Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][C:14](Cl)=[O:15].COC1C=CC([N+]([O-])=O)=CC=1CCC(O)=O.S(Cl)(Cl)=O.[CH:37]([NH:40][CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38]>ClCCl>[CH:37]([N:40]([CH:41]([CH3:43])[CH3:42])[C:14](=[O:15])[CH2:13][CH2:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:39])[CH3:38]
Reactant: COc1ccc([N+](=O)[O-])cc1CCC(=O)Cl
Reactant: CC(C)NC(C)C
Agent: COc1ccc([N+](=O)[O-])cc1CCC(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc([N+](=O)[O-])cc1CCC(=O)N(C(C)C)C(C)C
Reaction time: 16 h

Procedure:
A solution of 3-(2-methoxy-5-nitrophenyl)propionyl chloride(0.46 g, 1.9 mmol), prepared from 3-(2-methoxy-5-nitrophenyl)propionic acid (Asano et al., J. Pharm. Soc. Japan, 1950, 70, 480) and thionyl chloride, in dichloromethane (5 mL) was added in one portion to a solution of diisopropylamine (0.67 g, 6.6 mmol) in dichloromethane (20 mL), stirred for 16 h, washed with water (2×20 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound: MS(ES) m/3 309.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.[NH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH2:33])=[O:26])[CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: N
Reactant: C=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: C=C(CC)C1N(CC(N)=O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 40 %

Procedure:
Racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.21 mmol) prepared in example 107a was stirred in a methanolic ammonia solution (7N, 10 mL) at room temperature for 18 h. The reaction mixture was concentrated, and the residue was purified by chromatography (EtOAc:MeOH=10:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-1′-[aminocarbonyl-methyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 41 mg, 40%).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[NH:4][C:3]1=[O:14].[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>ClCCl.O>[CH3:13][O:12][C:10]([CH2:9][CH2:8][CH2:7][O:6][C@@H:5]1[NH:4][C:3](=[O:14])[C@H:2]1[NH:1][C:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:11]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCCO[C@@H]1NC(=O)[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCO[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10.6 %

Procedure:
(3S,4S)-3-Amino-4-[3-(methoxycarbonyl)propoxy]azetidin-2-one (30 mg, 0.148 mmol) was dissolved in dry dichloromethane (2 mL) and treated with triphenylmethyl chloride (41 mg, 0.148 mmol) followed by diisopropylethylamine (19 mg, 0.148 mmol). The solution was stirred at RT under argon for 5 h, diluted with water and extracted with dichloromethane. The organic phases were combined, washed with water and brine, dried (magnesium sulfate), filtered, and concentrated. The residue was purified by preparative thin layer chromatography (Whatman, silica gel 60A, 20×20 cm, 1000 um, 40% ethyl acetate:hexane) to give the title compound (7 mg). MS(ES) m/e 445.2 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.C(O)CCC.Cl.[CH3:17][O:18][NH2:19]>O>[CH3:17][O:18][NH:19][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12
Reactant: CON
Reactant: Clc1nccc2ccoc12
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CONc1nccc2ccoc12
Temperature: 125 °C

Procedure:
A three-necked flask was charged with 7-chloro-furo[2,3-c]pyridine (40 g, 0.26 mol) and n-butanol (300 mL) and heated at 125° C. Methoxyamine hydrochloride (54 g, 0.65 mol) was added as a solid and then additional methoxyamine hydrochloride (54 g, 0.65 mol) dissolved in water (50 mL) was added slowly. The resulting mixture was heated at reflux overnight. After cooling to RT, the reaction mixture was concentrated in vacuo. The remaining aqueous solution was basified to pH ˜8.5 with saturated NaHCO3 and extracted several times with DCM. The combined DCM extracts were washed with saturated NaHCO3 and brine. This solution was concentrated in vacuo leaving a dark brown syrup which was used without further purification.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6]([N+:12]([O-])=O)=[C:5]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])[C:4]=1[F:24].C(OCC)(=O)C>C1COCC1.CCCCCC.[Zn]>[F:2][C:3]1[C:8]2[CH:9]=[CH:10][O:11][C:7]=2[C:6]([NH2:12])=[C:5]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])[C:4]=1[F:24]
Reactant: O=[N+]([O-])c1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Temperature: 30 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Concentrated HCl (1 mL) was added to a solution of (4,5-difluoro-7-nitro-benzofuran-6-yl)-(2-fluoro-4-iodo-phenyl)-amine (0.260 g, 0.599 mmol) in THF (5 mL) at 0° C. This was followed by the addition of zinc dust (0.179 g, 5.99 mmol) at 0° C. The reaction mass was stirred for 1 hour at 20-40° C. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate (50 mL). The organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 0.240 g of the crude compound which used for the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.53 (d, 1H), 7.49 (dd, 1H), 7.20 (d, 1H), 6.00 (d, 1H), 6.20 (t, 1H), 5.42 (bs, 1H), 4.10 (bs, 2H).
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][N:18]=1.C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:14]1[C:6]2[C:5]3[S:15][C:2]([C:20]4[CH:21]=[CH:22][C:17]([NH2:16])=[N:18][CH:19]=4)=[CH:3][C:4]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cc2c(s1)-c1ncccc1OCC2
Reactant: Nc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1
Yield: 36 %

