Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2O.P(Cl)(Cl)([Cl:27])=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[C:5]2[Cl:27]
Reactant: Cc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A round-bottomed flask containing a mixture of 6-bromo-2-methyl-3-(4-(trifluoromethyl)benzyl)quinolin-4-ol (5.00 g, 12.6 mmol, Intermediate 26: step b), phosphorous oxychloride (5.90 mL, 63.1 mmol) and acetonitrile (42 mL) was warmed to 90° C. After 3 hours, the reaction mixture was cooled to room temperature. The acetonitrile and excess phosphorous oxychloride was removed by rotary evaporation. The residue was dissolved in dichloromethane (100 mL) and the solution was cooled in an ice-water bath. Ice (100 mL) was added. Concentrated aqueous ammonia solution was added dropwise until the pH=˜9 by litmus paper test. The biphasic mixture was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organics were dried with magnesium sulfate and the dried solution was filtered. Celite® (5 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with hexanes initially, grading to 20% ethyl acetate-hexanes provided the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[N:6]=[C:5]2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(OCC)(=O)C>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:6]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccc(F)cc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccc(F)cc12

Procedure:
Ethyl 2-[5-fluoro-1-(4-nitrobenzyl)-1H-indazol-3-yl]acetate (137 mg, 0.383 mmol) was dissolved in methanol (20 mL). 10% Pd/C (10 mg) was added, and reacted under hydrogen atmosphere for half an hour. TLC (petroleum ether:ethyl acetate=2:1) indicated that starting material disappeared. It was filtered to remove solid, rotate evaporated to dryness to remove the solvent, and the resulting solid was used for the next step directly.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[N:9][N:8]=1)C.[ClH:21].[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[OH:32])[CH2:26][CH2:27][NH2:28].C(O)C.Cl>O>[ClH:21].[C:12]1([N:11]2[C:7]([NH:6][CH2:5][CH:4]3[C:29]4[C:25](=[CH:24][C:23]([OH:22])=[C:31]([OH:32])[CH:30]=4)[CH2:26][CH2:27][NH:28]3)=[N:8][N:9]=[N:10]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(CNc1nnnn1-c1ccccc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1cc2c(cc1O)C(CNc1nnnn1-c1ccccc1)NCC2
Yield: 59.7 %

Procedure:
(1-phenyl-1H-tetrazol-5-yl)aminoacetaldehyde diethyl acetal (11 g.) and 3,4-dihydroxyphenethylamine hydrochloride (5.0 g.) were added to a mixture of ethanol (55 ml.) and water (20 ml.), and dissolved with heating and stirring. Conc. hydrochloric acid (6.0 g.) was added thereto and the mixture was refluxed for 8 hours. The reaction mixture was allowed to stand and the precipitated crystals were collected by filtration to give 1-(1-phenyl-1H-tetrazol-5-yl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.9 g.). The crystals were recrystallized from a mixture of isopropyl alcohol and water to give pure crystals (4.2 g.), mp 236° to 241° C (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26](=[O:28])[O:25][N:24]=2)=[CH:19][C:18]=1[O:29][C:30]([F:33])([F:32])[F:31].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26](=[O:28])[O:25][N:24]=2)=[CH:19][C:18]=1[O:29][C:30]([F:31])([F:33])[F:32])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the solution of 95 mg of 3-(4-amino-3-trifluoromethoxyphenyl)-4H-[1,2,4]-oxadiazol-5-one hydrochloride and 0.054 ml of Hünig's base in 4 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off with suction and dried under reduced pressure.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19].C(OCC)(=O)C>C(#N)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:25])([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2cnc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-piperazin-1-yl-quinoxaline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][C@@H:5]2[C@@H:14]([C@:15]3([CH3:22])[C:20]\1=[CH:19][C:18](=O)[CH2:17][CH2:16]3)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]2[CH2:7][CH2:8][C:9]1=[O:23].Cl.Cl.[NH:26]1[CH2:30][CH2:29][C@H:28]([O:31][NH2:32])[CH2:27]1>>[NH:26]1[CH2:30][CH2:29][C@H:28]([O:31][N:32]=[C:18]2[CH2:17][CH2:16][C@@:15]3([CH3:22])[C:20](/[C:3](=[N:2]/[OH:1])/[CH2:4][C@@H:5]4[C@@H:14]3[CH2:13][CH2:12][C@@:10]3([CH3:11])[C@H:6]4[CH2:7][CH2:8][C:9]3=[O:23])=[CH:19]2)[CH2:27]1
Reactant: C[C@]12CCC(=O)C=C1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NO[C@H]1CCNC1
Agent: Cl
Product: C[C@]12CCC(=NO[C@H]3CCNC3)C=C1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 65 %

