Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2([C:33](=[O:42])[NH:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:17]2([C:33](=[O:42])[NH:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)(=[O:15])=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)NOC2CCCCO2)(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(NOC1CCCCO1)C1(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CCNCC1

Procedure:
4-((4-Phenoxyphenyl)sulfonyl)-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)piperidine was synthesized as shown in FIG. 13. A 200 ml RBF equipped with magnetic stir bar was charged with the 1.5 g of benzyl 4-((4-phenoxyphenyl)sulfonyl)-4-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)piperidine-1-carboxylate compound and 100 mg wet Degussa 5% Palladium on Carbon in 45 ml Methanol. The reaction mixture was purged with Argon for 5 minutes. Hydrogen was then bubbled over the solution for 1 hr. MS analysis (direct infusion) at this point indicated that the reaction was complete. The crude was filtered through Celite and the Celite was washed with 40 ml additional methanol. The methanol solution was concentrated in vacuo to 1.2 g white solid that was vacuum dried for 4 hours to yield 1.1 g product that was used in Step 5. HRMS(observed) M H=451.1737 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][N:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>C(#N)C>[CH3:1][C:2]1[CH2:6][N:5]([C:7]([CH3:11])([CH3:12])[C:8]([O:10][CH2:28][CH:27]=[CH2:26])=[O:9])[C:4](=[O:13])[C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)C1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOC(=O)C(C)(C)N1CC(C)=C(c2ccccc2)C1=O
Yield: 80.6 %

Procedure:
1.5 g (5.8 mmol) of 2-(4-methyl-2-oxo-3-phenyl-3-pyrrolin-1-yl)isobutyric acid was dissolved in 50 ml of acetonitrile, and 0.83 g (6 mmol) of potassium carbonate and 0.73 g (6 mmol) of allyl bromide were added thereto. The mixture was refluxed under heating for 1 hour. After completion of the reaction, acetonitrile was distilled off, and ice water was added to the residue. The mixture was extracted with ethyl acetate. The extract was treated by a conventional method to obtain 1.7 g of a crude product. This crude product was purified by column chromatography to obtain 1.4 g (yield: 82%) of the desired product having a melting point of from 65° to 67° C.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7][CH2:8][S:9]([CH3:11])=[O:10])=[CH:3][CH:2]=1.[H-].[Na+].[C:15](#[N:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)Cl>C1COCC1.O>[CH3:11][S:9]([C:8]([S:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=1)=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10]
Reactant: Cc1ccc(SCS(C)=O)cc1
Reactant: N#Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(SC(=C(N)c2ccccc2)S(C)=O)cc1
Temperature: 25 °C

Procedure:
1.20 Grams of methyl p-tolylthiomethyl sulfoxide was dissolved in 15 ml of THF, and added with 165 mg of sodium hydride under cooling with ice, followed by stirring for an hour at room temperature. Then 1 ml of benzonitrile was added to the solution, and stirred for 16.5 hours at room temperature and for 5 hours at 60°C., followed by addition of methylene chloride and 2 ml of water. After drying with Glauber's salt and filtration, the filtrate was concentrated under reduced pressure. The residue was washed with cyclohexane to obtain 1.212 g of 1-methylsulfinyl-1-(p-tolylthio)-2-amino-2-phenylethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:62]3[CH2:63][CH2:64][N:59]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH3:52])[CH2:60][CH2:61]3)[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC2CO2)C1
Reactant: Cc1ccccc1N1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)c([N+](=O)[O-])c3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A solution of 1-[3-(4-chloro-3-nitro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.754 g, 2.0 mmol) in dichloromethane (10 mL) was treated with ytterbium(III) triflate (0.25 g, 0.40 mmol) and 1-(2-methylphenyl)-piperazine (0.705 g, 4.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and diluted with dichloromethane (100 mL) and water (50 mL). The organic layer was separated, washed with water (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH/CH2Cl2) to afford 0.98 g (90%) of the desired product as a light yellow solid. MS (electrospray): m/z 553.2 (553.2, calculated for C28H33ClN6O4, [M+H]+). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 8.25-8.15 (m, 1H), 7.75-7.70 (m, 1H), 7.63-7.55 (m, 1H) 7.20-7.10 (m, 2H), 7.05-6.95 (m, 2H), 4.90-4.70 (m, 1H), 4.65 (s, 1H), 4.30-4.15 (m, 2H), 4.10-3.70 (m, 4H), 3.00-2.40 (m, 12H), 2.20 (s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).
Reaction SMILES: [C:1]1(NC(N)=O)C=CC=CC=1.[C:11]1([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])C=CC=CC=1>>[C:21]1([NH:20][C:18]([N:17]([CH3:11])[CH3:1])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Reactant: NC(=O)Nc1ccccc1
Product: CN(C)C(=O)Nc1ccccc1

