Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Cl:22]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([Cl:22])[C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCOc1cc(NC(C)=O)ccc1C(=O)OC
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Temperature: 70 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-acetylamino-2-hexyloxybenzoic acid methyl ester (2.6 g) in dimethylformamide (20 ml) is added N-chlorosuccinimide (1.4 g), and the resulting mixture is stirred at 70° C. for 1 hour. The reaction mixture is poured into ice-water and extracted with diethyl ether. The organic layer is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to give 4-acetylamino-5-chloro-2-hexyloxybenzoic acid methyl ester (2.1 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[C:32]1([CH3:44])[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:41]3[CH2:42][CH2:43][N:38]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH3:44])[CH2:39][CH2:40]3)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Reactant: Cc1ccccc1N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)C(C)(C)C2
Temperature: 120 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (410 mg, 1 mmol), palladium acetate (6.73 mg, 0.03 mmol), cesium carbonate (0.65 g, 2 mmol), xantphos (23 mg, 0.04 mmol) and 1-(ortho-tolyl)piperazine hydrochloride (320 mg, 1.5 mmol) in toluene (10 mL) was stirred at 120° C. for 12 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium chloride (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(20% ethyl acetate/hexanes) to afford 6-chloro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.36 g, 73%) as a white solid: LC/MS m/e calcd for C30H34ClN3O2 M+: 505.08, observed: 504.2.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)(=[O:28])=[O:27])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 2-thiophenesulfonyl chloride (530 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(2-thiophenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (759 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:16][CH2:15]1)[CH2:9][CH2:10][C:11]([O-])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([N:8]([CH:14]1[CH2:15][CH2:16]1)[CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)[O-])C1CC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N(CCCO)C1CC1

Procedure:
This compound was prepared from N-tert-butoxycarbonyl-3-cyclopropylamino-propanoate (5a, 2.06 g, 8.0 mmol) using the procedure described in Example 2b. Yield: 1.22 g (71%). ESI-MS: 216.2 (M+H)+, 160.2 (M+H—C4H8)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.21.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cccc2[nH]cnc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-n2cnc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 15.6 %

Procedure:
A round bottom flask charged with molecular sieves, 4A (189 mg, 1.918 mmol) was flame-dried, then allowed to cool to room temperature. To this vial were added 4-bromo-1H-benzo[d]imidazole (0.378 g, 1.918 mmol), copper (II) acetate (0.523 g, 2.88 mmol), and 4-fluorophenylboronic acid (0.805 g, 5.76 mmol) followed by CH2Cl2 (Volume: 9.59 ml) and triethylamine (0.695 ml, 4.99 mmol). The heterogeneous green reaction was stirred at room temperature. After 19 h, the reaction mixture was filtered through a disposable filter funnel and the filter cake rinsed with CH2Cl2. The filtrate was concentrated to afford a green residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 0-100% EtOAc in hexanes over 25 min, tr=13 min) gave 4-bromo-1-(4-fluorophenyl)-1H-benzo[d]imidazole (158 mg, 0.299 mmol, 15.56% yield) as a white solid. LC-MS showed by-product was present. The material was re-dissolved in a minimal amount of CH2Cl2 (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (12 g column, 30 mL/min, 0-25% EtOAc in hexanes over 13 min, tr=10 min) gave Preparation 47A (158 mg, 0.299 mmol, 15.56% yield) as a white solid. LC-MS showed the product was 55% pure. The mixture was further purified by MPLC (40 g column, 36 mL/min, 30-60% EtOAc in hexanes) to afford Preparation 47A as a white solid (51 mg, 9.1%). MS (ESI): m/z=291.0 [M+H]+. HPLC Peak tr=1.70 minutes was product. HPLC conditions: Column:Luna C18 4.6×30 mm 3u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccnc1Cl
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2ncccc2F)CC1
Yield: 6.7 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-fluoropyridine (100 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (9 mg), a yellow solid, in 7% yield.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]1([C:22]2[N:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O.O1CCCC1.CCCCCC>[OH:37][CH:30]([C:26]1[CH:27]=[C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]=[N:24][C:25]=1[O:28][CH3:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(-c2ccccc2)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1nnc(-c2ccccc2)cc1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
7,7 ml of a hexane solution containing 1.52 mol of normal butyllithium was slowly added dropwise into a solution of 50 ml of tetrahydrofuran containing 2.0 ml of 2,2,6,6-tetramethylpiperidine under ice-cooling. After stirring for one hour under ice-cooling, it was cooled to −78° C. and 10 ml of a tetrahydrofuran solution containing 1.68 g of 3-phenyl-6-methoxypyridazine was slowly added dropwise thereinto. After stirirng at −78° C. for 2 hours, benzaldehyde was slowly added dropwise thereinto. After stirring at −78° C. for further 30 minutes, it was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate and the organic phase was washed with brine. After removing the solvent, the residue was subjected to NH-silica gel (Fuji Silicia) chromatography and eluted with hexane/ethyl acetate (3:1) and then with hexane/ethyl acetate (1:1), to give 1.39 g of the target compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[C:12]1([C:17]([NH:19][NH2:20])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[Cl:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[C:12]1([C:17]([NH:19][NH:20][C:3](=[S:4])[NH:2][CH3:1])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN=C=S
Reactant: Cc1csc(C2(C(=O)NN)CCCC2)c1Cl
Solvent: CCO
Product: CNC(=S)NNC(=O)C1(c2scc(C)c2Cl)CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
Methyl isothiocyanate (62 mg) was added to an ethanol (10 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbohydrazide (200 mg), followed by stirring at 75° C. for 3 hours. The reaction solution was subjected to evaporation under reduced pressure and the resulting crude product washed with ether to obtain 167 mg of 2-{[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]carbonyl}-N-methylhydrazinecarbothioamide.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([N+:14]1[C:18]2[CH:19]=[C:20]([NH:23][S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:26])=[O:25])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[CH3:33])[CH3:13].[C:34]1([N:40](C2C=CC=CC=2)[CH:41]=N)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH:40]([CH:41]=[CH:33][C:15]1[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:25])=[O:26])=[CH:19][C:18]=2[N+:14]=1[CH2:12][CH3:13])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCCCCS(=O)(=O)Nc1ccc2oc(C)[n+](CC)c2c1
Reactant: N=CN(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC(C)=O
Product: CCCCCCS(=O)(=O)Nc1ccc2oc(C=CNc3ccccc3)[n+](CC)c2c1
Reaction time: 0.42 h
Yield: 87.8 %

