Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)CC)C>C(#N)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(Br)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cn2)CC1
Yield: 36.9 %

Procedure:
Tert-butyl piperazine-1-carboxylate (300 mg, 1.611 mmol) and 2-bromo-5-chloropyridine (465 mg, 2.416 mmol) were dissolved in acetonitrile (3 ml), followed by addition of triethylamine (0.45 ml, 3.222 mmol), and then the resulting liquid was subjected to microwave irradiation at 150° C. for 2 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of a saturated aqueous ammonium chloride solution (10 ml), and extracted with MC (15 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 177 mg of colorless oil (37%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:15][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(Sc2ccccc2)cc1N

Procedure:
4.5 Kg. of 1-amino-2-nitro-5-phenylthiobenzene in 60 l. of methanol and 30 l. of water is treated, under nitrogen, with 8.0 kg. of sodium dithionite and 2.0 kg. of sodium carbonate at reflux. The mixture is heated for 2 hours and the methanol is removed by distillation. The mixture is cooled and extracted with dichloromethane. The dichloromethane solution is filtered, dried over sodium sulfate, and 1,2-diamino-4-phenylthiobenzene is isolated by evaporation.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17]>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:16]([C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)=[O:17]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)c1ccco1

Procedure:
Using 2-amino-benzothiazole and furan-2-carboxylic acid chloride in pyridine the title compound was obtained as a white solid (83% yield), MS: m/e=244 (M+).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([Cl:32])=[CH:27][CH:26]=2)=[O:22])=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:21]([NH:20][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:14][C@H:9]1[NH2:8])=[O:22])=[CH:31]2
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](N)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(1S,2R,4S)—N2-(tert-Butoxycarbonyl)-N1-[(5-chloroindol-2-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediamine (200 mg) was dissolved in dichloromethane (6 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure to obtain (1S,2R,4S)—N1-[(5-chloroindol-2-yl)carbonyl]-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine trifluoroacetate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH2:5][CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O.C(OCC)(=O)C.CCCCCC>O.C(#N)C>[C:27]1(=[O:36])[N:13]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH3:2])=[O:14])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: COC(=O)CC(N)c1ccccc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a stirred solution of 3-amino-3-phenylpropionic acid methyl ester hydrochloride (0.50 g, 2.3 mmol) and sodium carbonate (0.25 g, 2.3 mmol) in 10 mL of water was added N-carboethoxyphthalimide (0.51 g, 2.3 mmol) in 7 mL of acetonitrile. The reaction progress was monitored by TLC (ethyl acetate/hexane; 1:2) which showed that the reaction was complete in one hour. The reaction mixture was partially concentrated to remove the acetonitrile. The resulting slurry was filtered and the solid was washed with 20 mL of water. The solid was dried in vacuo (60° C., <1 mm) to afford 280 mg (39.4%) of methyl 3-phthalimido-3-phenylpropionate as a white powder: mp 75°-76° C.; 1H NMR (DMSO-6, 250 MHz) δ7.26-7.83 (m, 9H), 5.68-5.75 (m, 1H), 3.55 (S, 3H), 3.37-3.66 (m, 2H); 13C NMR (DMSO-d6) δ170.7, 167.6, 138.6, 134.7, 131.0, 128.6, 127.8, 126.9, 123.3, 51.6, 49.9, 35.3. Anal. Calcd for C18 H15NO4 : C, 69.89; H, 4.89; N, 4.53; Found: C, 69.69; H, 4.83; N, 4.49.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10].[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl.O>[Cl:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:11](=[O:15])[C:12](=[O:13])[NH:8]2)=[C:3]([CH3:10])[CH:4]=1
Reactant: Cc1cc(Cl)cc(N)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cc1cc(Cl)cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
123 g (0.79 mol) of 2,3-diamino-5-chlorotoluene and 106.2 g (1.18 mol) of oxalic acid are heated at reflux for 5 hours in 800 ml of 4N hydrochloric acid. The reaction mixture is allowed to cool, and is diluted with water, filtered off on a suction filter and washed with water. The product is then stirred in hot ethanol, filtered off on a suction filter and the suction filter material is dried in vacuo at 60°. The title compound is obtained as slightly grayish crystals of m.p.>250°.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[C:40]([C:42]([NH:44][CH3:45])=[O:43])[CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[N:41]=[C:40]([C:42]([NH:44][CH3:45])=[O:43])[CH:39]=[CH:38][CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)n1
Yield: 30 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-methyl-2-pyridinecarboxamide (1.44 g) and pyridine hydrochloride (550 mg), the title compound (255 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)[CH:3]=1.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:1][C:2]1[S:6][CH:5]=[C:4]([CH2:7][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: O=C(c1csc(Br)c1)N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Product: Brc1cc(CN2CCCCC2)cs1
Yield: 35.1 %

