Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:3].[H-].[Na+].[CH3:33][N:34]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35](=[O:38])[CH2:36]Br>O1CCCC1>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([CH2:36][C:35]([N:34]([CH3:33])[CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: CN(CCc1ccccc1)C(=O)CBr
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
2.1 g of 5-benzyloxy-4-methoxymethyl-9H-pyrido-[3,4-b]indole-3-carboxylic acid-(1-methylethyl)ester is added to a suspension of 168 mg of sodium hydride (80% in mineral oil) in 25 ml of tetrahydrofuran at 0° C., it is stirred for 10 minutes at 0° C., then mixed with a solution of 1.6 g of N-methyl-N-2-phenylethyl-2-bromoacetamide and stirred for 18 hours at 24° C. Then, it is suctioned off on Celite, concentrated by evaporation in a vacuum, and the residue is purified by chromatography on silica gel. 2.8 g of 5-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained as weak, yellowish crystals with a melting point of 146°-147° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11]([O:13][CH2:14]C)=[O:12].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1.O>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:4][C:3]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1sc2ncccc2c1N
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1sc2ncccc2c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.8 %

Procedure:
To a solution of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate (0.3 g; 1.35 mmol) in pyridine (10 mL) was added 4-tert-butylbenzenesulfonyl chloride (0.48 g; 2.03 mol). The reaction was stirred at room temperature for 18 hours and then diluted with water and extracted with ethyl acetate. The organic layer was separated and successively washed with aqueous hydrochloric acid (2N) and aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate to yield the title compound as a white solid (0.070 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH2:17][CH3:18])[C:9]2[C:14]([C:15]=1[NH2:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])C.[OH-].[Na+].C(O)C>C(O)(=O)C>[NH2:16][C:15]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][CH3:18])[C:7](=[O:19])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(N)c2cccnc2n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCn1c(=O)c(C(=O)O)c(N)c2cccnc21

Procedure:
A stirred mixture of 2 g. of 4-amino-1-ethyl-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 20 ml. of 10% aqueous sodium hydroxide containing 5 ml. of ethanol was heated under reflux for 3 hours to saponify the ester. The solution was cooled and was acidified with glacial acetic acid. The precipitate which formed was collected, air dried, and was recrystallized from ethanol to give 0.4 g. of product, m.p. 245°-248° C.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[C:7]([NH:10][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)(=[O:9])[CH3:8].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:17][CH2:16][C:15]1[CH:20]=[CH:21][C:12]([CH2:11][NH:10][C:7](=[O:9])[CH3:8])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(CNC(C)=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of aluminum lithium hydride (570 mg) in tetrahydrofuran (80 ml) was added a solution of methyl 4-acetamidomethylbenzoate (3.1 g) in tetrahydrofuran (20 ml) under ice-cooling. The mixture was stirred at room temperature for 1.5 hr and a saturated aqueous sodium sulfate solution (7 ml) was added at 100° C. The mixture was stirred at room temperature for 1 hr. The sediment was filtrated and the solvent was evaporated to give the title substance (2.8 g) as a white solid.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(F)cc1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(F)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
2.20 g (about 88% pure, 6.96 mmol) of (+/−)-tert-butyl cyclopentyl(4-fluorophenyl)acetate were dissolved in 2.9 ml of dichloromethane, and 10.7 ml of trifluoroacetic acid were added at RT. The mixture was stirred at RT for 3 h and then concentrated under reduced pressure. The residue was dried under high vacuum overnight. The solid obtained was triturated with acetonitrile and then filtered off with suction and washed with a little acetonitrile. Drying under high vacuum gave 720 mg of a first solids batch. The filtrate obtained above was concentrated and the residue was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave a further 529 mg of the target product (overall yield 80.8% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[C:19]([CH2:37][CH3:38])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[C:19]([CH2:37][CH3:38])=[C:20]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]4)[CH:21]=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCOC(=O)C1CCN(CCc2cccc(-c3nnc(-c4ccc(CC(C)C)c(C#N)c4)s3)c2CC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
To a solution of ethyl 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-4-piperidinecarboxylate (D33) (64 mg) in isopropanol (3 mL) and water (3 mL) was added sodium hydroxide (50 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 1 M HCl solution. The solvent was removed in vacuo. The residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-4-piperidinecarboxylic acid (E11) (15 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 0.93 (6H, d), 1.12 (3H, t), 1.57 (2H, m), 1.79 (2H, m), 2.03 (3H, m), 2.20 (1H, m), 2.81 (8H, m), 3.25 (2H, m), 7.32 (1H, t), 7.44 (2H, d), 7.67 (1H, d), 8.31 (1H, dd), 8.45 (1H, s), 12.06 (1H, br s). MS (ES): C29H34N4O2S requires 502. found 503.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:3][CH2:4]O.O.[BrH:14]>>[Br:14][CH2:4][CH2:3][C:2]([CH3:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1]
Reactant: CC(C)(CCO)c1ccccc1
Reactant: Br
Solvent: O
Product: CC(C)(CCBr)c1ccccc1

