Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:19](=[O:21])[CH3:20])[CH:8]=[C:9]([O:11][CH:12]([CH2:16][O:17][CH3:18])[CH2:13][O:14][CH3:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.C1COCC1.C(Cl)Cl>[Br:22][CH2:20][C:19]([C:7]1[CH:8]=[C:9]([O:11][CH:12]([CH2:16][O:17][CH3:18])[CH2:13][O:14][CH3:15])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:21]
Reactant: [Br-]
Reactant: COCC(COC)Oc1cc(C(C)=O)cc(C(C)(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COCC(COC)Oc1cc(C(=O)CBr)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
1-[3-tert-Butyl-5-(2-methoxy-1-methoxymethylethoxy)phenyl]ethanone (O2.072; 1.64 g) was dissolved in methanol/THF (30/30 ml) and admixed while stirring with phenyltrimethylammonium tribromide (2.09 g). The mixture was stirred at RT for 1 h, then diluted with DCM and washed once with 5% sodium thiosulfate solution. The DCM phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/MtB ether gradient of 0-30% within 60 min). 890 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([S:8]([CH2:11][CH2:12]Cl)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([S:8]([CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCS(=O)(=O)CCCl
Reactant: C1CCNCC1
Product: CCCCCCCS(=O)(=O)CCN1CCCCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Mix 2-chloroethyl heptyl sulfone (1.1 g, 5 mmol) and piperidine (10 mL). Stir at 60° C. overnight. Add addition piperidine (5 mL) and stir at 60° C. overnight. Cool to room temperature, partition between 5N sodium hydroxide and ethyl ether. Separate the organic phase and extract the aqueous phase with ethyl ether (2×25 mL). Combine the organic phases, dry (MgSO4) and evaporate in vacuo to yield 1.2 g orange oil which crystallizes. Purify by silica gel chromatography (ethyl acetate) to yield 930 mg. Purify again by silica gel chromatography (hexane, then 10% ethyl acetate/hexane, then 50% ethyl acetate/hexane) to yield 360 mg of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].Cl.[CH3:14][CH2:15]O>>[CH2:14]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([O:11][CH3:12])[CH:4]=1)[CH3:15]
Reactant: CCO
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Product: CCOC(=O)c1ccc(N)c(OC)c1

Procedure:
To a solution of 3.343 g (20 mmole) of 4-amino-3-methoxybenzoic acid in 200 mL EtOH is bubbled a stream of HCl gas for three minutes. The HCl saturated solution is stirred at room temperature for two days. Solvent is evaporated under vacuum and the resulting residue is dissolved in 100 mL water. The water layer is basified with K2CO3 and extracted with CH2Cl2 (3×200 mL). The combined CH2Cl2 layer is washed with saturated NaHCO3 (200 mL), brine and then dried over MgSO4, filtered and evaporated under reduced pressure to give the desired product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=1)=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CNC(=O)c2ccc(Cl)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.9 %

Procedure:
In a 50 mL round-bottomed flask, 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester hydrochloride (intermediate I) (0.30 g, 0.791 mmol) and 4-chlorobenzoyl chloride (138 mg, 0.791 mmol) were added at 0° C. to 15 mL CH2Cl2. The reaction was stirred at 0° C. for 5 min. and then N,N-diisopropylethylamine (511 mg, 3.96 mmol) was added. The reaction mixture was stirred at 0° C. for 1 hr. The mixture was concentrated to dryness and then purified by flash chromatography using 40% ethyl acetate-hexanes. The desired product 7-chloro-3-[(4-chloro-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (171 mg, 45%) was obtained as a white solid.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[O:18]1[CH2:17][CH:16]1[CH2:14][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(ccn2CC2CO2)c1
Reaction time: 8 h

Procedure:
2.07 g (42 mmol) pulverized, 88% potassium hydroxide, 3.0 g (0.021 mol) indole-5-carbonitrile and 0.68 g (2 mmol) tetrabutylammoniumbromide are jointly weighed out in the given order and mixed with 9.9 ml (126 mmol) epichlorohydrine with stirring. Stirring is continued overnight. Following hydrolysis and three extractions using ethyl acetate, the combined organic phases are washed three times with water. Drying of the organic phase using sodium sulfate and concentration of the solvent on the rotary evaporator leaves a solid which is purified on silica gel by column chromatography (flow agent: hexane/ethyl acetate 7:3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH:19]([CH3:21])[CH3:20])[C:11]3=[O:22])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[N:25]1[C:26]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[NH:32][C:24]=1[N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH:19]([CH3:20])[CH3:21])[C:11]3=[O:22])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1nc2cccnc2[nH]1
Reactant: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3c2nc3cccnc3[nH]2)c2ncccc21
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 5.4 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg) and 2-chloro-3H-imidazo[4,5-b]pyridine (115 mg) in NMP (4 mL) was stirred at 140° C. for 1.5 h, treated with saturated NaHCO3, and extracted with AcOEt. The organic layer was dried over MgSO4, passed through celite pad covered with activated carbon and concentrated in vacuo. The residue was purified by prep. HPLC. The product was crystallized from EtOH/hexane to give the title compound (15.0 mg).
