Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[OH:34])[CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[C:20]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.N1CCCN2CCCCCC=12.[C:65]([O:68][CH2:69][CH2:70][CH2:71][S:72]([NH2:75])(=[O:74])=[O:73])(=[O:67])[CH3:66]>CN(C)C=O>[C:65]([O:68][CH2:69][CH2:70][CH2:71][S:72]([NH:75][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:32][C@@H:33]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[OH:34])=[CH:17][CH:16]=2)=[CH:19][C:20]=1[O:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[O:26])(=[O:73])=[O:74])(=[O:67])[CH3:66]
Reactant: CC(=O)OCCCS(N)(=O)=O
Reactant: CC(C)COc1cc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(NCCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1OCC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.4 %

Procedure:
To a solution of 4′-[[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3-isobutoxy-4-biphenylcarboxylic acid (60.0 mg) in N,N-dimethylformamide (0.450 ml) was added 1,1′-carbonylbis-1H-imidazole (18.3 mg) and the mixture was stirred at room temperature for 1.5 hours under nitrogen atmosphere. To the mixture were added 2,3,4,6,7,8,9,10-octahydropyrimido-[1,2-a]azepine (0.0185 ml) and a solution of 3-(aminosulfonyl)propyl acetate (22.4 mg) in N,N-dimethylformamide (0.300 ml) and the mixture was stirred at room temperature for 2 days. The reaction mixture was warmed to 120° C. and stirred at the same temperature for 2 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation gave the crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3 to 1/1) to give 3-[[[[4′-[[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3-isobutoxy-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (34.1 mg) as a yellow paste.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:20]2[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:25])[CH2:7]1
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1c(Cl)cccc1Cl)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 11.9 %

Procedure:
Example 20 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (2,6-dichlorophenyl)acetic acid (0.041 g) to give the title compound (0.011 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]4)=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:19]4[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a cooled suspension (0° C.) of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)piperidin-4-ol (described in example 1k) (6.95 g, 19.6 mmol) in diethyl ether (200 mL) under nitrogen was added lithium aluminum hydride (1.49 g, 39.2 mmol, 8 eq of hydride) in portions. The suspension was stirred at 0° C. for 30 min and warmed to room temperature. After 18 h at room temperature, the excess reagent was carefully quenched with the following in sequence: water (1.5 mL), 2.5N NaOH (1.5 mL) and additional water (4.5 mL). The suspension was stirred vigorously until the aluminum salts became a granular white solid. The suspension was diluted with ethyl acetate (100 mL), dried with a small amount of anhydrous magnesium sulfate and filtered. The filter cake was rinsed thoroughly with ethyl acetate. The solvent was removed to yield 6.16 g (92%) of the title compound as a white solid. No additional purification was required. TLC analysis (Rf 0.15, 50% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 7.20 (m, 4H), 6.95 (m, 3H), 4.60 (s, 1H), 4.24 (s, 1H), 3.70 (m 1H), 3.34 (s, 2H), 2.88 (m, 2H), 2.58 (s, 2H), 2.37 (m, 2H), 1.85 (m, 2H), 1.57 (m, 2H) MS (CI, CH4) m/z 340 (M+1,98), 342 (33), 322 (100), 368 (M+29, 22), 114 (26).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:40]2[CH2:39][CH2:38][N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH3:29])[CH2:42][CH2:41]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccccc3F)noc2C)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (532 mg, 1.35 mmol, 73%) was obtained.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH2:17][C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)=[O:11])[CH:7]=[CH2:8].O>CN(C=O)C>[C:1]([S:3][C@H:14]1[CH2:15][C@@H:16]([CH2:17][C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[N:12]([C:10]([O:9][CH2:6][CH:7]=[CH2:8])=[O:11])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cc1csc2cncn12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cc1csc2cncn12
Temperature: 70 °C
Reaction time: 8.5 h
Yield: 92.4 %

