Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[K+:3].[CH2:4]([C:6]1[S:10][C:9](=[N:11][C:12]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]([OH:21])=[O:20])=[O:13])[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[N:7]=1)[CH3:5]>C(O)C>[CH2:4]([C:6]1[S:10][C:9](=[N:11][C:12]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]([O-:21])=[O:20])=[O:13])[N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:27][CH:28]=2)[N:7]=1)[CH3:5].[K+:3].[K+:3].[CH2:4]([C:6]1[S:10][C:9](=[N:11][C:12]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]([O-:21])=[O:20])=[O:13])[N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:27][CH:28]=2)[N:7]=1)[CH3:5]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)[O-])CCC2)s1
Reaction time: 8 h

Procedure:
In a mixed solution containing 15 ml of water and 16 ml of a 0.5N potassium hydroxide solution in ethanol, 2.0 g of 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazolin-2-yliden]aminocarbonyl]-1-cyclopentenecarboxylic acid was dissolved. From the resulting solution, the solvent was distilled off. To the residue, 50 ml of ethanol was added, and the resulting mixture was allowed to stand overnight. The crystals so precipitated were collected by filtration and dried, whereby 2.24 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])[CH:19]=[CH:18][C:3]=1[NH:4][C:5](=[O:17])[CH:6]([C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])Br.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])[CH:19]=[CH:18][C:3]=1[NH:4][C:5](=[O:17])[CH:6]([C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[N:41]1[C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]2[C:37]1=[O:47]
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(NC(=O)C(Br)C(=O)c2ccccc2C)c(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)c1ccc(NC(=O)C(C(=O)c2ccccc2C)N2C(=O)c3ccccc3C2=O)c(Cl)c1

Procedure:
29 g of 2'-chloro-4'-dodecyloxycarbonyl-2-methyl-α-bromo-benzoylacetanilide, 29 g of phthalimide and 20 g of triethylamine were stirred for 3 hours at room temperature in 200 ml of dimethylformamide. The reaction mixture was processed in a manner similar to Synthesis example 1 except for using ligroin for recrystallization to obtain 20 g of coupler 9 having a melting point of from 100° to 101° C.
Reaction SMILES: [C:1]1([S:7][CH:8]=[CH:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[S:18][C:17]([S:19][CH3:20])=[N:16][CH:15]=1>C(#N)C.C(N(CC)CC)C>[CH3:20][S:19][C:17]1[S:18][C:14]([NH:13][C:10](=[O:12])[CH:9]=[CH:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][N:16]=1
Reactant: O=C(O)C=CSc1ccccc1
Reactant: CSc1ncc(N)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1ncc(NC(=O)C=CSc2ccccc2)s1
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 3-(phenylthio)acrylic acid (3.69 g) in acetonitrile (50 mL) were added a solution of 5-amino-2-(methylthio)thiazole (3.00 g) in acetonitrile (10 mL) and triethylamine (2.80 mL) under ice-cooling. The mixture was stirred at the same temperature for 2 hours and then at room temperature for 3 hours, and then concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (50 mL), which was extracted with ethyl acetate (100 mL) twice. The organic layers were combined, washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain N-[2-(methylthio)thiazol-5-yl]-3-(phenylthio)acrylamide (1.90 g) as a dark yellow crystal.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([CH2:20][OH:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.O>CN(C)C=O.C(Cl)Cl>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([O:21][CH2:20][CH:9]2[CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCC1CN(c2ccccc2)CCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 20 h

Procedure:
Suspend 4-phenyl-1-(phenylmethyl)-2-piperazinemethanol (7.8 g, 27.6 mmol) in dimethylformamide under nitrogen and add 60% sodium hydride (1.22 g, 30.4 mmol). Stir for 20 h as solid slowly dissolves. Add 1-fluoro-4-nitrobenzene (4.29 g, 30.4 mmol) and stir at room temperature. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction, add water (100 mL) to the reaction mixture andextract with methylene chloride (2×100 mL). Remove the solvent in vacuo and recrystallize the residue from ethyl acetate/hexanes (1/1) (80 mL) to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[NH:8][CH2:9][CH2:10][N:11]=2)=[C:5]([N+:12]([O-])=O)[C:4]([CH3:15])=[N:3]1.[CH2:16](OC(OCC)OCC)C.CS(O)(=O)=O>C(O)C>[CH3:1][N:2]1[C:6]2[C:7]3[N:8]([CH2:9][CH2:10][N:11]=3)[CH:16]=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1nn(C)c(C2=NCCN2)c1[N+](=O)[O-]
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Cc1nn(C)c2c1N=CN1CCN=C21

