Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])=[C:15]([O:26][CH3:27])[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.O>CN(C)C=O>[CH3:27][O:26][C:15]1[CH:14]=[C:13]([O:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:38][C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[C:3]([O:28][CH3:29])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH:18]=[CH:17][C:16]=1[NH:19][C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1OC
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccncc4)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A starting compound (N-{4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (48 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 65 mg (yield 67%) of the title compound.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].BrBr.[F:19][C:20]([F:25])([F:24])[C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CC(C)=O.O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:16])[CH:14]([NH:23][C:21](=[O:22])[C:20]([F:25])([F:24])[F:19])[CH3:15])=[CH:11][CH:12]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCC(=O)c1ccc(OCCC(C)C)cc1
Reactant: NC(=O)C(F)(F)F
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)CCOc1ccc(C(=O)C(C)NC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4'-Isoamyloxypropiophenone (100 g, 45.5 mmol) was dissolved in chloroform (100 ml), and bromine (7.63 g, 47.7 mmol) was dropwise added thereto under ice-cooling. The mixture was stirred for 3 hours, and poured into water after disappearance of bromine colour. The aqueous mixture was extracted with dichloromethane, and the extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated off, which gave a crude intermediate product. The product was dissolved, without purification, in acetone (100 ml) followed by the addition of trifluoroacetamide (10.2 g, 90 mmol) and anhydrous potassium carbonate (12.4 g, 90 mmol). After 1.5 hours heating under reflux, the mixture was cooled to room temperature, and the acetone was evaporated off. The residue was taken in dichloromethane, and the organic solution was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Evaporation of the organic solvent provided a crude product which was purified by silica gel chromatography. The title compound was thus obtained. Yield: 4.44 g (29%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C@@H:2]1[C:10]([OH:12])=[O:11].[H][H].[C:15]([OH:18])(=[O:17])C>[Rh]>[N:3]1([C:15]([O:18][C:9]([CH3:1])([CH3:4])[CH3:8])=[O:17])[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:1][C@H:2]1[C:10]([OH:12])=[O:11]
Reactant: CC(=O)O
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Reactant: [H][H]
Agent: [Rh]
Product: CC(C)(C)OC(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
In an acetic acid solution containing 2.0 g of L-indoline-2-carboxylic acid, 5% Rh/Al2O3 was added and the resultant mixture was stirred for 3 days in a hydrogen gas atmosphere (4.5 kg/cm2). The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The resultant residue was tert-butoxycarbonylated to give 0.6 g of the title compound.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH3+:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:11]=1[O:23][C:24](=[O:27])[NH:25][CH3:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:35]([O:42][C:43]([NH:45][C@@H:46]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[C:53]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:52]=1)[C:47](O)=[O:48])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:21][O:20][C:18](=[O:19])[C@@H:17]([NH:22][C:47](=[O:48])[C@@H:46]([NH:45][C:43]([O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:44])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[C:53]([O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:52]=1)[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:11]([O:23][C:24](=[O:27])[NH:25][CH3:26])[CH:12]=1
Reactant: CNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)OC)ccc1OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O)OCc1ccccc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CNC(=O)Oc1cc(C[C@H](NC(=O)[C@H](Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)NC(=O)OCc2ccccc2)C(=O)OC)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(S)-2-(4-Benzyloxy-3-methylcarbamoyloxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride (0.2 g, 0.506 mmol) was suspended in dichloromethane (20 ml), then triethylamine (0.068 g, 0.678 mmol) was added, followed by the addition of (S)-2-benzyloxycarbonylamino-3-(3,4-bis-benzyloxy-phenyl)-propionic acid (0.31 g, 0.678 mmol) [see German patent DE 2121187] and HOBt (0.092 g, 0.678 mmol). The mixture was stirred at room temperature for 20 min. EDC (0.130 g, 0.678 mmol) was added. The stirring was continued overnight. The mixture was washed with sodium bicarbonate, dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (1:2). (S)-2-[(S)-2-benzyloxycarbonylamino-3-(3,4-bis-benzyloxy-phenyl)-propionylamino]-3-(4-benzyloxy-3-methylcarbamoyloxy-phenyl)-propionic acid methyl ester was obtained as a white solid, 0.43 g. 1H NMR (400 MHz, CDCl3) 2.62 (d, J=4.6 Hz, 3H), 2.88-3.00 (m, 3H), 3.35 (s, 1H), 3.56 (s, 3H), 4.24-4.30 (m, 1H), 4.43-4.49 (m, 1H), 4.95 (m, 2H), 5.06 (m, 6H), 6.80 (m, 1H), 6.92-7.09 (m, 5H), 7.23-7.45 (m, 21H), 7.59 (m, 1H), 8.46 (d, J=7.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]2O)[CH:5]=[CH:6][C:7]=1[Cl:8].[F-:18].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]2[F:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [F-]