Procedure:
A combination of 10 g Intermediate B and 8 g N,N-diphenylformamidine was thoroughly mixed and heated with stirring at 150°-160° C. for 25 minutes. The flask was then fitted with a condenser and 50 ml hot acetone was cautiously added. An orange precipitate formed. The flask was removed from the heat, cooled, and chilled in ice. After 1 hour, the reddish precipitate was filtered off and discarded. The filtrate was poured into 300 ml diethyl ether and stirred for 2 hors. The resulting yellow-orange powder was filtered, washed with ether, and dried to yield 10.6 g of 2-(2-anilinovinyl)-3-ethyl-5-hexylsulfonamidobenzoxazolium p-toluenesulfonate (Intermediate C).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH3:8].[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>O1CCCC1>[C:14]([O:13][C:7]([CH3:8])([CH2:9][CH2:10][CH2:11][CH3:12])[CH3:6])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: CCCCC(C)(C)O
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(C)(C)CCCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
To a flame-dried, nitrogen-purged 500 mL 3-neck roundbottom flask with 250 mL pressure-equalizing addition funnel and magnetic stirbar was charged 81 mL n-butyl lithium (129 mmol, 1 equiv., 1.6 M in hexanes). A degassed solution of 15.0 g 2-methyl-2-hexanol (129 mmol, 1 eq.) in 100 mL anhydrous tetrahydrofuran was charged to the addition funnel and added to the reaction mixture dropwise at 0° C. over 60 minutes. The reaction mixture was warmed for 15 minutes on hot water bath to ensure the reaction was complete. The reaction vessel was cooled to 0° C. and 14.2 g methacryloyl chloride (135 mmol, 1.05 eq.) was added dropwise and allowed to stir for 15 minutes. The addition funnel was replaced with a reflux condenser and the reaction heated to reflux for 20 hours. After the reaction was complete, it was cooled to 0° C. and quenched aqueous sodium bicarbonate. The product was extracted into ethyl ether and the organic phase washed sequentially with aqueous sodium bicarbonate, water, and brine and then dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. The crude product mixture was vacuum distilled through a vacuum-jacketed short-path distillation head to afford 14 g (59%) of 2-methylhexan-2-yl methacrylate (XIII) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C@H:8]2[OH:11])=[CH:4][CH:3]=1>C(O)C.CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][C@@H:8]2[OH:11])=[CH:4][CH:3]=1
Reactant: O[C@@H]1C[C@H](c2ccccc2)c2ccc(Cl)cc21
Solvent: CO
Solvent: CCO
Product: O[C@H]1C[C@@H](c2ccccc2)c2ccc(Cl)cc21

