Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:7]=1)C.CO.[NH3:26]>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]([NH2:26])=[O:3])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[CH:9]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)cc2c1CCCC2
Reactant: N
Solvent: CO
Product: CN1CCN(c2cc3c(c(CC(N)=O)c2)CCCC3)CC1
Reaction time: 48 h

Procedure:
A solution of compound of step e) (394 mg, 1.2 mmol) in methanol/NH3 (4 molar) is transferred into an autoclave and kept at 120° C. for 48 hours. After cooling the reaction is concentrated and the crude residue is purified on silica gel (methylene chloride/methanol 90/105) affording the pure title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[N:13]=2)=[CH:5][CH:4]=1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OC)(OC)OC>[CH3:21][O:16][C:15](=[O:17])[CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=2)[S:10][CH:11]=1
Reactant: O=C(O)Cc1csc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Solvent: CO
Product: COC(=O)Cc1csc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 338.5 %

Procedure:
A solution of [2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid (3 g, 10.4 mmol) and p-toluenesulfonic acid mono-hydrate (0.5 g, 2.6 mmol) in methanol (30 ml) and trimethyl orthoformate (2 ml) was heated under reflux for 5 hours. After neutralization with aqueous sodium bicarbonate solution and evaporation of the solvents under reduced pressure, the residue was redissolved in tert-butyl methyl ether and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2.65 g (8.8 mmol, 84%) of [2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid methyl ester as light brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH3:24])[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C=O)C>[CH3:24][N:12]([CH2:11][C:10]1[CH:25]=[CH:26][CH:27]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:7][CH:6]=2)[CH:9]=1)[C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: C1CNCCN1
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (2.35 g) was dissolved in DMF (50 ml), and piperazine was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc, and then the organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 10% MeOH/CHCl3) to obtain tert-butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (1.8 g).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15]>>[CH2:7]([N:6]1[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:17]([NH:16][C:14](=[O:15])[C:13]([F:24])([F:12])[F:25])[CH2:18][CH2:19]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1ncc([N+](=O)[O-])c1Cl
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Product: CCn1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 60 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-ethyl-4-nitro-1H-pyrazole and (R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide (0.1 g, 0.476 mmol) gave (R) —N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.1 g, 60%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.39-6.36 (m, 1H), 4.23-4.19 (m, 1H), 4.12 (q, J=7 Hz, 2H), 3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](=[O:42])[C:39](O)=[O:40])=[CH:30]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:39](=[O:40])[C:38]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:29][CH:30]=3)=[O:42])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Reactant: O=C(O)C(=O)c1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)C(=O)c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (209 mg, 0.51 mmol) in dry N,N-dimethylformamide (4 ml) was added 3-indole-glyoxylic acid (141 mg, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (152 mg, 0.76 mmol), and 1-hydroxy-benzotriazole (100 mg, 0.74 mmol). The mixture was stirred at room temperature for 16 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered, and concentrated in vacuo. The residue was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (2:5) as eluent, which afforded 143 mg (40. %) of 2-amino-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Mg]Cl)(C)C.[Cu]C#N.[CH2:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:28]1[O:30][CH2:29]1>O1CCCC1>[CH2:32]([O:31][CH2:27][C@@H:28]([OH:30])[CH2:29][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[CH:5]=[C:6]([F:8])[CH:7]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: COc1c(Br)cc(F)cc1-c1c(Cl)cccc1Cl
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1c(C[C@H](O)COCc2ccccc2)cc(F)cc1-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of 3-bromo-2′,6′-dichloro-5-fluoro-2-methoxy-biphenyl (2.2 g, 6.3 mmol) in anhydrous tetrahydrofuran at 0° C. was added isopropylmagnesium chloride (3.45 ml, 2.0 M in hexane) and the resulting mixture was allowed to stir at 0° C. for 4 h. The reaction mixture was cooled to −30° C. and copper(I) cyanide (0.28 g, 3.1 mmol) in tetrahydrofuran was added and the reaction mixture was allowed to stir at −30° C. for 1 h. Benzyl(S)-(+)-glycidyl ether (0.48 ml, 3.1 mmol) was then added at −30° C. and the reaction mixture was allowed to warm to room temperature for 12 h. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 1.28 g (94%) of (S)-1-benzyloxy-3-(2′,6′-dichlor-5-fluoro-2-methoxybiphenyl-3-yl)propan-2-ol as a colorless oil. HRMS ESI m/e 435.0946 [M−H]−, Calc'd 435.0930; [α]D25=+2.8 (c 8.14 in dimethylsulfoxide).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([O:15][C:16]([NH:18][C@H:19]([CH2:23][NH2:24])[C:20]([OH:22])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([O:15][C:16]([NH:18][C@H:19]([CH2:23][NH:24][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[C:20]([OH:22])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)N[C@H](CN)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 2-fluoronitrobenzene (3.45 g) in N,N-dimethylformamide (60 mL), (R)-(−)-2-tert-butoxycarbonylamino-3-amino-propionic acid (5 g) and potassium carbonate (6.77 g) were added, followed by stirring overnight at 70° C. The reaction mixture was allowed to cool down, poured into ice water, and then extracted with ethyl acetate. After 1 N hydrochloric acid was added to the aqueous layer to adjust pH to 3, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. n-Hexane was added to the residue to for crystallization. The resultant crystals were collected by filtration, whereby the title compound (7.9 g) was obtained. Yield: 99%.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].[NH:35]1[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]2)=[O:29])=[CH:31][CH:32]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ccc(C(F)(F)F)cn4)cc3C)cc2)C1