Procedure:
Phenylurea or 1,3-diphenylurea; 83(22):180415j.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([C:9]#[N:10])=O.C(=O)(O)O.[NH2:20][NH:21][C:22]([NH2:24])=[NH:23]>O>[C:22]([NH:21][N:20]=[C:7]([C:9]#[N:10])[C:6]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:5]=1[Cl:4])(=[NH:23])[NH2:24]
Reactant: N=C(N)NN
Reactant: N#CC(=O)c1cccc(Cl)c1Cl
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: N#CC(=NNC(=N)N)c1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
Reactor (0.5 L) was charged under nitrogen with acetonitrile (200 ml) and polyphosphoric acid (220 g), and the mixture was stirred for 0.5 hour to obtain an emulsion. Solid 2,3-dichlorobenzoyl cyanide (41 g, 0.2 mole; assay 97.5%) was added to the emulsion. Aminoguanidine bicarbonate (41 g, 0.3 mole; assay 99.0%) was added to the mixture in 5 equal portions during 2 hours at 30-40° C. The reaction mixture was stirred at 50° C. during 22 hours. Water (40 ml) was then added to the reaction mixture to obtain a clear homogeneous mixture. The mixture was dropped to water at slow stirring for 0.5 hour, and the precipitate was collected by filtration to give wet phosphate salt of 2,3-dichlorobenzoyl cyanide amidinohydrazone.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:6]=1[N+:18]([O-])=O)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:7][C:6]=1[NH2:18])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Oc1ccc(N2CCN(C)CC2)cc1N
Reaction time: 22 h
Yield: 62.9 %

Procedure:
A mixture of 0.57 g of 1-(4-isopropoxy-3-nitrophenyl)-4-methylpiperazine and 65 mg of 10% palladium-on-carbon in 200 ml of ethanol is hydrogenated at 25° C. under 1 bar for 22 h. The mixture is filtered on Clarcel and the Clarcel is rinsed with methanol. The filtrate is concentrated to dryness under reduced pressure and the residue is purified by chromatography on a 25 g silica cartridge, elution being carried out with pure dichloromethane and then successively with 98/2 and 95/5 v/v dichloromethane/methanol mixtures at a flow rate of 30 ml/min, so as to obtain 0.32 g of 2-isopropoxy-5-(4-methylpiperazin-1-yl)phenylamine in the form of a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=[O:8])[C:3]1=[O:11].C[Si](C)(C)[O-].[K+].Cl>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[C:3]1=[O:11]
Reactant: COC(=O)C1CCN(C)C1=O
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A 250 mL round-bottomed flask was charged with methyl 1-methyl-2-oxopyrrolidine-3-carboxylate (1.89 g, 12.0 mmol), potassium trimethylsilanolate (4.64 g, 36.1 mmol), and THF (100 mL). The reaction mixture was stirred at room temperature overnight, then HCl (50 mL, 2.0 M in Et2O) was added and the reaction mixture was stirred for 5 minutes. The solid was removed by filtration and the filtrate concentrated to give the crude product 1.28 g (74.2%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.40-3.49 (m, 3H), 2.94 (s, 3H), 2.37-2.47 (m, 2H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]1([CH3:25])[C:13]([C:18]([NH:20][CH2:21][CH:22]([OH:24])[CH3:23])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1>ClCCl>[C:12]1([CH3:25])[C:13]([C:18]([NH:20][CH2:21][C:22](=[O:24])[CH3:23])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccccc1C(=O)NCC(C)O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)CNC(=O)c1ccccc1C
Yield: 81.2 %