Procedure:
Potassium thioacetate (365 mg) is added to a solution of 427.7 mg of (3R,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methyl-3-methanesulfonyloxypyrrolidine in 4.5 ml of DMF, and the mixture is stirred under an argon stream at 70° C. for 8.5 hr. The reaction solution is cooled, water is added thereto, and the mixture is extracted four times with ethyl acetate. The organic layer is washed once with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 374.7 mg of the title compound as a brown viscous material.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[C:11]([N+:24]([O-:26])=[O:25])[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[C:11]([N+:24]([O-:26])=[O:25])[C:5]2[N:6]([CH3:29])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c([N+](=O)[O-])c2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
2-[7-Fluoro-5-nitro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.3 g) was dissolved in anhydrous dimethylformamide (15 ml) and was slowly added to a stirred suspension of sodium hydride (0.11 g) in dimethylformamide (15 ml) under ice cooling. Solution was stirred for 0.5 hr followed by the addition of methyl iodide (2.03 g). After stirring for 2 hr at ambient temperature, solution was added to ice-water and product was isolated by partitioning with ethyl acetate. Purification by column chromatography on silica gel in hexane-ethyl acetate (3:1) afforded the title compound (0.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:14]2[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:12][CH2:13]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3Cl)CC2)CC1

Procedure:
The title compound was prepared as described on example 1 from (2,4-Dichloro-phenyl)-piperidin-4-yl-methanone and Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butylester (m/e): 483.4 (M+H+)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[N:2]1.Cl[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15]>C1(C)C=CC=CC=1>[N:17]([S:14]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]1[CH:4]=[CH:5][O:1][N:2]=1)(=[O:16])=[O:15])=[C:18]=[O:19]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1-c1ccon1
Solvent: Cc1ccccc1
Product: O=C=NS(=O)(=O)Oc1ccccc1-c1ccon1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution containing 30 g of 2-(isoxazol-3-yl)phenol [prepared by the procedure of R. Beugelmans and C. Morin, J. Org. Chem., 42, 1356 (1977)] in 200 ml of dry toluene was added slowly 26.3 g of chlorosulfonyl isocyanate while maintaining the temperature at 20° to 30° C. with external cooling. The resulting suspension containing a white solid was stirred at 25° C. for 1 hour, then heated at 100° to 110° C. for 1 hour. The resulting slightly cloudy solution was cooled to 25° C., filtered, and the filtrate was concentrated in vacuo to yield 45 g of the title compound as a crude oil. The IR spectrum showed an isocyanate absorption at 2220 cm-1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[C:12]([NH2:20])=[N:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21]C(N1CCCCC1)CCBr>>[N:1]1([CH:7]([CH3:21])[CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[C:12]([NH2:20])=[N:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nn(CCCN2CCCCC2)c2ccc(Cl)cc12
Reactant: CC(CCBr)N1CCCCC1
Product: CC(CCn1nc(N)c2cc(Cl)ccc21)N1CCCCC1

Procedure:
The same procedures for preparing 1-(3-piperidinopropyl)-3-amino-5-chloroindazole as described in Example 100 were repeated except that 1-(1-methyl-3-bromopropyl)piperidine was employed instead of the 3-bromopropylpiperidine. As a result, 1-(3-piperidinobutyl)-3-amino-5-chloroindazole was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([N:30]4[CH:34]=[CH:33][N:32]=[CH:31]4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Br)cc2)CC1)c1ccc(F)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(-n3ccnc3)cc2)CC1)c1ccc(F)cc1