Procedure:
Racemic cis-6-chloro-3-phenylindan-1-ol (V) (prepared as described in PCT/DK04/000546, i.e. adapting the method described in Bøgesø et al. J. Med. Chem. 1995, 38, 4380-4392 using ethanol as solvent, and performing the reaction at approximately 0° C.) (492 grams) is resolved by preparative chromatography, using a CHIRALPAK® AD column, 10 cm ID×50 cm L, 10 μm at 40° C. Methanol is used as mobile phase at a flow rate of 190 ml/min, detection is performed using a UV detector at 287 nm. The racemic alcohol (V) is injected as a 50,000 ppm solution in methanol; 90 ml is injected with intervals of 28 min. All the fractions, which contain the title compound with more than 98% enantiomeric excess, are combined and evaporated to dryness using a rotary evaporator, followed by drying in vacuo at 40° C. Yield 220 grams as a solid. Elemental analysis and NMR conform to the structure, the enantiomeric excess is higher than 98% according to chiral HPLC, [α]D20 +44.5° (c=1.0, methanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][N:6]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:10])=[O:9])[CH:5]([CH2:20][C:21](O)=[O:22])[C:4](=[O:24])[NH:3]1.[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)CCl.CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:26]1([NH:33][C:21](=[O:22])[CH2:20][CH:5]2[C:4](=[O:24])[NH:3][C:2]([CH3:1])([CH3:25])[CH2:7][N:6]2[S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:9])=[O:10])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NC1CCCCCC1
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)O)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)NC2CCCCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5,5-dimethyl-3-oxo-1-(2,4,6-trimethylbenzene-sulfonyl)piperazin-2-yl)acetic acid (0.32 g, 0.94 mmol) in DMF (3 mL) was added cycloheptyl amine (0.5 mL), EDC (0.5 g, 2.5 mmol), and DMAP (0.3 g, 2.6 mmol). The mixture was stirred at RT overnight. TLC indicated that the reaction was not complete. Additional EDC (0.3 g) was added and the mixture was heated at 65° C. for 1 h. The mixture was cooled to RT. EtOAc (80 mL) was added and mixture was washed with dilute HCl in brine. The EtOAc solution was dried and evaporated to give the crude compound. Column chromatograph purification (silica gel, 0-2% MeOH/CH2Cl2) gave the titled compound. MS: 464.1 (M+1)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([NH2:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:1]1([N:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[CH:10][C:9]([NH:16][C:18](=[O:19])[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(C(F)(F)F)n(-c2ccccc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)n(-c2ccccc2)n1)Oc1ccccc1
Yield: 78.8 %

Procedure:
Using the procedure described in Example 161C, 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (0.665 g, 2.9 mmol) and phenyl chloroformate (0.548 g, 3.5 mmol) were reacted in the presence of K2CO3 (0.691 g, 5 mmol) in THF (20 mL) and purified by silica gel chromatography with 10-20% EtOAc/hexane as eluants to afford phenyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate as a solid (0.794 g, 79%). 1H NMR (300 MHz, CDCl3) δ 7.97 (br, 1H), 7.38-7.46 (m, 7H), 7.14-7.29 (m, 4H); LC-MS (ESI) m/z 348 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:16])[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C(NN)=NN=C(N(CCO)CCO)C=1.Cl.Cl>N1C=CC=CC=1.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[N:26][C:18]=3[CH3:17])[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Nc1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NNc1ccc(N(CCO)CCO)nn1
Solvent: O=CO
Solvent: c1ccncc1
Product: Cc1ncccc1C(=O)Nc1c(F)c(Cl)cc2c1[nH]c1cnccc12
Temperature: 100 °C

