Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][CH3:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH2:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2)[CH3:16]
Reactant: CCOC(=O)c1cc2cc(CC)ccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: CCc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-ethyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale brown solid. MS: 328.3 ([M−H]−).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[NH:12]1)[CH2:8]2.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[CH2:16]([CH:13]1[N:12]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[C:21]([F:20])([F:30])[F:31])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15])[CH2:17][CH2:18][CH3:19]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCCCC1NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CCCCC1C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1C(F)(F)F

Procedure:
2-(Adamantan-2-yl)-4-butyl-1,2-diazetidin-3-one and 2-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(O)C>[C:2]([NH:5][C:6]([CH2:30][C:29]1[O:32][C:26]([C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[CH:27][CH:28]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(-c2ccc(CCl)o2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1)(NC(C)=O)C(=O)OCC
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
To 300 ml of absolute ethanol was added in portions 2.4 g (0.104 mole) of sodium followed by 21.7 g (0.10 mole) of diethyl acetamidomalonate and stirring was continued for 10 minutes. 5-(4-Nitrophenyl)furfuryl chloride (23.7 g, 0.10 mole) was then added in portions, and the mixture was heated under reflux for 5 hrs. The mixture was filtered hot to remove the insoluble sodium chloride. The filtrate was cooled in a refrigerator, and the solid which was deposited was collected by filtration and washed with ether. The solid was stirred in water, collected by filtration, and dried in an oven at 100° for 2 hrs. to give 21 g (50%) of diethyl acetamido[5-(4-nitrophenyl)furfuryl]malonate. Recrystallization from SDA-32 gave an analytical sample, m.p. 183°-185°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[CH:17]3[CH:12]([CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16]3)[NH:11][C:10](=[O:22])[C:9]=2[SH:23])[CH:7]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Br.[OH-].[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]2[CH:17]3[CH:12]([CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16]3)[NH:11][C:10](=[O:22])[C:9]=2[S:23][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:7]=1
Reactant: BrCC1CO1
Reactant: COc1ccc(Cl)cc1C1=C(S)C(=O)NC2C=CC(C(F)(F)F)=CC12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cl)cc1C1=C(SCC2CO2)C(=O)NC2C=CC(C(F)(F)F)=CC12
Yield: 70 %

Procedure:
4-(5-Chloro-2-methoxy-phenyl)-3-oxiranylmethylsulfanyl-6-trifluoromethyl-4a,8a-dihydro-1H-quinolin-2-one (VIII) was prepared by alkylation of 4-(5-Chloro-2-methoxy-phenyl)-3-mercapto-6-trifluoromethyl-4a,8a-dihydro-1H-quinolin-2-one (Ie) with epibromohydrin. To a warm solution of Ie (2.6 mmol) and epibromohydrin (3.9 mmol) in abs. EtOH was added dropwise NaOH solution (1 Molar, 3.9 mL) forming a yellow solution. The alkylation was allowed to proceed at room temperature for an hour. The mixture was evaporated to dryness, redissolved into methylene chloride, washed with water and the organic layer dried over MgSO4. The desired product was purified by a silica-gel column eluted with mixtures of hexanes and ethyl acetate. The desired product (5) was obtained as an off-white solid in 70% yield, mp 211–212° C. Calcd. for C20H15Cl1F3N1O3S1: C, 54.34; H, 3.42; N, 3.17. Found: C, 54.35; H, 3.43, N, 3.01. 1H NMR (300 MHz, DMSO-d6) δ 7.94–7.83 (m, 2H), 7.64 (dt, J=9.0, 2.4 Hz, 1H), 7.39–7.32 (m, 3H), 5.27–5.21 (m, 1H), 4.53–4.51 (m, 1H), 3.99–3.66 (m, 4H), 3.26–3.24 (m, 1H), 3.12–3.02 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[C:16]([O:26][CH3:27])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:23])=[O:24])=[C:16]([O:26][CH3:27])[CH:15]=1
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Reactant: Cc1ccc(S(N)(=O)=O)c(N)c1
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1cc(C)ccc1S(N)(=O)=O
Yield: 69 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 69% yield, starting from 2-amino-4-methylbenzenesulfonamide and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride (1.5 equiv.). Purification by column chromatography, using chloroform/methanol (95:5) as the eluent.
Reaction SMILES: [F:1][C:2]1[C:24]([S:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:37])([CH3:36])[C:33]([OH:35])=O)[CH2:28][CH2:27]2)=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.CC[N:40](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.N.CCN=C=NCCCN(C)C>CN(C=O)C>[F:1][C:2]1[C:24]([S:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([CH3:36])([CH3:37])[C:33]([NH2:40])=[O:35])[CH2:28][CH2:27]2)=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:21])[CH3:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)C(=O)O)CC4)c(F)cc2OCC3)n(C(C)C)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)C(N)=O)CC4)c(F)cc2OCC3)n(C(C)C)n1
Yield: 55.3 %