Procedure:
The title compound I-dw was obtained following the procedure described in Example 100 and starting from 6-(E)-hydroxyiminoandrost-4-ene-3,17-dione (II-bw, Prepn. 63, 200 mg) and 3-(S)-pyrrolidinyloxyamine dihydrochloride (III-d, Prepn. 4) (110 mg). The crude product (1/1 ratio of the E/Z isomers) was purified by flash chromatography (SiO2, CH2Cl2/MeOH/26% NH4OH 90/10/1). The less polar fractions were evaporated to dryness to give the title compound I-dw in 65% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.72 (1H, bs), 6.16 (1H, bs), 4.69 (1H, m), 3.36-3.10 (7H, m), 2.60-1.10 (16H, m), 0.96 (3H, s), 0.83 (3H, s).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH2:30]1[NH:33][CH2:32][CH:31]1[OH:34].Cl>C(Cl)Cl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:33]1[CH2:30][CH:31]([OH:34])[CH2:32]1)=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(O)C3)nc2c1C#N

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (100 mg, 0.35 mmol) was dissolved in methylene chloride (2 ml), then diisopropylethylamine (237 μl, 1.39 mmol) and 3-hydroxy-1-azetidine hydrochloride (76 mg, 0.70 mmol) were added, followed by heating under reflux in a sealed tube under nitrogen atmosphere for 6 hours. After cooling, dilution with methylene chloride and washing with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resisting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (123 mg, quant) as a yellow white solid.
Reaction SMILES: CO[C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:25][NH:26][C:27]([NH2:29])=[O:28].C[O-].[Mg+2].C[O-].CO>C(OCC)(=O)C>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:21])([F:23])[F:22])(=[O:19])=[O:18])[CH:12]=2)[C:3]([NH:29][C:27]([NH:26][CH3:25])=[O:28])=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
3-Cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid methyl ester (500 mg, 1.37 mmol) and methyl urea (305 mg, 4.12 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 5.9 mL, 4.12 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C., diluted with ethyl acetate (10 mL), and then filtered through celite. The celite was thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl-urea (253 mg, 45%) as a white foam: mp 59-62° C. (foam to gel); EI-HRMS m/e calcd for C17H21F3N2O4S (M+) 406.1174, found 406.1178.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([Cl:35])[C:29]([CH2:33]Br)=[C:30]([Cl:32])[CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:33][C:29]1[C:28]([Cl:35])=[CH:27][C:26]([O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:31][C:30]=1[Cl:32])([CH2:11][CH:12]([O:13][CH3:14])[O:15][CH3:16])[C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH3:10]
Reactant: CCOC(=O)C(CC(OC)OC)C(=O)OCC
