Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:21]4[CH:26]=[C:25]([NH2:27])[C:24]([F:28])=[CH:23][C:22]=4[F:29])[C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:27][C:25]1[C:24]([F:28])=[CH:23][C:22]([F:29])=[C:21]([C:14]2[C:15](=[O:20])[N:16]([CH3:19])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:26]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2F)c(=O)n3C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1F)c(=O)n2C
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.7 %

Procedure:
To a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 6.8 mmol) in DCM (100 mL) was added CF3COOH (20 mL) and the resulting mixture was stirred at 25° C. for 6 h. Water was added and the mixture was extracted with water. The combined aqueous layers were neutralized with NH3H2O to pH 7. The precipitate was collected by filtration and dried to give 3-(5-amino-2,4-difluorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (661 mg, 30% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.39 (s, 1 H), 7.78 (s, 1 H), 7.08-6.93 (m, 2 H), 6.80 (dd, J=10.2, 8.1 Hz, 1H), 6.16 (s, 1 H), 5.00 (s, 2 H), 3.50 (s, 3 H), 2.84 (d, J=4.8 Hz, 3 H); MS (ESI) m/z: 317.0[M+H]+.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([CH3:22])[CH:4]=1)=[O:16])[CH3:19]
Reactant: CI
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CN(C)CCc2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (0.15 g 0.6 mmol) in DMF (2 mL) was added sodium hydride (60%, 28 mg, 0.7 mmol) at 0° C. and a solution of MeI (38 μL, 0.7 mmol). The mixture was stirred for 30 min at 0° C. Water was added to the reaction mixture, which was then extracted by DCM. The combined organic layer was washed with water and dried over magnesium sulfate. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (5:95) and then further purified by preparative HPLC to afford the title compound (86 mg); 1H-NMR (CDCl3): δ 10.50 (1H, s), 8.26 (1H, m), 7.77 (1H, s), 7.40 (1H, d), 7.31 (1H, d), 7.05 (2H, m), 5.35 (1H, s), 4.28 (2H, q), 3.54 (2H, t), 3.26 (3H, s), 3.14 (2H, m), 1.36 (3H, t). MS (ES): 271 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[Cl:31])[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:31][C:22]1[CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:26][C:21]=1[CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8])=[O:32]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(2-chloro-4-methanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[OH:20])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[Br:1][C:15]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:14]=1[OH:20]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(O)c(C(C)(C)C)c1

Procedure:
Under nitrogen atmosphere, a dimethylformamide 100 ml solution of N-bromosuccinimide (22.25 g, 125 mmol) was added dropwise at 0° C. to a dimethylformamide 100 ml solution of 2-tert-butyl-4-methylphenol (20.53 g, 125 mmol) with stirring, the resulting reaction mixture was brought up to room temperature and stirred for 5 hours.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[O:17])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35].[OH-].[Na+]>CO.O1CCOCC1>[OH:35][C:5]1[C:6]([CH2:32][CH2:33][CH3:34])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[CH:19]=2)=[O:17])[CH:8]=[CH:9][C:4]=1[C:3]([OH:36])=[O:2]
Reactant: CCCc1c(OCCCCCC(=O)c2ccc3cc(OC)c(OC)cc3c2)ccc(C(=O)OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCc1c(OCCCCCC(=O)c2ccc3cc(OC)c(OC)cc3c2)ccc(C(=O)O)c1O

Procedure:
A solution of 4.2 g (0.0085 mole) of 2-hydroxy-4-[[6-(6,7-dimethoxy-2-naphthalenyl)-6-oxohexyl]oxy]-3-propylbenzoic acid methyl ester in 100 mL of methanol, 50 mL of dioxane and 34 mL (0.034 mole) of 1N sodium hydroxide was stirred at reflux for 8 hours. The reaction mixture was concentrated under reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated and the crude product was recrystallized from a methanol and water mixture to give 3.48 g, mp 144°-146°, of 2-hydroxy-4-[[6-(6,7-dimethoxy-2-naphthalenyl)-6-oxohexyl]oxy-3-propylbenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].C(O)(=O)C.[CH:16](N)=[NH:17]>C(OCCO)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[NH:17][CH:16]=[N:11]2
Reactant: N=CN
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: CC(=O)O
Solvent: CCOCCO
Product: Cc1cccc2nc[nH]c(=O)c12
Yield: 68.1 %