Procedure:
The above nitro compound (8.4 g, 0.04 mol) is dissolved in 150 ml of methanol and hydrogenated (initial hydrogen pressure=51 psi) in the presence of 0.5 g of Raney nickel until the theoretical uptake of hydrogen is observed. The catalyst is removed by filtering; the filtrate is evaporated in vacuo to give 7.4 g (0.04 mol) of a purple oil (characterized by its IR-spectrum) of 2-(4-amino-1,3-dimethyl-5-pyrazolyl)imidazoline. This amine (7.4 g, 0.04 mol) is stirred under reflux 1.5 hr in a mixture of 20 ml absolute ethanol, 50 ml of triethylorthoformate and 1 ml of methanesulfonic acid. The mixture is evaporated in vacuo. The product is dissolved in methylenedichloride (100 ml) and washed with 100 ml of dilute ammonium hydroxide; the organic layer is dried over MgSO4 and evaporated in vacuo to give 7,8-dihydro-1,3-dimethyl-1H-imdazo[1,2-c]pyrazolo[3,4-e]pyrimidine 1.5 hydrate, mp 80°-82° C. from ethyl acetate-pet ether.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:53][OH:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:51])([F:52])[F:50])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:53]=[O:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: ClCCl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl) phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 17h (5.5 g, 7.2 mmol) in dichloromethane (200 mL) was added 2-iodoxybenzoic acid (4.1 g, 14.4 mmol) at −5° C. The mixture was stirred at −5° C. for 1 hour, and then refluxed at 45° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give the title compound 17i as pale yellow oil (5.3 mg, 96.3%). This material was not further purified.
Reaction SMILES: Cl(O[C:6]([C:44]1[CH:49]=[CH:48][C:47]([N:50]([CH2:53][CH3:54])[CH2:51][CH3:52])=[CH:46][CH:45]=1)([C:33]1[CH:38]=[CH:37][C:36]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:35][CH:34]=1)[CH:7]=[CH:8][CH:9]=[C:10]([C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=1)(=O)(=O)=O.[OH-:55].[Na+]>CO>[CH2:51]([N:50]([CH2:53][CH3:54])[C:47]1[CH:46]=[CH:45][C:44]([C:6]([C:33]2[CH:34]=[CH:35][C:36]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:37][CH:38]=2)=[CH:7][CH:8]([OH:55])[CH:9]=[C:10]([C:22]2[CH:23]=[CH:24][C:25]([N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:26][CH:27]=2)[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:49][CH:48]=1)[CH3:52]
Reactant: CCN(CC)c1ccc(C(=CC=CC(O[Cl+3]([O-])([O-])[O-])(c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)c1ccc(C(=CC(O)C=C(c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)cc1
Yield: 87 %

Procedure:
15.1 g of 1,1,5,5-tetra-(p-diethylaminophenyl)-2,4-pentadiene-1ol perchlorate prepared in Synthesis Example 5 was dissolved in 200 ml of methanol. To this solution, 2.53 g of sodium hydroxide was added. The mixture was refluxed for 2 hours and then cooled. Crystals separated out in the reaction mixture. The crystals were filtered off, washed with water several times, and dried in reduced pressure. The crystals were recrystallized from cyclohexane, whereby 11.7 g of 1,1,5,5-tetra-(p-diethylaminophenyl)-3-hydroxy-1,4-pentadiene was obtained in the form of light green crystals. The melting point of the product was 136.5° to 137.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[I-:11].[K+].CC1C=CC(S(NCl)(=O)=O)=CC=1>C(#N)C.O>[I:11][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:10]
Reactant: [I-]
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1cc(Br)cc(I)c1O
Temperature: 50 °C
Yield: 79.5 %