Reaction SMILES: [F:1][C:2]([F:44])([C:25]1[CH:26]=[C:27]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=2[N+:41]([O-:43])=[O:42])[CH:28]=[CH:29][CH:30]=1)[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[CH2:45](Br)[CH:46]=[CH2:47].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH2:47]([N:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:2]([F:44])([F:1])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[CH:26]=1)[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=1[N+:41]([O-:43])=[O:42])[CH:46]=[CH2:45]
Reactant: O=[N+]([O-])c1ccc(Nc2cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2)c([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C=CCN(c1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
A mixture of N-[3-(perfluorooctyl)phenyl]-2,4-dinitrobenzenamine (5.4 g), allyl bromide (1.5 mL), potassium carbonate (2.6 g) and N-methyl pyrrolidone (15 mL) was heated to 60-70° C. for 5.5 hr. Extraction in the normal fashion gave 5.6 g of N-allyl-N-[3-(perfluorooctyl)phenyl]-2,4-dinitrobenzenamine.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:11]1([CH3:20])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1Br.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:12]1[C:13]([CH3:18])=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(P(C(C)(C)C)C(C)(C)C)c(C)c1
Temperature: 73 °C
Yield: 90 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 20 ml of tetrahydrofuran, 9.0 g (0.05 mol) of di-tert-butylphosphinous chloride and 0.05 g (0.0005 mol (corresponding to 1% by mol)) of copper(I) chloride were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 14.9 g (0.075 mol) of mesityl bromide and 2.2 g (0.090 mol) of metallic magnesium in 100 ml of tetrahydrofuran was dropwise added over a period of 1 hour at 50° C. After the dropwise addition was completed, stirring was conducted under reflux at 73° C. for 4 hours. After the temperature of the reaction solution was returned to room temperature, 40 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, a small amount of MeOH was added, and the whole system was cooled to −30° C. to precipitate solids. The solids were filtered off to obtain 11.9 g (purity: 97.5%) of the aimed di-tert-butyl(2,4,6-trimethylphenyl)phosphine as white solids. The yield was 88.0%. Melting point: 36-37° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:34])[CH2:14][N:15]([C@@H:26]([C:31](=[O:33])[NH2:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(C)(C)C>C(Cl)Cl>[C:31]([C@H:26]([N:15]([CH2:14][C:13]([OH:34])=[O:12])[S:16]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)(=[O:17])=[O:18])[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:33])[NH2:32]
Reactant: CC(C)C[C@H](C(N)=O)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](C(N)=O)N(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (15 mL) was added to a solution of {N-[(1R)-1-carbamoyl-3-methyl-butyl]-N-(4-chlorobenzenesulfonyl)amino}acetic acid tert-butyl ester (0.50 g, 1.2 mmol) in CH2Cl2 (15 mL). The reaction was stirred at rt for 4 h. The reaction was then concentrated to a white solid (0.40 g, 92%), which was used without further purification. MS (ESI), (M+H)+363.1; 1H NMR (DMSO-d6, 500 MHz) δ 7.90 (dd, 2H, J=2.0, 6.8), 7.65 (dd, 2H, J=2.0, 6.8), 7.60 (s, 1H), 7.06 (s, 1H), 4.32 (d, 1H, J=18), 4.12 (t, 1H, J=8.0), 4.02 (d, 1H, J=18), 1.55-1.65 (m, 1H), 1.35-1.45 (m, 2H), 0.78 (d, 3H, J=6.1), 0.73 (d, 3H, J=6.1).
