Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Si:13]([C:17]#[CH:18])([CH3:16])([CH3:15])[CH3:14]>C1COCC1.C(OCC)(=O)C.[Cu](I)I>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([C:18]#[C:17][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([NH2:12])=[N:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(C(F)(F)F)cc1I
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C
Yield: 101.8 %

Procedure:
To a stirred solution of 3-Iodo-5-trifluoromethylpyridin-2-amine (61.38 g, 213 mmol) in anhydrous THF (200 mL) under a nitrogen atmosphere was added Pd(PPh)3Cl2 (1.5 g, 2.1 mmol), and copper iodide (0.406 g, 2.1 mmol) and the reaction mixture degassed under nitrogen. The reaction mixture was cooled in an ice bath and TMS acetylene (36 mL, 256 mmol) was added dropwise over 30 minutes. Upon complete addition the reaction was allowed to warm to room temperature and monitored until the reaction was complete. The mixture was diluted with ethyl acetate (200 mL) and filtered through silica washed through with 4×150 mL ethyl acetate. The filtrates were concentrated and the solid was triturated from heptane (250 mL) to give 56 g of product.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)SC)#[N:2].[CH:14]1[C:24]2[CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[CH:19]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>N1C=CC=CC=1.C(OCC)C>[CH:25]1[C:21]2[CH2:22][CH2:23][C:24]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:19]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:4]([NH:3][C:1]#[N:2])=[N:7][C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[C:20]=2[CH:28]=[CH:27][CH:26]=1
Reactant: CSC(=Nc1ccncc1)NC#N
Reactant: NCCCCCOC1c2ccccc2CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#CNC(=Nc1ccncc1)NCCCCCOC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
1-Cyano-2-methyl-3-pyridin-4-yl-isothiourea (573 mg, 3.00 mmol) and 5-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-pentylamine (886 mg, 3.00 mmol) were dissolved in pyridine (20 mL). Triethylamine (2 mL, 14 mmol) was added followed by (4-dimethylamino)pyridine (5.0 mg, 0.04 mmol). The reaction mixture was stirred at 86□ C. for 12 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (50 mL). The resulting precipitate was collected by filtration and washed with diethyl ether. The crude product was recrystalized from methanol and diethyl ether to give the desired product as a white crystalline solid (yield 85%). 1H NMR (CDCl3, ppm): 8.54 (dd, 2H), 7.41-7.12 (m, 10H), 5.29 (s, 1H), 3.56-3.41 (m, 4H), 3.32 (dd, 2H), 3.05-2.95 (m, 2H), 1.71-1.41 (m, 6H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[O:30]1[C:34]2([CH2:39][CH2:38]C(O)[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>C(Cl)Cl>[Br:5][CH:1]1[CH2:38][CH2:39][C:34]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:35][CH2:36]1
Reactant: BrC(Br)(Br)Br
Reactant: OC1CCC2(CC1)OCCO2
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Carbon tetrabromide (11.0 g, 33.2 mmol) was added to a solution of triphenylphosphine (8.70 g, 33.2 mmol), imidazole (2.47 g, 36.3 mmol), and 1,4-dioxaspiro[4.5]decan-8-ol (5.0 g, 31.6 mmol) in DCM (150 mL) under argon at 0° C. The ice bath was removed and the mixture was stirred for 24 h at RT. The solvent was removed in vacuo to give an oil that was purified by silica gel chromatography to give 8-Bromo-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4]C=1.C(C1C=CC(B(O)O)=CC=1F)#[N:39]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[N:39][CH:2]=[CH:7][CH:6]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cccnc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-cyano-3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=498, obsd.=498).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH2:4][CH:3]1[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[H-].[Na+].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>O1CCCC1>[C:39]([O:38][C:36]([CH2:35][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH2:4][CH:3]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:2]1=[O:1])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C(NC1CN(C(=O)C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)CN(C(=O)C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Under ice-cooling, 2-oxo-3-benzyloxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (800 mg) was added to a suspension of 60% sodium hydride (152 mg) in tetrahydrofuran (50 ml), the mixture was stirred at room temperature for one hour. Subsequently, tert-butyl bromoacetate (390 mg) was added and stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, Water was added to the residue and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodiun sulfate, and the mixture was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 640 mg of the title compound (Yield: 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)c1

