Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=O.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>>[CH2:12]([NH:15][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:9]([OH:10])=[C:8]([Cl:11])[CH:7]=1)[CH:13]=[CH2:14]
Reactant: C=CCN
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Product: C=CCNCc1cc(Cl)c(O)c(Cl)c1

Procedure:
Prepared from 3,5-dichloro-4-hydroxybenzaldehyde and allylamine using the method of preparation 90 to give the title compound as a colourless oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=1)[C:10](=[O:19])[C:11]([C:14]1[NH:18][N:17]=[N:16][N:15]=1)=[CH:12][N:13]=2)[CH2:2][CH2:3][CH3:4].[C:21]([C:23](=CNC1C=CC(C2C=CC=CC=2)=CN=1)C(OCC)=O)#N>>[C:1]1([C:5]2[CH:6]=[CH:7][C:8]3[N:9]([CH:20]=2)[C:10](=[O:19])[C:11]([C:14]2[NH:15][N:16]=[N:17][N:18]=2)=[CH:12][N:13]=3)[CH:23]=[CH:21][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCc1ccc2ncc(-c3nnn[nH]3)c(=O)n2c1
Reactant: CCOC(=O)C(C#N)=CNc1ccc(-c2ccccc2)cn1
Product: O=c1c(-c2nnn[nH]2)cnc2ccc(-c3ccccc3)cn12
Yield: 31 %

Procedure:
In a manner similar to that described for the preparation of 7-n-butyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 7, the title compound (m.p. 308°-309° decomp) was prepared in 31% yield from ethyl 2-cyano-3-(5-phenyl-2-pyridylamino)acrylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:24]C(=O)C(C)(C)C)=[C:6]([C:22]=1[CH3:23])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].CO>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C:22]=1[CH3:23])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])=[O:8]
Reactant: COc1cc(C)c(C(=O)c2c(OC(=O)C(C)(C)C)ccc(Br)c2C)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(C(=O)c2c(O)ccc(Br)c2C)c(OC)c1OC
Reaction time: 1 h

Procedure:
A mixture of 50B (5.1 g, 10.6 mmol), sodium carbonate (3.65 g), methanol (100 ml) and water (30 ml) is heated to reflux with stirring for 1 hour. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is separated and concentrated. The residue is recrystallized from petrol ethers/ethyl acetate (95:5 v/v) The pure product is obtained as yellowish crystals, 3.70 g (88.3%), mp. 119-120° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:13]([F:21])=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[C:13]=1[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cccc(Cl)c1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 47.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 3-chloro-2-fluorophenylboronic acid (Aldrich; 584 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(3-chloro-2-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (434 mg, 46%) as a colorless oil which solidified on standing.
Reaction SMILES: Cl.Cl[CH:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[C:15]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[CH:14]2.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>C(#N)C>[N:34]1([CH:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([NH2:21])[C:15]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:14]3)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: c1c[nH]cn1
Reactant: Cc1cccc(C(Cl)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(C(c2ccccc2)n2ccnc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a small, sealed Smith synthesizer vial, 6-(2-(chloro(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine hydrochloride (0.030 g, 0.062 mmol) and imidazole (0.021 g, 0.312 mmol) were treated with ACN (0.416 mL). The solution was stirred at ambient temperature for 1 h. The reaction mixture was warmed to 100° C. for 1 h and then allowed to cool to ambient temperature. The mixture was purified by HPLC (1-70% acetonitrile/H2O, TFA modifier). A single clean fraction was treated with NH4OH and concentrated to ¼ volume. The resulting precipitate was collected and dried under a stream of N2 to afford 6-(2-((1H-imidazol-1-yl)(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine. MS (ESI, pos. ion) m/z: 476 (M+1).
Reaction SMILES: F[C:2]1([O:9][C:10]#[C:11][CH3:12])[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][CH2:3]1.[F:13]C1C=C(O)C=C(F)C=1>>[F:8][C:6]1[CH:7]=[C:2]([O:9][CH2:10][C:11]#[CH:12])[CH:3]=[C:4]([F:13])[CH:5]=1
Reactant: CC#COC1(F)C=C(F)C=CC1
Reactant: Oc1cc(F)cc(F)c1
Product: C#CCOc1cc(F)cc(F)c1
Yield: 67 %