Procedure:
To a suspension of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid (174 mg, 0.329 mmol) in DMF (5 mL) were added DIPEA (169 l, 0.987 mmol), HOBt.NH3 (75 mg, 0.494 mmol) and EDCI (95 mg, 0.494 mmol) and the reaction mixture was stirred at RT for 18 h. The mixture was then partitioned between EtOAc and water and the aqueous phase was further extracted with EtOAc (×3). The combined organic layers were washed with water, followed by brine, then dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 3-15% MeOH in DCM) affording the title compound as a colorless sticky solid (96 mg, 56%). LCMS: RT 2.16 min [M+H]+ 527.8
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([NH:15][C:16]([NH:18][CH2:19][CH:20]([C:25]([OH:27])=O)[C:21]([F:24])([F:23])[F:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([N:15]1[C:25](=[O:27])[CH:20]([C:21]([F:24])([F:23])[F:22])[CH2:19][NH:18][C:16]1=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCc1ccccc1)NCC(C(=O)O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1Cc1ccccc1
Yield: 64.7 %

Procedure:
Acetic anhydride (5 ml) was added to 290 mg (1.0 mmole) of 1-benzyl-3-(2-hydroxycarbonyl-3,3,3-trifluoropropyl)urea synthesized in Example 12, and the mixture was heated under reflux for 30 minutes. The solvent was evaporated under reduced pressure. The residue was purified by a column chromatography on silica gel (ethyl acetate:chloroform=1:1) to give 176 mg (yield: 65%) of 3-benzyl-5-trifluoromethyl-5,6-dihydrouracil.
Reaction SMILES: B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.Cl.[Cl:24][CH2:25][C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27].C(N(CC)CC)C.O>C1COCC1.C(OCC)(=O)C>[Cl:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[OH:27]
Reactant: O=C(CCl)c1cccnc1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O[C@@H](CCl)c1cccnc1
Temperature: -25 °C
Reaction time: 96 h
Yield: 68.3 %