Procedure:
The title compound, MS: m/e=324.8 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-methoxy-benzene boronic acid.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.C(N(CC)CC)C.[O:30]=[C:31]1[N:35]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH2:33][O:32]1.Cl>ClCCl>[C:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][S:36]([N:35]1[CH2:34][CH2:33][O:32][C:31]1=[O:30])(=[O:38])=[O:37])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C1OCCN1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCC[C@H](NS(=O)(=O)N1CCOC1=O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A suspension of 5.39 g of H-Lys(Boc)-OtBu hydrochloride (15.9 mmol, 1.0 eq) and 7.1 ml of triethylamine (50.9 mmol, 3.2 eq) in dichloromethane (70 ml) was added to the solution obtained in Example 143d), in such a way that the temperatures did not exceed 10° C. After the addition was complete, the mixture was allowed to reach RT and was stirred for a further 2 h. The reaction mixture was then mixed with 200 ml of 0.2 M hydrochloride acid, and the organic phase was separated off and washed with 100 ml of 0.2 M hydrochloric acid and concentrated. 5.5 g of the desired material were obtained as a colorless oil, which crystallized on standing.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[Cl:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[Cl:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([NH:40][CH3:39])=[O:3])[CH:14]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(Cl)c2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
3-(3-Chloro-1H-indazol-5-yl)-N-methyl 3-phenyl-acrylamide CCXVI was prepared from 3-(3-chloro-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](Br)[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[NH4+].[OH-].[CH3:20][N:21](C)C=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:20]#[N:21])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c(Br)c(OC)ccc12
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(C#N)c(OC)ccc12
Temperature: 180 °C

Procedure:
A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml) was added dropwise to a cooled suspension of 6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.139 moles) in glacial acid (2.75 ml). The precipitate was collected, washed with water and crystallized from ethanol to give 33.3 g of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119° C.; NMR (CDCl3) δ3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J=9.25 Hz, 1H), 7.4 (m, 1H), 8.05 (d, J=6.75 Hz, 1H), 8.45 (d, J=8.25 Hz, 1H), 8.9 (d, J=9.25, 1H). The latter ester (10.1 g, 34 mmoles) and Cu2 (CN)2.H2O (3.4 g, 17 mmoles) in distilled dimethylformamide (75 ml) containing 15 drops of pyridine was heated at 180° C. for 5 hr. The hot mixture was poured into a mixture of ice (50 g) and conc. NH4OH (50 ml). The resulting precipitate was collected, washed with water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210°-211° C., NMR (CDCl3) δ3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20°-22° C., 4N aqueous NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20°-22° C. for 60 hr, diluted with water, cooled to 0° C. and rendered acidic with 1N aqueous HCl. The precipitate was colleced and dried to yield 5.6 g of the title compound; mp >290° C.; NMR (DMSO-d 6) δ4.1 (s, 3H), 8.1 (m, 5H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1.C1CCN2C(=NCCC2)CC1>O1CCOCC1.O>[OH:16][CH:13]1[CH2:14][CH2:15][N:11]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH2:12]1
Reactant: OC1CCNC1
Reactant: COC(=O)c1cnc(Br)s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCC(O)C2)s1
Temperature: 82.5 °C

Procedure:
A mixture of methyl 2-bromo-1,3-thiazole-5-carboxylate (3 g, 13.5 mmol), 3-pyrrolidinol (1.3 g, 14.9 mmol) and DBU (4.1 mL, 27 mmol) in dioxane (50 mL) was heated at 80-85° C. overnight. After cooling, the mixture was diluted with water and extracted five times with EtOAc. The combined EtOAc extracts were washed with water, dried (Na2SO4) and concentrated to give the crude title compound as a light brown solid. 1H NMR (400 MHz, acetone-d6): δ 7.83 (s, 1H), 4.65 (m, 1 H), 4.33 (m, 1 H), 3.79 (s, 3 H), 3.67-3.45 (m, 4 H), 2.29-2.19 (m, 1 H), 2.11 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH2:32]([S:39](Cl)(=[O:41])=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)Cc4ccccc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and benzylsulfonyl chloride. Purity (ELSD, based on MW=575.7)=80%.
Reaction SMILES: CS(O[C@H:6]([C:16]1[CH:17]=[N:18][C:19]([CH:22]([F:24])[F:23])=[CH:20][CH:21]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C@@H:6]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[N:18][CH:17]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(C(F)F)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N=[N+]=[N-])c1ccc(C(F)F)nc1
Temperature: 60 °C
Yield: 84.5 %