Procedure:
This compound was prepared analogously to 2,4-difluoro-2-propynyloxybenzene but using 3,5-difluoro-phenol (14 g, 107 mmol) to give 1,3-difluoro-5-prop-2-ynyloxy-benzene 12 g (67%).
Reaction SMILES: O=[C:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].C(C1C=C(N)[O:17][N:16]=1)(C)C>>[O:9]1[CH2:10][CH2:11][CH:6]([C:2]2[CH:3]=[C:4]([NH2:5])[O:17][N:16]=2)[CH2:7][CH2:8]1
Reactant: N#CCC(=O)C1CCOCC1
Reactant: CC(C)c1cc(N)on1
Product: Nc1cc(C2CCOCC2)no1
Yield: 44 %

Procedure:
Prepared from 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile (350 mg, 2.29 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-amine as a colorless solid (170 mg, 44%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.01 (s, 1H), 4.40 (brs, 2H), 4.02-4.05 (m, 2H), 3.46-3.55 (m, 2H), 2.87 (m, 1H), 1.71-1.84 (m, 4H); LC-MS (ESI) m/z 169 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]P(Br)Br>C(OCC)C>[Br:11][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:9]
Reactant: CC(O)c1cccc(Cl)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(Br)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 1-(3-chlorophenyl)ethanol (0.2 g, 1.28 mmol) in diethyl ether (10 mL) at 0° C. was added tribromophosphine (0.38 g, 1.41 mmol). The mixture was warmed to room temperature and stirred overnight, then diluted with ether (10 mL). After quenching with water (10 mL), the organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel and eluted with petroleum ether to give the title compound as an oil (0.16 g, yield 57.1%).
Reaction SMILES: N1C=[CH:4][CH:3]=[C:2]1[C:6](Cl)=O.[CH3:9][N:10]([CH3:18])[C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12]>>[CH3:9][N:10]([CH3:18])[C:11]([C:13]1[N:14]([CH2:6][CH2:2][CH2:3][CH3:4])[CH:15]=[CH:16][CH:17]=1)=[O:12]
Reactant: CN(C)C(=O)c1ccc[nH]1
Reactant: O=C(Cl)c1ccc[nH]1
Product: CCCCn1cccc1C(=O)N(C)C

Procedure:
Likewise, by the method of part B of this Preparation, pyrrole-2-carbonyl chloride, obtained as described by R. J. Boatman et al., in J. Org. Chem. 41, p. 3050 (1976), is converted into N,N-dimethylpyrrole-2-carbox-amide, m.p. 100.5°-102° C.
Reaction SMILES: C(O[C:6]([N:8]([N:10]1[C:19]2[C:14](=[C:15]([F:23])[C:16]([F:22])=[C:17]([F:21])[C:18]=2[F:20])[C:13](=[O:24])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11]1)C)=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[CH3:6][NH:8][N:10]1[C:19]2[C:14](=[C:15]([F:23])[C:16]([F:22])=[C:17]([F:21])[C:18]=2[F:20])[C:13](=[O:24])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11]1
Reactant: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)c(F)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
4.2 g of the compound (193) obtained above was dissolved in 30 ml of ethyl acetate, and while cooling with ice, 40 ml of 4N hydrochloric acid solution in dioxane was added to the solution. The solution was stirred overnight at room temperature, and the solvent was removed by distillation. The residue was dissolved in 100 ml of chloroform, and 50 ml of aqueous 10% sodium carbonate solution was added to the solution. The solution was stirred for 30 minutes at room temperature. The organic layer was separated and after drying over magnesium sulfate, the solvent was removed by distillation. Crystals were dispersed in ether and filtered to obtain 2.9 g of the subject compound (194) in a 91% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:12]1=[O:26])(=[O:10])=[O:9].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:15][C@@H:14]([C:16]([N:38]2[CH2:39][CH2:40][N:35]([C:29]3[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=3[CH3:27])[CH2:36][CH2:37]2)=[O:18])[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:12]1=[O:26])(=[O:9])=[O:10]
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: O=C(O)[C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1c1ccccc1Cl
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4Cl)C(=O)N3c3ccccc3Cl)CC2)c1

Procedure:
Steps 4 and 5: In analogy to example 1, (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid methyl ester was hydrolyzed using sodium hydroxide solution to give (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid. Finally, (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 587.2 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (5.85 g) was dissolved in methanol (20 ml), 4M hydrogen chloride-ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, the residue was diluted with aqueous sodium bicarbonate, and, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (4.40 g).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[CH:44]1([NH2:47])[CH2:46][CH2:45]1>ClCCl>[CH:44]1([NH:47][S:2]([C:5]2[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=3[C:15]=2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[O:17])=[O:9])(=[O:4])=[O:3])[CH2:46][CH2:45]1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Reactant: NC1CC1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)NC5CC5)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.00 g of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.22 mL of cyclopropylamine, and 10 mL of dichloromethane was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 850 mg of methyl 4-[2-(4-{[(2-{[3-(cyclopropylsulfamoyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate as a pale yellow solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][CH2:10][CH2:11][C:12](O)=O>Cl>[Cl:9][CH2:10][CH2:11][C:12]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CCCl
Agent: Cl
Product: ClCCc1nc2ccccc2[nH]1
Yield: 32.3 %