Reactant: CC1=C(C)C(O)N(c2ccc(Cl)c(Cl)c2)C1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC1=C(C)C(F)N(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
23.2 g N-(3,4-dichlorophenyl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (see Example 3) is refluxed together with 11.6 g of potassium fluoride and 0.3 g of 18-crown-6 (cyclic polyethylene ether) in 50 ml of acetonitrile for 14 hours. After cooling, undissolved constituents are filtered off, and the filtrate is concentrated by evaporation. The residue is recrystallised from methanol to yield 8 g (35% of theory) of the above product in the form of colourless crystals, m.p. 102°-103°.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[C:23]([C:28](O)=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[F:32][C:20]([F:19])([F:31])[O:21][C:22]1[C:23]([C:28]([NH:16][C@H:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[NH:10][C:7]2[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=2)=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1ncccc1OC(F)(F)F
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1OC(F)(F)F

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 70 mg, 0.25 mmol), 3-(trifluoromethoxy)pyridine-2-carboxylic acid (CAS number 1221171-81-8; 86 mg, 0.42 mmol), EDC (71 mg, 0.37 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (51 mg, 0.37 mmol) and triethylamine (0.104 ml, 0.74 mmol) in DCM (1 ml) was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate (25 ml) and water (10 ml). The organics were washed with water (2×10 ml) and brine (10 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[CH:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:24]=1)=[O:5].[C:30](OC(=O)C)(=[O:32])[CH3:31].N1C=CC=CC=1.C(Cl)(=O)C>C(N(CC)CC)C>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:30](=[O:32])[CH3:31])=[CH:19][CH:18]=3)=[CH:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:24]=1)=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C2=CCCCc3cc(NC(=O)c4c(F)cccc4F)ccc32)cc1
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C2=CCCCc3cc(NC(=O)c4c(F)cccc4F)ccc32)cc1

Procedure:
Compound 9 was prepared by reacting Compound 8 with acetic anhydride in the presence of pyridine or by reacting Compound 8 with acetyl chloride in the presence of triethyl amine.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[ClH:23].Cl.NCC[NH:28][OH:29].[N:30]1C=CC=[CH:32][CH:31]=1>C(O)C>[ClH:23].[ClH:23].[NH2:30][CH2:31][CH2:32][O:29][N:28]=[C:4]([CH:1]1[CH2:3][CH2:2]1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1
Reactant: NCCNO
Reactant: c1ccncc1
Reactant: O=C(c1ccc(-n2ccnc2-c2ccccc2)cc1)C1CC1
Agent: Cl
Solvent: CCO
Product: NCCON=C(c1ccc(-n2ccnc2-c2ccccc2)cc1)C1CC1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A mixture of cyclopropyl-[4-(2-phenyl-1-imidazolyl)phenyl]methanone (2.6 g), aminoethylhydroxylamine dihydrochloride (1.95 g), and 3 equivalents of pyridine, in absolute ethanol (30 ml) was heated under reflux, under nitrogen, with stirring, overnight. The reaction mixture was evaporated, the residue was taken up in ethyl acetate and washed with a 10% sodium hydroxide solution. The organic extracts were evaporated and the residue purified by high performance liquid chromatography (silica gel, 185:14:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was taken up in ethanol and treated with ethereal hydrogen chloride. The mixture was evaporated. The residue was recrystallized from ethanol/ether to give 3.06 g (80.9%) of product, mp >220° C. (dec).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Si:20]([O:1][CH2:2][C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: OCC1(CO)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1(CO)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,1-Bis(hydroxymethyl)cyclopropane (1.0 g, 0.0098 mol), triethylamine (TEA) (2.0 mL, 0.015 mol), and 1H-imidazole (0.13 g, 0.0020 mol) were dissolved in anhydrous DCM (15 mL) and the solution was cooled to 0° C. A solution of tert-butyldimethylsilyl chloride (1.55 g, 0.0103 mol) in DCM (5 mL) was added drop-wise and the resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM (3×). The organic extract was dried (magnesium sulfate), filtered, and concentrated in vacuo. The crude product was identified by 1H NMR and used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[S:12]1.C[Si](C)(C)Cl.[OH:32]O.O>C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[C:11](=[O:32])[C:16](=[O:17])[N:15]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[S:12]1