Procedure:
To a solution of 5-bromosalicylaldehyde (20.0 g, 0.1 mole) and potassium iodide (17 g, 0.1 mole) in acetonitrile (150 mL) and water (50 mL) in a 500 mL round bottom flask with magnetic stirrer was added chloramine T (23 g, 0.1 mole). The mixture was allowed to react for one hour. The reaction mixture was partitioned between hydrochloric acid (10%, 200 mL) and ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. To the residue was added hexanes and the reaction mixture heated to 50° C. for 15 minutes. The undissolved material was removed by filtration. The filtrate was concentrated in vacuo to leave canary yellow 3-iodo-5-bromosalicylaldehyde (26 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C@H:12]([CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:13][OH:14].C(N(CC)CC)C>ClCCl>[CH3:11][C@H:12]([CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH:13]=[O:14]
Reactant: COc1ccccc1SC[C@@H](C)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccccc1SC[C@@H](C)C=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
0.61 ml (0.007 mol) of oxalyl chloride and 20 ml of dichloromethane are introduced into a round-bottomed flask kept under an inert atmosphere. The mixture is cooled to −78° C. and then 1 ml (0.014 mol) of dimethyl sulfoxide is introduced. After stirring at −78° C. for 15 minutes, 1.5 g (0.007 mol) of 2-(S)-methyl-3-(2-methoxyphenylthio)propan-1-ol (XXb-1), in solution in 15 ml of dichloromethane, are added dropwise. The mixture is stirred at −78° C. for 1 hour and then 2 ml (0.014 mol) of triethylamine are added. After 15 minutes at −78° C., the mixture is reheated to −10° C. and stirred at this temperature for 45 minutes. The aldehyde is not isolated at this stage but is used in situ in the following reductive amination reaction.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH:2]([CH2:4][OH:5])[OH:3].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[Si:14]([O:5][CH2:4][CH:2]([OH:3])[C:1]([O:7][CH3:8])=[O:6])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(O)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: COC(=O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a solution of methyl glycerate (25.88 g, 215 mmol) and imidazole (22.0 g, 323 mmol, 1.5 eq) in tetrahydrofuran (250 mL) was added t-butyldiphenylsilyl chloride (53.0 mL, 204 mmol, 0.95 eq) at 0° C. After stirring for 18 h the reaction was quenched by the addition of saturated ammonium chloride and the aqueous phase was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and evaporated under reduced pressure. The crude material was purified by flash chromatography with a mixture of hexanes and ethyl acetate (80:20) to give the compound (68.89 g) in 94% yield.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N:12]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc2nc(N3CCNCC3)ccc2c1

Procedure:
A suspension of 3.65 g (0.022 mol) of 2-chloroquinoline, 6.88 g (0.08 mol) of piperazine and 1.12 g (0.02 mol) of potassium carbonate in 150 ml of toluene is refluxed for five hours. After cooling it is extracted twice with water, the organic phase is dried over sodium sulphate and the solvent is concentrated by evaporation. The residue is combined with methanol. Then it is filtered and the filtrate is concentrated by evaporation.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[C:9]2[O:10][C:11]3([O:17][C:8]=2[C:7]([C:18]([OH:20])=[O:19])=[CH:6][CH:5]=1)[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].COC(C)(C)C.CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:21][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3([O:17][C:8]=2[C:7]([C:18]([O:20][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:19])=[CH:6][CH:5]=1)[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3
Reactant: O=C(O)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
7-Difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylic acid (344 mg) was dissolved in dry DMF (3 mL). 4-Nitrophenol (226 mg) Ethyl-dimethylaminopropylcarbodiimide hydrochloride (312 mg) and N,N-Dimethyl-4-aminopyridine (198 mg) was added. After stirring at room temperature for 20 hours, aqueous work up with tert-Butyl methyl ether and chromatography of the organics in a gradient from 0 to 40% EtOAc in pentanes afforded the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Cl:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=2)[N:14]=1>C(O)(C)C>[ClH:12].[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:17]3[N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:21]=4)[N:14]=[CH:13][N:18]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: Cc1n[nH]c2cc(N)ccc12
Solvent: CC(C)O
Product: Cc1n[nH]c2cc(Nc3ncnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc12
Product: Cl

