Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C1C(=O)N([I:24])C(=O)C1>CN(C=O)C>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:5][C:6]([CH2:9][CH3:10])=[C:7]([I:24])[N:8]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cnc(CC)c(NC(CC)CC)n1
Solvent: CN(C)C=O
Product: CCc1nc(NC(CC)CC)c(CC)nc1I
Yield: 74 %

Procedure:
A solution of 3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine, NIS (5.37 g, 23.9 mmol) and anhydrous DMF (100 mL) under N2 was heated at 50° C. for 4 h. The solution was partitioned between ethyl acetate and H2O and separated. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with H2O, brine and dried (MgSO4). The mixture was filtered and concentrated to give a brown oil which was purified by flash chromatography (20% ethyl acetate in heptane) to give 5.57 g (74%) of 3,6-diethyl-N-(1-ethylpropyl)-5-iodopyrazin-2-amine as a light brown oil. 1H NMR (400 MHz, CDCl3) δ 4.02 (m, 2 H), 2.76 (q, 2 H), 2.57 (q, 2 H), 1.60-1.70 (m, 2 H), 1.45-1.55 (m, 2 H) 1.20-1.30 (m, 6 H), 0.92 (q, 6 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:40][O:41][C@@H:42]1[CH2:46][CH2:45][NH:44][CH2:43]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:44]3[CH2:45][CH2:46][C@@H:42]([O:41][CH3:40])[CH2:43]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CCNC1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CO[C@@H]1CCN(CCc2nc(-c3ccc(Br)cc3)oc2C)C1
Yield: 76.9 %

Procedure:
Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.32 g, 0.89 mmole), anhydrous acetonitrile (4 mL), potassium carbonate (0.43 g, 3.11 mmol), potassium iodide (0.015 g, 0.09 mmol) and (3R)-3-methoxypyrrolidine 4-methylbenzenesulfonate (salt) (See Intermediate 59) (0.25 g, 0.91 mmol) to give the title compound as a pale orange oil (0.25 g): MS (m/e) (79Br/81Br): 365, 367(M+1)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[S:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccc(Br)cc2)cc1
Yield: 66 %

Procedure:
A solution of 4-bromobenzaldehyde (5 mmol) and 4-sulfamylphenyl-hydrazine hydrochloride was subjected to the General Procedure. The title compound, melting point 190–192° C., was obtained in 66% yield.
Reaction SMILES: CN(C=O)C.Cl[N:7]([C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1)[C:8]([CH3:10])=[O:9].O.O.[S:19]1([C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:23](=[O:24])[NH:22]1)(=[O:21])=[O:20].[Na]>O>[CH3:16][C:14]1[O:13][N:12]=[C:11]([NH:7][C:8](=[O:9])[CH2:10][N:22]2[C:23](=[O:24])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[S:19]2(=[O:20])=[O:21])[CH:15]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(=O)N(Cl)c1cc(C)on1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NC(=O)CN2C(=O)c3ccccc3S2(=O)=O)no1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
To 2.31 liters of DMF is added 479 grams (2.75 moles) of 3-(chloroacetamino)-5-methylisoxazole followed by 699 grams (2.9 moles) of sodium saccharin dihydrate. The mixture is heated to 100° C. and this temperature is maintained for 2 hours. The cooled reaction mixture is poured into 8 liters of water, filtered and the wet cake is recrystallized from 15 liters of ethanol to give 658 grams (74.8%) of 2,3,dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide 1,1-dioxide, mp 218°-220° C.; I.R. and NMR spectra are consistant with the structure.
Reaction SMILES: [P:1]([O:6]C)([O:4][CH3:5])[O:2][CH3:3].Cl[C:9]1[N:14]([CH3:15])[S:13](=[O:17])(=[O:16])[N:12]=[C:11]([O:18][CH3:19])[N:10]=1>C1(C)C=CC=CC=1>[CH3:15][N:14]1[S:13](=[O:17])(=[O:16])[N:12]=[C:11]([O:18][CH3:19])[N:10]=[C:9]1[P:1]([O:2][CH3:3])([O:4][CH3:5])=[O:6]
Reactant: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COC1=NS(=O)(=O)N(C)C(P(=O)(OC)OC)=N1
Temperature: 70 °C