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)(CC(OC)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Cool 2-(2,2-Dimethoxy-ethyl)-malonic acid diethyl ester (4.5 g, 16.3 mmol) in 50 mL THF to −78° C. and add lithium hexamethylsilane amide (1M, 17 mL) drop wise. After 15 min, add 5-benzyloxy-2-bromomethyl-1,3-dichloro-benzene (17.9 mmol 6.2 g) in 10 mL THF. Warm this mixture to ambient temperature, acidify with 1N HCl, and extract with ethyl acetate. Concentrate the organics and purify by normal phase column chromatography to afford the title compound as a white solid (7.0 g, 80%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[Na+]>O.C(O)(=O)C>[F:1][C:2]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[I:22])([F:12])[F:11]
Reactant: [I-]
Reactant: Nc1ccccc1SC(F)(F)F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)Sc1ccccc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
2-(trifluoromethylthio)benzenamine (1 g, 5.18 mmol) prepared in accordance with a method described in J. Fluorin. Chem. 1994, 69, 207 to 212, 5 ml of glacial acetic acid, and 3 ml of 50% sulfuric acid were added into a 50-ml eggplant flask equipped with a stirrer, and were dissolved. Then the mixture was cooled to 0° C. on an ice bath. To the mixture, 1 ml of an aqueous solution of sodium nitrite (0.43 g, 6.22 mmol) was added and the mixture was stirred for 1.5 hours. 1 ml of an aqueous solution of sodium iodide (0.95 g, 6.3 mmol) was added dropwise at 0° C. and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction solution was gradually heated to room temperature and added to water, and the solution was extracted three times with ether. The obtained organic layer was washed three times with water, two times with a saturated sodium bisulfite aqueous solution, and three times with water, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (Hexane 100) to give target (trifluoromethyl)-(2-iodophenyl)sulfide (1.5 g, 95%) as a yellow oil.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:23][CH2:24][C:25]1[S:29][C:28]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:23][CH2:24][C:25]1[S:29][C:28]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:26]=1
Reactant: CC(C)OC(=O)c1ccc(CCO)s1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1ccc(CCBr)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Bromine (1.74 mL, 33.9 mmol) was added slowly to a solution of triphenylphosphine (8.9 g, 33.9 mmol) in CH2Cl2 (65 mL) at −40° C. After 1 h at −40° C., a solution of the alcohol from step 1 (6.6 g, 30.8 mmol) and pyridine (2.5 mL, 30.9 mmol) in CH2Cl2 (65 mL) was added via cannula. The mixture was allowed to warm to room temperature and was stirred overnight. The reaction was concentrated in vacuo to a brown slurry. The mixture was triturated with hexanes (150 mL) and stirred vigorously. The solids were removed by filtration and the filtrate was concentrated in vacuo to afford 6.2 g (73%) of isopropyl 5-(2-bromoethyl)thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[CH3:13].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:13][C:12]1[CH:11]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:9](=[O:10])[N:19]([C:18]1[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=1)[C:6]2=[O:8]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc2c(cc1C)C(=O)OC2=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C)C(=O)N(c1ccc(F)cc1)C2=O
Yield: 77.4 %

