Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[CH:15]=[C:16]1[C:22]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=2[CH2:20][CH2:19][C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]2[C:16](=[CH:15][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:13])([F:12])[F:1])[C:17]3[CH:31]=[CH:30][CH:29]=[CH:28][C:18]=3[CH2:19][CH2:20][C:21]=2[CH:26]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Product: FC(F)(F)c1ccccc1C=C1c2ccccc2CCc2cc(Cl)ccc21
Yield: 90 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 2-(trifluoromethyl)phenylboronic acid (59 mg, 0.31 mmol) and 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (91 mg, 0.28 mmol) provides 97 mg (90%) title compound. GC/MS data: retention times in minutes (MS data for M+.ion): 18.19 (384), 18.38(384)Mass Spec (EI+) 384
Reaction SMILES: [SH:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][S:8][CH2:7]1)=[O:5].C(=O)([O-])O.[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[S:30](=[O:33])(=[O:32])[NH2:31].Cl>O>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([S:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]2[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][S:8][CH2:7]2)=[O:5])=[O:26])=[CH:23][C:22]=1[S:30](=[O:32])(=[O:33])[NH2:31]
Reactant: C[C@H](CS)C(=O)N1CSC[C@H]1C(=O)O
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C[C@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)N1CSC[C@H]1C(=O)O

Procedure:
2.5 g of 3-[3-mercapto-2(S)-methylpropionyl]-4(R)-thiazolidinecarboxylic acid and 2 g of sodium hydrogen carbonate are added to 150 ml of water whereupon 2.5 g of 4-chloro-3-sulfamoylbenzoyl chloride is added slowly under ice-cooling and stirring, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is then made acidic with dilute hydrochloric acid under ice-cooling, and the non-crystalline solid is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The non-crystalline solid thus obtained is purified by column chromatography on silica gel with ethyl acetate-hexane (4:1) eluants. Thusis obtained 3-[3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionyl]-4(R)-thiazolidinecarboxylic acid as white non-crystalline powder, [α]D25 -118.8 (methanol). The dicylohexylamine salt of this product has a meltingof 173°-176° C.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.N>C(O)(=O)C>[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:6]3[CH2:5][CH2:4][NH:3][CH2:8][CH:7]=3)=[CH:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCNCC1
Reactant: c1ccc(-n2ccc3ccccc32)cc1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2cn(-c3ccccc3)c3ccccc23)CCNC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a heated (110° C.) mixture of 4-piperidone monohydrate hydrochloride (8.2 g), acetic acid (15 mL) and trifluoroacetic acid (30 mL) was added 1-phenyl-1H-indole (3.1 g) under nitrogen atmosphere over a period of 25 min. The mixture was stirred for 30 minutes at 120° C., then cooled and poured into ice. This was neutralized with conc. ammonia water under cooling and the product was extracted thrice with ethyl acetate. The combined extract was washed with water followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was provided for the next reaction without further purification. Yield 63%. Amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1OS(C(F)(F)F)(=O)=O.CC1(C)C(C)(C)OB([C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]([CH3:36])([CH3:35])[CH:28]=2)O1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[C:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]([CH3:36])([CH3:35])[CH:28]=1
Reactant: O=[N+]([O-])c1cccc(F)c1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)C=C(c2c(F)cccc2[N+](=O)[O-])CC(C)(C)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a mixture of trifluoromethanesulfonic acid 2-fluoro-6-nitrophenyl ester (2.89 g, 10 mmol) produced in Example (97a), 4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane (3.17 g, 12 mmol) produced in Example (4b), toluene (30 mL) and ethanol (15 mL) were added sodium carbonate (1.6 g, 15.1 mmol), purified water (0.9 mL) and tetrakis(triphenylphosphine)palladium(0) (1.15 g, 1 mmol), followed by stirring for 2 hours at an external temperature of 100° C. under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2.25 g of the title compound as a light yellow oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@@H:13]([N:17]([CH3:19])[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:22][N:23]1[C:27]([CH3:28])=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]([CH3:38])=[N:24]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][N:17]([CH3:19])[C@@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:26]2[C:25]([CH3:38])=[N:24][N:23]([CH3:22])[C:27]=2[CH3:28])[CH2:12]1
