Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]=[C:11]2[CH3:35])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCc1nc(C)n(-c2ccc(OC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(O)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101 %

Procedure:
To a solution of 4′-{[1-(3-fluoro-4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (6.40 g) in methylene chloride (30 mL) was added boron tribromide (1.0 M methylene chloride solution, 27 mL), and the mixture was stirred at room temperature for 2 days. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (6.27 g, 100%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:27][CH3:28])[C:11]1[C:16]([O:17][CH2:18][O:19][CH3:20])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[CH:13][C:12]=1[CH2:25][OH:26].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(OCC)(=O)C>[CH3:29][S:30]([O:26][CH2:25][C:12]1[CH:13]=[CH:14][C:15]([C:21]([F:22])([F:23])[F:24])=[C:16]([O:17][CH2:18][O:19][CH3:20])[C:11]=1[CH:10]([O:9][CH3:8])[O:27][CH3:28])(=[O:32])=[O:31]
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCOc1c(C(F)(F)F)ccc(COS(C)(=O)=O)c1C(OC)OC
Reaction time: 0.5 h

Procedure:
Triethylamine (2.74 ml, 19.7 mmol) was added to a solution of [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (5.09 g, 16.4 mmol) obtained in Example (6-6) in ethyl acetate (50 ml). After methanesulfonyl chloride (1.33 ml, 17.2 mmol) was added dropwise to the mixture under ice-cooling, the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was filtered through Celite. The filtrate was successively washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. n-Hexane was added to the residue obtained by removing the solvent under reduced pressure. The precipitated crystals were filtered to give 2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl methanesulfonate as a pale yellow compound (5.37 g, yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][C:11]1[CH:10]=[N:9][N:5]2[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[N:3][C:4]=12
Reactant: Clc1cc(Cl)n2nccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Clc1cc(Cl)n2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.3 %

Procedure:
To a solution of 5.3 g of 5,7-dichloropyrazolo(1,5-a)pyrimidine in 70 ml of chloroform was added portionwise 6 g of N-bromosuccinimide while keeping the temperature below 40° C. The resulting solution was refluxed for 30 minutes and was then stirred at room temperature for 12 hours. The suspension was then filtered. The filtrate was washed with 50 ml of cold 10% sodium hydroxide aqueous solution twice and was then dried over MgSO4. The chloroform solution was then concentrated under reduced pressure to give 7.47 g of the desired product, m.p. 73°-75° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:23])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
3-(2-Methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (500 mg) was dissolved in chloroform (20 mL), and oxalyl chloride (500 mg) and a catalytic amount of DMF were added, followed by stirring at room temperature for 3 hours. Under reduced pressure, the solvent and an excess reagent were distilled off to obtain 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoyl chloride (520 mg) as an oily product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[C:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11].O>C(OC(=O)C)(=O)C>[CH3:5][O:6][C:7]1[C:8]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:9]([C:14]([N+:1]([O-:4])=[O:2])=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)c(OC)c1OS(C)(=O)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c([N+](=O)[O-])cc(OC)c(OC)c1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Concentrated nitric acid (0.62 ml) was added dropwise to an ice cooled solution of methyl 3,4-dimethoxy-2-methanesulfonyloxybenzoate (1.94 g, 0.0067 mol) in acetic anhydride (3 ml) and the reaction stirred for 1 hour. Water (20 ml) was carefully added, and the resulting precipitate filtered and washed with further water. Drying under suction filtration gave the subtitle compound as a white solid (1.94 g, 86%). 1H-NMR (CDCl3): δ=3.34 (3H, s), 3.94 (3H, s), 4.00 (3H, s), 4.18 (3H, s), 7.68 (1H, s).
Reaction SMILES: [O:1]([C@H:8]1[C@H:14]([OH:15])[C:13]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1.O>CN(C)C=O>[O:1]([C@H:8]1[C@@H:14]([OH:15])[C:13]2[CH:16]=[C:17]([O:20][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Oc1ccccc1)CCO2
Reactant: ClCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H]1c2cc(OCc3ccc4ccccc4n3)ccc2OCC[C@H]1Oc1ccccc1
Reaction time: 0.33 h
Yield: 13.9 %