Procedure:
To a solution of (5-bromothiophen-3-yl)-piperidin-1-yl-methanone (907 mg, 3.30 mmol) in DCM (33 mL) was added tetrabutylammonium borohydride (2.54 g, 9.90 mmol) portionwise over 10 minutes. The reaction mixture was heated under reflux for 19 h then further tetrabutylammonium borohydride (2.54 mg, 9.90 mmol) was added to the reaction mixture, in four portions over 6 h. and then the reaction mixture was heated under reflux for 18 h. After this time the reaction mixture was partitioned between DCM (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-50% ethyl acetate in cyclohexane) to afford an oil which solidified on standing to afford the title compound as a white solid (301 mg, 35%). 1H NMR (CDCl3, 300 MHz):7.23 (d, J=1.7 Hz, 1H), 7.15 (d, J=1.7 Hz, 1H), 3.91 (s, 2H), 2.97-2.87 (m, 2H), 2.72-2.62 (m, 2H), 2.15-2.06 (m, 2H), 1.70-1.52 (m, 2H), 1.41-1.25 (m, 2H); LCMS (Method B): RT=4.0 min, M+H+=260.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]1[CH:14]2[CH2:15][NH:16][CH2:17][CH:13]2[CH2:12][O:11]1.[OH-].[Na+]>O>[C:1]([N:16]1[CH2:17][CH:13]2[CH2:12][O:11][CH2:10][CH:14]2[CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1NCC2COCC12
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccccc1)N1CC2COCC2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Benzoyl chloride (14.06 grams, 0.1 mole), Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, was slowly added to a mixture of [compound (X)] hexahydro-1H-furo(3,4-c)pyrrole (11.3 grams, 0.1 mole) and sodium hydroxide (10 grams) in 300 ml of water at 10°C. After the addition of benzoyl chloride, the reaction mixture was stirred at room temperature for 2 to 3 hours and the product was extracted with diethyl ether (4 × 200 ml). Removal of the ether gave the product 5-benzoyl-hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (XI), as a clear viscous liquid which solidified on standing. The product was crystallized from diethyl ether and had a melting point of 47° to 48°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[C:9]([OH:12])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][O:3]1.CN(C=O)C.Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)[CH2:4][O:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1(C)Cc2c(O)cccc2CO1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(cccc2Oc2ccc([N+](=O)[O-])cn2)CO1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a solution of 3,3-dimethylisochroman-5-ol (Intermediate 170, 65 mg, 0.36 mmol) in dry DMF (3 ml) potassium carbonate (207 mg, 1.5 mmol) and then 2-chloro-5-nitropyridine (50.8 mg, 0.32 mmol) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (2 ml), diluted with brine (10 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried over sodium sulfate, filtered and evaporated affording the title compound (80 mg) as an orange solid that was used in the next step as crude without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:28]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
