Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:22]([O:24]C)=[O:23])=[O:17])[CH2:6]1.CO>C1COCC1>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=2[CH3:29])[C:22]([OH:24])=[O:23])=[O:17])[CH2:6]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCCC(CO)C2)cc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A solution of aqueous 4N NaOH (4.00 ml) is added to a stirred solution of methyl 3-[[5-[3-(hydroxymethyl)-1-piperidyl]-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (0.4 g, 0.975 mmol) in THF:MeOH (10 ml:5 ml). After 4 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl, and extracted twice with 10% IPA in CH2Cl2. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a light brown solid (0.28 g, 72.5%). Mass spectrum (m/z): 397.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(N3CCOCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 47.2 %

Procedure:
A mixture of 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide (0.1 mmol) and morpholine (0.087 ml, 1.0 mmol) in DMSO (0.5 ml) is heated at 80° C. for 6 h. The resulting mixture is diluted with CH2Cl2 (2 ml), washed with 0.01 N NaOH, and dried over sodium sulfate. After evaporation to dryness, the residue is purified by column chromatography on silica gel (50% EtOAc in hexane) to give 3-fluoro-5-morpholin-4-yl-N-{4-[(2-morpholin-4-ylpyrimidin-4-yl)oxy]-1-naphthyl}benzamide as a white solid (25 mg). Mp: 104-106° C.; 1H NMR (300 MHz, CDCl3) δ 3.26 (bs, 4H), 3.64 (bs, 8H), 3.87 (bs, 4H), 6.07 (d, J=4.5 Hz, 1H), 6.77 (d, J=11.7 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 7.32 (bs, 2H), 7.52-7.59 (m, 2H), 7.89-8.00 (m, 3H), 8.12-8.19(m, 2H); MS: 530 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[C:6]([CH:12]([OH:14])[CH3:13])[O:7]2.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:14][C@@H:12]([C:6]1[O:7][C:8]2[C:3]([C:4](=[O:22])[C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[CH3:13])(=[O:33])=[O:32]
Reactant: CC(O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OS(C)(=O)=O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of (+)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one (0.800 g, 2.63 mmol) in dichloromethane (16 ml) and triethylamine (1.10 ml, 7.91 mmol), methanesulphonyl chloride (0.400 ml, 5.27 mmol) is added stirred at room temperature for 2 h. The reaction mass is quenched with water, extracted with dichloromethane, dried over sodium sulphate and concentrated to afford the title compound as brown solid which is used as such in next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:27].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:27][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[C:39]([F:41])([F:40])[F:42]
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1OCc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of [4-(6-amino-5-hydroxy-pyridin-3-yl)-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone (100 mg, 0.27 mmol) in anhydrous DMF (15 mL) under a N2 atmosphere containing, at 0° C., sodium hydride (60% dispersion in mineral oil, 11 mg, 0.49 mmol) was added. The mixture was allowed to stir at 0° C. for 30 min. 1-(Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (0.046 mL, 0.27 mmol) was added. The mixture was stirred at room temperature for 2 hr. The reaction was diluted with EtOAc, and partitioned with H2O. The aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were combined, washed with H2O (1×15 mL), brine (1×15 mL), dried over MgSO4, filtered, concentrated, and purified on a silica gel column to yield {4-[6-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone as off-white crystals.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](Cl)=[O:18])=[CH:11][CH:10]=1>C(OCC)C>[CH3:5][O:4][P:1]([C:17](=[O:18])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:2])[O:6][CH3:7]
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Reactant: COP(OC)OC
Solvent: CCOCC
Product: COP(=O)(OC)C(=O)CCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 74.8 %

Procedure:
At 0° C., a solution of 3.6 g of trimethyl phosphite in 10 ml of diethyl ether is added dropwise to a solution of 5.1 g of 3-(4-chlorophenyl)propionic acid chloride in 25 ml of diethyl ether. The mixture is first stirred for 2.5 hours at 0° C., then another 2 hours at room temperature. After concentration of the solution, the residue is distilled with the use of a bulb tube at 200°-205° C. and a pressure of 0.02 mm, yielding 5.2 g (74%) of 3-(4-chlorophenyl)-1-oxopropane-1-phosphonic acid dimethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.[OH:25][CH2:26][C:27](O)=[O:28].Cl>C(Cl)Cl.C(N(CC)CC)C>[OH:28][CH2:27][C:26]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[O:25]
Reactant: O=C(O)CO
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)CO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a solution of 3.0 g of tert-butyl piperidin-4-ylcarbamate in 60 ml of methylene chloride, were added 2.5 ml of triethylamine, 2.4 g of HOBt, 1.3 g of hydroxyacetic acid and 3.5 g of WSCD hydrochloride, and the reaction mixture was stirred at room temperature for 18 hours. 1 M hydrochloric acid was added to the reaction mixture, and this was extracted with EtOAc. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, water and brine. This was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified with silica gel column chromatography (eluent: chloroform/MeOH=50/1) to obtain 2.8 g of tert-butyl [1-(hydroxyacetyl)piperidin-4-yl]carbamate.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21]1([CH3:28])[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][CH2:28][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: Cc1cccc(C)c1
Product: Cc1cccc(CON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)c1
Yield: 29.5 %