Reaction SMILES: FC(C1C=CC=C(C2N[N:33]=[N:32][N:31]=2)C=1)C1C=CC(COC2C=CC(C(=O)C)=C(O)C=2CCC)=CC=1.[C:35]([C:38]1[CH:61]=[CH:60][C:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]([C:52]3[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=3)[C:55]#[N:56])=[CH2:51])=[CH:46][CH:45]=2)=[C:40]([CH2:62][CH2:63][CH3:64])[C:39]=1[OH:65])(=[O:37])[CH3:36]>>[OH:65][C:39]1[C:40]([CH2:62][CH2:63][CH3:64])=[C:41]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]([C:52]3[CH:59]=[CH:58][CH:57]=[C:54]([C:55]4[NH:33][N:32]=[N:31][N:56]=4)[CH:53]=3)=[CH2:51])=[CH:48][CH:49]=2)[CH:60]=[CH:61][C:38]=1[C:35](=[O:37])[CH3:36]
Reactant: CCCc1c(OCc2ccc(C(F)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Reactant: C=C(c1ccc(COc2ccc(C(C)=O)c(O)c2CCC)cc1)c1cccc(C#N)c1
Product: C=C(c1ccc(COc2ccc(C(C)=O)c(O)c2CCC)cc1)c1cccc(-c2nnn[nH]2)c1
Yield: 65 %

Procedure:
The title compound is prepared essentially as described for 1-[4-(4-{fluoro-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone employing 3-{1-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-vinyl}-benzonitrile to give 72 mg, of the title compound as a tan solid 65%. 1H NMR (CDCl3) δ 12.87 (s, 1H), 8.00-8.07 (m, 2H), 7.83-7.86 (m, 2H), 7.65 (t, 1H), 7.39-7.54 (m, 4H), 6.76 (d, 1H), 5.68 (s, 1H), 5.63 (s, 1H), 5.32 (s, 2H), 2.58-2.65 (m, 5H), 1.48-1.53 (m, 2H), 0.89 (t, 3H). LCMS M−1 453.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH2:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[CH:24]([CH3:26])[CH3:25]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)CBr
Product: CC(C)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 126 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-bromo-2-methylpropane and conditions outlined in procedure V. M.p.=158-161° C.; 400 MHz 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 2.9 (s, 2H), 2.75 (d, 2H), 2.4 (t, 2H), 2.15 (d, 2H), 2.1 (d, 2H), 1.75-1.9 (m, 3H), 0.9 (s, 6H); LCMS: 358 [M+H].
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC=CC=1>O1CCCC1>[N:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1CCCC1
Temperature: 0 °C

Procedure:
To an ice bath-cooled solution of 213.4 g (3 mol) of pyrrolidine in 450 mL of tetrahydrofuran was added dropwise over about 2 hours 250.5 g (1.5 mol) of ethyl bromoacetate, maintaining the temperature below 30° C. To this solution was added 150 mL of toluene to precipitate pyrrolidinium bromide, which was separated by filtration. The filtrate was evaporated under vacuum to provide a residue of about 241 g of ethyl 1-pyrrolinidineacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccccc1
Agent: Cl
Product: O=S(=O)(Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The potassium salt of fluorobenzene-2,4-disulfonic acid can be obtained in accordance with the following working procedure: 93.3 ml (1 mol) of fluorobenzene were added dropwise to 200 ml of chlorosulfonic acid over one hour. When the evolution of hydrogen chloride had ceased, the reaction mixture was stirred at room temperature for 2 hours and then poured onto 300 g of ice. It was extracted with chloroform, and the organic phase was washed with 50 ml of water and saturated sodium hydrogen carbonate solution. Distillation of the organic phase in vacuo gave 175 g (90% of theory) of p-FC6H4SO2Cl (boiling point: 86 to 88° C. at 0.1 mbar; melting point: 35 to 38° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[C:12](C1NC=CN=1)(C1NC=CN=1)=[S:13]>C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2)=[C:12]=[S:13]
Reactant: Cn1ccc2cc(N)ccc21
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: Cn1ccc2cc(N=C=S)ccc21
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A flask was charged with 5-amino-1-methyl-1H-indole (8.8 g; 60 mmol), thiocarbonyl diimidazole (10.7 g; 60 mmol) and ethyl acetate (200 mL). The reaction was heated at 50° C. for five minutes, and after cooling, the solvent was evaporated. The crude material was dissolved in dichloromethane (100 mL) and filtered through a short plug of silica gel, which was washed with another bolus of dichloromethane (100 mL). The organic eluent was evaporated to give 5-isothiocyanato-1-methyl-1H-indole (8.9 g; 47 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:36]4[CH2:37][CH2:38][C@@H:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:13][CH2:12][N:11]([C:14]([C:16]3([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:32]4[CH2:38][CH2:37][C@@H:36]3[CH2:35][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:33]4)[CH2:13][CH2:12][N:11]([C:14]([C:16]3([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C2(NC(=O)OC(C)(C)C)CCCC2)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C2(N)CCCC2)CC1