Procedure:
Pyridinium chlorochromate (15.91 g) was added to 143 ml of a suspension of 7.13 g of 1-(o-toluoylamino)-2-propanol and 15.91 g of celite in dichloromethane with stirring. The mixture was stirred for 4 hours at room temperature. The reaction solution was purified by silica gel column chromatography (Wakogel® C-200, chloroform) and the solvent was distilled off under reduced pressure. The eluate was purified again by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=1:2) to provide 5.73 g of the objective compound as colorless crystals. M.p. 65-66° C.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH2:10]([CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)[CH3:11]>>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:12]2[CH2:10][CH3:11])[C:7]=1[F:8]
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CCC1CCCCCN1
Product: CCC1CCCCCN1c1ncnc(Cl)c1F
Reaction time: 1 h
Yield: 97.2 %

Procedure:
0.4 g of 4,6-dichloro-5-fluoropyrimidine and 0.61 g of 2-ethylhexahydro-1H-azepine were mixed and left for 1 hour at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.6 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-2-ethylhexahydro-1H-azepine.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:6]=[C:5]([N+:14]([O-:16])=[O:15])[C:4]=1[OH:17]>Br>[N+:14]([C:5]1[CH:6]=[C:7]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:8]=[C:3]([OH:2])[C:4]=1[OH:17])([O-:16])=[O:15]
Reactant: COc1cc(-c2nnn[nH]2)cc([N+](=O)[O-])c1O
Agent: Br
Product: O=[N+]([O-])c1cc(-c2nnn[nH]2)cc(O)c1O
Reaction time: 8 h

Procedure:
4.0 g of 2-methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenol are treated with 40 ml of constant-boiling hydrobromic acid, whereupon the mixture is stirred at 140° for 8 hours under a nitrogen atmosphere. After cooling, the mixture is poured on to ice. The separated precipitate is filtered under suction and recrystallized from ether. There is obtained 3-nitro-5-(1H-tetrazol-5-yl)-pyrocatechol in the form of orange crystals of m.p. >240° (dec.).
Reaction SMILES: [ClH:1].C([O:4][C:5]([CH:7](C(OCC)=O)[CH2:8][CH2:9][CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][N:11]1[CH2:23][CH3:24])=[O:6])C>CO>[ClH:1].[C:5]([CH2:7][CH2:8][CH2:9][CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][N:11]1[CH2:23][CH3:24])([OH:6])=[O:4]
Reactant: CCOC(=O)C(CCC1c2[nH]c3ccccc3c2CCN1CC)C(=O)OCC
Agent: Cl
Solvent: CO
Product: CCN1CCc2c([nH]c3ccccc23)C1CCCC(=O)O
Temperature: 120 °C
Reaction time: 7 h
Yield: 73.5 %

Procedure:
2 ml of methanol, 2 ml of conc. hydrochloric acid and 10 ml of 10% hydrochloric acid were added to 0.7 g of 1,2,3,4-tetrahydro-1-[3,3-bis(ethoxycarbonyl)propyl]-2-ethyl-β-carboline, and the mixture was stirred at 120° C. for 7 hours. After the reaction was completed, the mixture was evaporated under reduced pressure to remove solvent. The residue thus obtained was recrystallized from a mixture of ethanol and ether. 0.49 g of 1,2,3,4-tetrahydro-1-(3-carboxypropyl)-2-ethyl-β-carboline hydrochloride was obtained. M.p. 194°-197° C. (decomp.) Yield: 73.5%
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[S:4]([OH:7])(=[O:6])=[O:5].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1.Cl>O>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([NH:12][C:10]3[CH:9]=[CH:8][C:3]([S:4]([OH:7])(=[O:5])=[O:6])=[C:2]([Cl:1])[CH:11]=3)=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(S(=O)(=O)O)c(Cl)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: O
Product: O=S(=O)(O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1Cl