Procedure:
6-Methylanthranilic acid (5 g, 33 mmol) and formamidine acetate (0.4 g, 41 mmol) were refluxed in 2-ethyoxyethanol (50 ml) for 16 h. On cooling the solvent was removed in vacuo, the residue slurried in diethyl ether, the solid filtered, washed with diethyl ether and dried to yield 3.6 g of the title compound. δH (DMSO d6), 7.97 (1H, s), 7.60 (1H, dd, J 7.9, 7.6 Hz), 7.43 (1H, d, J 8.0 Hz), 7.21 (1H, d, J 7.3 Hz), 2.76 (3H, s); m/z (ES+70V)161 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][C:14]=2[NH2:16])[C@H:9]([N:18]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:8][C@@H:7]1[CH3:38])=[O:5])[CH3:2].ClCCl.N1C=CC=CC=1.Cl[C:49]([O:51][CH3:52])=[O:50]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][C:14]=2[NH:16][C:49]([O:51][CH3:52])=[O:50])[C@H:9]([N:18]([CH2:23][C:24]2[CH:25]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:8][C@@H:7]1[CH3:38])=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N1c2c(N)cc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)N1c2c(NC(=O)OC)cc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 87.4 %

Procedure:
To a pre-dried flask under nitrogen atmosphere was added cis-8-amino-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 109) (30 mg, 0.053 mmol), followed by anhydrous dichloromethane (2 mL), pyridine (0.5 mL), and methyl chloroformate (0.016 mL, 0.21 mmol). The reaction was stirred overnight at room temperature before ethyl acetate was added, and the mixture was extracted three times with 1N HCl, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (29 mg, 87%). MS m/z 626 (M++H); 1H NMR (CDCl3) δ 7.82 (bs, 1H), 7.8 (bs, 1H), 7.7 (bs, 1H), 6.68 (bs, 1H), 6.7 (bs, 1H), 3.8 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7]C=1.[NH2:19]C1C=CC=CC=1O.ClC1C2C(=CC=CC=2)N=CC=1.[H-].[Na+]>CS(C)=O>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:19]=1
Reactant: Nc1ccccc1Oc1ccnc2ccccc12
Reactant: Nc1ccccc1O
Agent: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccccc1Oc1ncnc2ccccc12

Procedure:
Alternatively, the 4-(aminophenoxy)quinoline derivative can be produced by reacting an aminophenol derivative with the 4-chloroquinoline derivative in a suitable solvent, for example, dimethyl sulfoxide, in the presence of a base, for example, sodium hydride. Alternatively, the 4-(aminophenoxy)quinazoline derivative can also be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two-phase reaction with a solution of the 4-chloroquinazoline derivative in a suitable organic solvent, for example, ethyl methyl ketone, in the presence of a phase transfer catalyst, for example, tetra-n-butylammonium chloride, or in the absence of a catalyst (Scheme 2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].[C:30](#N)[CH3:31].C(=O)([O-])[O-].[K+].[K+].ICC>O>[CH2:30]([N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[S:12]([C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])(=[O:14])=[O:13])[CH3:31]
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)cc1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCN(c1ccc(C(=O)OC)cc1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixture of 320 mg of 2-(trimethylsilyl)ethyl 3-{[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoate and 5 mL of acetonitrile were added 203 mg of potassium carbonate and 0.119 mL of iodoethane. After stirring at 70° C. for 5 hours, 102 mg of potassium carbonate and 0.059 mL of iodoethane were added thereto, followed by stirring at 70° C. for 10 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 334 mg of a 2-(trimethylsilyl)ethyl 3-{ethyl[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoate as a colorless oily substance. ESI+: 464
Reaction SMILES: OC1C(C)=NC([Br:9])=CN=1.O[C:11]1[C:16]([CH2:17][CH3:18])=[N:15][C:14]([Br:19])=[CH:13][N:12]=1>>[Br:9][C:11]1[C:16]([CH2:17][CH3:18])=[N:15][C:14]([Br:19])=[CH:13][N:12]=1
Reactant: CCc1nc(Br)cnc1O
Reactant: Cc1nc(Br)cnc1O
Product: CCc1nc(Br)cnc1Br

