Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH:27]=[O:28])[C:14]=2[CH3:29])=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27][OH:28])[C:14]=2[CH3:29])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(C=O)c2C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(CO)c2C)cc1
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
A stirred, cooled (ice bath) solution of [4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 142, 0.172 g, 0.42 mmol) in methanol (4 mL) was treated with sodium borohydride (0.02 g, 0.51 mmol) and the resulting reaction mixture was stirred for 1.5 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic phase was washed with water (×1) and brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 15–20% ethyl acetate in hexane as the eluent to afford the title product as a white solid (0.15 g, 88%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[CH:5][C:4]([C:12]([F:15])([F:14])[F:13])=[N:3]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][N:11]=2)=[CH:5][C:4]([C:12]([F:15])([F:13])[F:14])=[N:3]1
Reactant: CCOC(=O)Cl
Reactant: Cn1nc(C(F)(F)F)cc1-c1nccs1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(-c2cc(C(F)(F)F)nn2C)s1
Reaction time: 1.5 h

Procedure:
2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole and THF at −50° C. or below, followed by stirring at −50° C. or below for 90 minutes. Ethyl chloroformate was added to the reaction solution at −20° C. or below. After stirring at −20° C. or below for 15 minutes, it was subjected to purification in the usual way to give ethyl 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylate. This was hydrolyzed with a base in the usual way to give 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:34][C:35]3[CH:48]=[CH:47][C:38]4[C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][O:41][C:37]=4[CH:36]=3)[CH:28]=2)=[C:22]([CH3:49])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:20]2[CH:21]=[C:22]([CH3:49])[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:34][C:35]4[CH:48]=[CH:47][C:38]5[C@H:39]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:40][O:41][C:37]=5[CH:36]=4)[CH:28]=3)=[C:24]([CH3:26])[CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)cc4C)c3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(C(=O)OC(C)(C)C)CC5)cc4C)c3)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
4-[(Methylsulfonyl)oxy]piperidine-1-carboxylic acid tert-butyl ester (134 mg, 0.48 mmol), (S)-methyl 2-(6-((4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3 h (200 mg, 0.48 mmol) and cesium carbonate (470 mg, 1.43 mmol) were dissolved in 10 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting solution was mixed with 30 mL of ethyl acetate. The organic phase was washed with water (20 mL×2) and saturated sodium chloride solution (20 mL) successively, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by elution system B to obtain the title compound methyl (S)-2-(6-((4′-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 3j (101 mg, yield 35.0%) as a colorless slime.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:11][CH:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:13][CH:14]=1)=[O:3]
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(N)cc2)s1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(NC=O)cc2)s1
Temperature: 50 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of acetic anhydride (1.1 g) and formic acid (0.8 g) was heated at 50° C. for 30 minutes. To the mixture was added ethyl 5-(4-aminophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.5 g). The mixture was stirred at ambient temperature for 4 hours and poured into ice-water. The precipitates were collected, washed with water, and dried in vacuo to give ethyl 5-[4-(formylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23](O)=[O:24])[N:21]=1)=[CH:5]2.C(N(CC)CC)C.C(Cl)(=O)C(C)C.[BH4-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][OH:24])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: CC(C)C(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid (391 mg, 1 mmol) prepared in Example 4 was dissolved in DCM (10 mL). Triethylamine (280 ul, 2 mmol) and isobutyric acid chloride (106 mg, 1 mmol) were added thereto, and the mixture was stirred for 30 min at 0° C. After completion of the reaction, the solvent was removed under reduced pressure. The residue was diluted with THF. NaBH4 (74 mg, 2 mmol) was added thereto, and the mixture was stirred for 12 h. The reaction was quenched with a small amount of water. Again, excess water was added to the reaction mixture, which was then stirred for 30 min, extracted with EtOAc, dried over MgSO4, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (272 mg, Yield 72%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:25]([F:28])([F:27])[F:26])(=O)OC.O.[NH2:31][NH2:32]>>[CH3:1][C:2]1([CH3:9])[CH2:6][C:5]2[N:31]=[N:32][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:28])([F:27])[F:26])=[CH:16][C:4]=2[CH2:3]1
Reactant: NN
Reactant: CC1(C)CC(=O)C(=O)C1
Reactant: COP(=O)(CC(=O)c1ccccc1OC(F)(F)F)OC
Solvent: O
Product: CC1(C)Cc2cc(-c3ccccc3OC(F)(F)F)nnc2C1

