[CH2:21][NH:22][C:23](=[O:43])[NH:24][C:25]1[CH:26]=[C:27]([CH:31]([CH3:42])[C:32]([O:34]CC2C=CC=CC=2)=[O:33])[CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:9]1[C:20](=[O:44])[CH2:21][NH:22][C:23](=[O:43])[NH:24][C:25]1[CH:26]=[C:27]([CH:31]([CH3:42])[C:32]([OH:34])=[O:33])[CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C(=O)OCc1ccccc1)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Product: CC(C(=O)O)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3F)SC[C@H]2C(=O)OC(C)(C)C)c1
Yield: 43.1 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 84, but starting from 3.8 g of benzyl 2-{3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenyl}propionate (A form) and 0.8 g of 10% palladinized charcoal. 1.4 g of 2-{3-{3-{2-[(2R,4R)-4-tert-butoxycarbonyl-2-(2-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}phenyl}propionic acid (A form), melting at 145° C., are thus obtained. [α]D20 =+20.0°±11° (C=0.539%; DMF)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C1COCC1.O>[CH2:15]([O:14][C:12]([N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 4-piperidone hydrochloride (79.0 g) in THF and water (4: 1,75 ml), was added 4N NaOH (105 ml) solution followed by benzyl chloroformate (66 ml) at 0° C. The resulting mixture was stirred at the same temperature for 1 h. At the end of this time, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulphate. The solvent was removed by distillation under reduced pressure to give 135 g (99.5%) of the title compound as a dark thick liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[C:8]([CH3:14])[C:7]=2[CH:15]=1)#[N:2].[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]3)=[O:13])=[C:8]([CH3:14])[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)oc2ccc(C#N)cc12
Product: Cc1c(C(=O)N[C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)oc2ccc(C#N)cc12

Procedure:
In the same manner as in Example 1 (2), 5-cyano-3-methyl-2-benzofurancarboxylic acid (312 mg, 1.55 mmol) and t-butyl trans-(4-aminocyclohexyloxy)acetate (380 mg, 1.66 mmol) were condensed to give 534 mg of t-butyl trans-[4-[(5-cyano-3-methyl-2-benzofuranyl) carbonylamino]cyclohexyloxy]acetate as a colorless solid (84%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[O:19][C:20]1[C:21]([F:42])=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([O:31]C1C=CC([N+]([O-])=O)=CC=1)=O)[C:24]([CH3:41])=[CH:23]2>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[O:19][C:20]1[C:21]([F:42])=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([NH:4][CH2:1][CH2:2][CH3:3])=[O:31])[C:24]([CH3:41])=[CH:23]2
Reactant: COc1cc2ncnc(Oc3ccc4c(cc(C)n4C(=O)Oc4ccc([N+](=O)[O-])cc4)c3F)c2cc1OC
Reactant: CCCN
Solvent: CN(C)C=O
Product: CCCNC(=O)n1c(C)cc2c(F)c(Oc3ncnc4cc(OC)c(OC)cc34)ccc21
Reaction time: 0.67 h
Yield: 7 %

Procedure:
n-Propylamine (210 μL, 2.55 mmol) was added to a solution of Compound 12 in dry N,N-dimethylformamide and the reaction stirred for 40 minutes. The solvent was removed by rotary evaporator and the crude residue suspended in saturated aqueous NaHCO3. Precipitate was filtered and washed with additional NaHCO3 (20 mL×2) and diethyl ether (20 mL). Solids were dissolved in a minimal amount of methylene chloride and precipitated from diethyl ether. Precipitate was filtered and purified by reverse phase HPLC to give 27 mg of Compound 13 (two-step yield=7%) as a tan solid. m/z 439.2 (M+H, 100%) (positive ionization mode). 1H-NMR (CDCl3, 400 MHz): δ 1.06 (3H, t); 1.74 (2H, m); 2.60 (3H, s); 4.08 (6H, d); 5.69 (1H, t); 6.47 (1H, s); 7.12 (1H, dd); 7.35 (1H, s); 7.48 (1H, d); 7.63 (1H, s); 8.61 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[NH:5][CH2:6][CH2:7][CH2:8][CH3:9].Br[CH2:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([N:5]([CH2:15][C:16]2[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=2)[CH2:6][CH2:7][CH2:8][CH3:9])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: CCCCNc1cccc(Br)c1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Yield: 57.8 %