Procedure:
To a stirred solution of 3.67 g (11.5 mmol) of (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] in 11 mL of THF at -25° C. was added a slurry of 1.00 g (5.21 mmol) of the product from Example 14 in 5 mL of THF via a cannula. Following the addition of 0.80 mL (5.79 mmol) of triethylamine, the reaction mixture was stirred at -25° C. for 4 days. To the mixture was added 10 mL of water which was then allowed to warm to room temperature. To the mixture was added 20 mL of ethyl acetate and the organic phase separated. The aqueous phase was neutralized with saturated NaHCO3 solution then extracted six times with ethyl acetate. The combined organic phase was concentrated in vacuo to afford a yellow oil. Flash chromatography (silica gel, 75-100% ethyl acetate-hexanes) afforded 561 mg (68%) of the title compound as a pale yellow oil: 1H NMR (400 MHz, CD3OD) δ8.58 (d, 1H, J=1.8 Hz), 8.46 (dd, 1H, J=4.9, 1.5 Hz), 7.90 (d, 1H, J=7.9 Hz), 7.44 (dd, 1H, J=7.9, 4.9 Hz), 4.93 (m, 1H), 3.75 (m, 2H).
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[Cl-:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S+:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]2=3)=[CH:14][C:13]=1[CH2:31][C:32]([O:34][CH2:35][C:36]([O:38]C1(C)C2CC3CC(CC1C3)C2)=[O:37])=[O:33]>C(Cl)Cl>[Cl-:9].[C:36]([CH2:35][O:34][C:32](=[O:33])[CH2:31][C:13]1[CH:14]=[C:15]([S+:18]2[C:19]3[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=3)[CH:16]=[CH:17][C:12]=1[O:11][CH3:10])([OH:38])=[O:37]
Reactant: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)OCC(=O)OC1(C)C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(-[s+]2c3ccccc3c3ccccc32)cc1CC(=O)OCC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
Triflic acid (trifluoromethansulfonic acid) (0.5 mL) was added to a solution of 5-(4-methoxy-3-(2-(2-((2-methyladamantan-2-yl)oxy)-2-oxoethoxy)-2-oxoethyl)phenyl)-dibenzothiophenium chloride (3.00 g, 5.07 mmol) in DCM (50 mL) and stirred at 25° C. for 48 h. The precipitate was filtered, washed with MTBE:Acetone (50 mL) and MTBE (2×100 mL) to afford the title compound (2.05 g, 91%) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ: 12.5 (brs, COOH), 8.52 (d, J=7.8 Hz, 2H), 8.29 (d, J=8.1 Hz, 2H), 7.95 (t, J=7.5 Hz, 2H), 7.67-7.79 (m, 3H), 7.38 (vis s, 1H), 7.22 (d, J=8.1 Hz, 1H), 4.51 (s, 2H), 3.81 (s, 3H), 3.66 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]([OH:33])([CH2:31][CH3:32])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[O:12][CH2:13][C:14]1[CH:15]=[C:16]([C:24](OC)=[O:25])[C:17](=[CH:22][CH:23]=1)[C:18](OC)=[O:19])/[CH3:8])[CH3:2].[BH4-].[Li+]>>[OH:25][CH2:24][C:16]1[CH:15]=[C:14]([CH:23]=[CH:22][C:17]=1[CH2:18][OH:19])[CH2:13][O:12][C:11]1[CH:10]=[C:9](/[C:7](/[CH3:8])=[CH:6]\[CH:5]=[CH:4]\[C:3]([CH2:31][CH3:32])([OH:33])[CH2:1][CH3:2])[CH:30]=[CH:29][CH:28]=1
Reactant: CCC(O)(/C=C/C=C(/C)c1cccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)c1)CC
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)(/C=C/C=C(/C)c1cccc(OCc2ccc(CO)c(CO)c2)c1)CC

Procedure:
In a manner similar to Example 53(e), by reacting 106 mg (0.23 mmol) of dimethyl 4-[3-((1Z,3E)-5-ethyl-5-hydroxy-1-methylhepta-1,3-dienyl)phenoxymethyl]phthalate with 20 mg (0.94 mmol) of lithium borohydride, a colourless oil is obtained (m=50 mg; Y=55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@H:25]4[CH3:37])[CH:19]=[N:20][C:21]=3[F:22])[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:7][C:6]3[CH:47]=[CH:48][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[CH:17][C:18]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:26][C@H:25]2[CH3:37])=[CH:19][N:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@H]4C)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a slightly cooled stirred solution of (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (1.01 g, 1.535 mmol) in DCM (5.0 mL, 78 mmol) was added slowly TFA (4.00 mL, 51.9 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and the sticky residue was taken up in a solution of DCM (10.0 mL) to which TEA (2.140 mL, 15.35 mmol) and methanesulfonyl chloride (0.598 mL, 7.68 mmol) was slowly added subsequently at 0° C. The mixture was stirred at the same temperature for 1 h, concentrated, and the crude product was partitioned between 1 N NaOH(aq) and DCM (20 mL each). The separated aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 10% ethyl acetate/hexanes to 70% ethyl acetates in hexanes) to obtain the desired product (R)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.4779 g, 0.752 mmol, 49.0% yield) as a pale yellow foam. m/z (ESI, +ve ion) 636 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-])=O>CO.[Pd]>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]1[C:8]([NH2:17])=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=1
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N
Reaction time: 8 h

