Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2([C:13]3[S:14][C:15]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:16][N:17]=3)[CH2:12][O:11][CH2:10]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(COC2(c3nccs3)COC2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(OCc3ccc(OC)cc3)COC2)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of the 2-(3-(4-methoxybenzyloxy)oxetan-3-yl)thiazole (Example 11D) (1.8 g, 6.49 mmol) in tetrahydrofuran (11 mL) was added a solution of lithium diisopropylamide (7.79 mmol in 10 mL tetrahydrofuran) dropwise. The solution was stirred at −78° C. for 45 minutes, and tributyltin chloride (2.11 mL, 7.79 mmol) was added dropwise. The cold bath was removed, and the reaction slowly warmed to room temperature. The ambient reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and diethyl ether. The layers were separated, and the aqueous layer was extracted with additional diethyl ether. The combined organics were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 568.7 [M+H]+.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]4[S:30][C:29]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C:23]=5[C:22]=4[CH:31]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[BH3-][C:33]#N.[Na+].C(O)(=O)C.[OH-].[Na+]>O.C(#N)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]4[S:30][C:29]5[CH2:28][CH2:27][N:26]([CH3:33])[CH2:25][CH2:24][C:23]=5[C:22]=4[CH:31]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: [BH3-]C#N
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4sc5c(c4c3)CCNCC5)nc2)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCc2sc3ccc(C#Cc4ccc(-c5ccc(Cl)cc5)cn4)cc3c2CC1
Reaction time: 8 h

Procedure:
0.18 mL (2.41 mmol) 37% formalin solution in water are added to a solution of 100 mg (0.24 mmol) 3-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene (see 3.60f) in 5 mL acetonitrile. Then 60 mg (0.96 mmol) NaBH3CN and 56 μL (0.96 mmol) acetic acid are added and the reaction mixture is stirred overnight. The solution is combined with 2 M NaOH and extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography by HPLC-MS.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:8]=[N:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:12][CH:11]=1.[BH4-].[Na+]>O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:14][CH:15]=1
Reactant: O=C1NC(=O)C(c2ccc(N=Cc3ccc(Cl)c(Cl)c3)cc2)S1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1NC(=O)C(c2ccc(NCc3ccc(Cl)c(Cl)c3)cc2)S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Into 40 ml of ethanol were suspended 0.40 g of 5-(4-(3,4-dichlorobenzylideneamino) phenyl)thiazolidine-2,4-dione, and, after added 0.24 g of sodium borohydride, the suspension was stirred for 2 hours at 50° C. The reaction mixture was poured into 200 ml of water, which was extracted with ethyl acetate. The organic layer was washed with water and dried. Then, solvent was distilled off. The residue was recrystallized from iso-propanol to obtain 0.20 g of title compound.
Reaction SMILES: C[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH:5]([C:12]([OH:14])=O)[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:38]([C:41]1[CH:42]=[C:43](C2C=CC(O)=CC=2)[CH:44]=[CH:45][CH:46]=1)[CH2:39][CH3:40].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:41]1([CH2:38][CH2:39][CH2:40][C:17]2[CH:18]=[CH:2][C:3]([O:4][CH:5]3[CH2:6][CH:7]([C:9]([O:11][CH3:19])=[O:10])[NH:8][C:12]3=[O:14])=[CH:15][CH:16]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccccc1OC(C[C@H](N)C(=O)O)C(=O)O
Reactant: CCCc1cccc(-c2ccc(O)cc2)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2ccc(CCCc3ccccc3)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 28.5 h
Yield: 122.7 %