Procedure:
145 parts of trimethyl phosphite were added, in the course of 40 minutes, to 165 parts of 5-chloro-6-methyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide in 550 parts of toluene at from 38° to 41° C., while stirring. The reaction mixture was heated to 70° C. in the course of 30 minutes, and stirring was continued at this temperature for 13/4 hours. Thereafter, the solution was decanted off from the small amount of tacky residue, and was freed from volatile constituents at 80° C./0.2 mbar. The residue was dissolved in 300 parts of ethyl acetate, and the solution was chromatographed over neutral aluminum oxide. After evaporating down under reduced pressure, 192 parts (96% of theory) of 6-methyl-3-methoxy-5-dimethylphosphono-6H-1,2,4,6-thiatriazine-1,1-dioxide of nD25 =1.4998 were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[CH:36]=[CH:37][CH:38]=[CH:39][C:40](Cl)=[O:41]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:40](=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][C:30]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:29]=2[Cl:28])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C=CC=Cc1ccc(Cl)cc1Cl
Reactant: Fc1ccc(CNCC=Cc2ccc(Cl)cc2)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=CC=Cc1ccc(Cl)cc1Cl)N(CC=Cc1ccc(Cl)cc1)Cc1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amine (1.49 g, 5.1 mmol), triethylamine (1.06 mL, 7.6 mmol, 1.5 eq.), DMAP (i.e., dimethylaminopyridine) (62 mg, 0.51 mmol, 0.1 eq.) in 15 mL dichloromethane at 0° C. was added a solution of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoyl chloride (6.3 mmol) in 15 mL dichloromethane and stirred for 1 hr. After aqueous work-up, the crude product was purified by chromatography with 20% ethyl acetate-hexanes to provide 2.05 g of 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:20])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([Cl:19])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOC(C)=O.O.C(=O)([O-])O.[Na+]>[CH2:21]([S:28][C:2]1[CH:3]=[C:4]([F:20])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([Cl:19])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1ccc(Oc2c(F)cc(Br)cc2C#N)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2c(F)cc(SCc3ccccc3)cc2C#N)cc1Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
The title compound was prepared according to the method described for Preparation at reflux using 5-bromo-2-(4-cyano-3-chlorophenoxy)-3-fluorobenzonitrile (Preparation 41) and benzyl mercaptan. The reaction was allowed to cool to room temperature and diluted with EtOAc (100 mL), water (50 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL). The organic was separated and the aqueous was re-extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was absorbed onto silica and purified by silica gel column chromatography eluting with 10% EtOAc in heptanes to afford the title compound as a yellow solid (115 mg, 28%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:20]=[C:19]([C:21]([F:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:18]=[C:17]([Cl:31])[C:15]=1[NH2:16]>N1C=CC=CC=1.O>[Cl:13][C:14]1[CH:20]=[C:19]([C:21]([F:30])([C:26]([F:27])([F:28])[F:29])[C:22]([F:25])([F:24])[F:23])[CH:18]=[C:17]([Cl:31])[C:15]=1[NH:16][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Cl
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
4-Nitrobenzoyl chloride (4.55 g) was dissolved in a pyridine (30 ml) solution of 2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)aniline (2.7 g). The solution was refluxed under heating for 3 hours. After cooling to room temperature, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml), and an aqueous solution (5 ml) containing sodium hydroxide (2.0 g) was added, and then stirred at room temperature for 4 hours. The reaction solution was extracted twice with ethyl acetate. The organic phases were combined, washed with 1 N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The drying agent (i.e., anhydrous magnesium sulfate) was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-4-nitrobenzamide (3.27 g, yield 83.4%).
Reaction SMILES: [CH2:1](C([SnH3])=C(CCCC)CCCC)[CH2:2]CC.[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[C:31](I)[CH:32]=3)[N:27]([CH3:37])[CH:26]=2)=[O:24])=[CH:19][CH:18]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][NH:22][C:23]([C:25]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH:1]=[CH2:2])[CH:32]=3)[N:27]([CH3:37])[CH:26]=2)=[O:24])=[CH:19][CH:18]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Product: C=Cc1ccc2c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Tributylvinylstannane (0.32 mL) is added to a solution of N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.45 g) from Preparation No. 39 and PdCl2(PPh3)2 (70 mg). The mixture is stirred at room temperature for 1 h and then is heated to 60° C. for 30 min. After cooling to room temperature, the reaction mixture is poured into water (60 mL), filtered, and washed with water (20 mL) and diethyl ether (20 mL). The crude product is purified by recrystallization from acetonitrile to afford 0.20 g (57%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.I[C:16]1[C:21]2[S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:20]=2[CH:19]=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.O1CCOCC1>[CH:19]1[C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[S:22][C:21]=2[C:16]([N:6]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:17][CH:18]=1
Reactant: Ic1cccc2c1sc1ccccc12
Reactant: Fc1ccc2[nH]c3ccccc3c2c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Fc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Yield: 48.1 %