Procedure:
4,5-dimethylphthalic anhydride (1.7 g, 9.6 mmol) and 4-fluoroaniline (1.1 g, 9.6 mmol) were stirred with heating in dimethylformamide at 150° C. for 1 hr. After cooling, water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried. The resulting crystals were purified by silica gel chromatography (chloroform) to give 2.0 g of 5,6-dimethyl-2-(4-fluorophenyl)isoindolin-1,3-dione.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[CH:48][CH:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:53]1[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=1[C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[CH:51][CH:50]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: ClCc1ccc(-c2ccccn2)cc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(-c3ccccn3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 2-(4-(chloromethyl)phenyl)pyridine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-(4-pyridin-2-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 217-219° C.; 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J=4.3 Hz, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.78-7.64 (m, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.25-7.11 (m, 3H), 7.00 (dd, J=7.6, 7.6 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.49 (s, 1H), 6.42 (s, 1H), 5.00 (ABq, 2H), 4.85 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.09-2.87 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 161.7, 161.2, 156.7, 149.6, 141.9, 138.9, 136.7, 136.4, 132.6, 128.6, 127.8, 127.3, 123.8, 123.4, 122.2, 120.4, 120.1, 119.9, 118.8, 109.3, 93.2, 80.6, 72.3, 57.7, 43.8, 29.0; MS (ES+) m/z 447.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[C:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCCc1ccccc1
Solvent: CCO
Product: N#Cc1c(NCCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and phenylpropylamine in ethanol. ES-MS m/e (%): 320 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:13])[CH3:12].CC([O-])=O.[Na+].CC(OC(C)=O)=O>>[C:11]([NH:14][C:15](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1)[C:16]([OH:18])=[O:17])(=[O:13])[CH3:12]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(=Cc1ccc(F)c(Br)c1)C(=O)O
Temperature: 130 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (50.0 g, 0.25 mol), N-acetylglycine (26.2 g, 0.22 mol), NaOAc (13.8 g, 0.56 mol), and Ac2O (52 mL) was heated at 130° C. for 10 h in a flask fitted with a reflux condenser. The resulting precipitate was collected by filtration, washed with water, and suspended in AcOH (250 mL). This mixture was heated at 100° C. for 1 h in a flask fitted with a reflux condenser, and then was cooled to 0° C. The solids were collected by filtration, washing with water, to give the product as a yellow solid (53.5 g, 76%). MS (ESI−): mass calcd. for C11H9BrFNO3, 301.0; m/z found, 299.9 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 12.80 (br s, 1H), 9.52 (br s, 1H), 7.93 (dd, J=6.9, 1.9, 1H), 7.66 (ddd, J=8.4, 4.8, 1.9, 1H), 7.42 (t, J=8.7, 1H), 7.19 (s, 1H), 1.98 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:29]=[CH:28][C:18]([C:19]([NH:21][CH2:22][C:23](=[O:27])[O:24]CC)=[O:20])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:29]=[CH:28][C:18]([C:19]([NH:21][CH2:22][C:23]([OH:27])=[O:24])=[O:20])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)NCC(=O)OCC)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)NCC(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 3 (430 mg, 0.851 mmoles) was taken up in a mixture of THF (10 ml), 1N NaOH (1.8 ml) and water (8.2 ml). The reaction mixture was stirred at room temperature under nitrogen for two hours. The THF was then removed in vacuo and the residue was diluted with water and filtered. The aqueous solution was acidified with dilute HCl and extracted with chloroform. The combined chloroform extracts were dried and concentrated in vacuo to afford the title compound which was recrystallized from ethyl acetate/hexane, m.p. 171°-173°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][N:23]3[C@H:28]4[CH2:29][CH2:30][C@@H:24]3[CH2:25][CH:26]([N:31]3[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=[C:32]3[CH3:40])[CH2:27]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH2:20])[CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:41][CH2:42][C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>>[Cl:41][CH2:42][C:43]([NH:20][C@H:16]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:21][CH2:22][N:23]2[C@H:24]3[CH2:30][CH2:29][C@@H:28]2[CH2:27][CH:26]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[CH2:25]3)[CH2:9][CH2:10]1)=[O:15])[CH:17]([CH3:18])[CH3:19])=[O:44]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](N)C(C)C)CC1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)CCl)C(C)C)CC1
Yield: 66.1 %

Procedure:
2-chloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}carbamate (0.614 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.512 g, 99%). {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2-methylpropyl}amine (0.050 g, 0.09 mmol), Chloro-acetyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-N{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2-methylpropyl}acetamide (0.037 g, 66%) as an oil. ES-LCMS m/z 622 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[F:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:14][C:15]1[N:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)[CH2:22]2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NC1CCN(c2ccc(F)nc2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: Fc1ccc(N2CC[C@H](NCc3ccc(C(F)(F)F)cc3)C2)cn1
Reaction time: 18 h

Procedure:
Add 4-(trifluoromethyl)benzaldehyde (30 μL, 0.22 mmol) to a solution of 1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride (43 mg, 0.2 mmol) and triethylamine (90 μL, 0.66 mmol) in methanol (1 mL). Vortex the resulting mixture and allow to sit for 18 h. Add sodium borohydride (12-15 mg, 0.3-0.4 mmol). When the bubbling begins to subside, vortex and allow to sit for 1 h. Dilute the reaction mixture with methanol (2 mL) and pour onto a column of Dowex® 50Wx2 (H+ form). Rinse the column with methanol, elute the product with 5% triethylamine in methanol and concentrate. Redissolve the residue in methanol, dilute with acetonitrile and concentrate to dryness to give the title compound as a residue.