Procedure:
A mixture of the compound prepared as described in Example 4 (0.5349 g), triphenylphosphine (1.00 g), and 4-(3-propylphenyl) phenol (0.8100 g) in tetrahydrofuran (4.7 ml) was cooled to approximately 1°-2° C., and treated with a solution of diethylazodicarboxylate (0.6645 g) over a two minute period. After the addition was complete, the reaction suspension was allowed to warm to room temperature. After about 28.5 hours, the resulting brown solution was concentrated in vacuo. The residue was diluted with chloroform (2 ml), the insoluble material removed by filtration, and the filtrate concentrated in vacuo to an oil. The oil was dissolved in methylene chloride and purified by preparative centrifugal thin-layer chromatography (4 mm plate, flow rate=8 ml/min), eluting with 50% ethyl acetate/hexane until the first band elutes then solvent switched to 100% ethyl acetate. The fractions containing the desired compound were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.916 g of methyl 3-(4-(3-phenylpropyl)phenoxy]-2-pyrrolidone-5-carboxylate as a white solid.
Reaction SMILES: [C:1]1([C:7]2([C:11]([Cl:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1>CS(C)=O.C(O)(C(F)(F)F)=O>[ClH:13].[C:1]1([C:7]2([C:11]([O:21][CH:18]3[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]3)=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C1(c2ccccc2)CCC1
Reactant: CN1CCC(O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CN1CCC(OC(=O)C2(c3ccccc3)CCC2)CC1
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 by reacting 1-phenylcyclobutanecarbonyl chloride with 1-methyl-4-hydroxypiperidine at 80° C. for 20 h. The yield was 0.77 g (44%); mp 203-206° C.; 1H NMR (DMSO-d6, 1% TFA) δ 1.76 (d, 2H), 1.83 (m, 1H), 1.96 (m, 2H), 2.05 (t, 1H), 2.41-2.51 (m, 2H), 2.53-2.85 (m, 6H), 3.03 (q, 1H), 3.20 (d, 1H), 3.34 (d, 1H), 4.8 (m, 0.4H), 4.93 (m, 0.6H), 7.23-7.40 (m, 5H). Anal. (C17H23NO2.HCl) C, H. N. The compound exists in two forms in DMSO-TFA solution.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([CH3:36])[CH:30]=1>C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][C:31]=1[CH3:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: Cc1cc(Br)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(Br)ccc1NC(=O)C1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2 g, 9.3 mmol) was dissolved in 100 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (4.5 mL, 55 mmol) followed by the dropwise addition of oxalyl chloride (2.4 mL, 27 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off white oil. Redissolved (0.95 g, 4.0 mmol) oil in 40 mL dry DCM under Ar, cooled to 0° C., added 1.3 mL pyridine followed by 4-bromo-2-methylaniline (0.75 g, 4.0 mmol). The reaction was allowed to warm to ambient temperature, stirred overnight then concentrated. Redissolved in 100 mL EtOAc, washed with 1 N HCl (3×50 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound. (1.09 g, 70%) APCI (AP−): 381.0, 383.0 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:10]([CH2:27][OH:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:10]([CH2:27][O:28][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCN(Cc2ccccc2)CC1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCN(Cc2ccccc2)CC1COS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
To a vigorously stirred solution of Example 45E (1 g, 2.59 mmol) in dichloromethane (5.19 mL) was added triethylamine (0.542 mL, 3.89 mmol) and methanesulfonyl chloride (0.253 mL, 3.24 mmol). The reaction was stirred for 10 minutes and then quenched with brine, extracted twice with dichloromethane, dried over sodium sulfate, and the solvent was evaporated to afford the title compound. MS (ESI+) m/z 464.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[S:5][C:6]=1[C:7](=O)[CH2:8][Cl:9].[OH:13][CH2:14][C:15]([NH:18][C:19]([NH2:21])=[S:20])([CH3:17])[CH3:16]>C(O)C>[ClH:9].[Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[S:5][C:6]=1[C:7]1[N:21]=[C:19]([NH:18][C:15]([CH3:17])([CH3:16])[CH2:14][OH:13])[S:20][CH:8]=1
Reactant: N#Cc1cc(Br)c(C(=O)CCl)s1
Reactant: CC(C)(CO)NC(N)=S
Solvent: CCO
Product: CC(C)(CO)Nc1nc(-c2sc(C#N)cc2Br)cs1
Product: Cl
Yield: 58.2 %