Procedure:
A mixture of 6.7 g (36.2 mmole) 3-fluoro-9H-carbazole, 11.2 g (36.2 mmole) of 4-iododibenzo[b,d]thiophene, 17.1 g (90 mmole) of copper(I) iodide, 19.1 g (90 mmole) of potassium phosphate, 10.3 g (90 mmole) of trans-1,2-cyclohexanediamine and 1,4-dioxane 700 ml were refluxed under nitrogen for about overnight. Then, the solution was filtered at 110° C. To receive the filtrate, And the 1,4-dioxane was removed under reduced pressure from the filtrate. The filtrate was extracted with 500 ml dichloromethane and 2000 ml water, the organic layer was dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-ethyl acetate) to give product 6.4 g (48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([CH3:22])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([CH3:22])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc2c(c1)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1cnc2c(c1)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to Example 3, intermediate n) from (R)-4,7-dimethyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium cyanoborohydride.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[S:10](=[O:21])(=[O:20])[CH2:11][C:12]3[N:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:18]=2[OH:19])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[Br:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[S:10](=[O:21])(=[O:20])[CH2:11][C:12]3[N:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:18]=2[O:19][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=S1(=O)Cc2nccnc2C(O)=C1c1c(F)ccc(Br)c1Cl
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)OC1=C(c2c(F)ccc(Br)c2Cl)S(=O)(=O)Cc2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(3-bromo-2-chloro-6-fluoro-phenyl)-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-ol (Compound C21 of Table C) (0.5 g) in dichloromethane (5 ml) at 0° C. was added pyridine (0.12 ml) followed by drop wise addition of isobutyryl chloride (0.142 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: 0-100% v/v ethyl acetate in hexane) to give isobutyric acid 7-(3-bromo-2-chloro-6-fluoro-phenyl)-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-yl ester (0.17 g) 1H-NMR (400 MHz, CDCl3): 1.15 (6H, d), 2.80 (1H, quin), 5.00 (2H, s), 7.10 (1H, t), 7.70 (1H, m), 8.65 (1H, d), 8.70 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH:9]=[N:8]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[N:8]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(CCc5cccc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 38.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorophenethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methane sulfonamide (27 mg, 0.0409 mmol) was hydrolyzed by lithium hydroxide (34 mg, 0.818 mmol) in THF/methanol/water (2/2/1 ml) to yield 8 mg (40.0% yield) of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.7 (s, 1H), 9.04 (s, 1H), 8.43-8.42 (d, 1H), 8.176-8.170 (d, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.69-7.68 (d, 1H), 7.58-7.57 (m, 2H), 7.32-7.19 (m, 2H), 7.06-7.01 (m, 2H), 4.33-4.38 (t, 2H), 3.89 (s, 3H), 3.21-3.16 (t, 2H), 3.00 (s, 3H). MS: m/z=506.1 (M+1), HPLC: 91.31% in method B.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24])[O:12]1.[NH3:27]>CN(C)C=O.CO>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23]([NH2:27])(=[O:25])=[O:24])[O:12]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(=O)(=O)Cl)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: N
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
2-[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]ethanesulfonyl chloride (100.0 mg, 0.0002362 mol) was dissolved in N,N-Dimethylformamide (2.0 mL). 7.00 M of Ammonia in Methanol (0.500 mL) was added at 0° C. and the mixture was stirred for 30 minutes, allowing to warm to room temperature. The reaction was concentrated in vacuo and the residue was diluted with brine and extracted with EtOAc. The organic phase was brine washed, water washed and evaporated. The residue was purified by flash chromatography (0 to 100% EtOAc/Hexanes) to yield the product (40 mg, 42%).
Reaction SMILES: ClC1C=CC(C2(O)CCN(CCC=C3C4C(=NC=CC=4)OC4C=CC=C(OCC(OCC)=O)C=4C3)CC2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2([OH:82])[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH:55]=[C:56]3[C:66]4[C:61](=[N:62][CH:63]=[CH:64][CH:65]=4)[O:60][C:59]4[CH:67]=[CH:68][CH:69]=[C:70]([O:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][C:77]([O:79]CC)=[O:78])[C:58]=4[CH2:57]3)[CH2:49][CH2:48]2)=[CH:43][CH:42]=1>>[C:77]([CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][O:71][C:70]1[C:58]2[CH2:57][C:56](=[CH:55][CH2:54][CH2:53][N:50]3[CH2:49][CH2:48][C:47]([C:44]4[CH:43]=[CH:42][C:41]([Cl:40])=[CH:46][CH:45]=4)([OH:82])[CH2:52][CH2:51]3)[C:66]3[C:61]([O:60][C:59]=2[CH:67]=[CH:68][CH:69]=1)=[N:62][CH:63]=[CH:64][CH:65]=3)([OH:79])=[O:78]
Reactant: CCOC(=O)CCCCCOc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: CCOC(=O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: O=C(O)CCCCCOc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of Example 133, but replacing the product of Example 48 with the product of step 1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[C:19]([C:42]([F:45])([F:44])[F:43])=[N:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:17][C:18]1[C:19]([C:42]([F:45])([F:43])[F:44])=[N:20][N:21]([C:23]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1
Reactant: Cn1[nH]c(=O)c2c1[C@@]1(C)CC[C@@H]2C1(C)C
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1C(F)(F)F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 58.7 %