Procedure:
A mixture of 1,2-Phenylenediamine (1.3 g, 12.0 mmol) and 3-chloropropionic acid (2.0 g, 18.5 mmol) were refluxed in 4N HCl (13 mL) for 16 hours to give the title compound as white solid (700 mg, 32%). 1H NMR (CD3OD) □3.35 (t, 2H, J=6.8 Hz), 4.00 (t, 2H, J=6.8 Hz), 7.18-7.25 (m, 2H), 7.49-7.55 (m, 2H); ES-MS m/z 181.0 (M+H).
Reaction SMILES: O=[C:2]([CH3:19])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[CH3:20][CH:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[CH3:20][CH:21]([NH:29][CH:2]([CH3:19])[CH2:3][O:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:9][CH2:10]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(N)Cc1ccccc1
Reactant: CC(=O)COC1CCC(C(=O)c2ccccc2)CC1
Solvent: O
Solvent: c1ccccc1
Product: CC(COC1CCC(C(=O)c2ccccc2)CC1)NC(C)Cc1ccccc1

Procedure:
4-(2-oxo-propoxy)-cyclohexanophenone (0.02 mole) and α-methyl-phenethylamine (0.02 mole) are then heated in benzene solution. The water formed is removed by means of a Dean-Stark apparatus.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]1[CH2:14][CH3:15])=[O:25]
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 190.4 %