Procedure:
A mixture of 4-bromo-5-(chloroacetyl)thiophene-2-carbonitrile (430 mg, 1.6 mmol), prepared in the previous step, and N-(2-hydroxy-1,1-dimethylethyl)thiourea (241.2 mg, 1.6 mmol), prepared in step 2 of Example 52, in 10 mL of absolute ethanol was refluxed under nitrogen for 2.5 h. The solvent was concentrated to approximately two thirds its volume. The solid present was collected by filtration and dried under reduced pressure to give 4-bromo-5-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}thiophene-2-carbonitrile hydrochloride (367.8 mg, 58%) as a yellow solid, mp 177.5-178.5° C.; MS (ESI) m/z 358 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:12][N+:13]([O-:15])=[O:14])(=[O:11])=[O:10])=[C:4]([CH3:16])[CH:3]=1.[C:17](Cl)(=[O:21])[C:18](Cl)=[O:19].C(=O)([O-])[O-].[Ca+2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>C(COC)OC>[CH2:28]([N:30]([CH2:31][CH3:32])[C:18]([C:17]([NH:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([S:9]([CH2:12][N+:13]([O-:15])=[O:14])(=[O:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1)=[O:21])=[O:19])[CH3:29]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Product: CCN(CC)C(=O)C(=O)Nc1cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c1
Reaction time: 0.5 h

Procedure:
(4-Amino-2,6-dimethylphenylsulfonyl)nitromethane (1.0 g) was added in portions during 10 minutes to a stirred solution of oxalyl chloride (2.0 g) in dimethoxyethane (50 mL) containing calcium carbonate (1.63 g), maintained at about 0°-5° C. The mixture was then further stirred at the same temperature for 30 minutes. Diethylamine (3.4 g) was then added dropwise during 5 minutes. When the addition was complete, the reaction mixture was allowed to attain ambient temperature and the solvent was removed by evaporation in vacuo. Water (50 mL) was then added. The solid which formed was collected by filtration and purified by chromatogaphy on silica using toluene containing increasing amounts of ethyl acetate as eluant. The solid obtained from the major fractions was crystallised first from carbon tetrachloride and then from 2-propanol to give N,N-diethyl-N'-(3,5-dimethyl-4-[nitromethylsulfonyl]phenyl)oxamide as a solid, m.p. 128°-129° C.; microanalysis, found: C,48.2; H,5.5; N,11.2%; C15H21N3O6S requires: C,48.5; H,5.7; N,11.3%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([C:17]2[C:25]([CH:26]=[CH:27][C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:36][CH2:37][OH:38])=[O:29])=[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]3[N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]1([C:17]2[C:25]([CH:26]=[CH:27][C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:36][CH:37]=[O:38])=[O:29])=[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]3[N:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(C=Cc1c(-c2ccccc2)nn2ccccc12)N1CCCC[C@@H]1CCO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: -45 °C
Reaction time: 0.17 h
Yield: 38.4 %