Procedure:
To N-(3-(dimethylamino)propyl)-N-methyl-2-nitro-4-(trifluoromethyl)benzenamine (Step a, 1.42 g, 4.65 mmol) in MeOH (47 mL) was added Pd/C (10%, 493 mg, 0.465 mmol). The mixture was stirred overnight under an atmosphere of H2. The mixture was filtered through a pad of Celite and concentrated to afford the title compound as a brown oil. M+H-276. Calc'd for C13H20F3N3-275.32.
Reaction SMILES: N1(C2C=CC([C:12]34[CH2:31][CH:16]5[CH2:17][C:18]([NH:20][CH2:21][C:22]([N:24]6[CH2:28][CH2:27][CH2:26][C@H:25]6[C:29]#[N:30])=[O:23])([CH2:19]3)[CH:14]([CH2:15]5)[CH2:13]4)=CC=2)C=CC=C1.[Si](Cl)(C)(C)C>CO>[CH:16]12[CH2:31][CH:12]3[CH2:13][CH:14]([CH2:15]1)[C:18]([NH:20][CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[N:30])=[O:23])([CH2:19]3)[CH2:17]2
Reactant: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(-n4cccc4)cc1)(C3)C2
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC(CC1C3)C2
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
To a stirred solution of the compound obtained in example 18 (27 mg, 0.1 mmol) in methanol (2 mL) cooled to 0° C. was added TMS-Cl (25 μL, 0.2 mmol). After 30 minutes, the volatiles were removed under reduced pressure and the residue was triturated several times with diethyl ether to obtain hydrochloride salt of (2S)-1-[(tricyclo[3.3.1.03,7]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile as an off-white solid (31 mg). m/z (M+1) 274; 1H NMR (DMSO-d6) 300 MHz δ 9.44 (s (br), 2H), 4.86 (dd, J=4.4, 7.0 Hz, 1H), 4.10-3.88 (m, 2H), 3.78-3.65 (m, 1H), 3.60-3.47 (m, 1H), 2.48-2.41 (m, 1H), 2.34-2.27 (m, 2H), 2.26-2.17 (m, 2H), 2.10-1.99 (m, 2H), 1.99-1.83 (m, 6H), 1.63-1.43 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.Cl.[NH:17]1[CH2:20][CH:19]([C:21]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:23]=3[N:22]=2)[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:30][C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:21]([CH:19]3[CH2:18][N:17]([C:2]4[CH:7]=[C:6]([O:8][CH:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)[CH:5]=[CH:4][N:3]=4)[CH2:20]3)=[N:22][C:23]=2[CH:29]=1
Reactant: Clc1cc(OC2CCOCC2)ccn1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1ccc2[nH]c(C3CN(c4cc(OC5CCOCC5)ccn4)C3)nc2c1
Temperature: 130 °C
Yield: 23 %