Reactant: CN(C)[C@@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@@H](N(C)C)C2
Reaction time: 2 h

Procedure:
(6R)-6-(Dimethylamino)-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (2.5 g, 7.731 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (2.10 g, 8.893 mmol) and Pd(PPh3)4 (1.2 g, 1.038 mmol) were added to a solution of K2CO3 (2.15 g, 15.556 mmol) in a mixture of 1,2-dimethoxyethane (60 mL) and H2O (8 mL). The reaction mixture was purged with N2 (g) for 10 min, and warmed up to reflux. The reaction was completed in 2 h. It was allowed to reach room temperature, diluted with H2O (200 mL) and extracted with AcOEt (1×400 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-10-20% Et3N/AcOEt) to afford the desired product as a brown-colored oil. The material was dissolved in CH2Cl2 (200 mL) and acidified with HCl aqueous solution (6 N). The organic layer was discarded, and the aqueous layer was taken to pH>13 with NaOH aqueous solution (6 N). It was extracted with CH2Cl2 (3×300 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated, to give 1.45 g of the coupling product (Rf=0.2 (10% Et3N/AcOEt), colorless oil, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([C:13]([O:15]C)=O)[N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[NH3:24]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([C:13](=[O:15])[NH2:24])[N:8]=[C:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: N
Reactant: COC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Solvent: CO
Product: NC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Yield: 74 %

Procedure:
10 g. of 7-chloro-3-methoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine and 200 ml. of a 13.6% solution of ammonia in methanol are left together overnight at room temperature. The solid rapidly dissolves and after several hours a precipitate gradually forms which increases in quantity with passage of time, until the whole mass has solidified. The solid is filtered by suction and washed with methanol. An additional small quantity of the same product is obtained by concentrating the solution to dryness. The two crops are combined and recrystallized from methanol. Colorless crystals are obtained (7 g.); m.p. 255°-256°C.; yield 74%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[C:16](Cl)[N:17]=[N:18][CH:19]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Sn](C)(C)C)[CH:29]=2)[NH:24][N:23]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.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].C(OCC)(=O)C>[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:16]3[N:17]=[N:18][CH:19]=[C:14]([N:11]4[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]4)[N:15]=3)[CH:29]=2)[NH:24][N:23]=1
Reactant: Cc1n[nH]c2ccc([Sn](C)(C)C)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnnc(Cl)n2)CC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1n[nH]c2ccc(-c3nncc(N4CCN(C(=O)OC(C)(C)C)CC4)n3)cc12
Temperature: 180 °C
Yield: 7.8 %

Procedure:
To a solution of 5-(4-Boc-piperazin-1-yl)-3-chloro[1,2,4]triazine 151 (50 mg, 0.167 mmol.) in anhydrous DMF (3 mL) was added 3-methyl-5-trimethylstannanylindazole 152 (49 mg, 0.166 mmol.), tris(dibenzylideneacetone)dipalladium (15 mg, 0.016 mmol.), tri-o-tolylphosphine (10 mg, 0.033 mmol.) and triethylamine (17 mg, 0.168 mmol.). The reaction mixture was heated in a microwave reactor at 180° C. for 20 minutes. Ethyl acetate (50 mL) was added. The organic layer was washed with water and brine. The organic layer was filtered through Celite and dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 3-(3-methylindazol-5-yl)-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 153 (5.1 mg, 0.013 mmol.).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[Br:8][C:6]1[N:7]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)nc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)c1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-pyrazin-2-one (2.025 mmol; 542.4 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (2.025 mmol; 405.5 mg), cesium carbonate (4.049 mmol; 1319 mg), Xantphos (0.1721 mmol; 102.7 mg), and tris(dibenzylideneacetone)dipalladium(0) (0.1012 mmol; 93.63 mg) in 1,4-dioxane (10 mL) was purged with Argon, then sealed and stirred at 110° C. overnight. