Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:15](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]1[O:12][C:11]2[C:2](=[C:3]([CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[C:4]([O:6][CH3:7])=[O:5])[O:1]1
Reactant: ClCCl
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1OCO2
Temperature: 105 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
Compound 121 (16.12 g, 0.081 mol) was dissolved in 500 mL of DMF. Then 100 mL of methylene chloride and 26 g (0.464 mol) of potassium carbonate were added. The mixture was heated to 105° C. with vigorous stirring for 6 hours. The potassium carbonate was filtered and the DMF was removed in vacuo. The residue was poured into ice-water and let stand overnight. The precipitated product 122 was filtered and washed with water until neutral. The dried gray white solid weighed 15.60 g (yield 91%) and was recrystallized from methanol as brilliant long needles, m.p. 122°-124° C. IR cm-1 1710 (ester C=O); 1H NMR δ ppm 3.90 (s, 3H, OCH3), 3.95 (s, 3H, ArOCH3), 6.11 (s, 2H, OCH2O), 6.57 and 7.45 (each d, J=9 Hz, 1H, ArH). Anal. (C10H10O5)C, H.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].[OH-:25].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:25])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a 25 mL volume three-necked flask with Dean-Stark, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39) (1.31 g), toluene (4.55 ml), tetrabutylammonium bromide (61 mg), and 48 w/w % of aqueous sodium hydroxide solution (1.25 g) were added under a nitrogen atmosphere. Water was removed by azeotropic distillation under atmospheric pressure for 22 hours. The reaction mixture was cooled to room temperature, added water, and washed with toluene. To the resulting aqueous layer, 10 w/w % of hydrochloric acid was added to adjust pH to less than 3. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give 0.949 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[C:35]#[N:36])=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-:14])=[O:13].O>CN(C)C=O>[N+:12]([C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[C:35]#[N:36])=[CH:20][C:16]=1[C:17]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:18])([O-:14])=[O:13]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl]phthalimide.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([F:11])([F:23])[F:24])(=[O:21])=[O:20])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
Orcinol monohydrate (2.84 g. 20.0 mmol) and 2-trifluoromethylbenzenesulfonyl chloride (4.90 g, 20.0 mmol) were mixed in saturated NaHCO3 (70 mL) and diethyl ether (70 mL). The biphasic mixture was stirred vigorously at room temperature overnight. The reaction mixture was quenched with water (100 mL) and extracted into ethyl acetate (3×80 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as a white solid (3.65 g, 55%). 1H-NMR (300 MHz, CDCl3) δ8.12 (d, J=8.0 Hz, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.80 (t, J=8.2 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 6.55 (s, 1H), 6.48 (s, 1H), 6.39 (s, 1H), 5.11 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C1COCC1.O>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH2:13][OH:14])[CH:16]=[CH:17][CH:18]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc(CO)c1)N1CCCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 105.6 %

Procedure:
3-(Piperidin-1-ylsulfonyl)benzoic acid (7.00 g) was dissolved in THF (70 mL), and at 0° C., N,N′-carbodiimidazole (6.32 g) was added thereto and stirred at 0° C. for 4 hours. A solution prepared by dissolving sodium borohydride (1.97 g) in water (10 mL) was dropwise added to the reaction liquid, and then stirred at 0° C. for 1 hour. Water was added thereto, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 100%, gradient) to give the entitled compound (7.01 g, 100%) as a colorless oil.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([O:36][CH3:37])[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH2:21][C:22]4([O:36][CH3:37])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(COc2cccc3ccc(-c4nnc5ccccn45)nc23)CCCNCC1
Yield: 50.2 %

Procedure:
tert-Butyl 4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-methoxyazepane-1-carboxylate (0.040 g, 0.079 mmol) was added to a mixture of trifluoroacetic acid and DCM (1:1) for 30 minutes, and the reaction was concentrated. Ethyl acetate was added and the suspension was filtered through a Waters filter (to remove any errant silica gel), and the filtrate was concentrated. DCM was added followed by precipitation with HCl dissolved in diethyl ether, evaporated, co-evaporated in diethyl ether to yield 16 mgs of the desired product as a yellow solid (95% pure by LC). MS ESI (+) m/z 404 (M+1) detected.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(O[C:16]([N:18]1[CH2:22][CH2:21][C@@H:20](COS(C)(=O)=O)[CH2:19]1)=O)(C)(C)C>C1(C)C=CC=CC=1>[OH:9][CH2:8][CH:7]([NH:10][CH2:16][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: Cc1ccccc1
Product: OCC(NCN1CCCC1)c1ccccc1
Yield: 126.8 %

