Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([CH:11]=[O:12])[C:6]=2[N:7]=1.S(=O)(=O)([OH:15])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]([OH:15])=[O:12])[C:6]=2[N:7]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1csc2cnc(Cl)nc12
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1csc2cnc(Cl)nc12
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 2-chloro-thieno[3,2-d]pyrimidine-7-carbaldehyde (0.6 g) in a mixture of tert-butanol/tertrahydrofuran/water (1/1/1, 45 mL) was added sulfamic acid (1.0 g) followed by a solution of sodium chlorite (0.9 g) and potassium dihydrogen phosphate (3.0 g) in water (10 mL) and the resulting mixture was stirred for 1 hour. The reaction mixture was then diluted with ethyl acetate; the organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was triturated with ethyl acetate and the solid was collected by filtration to give 0.5 g of 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:7]([C:19]([OH:21])=O)=[CH:6]2.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([NH:31][C:19]([C:7]2[N:8]([CH2:12][C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:11][CH:10]=3)=[O:21])=[CH:29][CH:30]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2n1Cc1ccncc1
Product: O=C(Nc1ccc(Cl)nc1)c1cc2cc(C(F)(F)F)ccc2n1Cc1ccncc1
Yield: 74.4 %

Procedure:
The process is carried out according to the method described in example 3.1, using 0.5 g (1.56 mmol) of 5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylic acid, prepared in step 16.1, and 0.22 g (1.72 mmol) of 2-chloro-5-aminopyridine. 0.5 g of the expected product is isolated by this method, which product is used as it is in the rest of the synthesis.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:33]4[CH:32]=[N:31][C:30]([O:29][CH3:28])=[N:35][CH:34]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)nc23)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnc(OC)nc4)nc23)c1F
Temperature: 160 °C
Yield: 31.6 %

Procedure:
In a microwave tube, propane-1-sulfonic acid [3-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl)-2,4-difluoro-phenyl]-amide (P-0002, 95.0 mg, 0.207 mmol) and 2-methoxypyrimidine-5-boronic acid (10, 38.0 mg, 0.247 mmol) were added, followed by 1.4 mL of acetonitrile and 0.70 mL of 1.00 M potassium carbonate in water. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.6 mg, 0.010 mmol) was added to reaction mixture and the resulting mixture was heated at 160° C. in the microwave for a total of 10 minutes. The reaction solution was extracted with ethyl acetate and water, followed by saturated sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum. The crude material was purified by silica gel chromatography eluting with a gradient of 10 to 70% ethyl acetate in hexanes. The resulting material was further purified by silica gel chromatography eluting with a gradient of 1 to 3% methanol in dichloromethane, and fractions containing the desired compound were extracted with 10 mL each of ethyl acetate and 1 M sodium hydroxide. The aqueous layer was treated with 0.8 ml, of 6 N hydrochloric acid, then extracted with 2×10 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound as a white solid (P-0004, 32 mg). MS (ESI) [M+H+]+=489.3.
Reaction SMILES: [F:1][C:2]1[C:24]([S:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]2)=[O:26])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=[O:37].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:27]2[CH2:28][CH2:29][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:32]2)(=[O:37])=[O:26])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 41.7 %

Procedure:
To an ice-cooled solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidine-4-sulfinyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 210 (51 mg, 0.102 mmol) in DCM (8 mL) was added TFA (24 μL, 0.306 mmol) followed by a slow addition of a solution of m-CPBA (21 mg, 0.122 mmol) in DCM (1 mL) and the resulting mixture was stirred for 2.5 h at 0° C. Additional m-CPBA (9 mg) in DCM (0.5 mL) was added and the mixture was stirred for 1 h at RT. Volatiles were then removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 20-50% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 5-10% MeOH in DCM) afforded 211 as a white solid (22 mg, 41%). LCMS: RT 2.76 min [M+H]+ 517.1. 1H NMR (DMSO, 400 MHz): δ 8.88 (1H, d, J=8.22 Hz), 7.94 (1H, s), 7.25 (1H, d, J=11.17 Hz), 5.67-5.55 (1H, m), 4.73-4.54 (4H, m), 3.28-3.15 (1H, m), 2.89-2.79 (2H, m), 2.72-2.60 (1H, m), 2.26 (3H, s), 2.13 (2H, bt, J=11.43 Hz), 1.89 (2H, bd, J=12.04 Hz), 1.58-1.41 (8H, m), 0.91 (6H, d, J=6.55 Hz)
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3(O)[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH:18]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CC(C)(C)CC(O)(c2ccccc2N2CCN(CC3CC3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C)C=C(c2ccccc2N2CCN(CC3CC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 21 h
Yield: 91.6 %