Procedure:
Trans-4-(4-Bromo-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 115, 80 mg, 0.166 mmol), imidazole (14 mg, 0.199 mmol), polyethylene glycol (30 mg), Cs2CO3 (76 mg, 0.232 mmol), and Copper II oxide (2 mg, 0.01 mmol) were weighed into a microwave vial. The vial was flushed with N2, NMP was added and the reaction mixture was microwaved at 200° C. After 20 min. the reaction mixture was diluted with EtOAc (50 ml) and filtered through celite. The filtrate was concentrated in vacuo and the residue was passed through a 25+S biotage column with an isocratic gradient of 10% MeOH in EtOAc. Product fractions combined and concentrated. The crude product was repurified via reverse phase chromatography on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA) and the fractions containing the product were lyophilized to yield the title compound as a white solid (6.3 mg). MS MH+ 471.1
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)[CH3:3].[K+].O[C:8]1[CH:16]=[CH:15]C=[C:13]2[C:9]=1[CH2:10][CH2:11][C:12]2=O>CCOCC>[CH:10](=[C:9]1[C:8]2[CH:16]=[CH:15][CH:3]=[C:2]([OH:5])[C:1]=2[CH2:12][CH2:13]1)[CH3:11]
Reactant: O=C1CCc2c(O)cccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC=C1CCc2c(O)cccc21
Reaction time: 0.25 h
Yield: 17.1 %

Procedure:
To a suspension of CH3CH2PPh3I (677 mg, 1.62 mmol) in Et2O (10 mL) was added t-BuOK (181 mg, 1.62 mmol). The mixture was stirred for 15 minutes, to which was added dropwise 4-hydroxy-indan-1-one (200 mg, 1.35 mmol). The mixture was stirred at room temperature overnight and then diluted with diethylether. The mixture was filtered on a pad of celite, and the filtrate was concentrated. The crude residue was purified by column chromatography to give 1-ethylidene-indan-4-ol (37 mg, 17%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.Cl.[CH2:12]([NH:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH2:12]([N:19]1[C:6]([NH2:7])=[C:5]2[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=[CH:8]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c2ccc(Br)cc2nn1Cc1ccccc1
Temperature: 140 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To a dried flask charged with 4-bromo-2-fluorobenzonitrile (5.0 g, 22.5 mmol) in n-butanol (60 mL) was added a solution of benzylhydrazine hydrochloride (17.56 g, 90 mmol, 4.0 eq) and diisopropylethylamine (32.1 mL, 184.48 mmol, 8.2 eq). The reaction mixture was stirred at 140° C. under N2 for 3 days. The mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO® instrument (gradient 5 to 60% EtOH/DCM) and the product containing fractions were concentrated to give 3.4 g (50%) of the title compound as beige solid. 1H NMR (300 MHz, CD2Cl2) δ 7.63 (dd, 1H), 7.37 to 7.30 (m, 4H), 7.20 to 7.16 (m, 2H), 6.94 (dd, 1H), 5.44 (s, 2H), 4.02 (broad s, 2H); ES-MS m/z 302.3/304.3 [M+H]+, RT (min) 2.34.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@@H:17]([Cl:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@@H:17]([Cl:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@@H]1Cl
Temperature: 75 °C
Reaction time: 4 h
Yield: 36.4 %