Yield: 99.6 %

Procedure:
2,2,2-trifluoro-N-{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]cyclopentyl}acetamide was obtained from treating 1,1-dimethylethyl {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]cyclopentyl}carbamate (0.627 g, 0.95 mmol) with HCl as outlined in the procedure for Example 890 to form 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]cyclopentanamine (0.528 g, 99%). 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]cyclopentanamine (0.050 g, 0.09 mmol), trifluoroacetic anhydride (0.019 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, 2,2,2-trifluoro-N-{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]cyclopentyl}acetamide (0.027 g, 46%) as an oil. ES-LCMS m/z 654 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([C:22]([O:24]CC)=O)=[CH:10][C:9]=2[O:27][CH2:28][CH2:29][CH3:30])=[CH:4][CH:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:31]1([C:13]2[CH:12]=[C:11]([CH2:22][OH:24])[CH:10]=[C:9]([O:27][CH2:28][CH2:29][CH3:30])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: CCCOc1cc(C(=O)OCC)cc(OS(=O)(=O)C(F)(F)F)c1-c1ccc(F)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCOc1cc(CO)cc(C2CC2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (6.65 g) was added to a mixture of ethyl 4′-fluoro-2-propoxy-6-(((trifluoromethyl)sulfonyl)oxy)biphenyl-4-carboxylate (44.6 g), cyclopropylboronic acid (22.3 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (6.38 g), a 2 M aqueous sodium carbonate solution (156 mL), and toluene (250 mL), and the resultant mixture was stirred at 100° C. for 4 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate). A THF (150 mL) solution of the obtained purified product was added to a THF (150 mL) suspension of lithium aluminum hydride (3.50 g) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (3.5 mL) and a 15% aqueous sodium hydroxide solution (3.5 mL) were added thereto, and the mixture was stirred for 5 minutes. Then, water (10.5 mL) was further added thereto, and the mixture was stirred for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (29.8 g).
Reaction SMILES: [Br:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:10](Cl)(=O)[C:11](Cl)=O.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)C1(Br)CCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(Br)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DMF (a few drops) was added to a mixture of 1-bromocyclopentane-carboxylic acid (23.9 g, 124 mmol) and oxalyl chloride (11.6 mL, 130 mmol) in 250 mL of CH2Cl2. The mixture was stirred at ambient temperature for 2 h. After removing the low-boiling solvents in vacuo, ethanol (50 mL) was added to the residue followed by the addition of N,N-diisopropylethylamine (22.7 mL, 130 mmol). The mixture was stirred at ambient temperature for 20 min. After removing the low-boiling solvents in vacuo, the residue was partitioned between diethyl ether and water. The organic portion was washed with water and brine, and conc. in vacuo. The crude product was filtered through a plug of silica gel using 0 to 10% EtOAc in hexanes as the eluant. The title compound was obtained as a pale oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2([CH3:22])[CH3:21])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:17][C:16]2([CH3:22])[CH3:21])=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCNCC2(C)C)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCN(Cc3ccc(NC(=O)OC(C)(C)C)nc3)C(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
A mixture of [5-(2,2-dimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 109.3) (3.85 g, 12 mmol), 4-methoxybenzyl bromide (2.6 mL, 18 mmol, 1.5 equiv) and triethylamine (1.83 mL, 13.2 mmol, 1.1 equiv) in DCM (25 mL) was stirred for 16 h at rt and concentrated. The residue was purified by silica gel column chromatography (DCM→DCM/MeOH, 97:3) to afford 1.88 g of the title compound as a white solid. Title compound: ESI-MS: 441.3 [M+H]+; tR=3.12 min (System 1).