Procedure:
To a solution of 950 mg of the cis-title product of Example 29 in 25 ml of dimethylformamide was added 173 mg of 50% sodium hydride. After stirring for 20 minutes, 641 mg of 2-chloromethylquinoline was added. The reaction was stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo to afford the crude product which was purified by recrystallization from methyl acetate/hexane to afford 200 mg of title product, m.p. 130-132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:27]([C:30]1[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2](/[N:1]=[CH:35]/[C:33]4[O:34][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[O:18][C:17]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Nc1ccc(N2CCC(c3nn(Cc4ccccc4)c(=O)o3)CC2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: O=c1oc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)nn1Cc1ccccc1
Yield: 88 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7d, 0.35 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-benzyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9d, 416 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:24][O:25][NH:26][CH3:27]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:26]([O:25][CH3:24])[CH3:27])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)c(Br)c1
Reaction time: 8 h

Procedure:
A solution of 3-bromo-4-fluorobenzoic acid (100 g, 0.456 mol) and CDI (77.2 g, 0.547 mol) in 1 L of dry DCM was stirred at r.t. for 30 min and then O,N-dimethyl-hydroxylamine (53.4 g, 0.547 mol) was added. The resulted mixture was stirred overnight. The solvents were removed under vacuum and the residue was purified via column chromatograph to afford the title compound.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([C:1]2[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=2)=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=C(O)CCCc1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 14.4 gm of 4-(4-biphenylyl)-butyric acid in 72 ml of glacial acetic acid at 24°-27° C. 24 ml of fuming nitric acid (d=1.52) were added dropwise. After stirring for 5 minutes, the mixture was poured into ice water while stirring, and the aqueous mixture was extracted with benzene. The benzene phase was washed with water, dried and evaporated; the residue was dissolved in 100 ml of acetone and admixed with 6.8 ml of cyclohexylamine. The thus obtained cyclohexylamine salt had a melting point of 160°-161° C. (after recrystallization from 200 ml of isopropanol). Melting point of the free acid: 124° C. (from carbon tetrachloride).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[CH2:17]OC)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:29])[CH2:27][CH2:26]1)=[O:24].[CH:38]1(C(O)=O)[CH2:41]C[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:17]1([C:16]([NH:15][C:11]2[CH:10]=[C:9]([O:8][C:6]3[C:5]([F:21])=[CH:4][C:3]([NH:22][C:23]([C:25]4([C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)=[O:29])[CH2:26][CH2:27]4)=[O:24])=[C:2]([F:1])[CH:7]=3)[CH:14]=[CH:13][N:12]=2)=[O:20])[CH2:41][CH2:38][CH2:39]1
Reactant: O=C(O)C1CCC1
Reactant: COCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)C1CCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.45 mmol) (as prepared in Example 9) and cyclobutanecarboxylic acid (90 mg, 0.9 mmol) in DMF (3 ml) was added HATU (513 mg, 1.35 mmol), followed by DIEA (516 mg, 4 mmol). The mixture was sparged with nitrogen and stirred overnight at 60° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-(4-(2-(cyclobutanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (97 mg, yield 41.1%). 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 10.42 (s, 1H), 9.80 (s, 1H), 8.18 (d, J=6.0 Hz, 1H), 8.08 (dd, J=12.4, 6.8 Hz, 1H), 7.68 (s, 1H), 7.60-7.54 (m, 3H), 7.17 (t, J=8.8 Hz, 2H), 6.73 (dd, J=5.6, 2.4 Hz, 1H), 2.18-2.02 (m, 4H), 1.92-1.83 (m, 1H), 1.76-7.69 (m, 1H), 1.62-1.55 (m, 4H); MS (ESI): m/z 525.1 [M+H]
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.Br[CH:16]([CH3:24])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH:16]([CH3:24])[C:17](=[O:18])[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)c1c(C)[nH]c2ccccc12
Reactant: CC(Br)C(=O)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)n(C(C)C(=O)N2CCCC2)c2ccccc12
Temperature: 100 °C
Yield: 61.2 %

Procedure:
To a solution of methyl 2-methyl-1H-indole-3-carboxylate (0.52 mmol, 0.1 g) in N,N-dimethylformamide (5 mL), 2-bromo-1-(pyrrolidin-1-yl)propan-1-one (0.52 mmol, 0.137 mg) and cesium carbonate (1.05 mmol, 384 mg) was added. The reaction mixture was heated at 100° C. for 12 hours. LC-MS showed the start material was consumed. The solvent was evaporated and the residue was washed with water (10 ml), extracted with dichloromethane (20 ml). The organic layer was separated, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=45:1) to give methyl 2-methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-indole-3-carboxylate (100 mg, 93%). 1H NMR (300 MHz, CD3OD): δ 8.07-8.03 (m, 1H), 7.44-7.40 (m, 1H), 7.19-7.14 (m, 2H), 5.53-5.49 (m, 1H), 3.90 (s, 3H), 2.80 (s, 3H), 2.00-1.80 (m, 2H), 1.74 (d, J=5.1 Hz, 3H), 1.67-1.64 (m, 4H), 1.32-1.28 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH:11]2[CH2:13][CH2:12]2)=[N:9]/[OH:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].Cl[CH2:19][C:20]1[C:21]([CH3:32])=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1>C(O)C>[CH3:32][C:21]1[C:20]([CH2:19][O:10]/[N:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)\[CH:11]2[CH2:12][CH2:13]2)=[CH:25][CH:24]=[CH:23][C:22]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1c(CCl)cccc1-c1ccccc1
Reactant: O/N=C(/c1ccc(Cl)cc1)C1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(CO/N=C(/c2ccc(Cl)cc2)C2CC2)cccc1-c1ccccc1