Procedure:
A solution of 4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)butyl)amino)benzoic acid obtained in step H, ethyl (3R)-piperidine-3-carboxylate (5.05 mL), 1-hydroxybenzotriazole (4.43 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.28 g), diisopropylethylamine (5.72 mL) in dimethylformamide (91 mL) was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (15.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]1[N:14]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH:15]=[CH:16][N:17]=1.C(O)(=O)C.C(O[BH-](O[C:40](=[O:42])[CH3:41])OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N:14]3[CH:15]=[CH:16][N:17]=[C:13]3[CH3:12])=[CH:19][CH:20]=2)[C:40](=[O:42])[CH2:41]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1nccn1-c1ccc(C=O)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nccn1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)ethylenediamine (431 mg) and 4-(2-methyl-1H-imidazol-1-yl)benzaldehyde (500 mg) in dichloromethane (10 ml) was added acetic acid (323 mg), and the mixture was stirred at room temperature for 1 hour. To the mixture was added, under ice-cooling, sodium triacetoxyborohydride (855 mg), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate. The solution was extracted with water, and the aqueous layer was made alkaline with sodium hydroxide solution. The mixture was extracted with dichloromethane and dried with sodium sulfate, and sodium sulfate was filtered of f. To the filtrate was added triethylamine (543 mg) and then was added at 0° C. chloroacetyl chloride (455 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with sodium bicarbonate solution and brine, dried and concentrated, and the residue was dissolved in DMF (15 ml). To the solution was added sodium hydride in oil (129 mg), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried and concentrated, and the residue was purified with column chromatography (ethyl acetate) to give 4-(tert-butoxycarbonyl)-1-[4-(2-methyl-1H-imidazol-1-yl)benzyl]-2-piperazinone. To the obtained 4-(tert-butoxycarbonyl)-1-[4-(2-methyl-1H-imidazol-1-yl)benzyl]-2-piperazinone was added trifluoroacetic acid (8 ml), and the mixture was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in dichloromethane (20 ml). To the solution was added triethylamine (1.58 g) and then was added 6-chloronaphthanlene-2-sulfonyl chloride (700 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was separated, and the organic layer was washed with brine, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (70 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([F:28])[C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:22]3[C:21]([F:28])=[CH:20][C:19]([Cl:18])=[CH:24][N:23]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1F
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3F)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-chloro-3-fluoro-pyridine-2-carboxylic acid (CAS 207994-08-9) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=399.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[CH2:24]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)[CH3:25]>>[CH2:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:34])[CH:29]=[CH:30][CH:31]=1)[CH3:25]
Reactant: CCc1cccc(N=C=O)c1
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Product: CCc1cccc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3-ethylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:19])[CH2:8]/[CH:9]=[CH:10]/[C@H:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni].C(OCC)(=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][CH:11]([CH3:18])[CH2:10][CH2:9][CH2:8][CH:7]([CH3:19])[CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17]
Reactant: CCOC(=O)C[C@@H](C)/C=C/C[C@@H](C)COC(C)(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)CCCC(C)COC(C)(C)C