Procedure:
To a solution of 3-bromo-N-butyl-2-methylaniline (700 mg, 2.89 mmol) in dry acetonitrile (75 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (830 mg, 2.89 mmol) and N,N-diisopropylethylamine (331 μL, 1.9 mmol). The resultant mixture was heated at 80° C. for 3 h. The reaction mixture was cooled and the solvents removed in vacuo, diluted with water (50 mL) and extracted with CH2Cl2 (2×100 mL). The organic solution was dried (Na2SO4) and the solvents removed in vacuo. Purification by SPE (silica, 20 g) eluted with 100:2 to 100:5 cylclohexane:EtOAc afforded the title compound as a colourless oil (749 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[C@@H:13](Br)[C@H:12]([OH:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[O:5]1>CS(C)=O>[CH3:3][C:4]1([CH3:18])[CH:13]2[O:15][CH:12]2[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[O:5]1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reaction time: 1 h

Procedure:
0.4 g of a 60% dispersion of NaH in oil is added with stirring to a solution of 2.82 g of trans-2,2-dimethyl-3-bromo-6-cyanochroman-4-ol in 15 ml of DMSO. The mixture is stirred for 1 hour, 2,2-dimethyl-3,4-epoxy-6-cyanochroman being formed as an intermediate. 1.43 9 of 1H-2-pyridone and a further 0.5 g of the NaH dispersion are added and the mixture is stirred for 16 hours at 20°. Working up analogously to Example 1 gives "A" (m.p. 146-148°) and "B" (m.p. 244°).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[C:15]([NH:23][CH3:24])[CH:14]=1>>[F:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:18])[CH2:6][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[C:15]([NH:23][CH3:24])[CH:14]=1
Reactant: CNS(C)(=O)=O
Reactant: CNc1cc(F)ccc1C(=O)OC
Agent: [Li]CCCC
Product: CNc1cc(F)ccc1C(=O)CS(=O)(=O)NC

Procedure:
In a similar manner to that described in Example 12(a), N-methylmethanesulphonamide was reacted with n-butyl lithium and the product reacted with methyl 4-fluoro-2-methylaminobenzoate to give the novel compound 1-(4-fluoro-2-methylaminophenyl)-2-(N-methylsulphamoyl)ethanone, m.p. 140°-142°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:12][C:13]1[O:8][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N)c(C(=O)O)c1
Product: Cc1ccc2nc(C)oc(=O)c2c1

Procedure:
45.5 g (0.3 mol) of 5-Methylanthranilic acid are refluxed together with 130 g of acetic anhydride for 3 hours. After the solvent has been evaporated in vacuo, the residue is dissolved in 200 ml of dichloromethane, and the solution is filtered through silica gel. The concentrated filtrate is induced to crystallise with isopropyl ether.
Reaction SMILES: Cl[C:2](OCC)=[O:3].[NH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH2:15])=[O:14].N1C=CC=CC=1>O1CCOCC1>[NH:7]1[C:2](=[O:3])[NH:15][C:13](=[O:14])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]12
Reactant: CCOC(=O)Cl
Reactant: NC(=O)c1cccn1N
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)c2cccn2[nH]1
Temperature: 155 °C
Yield: 63 %

Procedure:
Ethyl chloroformate (4.9 ml, 51 mmole) was added dropwise to a stirred mixture of 1-amino-1H-pyrrole-2-carboxamide (5.85 gm, 46.7 mmole, Journal of Heterocyclic Chemistry, 1994, 31, 781) and dry pyridine (4.2 mL, 51 mmole) in dry dioxane (48 mL) under N2 at RT. This was heated at reflux for 1 hr and then the solvent was removed. The residue was heated at 155° C. for 17 hr and then allowed to cool to RT. This was triturated with methanol and the solid was collected by filtration and washed with cold methanol to give the product, 4.43 gm (63% yield): MS: 152 (M+H)+; HPLC Ret Time: 0.36 min (YMC Xterra S7 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-:11].[K+]>C(O)C>[NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:11]
Reactant: [OH-]
Reactant: Cc1ccc(C#N)c(N)c1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(C(N)=O)c(N)c1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
2-amino-4-methylbenzonitrile (10 g, 75.7 mmol) was dissolved in ethanol, added with potassium hydroxide (21.2 g, 378 mmol), followed by refluxing for 8 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in ethyl acetate. The organic layer formed was washed with a saturated aqueous solution of sodium bicarbonate and brine. The obtained organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain the title compound (4.9 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:12][N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18](=O)[C:17]=2[CH:16]=[CH:15][C:14]1=[O:24]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][CH:18]2[CH2:19][CH2:20][CH2:21][C:22]3[N:13]([CH3:12])[C:14](=[O:24])[CH:15]=[CH:16][C:17]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc(Cl)c(Cl)c1)CCC2
Temperature: 25 °C
Reaction time: 41 h
Yield: 63.9 %