Procedure:
A mixture of 9-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (113 mg, 0.400 mmol), 2-aminopyridine-5-boronic acid, pinacol ester (96.8 mg, 0.440 mmol) and bis(triphenylphosphine)palladium(II) chloride (14.0 mg, 0.0200 mmol) in 1.0 M of sodium carbonate in water (0.500 mL) and acetonitrile (3 mL, 60 mmol) was degassed and microwaved on 300 watts at 140° C. for 20 minutes. The reaction mixture was partitioned between ethyl acetate and water and filtered from inorganic salts. The organic layer was washed with water, brine, dried over MgSO4 and evaporated to dryness. The crude residue was purified on silicagel column, eluting with 50% of ethyl acetate in methylene chloride to give 142 (yield 43 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=2.3, 1H), 8.21 (dd, J=1.4, 4.5, 1H), 7.68 (dd, J=2.5, 8.6, 1H), 7.38 (dd, J=1.4, 8.1, 1H), 7.21 (s, 1H), 7.17 (dd, J=4.5, 8.1, 1H), 6.50 (d, J=8.7, 1H), 6.21 (s, 2H), 4.32 (t, J=4.8, 2H), 3.19 (t, J=4.8, 2H). MS: (ESI+) 296.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:19][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[CH:23]=[C:24]([CH3:25])[C:16]=3[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:17]=2[C:18]([N:28]([CH3:27])[NH2:29])=[O:20])=[O:19])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: CNN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)cn3-c3ncccc3Cl)nc12
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)N(C)N)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
A mixture of 0.86 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.11 g of methylhydrazine and 15 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.17 g of 4-bromo-N-[4-chloro-2-(N-methylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: Cl.[N:2]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH:17]([C@@H:19]1[C@@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][N:21]([C@H:30]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[C:31]([O:33]CC2C=CC(OC)=CC=2)=[O:32])[CH2:20]1)=O.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>C(O)=O>[N:2]1([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:19]3[C@@H:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][N:21]([C@H:30]([CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:31]([OH:33])=[O:32])[CH2:20]3)[CH2:13][CH2:12]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc2c(c1)nnn2C1CCNCC1
Agent: Cl
Solvent: O=CO
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(n3nnc4ccccc43)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 4-benzotriazol-1-yl-piperidine HCl salt and of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) using procedures analogous to those described in Example 89 Steps C and D except TFA and anisole were used in place of formic acid in Example 89, Step D. ESI-MS 502 (M+1); HPLC A: 2.02 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:5]=[C:4]([CH:19]=[O:20])[N:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:5]=[C:4]([CH2:19][OH:20])[N:3]=1
Reactant: O=Cc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of 4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidine-2-carbaldehyde (70 mg, 0.21 mmol) in MeOH (4 mL) is added sodium borohydride (24 mg, 0.63 mmol). The mixture is stirred for 4 hours at ambient temperature. Water (20 mL) is added and the mixture is extracted thrice with ethyl acetate (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford {4-chloro-6-[2-(2,4-dichloro-phenyl)-ethylamino]-pyrimidin-2-yl}-methanol (67 mg) as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.C1COCC1.[BH4-].[Na+]>O>[OH:3][CH:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: C=CCOC(=O)c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCOC(=O)c1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.1 g (15 mmol) of the allyl ester obtained above in (a), 20 ml of methyl alcohol and 20 ml of THF are introduced into a round-bottomed flask. While cooling in an icebath, 285 mg (7.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. 3.1 g (100%) of the expected product are collected in the form of a colorless oil.
Reaction SMILES: [CH2:1]([CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH:9]([OH:21])[CH2:10][CH:11]([C:18](=[O:20])[NH2:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1.C(Cl)Cl>[C:18]([CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([O:21][C:44](=[O:46])[CH3:45])[CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[NH2:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(N)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(CC(CCC(C)(C)F)C(N)=O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Reaction time: 2 h
Yield: 106.6 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide (1.01 g, 2.14 mmol) in pyridine (4 mL) was added dimethylaminopyridine (DMAP) (65 mg, 0.533 mmol) and acetic anhydride (0.400 mL, 4.23 mmol). The resulting solution was stirred for 2 hours, then diluted with methylene chloride and washed with 1 M hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (1.16 g, >100%).
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1>C(N(CC)CC)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][CH2:6][NH:5][C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCCNc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1NCCNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
Chloroform (1000 ml) was added to N-(2-aminoethyl)-p-chloroaniline (116.67 g) and the mixture was dissolved. Triethylamine (83.02 g) and 2-chloro-3-nitropyridine (108.40 g) were added to the resultant solution on ice in this order and stirred for 2 hours at room temperature. Subsequently, the resultant mixture was refluxed for one hour, cooled, washed with water (500 ml×2), and the aqueous layer was extracted with chloroform (500 ml). The aqueous layer was combined with the chloroform layer, washed with saturated brine, and dehydrated over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure. The thus-obtained crystalline residue was purified by silica gel chromatography (elution solvent=chloroform:methanol=100:5), to thereby obtain the target compound in the form of colorless crystals (195.97 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](=O)[CH2:13]Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]([NH2:23])=[S:22].CCOCC>C(O)C>[NH2:23][C:21]1[S:22][CH:13]=[C:12]([C:11]2[CH:16]=[CH:17][C:8]([O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:20]=1
Reactant: O=C(CCl)c1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: NC(N)=S
Solvent: CCOCC
Solvent: CCO
Product: Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1