Procedure:
a solution of (RS) 4-tert-butoxycarbonyl-2-ethylpiperazine (3.95 g) and pyridine (1.64 ml) in DCM (35 ml) was added dropwise to a stirred solution of triphosgene (2.1 g) in DCM (100 ml) at 0° C. under Ar. The mixture was warmed to room temperature, stirred for 30 min then washed with water (100 ml) and brine (100 ml). The organic solution was dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in isohexane, filtered and concentrated in vacuo to give the product as a clear oil (3.73 g) which was used without further purification; δH (400 MHz, CDCl3) 4.39–3.80 (4H, m), 3.39–2.69 (3H, m), 1.66 (2H, m), 1.47 (9H, s), 0.96 (2.7H, d, J 7 Hz) and 0.89 (0.3H, d, J 7 Hz); GC (150° C.-10 min-320° C.) 83%, 8.72 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:20])([CH3:19])[CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1.[CH:21](O)=[O:22]>>[CH:21]([O:18][CH2:17][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:10][CH:11]=1)([OH:20])[CH3:19])=[O:22]
Reactant: O=CO
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Product: CC(O)(CCOC=O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3 g. of 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol and 15 ml. of formic acid are warmed to 80° for 2 hours. The mixture is cooled and worked up in the customary manner to give 1-formyloxy-3-(2',4'-difluoro-4-biphenylyl)butan-3-ol.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:15]([O:19][C:20]([CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:1]([N:26]1[CH2:27][CH2:28][CH:24]([NH:23][CH2:22][C:20]([O:19][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:21])[CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)CNC1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(NCC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
Under nitrogen atmosphere, acetic anhydride (707 μl, 7.49 mmol) and triethylamine (1.39 ml, 9.98 mmol) were added to a dichloromethane (25 ml) solution of 3-(tert-butoxycarbonylmethylamino)pyrrolidine (1.00 g, 4.99 mmol) with cooling with ice, followed by stirring at room temperature for 17 hours. The solvent was evaporated away under reduced pressure, then the resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate gave the entitled compound (1.10 g, 91%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=1[CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[Cl:22][C:23]1[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=1[CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:15])[CH2:27]1
Reactant: Clc1ccccc1CC1CCNC1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(Cc2ccccc2Cl)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(2-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (6.5 mg). Calcd for C21H18C12 N2O2: 400.0745, found 400.0746.
Reaction SMILES: [NH3:1].[I:2][C:3]1[C:8]2[N:9]=[C:10]([CH3:14])[O:11][C:12](=O)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH3:15]>CCOC(C)=O>[I:2][C:3]1[C:4]([CH3:15])=[CH:5][CH:6]=[C:7]2[C:8]=1[N:9]=[C:10]([CH3:14])[NH:1][C:12]2=[O:11]
Reactant: N
Reactant: Cc1nc2c(I)c(C)ccc2c(=O)o1
Solvent: CCOC(C)=O
Product: Cc1nc2c(I)c(C)ccc2c(=O)[nH]1
Temperature: -78 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Anhydrous ammonia (50 mL) was condensed in a 500 mL 3 necked flasked containing 8-iodo-2,7-dimethyl-4H-benzo[d][1,3]oxazin-4-one (8.5 g, 28 mmol) cooled to −78° C., and the reaction was stirred for 3 h. The cooling bath was removed and the solvent was allowed to evaporate at RT. 1 N Sodium hydroxide (100 mL) was added to the reaction and stirred at reflux for 1 h. The reaction was cooled down to 0° C. and acidified to pH 3 with 5 N HCl. The resulting precipitate was collected by filtration, washed with water and dried in a vacuum oven at 60° C. overnight. 8-Iodo-2,7-dimethylquinazolin-4(3H)-one (8 g, 94% yield) was obtained as a white solid. MS (M+H)+ 301.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:21]=[CH:22][N:23](C)C)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl.N[OH:28]>CO>[Br:1][C:2]1[C:3]([N:21]=[CH:22][NH:23][OH:28])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: NO
Reactant: CN(C)C=Nc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1Br
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(N=CNO)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(5-bromo-4-(((dimethylamino)methylene)amino)pyrimidin-2-yl)piperazine-1-carboxylate (2.0 g) and methanol (30 mL). To the above solution was added hydroxylamine hydrochloride (0.5 g, 7.3 mmol) in one portion. The resulting mixture was stirred at room temperature for 12 h. Work-up: the solvent was evaporated. The resulting crystalline solid was washed with water and collected by filtration. The solid was washed with ethanol (100 mL) and dried, to afford 1.0 g (80%) of the product as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]([CH2:22][C:23]([O:25]C)=[O:24])[C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:22][C:23]([OH:25])=[O:24])[C:10](=[O:21])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH3:20])=[CH:16][CH:17]=2)=[CH:27][CH:28]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(CC(=O)N(CC(=O)OC)Cc2ccc(CCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1ccc(CC(=O)N(CC(=O)O)Cc2ccc(CCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
Methyl 2-(N-(4-propylbenzyl)-2-(4-propylphenyl)acetamido)-acetate (30.0 mg, 0.0786 mmol) was dissolved in 0.5 mL of methanol, and then 100 μL of 20% aqueous sodium hydroxide solution was added, and the reaction mixture was stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction solution was diluted with 2 mL of ethyl acetate and neutralized by adding 200 μL of 10% aqueous hydrogen chloride solution. After removing water with anhydrous magnesium sulfate and filtering out the precipitate, the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 26.4 mg (0.0718 mmol, 91%) of the desired compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[O:14]C)=[O:4].B(Br)(Br)Br.O>ClCCl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[OH:14])=[O:4]
Reactant: COc1ccc(OC)c(NC(=O)CCl)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)Nc1cc(O)ccc1O
Reaction time: 8 h

Procedure:
Compound 46 (5 g, 21.7 mmol) was dissolved in dichloromethane followed by the dropwise addition of boron tribromide (1M solution in dichloromethane, 84 ml, 84 mmol) at 0° C. The reaction mixture was left at 4° C. overnight. Water (100 ml) was added carefully to destroy excess boron tribromide. The solid precipitation was filtered off to yield brownish pure compound. Yield=4.15 g. (94%). 1H NMR (dmso-d6): 9.29 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 7.46 (d, 1H, J=3.02 Hz), 6.65 (d, 1H, J=8.89 Hz), 6.33 (dd, 1H, J=8.95 and 2.98 Hz), 4.35 (s, 2H). 13C NMR (dmso-d6): 165.0, 150.3, 150.2, 140.2, 126.6, 116.2, 111.6, 44.1. ES-HRMS [M+H]+202.0271. Calcd for (C8H9NO3):202.0278.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:8]#[C:9]Br.[OH-].[Na+].[Na+].[OH-]>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]#[N:8])[CH2:4][CH2:3]1
Reactant: CC1CCNCC1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Product: CC1CCN(C#N)CC1

Procedure:
In the manner given in Example 1, 4-methylpiperidine is treated with cyanogen bromide and aqueous sodium sodium hydroxide to give 4-methyl-1-piperidinecarbonitrile.