Procedure:
A mixture of 1.104 g. (4.084 mmoles) of (3R,7R)-E-Ethyl 8-tert. butoxy-3,7-dimethyl-4-octenoate, a small amount of Raney nickel, and 30 ml. of ethyl acetate was stirred in an atmosphere of hydrogen, at room temperture, for 2 hours during which time approximately one equivalent of hydrogen was taken up. The catalyst was filtered off and washed with ethyl acetate. Concentration of the combined filtrate and washes in vacuo followed by evaporative distillation afforded 1.045 g. (95%) of saturated ester (3S,7R)-Ethyl 8-tert. butoxy-3,7-dimethyloloctanoate as a colorless oil, b.p. 80°-83° C. (bath temperature) (0.15 mm Hg.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:16]3[C:11](=[CH:12][C:13](F)=[CH:14][CH:15]=3)[C@H:10]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]3)[CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O.CN(C=O)C>C(Cl)Cl>[ClH:29].[ClH:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:10]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][Cl:29])[CH2:20][CH2:19]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCN1CCN([C@@H]2C[C@@H](c3ccc(F)cc3)c3ccc(F)cc32)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: Fc1ccc([C@@H]2C[C@@H](N3CCN(CCCl)CC3)c3ccccc32)cc1

Procedure:
A mixture of trans-4-[3-(4-fluorophenyl)-6-fluoro-indan-1-yl]-1-piperazineethanol (40 g, 0.11 mol), thionylchloride (15 ml) and DMF (0.7 ml) in methylene chloride (400 ml) was refluxed for 1 hour. After cooling, the crystalline solid was filtered and washed on the filter with ethyl acetate and ether to give trans 1-[3-(4-fluorophenyl)-indan-1-yl]-4-(2-chloroethyl)piperazine, dihydrochloride (45 g). Mp: 250°-255° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](Cl)=[O:11].[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)C1C=CC=CC=1>>[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:11]
Reactant: O=C(Cl)C1Cc2ccccc2C1
Reactant: O=C(NCCCCO)c1ccccc1
Product: O=C(NCCCCO)C1Cc2ccccc2C1
Yield: 62 %

Procedure:
Indane-2-carboxylic acid-(4-hydroxybutyl)amide (26B) is prepared from 26A as described for 1D.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17](O)(=O)[CH:18]([CH3:20])[OH:19].C>Cl>[CH3:17][CH:18]([C:20]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[OH:19]
Reactant: CC(O)C(=O)O
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Agent: Cl
Product: CC(C)Cn1c(C(C)O)nc2cnc3ccccc3c21
Temperature: 140 °C