Procedure:
A solution of (4R,7S)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 48; 250 mg, 1.2 mmol) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole (Intermediate 2; 580 mg, 1.2 mmol) in dimethylformamide (12 mL) was heated at 100° C. for 4.5 h. The solvent was evaporated and the residue was purified on a Biotage 40S chromatography system, eluting with 0-3% methanol/dichloromethane. Fractions homogeneous for the product were concentrated and the residue held under high vacuum to give (4R,7S)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (420 mg, 58%) as a viscous golden orange oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([NH2:21])[C:16]([NH2:20])=[CH:17][C:18]=1[Cl:19]>FC(F)(F)C(O)=O.Cl>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:18]([Cl:19])=[CH:17][C:16]2[N:20]=[C:3]([C:2]([F:23])([F:22])[F:1])[NH:21][C:15]=2[CH:14]=1
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2C(F)(F)F)cc1N
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)F)nc3cc2Cl)c(C(F)(F)F)c1
Yield: 72.4 %

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (6 g, 20.1 mmol) in dioxane (100 ml) and water (10 ml) which was purged and maintained with an inert atmosphere of nitrogen was added[2,4-bis(trifluoromethyl)phenyl]boronic acid (10.3 g, 40.01 mmol), K3PO4 (8.6 g, 40.70 mmol) and Pd(pph3)4 (2.3 g, 2.04 mmol) at room temperature. The resulting solution was stirred overnight at 95° C. in an oil bath. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 2% to 3% ethyl acetate in petroleum ether to produce 4-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-nitroaniline as a crude light yellow solid (2.2 g, crude). Next, to a solution of 4-[2,4-bis(trifluoro-methyl)phenyl]-5-chloro-2-nitroaniline (2.2 g, crude) in ethanol (50 ml) was added hydrogen chloride (conc, 1.5 ml) and Zn powder (2.2 g, 33.85 mmol). The resulting solution was stirred for 2 h at 90° C. in an oil bath. The reaction was then quenched by the addition of water (300 ml), adjusted pH to 8 with aqueous sodium carbonate and then extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (200 ml), dried and concentrated under vacuum to produce 4-[2,4-bis(trifluoromethyl) phenyl]-5-chlorobenzene-1,2-diamine as a crude brown solid (1.75 g, crude). Finally, a Solution of 4-[2,4-bis(trifluoromethyl)phenyl]-5-chlorobenzene-1,2-diamine (300 mg, crude) in trifluoroacetic acid (10 ml) and hydrogen chloride (conc, 2 ml) was stirred overnight at 80° C. in an oil bath. The solution was evaporated and dissolved in water (30 ml), adjusted to pH 8 with aqueous sodium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 6-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-(trifluoromethyl)-1H-1,3-benzodiazole as a off-white solid (132.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[I:12]Cl>CC(O)=O.CC([O-])=O.[Na+]>[Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-chloro-2-nitroaniline by iodination with iodine monochloride in HOAc/NaOAc according to the general procedure A (80° C.). Obtained as an orange solid.