Procedure:
A solution of dimethyl sulfoxide (202 mg) in methylene chloride (1.0 ml) was added dropwise to a solution of oxalyl dichloride (247 mg) in methylene chloride (10 ml) over 5 minutes at -78° C. After 10 minutes, a solution of (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(2-hydroxyethyl)piperidine (trans isomer) (364 mg) in methylene chloride (3.4 mg) was added dropwise over 10 minutes at -78° C. The solution was stirred at -78° C. for 20 minutes and at -45° C. for 1 hour. Triethylamine (986 μl) was added to the solution and the mixture was stirred at -20°~0° C. for 20 minutes. Saturated ammonium chloride solution (20 ml) was added to the reaction mixture and the mixture was extracted with methylene chloride (10 ml×2). The combined extracts were washed with brine (10 ml), dried over magnesium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (10 g) with a mixture of methylene chloride and ethyl acetate (10:1) as an eluent to give (2R)-1-[3-(2-phenylpyrazolo-[1,5-a]pyridin-3-yl)acryloyl]-2-(formylmethyl)piperidine (trans isomer) (139.0 mg) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[CH3:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH:4]([CH2:3][CH2:2][N:29]3[N:30]=[N:31][C:27]([CH3:26])=[N:28]3)[CH2:8][CH2:7]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Reactant: Cc1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3nnc(C)n3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=430.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 5-methyl-1H-tetrazole.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([S:10](=[O:11])(=[O:12])[NH:13][C:14]3[C:15]2=[CH:16][CH:17]=[C:18]2[C:23]=3[N:22]=[CH:21][CH:20]=[CH:19]2)=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1cc(S(=O)(=O)Nc2cccc3cccnc23)c(N)cc1F
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1F)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 15.4 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-fluoro-5-methyl-N-quinolin-8-yl-benzenesulfonamide (Intermediate 299) (340 mg, 1.03 mmol), t-butyl nitrite (0.18 ml, 1.54 mmol), AcOH (3.4 ml) and THF (3.4 ml) gave the title compound (50 mg, 15%) after purification by column chromatography with DCM/MeOH (90:10) as the eluent.
Reaction SMILES: N#N.[F:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1.C([O-])(=O)C.[NH4+:22].[BH3-]C#[N:25].[Na+]>CO>[NH2:25][C@@H:9]1[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][C@H:4]1[F:3].[NH2:22][C@H:9]1[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:5][C@H:4]1[F:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (0.80 g, 3.68 mmol) in MeOH (10 mL) was added ammonium acetate (1.99 g, 25.80 mmol) and the resulting solution stirred at rt for 2 h. NaCNBH3 (0.29 g, 4.42 mmol) was then added and the solution stirred at rt overnight. The reaction mixture was concentrated to dryness and the organics extracted with EA from a 1% aq. solution of Na2CO3. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified with FC (CH2Cl2/MeOH, 9:1) to afford trans-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate and cis-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate both as colorless oils which solidified upon standing. LC-MS-conditions 08: tR=0.48 min; [M-CH3+H]+=204.25 and tR=0.46; [M+H]+=219.26; TLC: rf (CH2Cl2/MeOH, 9:1)=0.30 and 0.09.
Reaction SMILES: [CH3:1][C@@H:2]1[O:9][C:7](=[O:8])[C@H:6]([CH3:10])[O:5][C:3]1=[O:4].[CH2:11]1[O:18]C(=O)C[O:14][C:12]1=[O:13]>C1(=O)OCCCCC1.C([O-])(=O)CCCCCCC.[Sn+4].C([O-])(=O)CCCCCCC.C([O-])(=O)CCCCCCC.C([O-])(=O)CCCCCCC.C(Cl)(Cl)Cl>[C:3]([OH:5])(=[O:4])[CH:2]([CH3:1])[OH:9].[C:12]([OH:14])(=[O:13])[CH2:11][OH:18].[C:7]1(=[O:8])[O:9][CH2:2][CH2:3][CH2:11][CH2:10][CH2:6]1
Reactant: O=C1COC(=O)CO1
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: CCCCCCCC(=O)[O-]
Agent: O=C1CCCCCO1
Agent: [Sn+4]
Solvent: ClC(Cl)Cl
Product: CC(O)C(=O)O
Product: O=C(O)CO

Procedure:
A reactor equipped with an exhaust vent and a thermometer was charged with 263 g of L-lactide (reagent, supplied by SIGMA-ALDRICH JAPAN K.K.), 42 g of glycollide (prepared under the same conditions as those in Example 1), 194 g of ε-caprolactone (reagent, supplied by TOKYO CHEMICAL INDUSTRY CO., LTD.) and 0.01 g of tin octanoate (reagent, supplied by SIGMA-ALDRICH JAPAN K.K.) as a catalyst, and the pressure inside the reactor was reduced to 1×10−3 mmHg with a vacuum pump, followed by polymerization at 190° C. for 24 hours. After the reaction, a copolymer was dissolved in chloroform and purified by precipitation in methanol, to give a lactic acid/glycolic acid/ε-caprolactone copolymer.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C1COCC1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:21]=1>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:29]1[CH2:30][CH2:31][N:26]([C:22]2[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[CH:24][N:23]=2)[CH2:27][CH2:28]1)=[O:12]
Reactant: COc1ccnc(N2CCNCC2)n1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccnc(N2CCN(C(=O)c3cc4ccccc4[nH]3)CC2)n1
Reaction time: 8 h