Procedure:
3-Amino-4-(2-methylpropylamino) quinoline (29.0 g; 0.135 mol) and lactic acid (36 mL; 0.48 mol) were mixed and heated at 140° C. for 6 hr. The mixture was then dissolved in dilute hydrochloric acid and treated with charcoal. The solids were filtered from the mixture. The filtrate was made basic with ammonium hydroxide to precipitate the product as an oil. The oil was extracted into ethyl acetate. The ethyl acetate solution was treated with decolorizing carbon and the solids were filtered from the mixture. The filtrate was evaporated to dryness to yield a greenish oil which was pure enough for further reactions. A small sample was triturated with hexane to obtain a solid which was recrystallized from ethyl acetate for analysis. m.p. 152°-166° C.
Reaction SMILES: C[N:2]([CH:4]=O)[CH3:3].O=P(Cl)(Cl)[Cl:8].[F:11][CH:12]([F:20])[C:13]1[CH:17]=[C:16]([OH:18])N(C)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Cl:8][C:4]1[N:2]([CH3:3])[N:14]=[C:13]([CH:12]([F:20])[F:11])[C:17]=1[CH:16]=[O:18]
Reactant: Cn1nc(C(F)F)cc1O
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cn1nc(C(F)F)c(C=O)c1Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To DMF (40.84 g, 0.56 mol) was added POCl3 (104.4 mL, 1.12 mol) at 0° C. After 30 min, to the resulting Vilsmier reagent was added 3-(difluoromethyl)-1-methyl-1H-pyrazol-5-ol from step 1 above (69.1 g, 0.46 mol), and the mixture was heated at 80° C. for 16 h. Then reaction was diluted with dichloromethane (400 mL), and treated with a solution of potassium carbonate (780 g) in water (2 L) at 0° C. The organic layer was separated, and the aqueous layer extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with water (500 mL), passed through a layer of silica gel (10×10 cm), and evaporated. The residue was crystallized from ether (100 mL) and hexane (100 mL) to give 69 g (77%) of the title product.
Reaction SMILES: [N+](=C)=[N-].[C:4]([CH:7]([CH2:20][CH2:21][CH2:22][CH:23]([OH:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:6])[CH3:5].[C:30](O)(=O)C>CCOCC>[C:4]([CH:7]([CH2:20][CH2:21][CH2:22][CH:23]([OH:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:30])=[O:16])=[CH:18][CH:19]=1)(=[O:6])[CH3:5]
Reactant: CC(=O)O
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC(O)CCCC(CCCc1ccc(C(=O)OC)cc1)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 4-(4-acetyl-8-hydroxytridecyl)benzoic acid (10.8 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 4-(4-acetyl-8-hydroxytridecyl)benzoate, a colorless viscous oil.
Reaction SMILES: [P:1]([OH:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)(O)[O-].[Na+].S([O-])(O)(=O)=O.S(Cl)(O[CH2:28][Cl:29])(=O)=O>O.ClCCl>[P:1]([O:13][CH2:28][Cl:29])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: O=S(=O)(Cl)OCCl
Reactant: CC(C)(C)OP(=O)(O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Yield: 52.3 %

Procedure:
To a well stirred suspension of di-tert-butyl hydrogen phosphate (4.7 g, 22.47 mmol) in water (186 ml) was added sodium bicarbonate (7.5 g, 89.52 mmol) followed by tetra-n-butylammomium hydrogen sulphate (760 mg, 2.238 mmol). The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture was added dichloromethane (112 ml) at 0° C. and it was stirred for 10 min followed by the addition of chloromethyl chlorosulphate (4.4 g, 26.85 mmol) in dichloromethane (75 ml) at same temperature. The resultant mixture was vigorously stirred overnight at room temperature. The organic layer was separated, washed with brine and evaporated under reduced pressure to yield 3.04 g of product as pale yellow oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N+:7]([C:10]1[CH:18]=[CH:17]C(C(O)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)(Cl)Cl.CN(C=O)C>[N+:7]([C:10]1[CH:18]=[CH:17][C:1]([C:2]([Cl:4])=[O:3])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
Oxalyl chloride (4.78 g, 37.6 mmol) was added drop wise to a stirred solution of 4-nitrobenzoic acid (4.2 g, 25 mmol) in chloroform (50 mL). After 5 mins DMF (2 drops) was added and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed to afford 4.7 g (98%) of 4-nitro-benzoyl chloride which was used for next step without further purification.