Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(N4CCOCC4)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccc(N4CCOCC4)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-morpholin-4-yl-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (44 mg, 0.093 mmol), β-alanine (666 mg, 7.5 mmol) and NaOMe solution (11 mL, 5.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 32 mg of the title compound. MS: (+) m/z 529.34 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH:15]=[CH:14][N:13]=1>O.C(O)(C)C.Cl>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([C:11]([F:27])([F:10])[F:26])[CH:17]=3)=[CH:20][CH:21]=2)[CH:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
A stirred solution containing 2-amino-4,6-dichloropyrimidine (17.74 g, 0.11 mol) and 4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}aniline (Intermediate 2U) in water (400 mL), isopropanol (100 mL) and concentrated hydrochloric acid (5 mL) was heated at 65° C. for 18 h. The reaction was cooled to 0° C. and the yellow-tan solid was collected by suction filtration and washed with water. The filtered product was dissolved in hot N,N-dimethylformamide (90° C.) and triethylamine was slowly added until the solution was slightly basic (pH˜8). The solution was then cooled to rt, added to vigorously stirred ice water (1.2 L), and stirring was continued for 1 h. The tan solids were collected by suction filtration and washed sequentially with water, isopropanol, diethyl ether and finally hexane. The material was dried by air suction to afford a light tan solid, 28.8 g (77%). 1H NMR (DMSO-d6) δ ppm 9.46 (s, 1H), 8.59 (d, 1H, J=5.6 Hz), 7.81 (d, 2H, J=9.0), 7.37 (d, 1H, J=2.4 Hz), 7.17 (d, 2H, J=9.0 Hz), 7.11 (dd, 1H, J=2.6, 5.6 Hz), 6.78 (s, 2H), 6.00 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].Cl[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>CN(C)C=O>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][N:7]2[C:8]3[C:3](=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[N:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: Cc1cc(C)c2ccc(=O)[nH]c2n1
Reactant: O=C1c2ccccc2C(=O)N1CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2ccc(=O)n(CCN3C(=O)c4ccccc4C3=O)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5,7-dimethyl-1,8-naphthyridin-2(1H)-one (3.5 g., 0.02 mole) in 25 ml. of dry dimethyl formamide under nitrogen atmosphere is added a 57% suspension of sodium hydride in mineral oil (0.84 g., 0.02 mole). This mixture is stirred at room temperature for 1/2 hour. A mixture of N-(2-chloroethyl) phthalimide (4.6 g., 0.022 mole) in 25 ml. of dry dimethylformamide is added to the first suspension. The mixture is stirred at steam bath temperature for 16 hours. On cooling, it is filtered to remove salt and the filtrate evaporated to dryness in vacuo to afford 1-(2-phthalimidoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one.
Reaction SMILES: Cl.[Si]([O:9][C@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:11]1)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>CO.O>[OH:9][C@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](Cn2ccnc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
Conc. hydrochloric acid (0.5 ml) was added to a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine (1.55 g) in methanol (15 ml). After stirring at ambient temperature for one hour, saturated aqueous sodium hydrogen carbonate (3 ml) was added to the mixture. The reaction mixture was concentrated under reduced pressure to give a residue. To the residue was added a mixture of chloroform (30 ml) and water (30 ml). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98, V/V) to give (2S,4R)-4-hydroxy-2-(imidazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (0.80 g).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][OH:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CCO.[Pd]>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC#Cc1ccc(CN2CCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCCc1ccc(CN2CCCC2)cc1

Procedure:
A solution of 1.65 g (7.66 mmol) 3-(4-pyrrolidin-1-ylmethyl-phenyl)-prop-2-yn-1-ol in 20 mL EtOH is combined with 200 mg 10% Pd/C and hydrogenated in the autoclave at RT and 30 psi H2 until the theoretical uptake of hydrogen is achieved. The catalyst is suction filtered, the filtrate concentrated by evaporation and the residue is purified on silica gel (EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[CH2:6][CH2:5]2)[O:3]C1.Cl>CC(C)=O>[N:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)=[N:11][CH:12]=1
Reactant: c1cc(N2CCC3(CC2)OCCO3)ncn1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCN(c2ccncn2)CC1

Procedure:
The 1-(pyrimidin-4-yl)-4-piperidone ethylene ketal was dissolved in acetone (25 ml) and 1 N HCl (25 ml) was stirred for 18 hr. The acetone was removed in vacuo and the mixture made basic with saturated sodium carbonate. The mixture was extracted twice with ethyl acetate. The extracts were combined, dried with brine, and concentrated in vacuo to give 1-(pyrimidin-4-yl)-4-piperidone as a white powder (0.80 g, 51.4% for two steps, mp: 61-65° C.).