Procedure:
3-Metyl-3-phenylbutanol (0.82 g) was refluxed in 47% hydrobromic acid (5 ml) under heating for 7 hours. To the reaction solution was added water and the solution was extracted with ether. After washing with a saturated aqueous solution of sodium chloride, the ether layer was dried over anhydrous magnesium sulfate, and the residue was then subjected to silica gel column chromatography. Elution with a hexane - ethyl acetate 10:1) mixture gave 1.02 of 1-bromo-3-methyl-3-phenylbutane.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(NCCN(C)C)cc1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A solution of ethyl 4-fluorobenzoate (20 g), N,N-dimethylethylenediamine (20 g) and potassium carbonate (32.9 g) in dimethylsulfoxide (200 mL) is stirred at 80° C. for 3 days. After cooling to room temperature, to the reaction mixture is added ethyl acetate and water, and the mixture is stirred and extracted with ethyl acetate (×2). The organic layer is treated with 10% HCl to transfer basic materials to the aqueous layer. The aqueous layer is washed with ethyl acetate, neutralized with 10% sodium hydroxide solution and extracted with ethyl acetate (×3). The combined extract is dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant crude product is purified by flash column chromatography on NH-silica gel (Solvent; n-hexane:ethyl acetate=8:1→4:1) to give ethyl 4-[[2-(dimethylamino)ethyl]amino]-benzoate (12.45 g, yield; 44%) as an oil. MS (APCI) m/z: 237 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:49])([CH3:48])[O:40][CH2:41][C@@H:42]([OH:47])[CH2:43][N:44]([CH3:46])[CH3:45])[N:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:46][N:44]([CH3:45])[CH2:43][C@H:42]([OH:47])[CH2:41][O:40][C:39]([CH3:48])([CH3:49])[CH2:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])=[N:34]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C[C@H](O)COC(C)(C)Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C[C@H](O)COC(C)(C)Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 180.7 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), (S)-1-[2-(3-amino-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-3-dimethylamino-propan-2-ol (370 mg, 1.44 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 950 mg, 2.5 mmol) and iPr2NEt (1.4 mL, 8 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (15-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((5)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (255 mg, 18%) as an off-white powder. The racemate mixture was submitted for SFC purification to of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (85.1 mg, 6.1%) as an white powder. HRMS (ES+) m/z Calcd for C35H44Cl2F2N6O3+H [(M+H)+]: 705.2893. found: 705.2891. and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (23.1 mg, 20.8%) as an off-white powder. HRMS (ES+) m/z Calcd for C35H44Cl2F2N6O3+H [(M+H)+]: 705.2893. found: 705.2889.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH3:36])[C:31](=[O:37])[CH:30]=[CH:29]3)[CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1.CO.[ClH:41]>C(OCC)(=O)C.O>[ClH:41].[ClH:41].[OH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][N:13]([CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[C:31](=[O:37])[CH:30]=[CH:29]2)[CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccc(CN(CCCOc2ccc3c(ccc(=O)n3C)c2)CCc2cccnc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)ccc2cc(OCCCN(CCc3cccnc3)Cc3cccc(CO)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (16.5 mg) was added to a THE solution (4 ml) of 3-{[N-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]-N-(2-pyridin-3-ylethyl)amino]methyl}benzoic acid methyl ester (192 mg). Methanol (1 ml) was added to the mixture and stirred for 1.5 hour while heated under reflux. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→4:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride in ethyl acetate solution (0.082 ml) was added to a ethyl acetate solution (1 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (53.4 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19]3[O:26][NH:33][C:21](=[O:22])[CH:20]=3)[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(C(F)(F)F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
Cis-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (1.489 g, 3.40 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.896 mL, 3.40 mmol) dissolved in water (1.500 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.209 mL, 3.40 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of hydrogen chloride (17.59 mL, 105.54 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (100 mL) and water (100 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.594 g, 42.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.82-1.89 (m, 1H), 2.08-2.16 (m, 1H), 2.19-2.27 (m, 1H), 2.32-2.38 (m, 1H), 3.04-3.11 (m, 1H), 3.34-3.41 (m, 1H), 3.68 (s, 3H), 4.09-4.15 (m, 1H), 5.04-5.08 (m, 1H), 5.57 (s, 1H), 6.80 (d, 2H).
Reaction SMILES: CS(Cl)(=O)=O.N1(C[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3CCCO)C=NC=N1.C(N(CC)CC)C.FC1C=C(CCN2CCNCC2)C=CC=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>C1COCC1>[NH:17]1[C:18]2[C:14](=[CH:13][CH:12]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: OCCCc1c[nH]c2ccc(Cn3cncn3)cc12
Agent: CS(=O)(=O)Cl
Agent: Fc1cccc(CCN2CCNCC2)c1
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 267 %

