Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[S+](C)(C)=O.[H-].[Na+].[CH2:9]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25](OCC)(=O)C>CS(C)=O>[CH2:9]([N:16]1[CH:17]2[CH2:23][CH2:22][CH:21]1[CH2:20][C:19]1([CH2:18]2)[CH2:25][O:24]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: CCOC(C)=O
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: c1ccc(CN2C3CCC2CC2(CO2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trimethyl sulfoxonium iodide (3.07 g, 13.9 mmol) is placed in 18 ml of DMSO under nitrogen in the presence of sodium hydride dispersed at 60% in oil (0.56 g, 13.9 mmol). After stirring for 30 min at ambient temperature, 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (2.0 g, 9.3 mmol) solubilized in 3 ml of DMSO is slowly added. The reaction medium is kept stirring for 4 h and then kept without stirring for 60 h, After hydrolysis, and extraction with ethyl acetate, the organic phase is washed with a saturated aqueous sodium chloride solution and dried over MgSO4. 2.04 g of 8-benzyl-spiro[8-azabicyclo[3.2.1]octane-3,2′-oxirane], subsequently used as it is, are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11].[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cccc(-c2ccccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 161.4 %

Procedure:
To a solution of methyl 3-(pyridin-2-yl)benzoate (300 mg, 1.40 mmol) in MeOH (3 mL) was added aqueous NaOH (1 mL, 0.4M). The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated and the residue dissolved in water and adjust pH to 5˜6 with 2N of HCl. The solution was extracted with EtOAc (3×20 mL) and the combined organic layers concentrated to give the desired crude product (450 mg, Yield 90%) which was used in the next step without further purification. LCMS (m/z): 200.1 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])=[CH:15][N:16]=1>O.CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([OH:24])=[C:17]([C:14]2[S:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])=[N:16][CH:15]=2)[CH:22]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2cc(Cl)ccc2O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCc1ncc(-c2cc(Cl)ccc2O)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
Add a solution of sodium hydroxide (2.60 g, 65 mmol) in water (50 mL) to a solution of 7-[5-(5-chloro-2-hydroxyphenyl)thiazol-2-yl]heptanoic acid methyl ester (5.76 g, 16 mmol) in methanol (100 mL) at 0° C. under nitrogen, warm the mixture to room temperature, and stir for a total of 1.5 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL), cool to 0° C., and acidify to pH 1 with 1 N HCl. Collect the precipitate by filtration to afford 7-[5-(5-chloro-2-hydroxyphenyl)thiazol-2-yl]heptanoic acid (5.21 g, 95%): APCI mass spectrum m/z 338 [C16H18ClNO3S−H]—.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17]2[C:22]([CH2:23][OH:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:26]I>CS(C)=O.O>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17]2[C:22]([CH2:23][O:24][CH3:26])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(c1ncccc1CO)C1CCN(Cc2ccccc2)CC1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a mixture of powdered potassium hydroxide (356 mg) in dry dimethylsulfoxide (2 ml) under nitrogen is added a solution of 1-benzyl-4-(N-methyl-N-(3-hydroxymethyl-2-pyridyl)amino)piperidine (XXX, EXAMPLE 35, 494 mg) in dry dimethylsulfoxide (1.2 ml) followed by methyl iodide (118 μl). The resulting mixture is stirred at 20°-25° for 30 min and is then diluted with water (15 ml) and extracted with methylene chloride (2×20 ml). The combined organic phases are washed with water (2×10 ml) and saline (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give a concentrate which is then chromatographed (silica gel, a gradient of ethyl acetate/hexane (20/80→40/60)) to give the title compound, NMR (CDCl3, 400 MHz) 8.22, 7.67, 7.31, 7.25, 6.89, 4.40, 3.50, 3.41, 3.28, 2.94, 2.77, 2.01, 1.86 and 1.70δ.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[NH2:18].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:23][O:22][C:20]1[CH:19]=[C:17]([NH:18][CH2:9][C:8]2[C:3]([NH:2][CH3:1])=[N:4][C:5]([S:11][CH3:12])=[N:6][CH:7]=2)[CH:16]=[C:15]([O:14][CH3:13])[CH:21]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CNc1nc(SC)ncc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1nc(SC)ncc1CNc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (1.0 g, 5.46 mmol) and 3,5-dimethoxyaniline (840 mg, 5.46 mmol) in methanol (60 mL) was stirred at RT for 3 h, followed by the addition of sodium cyanoborohydride (520 mg, 8.20 mmol) and 1 mL of acetic acid. The reaction mixture was then stirred at RT for another 4 h. LCMS showed the reaction was completed. The reaction was quenched by 30 mL of 1N HCl, then stirred for 0.5 h and extracted with ethyl acetate (3×50 mL). The organic layers were separated, combined, washed with saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (crude 1.2 g, 69%) as a white solid, which was directly used in the next step without further purification. MS (ES+) C15H20N4O2S requires: 320. Found: 321 [M+H]+.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][O+](C)C.[CH2:10]([N:12]([CH2:28][CH3:29])[CH2:13][CH2:14][CH2:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[NH:18])=[O:17])[CH3:11].O.[OH-].[Na+]>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:28]([N+:12]([CH2:10][CH3:11])([CH3:6])[CH2:13][CH2:14][CH2:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)(=[NH:18])=[O:17])[CH3:29]
Reactant: C[O+](C)C
Reactant: CCN(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC[N+](C)(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Trimethyloxonium fluoroborate (3.81 g, 25.6 mmol) was added to a solution of N,N-diethyl-3-[S-(4-nitrophenyl)sulfonimidoyl]-1-propanamine (7.7 g, 25.6 mmol) in methylene chloride (50 mL) maintained at -20° C. After 15 min the reaction mixture was warmed to 0° C. for 30 min and then to ambient temperature for 1 h. Water (100 mL) was added to the reaction mixture, and the reaction mixture was made basic with 10% sodium hydroxide. The biphasic mixture containing insoluble material was filtered. The solid that was collected by filtration was recrystallized from a methanol/ethanol mixture. The white solid that formed was collected by filtration to give 0.51 g(4.9%), mp 125°-126.5° C.
Reaction SMILES: C(S[C:4](=[O:25])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[O:14])[CH2:8][CH2:7]1)C.C.C([SiH](CC)CC)C.CCCCCCC.C([O-])(=O)C>CC(C)=O.C(Cl)Cl.[Pd]>[O:25]=[CH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[O:14])[CH2:8][CH2:7]1
Reactant: CCSC(=O)C[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=CC[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
Trans-{4-[(Quinoline-4-carbonyl)-amino]-cyclohexyl}-thioacetic acid S— ethyl ester (1.87 g, 5 mmol) was solved in acetone/methylene chloride (40/40 mL), 0.8 g of molecular sieves were added to the mixture and the solution was stirred for 0.5 h. Then 0.558 g (1 mmol) of palladium on active charcoal 10% was added followed by 1.25 mL (8 mmol) of triethyl-silane. The reaction was stirred for 1.5 hours at room temperature and additional 0.558 g (1 mmol) of palladium on active charcoal 10% and 1.25 mL (8 mmol) of triethyl-silane were added and the stirring was continued for another hour. The mixture was filtrated through celite and the mother liquid was concentrated to obtain after chromatography using heptane/acetate 1:1 1.1 (37.1 mmol, 70.8% yield) of the final compound. MS (m/e): 297.3 (M+H+)
Reaction SMILES: [C:1]1([CH3:30])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:29])[N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:31](=O)[CH3:32].C=O>>[CH3:31][CH:32]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:20](=[O:29])[N:21]([CH3:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=2)[CH2:12][CH2:11][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:30])=[CH:6][CH:5]=1)(=[O:8])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NCCc2ccc(OC(=O)N(C)c3ccccc3)cc2)cc1
Reactant: CC=O
Agent: C=O
Product: Cc1ccc(S(=O)(=O)N2CCc3ccc(OC(=O)N(C)c4ccccc4)cc3C2C)cc1