Procedure:
A solution of (R)-(-)-phenylglycinol (2.20 g, 16.1 mmol) and (3R)-N-tert-butyloxycarbonyl-3-methylsulphonyloxymethylpyrrolidine (Intermediate 1 part b; 1.0 g, 3.58 mmol), in toluene (20 ml), was heated at 150° C. for 6 h in a sealed pressure tube (Aldrich). The solvent was then removed under vacuum and the residue taken up into ethyl acetate (200 ml) and washed with water (×4). The organic was dried (MgSO4) and evaporated and the crude product chromatographed on silica gel eluting with CH2Cl2 /MeOH (97:3) to give the title-α-(hydroxymethyl) benzylaminomethylpyrrolidine (1.0 g, 87%), δ (360 MHz,CDCl3) 1.45 (9H, s, OC(Me)3), 1.52-2.60 (5H, m, CH2 and CH), 2.90-3.76 (7H, m, 3 of CH2 and CH), 7.25-7.39 (5H, m, Ar--H).
Reaction SMILES: [F:1][C:2]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:29]>>[F:1][C:2]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:29])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Fc1ccc(F)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c1F
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of yellow mercuric oxide (1.23g, 0,056 mol), N-[3-(2,3,6-trifluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (2.00g 0.0047mol) and methanolic ammonia solution (40 ml) was stirred for 1 day at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent, trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 1.20 g (63%), m.p. 153°-156 ° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].FC1C=CC([B:23]([OH:25])[OH:24])=C(O[C@H](CC=C)C)C=1>>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([B:23]([OH:25])[OH:24])=[C:3]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:4]=1
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1Br
Product: C=CC[C@H](C)Oc1cc(F)c(F)cc1B(O)O
Yield: 100 %

Procedure:
Prepared from (S)-1-bromo-4,5-difluoro-2-(pent-4-en-2-yloxy)benzene in 100% yield following the same procedure as (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid. NMR is complex and suggests an oligomeric mixture. The material, however, was used as is and was fully compentent for undergoing a Suzuki coupling.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:41])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[O:15])[O:10][C:11]=1[CH2:12][CH3:13].NN>O1CCCC1.CO>[NH2:19][CH2:18][C@@H:17]([NH:16][C:14]([C:9]1[O:10][C:11]([CH2:12][CH3:13])=[C:7]([C:6]2[N:5]([CH3:41])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:15])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38]
Reactant: CCc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CCc1oc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Yield: 69.8 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide (250 mg, 0.43 mmol) in tetrahydrofuran (1.8 ml) and methanol (1.8 ml) at 25° C. was added hydrazine (0.13 ml, 4.27 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in Ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxamide (166 mg, 0.30 mmol, 70% yield) as a yellow solid: LCMS (ES) m/z=455, 457 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (br. s., 1H) 8.06 (br. s., 3H) 7.67 (s, 1H) 7.70 (d, J=7.83 Hz, 1H) 7.59 (d, J=4.29 Hz, 2H) 7.44 (d, J=4.04 Hz, 1H) 7.31 (d, J=5.81 Hz, 1H) 4.50-4.57 (m, 1H) 3.72 (s, 3H) 2.99-3.12 (m, 4H) 2.63 (q, J=7.33 Hz, 2H) 1.21 (t, J=7.45 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[N:9]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:10]([SH:13])=[N:11][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:7][C:8]1[N:9]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:10]([S:13][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[N:11][N:12]=1
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 2-chloroacetate (0.73 mL, 8.3 mmol) was added dropwise over 5 mins to a suspension of 5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol (2.24 g, 7.9 mmol) and potassium carbonate (1.21 g, 8.7 mmol) in DMF (40 mL) at room temperature. The reaction was stirred at room temperature for 24 h and slowly poured into a stirred ice-cold water solution. The tan precipitate was collected by vacuum filtration and dried under high vacuum at 50° C. for 16 h in the presence of P2O5 to yield methyl 2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Na].[CH3:10][SH:11].O>C(O)C>[CH3:10][S:11][C:2]1([Cl:1])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=C1CCCCC1Cl
Reactant: CS
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CSC1(Cl)CCCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
In a 300-ml egg-plant type flask 7.07 g (0.053 mol) of 2-chlorocyclohexanone was dissolved in 50 ml of ethanol, and 25 ml of 15% aqueous solution of sodium salt of methylmercaptan was added dropwise with a dropping funnel, and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into 300 ml of water, and an organic layer was extracted with methylene chloride, dried with magnesium sulfate and distilled to remove methylene chloride. After that reduced pressure distillation was performed to obtain 6.0 g of methylmercapto-2-chlorocyclohexanone (78% yield; b.p. 48.5°-47.5° C./0.3 mmHg).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22](=[O:27])C(Cl)(Cl)Cl)=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[CH:3][CH:2]=1.CS(C)=O.[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>C(#N)C>[C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:27])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[CH:5][CH:6]=1
Reactant: NCc1cccnc1
Reactant: O=C(c1ccc2n1Cc1ccccc1N(Cc1ccc(-c3ccccc3)cc1)C2)C(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(Cc1ccc(-c3ccccc3)cc1)C2
Yield: 12 %