Procedure:
light yellow oil. MS (ESI): 309.0 (MH+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [2-Oxo-2-(2-trifluoromethoxy-phenyl)-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@:15]([C:17]#[CH:18])([OH:16])[C@H:14]([O:19]C(=O)C4C=CC(C)=CC=4)[C@@H:13]([CH2:29][O:30]C(=O)C4C=CC(C)=CC=4)[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C[O-].[Na+].Cl>CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@:15]([C:17]#[CH:18])([OH:16])[C@H:14]([OH:19])[C@@H:13]([CH2:29][OH:30])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#C[C@@]1(O)[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O[C@H]1n1ccc2c(Cl)ncnc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C#C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Crude intermediate (2R,3R,4R,5R)-2-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(4-methylbenzoyloxy)-5-(4-methylbenzoyloxymethyl)-3-ethynyl-tetrahydro-furan-3-ol (434 mg, 0.74 mmol) is dissolved in MeOH (5 ml) and CH2Cl2 (5 ml). 30% sodium methoxide in methanol solution (1.38 ml, 7.4 mmol, 10 equiv.) is added and the mixture is stirred at room temperature for 15 mins. The mixture is neutralized to pH 7.0 by addition of 1N HCl solution and evaporated under vacuum to dry, purified by flash chromatography (CH2Cl2:MeOH=92:8) to yield (2R,3R,4R,5R)-2-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-ethynyl-5-hydroxymethyl-tetrahydrofuran-3,4-diol. 1H-NMR (CDCl3): δ 8.58 (s, 1H), 8.00 (d, 1H, J=3.9 Hz), 6.68 (d, 1H, J=3.9 Hz), 6.49 (s, 1H), 4.51 (d, 1H, J=9.0 Hz), 4.20-3.75 (m, 3H), 2.51 (s, 1H). ESI-MS: calcd. for C13H12ClN3O4 (309.05). found: 310.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1.C(OCC)(=O)C>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc([N+](=O)[O-])cc3)cc12
Yield: 115.9 %

Procedure:
246 mg of 4-bromonitrobenzene, 1.2 g of sodium carbonate in 20 cm3 of water and 365 mg of tetrakis(triphenylphosphine)palladium are added to 2 g of N-[6-chloro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 100 cm3 of dioxane. The medium is then refluxed for 20 hours and the resulting mixture is then allowed to return to room temperature and 100 cm3 of ethyl acetate and 100 cm3 of water are added. The reaction medium is filtered through a sinter funnel packed with Celite and the organic phase is separated out after settling of the phases has taken place, washed with 100 cm3 of water, with 100 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60/μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (85/15 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 690 mg of N-[6-chloro-5-(4-nitrophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of yellow crystals.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20][CH2:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:17]1([C:2]2[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
To a stirred solution of 3-bromo-5-nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (Example 1a) (6 g, 19.9 mmol) in DMF (30 mL) was added 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9) (4.64 g, 23.9 mmol) and K2CO3 (8.2 g, 59.8 mmol) at 25° C. and the reaction mixture was degassed with argon over 30 min. To this was added PdCl2 (dppf)2 dichloromethane complex (814 mg, 1.1 mmol) and the reaction mixture was heated to 80° C. for 20 h. The reaction mixture cooled to 25° C., water (50 mL) was added, the mixture was extracted with ethyl acetate (4×50 mL), washed with water (200 mL), brine, dried with Na2SO4 and concentrated. The crude material was purified by column chromatography (Combi-Flash, 40 g, 2% dichloromethane/hexane) to get the title compound (2.5 g, 43.51%) as pale white solid; NMR complies.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>C(O)CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:14])[NH:4][CH:3]=[C:2]2[N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)[nH]cc(N3CCN(C)CC3)c2c1
Yield: 59.5 %