Procedure:
The title compound was prepared using methyl-phenyl-carbamic acid 4-[2-(toluene-4-sulfonylamino)-ethyl]-phenyl ester as the sulfonamide and acetaldehyde in stead of formaldehyde. The crude product was purified by preparative HPLC (Gilson) (22%, brown oil).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:16]([NH:26][CH2:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([O-:33])=[O:32])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[Cs+]>>[C:16]([NH:26][CH2:27][C:28](=[O:34])[CH2:29][CH2:30][C:31]([O:33][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:32])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C([O-])CCC(=O)CNC(=O)OCc1ccccc1
Reactant: O=C(CCCCBr)OCc1ccccc1
Agent: [Cs+]
Product: O=C(CCC(=O)OCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1

Procedure:
This compound was prepared from the products of 8a (0.73 g; 2.7 mmol) and 8b (1.0 g; 2.5 mmol) according to Procedure C. The crude product was purified on a 75×45 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL) collecting 13×50 mL fractions. Fractions containing the product (5-8) were collected, and after evaporation 0.82 g (72%) product was obtained (yellowish solid, mp 53-56° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1.[CH:15]1([C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=3)[S:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26](/[CH:25]=[CH:24]/[C:21]3[S:22][CH:23]=[C:19]([CH:15]4[CH2:18][CH2:17][CH2:16]4)[N:20]=3)[CH:27]=2)=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)cc1
Reaction time: 16 h
Yield: 95.7 %