Procedure:
A mixture of 13.77 g (0.05 mol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of m-xylene under a nitrogen atmosphere is heated at reflux for 50 hours. The reaction mixture is filtered to remove the hydroxylamine, and the filtrate is washed with 10 w/v % ascorbic acid (1×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from isopropyl alcohol to give 5.62 g (59% yield) of a white solid melting at 64-65° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.I[CH2:13][CH2:14][CH2:15][N:16]([CH2:29][CH2:30][N:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18].[CH2:42]([N:44]1[C:50](=[O:51])[C:49]([CH3:53])([CH3:52])[C:48](=[O:54])[N:47]([CH3:55])[C:46]2[CH:56]=[C:57]([OH:60])[CH:58]=[CH:59][C:45]1=2)[CH3:43]>C(OCC)(=O)C>[CH2:42]([N:44]1[C:50](=[O:51])[C:49]([CH3:53])([CH3:52])[C:48](=[O:54])[N:47]([CH3:55])[C:46]2[CH:56]=[C:57]([O:60][CH2:13][CH2:14][CH2:15][N:16]([CH2:29][CH2:30][N:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:41])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18])[CH:58]=[CH:59][C:45]1=2)[CH3:43]
Reactant: O=c1c2ccccc2ccn1CCN(CCCI)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCn3ccc4ccccc4c3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Potassium carbonate (0.22 g, 1.6 mmol) was added to a DMF solution (10 ml) of N-(3-iodopropyl)-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide (0.57 g, 1.05 mmol) and 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.33 g, 1.26 mmol), and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with 1N-sodium hydroxide aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→0:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 0.49 g (yield: 69%) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide as a white amorphous solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18]O)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(Cl)(Cl)(Cl)[Cl:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][Cl:21])[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: OCCCN1CCN(c2cccc3sccc23)CC1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: ClCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C

Procedure:
3.56 g (12.9 mmol) of 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol was suspended in 30 ml of dichloromethane, and carbon tetrachloride (30 ml) and triphenyl phosphine (4.06 g, 15.5 mmol) were added thereto. The mixture was refluxed with heating for 3 hours. The reaction solution was cooled to room temperature, then methanol and dichloromethane were added thereto to homogenize the mixture. Silica gel (30 g) was added to the solution, and the solvent was evaporated under reduced pressure. The obtained residue was loaded on silica gel column (300 g) and extracted with a solvent mixture of n-hexane:ethyl acetate=2:1. The extraction solution was concentrated under reduced pressure to obtain 1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine (2.36 g) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:8][C:7]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=1)=[O:9]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(C)cs1
Product: Cc1csc(C(=O)C=CN(C)C)c1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 1-(4-methyl-2-thienyl)ethanone (70.8 mmol) and N,N-dimethylformamide dimethyl acetal (105.1 mmol) was refluxed overnight and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 13.8 g (100% yield) of 3-(dimethylamino)-1-(4-methyl-2-thienyl)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[C:22]([CH2:25]Cl)[CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH3:27])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:9]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[C:22]([CH2:25][NH:1][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=4)[CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH3:27])=[CH:11][CH:10]=1
Reactant: Cc1nc2ccc(CCl)cc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNCc3ccccn3)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-Aminomethylpyridine (0.372 g) was added to a solution of 0.597 g of 1-(biphenyl-4-ylmethyl)-6-chloromethyl-2-methylbenzimidazole and 0.350 g of potassium carbonate in 3 ml of N,N-dimethylformamide, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was extracted with water and with ethyl acetate. The organic layer was washed twice with water, and the solvent was distilled off under reduced pressure. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 9:1), and was recrystallized from a mixed solvent of ethyl acetate and hexane to give 0.300 g of 1-(biphenyl-4-ylmethyl)-2-methyl-6-[2-pyridylmethyl)aminomethyl]benzimidazole (265).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][CH:29]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)[C@@H](Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 78.4 %