Procedure:
To a solution of 10-(1,1′-biphenyl-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (0.93 g, 2.65 mmol) and N,N-dimethylaniline (0.51 mL, 3.98 mmol) in dry dichloromethane (30 mL) at 0° C. under nitrogen was added dropwise trichloroacetyl chloride (0.33 mL, 2.92 mmol). The ice bath was removed and the reaction mixture stirred at room temperature for 19 hours. The reaction mixture was then quenched by the addition of 2 M sodium hydroxide (30 mL) then partitioned between additional dichloromethane (75 mL) and 2 M sodium hydroxide (75 mL). The separated organic phase was washed with 2 M sodium hydroxide (75 mL) and water (75 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow syrup (2.12 g). Purification by flash chromatography using a solvent gradient of 1-5% ethyl acetate in hexane afforded 1-{10-[(1,1′-biphenyl)-4-ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-trichloroethanone (0.88 g, 67%) as a cream foam. To a solution of 1-{10-[(1,1′-biphenyl)-4-ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-trichloroethanone (0.4 g, 0.807 mmol) and dimethyl sulfoxide (0.29 mL, 4.034 mmol) in dry acetonitrile (5 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.17 mL, 1.613 mmol) and the reaction mixture was heated to reflux for 2 days. The cooled mixture was concentrated in vacuo, the semi-solid residue dissolved in ethyl acetate (50 mL), filtered and concentrated in vacuo to afford a dark brown syrup. Purification by flash chromatography using a solvent gradient of 0.5 to 3% methanol in dichloromethane afforded an orange semi-solid that was crystallized from dichloromethane/hexane to give the title compound (0.047 g, 12%) as a cream solid, m.p. 161-165° C. (dec.).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH:31]4[CH2:32][NH:33][CH2:34]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC4CNC4)c4ccc(OC(F)F)cc34)nc12
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a stirred solution of tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (80 mg, 114 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo and the residue dissolved in 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane. After 1 h, the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(1-azetidin-3-ylmethyl-5-difluoromethoxy-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (22 mg, 41%).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH2:17][CH:18]3[CH2:20][O:19]3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=3>>[NH2:1][CH2:20][CH:18]([OH:19])[CH2:17][N:7]1[C:6]2[CH:5]=[CH:4][C:3]([Br:2])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([Br:16])[CH:12]=2
Reactant: N
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Product: NCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A solution of NH3 (9.4 mL of 7M in MeOH, 65.6 mmol) was added to 3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (0.500 g, 1.31 mmol). The vial was tightly sealed and the reaction mixture was heated to 100° C. and stirred for 1 hour. Volatile components were removed under vacuum. The residue was suspended in CH2Cl2 and the white precipitate was filtered. The filtrate was saved and CH2Cl2 was removed under vacuum to afford 0.3413 g white solid as crude product, which contained about 50% unidentified side-product. This crude product was used as is in next step without any further purification. Purification by flash chromatography on silica gel provided pure material.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:37][C:38]([F:53])([F:52])[C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[C:42](O)=[O:43]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:42](=[O:43])[C:41]2[CH:45]=[C:46]([C:48]([F:49])([F:50])[F:51])[CH:47]=[C:39]([C:38]([F:37])([F:52])[F:53])[CH:40]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and 3,5-bis(trifluoromethyl)benzoic acid (31.0 mg) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)=[CH:18][CH:17]=1>>[C:1]([O:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)=[CH:20][CH:21]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(Cl)ccc1C(=O)O
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Product: CC(=O)Oc1cc(Cl)ccc1C(=O)Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Yield: 74 %

Procedure:
Using 2-acetoxy-4-chlorobenzoic acid and 1-(4-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: C[C:2]1([CH3:12])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH:10]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:3][CH:2]=[CH:12]2)=[CH2:11]
Reactant: CC1(C)C=Cc2ccccc2N1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a 0° C. solution of 7-vinylindole 1 (0.95 g, 6.6 mmol) in anhydrous tetrahydrofuran (60 mL) was added 1 M borane-tetrahydrofuran complex in tetrahydrofuran (9.95 mL, 9.95 mmol) and the reaction stirred overnight at room temperature. 1 N sodium hydroxide (25 mL) and 30% hydrogen peroxide (35 mL) were then added and the mixture stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated aqueous sodium chloride (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 50% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 0.60 g (56%) of the desired compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17])([O-])=O>>[N:1]1([S:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH2:7])(=[O:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C1CCNCC1
Product: Nc1ccccc1S(=O)(=O)N1CCCCC1
Yield: 58 %

Procedure:
The title compound (0.59 g, 58%) was obtained as a brown solid from piperidine and 2-nitrobenzenesulfonylchloride following the same procedure as described in preparation 2.