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified on silica eluted with 0 to 20% EtOAc in DCM to afford tert-butyl N-[(3S)-1-(6-bromo-4-methyl-3-oxo-pyrazin-2-yl)-3-piperidyl]carbamate as a yellow solid (451.0 mg, 58%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[OH-].[Na+:10]>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[Na+:10]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Trifluoromethanesulfonic acid (17.50 g) was placed in a graduated cylinder and diluted with water (30 ml). The trifluoromethanesulfonic acid was neutralized with 10% sodium hydroxide to a pH of 7.2. The solution was transferred to a rotary evaporator, evaporated to dryness and placed under a vacuum overnight (20.2 g). The sample was collected, ground to a fine powder in mortar and pestle and dried to a constant weight (19.18 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:5]([N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:6].[CH2:35](B(O)O)[CH2:36][CH3:37]>>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:5](=[O:6])[C:4]2[CH:3]=[C:2]([CH2:35][CH2:36][CH3:37])[CH:33]=[C:32]([Cl:34])[CH:31]=2)=[CH:22][CH:23]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: CCCB(O)O
Reactant: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc(Br)c2)cc1
Product: CCCc1cc(Cl)cc(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound was prepared in analogy to example 3, using 3-bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (Example B176) and n-propylboronic acid. 516.2 [ISP (M+H)+]
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)=[O:12].Cl.N1C=CC=CC=1.C(Cl)Cl>Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:12]
Reactant: COc1ccc(C(=O)c2cc(OC)ccc2OC)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1cc(O)ccc1O
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of 4-methoxybenzoyl chloride (5.1 g, 30 mmol) and 1,4-dimethoxy benzene (4.1 g, 30 mmol) in dichloroethane (100 mL) was added aluminum chloride (4.0 g, 30 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction was then quenched with 2N HCl and the organic layer was separated and dried over MgSO4. The organic layer was concentrated to give an oil, which was purified by column chromatography(eluent 20% EtOAc/hexanes) to give an oil (4.7 g, 58% yield). The product, (2,5-dimethoxyphenyl)(4-methoxyphenyl)methanone (4.7 g, 17.2 mmol) and pyridine hydrochloride (20 g) was heated to 200° C. After 1 hr, the reaction was cooled, diluted with 2N HCl and extracted with EtOAc. The organic layer was dried over MgSO4, and concentrated to give an oil residue. The crude product was taken up into CH2Cl2 and a solid crystallized out which was collected by filtration (3.1 g, 78% yield); 1H NMR (DMSO-d6) 10.37 (s, 1H), 9.64 (s, 1H), 9.03 (s, 1H), 7.61 (d, 2H, J=8.6 Hz), 6.86-6.75 (m, 4H), 6.67 (d, 1H); MS m/e 229 (M−H)+.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:13]([N:15]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=2[N:38]([CH2:41][C@H:42]2[CH2:47][CH2:46][C@H:45]([CH2:48][C:49]([OH:51])=[O:50])[CH2:44][CH2:43]2)[CH2:39][CH3:40])[C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:18][N:17]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:54](O)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CCN=C=NCCCN(C)C.Cl.O>ClC(Cl)C.CN(C1C=CN=CC=1)C>[CH2:54]([O:50][C:49](=[O:51])[CH2:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([CH2:41][N:38]([C:29]2[CH:30]=[CH:31][C:32]([C:34]([F:36])([F:37])[F:35])=[CH:33][C:28]=2[CH2:27][N:15]([CH:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:52])[F:53])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH3:14])[C:16]2[N:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][S:25][CH3:26])=[CH:20][N:21]=2)[CH2:39][CH3:40])[CH2:43][CH2:44]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCN(C[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, a solution of the (S)-isomer-dominant semi-chiral compound (4) of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (744.1 g, 0.95 mol) obtained in Step 2 in anhydrous dichloroethane (11.6 L) was added with benzyl alcohol (113.1 g, 1.05 mol), WSC.HCl (200.5 g, 1.05 mol) and DMAP (11.9 g, 98 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was added with water (10 L), and the mixture was extracted with chloroform (19 L, 14 L). The organic layer was washed with saturated brine (12 L), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 28 g, developing solvent: heptane/ethyl acetate=6/1) to obtain a semi-chiral compound (5) of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid benzyl ester (yellow oil, 745.8 g, yield: 90%).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].O[N:6]=[C:7]([NH2:20])[CH2:8][C:9]1[C:18]([Br:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:19][C:18]1[C:9]([CH2:8][C:7]2[NH:20][S:1][O:2][N:6]=2)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: O=S(Cl)Cl