Reactant: OO
Reactant: CN(C)CCN1C(=O)C(=Cc2ccc(Cl)cc2Cl)Sc2ccccc21
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CCN1C(=O)C(=O)C(c2ccc(Cl)cc2Cl)Sc2ccccc21
Reaction time: 0.5 h
Yield: 105 %

Procedure:
The solution of 2-(2,4-dichlorophenylmethylidene)-4-(2-dimethylaminoethyl)-2H-1,4-benzothiazine-3(4H)-one hydrochloride (1 g) in 10 ml of chloroform was cooled below 0° C. and added with trimethylchlorosilane (2 ml), and then added with 30% hydrogen peroxide (0.29 g) for 30 minutes. The solution was stirred for 30 minutes below 0° C., and added with 1 ml of water. After further stirring for 1 hour at room temperature, 10 ml of water was added to the reaction mixture. The aqueous phase of the mixture was adjusted to a pH within 8-9 and the chloroform layer was separated from the mixture. The remaining aqueous phase was extracted with 10 ml of chloroform. The chloroform solutions wee combined, dried and evaporated under reduced pressure. The oily residue was purified by silicagel chromatography to give 2-(2,4-dichlorophenyl)-5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-3,4(5H)-dione (1.0 g) as oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11](Cl)=[O:12].C(=O)([O-])[O-].[K+].[K+].[NH2:20][C:21]1([C:30]#[N:31])[CH2:26][CH2:25][N:24]([O:27][CH2:28][CH3:29])[CH2:23][CH2:22]1>C(#N)C>[C:30]([C:21]1([NH:20][C:11](=[O:12])[CH2:10][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])[CH2:26][CH2:25][N:24]([O:27][CH2:28][CH3:29])[CH2:23][CH2:22]1)#[N:31]
Reactant: CCON1CCC(N)(C#N)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCON1CCC(C#N)(NC(=O)Cc2c(C)cc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
3.0 g of (2,4,6-trimethyl-phenyl)-acetyl chloride and 10 g of potassium carbonate in 90 ml of acetonitrile were treated at 0° C. with a solution of 3.6 g of 4-amino-1-ethoxy-piperidine-4-carbonitrile in 30 ml of acetonitrile. After stirring for 18 hours at room temperature the reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate. The organic phase was washed with brine and concentrated. Chromatography (heptane/ethyl acetate 5:1) yielded 4.5 g of N-(4-cyano-1-ethoxy-piperidin-4-yl)-2-(2,4,6-trimethyl-phenyl)-acetamide as a solid, mp: 194-195° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[N+:6]([C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)(=[O:16])=[O:17])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCNCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
Diethylamine (2.4 g) was dissolved in pyridine (15 ml) and 3-nitrobenzenesulfonyl chloride (6.7 g) was added, followed by stirring at 50° C for 2 hours. The residue obtained by an evaporation of pyridine under a reduced pressure was dissolved in methylene chloride (150 ml), washed with water, 1 N hydrochloric acid, water, and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of the solvent under a reduced pressure gave N,N-diethyl-3-(nitro)benzenesulfonamide (4.0 g).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[C:6]([CH3:13])=[CH:5][N:4]=1.[SH:14][C:15]1[NH:16][C:17]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:15]([S:14][CH2:2][C:3]3[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[C:6]([CH3:13])=[CH:5][N:4]=3)=[N:16][C:17]=2[CH:23]=1
Reactant: Cc1cnc(CCl)c(C)c1[N+](=O)[O-]
Reactant: COc1ccc2nc(S)[nH]c2c1
Product: COc1ccc2[nH]c(SCc3ncc(C)c([N+](=O)[O-])c3C)nc2c1

Procedure:
The 2-chloromethyl-3,5-dimethyl-4-nitropyridine of formula-III is dissolved in a protic solvent and reacted with 2-mercapto-5-methoxy benzimidazole of the formula-VII with a base to get 5-methoxy-2-(((3,5-dimethyl-4-nitro-2-pyridinyl)methyl)thio)-1H-benzimidazole of formula-VIII. After recrystallization from suitable solvents, pure compound-VIII is obtained with an impurity, 5-methoxy-2-(((3,5-dimethyl-4-chloro-2-pyridinyl)methyl)thio-1H-benzimidazole, of formula-XV less than 0.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[CH:16][NH:15][N:14]=1)(=[O:12])=[O:11].C1(C)C=CC(S([C:27]2[N:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[N:28]=2)(=O)=O)=CC=1.N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[CH:16][N:15]([C:27]2[N:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[N:28]=2)[N:14]=1)(=[O:11])=[O:12]
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)c2nc(C)cc(C)n2)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C)nc(-n2cnc(S(=O)(=O)Nc3c(Cl)cccc3Cl)n2)n1
Yield: 79.4 %

Procedure:
N-(2,6-dichlorophenyl)-1,2,4-triazole-3-sulphonamide (2.051 g) was heated for 1 hour at 125° C. with 1.82 g of 2-p-toluenesulphonyl-4,6-dimethylpyrimidine in the presence of 1,8-diazabicyclo(5,4,0)undec-7-ene (2.128 g) in dimethylformamide (35 ml). After distillation of the solvent, the residue was poured into a mixture of water (80 ml) and 1N hydrochloric acid (20 ml), and was then filtered off. This crude product was chromatographed on silica gel using methylene chloride/methanol (95/5) as eluent, to give 2.2 g of the desired product, mp 274°-275° C.