Procedure:
In a manner similar to General Procedure F of European Patent Publication No. 4,754, published Oct. 17, 1979, 1.96 g (0.01 mole) of (E)-(4-chlorophenyl)(cyclopropyl)methanone oxime was treated with 0.23 g (0.01 mole) of sodium ethoxide in 10 ml of ethanol, and the mixture was evaporated to dryness. The residue was dissolved in a minimum amount of solvent consisting of N,N-dimethylformamide and t-butanol (9:1 ratio) and treated with 2.16 g (0.01 mole) of 3-chloromethyl-2-methyl[1,1'-biphenyl] to yield, after purification by column chromatography, 0.83 g of (E)-(4-chlorophenyl)(cyclopropyl)methanone O-[(2-methyl[1,1'-biphenyl]-3-yl)methyl]oxime as an oil.
Reaction SMILES: B.[C:2]1([C@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@@H:11]3[CH2:18][N:19]([C:22](=O)[CH2:23][CH3:24])[CH2:20][CH2:21][N:10]3[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>O1CCCC1>[ClH:26].[ClH:26].[C:2]1([C@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@@H:11]3[CH2:18][N:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21][N:10]3[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CCCN1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1

Procedure:
To a stirred solution of 1.0 M borane in tetrahydrofuran (55 ml) maintained under nitrogen at 0° C. was added cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2-propionyl-2H-pyrazino[ 2,1-a]isoquinoline (5.3 g, 0.016 m) and the mixture heated to reflux for 3 hours, then cooled in an ice bath and carefully treated with 10% HCl (100 ml). This mixture was heated to reflux for 1 hour, then cooled, and the tetrahydrofuran removed on an aspirator. The remaining aqueous solution was basified to pH 11 with 50% NaOH and extracted with chloroform. The extracts were dried over MgSO4 and evaporated to a solid residue (6.0 g). This was dissolved in methanol (50 ml) and isopropanol (50 ml) and acidified with HCl gas. Upon cooling and standing, a white solid crystallized, which was collected by filtration and vacuum dried at 80° for 24 hours to give 4.6 g cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2-propyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 273°-274°.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:28]2[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:35])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=3)=[CH:13][C:12]=2[Cl:27])[CH:10]=1)=[O:5])C.CO.[OH-].[Na+].Cl>CCOC(C)=O>[Cl:27][C:12]1[CH:13]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:18]=2)[CH:15]=[CH:16][C:11]=1[N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]1[C:28]1[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: CCOC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2c(Cl)cccc2Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)O)nc3-c3c(Cl)cccc3Cl)c(Cl)c2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a 250 mL round bottom flask was added 1-(3-Chloro-3′-methanesulfonyl-biphenyl-4-yl)-2-(2,6-dichloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (4.07 g, 7.40 mmol), MeOH (72 mL), and 2N aq NaOH (18.5 mL). The reaction solution was allowed to stir at 50° C. for 2 hr. The reaction solution was diluted with EtOAc (200 mL), neutralized by the addition of aq 1 N HCl, and poured into a separatory funnel. The organic phase was partitioned, and the aqueous phase was and extracted with EtOAc (150 mL×2). The combined organic phases were dried over Na2SO4, filtered into a round bottom flask and concentrated on the rotavapor. The crude residue was reprecipitated in an EtOAc/hexane solution and the solid precipitate was filtered under vacuum to afford 3.22 g (83% yield) of title product. MS (ESI) 521.3, 523.3, 525.3 [M+H]+.
Reaction SMILES: Cl[CH:2]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)[CH3:3].[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CS(C)=O>O1CCCC1>[CH2:13]([O:20][NH:21][CH:2]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NOCc1ccccc1
Reactant: CC(Cl)c1cc2ccccc2s1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(NOCc1ccccc1)c1cc2ccccc2s1