Procedure:
A solution of 6-chloro-7-fluoro-9H-β-carbolin-8-ylamine (100 mg, 0.424 mmol) in pyridine (2.5 ml) was stirred at RT. 2-methyl nicotinic acid (70 mg, 0.509 mmol) was added, followed by EDCI (130 mg, 0.678 mmol). The suspension was stirred at 100° C. for a day. The pyridine was removed under reduced pressure and the resulting dark oil was triturated with saturated aqueous NaHCO3. The precipitate which formed was filtered and washed with MeOH. The material was treated with 2M HCl in Et2O to yield a gray solid, the di-HCl salt N-(6-chloro-7-fluoro-9H-β-carbolin-8-yl)-2-methyl-nicotinamide (110 mg). 1H-NMR (300 MHz, DMSO-d6): δ 13.15 (s, 1); 11.03 (s, 1); 9.33 (s, 1); 8.99-8.97 (m, 1); 8.92-8.89 (m, 1); 8.79-8.73 (m, 2); 8.50 (m, 1); 7.70 (m, 1); 2.80 (s, 3). HCOOH standard conditions. DAD Rf=0.91 min. MS (M+H+): 355.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10](=[O:13])([SH:12])[CH3:11]>C1COCC1>[C:10](=[O:13])([S:12][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9])[CH3:11]
Reactant: BrCCCCCBr
Reactant: CC(=O)S
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)SCCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of NaOH (2.1 g, 52.6 mmol) in dry THF (15.8 mL) was added 1,5-dibromopentane (21.75 g, 95 mmol), followed by ethanethioic S-acid (4 g, 52.6 mmol). The mixture was stirred at rt overnight. It was quenched by adding Et2O (20 mL). The reaction mixture was filtered through a pad of celite, and rinsed with Et2O. The filtrate was concentrated to afford crude product, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][NH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][N:11]3[C:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)=[CH:22][C:23](=[O:24])[NH:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Cc1ccc(-c2cn[nH]c2N)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2cnn3c(-c4ccc(F)cc4)cc(=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
4-(4-Methylphenyl)-1H-pyrazol-5-amine (170 mg) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (250 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 180 mg of the target compound.
Reaction SMILES: N1C=CN=C1.[I:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[C:14]([Si:18]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([I:6])[CH:8]=1)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(I)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.2 %

Procedure:
Imidazole (7.8 g, 115 mmol) was added to a solution of 3-iodophenol (12.7 g, 58 mmol) and tert-butyl(chloro)dimethylsilane (9.9 g, 65 mmol) in dichloromethane (80 mL) at 0° C. The reaction mixture was stirred at rt overnight. The suspension was washed three times with water and once with brine, dried and concentrated to give crude tert-butyl(3-iodophenoxy)dimethylsilane (20 g, 93%).
Reaction SMILES: [Si]([O:8][C:9]([C:18]1[CH:48]=[CH:47][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][C@@H:41]([CH2:44][CH3:45])[CH2:42][OH:43])=[O:39])=[C:33]([F:46])[CH:32]=3)=[O:30])[CH2:25][CH2:24]2)=[CH:20][CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])(C(C)(C)C)(C)C.[F-].[K+]>O1CCCC1>[F:46][C:33]1[CH:32]=[C:31]([C:29]([N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([C:9]([OH:8])([C:14]([F:16])([F:15])[F:17])[C:10]([F:13])([F:11])[F:12])=[CH:48][CH:47]=3)[CH2:28][CH2:27]2)=[O:30])[CH:36]=[CH:35][C:34]=1[NH:37][C:38]([NH:40][C@@H:41]([CH2:44][CH3:45])[CH2:42][OH:43])=[O:39]
Reactant: CC[C@@H](CO)NC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[C@@H](CO)NC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 80 °C
Yield: 73.5 %

Procedure:
To a stirring solution of (S)-1-(4-(4-(4-(2-(tert-butyldimethylsilyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)benzyl)piperazine-1-carbonyl)-2-fluorophenyl)-3-(1-hydroxybutan-2-yl)urea (0.303 mmol, 215 mg) in tetrahydrofuran (1 mL) was added potassium fluoride (50% weight on celite) (1.517 mmol, 176 mg). The resulting suspension was heated to 80° C. for 48 hours. The reaction mixture was filtered through celite and concentrated under vacuum. The resulting residue was purified by SCX chromatography to afford the title compound (132.4 mg).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.ICl.[I-].[K+].[I:27]([O-])(=O)=O.[K+].OO.[OH-].[Na+]>C(O)(=O)C.CO>[I:27][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)c1ccccc1
Agent: ClI
Agent: OO
Agent: [I-]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(Oc2ccc(I)cc2)cc1

Procedure:
In connection with the foregoing Reaction Scheme, p-phenoxyphenyl benzoate of formula VI is either reacted with iodine monochloride in aqueous acetic acid or treated with potassium iodide and an oxidizing agent, for example potassium iodate or hydrogen peroxide, in aqueous methanol, to afford the iodo derivative of formula VII. This iodo derivative is saponified by heating in alkali, for example alcoholic sodium hydroxide, to give p-(p-iodophenoxy)phenol of formula V.