Procedure:
A solution composed of 1.0 g of 4-carboxymethyl benzoic acid methyl ester, 1.3 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 1.0 g of N-ethyl-N-(dimethylaminopropyl) carbodiimide, 2.4 g of 4-dimethylaminopyridine and 75 ml of methylene chloride was stored at 0° C. After 16 hr. the reaction mixture was washed with 75 ml of water, dried (MgSO4) and the solvents removed by rotary evaporation. The residual materials were recrystallized with ethyl acetate to yield 2.1 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester; m.p. 163°-164° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[C:23](B(O)O)=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]=1[CH3:12]
Reactant: COc1ncccc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ncccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) in toluene (8.06 mL) was added 2-methoxypyridin-3-ylboronic acid (0.925 g, 6.05 mmol), potassium carbonate (1.67 g, 12.1 mmol) and palladium tetrakistriphenylphosphine (0.466 g, 0.403 mmol). The reaction was stirred at 100° C. and stirring continued for 18 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with (0-50% EtOAc in hexanes) to provide 4-chloro-5,7-difluoro-2-(2-methoxy-3-pyridinyl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=321.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19][CH:20]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:19][CH:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reactant: COC(=O)C(N)Cc1cccc(O)c1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cccc(O)c1)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and methyl 2-amino-3-(3-hydroxyphenyl)propionate (prepared from 2-amino-3-(3-hydroxyphenyl)propionate (Biosynth AG, Switzerland) and methanol using General Procedure H), the title compound was prepared as a solid (mp=155-159° C.). The reaction was monitored by tlc (Rf=0.4 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:51]12[CH2:58][CH2:57][CH:54]([CH2:55][CH2:56]1)[C@@H:53](O)[CH2:52]2>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7](=[O:9])[O:8][C@@H:53]2[CH:54]3[CH2:57][CH2:58][N:51]([CH2:56][CH2:55]3)[CH2:52]2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2
Reactant: CCOC(=O)c1cccc(NC(C(=O)O)c2csc3ccccc23)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2csc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
2-(Benzo[b]thiophen-3-yl)-2-(3-(ethoxycarbonyl)phenylamino)acetic acid (I49) (998 mg, 2.81 mmol), HOBT (430 mg, 2.81 mmol), and DCC (1159 mg, 5.62 mmol) were dissolved in THF (28 ml). The mixture was stirred at r.t. for 30 minutes, and then (R)-quinuclidin-3-ol (714 mg, 5.62 mmol) was added. The resulting reaction mixture was stirred at r.t. overnight. The solvent was evaporated, and the crude product was partitioned between EtOAc and sat. Na2CO3. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH=95/5) to collect ethyl 3-(1-(benzo[b]thiophen-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (222 mg, 17.0% yield over two steps).
Reaction SMILES: B.[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([NH2:10])=O)([O-:4])=[O:3].CO>C1COCC1>[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:15])([F:16])[F:17])[CH2:8][NH2:10])([O-:4])=[O:3]
Reactant: NC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reaction time: 72 h

Procedure:
A 1 M solution of Borane in THF (51 ml, 51 mmol) was added at 0° C. to 3-nitro-4-trifluoromethyl-benzoic acid amide (3.00 g, 12.8 mmol) in 50 ml THF and it was stirred for 3 days. Methanol was carefully added and it was stirred for 30 min at r.t and 2 h at reflux. Then it was concentrated i.vac.; NaOH was added (pH 8) and the mixture was extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated to furnish the crude subtitle compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(OCC)(=O)C>C(Cl)Cl.O>[Si:23]([O:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCNC(=O)OCc1ccccc1
Yield: 80.7 %

Procedure:
3-Benzyloxycarbonylamino-1-propanol (8.1 g) was dissolved in methylene chloride (200 ml), and to the resulting solution were added triethylamine (4.1 g) and t-butyldimethylsilyl chloride (7.1 g). The resultant mixture was stirred at room temperature for 1 day. Ethyl acetate and water were added to the reaction solution obtained. The organic layer so separated was dried over magnesium sulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus affording the titled compound (10.1 g; 82%).
Reaction SMILES: O.[OH-].[Na+].C([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Br:22])=[CH:17][N:16]=2)[C:13]=1[CH3:14])=[O:8])C.Cl>C(O)C>[Br:22][C:18]1[CH:19]=[C:20]([Cl:21])[C:15]([N:12]2[C:13]([CH3:14])=[C:9]([C:7]([OH:8])=[O:6])[CH:10]=[N:11]2)=[N:16][CH:17]=1
Reactant: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ncc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 78707.6 %