Procedure:
To a solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (0.25 g, 0.984 mmol) and 1-methylpiperazine (0.197 g, 1.968 mmol) in ethylene glycol (2 ml) was added DIPEA (0.516 ml, 2.95 mmol). The reaction was irradiated in microwave at 140° C. for 1 h. The reaction mixture was adsorbed on silica was purified by silica gel chromatography (30% ethyl acetate in pet ether) to get the desired compound (0.16 g, 53.5%) as solid. MS: MS m/z 274.18 (M++1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:16][C:17]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]1.Cl>O1CCCC1.C(Cl)Cl>[OH:16][C:17]1([C:20]([O:22][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(O)C1(O)CC1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1(O)CC1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Triethylamine (1.0 ml) and benzyl bromide (650 μl) were added to a solution of 1-hydroxycyclopropane-carboxylic acid (409 mg) in tetrahydrofuran (3.0 ml), and the mixture was stirred at room temperature for 23 hours. Methylene chloride and 1N hydrochloric acid were added to the reaction mixture to separate the mixture into two layers. An organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. A crude product was purified by column chromatography on silica gel (hexane:ethyl acetate=41) to obtain the title compound (607 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>C(#N)C>[Br-:26].[F:1][C:2]1[CH:3]=[C:4]([CH:8]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N+:14]([CH2:27][C:28](=[O:29])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1cccc(F)c1)N1CCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1cccc(F)c1)N1CCCCC1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
(R)-Quinuclidin-3-yl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (164 mg, 0.47 mmol) and 2-bromo-1-phenylethanone (104 mg, 0.52 mmol) were dissolved in acetonitrile (5 ml) and stirred at room temperature for 16 hours. The solvent was evaporated and the crude was triturated with Et2O, filtered under suction and washed with EtOAc and Et2O (1/1) to obtain (3R)-3-(2-(3-fluorophenyl)-2-(piperidin-1-yl)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (180.5 mg; 69.9% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:12])([CH2:9][CH2:10][NH2:11])[CH:3]1[CH3:13].Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:12])([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]1[CH3:13]
Reactant: BrCCCCBr
Reactant: CC1CCN(C)C(C)C1(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC1CCN(C)C(C)C1(C)CCN1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
A solution of 1,2,3,4-tetramethyl-3-piperidineethanamine (9.8 g, 53 mmol) in acetonitrile (50 mL) was added dropwise over about 2 hours to a suspension of 1,4-dibromobutane (6.6 mL, 55.7 mmol) and potassium carbonate (26 g, 200 mmol) in acetonitrile (250 mL). The reaction mixture was stirred at room temperature for 24 hours, diluted with ether and the inorganic salts were removed by filtration. The solvent was removed in vacuo and the oily residue was purified by column chromatography on silica gel eluting with 2% isopropylamine/hexanes to afford 5.8 g (46%) of 1,2,3,4-tetramethyl-3-[2-(1-pyrrolidinyl)ethyl]piperidine. The product was dissolved in ether (25 mL) and treated with 6.5N ethereal HCl (10 mL) at 0° C. The mixture was warmed to room temperature, diluted with ether (10 mL) and cooled back to 0° C. to precipitate the dihydrochloride salt. The salt (4.3 g) was isolated as a white solid and had a melting point of 225°-227° C. (dec.) when recrystallized from ether (35 mL).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(N(CC)CC)C>C(#N)C>[N:12]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To α-bromo-p-chloroacetophenone (4.64 g) in acetonitrile (50 ml) was added 1,2,4-triazole (1.4 g) followed by triethylamine (2 g). The mixture was stirred at room temperature for two hours and refluxed for one hour. The solvent was removed under reduced pressure and to the residue water was added. The yellow solid which precipitated was filtered, washed with water and dried. Crystallisation from ethanol-petroleum ether (60°-80°) gave α-1,2,4-triazol-1-yl-p-chloroacetophenone as cream coloured plates, m.p. 148°-150°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][Cl:27].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:24][CH2:25][CH2:26][Cl:27])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2Sc3cc(Cl)ccc3NC(=O)C2O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCCCl)C(=O)[C@@H]2O)cc1
Yield: 106.3 %

Procedure:
8.395 g (25.0 mmol) of 2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (IV-1), 4.723 g (30.0 mmol) of 1-bromo-3-chloropropane (V-1) and 4.146 g (30.0 mmol) of K2CO3 were dissolved in 168 ml of acetone, and the mixture was refluxed for 20 hours. The reaction mixture was evaporated under reduced pressure to give a residue, which was chromatographed on silica gel to give 10.96 g of cis-2-(4-methoxyphenyl)-3-hydroxy-5-(3-chloropropyl)-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (III-1) from dichloromethane effluent parts. The obtained compound was recrystallized from ethyl acetate to give 9.146 g as colorless prisms in 88.7% yield.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[N:18]=3)[S:14][C:13]=2[CH:34]=1)(C)(C)C.[Cl:36]C1N=C(C2SC3C=C(C#N)C=CC=3C=2)C(Cl)=CN=1.NCCCN1CCN(C)CC1>>[Cl:36][C:22]1[C:17]([C:15]2[S:14][C:13]3[CH:34]=[C:9]([C:8]#[N:7])[CH:10]=[CH:11][C:12]=3[CH:16]=2)=[N:18][C:19]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[N:20][CH:21]=1
Reactant: N#Cc1ccc2cc(-c3nc(Cl)ncc3Cl)sc2c1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccc(CNC(=O)OC(C)(C)C)cc4s3)n2)CC1
Agent: CN1CCN(CCCN)CC1
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(C#N)cc4s3)n2)CC1

Procedure:
Using the method of (2-{2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophen-6-ylmethyl)-carbamic acid tert-butyl ester, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)benzo[b]thiophene-6-carbonitrile and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a solid. ES+(m/z) 427 (35Cl) and 429 (37Cl) [M+H].
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[C:12]([C:22]([NH2:24])=[O:23])=[C:11]([NH2:25])[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:9]=1[CH3:36])=[O:7]>CN(C)C=O.O1CCCC1.O>[NH2:25][C:11]1[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:9]([CH3:36])=[C:8]([C:6]([OH:7])=[O:5])[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[C:12]=1[C:22]([NH2:24])=[O:23]
Reactant: CC1=C(C(=O)OCC[Si](C)(C)C)C(c2ccc(C#N)cc2)C(C(N)=O)=C(N)N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)C(C(N)=O)=C(N)N1c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 650 mg (1.2 mmol) of the compound of Example 59 in 2.4 ml dimethylformamide are added 1.2 ml (1.2 mmol) of a 1 M solution of tris(dimethylamino)sulfoniumdifluoro(trimethyl)silicate in tetrahydrofuran under argon at 0° C. After stirring the reaction mixture for 15 minutes at 0° C., stirring is continued at room temperature overnight. The reaction mixture is diluted with water and extracted four times with ethyl acetate. The combined organic phases are dried with sodium sulfate and concentrated in vacuo. The residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 1000 μl and 2000 μl methanol solution; number of injections: 2). The product containing fractions are combined and concentrated in vacuo.