To a suspension of sodium hydride (0.11 g, 2.78 mmol) in THF (5 mL) at 0° C. was added a solution of di-tert-butyl malonate (0.53 mL, 0.5 g, 2.31 mmol) in THF (1.5 mL). The mixture was warmed to room temperature and stirred for 10 min. To the mixture was slowly added a solution of ethyl 6-bromohexanoate (0.42 mL, 0.52 g, 2.31 mmol) in THF (0.5 mL) and the mixture was stirred at 70° C. for 10 hours. After dilution of the mixture with ethyl acetate (10 mL), the solution was washed with water (20 mL) and brine (20 mL), dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel (80:20 petroleum ether 60-80° C.:ethyl acetate) to give the 2-tert-butoxycarbonyloctanedioate 1-tert-butyl ester 8-ethyl ester (14a) as a clear oil (0.61 g, 74%); Rf=0.33 (5:1 petroleum ether 60-80° C.:ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 4.11 (2H, q, J=7.2 Hz, OCH2CH3), 3.37 (1H, t, J=5.7 Hz, COCH), 2.27 (2H, t, J=7.1 Hz, CH2CO), 1.87 (2H, br m, CHCH2CH2CH2CH2), 1.46 (2H, t, J=7.6 Hz, CHCH2), 1.37 (4H, br m, CHCH2CH2CH2), 1.22 (3H, t, J=7.2 Hz, OCH2CH3), 1.43 (18H, s, C(CH3)3); 13C NMR (75 MHz, CDCl3): δ 173.93 (CO), 173.93 (CO), 171.15 (CO), 61.14 (OCH2CH3), 51.66 (COCH), 33.89 (CH2CO), 29.44 (CH(CH3)3), 28.91 (CHCH2CH2CH2), 28.27 (CHCH2CH2), 26.83 (CHCH2CH2CH2CH2), 24.46 (CHCH2), 14.17 (OCH2CH3).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]([F:26])([F:25])[C:21](OC)=[O:22])=O)(C)(C)C>>[F:26][C:20]([F:25])([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[CH3:12])[CH2:21][OH:22]
Reactant: COC(=O)C(F)(F)C1CCCCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCCCC1C(F)(F)CO
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
To a solution of 2-(difluoro-methoxycarbonylmethyl)piperidine-1-carboxylic acid tert-butyl ester (1.14 g in 30 mL dry diethyl ether) at 0° C. was added 580 mg lithium aluminum hydride and the mixture stirred at low temperature. After 15 minutes, the reaction was quenched by the sequential addition of 0.58 mL water, 0.58 mL 2N sodium hydroxide and 0.74 mL water. The mixture was stirred vigorously for 1 hour then filtered over diatomaceous earth. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 85:15) to give the title compound (450 mg).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[F:10].C(N(C(C)C)CC)(C)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].O>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[Cl:28][CH2:29][C:30]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:6]2[CH:7]=[CH:8][C:9]([F:10])=[C:4]([F:3])[CH:5]=2)[CH2:13][CH2:14]1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: NC1CCN(Cc2ccc(F)c(F)c2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)NC1CCN(Cc2ccc(F)c(F)c2)CC1
Yield: 22.6 %