Procedure:
9.9 Grams of 2-chloro sulphanilic acid and 9.4 grams of 4,7-dichloroquinoline were suspended in 200 milliliters of water and concentrated hydrochloric acid added until the solution was just acid. The mixture was refluxed for 4 hours when a solid began to precipitate. After cooling the solid was collected, washed with water and dried to give 15.8 grams of 4-(7-chloro-4-quinolylamino)-2-chlorobenzenesulphonic acid. Melting point 280°-285°C with decompostion.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([CH3:29])=[CH:24][C:25]([OH:28])=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][N:32]1[C:36]([CH2:37]O)=[CH:35][C:34]([C:39]([F:42])([F:41])[F:40])=[N:33]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([CH3:29])=[CH:24][C:25]([O:28][CH2:37][C:36]3[N:32]([CH3:31])[N:33]=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:35]=3)=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1
Reactant: COC(=O)Cc1csc2c(F)c(O)cc(C)c12
Reactant: Cn1nc(C(F)(F)F)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(F)c(OCc3cc(C(F)(F)F)nn3C)cc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a mixture of tri-n-butylphosphine (0.338 mL), methyl(7-fluoro-6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetate (131.3 mg), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (93 mg) and THF (4.0 mL) was added ADDP (284 mg) at room temperature. The mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (205.9 mg). The compound was crystallized from EtOAc-hexane.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12].[CH3:13][O:14][CH2:15]Br>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH2:13][O:14][CH3:15]
Reactant: COc1ccc(Br)c(O)c1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(OC)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 92410.5 %

Procedure:
To a suspension of NaH (2.5 g, 0.06 mol) in dry DMF (100 mL) at 0° C. was added solution of 1-bromo-2-hydroxy-4-methoxybenzene (10.6 g, 0.05 mol). After stirring at 0° C. for 30 min. bromomethyl methyl ether (7.8 g, 0.06 mmol) were dropwise added. The mixture was warmed to room temperature over 20 min. and then stirred for 2 h, it was then quenched cautiously by the addition of cold dilute HCl and extracted with EtOAc. The EtOAc extract was washed successively with; H2O, 5% aqueous NaHCO3, H2O and finally brine. After drying (MgSO4) filtration and evaporation gave liquid. The product was purified by distillation (85° C., 0.2 mm Hg) to give the title compound as a colorless oil (13.7 g, 97%).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:7])[CH3:6])C>[OH-].[Na+]>[C:31]([O:30][C:28]([NH:27][CH2:26][CH2:25][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:35])=[O:3])[CH:9]=2)[NH:13][C:12]=1[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNC(=O)OC(C)(C)C)c2c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 90 °C
Yield: 102.1 %

Procedure:
To a stirred solution of 2-[3-(2-tertbutoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H--indol-5 -yl]-2-methyl-propionic acid ethyl ester (1.28 g in 25 mL ethanol) was added 30 mL of 0.5N sodium hydroxide and the mixture heated to 90° C. on an oil bath. After 30 hours the mixture was concentrated in vacuo, diluted with water and extracted with diethyl ether (3×). The aqueous layer was then made acidic by the addition of 0.5N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.23 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=1)(=O)=O.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([NH:24][C:25]2[CH:26]=[C:27]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=2)=[N:8]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C(C)(C)C
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1nccc2c1c(Nc1cccc(S(N)(=O)=O)c1)nn2C(C)(C)C
Yield: 13.9 %