Procedure:
A 8.0 g portion of 4-(4-chlorobenzyloxy)phenacyl chloride and 2.3 g of thiourea were stirred in 70 ml of ethanol under reflux for 1 hour. After cooling, 100 ml of ether was added, and the precipitating crystals were recovered by filtration, resulting in 7.8 g (82.1%) of hydrochloride of 2-amino-4-[4-(4-chlorobenzyloxy) phenyl]thiazole. Recrystallized from 80% ethanol m.p., 248°-250° C.
Reaction SMILES: [CH2:1]([C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br>CC(=O)CC>[CH2:1]([C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:36][CH2:35][CH2:34][CH2:33][Br:32])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)C(Cc2ccccc2)(c2ccccc2O)c2ccccc21
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1C(=O)C(Cc2ccccc2)(c2ccccc2OCCCCBr)c2ccccc21
Yield: 83.1 %

Procedure:
16.5 g (0.05 mol) of 3-benzyl-3-(2-hydroxyphenyl)-1- methylindolin-2-one in 250 ml of 2-butanone are stirred under reflux with 20.7 g (0.15 mol) of ground anhydrous potassium carbonate and 17.2 ml (0.15 mol) of 1,4-dibromobutane for 5 hours. The hot mixture is filtered with suction, and the filtrate is concentrated in vacuo. The crystalline residue is triturated with petroleum ether, and the product is isolated after removal of the solvent with suction. 19.3 g of product of melting point 174°-5° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].[H][H]>C(O)(=O)C.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:14])[N:2]([CH3:1])[C:6]=2[CH:7]=1
Reactant: [H][H]
Reactant: Cn1c(=O)oc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1c(=O)oc2ccc(N)cc21