Procedure:
Methanesulphonyl chloride (0.118 g, 1.03 mmol) was added to a stirred solution of 3-[5-(1,2,4-triazol-1-ylmethyl)-lH-indol-3-yl]propan-1-ol (0.22 g, 0.86 mmol) and triethylamine (0.104 g, 1.03 mmol), in anhydrous THF (30 ml) at +5° C. The solution was warmed to room temperature and stirred for 1.5 h. The solvent was removed under vacuum and the residue partitioned between CH2Cl2 (2×75 ml) and water (30 ml). The combined extracts were dried (Na2SO4) and evaporated and the residue redissolved in anhydrous THF (20 ml). To the solution was added 4-[2-(3-fluorophenyl)ethyl]piperazine (0.339 g, 1.63 mmol), K2CO3 (0.225 g, 1.63 mmol) and sodium iodide (0.245 g, 1.63 mmol) and the mixture refluxed for 2 h. The solvent was removed under vacuum and the residue partitioned between CH2Cl2 (2×100 ml) and water (40 ml). The combined extracts were dried (Na2SO4) and evaporated and the resulting residue chromatographed on silica gel eluting with CH2Cl2 /EtOH/NH3 (80:5:0.5) to give the title-indole (0.269 g, 70%). The dihydrogen maleate salt was prepared, mp 187° C., (Found: C, 60.01; H, 5.63; N, 12.12. C26H31N6F. 2(C4H4 04) requires C, 60.17; H, 5.79; N, 12.38%), m/e 447 (M+1)+, δ (360 MHz, D6 -DMSO) 1.90-2.02 (2H, m, CH2), 2.54-3.70 (16H, m, 8 of CH2), 5.44 (2H, s, CH2), 6.14 (maleate-H's), 7.00-7.14 (4H, m, Ar--H), 7.19 (1H, s, Ar--H), 7.31-7.36 (2H, m, Ar--H), 7.52 (1H, s, Ar--H), 7.95 (1H, s, Ar--H), 8.60 (1H, s, Ar--H), 10.90 (1H, s, NH).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)nc1Cl

Procedure:
To a solution of 2,6-dichloronicotinic acid (50 g, 0.26 mol) in methanol (250 mL) was added thionyl chloride (22.7 mL, 0.312 mol) slowly. The mixture was refluxed for 4 hours and concentrated to give methyl 2,6-dichloronicotinate as a white solid in quantitative yield.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15](=[O:28])[NH:14][C:13]1=[O:29])=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15](=[O:28])[NH:14][C:13]1=[O:29])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCCC1C(=O)NC(=O)N1CCCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCC1C(=O)NC(=O)N1CCCCCc1ccccc1

Procedure:
The foregoing ester (4.0 g) was hydrolysed by treatment with dilute sodium hydroxide solution and the product was purified by chromatography on silica gel, to give 5-(6-carboxyhexyl)-1-(5-phenylpentyl)hydantoin crystallising from ethyl acetate-light petroleum (b.p. 60°-80° C.) in colourless prismatic needles, m.p. 90°-92° C.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[O:7]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCCBr
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: BrCCCCCCCCOc1ccccc1
Yield: 75 %

Procedure:
Preparation analogously to Example 38 by the reaction of sodium phenolate with 1,8-dibromooctane to give 8-phenoxy-1-bromooctane (b.p.11 =196°-202°; yield 75%) which is reacted with excess 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate. Isolation is hydrochloride. Yield, after recrystallisation from ethanol/isopropanol: 62%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:25]([F:28])([F:27])[F:26])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.[ClH:29]>O1CCOCC1>[ClH:29].[CH3:1][C:2]1[C:3]([C:25]([F:27])([F:26])[F:28])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1.[ClH:29]
Reactant: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)n2C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-[6-methyl-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinecarboxylate (D59) (2.23 mmol, 900 mg) was treated with HCl (10 ml of a 4M solution in 1,4-dioxane) at room temperature; the mixture was stirred at room temperature overnight. Solvent was evaporated to afford the title compound, mono hydrochloride salt, complete conversion, M++H=300.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]1[CH:31]=[CH:30][C:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:19][CH2:18]3)[N:15]=[CH:16][C:11]=2[C:10]1=[O:32])[CH3:8].O.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl>[CH2:7]([N:9]1[CH:31]=[CH:30][C:12]2[NH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:19][CH2:18]3)=[N:15][CH2:16][C:11]=2[C:10]1=[O:32])[CH3:8]
Reactant: CCn1ccc2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1ccc2c(c1=O)CN=C(N1CCN(Cc3ccccc3)CC1)N2
Yield: 72.9 %

Procedure:
Added at room temperature to a suspension of 0.80 (21 mmol) of lithium aluminum hydride in THF (20 ml) was 1.5 g of 5,6-dihydro-6-ethyl-5-oxo-2-(4-benzylpiperazino)pyrido[4,3-d]pyrimidine (Referential Example 11). After refluxing the reaction mixture for 4 hours, the reaction mixture was added with water to decompose excess lithium aluminum hydride. An aqueous solution of sodium hydroxide and chloroform were added to the resultant mixture to extract the latter. After washing the chloroform layer with water, it was dried with anhydrous magnesium sulfate and was then concentrated to obtain 1.4 g of light yellowish crystals. The crude crystals were immersed in ethyl acetate to obtain 1.1 g of 1,4,5,6-Tetrahydro-6-ethyl-5-oxo-2-(4-benzylpiperazino)pyrido[4,3-d]pyrimidine as colorless crystals (yield: 72%).