Procedure:
To a stirred solution of (R)-2-(tert-Butyldimethylsilyloxy)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl methanesulfonate (2.24 g, 5.87 mmol) in dry DMF (15 mL) was added NaN3 (0.45 g, 7.05 mmol) and the resulting reaction mixture was heated at 60° C. for 2 h. After completion of the reaction the reaction mixture was treated with ice-cold water and extracted with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo to afford the title compound (1.63 g, 85% yield). MS: 328 [M+1]+; 1H-NMR (300 MHz, CDCl3): 8.60 (s, 1H), 7.82 (d, 1H, J=8.3 Hz), 7.64 (d, 1H, J=8.3 Hz), 6.64 (t, 1H, J=55.7 Hz), 4.65-4.70 (m 1H), 3.80-3.86 (m, 2H), 0.89 (s, 9H), 0.04-0.06 (m, 61-1).
Reaction SMILES: C=O.[NH3:3].Cl[CH2:5][C:6]([NH:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)=[O:7]>CO>[C:13]1([C:11]2[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[NH:8][C:6](=[O:7])[CH2:5][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CCl)Nc1ccccc1C(=O)c1ccccc1
Reactant: N
Agent: C=O
Solvent: CO
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1
Yield: 84.7 %

Procedure:
Paraformaldehyde (200 g., 91% flake) is placed in a stirred reactor equipped with a reflux condenser, decanter, and ammonia addition tube. Methanol (575 mls.) is added and then gaseous ammonia below the surface of the reaction mixture. 2-Chloroacetamido-benzophenone (273.7 g.) is then added. With a slow, continuous flow of ammonia to the reaction zone, the mixture is heated at reflux for 5 hours. The crystal slurry obtained is distilled to recover the methanol. Toluene (1350 mls.) is now added to the crystal residue and residual water is removed by azeotropic distillation through the decanter. When dry, the hot toluene solution is filtered, the filtrate is cooled for crystallization, and the product obtained isolated to give 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (200 g., 84.7%) m.p. 180°-181° C. (uncorr.).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:23]([OH:33])=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1>C1COCC1>[Cl:21][C:22]1[C:23]([OH:33])=[C:24]([S:29]([N:7]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=2)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: COC(=O)c1cccc(CNCc2ccc(F)cc2)n1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of methyl 6-((4-fluorobenzylamino)methyl)picolinate (140 mg, 0.51 mmol) in THF (3 mL) were added 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (147 mg, 0.56 mmol) and TEA (0.142 mL, 1.02 mmol). The reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated and lyophilized to give the desired product (0.19 g, 74%) as a white solid. 1H NMR (CD3OD) δ 7.93-7.80 (m, 2H), 7.65-7.53 (m, 3H), 7.27-7.25 (m, 2H), 6.94-6.90 (m, 2H), 4.68 (s, 2H), 4.65 (s, 2H), 3.98 (s, 3H). MS (ESI): 499.0 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH:7]=[CH2:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>C(O)C>[C:1]([O:6][CH:7]=[CH2:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:12]([O:5][CH2:1][CH3:2])(=[O:13])/[CH:11]=[CH:10]\[C:9]([O-:14])=[O:15]
Reactant: O=C1C=CC(=O)O1
Agent: C=COC(=O)CCC
Solvent: CCO
Product: CCOC(=O)/C=C\C(=O)[O-]
Temperature: 78 °C
Yield: 50 %

Procedure:
Into a 500 ml kettle was charged 96 g of the above vinyl butyrate/maleic anhydride copolymer and 144 g of absolute ethanol. The mixture was heated to 78° C. under a blanket of nitrogen for 5 hours to yield a 50% solid solution. The reaction mixture was then cooled to 40° C. and product, vinyl butyrate/ethyl maleate copolymer (42.29% solid copolymer in ethanol) was recovered and found to have a relative viscosity of 1.24 and a specific viscosity of 0.24. This product has a K value of 30.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:23][CH2:22][CH:21]([O:24][CH3:25])[CH2:20][CH2:19]3)[C:9]2=[N:12]S(C(C)(C)C)=O)=[CH:4][CH:3]=1.Cl>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:23][CH2:22][CH:21]([O:24][CH3:25])[CH2:20][CH2:19]3)[C:9]2=[NH:12])=[CH:4][CH:3]=1
Reactant: COC1CCC2(CCc3ccc(Br)cc3C2=NS(=O)C(C)(C)C)CC1
Agent: Cl
Product: COC1CCC2(CCc3ccc(Br)cc3C2=N)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
To N-(7′-bromo-4-methoxy-3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-naphthalene]-1′-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 13, 0.610 g, 1.43 mmol) under N2 (g) was added HCl (4 M in 1,4-dioxane, 3.58 mL, 14.3 mmol). The mixture was stirred at r.t. for 45 min and was then concentrated. DCM (approx. 2 mL) was added followed by Et2O. A solid formed and was filtered off and washed with Et2O. The solid was dissolved in DCM. NaHCO3 (sat. aq.) was added and the mixture was poured into a phase separator. The organic phase was collected and concentrated to give the title compound (0.35 g, 76% yield): MS (EI) m/z 321 M+.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[C:4]([OH:9])(=[O:8])[CH:5]([CH3:7])[OH:6].[Cl-].[Na+].[OH2:12]>>[C:4]([OH:9])(=[O:8])[CH2:7][C:5]([CH2:7][C:5]([OH:6])=[O:12])([C:4]([OH:9])=[O:8])[OH:6]
Reactant: CC(O)C(=O)O
Reactant: O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
The colouring agent and the flavouring agent were the same as in Example I. The mixture was treated in the same manner but the brine solution was now containing only 80 g of common salt besides 8 g of calcium chloride and having a pH-value which was adjusted at 5.0 by means of lactic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][NH2:4].[CH2:6]([O:9][C:10]1[C:18]([O:19][CH3:20])=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[O:21][CH3:22])[C:7]#[CH:8]>>[CH3:1][CH:2]([CH3:5])[CH2:3][NH:4][C:14](=[O:15])[C:13]1[CH:12]=[C:11]([O:21][CH3:22])[C:10]([O:9][CH2:6][C:7]#[CH:8])=[C:18]([O:19][CH3:20])[CH:17]=1
Reactant: CC(C)CN
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Product: C#CCOc1c(OC)cc(C(=O)NCC(C)C)cc1OC