Procedure:
heating 2-(1-chloroethyl)benzo[b]thiophene with O-benzylhydroxylamine in a solvent such as dimethyl sulphoxide or tetrahydrofuran to give 2-(1-(benzyloxyamino)ethyl)benzo[b]thiophene of formula: ##STR4##
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].CN1CCOCC1.[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[C:16]1([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:2][CH:3]2[CH2:8][CH2:7][O:6][C:4]2=[O:5])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1CCOC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1OCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
α-Aminobutyrolactone hydrobromide (10.0 g, 54.9 mmol), N-methylmorpholine (11.2 g, 110.0 mmol) and triphenylmethyl chloride (15.4 g, 55.2 mmol) were dissolved in N,N-dimethylformamide (DMF) (200 ml) (distilled from calcium hydride) and stirred at ambient temperature for 16 hours. The mixture was filtered, and water (200 ml) was added to the DMF-solution. The resulting slurry was stirred for 2 hours, the precipitate was filtered off and washed with a mixutre of DMF and water (1:1, 50 ml). The solid was resuspended in water (100 ml), filtered and dried at 50° C. in vacuo. N-triphenylmethyl-α-amino-butyrolactone was isolated as a white solid. Yield 17.55 g (93.2%), mp 164.5°-165.5° C. (uncorrected).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([C:23]([OH:25])=O)=[N:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N>CN(C)C=O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([C:23]([NH2:28])=[O:25])=[N:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxylic acid (E123a) (168 mg, 0.47 mmol) was dissolved in dry dimethylformamide (5 ml), treated with 1,1′-carbonyldiimidazole (230 mg, 1.42 mmol) and the resulting mixture stirred at room temperature for 1.5 hours. The mixture was treated with 0.880 ammonia (0.14 ml, 2.84 mmol) and stirred for 4 hours. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of (0.5:4.5:95) to afford the title compound; MS (ES+) m/e 339 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:8])=[O:7])#[N:2].[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[N:17]=1>ClCCCl>[ClH:8].[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[N:17]=1)=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: COC(=O)c1csc(N)n1
Solvent: ClCCCl
Product: COC(=O)c1csc(NC(=O)c2cccc(C#N)c2)n1
Product: Cl
Yield: 80 %

Procedure:
In 1 liter of toluene, 200 g of 3-cyanobenzoic acid were suspended, followed by the addition of 128 ml of thionyl chloride and 1 ml of N,N-dimethylformamide. The resulting mixture was stirred under heating at 80° C. for 5 hours. After cooling of the reaction mixture, the solvent was distilled off under reduced pressure. To the residue, n-hexane was added. By distilling off the solvent under reduced pressure, 3-cyanobenzoyl chloride was obtained. The resulting 3-cyanobenzoyl chloride was dissolved in 3 liters of dried 1,2-dichloroethane, followed by the addition of 200 g of 2-amino-4-methoxycarbonyl-1,3-thiazole. The resulting mixture was heated under reflux for 5 hours. The reaction mixture was cooled. Crystals so precipitated were collected by filtration and then washed with water, whereby 289 g of 2-[N-(3-cyanobenzoyl)amino]-4-methoxycarbonyl-1,3-thiazole.hydrochloride were obtained. Yield: 80%.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7]Br.C([O-])([O-])=O.[Na+].[Na+].Cl.[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH2:20]>C(Cl)Cl>[Br:7][CH2:6][C:2](=[O:1])[CH2:3][C:4]([NH:20][CH2:19][C:18]([O:17][CH3:16])=[O:21])=[O:5]
Reactant: COC(=O)CN
Reactant: BrBr
Reactant: C=C1CC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CNC(=O)CC(=O)CBr
Temperature: -50 °C
Reaction time: 2 h

Procedure:
4.8 ml Diketene are dissolved in 30 ml methylene chloride. The solution is cooled to -50° C. and a solution of 3.24 ml bromine dissolved in 20 ml methylene chloride is added dropwise over 30 min. The mixture is left stirring for 2 h at ambient temperature. At -40° is added, all at once, an intimate mixture of 20 g finely ground Na2CO3 and 7.9 g glycine methyl ester hydrochloride. Stirring is continued for 90 min, allowing the mixture to return to ambient temperature. The salt is filtered quickly, the filtrate is concentrated in vacuo at ambient temperature. The residual oil is purified by chromatography on silica, eluting with ethyl acetate. The desired compound is obtained as a white powder, m.p. 76°-77° C.