Reactant: NC(Cc1cc2ccccc2cc1Br)=NO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1cc2ccccc2cc1CC1=NOSN1
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
Thionyl chloride (2.0M/CH2Cl2 ; 7.4 mL, 0.015 mol) was added dropwise to a stirred suspension of N'-hydroxy-(3-bromo-2-naphthalenyl)ethanimidamide (3.29 g, 0.012 mol), methylene chloride (125 mL) and pyridine (2.4 mL, 0.03 mol) at 5° C. After 20 minutes at -5° C., the reaction solution was added to ice/H2O. The organic layer was separated, washed with saturated NaCl, dried over MgSO4 and concentrated in vacuo to a slurry (20 mL). Diethyl ether (20 mL) was added and the title compound (1.40 g, yield 36%) was collected (153°-154° C. decomp.).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH2:10]([N:17]1[C:29]2[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=2[C:23]2[C:18]1=[C:19]([Cl:31])[CH:20]=[CH:21][CH:22]=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[CH2:10]([N:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:30])[C:24]=2[C:23]2[C:18]1=[C:19]([Cl:31])[CH:20]=[CH:21][CH:22]=2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1cccc2c1c1cccc(Cl)c1n2Cc1ccccc1
Temperature: 75 °C
Reaction time: 5.5 h
Yield: 72 %

Procedure:
Pyridinium bromide perbromide (0.1856 g, 0.58 mmol) is added to a solution of 9-benzyl-8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one in THF (0.7 mL) and DMF (0.5 mL) and the mixture is heated to 75° C. After stirring for 5.5 h, THF is removed under reduced pressure and the residue is partitioned between dichloromethane and brine. The combined organic layers are washed with dilute sodium sulfate/brine and the aqueous layer is backwashed with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to give a residue. A mixture of the resulting residue, lithium bromide (0.0940 g, 0.0011 mol), lithium carbonate (0.0772 g, 0.0010 mol) and DMF (2 mL) is heated at 120° C. for two hours. The DMF is then removed under high vacuum and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (80 mL) using 15% ethyl acetate in heptane/dichloromethane (6:1) to give 0.1060 g (72%) of the title compound: mp 163-165.5° C.; MS (ESI−) for C19H14CINO m/z 306.1 (M−H)−; IR (drift) 3537, 1632, 1587, 1452, 1417, 1351, 1339, 1311, 1268, 1208, 1112, 1073, 789, 734, 729 cm−1; 1H NMR (CDCl3) δ5.42, 5.98, 6.59, 6.93, 7.09, 7.15-7.28, 7.36, 8.29. Anal. Calcd for C19H14ClNO: C, 74.15; H, 4.59; N, 4.55. Found: C, 73.22; H, 4.53; N, 4.62.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[O:9]C(=O)[NH:11][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+].Cl>CC(C)=O>[NH2:11][C:6]1[CH:5]=[CH:4][C:3]([NH:14][C:15]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:21])=[C:2]([CH3:1])[C:7]=1[C:8]([OH:13])=[O:9]
Reactant: Cc1c(NC(=O)OC(C)(C)C)ccc2[nH]c(=O)oc(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1c(NC(=O)OC(C)(C)C)ccc(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of the product of step C ((10.5 g, 36.0 mmol) in 15 mL of acetone was added 107 mL of 1N NaOH. After stirring at room temperature for 1 hour, the solution was acidified to pH 3 by the careful addition of 2N HCl. The mixture was extracted (2×) with EtOAc, dried (MgSO4), and concentrated under reduced pressure affording 8.35 g (87%) of 2-amino-5-[[(1,1-dimethylethoxy]carbonyl]amino]-6-methylbenzoic acid: Anal. Calc'd. for C13H18N2O4 : C, 58.64; H, 6.81; N, 10.52. Found: C, 58.26; H, 6.72; N, 10,42.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCS(=O)(=O)NCCCCn1c(C)nc2c(N)nc3ccccc3c21
Yield: 6.4 %

Procedure:
Using the general method of Example 232, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7 mmol) was reacted with ethanesulfonyl chloride (2.11 mL, 22.3 mmol) to provide 85 mg of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ethanesulfonamide as an off-white solid, m.p. 210.7-211.6° C.