Procedure:
A mixture of 2-(3,4-dichlorophenyl)ethylamine (3.8 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), and para-toluenesulfonic acid (130 mg) was heated in refluxing toluene (50 ml), with azeotropic removal of water, for 41 hrs. An additional 1 g of the amine and 0.1 g of para-toluenesulfonic acid were added, and the mixture was heated for an additional 24 hrs. The solution was cooled and the precipitate was collected. Sodium borohydride (0.6 g) was added to a solution of the precipitate in ethyl alcohol (50 ml), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in hot ethanol and treated with an equivalent amount of fumaric acid. The solid was collected and recrystallized from ethanol to provide 3.8 g (48%) of product, mp 172°-173° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([CH3:10])[C:5]([O:7]CC)=O.[C:12](#[N:14])[CH3:13]>C1COCC1>[F:11][C:4]([F:3])([CH3:10])[C:5](=[O:7])[CH2:13][C:12]#[N:14]
Reactant: CC#N
Reactant: CCOC(=O)C(C)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)C(=O)CC#N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
In a round bottomed flask flushed with argon, a suspension of sodium hydride 60% in mineral oil (1.30 g, 34 mmoles) was rinsed twice with hexane, and suspended in 20 mL of dry THF. The solution was heated to 75° C., and ethyl difluoropropionate (3.00 g, 22 mmoles) and acetonitrile (1.78 mL) in 5 ml of dry THF was added dropwise over 30 minutes. The temperature of the reaction was lowered to 65° C. and stirred overnight. The mixture was then concentrated to an oil and partitioned between water and ether, and extracted twice to remove any mineral oil and other impurities. The aqueous layer was acidified to pH=1 with 10% HCl, and the solution extracted twice. These extracts were dried over magnesium sulfate, filtered and concentrated to a crude oil. The crude product was purified using silica gel chromatography using a gradient of 10-40% ethyl acetate/hexane to afford 4,4-difluoro-3-oxo-pentanenitrile 1H(300 MHz, CDCl3) δ 3.95 (s, 2H), 1.86 (m, 3H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH3:30])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)=[O:12])[NH:8][N:7]=1)(=[O:5])[CH3:4].Cl.O>CCO.[BH4-].[Na+]>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]3[CH:10]=[C:6]([CH:3]([OH:5])[CH3:4])[NH:7][N:8]=3)=[O:12])[CH3:30])[N:17]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Sodium borohydride (0.930 g, 24.57 mmol) and EtOH (105 ml) were placed in to the reaction flask under nitrogen atmosphere. (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (15 g, 37.8 mmol) was added in small portions to keep temperature below 25° C. After 3.5 h sodium borohydride (0.07 g, 1.85 mmol) was added and the mixture was stirred for additional 60 min to complete the reaction. 16 ml of ˜10% HCl in EtOH was added carefully to set pH to 3.5 and the mixture was stirred overnight at RT. Water (30 ml) was added and the stirring was continued for 3 h. The precipitate was filtered, washed with 2×10 ml of cold water:EtOH (1:1) and dried under vacuum to obtain 12.2 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (, 3H), 1.39 (d, 3H), 4.24-4.52 (m, 3H), 4.76-4.86 (m, 1H), 5.42 (d, 1H), 6.42 (bs., 1H), 6.94 (d, 1H), 7.82 (d, 1H), 8.00 (bs, 2H), 8.09 (bs, 1H), 8.20 (d, 1H), 13.05 (bs, 1H).