Procedure:
A mixture of 2-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyridine (0.060 g, 0.27 mmol), 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride (as described in Preparation 5) (0.076 g, 0.27 mmol), and cesium carbonate (0.35 g, 1.09 mmol) in NMP (0.5 mL) was heated to 130° C. for 24 h, then cooled to RT. Ethyl acetate and saturated aqueous ammonium chloride were added and the resulting biphasic mixture was separated. The organic layer was washed with water (2×), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography to give 5-chloro-2-(1-(4-(tetrahydro-2H-pyran-4-yloxy)pyridin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.024 g, 0.062 mmol, 23% yield) as a light yellow solid. [M+1] 385. IC50 (uM) 1.087.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([F:17])([F:16])[F:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:10]([C:14]([F:17])([F:15])[F:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C1CN(Cc2ccccc2)CCN1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1CCN(Cc2ccccc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-3-(trifluoromethyl)piperazine 34a (1.0 mmol) and pyridine (1.1 mmol) in DCM (5 mL), is added ethyl chloroformate (1.1 mmol). The resulting mixture is stirred at rt for 1 h. After the reaction is complete, the reaction mixture is diluted with DCM (15 mL) and washed with water. The organic layer is separated, dried over Na2SO4, filtered, and concentrated to afford ethyl 4-benzyl-2-(trifluoromethyl)piperazine-1-carboxylate 34b, which is used without purification. MS (m/z) (M+1)+: 317.1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[C:6]([O:12]C)[C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:12])[C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(F)c(C=O)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)cc(O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
2-Fluoro-4,6-dimethoxybenzaldehyde (22 g) was dissolved in DCM (110 mL), and a solution of BBr3 in DCM (1 M, 300 mL) was added dropwise thereto under ice-cooling, followed by stirring at room temperature overnight. After confirming completion of the reaction, the reaction liquid was poured into ice-water (100 mL), followed by stirring for 1 hour and then extracting with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=80:20 to 60:40) to obtain 2-fluoro-4,6-dihydroxybenzaldehyde (12 g) as a white powder.
Reaction SMILES: CN1C2C(=CC(S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=CC=2)C(=O)C1=O.[O:29]([CH2:36][C@@H:37]1[CH2:40][CH2:39][N:38]1[S:41]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48](=[O:53])[C:47]2=[O:54])(=[O:43])=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Br[CH2:56][C:57]1[CH:62]=[CH:61][N:60]=[C:59]([F:63])[CH:58]=1>>[F:63][C:59]1[CH:58]=[C:57]([CH2:56][N:49]2[C:50]3[C:46](=[CH:45][C:44]([S:41]([N:38]4[CH2:39][CH2:40][C@H:37]4[CH2:36][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:43])=[O:42])=[CH:52][CH:51]=3)[C:47](=[O:54])[C:48]2=[O:53])[CH:62]=[CH:61][N:60]=1
Reactant: Fc1cc(CBr)ccn1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Agent: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: O=C1C(=O)N(Cc2ccnc(F)c2)c2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc21
Yield: 30 %

Procedure:
(S)-1-(2-Fluoropyridin-4-yl-methyl)-5-(2-phenoxymethylazetidine-1-sulfonyl)-1H-indole-2,3-dione (18h) was prepared according to the same procedure for compound 11a, except using compound 17 and 4-(bromomethyl)-2-fluoropyridine, and purified with ether to afford 36 mg (30%) of 18h as an orange solid, mp 159.0-159.9° C. 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=5.1 Hz, 1H), 8.08 (s, 1. H), 7.98 (dd, J=8.7 Hz, J=2.1 Hz, 1H), 7.22 (m, 2H), 7.10 (d, J=5.4 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 6.84-6.72 (m, 4H), 4.93 (s, 2H), 4.49 (m, 1H), 4.07 (m, 2H), 3.91-3.81 (m, 2H), 2.35-2.22 (m, 2H). Anal. Calcd for C24.FN3O5S.0.5H2O: C, 58.77, H, 4.32; N, 8.57. Found: C, 58.69, H, 4.45; N, 8.26.
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][CH:5]([C:7]([O:9]C)=[O:8])[CH2:4][CH:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:2]1.[OH-].[Na+]>CO>[C:18]([O:17][C:15]([N:1]1[CH2:2][CH:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH:5]([C:7]([OH:9])=[O:8])[CH2:6]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C1CC(C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CC(C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.3 %

Procedure:
1-tert-Butyl 3,5-dimethyl piperidine-1,3,5-tricarboxylate (75 g) was dissolved in methanol (375 ml), and 2M aqueous sodium hydroxide solution (125 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 14 hr, and methanol was evaporated under reduced pressure. The concentrate was diluted with saturated aqueous sodium hydrogen carbonate solution (100 ml) and washed twice with ethyl acetate. The basic aqueous layer was acidified (pH 2) with 6M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (71 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:26]=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCC>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:7])[N:29]([CH3:24])[CH2:28][CH2:27][CH3:26])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: CCCNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(Br)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (1.0 g, 3.86 mmol) and HATU (1.76 g, 4.63 mmol) in DMF (35 mL) was stirred at room temperature for 10 min. Then N-methylpropan-1-amine (0.28 g, 0.4 mL, 3.86 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O (3 times) and brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (1.2 g, 99% yield): HPLC retention time: 1.89 min (method A). MS (ESI) (M+H)+ 314.03.