Reaction SMILES: C(ON=O)(C)(C)C.[C:8](#[N:11])[CH:9]=[CH2:10].Cl[C:13]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].CCOCC.[ClH:33]>C(#N)C.O>[Cl:33][CH:9]([CH2:10][C:13]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:14]=1[C:15](=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:8]#[N:11]
Reactant: C=CC#N
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: N#CC(Cl)Cc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 92.7 g (0.4 mol) of 2-amino-5-chlorobenzephenone in 250 ml of acetonitrile was added to a mixture of 70 g (0.52 mol) of cupric chloride, 65 g (0.63 mole) of t-butylnitrite, 500 ml of acrylonitrile and 500 ml of acetonitrile. When the addition was complete, stirring at room temperature was continued for 2 hours. The mixture was diluted with 80 ml of 6 N hydrochloric acid and 1500 ml of water, extracted with ether and dried over anhydrous sodium sulfate. The ether solution was concentrated at reduced pressure to give a brown oil, which contained the end product and 2,5-dichlorobenzophenone. Trituration of the oil with a mixture of ether and petroleum ether gave the end product as a tan solid. Recrystallization of a small portion of the end product from a mixture of ether and petroleum ether gave pale yellow needles, mp 69°-71° C.
Reaction SMILES: [BH4-].[Na+].C[C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[C:15](=[O:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[CH3:27]N(C)C=O.O>CO>[OH:26][CH:15]([C:5]1[N:6]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:27])[CH:12]=[CH:11][CH:10]=2)[O:8][CH:4]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(C#N)cc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2nc(C(O)COc3ccc(C#N)cc3)co2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Sodium borohydride (0.654 mg) was added to a suspension of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]benzonitrile (5.5 g) in methanol (100 ml)-N,N-dimethylformamide (50 ml), followed by stirring at room temperature for 1 hour. The reaction solution was poured into water and the crystals which separated out were collected by filtration to give 4-[2-hydroxy-2-(5-methyl-phenyl-4-oxazolyl)ethoxy]benzonitrile (5.1 g, 92.7%). Recrystallization from acetone afforded colorless neddles, m.p. 176°-177° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25]Br)[CH3:21]>C1COCC1>[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25][CH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[CH3:21]
Reactant: CCOC(=O)CCBr
Reactant: Cc1cnccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCCc1cnccn1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
Butyllithium (1.6 M in hexane solution, 10 ml, 16 mmol) was added dropwise to a solution of diisopropylamine (2.25 ml, 16 mmol) in anhydrous THF (50 ml) at −20° C. under a nitrogen atmosphere. The mixture was stirred at −20° C. for 30 minutes and after cooling at −70° C. a solution of 2-methyl-pyrazine (1.47 ml, 16 mmol) in THF (10 ml) was added dropwise. After 15 minutes, a solution of 3-bromo-propionic acid ethyl ester (2.54 ml, 19.2 mmol) in THF (10 ml) was added and the mixture maintained at −70° C. for 2 hours and then stirred at room temperature overnight. The reaction was then quenched with a saturated solution of NH4Cl and extracted with ethyl acetate, the organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (hexane/ethyl acetate from 9/1 to 1/1 respectively) to give the title compound (1 g, 33% yield).
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O.[Br:15][C:16]1[CH:17]=[C:18]([C:22](=O)[CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=1.Cl>C(O)C>[Br:15][C:16]1[CH:17]=[C:18]([C:22]2[C:23]([CH3:24])=[C:7]([C:8]([OH:13])=[O:1])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([F:3])[CH:5]=3)[N:9]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CCC(=O)c1cccc(Br)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1c(-c2cccc(Br)c2)nc2ccc(F)cc2c1C(=O)O
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Potassium hydroxide (19.98 g, 356 mmol) was added to a suspension of 5-fluoro-1H-indole-2,3-dione (10 g, 59.4 mmol) in ethanol (96 mL). 1-(3-Bromophenyl)-1-propanone (13.91 g, 65.3 mmol) was added and the mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature and acidified to pH 3 with concentrated HCl. The solid was collected by filtration, washed with water, and dried to afford 2-(3-bromophenyl)-6-fluoro-3-methyl-4-quinolinecarboxylic acid (20.9 g, 98% yield). This material was used without further purification. MS (m/z) 360.0 (M+H+).