Procedure:
By replacing the 2-hydroxy-3-methyl-5-bromopyrazine used in Step A of Preparation 87 by an equivalent quantity of 2-hydroxy-3-ethyl-5-bromopyrazine and following substantially the same procedure, there is obtained 2,5-dibromo-3-ethylpyrazine.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])=[O:17])[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(N[C:37]1[CH:42]=CC=[CH:39][CH:38]=1)C>>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:20])=[O:21])=[O:17])[C:9]([N:11]([CH2:12][CH3:13])[C:14]2[CH:39]=[CH:38][CH:37]=[CH:42][CH:15]=2)=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCNc1ccccc1
Reactant: CCN(CC)C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: CCN(C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Yield: 103.9 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 111 (4) and N-ethylaniline (107 mg). This was purified by silica gel column chromatography to give the title compound (344 mg) as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:2][CH3:1])[N:8]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1cccc(CCO)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1cccc(CCOS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A mixture of 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol (300 mg, 1.9 mmol), triethylamine (0.3 ml, 2.2 mmol), methanesulfonyl chloride (0.17 ml, 2.2 mmol), and dichloromethane (15 ml) was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried with sodium sulfate, filtered, and evaporated under vacuum to give a yellow oil. The crude product was chromatographed over silica gel to yield 300 mg (69%) of 2-[6-(Methylamino)-2-pyridyl]ethyl methylsulfonate. NMR 1H Cl3CD δ: 7.45 (dd, 1H, J=7.2, 8.4 Hz), 6.51 (d, 1H, J=7.2 Hz), 6.33 (d, 1H, J=8.4 Hz), 4.65 (t, 2H, J=6.4 Hz), 3.06 (t, 2H, J=6.4 Hz), 2.92 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[CH2:15]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Br)[CH3:16].O>C1COCC1>[CH2:15]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][C:4]1([CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])[CH3:16]
Reactant: CC1CCc2ccccc2C1=O
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCCC1(C)CCc2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.86 g NaH in 40 mL of dry THF are added 5.0 g 2-methyl-1-tetralon in 20 mL of THF. After stirring for 30 min, 7.5 g ethyl-5-bromo-pentanoate in 20 mL of THF are added and the mixture is refluxed for 6 h. The cooled mixture is poured into water and extracted with ethylacetate. The extract is evaporated yielding crude ethyl-5-(2-Methyl-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoate (6a) which is purified by column chromatography, yielding 3.6 g of pure 6a. 6a is converted to 6b in an analogous manner to that described for the conversion of 1c to 1d in example 1. 6b was obtained as an oil, MS (APCI): 274.1 (M−1).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:17]([C:19]1[CH:52]=[CH:51][C:22]([C:23]([CH2:25][NH:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([O:35][C:36](=[O:50])[NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:31][CH2:30]2)=[O:24])=[CH:21][CH:20]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(C)C.C(O)(=O)C>[C:5]([CH:4]1[CH2:8][CH2:9][N:1]([CH2:17][C:19]2[CH:20]=[CH:21][C:22]([C:23]([CH2:25][NH:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36](=[O:50])[NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:31][CH2:30]3)=[O:24])=[CH:51][CH:52]=2)[CH2:2][CH2:3]1)(=[O:6])[NH2:7]
Reactant: NC(=O)C1CCNCC1
Reactant: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: NC(=O)C1CCN(Cc2ccc(C(=O)CNCCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a three-necked 2-L flask was added isonipecotamide (5.99 g, 40.0 mmol), acetic acid (2.57 mL), sodium sulfate (6.44 g) and isopropanol (400 mL). The reaction mixture was cooled to 0-10° C. with an ice bath and a solution of biphenyl-2-ylcarbamic acid 1-{2-[(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester (11 g, 22.7 mmol; prepared as described in Preparation 5) in isopropanol (300 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10° C. Sodium triacetoxyborohydride (15.16 g, 68.5 mmol) was added portion wise and this mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL and this mixture was acidified with 1N HCl (200 mL) to pH 3. The resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3×250 mL). The aqueous phase was then cooled to 0-5° C. with an ice bath and 50% aqueous NaOH solution was added to adjust the pH of the mixture to 10. This mixture was then extracted with isopropyl acetate (3×300 mL) and the combined organic layers were washed with water (100 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated to afford 10.8 g of the title compound (80% yield. MS m/z: [M+H+] calc'd for C35H43N5O4 598.3. found 598.6. Rf=2.32 min (10-70 ACN:H2O, reverse phase HPLC).
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:5]([C:6]([SH:8])=[S:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16].CO.[Zn:21]>[Pt].CCOCC>[OH:1][C:2]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:5]([C:6]([S-:8])=[S:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16].[OH:1][C:2]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:5]([C:6]([S-:8])=[S:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16].[Zn+2:21]
Reactant: [Zn]
Reactant: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Agent: [Pt]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)c1cc(C(=S)[S-])cc(C(C)(C)C)c1O
Product: [Zn+2]