Procedure:
A mixture of 1-[2-(4-cyclopropylmethylpiperazin-1-yl)phenyl]-3,3,5,5-tetramethylcyclohexanol (250 mg, 0.675 mmol) produced in Example (108b), water (0.12 mL) and trifluoroacetic acid (1.04 mL, 13.5 mmol) was stirred for 21 hours at an external temperature of room temperature. Aqueous solution of potassium carbonate was added to the reaction mixture and then extraction was performed with ethyl acetate. Organic layer was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 218 mg of the title compound as a colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:20]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:21]1[O:23][CH2:22]1>O1CCCC1.O>[C:25]1([S:24][CH2:20][CH:21]([OH:23])[CH2:22][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccnc1
Reactant: c1ccc(SCC2CO2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: OC(CCc1cccnc1)CSc1ccccc1
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
Under argon gas, a solution of diisopropylamine (0.835 g, 8.25 mmol) in tetrahydrofuran (5 mL) was added dropwise to n-butyllithium (1.53 M in hexane, 4.9 mL, 7.5 mmol) at 5° C. and the mixture was stirred for 30 minutes. To this was further added a solution of 3-methylpyridine (1.40 g, 15 mmol) in tetrahydrofuran (5 mL) dropwise at 5° C., and the mixture was stirred for 30 minutes. Then, a solution of phenyl glycidyl thioether (0.83 g, 5 mmol) in tetrahydrofuran (5 mL) was added at 5° C. and the reaction was carried out for 2 hours. This reaction mixture was diluted with 10 mL of water for hydrolysis, and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of water twice and the solvent was distilled off under reduced pressure to give a deep-red oil. This oil was purified by silica gel column chromatography (Merck's Kieselgel 60, hexane/ethyl acetate=1/2) to give 0.521 g (isolation yield: 41%) of 1-(phenylsulfanyl)-4-pyridin-3-ylbutan-2-ol (yellow oil).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:38])[O:30][CH:29]([C:31]2[N:32]=[C:33]([CH:36]=[O:37])[S:34][CH:35]=2)[CH2:28][O:27]1.C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:33]3[S:34][CH:35]=[C:31]([CH:29]4[CH2:28][O:27][C:26]([CH3:38])([CH3:25])[O:30]4)[N:32]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC1(C)OCC(c2csc(C=O)n2)O1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)OCC(c2csc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)n2)O1
Yield: 60 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 4-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole-2-carbaldehyde (0.37 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg), triethylamine (0.09 mL) and ethanol (6 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and the title compound (0.47% g, yield 60%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 562 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C@@H:18]3[C@@H:13]([C:14]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[C:15]=4[CH2:16][CH2:17]3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C([O-])(O)=O.[Na+]>Br>[CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C@@H:18]3[C@@H:13]([C:14]4[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:15]=4[CH2:16][CH2:17]3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCC1CCCCC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCC1CCCCC1
Temperature: 0 °C
Yield: 36.7 %

Procedure:
2.62 g (0.008 mol) of rac-cis-3-(3-cyclohexyl-propyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 0.09 l of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was poured into an ice-cold aqueous solution of 32 g (0.8 mol) of NaOH, whereupon, after the addition of solid NaHCO3, the mixture was extracted three times with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered and concentrated. By chromatography of the residue over silica gel with cyclohexane/ethyl acetate 1:1 there was obtained 0.92 g (37%) of oily rac-cis-3-(3-cyclohexyl-propyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=2)[NH2:16])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1([C:25]#[N:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1>[ClH:1].[C:2]1([CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([NH:16][C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[NH:26])[CH:17]=[CH:18][CH:19]=2)=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CN1CCCC1
Reactant: Nc1cccc(NC(=O)CCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Clc1ccccc1
Product: N=C(Nc1cccc(NC(=O)CCc2ccccc2)c1)N1CCCC1
Temperature: 25 °C

Procedure:
To a stirred suspension of the product of step (a), 2.0 g, 0.006 moles, in 35 ml of chlorobenzene was added 4-dimethylaminopyridine. To this was added 1-pyrrolidinecarbonitrile, 1.2 ml, 0.06 moles, and the reaction was heated to reflux for 4 hours. The reaction was cooled to room temperature and the solvent decanted. To the residue was added 25 ml of isopropanol and 150 ml of ethyl acetate. A solid crystallized and was collected by filtration. The above solid was then dried at 60° C. for 24 hours giving 700 mg of N-(3-(((2-phenylethyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide hydrochloride, m.p. 220-221° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=3[CH3:33])[C@H:15]2[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:32][C:26]1[C:25]([CH3:33])=[C:24]([C:14]2[C@@H:15]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C@@H:16]3[C@@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[N:13]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-((3S,3aR,4S)-4-(tert-butyldimethylsilyloxy)-3-(tetrahydro-2H-pyran-2-yloxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (120 mg, 0.245 mmol) in THF (2 mL) at 0° C. was added tetrabutylammonium fluoride (0.49 mL, 0.490 mmol, 1M solution in THF) and the reaction mixture was stirred at room temperature for 3 h. Once the starting material had disappeared (monitored by TLC), it was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification of crude by column chromatography over silica gel using 30% EtOAc in hexane provided the title compound.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[K].[C:23]([SH:27])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([S:27][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)S
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Agent: [K]
Product: CC(C)(C)Sc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with the potassium derivative of tertbutanethiol to obtain 4-(tert-butylthio)-7-nitro-2,5-bis-(trifluoromethyl)benzimidazole, m.w., 387.3.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:68](O)=[O:69])[C@H:64]([CH2:66][CH3:67])[CH3:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:68]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:69])[C@H:64]([CH2:66][CH3:67])[CH3:65]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.1 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (250 mg, 0.65 mmol), DCC (160 mg, 0.78 mmol) and DMAP (8 mg, 0.06 mmol) in ethyl acetate (15 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-isoleucine (228 mg, 0.65 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (275 mg) was dissolved in dry THF (10 mL) and cooled to 0° C. Dimethylamine (10 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 110 mg (31%) of the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH3:13][C:14]([CH3:19])=[CH:15][C:16]([NH2:18])=[O:17].CO[Si](OC)(OC)OC.[F-].[Cs+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3[C:14]([CH3:19])([CH3:13])[CH2:15][C:16](=[O:17])[NH:18][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: CC(C)=CC(N)=O
Agent: CO[Si](OC)(OC)OC
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)NC2=C1c1ccc(Cl)cc1CC2