Procedure:
To a solution of 0.83 g (5.15 mmol) of indol-2-carboxylic acid in 15 mL of dry THF 0.83 g (5.15 mmol) of N,N′-carbonyldiimidazol is added. After 30 minutes 1.0 g (5.15 mmol) of 4 methoxy-2-(1-piperazinyl) pyrimidine is added to the solution and it is left overnight with continuous stirring. The solvent is eliminated under reduced pressure and H2O added. This produces a precipitate which is filtered and dried, to give 1.7 g (5.04 mmol) of 2-[4-(2-indolylcarbonyl)-1-piperazinyl]-4-methoxypyrimidine. m.p.=202-203° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][Cl:20])=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3].C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[ClH:20].[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3]
Reactant: C1COCCN1
Reactant: C#CCOc1ccc(OCC(O)CCl)c2c1NC(=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCOc1ccc(OCC(O)CN2CCOCC2)c2c1NC(=O)CC2
Product: Cl
Yield: 62.4 %

Procedure:
1.0 g of 8-(2-propynyloxy)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril was dissolved in 20 ml of methanol. 0.7 g of anhydrous potassium carbonate and 1.7 g of morpholine were then added to the solution followed by stirring while refluxing for 4 hours. After completion of the reaction, the methanol and the unreacted morpholine were evaporated under reduced pressure, and the residual oil was converted into a hydrochloride with an aqueous hydrochloric acid, and washed with chloroform. The aqueous layer was separated, made alkaline with sodium hydroxide and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residue was converted into a hydrochloride with ehtanolhydrochloric acid. Recrystallization from water-ethanol gave 0.8 g of 8-(2-propynyloxy)-5-(2-hydroxy-3-morpholinopropoxy)-3,4-dihydrocarbostyril hydrochloride having a melting point of 234.5°-235° C.
Reaction SMILES: CC(N(C)C)=O.[CH3:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH3:14])[N:9]1[CH2:15][CH2:16][NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1)=[O:19].Cl[C:27]1[N:31](C(OC(C)(C)C)=O)[C:30]2[CH:39]=[CH:40][C:41]([C:43]([F:46])([F:45])[F:44])=[CH:42][C:29]=2[N:28]=1>C1(C)C(C)=CC=CC=1>[CH2:8]([NH:9][CH2:10][CH3:11])[CH3:7].[CH3:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([CH3:7])[N:9]1[CH2:15][CH2:16][NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:27]1[NH:28][C:29]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:30]=2[N:31]=1)=[O:19]
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1
Reactant: CC(C)(C)OC(=O)n1c(Cl)nc2cc(C(F)(F)F)ccc21
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1C
Product: CCNCC
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccc(C(F)(F)F)cc2[nH]1
Temperature: 80 °C
Yield: 48.6 %

Procedure:
Dimethylacetamide (0.5 ml) was added to a mixture of (2S)-N2-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-2-piperidinecarboxamide (134 mg) [see Preparation 15] and tert-butyl 2-chloro-5-(trifluoromethyl)-1H-1,3-benzimidazole-1-carboxylate (463 mg) [see Preparation 16]. The reaction mixture was heated to 80° C. for 12 hours, after which time the mixture was reduced to low volume, xylene (50 ml) was added, and all solvent was removed under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate, the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0, changing to 98:2, by volume, ethyl acetate:diethylamine, in 0.5% increments, to afford (2S)-N2-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-[6-(trifluoromethyl )-1H-1,3-benzimidazol-2-yl]-2-piperidinecarboxamide (55 mg) as a white solid.