Reaction SMILES: C[Si](Cl)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:12]([C:16]1[CH:17]=[C:18]([P:28]([C:42]2[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]([O:52][CH3:53])=[C:44]([C:54]([CH3:57])([CH3:56])[CH3:55])[CH:43]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[P:35](OCC)OCC)[CH:19]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]=1[O:22][CH3:23])([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>O.C1COCC1>[C:24]([C:20]1[CH:19]=[C:18]([P:28]([C:42]2[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]([O:52][CH3:53])=[C:44]([C:54]([CH3:57])([CH3:56])[CH3:55])[CH:43]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[PH2:35])[CH:17]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:21]=1[O:22][CH3:23])([CH3:25])([CH3:26])[CH3:27]
Reactant: CCOP(OCC)c1ccccc1P(c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Agent: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2P)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
Under a nitrogen atmosphere, 4.89 g (45.0 mmol) of trimethylsilyl chloride was added dropwise to a 75 mL THF suspension of 1.719 (45.0 mmol) of lithium aluminum hydride at −30° C. over a period of 30 minutes, and after the dropwise addition, the whole was stirred at room temperature for 1.5 hours. Then, a 50 mL THF solution of 10.0 g (15.0 mmol) of the diethyl 2-[bis(3,5-di-t-butyl-4-methoxyphenyl)phosphino]phenylphosphonite (8) was added dropwise at −30° C. over a period of 30 minutes and the whole was stirred at room temperature for 16 hours. Thereto was gradually added dropwise a 15 mL THF solution of 7.5 mL of water at 0° C. to 10° C., and then 30 mL of 1N sodium hydroxide aqueous solution was added. Under a nitrogen atmosphere, the organic layer was decanted and the solvent was removed by evaporation. The residue was dissolved in 30 mL of diethyl ether, and the solution was washed three times with 10 mL of water degassed beforehand and then dried over anhydrous sodium sulfate. The drying agent was removed and the solvent was removed by evaporation to obtain the title compound (8.20 g, a white viscous solid). Yield 94.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[Cl:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH:3]=2)[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Nc2cc(Cl)ncn2)ccc1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Nc2cc(Cl)ncn2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3′-amino-4′benzyloxyphenyl)amino-6-chloro-pyrimidine (630 mg) in dry dichloromethane was added pyridine (8 ml) followed by methane sulfonyl chloride (0.3 ml). The mixture was stirred at room temperature overnight then evaporated under reduced pressure. The residue was dissolved in water and dichloromethane and the organic phase separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was then subjected to column chromatography (SiO2;ethyl acetate:petroleum ether (40/60) 1:1) to afford N-{5-[6-chloropyrimidin-4-ylamino]-2-benzyloxy-phenyl}-methanesulfonamide (200 mg). δH (d6 DMSO): 3.14 (3H, s, SO2Me), 5.40 (2H, s, CH2Ph), 6.94 (1H, s, HetH), 7.30-7.40 (1H, m, ArH), 7.50-7.85 (7H, m, ArH), 8.70 (1H, s, HetH), 9.30 (1H, s, NH), 10.00 (1H, s, NH)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.N1C=CC=CC=1.[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[C:33]1=[O:40].O>C(Cl)Cl.C1COCC1>[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][N:34]([C:37]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:11]3[CH:10]=[CH:9][N:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:12]=3)=[CH:19][N:18]=2)=[O:38])[C:33]1=[O:40]
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: COCCCN1CCN(C(=O)Cl)C1=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCCN1CCN(C(=O)Nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cn2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A 0° C. mixture of Example A2 (0.160 g, 0.599 mmol) and pyridine (0.15 mL, 1.862 mmol) in DCM (5 mL) was treated with a solution of 3-(3-methoxypropyl)-2-oxoimidazolidine-1-carbonyl chloride (0.264 g, 1.197 mmol) in THF (5 mL), warmed to RT and stirred overnight. The mixture was treated with water, stirred for 10 min, the layers separated and the aqueous layer extracted with DCM (2×). The combined organics were dried over Na2SO4, concentrated to dryness, purified via silica gel chromatography (MeOH/DCM) and the resulting material was treated with Et2O and the solid collected via filtration to afford 3-(3-methoxypropyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (155 mg, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.22 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 7.96 (s, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 6.69 (dd, J=5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.81-3.79 (m, 2 H), 3.46 (m, 2 H), 3.34 (m, 2 H), 3.27 (m, 2 H), 3.22 (s, 3 H), 1.77-1.69 (m, 2 H); MS (ESI) m/z: 452.2 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH:4]=1>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC=C(CO)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC=C(C=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of tert-butyl 5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (14.65 g, 68.69 mmol) in dichloromethane was added MnO2 (89.58 g, 1030.36 mmol), then stirred overnight at room temperature. The reaction mixture was filtered through Celite®, the filtrate was concentrated under reduced pressure to give tert-butyl 5-formyl-3,6-dihydro-1(2H)-pyridinecarboxylate, which was pure enough to be used for the next reaction. (13.55 g, yield 94%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)(O)O.[NH:15]([C:17](=[NH:19])[NH2:18])[NH2:16].ClCCl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][NH:15][C:17](=[NH:18])[NH2:19])=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N=C(N)NNC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chlorobenzoyl chloride (10 g, 60 mmol, 1.00 equiv) and hydrazinecarboximidamide carbonic acid salt (11.6 g, 85 mmol, 1.49 equiv) in pyridine (10 mL) and dichloromethane (100 g, 1.18 mol, 41.21 equiv) was stirred for 3 h at 25° C. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified via silica gel column (ethyl acetate/petroleum ether (10/1)) resulting in 3 g (22%) of 2-(2-chlorobenzoyl)hydrazinecarboximidamide as yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([OH:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH:21]=1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: Oc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 110.2 %