Procedure:
A suspension of 127 g (0.7 mol) of 6-chloro-2-tetralone, 70.0 g (0.7 mol) of 3,3-dimethylacrylamide, 63.6 ml (0.42 mol) of tetramethoxysilane and 85.3 g (0.56 mol) of cesium fluoride in 400 ml of toluene is boiled under reflux for 18 hours. Distillation of the solvent in a vacuum, extraction with methylene chloride/ water. chromatography on silica gel with ethyl acetate/ hexane (1:1) and recrystallization from methylene chloride/hexane yields 8chloro-1,1-dimethyl-1,2,5,6-tetrahydrobenzo[f]-quinolin-3-one as white crystals With melting point 213°.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]([NH2:16])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1.O.CO>COC(OC)(C)C>[C:17](=[N:16][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:3]1[CH3:2])([CH3:22])[CH3:18]
Reactant: Cc1nc2cnc3ccccc3c2n1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: COC(C)(C)OC
Solvent: CO
Product: CC(C)=Nn1c(C)nc2cnc3ccccc3c21
Temperature: 100 °C
Reaction time: 24 h
Yield: 1461.4 %

Procedure:
A suspension of 2-methyl-1H-imidazo[4,5-c]quinolin-1-amine hydrochloride (1.79 g, 7.62 mmol) in 30 mL of 2,2-dimethoxypropane was treated with 90 mg of p-toluenesulfonic acid. The reaction mixture was heated to 100° C. overnight. The reaction mixture was then treated with 10 mL of H2O and 10 mL of MeOH, and heating was continued for 24 h. The reaction mixture was cooled and concentrated under reduced pressure. The resulting oil was dissolved in 50 mL of CHCl3 and washed with 2% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give N-isopropylidene(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.82 g) as a yellow solid.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.[Pd]>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)O

Procedure:
3.0 g Boc-Phe-βAla-OBzl was reduced in 50 ml MeOH in the presence of Pd-black as a catalyst, and this was followed by concentration; the resulting residue was dissolved in 30 ml AcOEt, after which it was crystallized with 0.80 ml CHA and collected by filtration.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].B(F)(F)F.CCOCC.[CH:21]([C:23]1(O)[CH2:26][CH2:25][CH2:24]1)=[CH2:22]>O1CCOCC1>[C:23]1(=[CH:21][CH2:22][C:8]2[C:6]([C:5]([CH3:9])=[C:4]([CH3:10])[C:3](=[O:11])[C:2]=2[CH3:1])=[O:7])[CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC1(O)CCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC1=C(C)C(=O)C(CC=C2CCC2)=C(C)C1=O
Yield: 46.3 %

Procedure:
To a solution of trimethyl hydroquinone (3 g) in 100 mL dioxane at room temperature, was added BF3.Et2O (4.26 g). While stirring, a solution of 1-vinylcyclobutanol (1.96 g) in 20 mL dioxane was added dropwise to the mixture. The reaction was stirred for 1 h and quenched by pouring onto ice (50 g). The aqueous layer was saturated with NaCl and extracted with 3:1 hexane/EtOAc. The combined organic phase was washed with brine and NaHCO3 solution, concentrated and diluted with EtOH (30 mL). 10% FeCl3 aqueous solution (40 mL) was added to the solution and the mixture was stirred for 2 h at room temperature. The mixture was diluted with hexane/EtOAc (4:1, 80 mL) and the aqueous layer was saturated with NaCl. After layer separation, the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was chromatographed to afford 2-(2-cyclobutylideneethyl)-3,5,6-trimethylbenzo-1,4-quinone (2.1 g). MS m/z=231 (M−OH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[Cl-].[NH4+].C1COCC1.O>CO.[Fe]>[NH2:19][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(Br)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc(Sc2ccc(Br)cc2N)cc1
Yield: 91.2 %

Procedure:
A solution of the product of Example 106a (1.4 g, 3.9 mmol), iron powder (0.874 g, 15.6 mmol) and ammonium chloride (0.253 g, 4.68 mmol) in a methanol (6 mL), THF (6 mL), and water (2 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate. The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.2 g, 92%).