Procedure:
A mixture of 391 mg of 2-benzyl-6-[(3S,4R)-3-chloro-4-methoxypyrrolidine-1-yl]-3-iodopyridine, 152 mg of (3R)-3-ethynyl-3-quinuclidinol, 105 mg of tetrakis(triphenylphosphine)palladium(0), 9 mg of cuprous iodide, 0.38 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring for 4 hours at 75° C. in a nitrogen atmosphere, followed by removing the solvent. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1) and then crystallized from hexane/ethyl acetate, to give 150 mg of the target compound.
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[CH:8][C:7]2=[O:17])[CH2:4][CH2:3][CH2:2]1.S(OC)(O[C:22](SC)([S:25][CH3:26])[S:23][CH3:24])(=O)=O.N1C=CC=CC=1>O1CCOCC1>[CH3:24][S:23][C:22]([S:25][CH3:26])=[C:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([NH:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:7]1=[O:17]
Reactant: O=c1cc(O)c2ccccc2n1NC1CCC1
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CSC(SC)=C1C(=O)c2ccccc2N(NC2CCC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of 1-(cyclobutylamino)-4-hydroxyquinolin-2(1H)-one (0.115 g, 0.5 mmol) and tris(methylthio)methyl methyl sulfate (prepared using the procedures in SYNTHESIS, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi) (0.27 g, 1.0 mmol) in pyridine (0.316 g, 4.0 mmol) and dioxane (5.0 mL) was heated at 60° C. for 30 minutes. Additional tris(methylthio)methyl methyl sulfate was added (0.27 g, 1.0 mmol) and heating continued for 30 minutes. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude material was chromatographed on silica gel eluting with 95/5 dichloromethane/ethyl acetate to give 3-[bis(methylthio)methylene]-1-(cyclobutylamino)quinoline-2,4(1H,3H)-dione (0.146 g, 87% yield). MS (ESI−) m/z 335 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 1.54 (m, 1 H) 1.66 (m, 1 H) 1.99 (m, 4 H) 2.61 (s, 6 H) 3.62 (m, 1 H) 6.18 (d, J=6.25 Hz, 1 H) 7.15 (t, J=7.54 Hz, 1 H) 7.63 (m, 1 H) 7.72 (d, J=8.09 Hz, 1 H) 7.98 (dd, J=7.91, 1.29 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)=[O:29])[C:7]([N:44]1[CH2:45][CH2:46][CH:41]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)[CH2:42][CH2:43]1)=[O:8]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1C

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methyl-4-piperidin-4-yl-piperazine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:19]=3[CH:37]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:38]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)([CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)[C:19]=3[CH:37]=2)=[O:38])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: O=C1Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc2C(C2CCCCC2)(C2CCCCC2)O1
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc2C(C2CCCCC2)(C2CCCCC2)O1

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:24][OH:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(=O)c1ccc(O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(=NO)c1ccc(O)cc1

Procedure:
To a mixture of 0.176 g. of p-nitrobenzyl p-hydroxyphenylglyoxylate and 1 g. of hydroxylamine hydrochloride were added 9 ml. of N,O-bis-trimethylsilyltrifluoroacetamide and the solution was stirred at a temperature of 140° C. for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue was taken up in ethyl acetate. The ethyl acetate solution was washed with water and was then dried and evaporated. The oxime product was purified and isolated over silica gel preparative plates using toluene:ethyl acetate, 7:3, for elution. The product was located on the plate by means of UV light and the silica gel was scraped from the plate and the product extracted therefrom with ethyl acetate. The ethyl acetate was evaporated to yield 186 mg. of product. The product was crystallized from methylene chloride to yield 103 mg. of the crystalline material. The filtrate from the crystallization was diluted with petroleum ether to yield a second crop of 20 mg.
Reaction SMILES: [BrH:1].O[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH3:4]>CC(O)=O>[Br:1][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH3:4]
Reactant: Br
Reactant: Cc1ccc(C(C)O)cc1
Solvent: CC(=O)O
Product: Cc1ccc(C(C)Br)cc1

Procedure:
This compound is prepared by the procedure described in Preparation 3.4 from 30 ml of a 33% solution of HBr in AcOH and 7 ml of 1-(1-hydroxyethyl)-4-methylbenzene. 9 g of the expected product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](O)=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(=O)O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103 %

Procedure:
4-(2-Carboxyphenyl)piperidine-1-carboxylic acid t-butyl ester (5.0 g, 16 mmol, 1.0 eq.) and THF (130 mL, 1.7 mol) were combined at room temperature under nitrogen. Borane dimethyl sulfide complex (2.9 mL, 33 mmol, 2.0 eq.) was added dropwise and the mixture was stirred for 5 minutes, then heated at reflux for 1 hour. The mixture was cooled to room temperature, and the reaction was quenched dropwise with MeOH (40 mL), then concentrated by rotary evaporation. The material was azeotroped with MeOH (2×40 mL). The mixture was then diluted with EtOAc (100 mL), and washed with 1 M HCl (2×50 mL), then NaHCO3 (2×50 mL), then saturated aqueous NaCl (1×50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield 4-(2-hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (4.8 g) as a clear, light yellow oil that solidified upon sitting.