Procedure:
To a solution of 1-tert-butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (200 mg) obtained in Step C of Example 86 in toluene (20 ml) were added 3-aminobenzenesulfonamide (146 mg), tris(dibenzylideneacetone)dipalladium (51.8 mg), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(92.6 mg) and cesium carbonate (369 mg), and the mixture was heated overnight with reflux under nitrogen atmosphere. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (29.6 mg).
Reaction SMILES: [C:1]([S:5]([NH:7][C:8]1([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[O:20]>>[C:1]([S:5]([NH:7][C:8]1([CH:12]([CH3:16])[C:13]([O:15][CH2:18][C:19](=[O:20])[C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)=[O:14])[CH2:9][O:10][CH2:11]1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C(=O)O)C1(NS(=O)C(C)(C)C)COC1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Product: CC(C(=O)OCC(=O)c1ccc(OC(F)(F)F)cc1)C1(NS(=O)C(C)(C)C)COC1
Yield: 66.1 %

Procedure:
Prepared by Method E using 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}propanoic acid (Preparation 26, 1.18 g, 4.733 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]-ethanone (1.47 g, 5.21 mmol). The residue was purified by silica gel column chromatography to afford the title compound (1.413 g, 66% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:31][C@@H:32]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[C:6]([C:8](=[O:10])[NH2:9])[N:7]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:10])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:4][C:3]=1[NH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(Br)nc4C(N)=O)cc3)CC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCN(C2CCN(c3ccc(Nc4nc(N[C@@H]5CCNC5)c(Br)nc4C(N)=O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
To a mixture of tert-butyl (3R)-3-{[3-bromo-5-carbamoyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (800 mg) was added 4 M hydrochloric acid (12.2 mL), followed by stirring at room temperature for 4 hours. To the reactant was added a 10% aqueous potassium carbonate solution, followed by extraction with a mixed solvent of chloroform:isopropanol (4:1). The organic phase was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated to obtain 6-bromo-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-[(3R)-pyrrolidin-3-ylamino]pyrazine-2-carboxamide (400 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[C@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[O:18])N(OC)C)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br-].O.Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[C@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[O:18])[CH2:10][CH2:9][CH:8]=[CH2:12])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)[C@@H]1CC[C@H](N(Cc2ccc(-c3ccccc3)cc2)C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)[C@@H]1CC[C@H](N(Cc2ccc(-c3ccccc3)cc2)C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.5 %

Procedure:
While under a nitrogen atmosphere, a solution of tert-Butyl-biphen-4-ylmethyl-{(1S,3R)-3-(methoxy(methyl)carbamoyl)-cyclopentyl}-carbamate (1.2 g, 2.74 mmol), in tetrahydrofuran (20 mL) was cooled to 0° C. and treated with 3-butenylmagnesiun bromide (0.5 M in THF, 13.7 mL, 6.85 mmol) in a drop wise manner. The solution was stirred for 1 hour at 0° C. then allowed to warm to room temperature overnight. The resulting solution was poured into water, acidified to pH 3-4 with 1 N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-30% ethyl acetate in heptane) gave tert-Butyl-biphen-4-ylmethyl-{(1S,3R)-3-pent-4-enoylcyclopentyl}-carbamate as a colorless oil (1.12 g, 94%); 1H NMR (CDCl3, 400 MHz) δ 7.62 d, J=7.5 Hz, (2H), 7.56 (d, J=7.5 Hz, 2H), 7.46 (t, J=7.5 Hz, 2H), 7.36 (m, 1H), 7.28 (m, 2H), 5.80 (m, 1H), 5.01 (m, 2H), 4.48 m, (3H), 2.92 (m, 1H), 2.54 (m, 2H), 2.37 (m, 2H), 2.04 (m, 1H), 1.74-1.94 (m, 4H), 1.48-1.66 (m, 1H), 1.43 (s, 9H).