Procedure:
The procedure described in Example 180 was repeated, except that (R)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (3.0 g) and ethyl 4-aminophenylacetate (1.40 g) were condensed in dichloromethane (30 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.93 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (3.34 g).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH2:11][C@H:7]2[O:8][CH2:9][CH2:10][C@@:6]2([C:12]([N:14]2[CH2:23][CH2:22][C:21]3[N:20]=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][C:16]=3[CH2:15]2)=[O:13])[CH2:5]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:46][O:47][C@H:48]1[C:53](=O)[CH2:52][CH2:51][O:50][CH2:49]1>ClCCCl.C(Cl)Cl.ClCCCl>[CH3:46][O:47][C@H:48]1[C@@H:53]([NH:3][C@@H:4]2[CH2:11][C@H:7]3[O:8][CH2:9][CH2:10][C@@:6]3([C:12]([N:14]3[CH2:23][CH2:22][C:21]4[N:20]=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][C:16]=4[CH2:15]3)=[O:13])[CH2:5]2)[CH2:52][CH2:51][O:50][CH2:49]1
Reactant: CO[C@@H]1COCCC1=O
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 16 °C
Reaction time: 0.12 h

Procedure:
To a mixture of the product of Step K (the free base) (619.7 g, 1.74 mol) in 1,2-dichloroethane/CH2Cl2 (˜10 L) was added acetic acid (glacial, 180 mL) and the mixture was cooled to 16° C. Solid Na(OAc)3BH (463 g, 2.18 mol) was added and the suspension was stirred for 5-10 min. A solution of (R)-3-methoxydihydro-2H-pyran-4(3H)-one (prepared as described in Intermediate 1, 213 g, 1.63 mol) in 1,2-dichloroethane (1.75 L) was added over 20 min and the resulting mixture was stirred at rt overnight. Additional acetic acid, (R)-3-methoxytetrahydro-4H-pyran-4-one (28 g) and Na(AcO)3BH were added until TLC showed the reaction was complete. The reaction was quenched with saturated aqueous NaHCO3, the organic layer was separated and the aqueous layer was back-extracted with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. Purification was affected by chromatography with MeOH (7N NH3) in CH2Cl2. The collected enriched isomer was further purified using chiral chromatography on chiralpak AD column using a mixture of heptanes/EtOH/isopropyl alcohol to provide the product of Step L.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.O1CCOCC1.Cl>C(OCC)(=O)C>[ClH:11].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:25]=[CH:24][C:22]([NH:23][CH:4]3[CH:5]4[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]4)[CH2:3]3)=[CH:21][CH:20]=2)=[CH:14][CH:13]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1ccc(Oc2ccc(NC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) was treated with 4-(4-chlorophenyloxy) aniline (Aldrich, 1.10 g, 5.0 mmol) according to the procedure of Example 30A. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.10) as a solid (1.52 g, yield, 93%). MS (DCl/NH3) m/z 329 (M+H)+, 331 (M+H)+. The free base (200 mg, 0.61 mmol) was treated with 4M HCl 1,4-dioxane (0.5 mL, 2.0 mmol) in ethyl acetate (5 mL). The hydrochloride salt of the title compound was obtained as a solid (195 mg, yield, 80%). 1H NMR (MeOH-d4, 300 MHz) δ 1.90–2.18 (m, 3H), 2.35–2.45 (m, 2H), 3.24 (ddd, J=12.5, 5.4, 2.3 Hz, 1H) 3.30–3.50 (m, 4H), 3.82 (ddd, J=12.2, 9.8, 2.7 Hz, 1H), 3.95–4.10 (m, 1H), 6.91 (dt, J=9.1, 2.3 Hz, 2H), 6.95–7.02 (m, 4H), 7.30(dt, J=9.2, 2.4 Hz, 1H), 7.26–7.32 (m, 2H) ppm. MS (DCl/NH3) m/z 329 (M+H)+, 331 (M+H)+. Anal Calculated for C19H21ClN2O.2.0HCl.0.5H2O: C, 55.56; H, 5.89; N, 6.82. Found: C, 55.78; H, 5.28; N, 6.62.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccncc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)sc2ccncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[3,2-c]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (186 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (186 mg, 93%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[C:9]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])[CH2:16]2)=[C:4]([F:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][CH:40]=[N:41]3)=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH2:23]([NH:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:15]([CH2:14][C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:43]=[C:42]5[C:37]([CH:38]=[CH:39][CH:40]=[N:41]5)=[CH:36][CH:35]=4)=[CH:3][C:4]=3[F:25])[C:12](=[O:13])[NH:11][N:10]=2)[CH2:16]1)=[O:21])[CH3:24]
Reactant: CCNC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCNC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of (3S)-3-{[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-N-ethyl-1-pyrrolidinecarboxamide (0.179 mmol) in dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.180 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (15 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110° C. for 1 h. The solution was cooled to room temperature and the dioxane layer separated from the aqueous layer. The dioxane layer was removed via pipette and was passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (2 mL). All dioxane filtrates were combined and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (29 mg, 35%). MS(ES)+ m/e 461.2 [M+H]+.