Procedure:
According to the same method as that of Production Example 1, 2-methylpropylamine was used in place of 2,2-dimethylpropylamine, 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(2-methylpropyl)-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 21 of the present invention) represented by the formula:
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[NH:18][C:19](=[O:21])[CH3:20].O>CC(C)=O>[C:19]([NH:18][C:17]1[CH:16]=[C:15]([NH:14][C:2]([NH2:3])=[S:1])[CH:24]=[CH:23][CH:22]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: CC(=O)Nc1cccc(NC(N)=S)c1
Temperature: 50 °C
Yield: 60.6 %

Procedure:
A mixture of ammonium thiocyanate (2.79 g) and benzoyl chloride (3.86 ml) in acetone (30 ml) was refluxed for 5 minutes. Then a solution of 3′-aminoacetanilide (5.00 g) in acetone (40 ml) was added thereto. The mixture was poured into water, and the resulting precipitate was separated by filtration. The crystals were heated at 50° C. for 3 hours with 1N sodium hydroxide (150 ml) solution. The mixture was poured into a mixture of ethyl acetate and water, and the resulting precipitate was collected and washed with ethyl acetate and water to give N-(3-acetylaminophenyl)thiourea (4.22 g).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:6]=1[NH2:7].[OH-].[Na+].O.[C:17](Cl)(=[O:21])[C:18](Cl)=[O:19]>C1(C)C(C)=CC=CC=1>[CH3:3][N:4]1[C:5]2[C:6](=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[NH:7][C:18](=[O:19])[C:17]1=[O:21]
Reactant: CNc1ccc(OC)cc1N
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc2c(c1)[nH]c(=O)c(=O)n2C
Temperature: 25 °C

Procedure:
2-Methylamino-5-methoxyaniline dihydrochloride (0.256 mol) is neutralized with sodium hydroxide (22 g., 0.5 mol) in 80 ml. of water. The free amine is extracted into 300 ml. of xylene, the solution dried over magnesium sulfate, and filtered. This solution is then added over 50 min. to a solution of oxalyl chloride (39 g., 0.307 mol) in 300 ml. of xylene held at 75°-90° C. After addition is complete, the resulting solution is heated to a bath temperature of 155° and then allowed to cool to room temperature. The flask is cooled to 0° and the gray precipitate collected by vacuum filtration. The solid product is then dried under high vacuum at 160° for two hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:24])[CH2:15][CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=2[N:30]=1.S1C2C=CC=CC=2N=C1NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(O)=O)=CC=2)=CC=1>>[Cl:35][C:33]1[CH:32]=[CH:31][C:29]2[N:30]=[C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:24])[CH2:15][CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:27][C:28]=2[CH:34]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CCCC(CC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC
Agent: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Product: CCCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1)C(=O)O
Yield: 18 %

Procedure:
This compound was prepared from methyl 2-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]-pentanoate (68 mg, 0.20 mmol) and 2,6-dichloro-1,3-benzothiazole (61.3 mg, 0.30 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 17.2 mg (18%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.10 (br s, 1H), 10.75 (br s, 1H), 7.75-8.05 (m, 9H), 7.60 (d, 1H), 7.35 (m, 1H), 3.40 (q, 1H), 3.10 (m, 1H), 1.55 (m, 2H), 1.35 (m, 2H), 0.85 (t, 3H). LC-MS m/z 479.3 (MH+), ret. time 3.88 min.