Procedure:
Zinc bis(4-hydroxy-3,5-di-tert.-butyl dithiobenzoate) was prepared as follows. The acid, 4-hydroxy-3,5-di-tert.-butyl dithiobenzoic acid (0.4 g) was dissolved in 15 ml. of methanol. Zinc wire (1.2 cm2) was made the anode and platinum wire (1.4 cm2) was made the cathode. The methanol/acid mixture was placed in a container housing the wire electrodes and 0.1 g of zinc metal was dissolved in 12 hours using 70 ma current and 12 volts. The resulting zinc bis(4-hydroxy-3,5-di-tert.butyl dithiobenzoate) was isolated from ether solution.
Reaction SMILES: [Na].C([O:5][CH:6]1[CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=[C:12]2Br)[CH2:9][CH:8]([CH2:23][O:24]C(=O)C)[CH:7]1[O:28]C(=O)C)(=O)C.[CH3:32][O-:33].[Na+].Cl>CO>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:15]2[N:11]([CH:10]3[CH:6]([OH:5])[CH:7]([OH:28])[CH:8]([CH2:23][OH:24])[CH2:9]3)[C:12]([O:33][CH3:32])=[N:13][C:14]=2[CH:19]=1
Reactant: C[O-]
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1nc2cc(Cl)c(Cl)cc2n1C1CC(CO)C(O)C1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium (spheres, 0.10 g, 4.8 mequiv) were added to dry methanol (15 mL). (±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (0.560 g, 0.958 mmol) was added to the sodium methoxide in methanol and the solution stirred at ambient temperature under nitrogen for 5 hours. The solution was then neutralized with 1N hydrochloric acid and volatiles removed in vacuo. The residual solid was chromatographed on silica gel. (±)-(1R*, 2S*, 3S*, 5S*)-5-(5,6-Dichloro-2-methoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol was eluted with 10% methanol-chloroform as a white powder, after trituration with diethyl ether (0.211 g, 64%), m.p. 204°-206° C. dec; 1H-NMR(DMSO-d6)δ: 7.82 and 7.67 (both s, 2, aromatic CH), 4.9 (m, 2,2 OH), 4.7-4.6 (m overlapping d at 4.61, J=4.1 Hz, 2 total, NCH and OH), 4.4-4.3 (m, 1, OCH), 4.11 (s, 3, OCH3), 3.8 (m, 1, OCH), 3.6-3.4 (m, 2, OCH2), 2.1-2.0 (m, 2, CH2), 1.9-1.8 (m, 1, CH); mass spectrum (CI): 347(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH:11][CH3:12])=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]([CH3:12])[C:13](=[O:15])[CH:14]=[C:7]2[OH:9]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc(Cl)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1c(=O)cc(O)c2cc(Cl)ccc21