Procedure:
3-Methyl-5-nitro-3H-benzooxazol-2-one (22.87 g) was dissolved in acetic acid (350 mL). Palladium on activated charcoal 10% (6.27 g) was added and an atmosphere of hydrogen was introduced at r.t. The mixture was stirred over night. The reaction mixture was filtered over dicalite speed plus (Acros) and the solvent was evaporated. The residue was dissolved in 2M aqueous HCl (500 mL) and stirred for 10 minutes. The resulting solution was basified with conc. aqueous NaOH (200 mL) to pH 11 and stirred for 20 minutes at r.t. The resulting precipitate was filtered off and washed with cold water. Residual water was removed by co-evaporation with toluene. The resulting solid was dried in vacuo. The title compound was obtained as a brown solid (18.72 g, 92%). MS (m/e)=165.2 [M+H+].
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[S:32]([N:35]=C=O)(=[O:34])=[O:33]>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[S:32]([NH:35][C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:1])[F:22])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1)[CH3:17])(=[O:33])=[O:34]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: O=C=NS(=O)(=O)c1cc(Cl)ccc1Cl
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)NS(=O)(=O)c1cc(Cl)ccc1Cl
Reaction time: 18 h

Procedure:
A solution of one gram (0.0031 mole) 2-[4-(4-trifluoromethylphenoxy)phenoxy]-propionic acid in dry CHCH3 was treated with 0.8 gram (g) (0.0081 mole) 2,5-dichlorobenzene sulfonyl isocyanate. The solution was stirred for approximately 18 hours, then heated to reflux for three hours, followed by cooling.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[Br:15]Br.S([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([Br:15])[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11]
Reactant: O=C(Cc1ccccc1Cl)C(F)(F)F
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(C(Br)c1ccccc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.1 %

Procedure:
2.0 g (9.0 mmole) of 1-(2-chlorophenyl)-3,3,3-trifluoro-2-propanone were dissolved in 30 ml of carbon tetrachloride, and then 0.46 ml (9.0 mmole) of bromine was added to the solution, which was then stirred at room temperature for 10 hours. At the end of this time, sodium hydrogensulfite was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes, after which insolubles were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 10:2 by volume mixture of toluene and ethyl acetate as the eluent, to give 0.87 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[CH:9]=[O:10].CC(C)=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[C:9]([OH:19])=[O:10]
Reactant: CC(C)=O
Reactant: COc1cc(-c2ccccc2)ccc1C=O
Product: COc1cc(-c2ccccc2)ccc1C(=O)O
Yield: 73.5 %

Procedure:
To a cold solution of 3-methoxy-biphenyl-4-carboxaldehyde (0.32 g, 1.5 mmol) in acetone (10 mL), the Jone's reagent was added slowly drop wise at 0° C. until the reaction completes. Acetone was removed completely and the resulting residue was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated to obtain the title compound (0.25 g, 73.5%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C=C(Cn2cncn2)Cn2cncn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Clc1ccc(CC(Cn2cncn2)Cn2cncn2)cc1

Procedure:
10% Palladium on charcoal (200 mg) was added under argon to a solution of 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-yl)-2-(1,2,4-triazol-1-ylmethyl)propene (750 mg) in absolute ethanol (50 ml). After uptake of the theoretical amount of hydrogen, the reaction mixture was filtered through Kieselguhr ( Celite-- trademark) and evaporated to dryness under reduced pressure. The residual oil was purified by chromatography on silica, using chloroform as eluent, and after evaporation of the solvent, the residue was treated with ethereal hydrogen chloride to give 2-(4-chlorobenzyl)1,3-bis(1,2,4-triazol-1-yl)propane: m.p. 107 -108 °.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>ClCCl>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])=[CH:5][CH:4]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(Br)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-benzylamine hydrochloride (367.8 mg, 1.7 mmol) was dissolved in dichloromethane (15 mL), and the solution was cooled to 0° C. DIEA (380 μL, 2.2 mmol) was then added, and the reaction was stirred at 0° C. for 5 minutes. Then cyclopropanecarbonyl chloride (180 μL, 2.3 mmol) was added, and the reaction was stirred at 0° C. for 20 minutes. The reaction was quenched with distilled water, and the solvents were removed. The resulting mixture was redissolved in DMF (10 mL) and purified by reverse phase HPLC to give the desired product.