Procedure:
Water (7 ml) and 4N aqueous solution of sodium hydroxide (7 ml) were added at room temperature to a solution of 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.00 mg) in ethanol (14 ml) and stirred at 80° C. for five hours. After completion of the reaction, the reaction solution was cooled to 0° C. and 1N hydrochloric acid aqueous solution (29 ml) was added. The precipitated solid was collected by filtration to give the titled compound (723 mg) as a light brown solid.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:8][CH2:7][CH2:6]1)=O.C(O)(=O)C.[CH:13]([NH2:15])=[NH:14]>C(O)CO.O>[CH:5]1([C:3]2[N:14]=[CH:13][NH:15][CH:2]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: N=CN
Reactant: O=C(CBr)C1CCC1
Solvent: O
Solvent: CC(=O)O
Solvent: OCCO
Product: c1nc(C2CCC2)c[nH]1
Temperature: 135 °C
Yield: 18.6 %

Procedure:
A mixture of 2-bromo-1-cyclobutylethanone (27.2 g, 154 mmol) and formamidine acetate (80.0 g, 768 mmol) in ethyleneglycol (150 mL) was heated to 135° C. for 18 h. The mixture was then diluted with H2O and then continuously extracted with Et2O for 18 h. The org. phase was then dried over Na2SO4, filtered and concentrated in vacuo. Purification by distillation in a Kugelrohr oven and flash chromatography (SiO2, DCM to DCM/MeOH 9:1) afforded the title compound (3.5 g). UPLC-MS: MS 123.1 (M+H+); UPLC rt 0.36 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([OH:12])[CH2:9][CH2:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCCC(O)c1cccc(Br)c1
Solvent: Cc1ccccc1
Product: CCCC(O)(Cl)c1cccc(Br)c1

Procedure:
4.0 g (17.5 mmol) of 1-(3-bromophenyl)-butanol is stirred with 4 ml of thionyl chloride for 1 hour at room temperature. 10 ml of toluene is added to the reaction mixture. 1-Chloro-1-(3-bromophenyl)-butanol is obtained after concentration by evaporation in a vacuum. 1.3 g of imidazole is dissolved in 20 ml of dimethylformamide and mixed with 0.6 g of sodium hydride (80% in oil) under argon protective gas atmosphere. It is stirred for 1 hour at room temperature. The chlorine compound is instilled into 15 ml of dimethylformamide and allowed to stand overnight. The mixture is precipitated in 200 ml of water and extracted with ethyl acetate. The organic phase is concentrated by evaporation in a vacuum and then distilled on a bulb tube at 150° C./0.03 mbar. 1.6 g of 1-[1-(3-bromophenyl)-butyl]-imidazole is obtained as a viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:15].[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:15])[CH2:4][CH2:5]2
Reactant: CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1C(=O)CCc2cc(N)ccc21
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a stirred suspension of 1-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 2, 1.04 g, 5.05 mmol) in EtOH (10 mL) and water (5 mL) is added ammonium chloride (2.70 g, 10.0 equiv.). To this mixture is added iron powder (0.85 g, 3.0 equiv.) in 3 portions. The resulting mixture is heated at reflux for 2 h and then is cooled to room temperature. The resulting mixture is filtered through celite and the filtrate is further diluted with water (100 mL). The filtrate is extracted with ethyl acetate (2×50 mL) and washed with saline (100 mL). The organic layers are combined, dried over MgSO4 and concentrated under reduced pressure to yield the title compound as a yellow solid (0.86 g, 97%), MS (m/z): 177.5 [M+H]+.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH2:39][C:40]#[N:41])[CH:37]=2)O1>>[CH3:24][N:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:33]5[CH:34]=[N:35][N:36]([CH2:38][CH2:39][C:40]#[N:41])[CH:37]=5)[N:10]4[N:9]=3)=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: CN1CCC(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Product: CN1CCC(c2ccc(Nc3ncc4ccc(-c5cnn(CCC#N)c5)n4n3)cc2)CC1

Procedure:
(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(1-methyl-piperidin-4-yl)-phenyl]-amine (1.00E2 mg, 0.259 mmol), and 3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-propionitrile (128 mg, 0.518 mmol) were reacted in an analogous manner to Example 881A at 80° C. for 8 h. The reaction mixture was purified via ISCO silica gel chromatography using an amine capped column 50-100% EtOAc in hexanes (32 mg, 29%). LCMS=427.0 (M+H), HPLC rt=1.889 min, 96% purity. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.32 (s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 7.65 (d, J=7.6 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.08 (d, J=4.3 Hz, 1H), 6.91 (d, J=4.7 Hz, 1H), 4.47 (t, J=6.4 Hz, 2H), 3.16 (t, J=6.5 Hz, 2H), 2.87 (d, J=10.8 Hz, 2H), 2.46-2.40 (m, 1H), 2.19 (s, 3H), 1.96 (t, J=10.8 Hz, 2H), 1.76-1.62 (m, 4H).