Procedure:
5-Chloro-N-methyl anthranilic acid (15g; 0.081 mole) was dissolved in acetic acid (41 ml) and acetic anhydride (41 ml) and the dark mixture refluxed for 12 hours. After cooling the red solution was poured onto crushed ice, basified with 2.5N sodium hydroxide and filtered free of tar. The filtrate on acidification to pH5 gave the carbostyril as a yellow solid, m.p. (AcOH) 317°-318° C (Found; C, 57.39; H, 3.98; N, 6.83; Cl, 16.69; C10H8NClO2 requires C, 57.29; H, 3.85; N, 6.68; Cl, 16.91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[O:51]1[CH:55]=[CH:54][CH:53]=[C:52]1[C:56]([NH:58][NH2:59])=[O:57]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([NH:59][NH:58][C:56]([C:52]1[O:51][CH:55]=[CH:54][CH:53]=1)=[O:57])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: NNC(=O)c1ccco1
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
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)NNC(=O)c1ccco1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
2-Carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) was added to [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (3.13 g) in dimethylformamide (10 ml) containing diisopropylethylamine (3.2 g) and the mixture stirred for 15 min. 2-Furoic acid hydrazide (1.04 g) was then added and stirring continued for 16 h. The reaction mixture was diluted with water and extracted with diethyl ether. The combined ether extracts were washed with water, dried and solvent removed at reduced pressure the residue was column chromatographed (silica gel, 20-50% ethyl acetate/hexane) to give the title compound (2.05 g).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([CH3:11])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([CH3:11])=[CH:5][CH:4]=1
Reactant: Cc1ccc(CO)nc1C#N
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(CCl)nc1C#N
Yield: 96 %

Procedure:
A solution of 6-(Hydroxymethyl)-3-methyl-2-pyridinecarbonitrile (148 mg) and thionyl chloride (0.16 ml) in dichloromethane (3.5 ml) was stirred at ambient temperature for 6 hours. Solvent was removed in vacuo and toluene (2 ml) added then removed in vacuo to afford the title compound (160 mg, 96%) as a pale grey-green solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH3:22].O>C(#N)C>[CH2:18]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:9]=[CH:10][C:2]=1[OH:1])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C1CCC(c2ccc(O)c(C(=O)O)c2)CC1
Reactant: CCCCCBr
Solvent: O
Solvent: CC#N
Product: CCCCCOC(=O)c1cc(C2CCC(=O)CC2)ccc1O

Procedure:
13.60 g (70 mmols) of 2-hydroxy-5-(4-oxocyclohexyl)benzoic acid was suspended in 90 ml of acetonitrile. 10.66 g (70 mmols) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) was added dropwise at 20° C. over a period of 10 minutes, followed by 11.63 g (77 mmols) pentyl bromide over a further period of 10 minutes. The suspension was then stirred under reflux for 18 hours. After cooling the reaction mixture was poured into 300 ml of water and extracted three times with 150 ml of acetic ester. The combined organic phases were washed once with 200 ml 1N HCl, three times with 150 ml of water, dried over magnesium sulphate and filtered. Removal of the solvent gave the crude product which was purified by chromatography on silica gel, eluting with cyclohexane/acetic ester to give 2-hydroxy-5-(4-oxocyclohexyl)benzoic acid pentyl ester.