Procedure:
Using the method of Example 21.2, 2-fluoro-5-nitrobenzotrifluoride (5.0 g) and 3-chloro-5-hydroxypyridine (3.1 g) were combined with potassium carbonate (5.4 g) in DMF and heated overnight at 60° C. Workup gave the title compound (8.4 g) as a crude yellow solid which was used directly in the next reaction.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]([O:18][C:19](=[O:34])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19](=[O:34])[C:20]1[CH:25]=[CH:24][C:23]([O:26][C@H:27]2[CH2:28][CH2:29][C@H:30]([NH:33][CH2:2][C:3]([N:5]3[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]3[C:12]#[N:13])=[O:4])[CH2:31][CH2:32]2)=[CH:22][CH:21]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CC(C)(C)OC(=O)c1ccc(OC2CCC(N)CC2)cc1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CN[C@H]1CC[C@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added 4-(4-aminocyclohexyloxy)-benzoic acid tert-butyl ester (89 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/97% dichloromethane to provide the titled compound. MS (ESI) m/z 452 (M+H)+; 1H NMR (CDCl3) δ 7.91 (d, 2H), 6.86 (d, 2H), 4.74 (m, 1H), 4.60 (m, 1H), 4.28 (m, 1H), 3.64 (m, 2H), 2.32-2.59 (m, 6H), 2.17 (m, 2H), 2.04 (m, 2H), 1.24-1.54 (m, 4H).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[C:31]1([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:31]1([CH2:37][CH2:38][CH2:39][CH:40]2[CH2:41][CH2:42][N:43]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:4]3)[CH2:44][CH2:45]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 34 mg (0.084 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 19 mg (0.093 mmol) of 4-(3-phenylpropyl) piperidine in 2 mL of CH2Cl2 at rt was added 27 mg (0.13 mmol) of sodium triacetoxyborohydride. After stirring for 1 h, the reaction was diluted with 25 mL of CH2Cl2 and washed with 25 mL of sat'd NaHCO3. After separating the phases, the aqueous layer was extracted with 25 mL of CH2Cl2. The combined organic phases were washed with 50 mL of sat'd NaCl, dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 50:1 v/v CH2Cl2/MeOH to give 37 mg (74%) of the title compound: 1H NMR (500 MHz) δ 0.99-2.91 (32H), 3.20-3.27 (3H1), 5.19 (ABq, J=19.7, 2H), 7.17-7.43 (15H); NH3-CI-MS 593 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1

Procedure:
1-fluoro-4-nitrobenzene (3.0 g 21.26 mmol), piperidin-4-ol (2.26 g, 22.32 mmol), K2CO3 (4.4 g, 31.89 mmol) was mixed in 20 mL DMF, reacted at 80° C. for 2.5 hours. Then the mixture was extracted by EA and brine, washed by brine and then water, dried over Na2SO4, concentrated. The crude product was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[NH3:26]>C(O)C>[NH2:26][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1
Reactant: N
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Solvent: CCO
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(N)nc32)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.05 g) was heated with 0.88 ammonia (2 ml) and ethanol (1 ml) in a sealed tube at 100° C. for 24 h. The volatiles were removed under reduced pressure and the residue triturated with ethyl acetate and methanol mixtures to leave the title product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][OH:18])[CH2:13][C:12]=2[CH:11]=[CH:10][C:9]=1[F:19].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:18][CH2:17][CH:14]2[CH2:13][C:12]3[CH:11]=[CH:10][C:9]([F:19])=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:16]=3[O:15]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCC1Cc2ccc(F)c(-c3ccccc3Cl)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Yield: 35.8 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.63 g, 29.4 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol) generally according to the procedure described for Intermediate 37 afforded 2.0 g (29%) of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether with hydrogen bromide (50 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (0.34 g, 14.35 mmol) and allyl bromide (1.74 g, 14.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 to provide 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.2 g, 4.56 mmol) with m-chloroperoxybenzoic acid (2.36 g, 13.68 mmol, 77%) and potassium carbonate (1.575 g, 11.4 mmol) generally according to the procedure described for Intermediate 9 afforded 0.7 g (55%) of (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 0.9 g (82%) of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.15 mmol) with sodium azide (0.4 g, 6.15 mmol) generally according to the procedure described for Intermediate 98 afforded 0.35 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran (0.35 g, 1.15 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.60 g, 2.3 mmol) generally according to the procedure described for Example 154 provided 0.170 g (47%) of (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 248-250° C.