Procedure:
1-[(3,4-Difluorophenyl)methyl]-piperidin-4-ylamine dihydrochloride (3.18 g) was dissolved in tetrahydrofuran (40 ml). Diisopropylethlamine (6.84 g) and chloroacetyl chloride (1.33 g) were added. After 3 hours water, brine and ethyl acetate were added the phase were separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluting with ethyl acetate to give the subtitle compound (0.728 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25]CC)=[N:8][N:9]([C:11]2[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=2[F:24])[CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[N:8][N:9]([C:11]2[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=2[F:24])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cc(SCC(F)(F)F)c(C)cc2F)nc1OCC
Agent: BrB(Br)Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1cn(-c2cc(SCC(F)(F)F)c(C)cc2F)nc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.3 %

Procedure:
Then, 1.0 g of ethyl-3-ethoxy-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazole-4-carboxylate was dissolved in 30 mL of dichloromethane, and 3.08 g of boron tribromide was added under cooling with ice, followed by stirring at room temperature for 12 hours. Then, 10 mL of a saturated aqueous solution of citric acid was added, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.45 g of ethyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole-4-carboxylate.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](Br)[CH:20]=2)[C:15]([CH3:24])([CH3:23])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31]>C(OCC)C>[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:20]=2)[C:15]([CH3:24])([CH3:23])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Reactant: CCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC(=O)c1cnc2c(c1)N(C(=O)OC(C)(C)C)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Butyllithium (12.0 mL, 2.5 M solution in hexanes, 30 mmol) was added dropwise to a solution of 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (8.0 g, 24.5 mmol) in diethyl ether (80 mL) at −78° C. The resulting orange slurry was stirred 30 minutes at this temperature before a solution of N-methoxy-N-methylbutyramide (prepared in a manner similar to that described in US2010/060696) (5.3 g, 36.6 mmol) in diethyl ether (40 mL) was added dropwise over 1 h. The reaction was allowed to warm to room temperature and stirred 1 h further, then quenched with saturated aqueous ammonium chloride and the two layers were separated. The aqueous fraction was further extracted with EtOAc (2×50 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated. Chromatography (0-30% EtOAc/petrol) gave the title compound (5.6 g, 72%) as a yellow solid. MS: [M+H]+=319.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.[I-].[Na+]>>[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(CCCCl)c1ccccc1
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: [I-]
Agent: [Na+]
Product: C[C@@H]1CCC[C@H](C)N1CCCC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 619 g. of γ-Chlorobutyrophenone, ethylene ketal, 700 g. of cis-2,6-dimethylpiperidine and 16 g. of sodium iodide is stirred and heated at reflux for 48 hours. The mixture is cooled, diluted with 1 l. of anhydrous ether and filtered to remove cis-2,6-dimethylpiperidine hydrochloride. The filter cake is washed with 1 l. of ether and the filtrate and washings combined. The resulting ether solution is washed five times with 500 ml. portions of water, then extracted with a solution of 300 ml. of concentrated hydrochloric acid in 3 l. of water. The acid extract is washed with 500 ml. of ether, then heated to 70°-80° and allowed to cool to room temperature over a period of 16 hours. The resulting solution is basified with 50% aqueous sodium hydroxide and the organic layer is separated. The aqueous layer is extracted with 500 ml. of ether and the extract is combined with the organic layer. The combined extract is washed several times with water, dried and evaporated. The oily residue is distilled at reduced pressure to give cis-γ-(2,6-dimethylpiperidino)butyrophenone; b.p. 138°-141° C./0.1 mm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O.ClCCl>[O:8]([CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
4-Pyridylcarbinol (8.5 g, 0.08 mol) was dissolved in a 9:1 mixture of N,N-dimethylformamide and dichloromethane (150 mL). t-Butyldimethylsilylchloride (13 g, 0.09 mol) and imidazole (6.4 g, 0.09 mol) were added and the solution was stirred for 12 hours at room temperature. The reaction mixture was concentrated at reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure to give the title compound (17.4 g, 92%) as a colorless oil; MS(ES) m/e 244 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:26](OCC)=[O:27])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+].[Cl-].[Na+]>C1(C)C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:26]([N:17]1[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:27])[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 12.5 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
(RS)-3-Quinuclidinol (7.23 g) was added to a solution of (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (10 g) in toluene (50 ml) at 25-30° C. under nitrogen atmosphere. Sodium hydride (60% w/w, 0.27 g) was added to the mixture and the reaction mass was heated to reflux for 24 h. The by-product ethanol was removed azeotropically with toluene and fresh toluene was added to maintain volume of reaction mass. The reaction mass was cooled to 10-15° C. and 10% w/w sodium chloride solution (30 ml) was added slowly at 10-25° C. Then the reaction mass was stirred for about 10 min and toluene layer was separated. The organic layer was then extracted with ˜18% w/w aqueous hydrochloric acid (100 ml) at 10-30° C. The aqueous layer was cooled to 5-10° C. and pH was adjusted to 7.0-7.5 using 40% w/w aqueous sodium hydroxide solution (36 ml). Thereafter, the pH was further adjusted to 9.5-10 using 10% w/w aqueous sodium hydroxide solution (11 ml). The product was extracted with ethyl acetate (100 ml) at 25-30° C. Then the organic layer was washed with water (30 ml) and then it was treated with carbon (0.5 g) at 25-30° C. for 30 min. The carbon was removed by filtration through hyflo and the residue was washed with ethyl acetate (20 ml). Thereafter, the filtrate was concentrated under reduced pressure at 40-50° C. to produce 12 g of (1S)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylic acid (3RS)-1-azabicyclo[2.2.2]oct-3-yl ester (Solifenacin and its diastereomer) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 70 %

Procedure:
As described for example 12, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mol) instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was converted using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine to the title compound (trituration with tert-butylmethylether, 178 mg, 70%) which was obtained as a white solid. MS: m/e=395.2 [M+H]+.