Procedure:
To a flask containing a magnetic stir bar was added 0.03 g (0.20 mmol) of 3-methyl-1H-indazol-6-amine and 0.060 g (0.20 mmol) of 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 2 mL of isopropanol and the resultant mixture was heated at reflux for ca. 16 hours. Upon cooling the reaction mixture a solid precipitated. The solid was filtered and washed with ethyl acetate (2×4 mL), acetonitrile (4 mL), and ethyl ether (4 mL) and dried under vacuum to give N2-(3-methyl-1H-indazol-6-yl)-N4-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diamine hydrochloride as a solid. The solid was purified by C-18 RP-HPLC using an acetonitrile/water gradient containing 0.5% trifluoroacetic acid buffer. Concentrating the proper fractions gave 0.015 g (10%) of N2-(3-methyl-1H-indazol-6-yl)-N4-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diamine trifluoroacetate as a white solid. HNMR: δ 12.4 (br s, 1H), 9.9 (br s, 1H), 8.34(s, 1H), 7.8 (br s, 1H), 7.67 (br s, 1H), 7.56 (d, 1H), 7.29(m, 2H), 7.02 (d, 1H), 4.34 (br s, 2H), 2.83 (br s, 3H), 2.40 (s, 3H). MS (ES+, m/z)=409 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.CO.C(I)(C)C>C(N(CC)CC)C>[CH:2]([NH2:1])([CH3:7])[CH3:3].[CH2:9]1[O:10][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=2[O:8]1
Reactant: Nc1ccc2c(c1)OCO2
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(C)I
Product: CC(C)N
Product: c1ccc2c(c1)OCO2

Procedure:
To a solution of 197 gms. of 1-amino-3,4-methylenedioxybenzene in 1500 mls. of methanol is added 110.3 mls. of isopropyl iodide and 154.8 mls. of triethylamine. The resulting solution is refluxed for 32 hours at the end of which time the solvent is stripped at reduced pressure. The oil thus obtained is extracted repeatedly with diethyl ether. The extracts are combined, filtered through Celite, and the ether stripped off to obtain 1-isopropylamine-3,4-methylenedioxybenzene as an oil.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[C:6]1([S:20]([OH:23])(=[O:22])=[O:21])[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[Na][Na]>>[C:6]1([S:20]([OH:23])(=[O:22])=[O:21])[C:15]2[CH:14]=[C:13]([S:1]([OH:5])(=[O:4])=[O:3])[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[C:10]=2[CH:9]=[C:8]([S:1]([OH:3])(=[O:5])=[O:4])[CH:7]=1
Reactant: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Reactant: O=S(=O)(O)O
Agent: [Na][Na]
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c2c1

Procedure:
To 240 ml. of 30-33% fuming sulfuric acid at 120° C. is added, portionwise, 60 g. of 1,5-naphthalenedisulfonic acid, disodium salt. The mixture is heated at 180°-190° C. for 23 hours. The solution is cooled, allowed to crystallize and filtered through a coarse, sintered glass funnel. The product is washed with concentrated sulfuric acid to give 1,3,5,7-naphthalenetetrasulfonic acid as an off-white pasty solid. Without further purification, the solid is added, portionwise, to 150 ml. of chlorosulfonic acid and the mixture is heated at 145°-150° C. for 1-5 hours. The mixture is cooled to room temperature and filtered. The product is washed, in order, with chlorosulfonic acid, methylene chloride, acetonitrile, water, acetonitrile and finally with ether. The product is air-dried and then dried further in an Abderhalden apparatus at 76° C. to provide 33.9 g. of the desired product as a colorless powder, mp. 263°-270° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([NH:18][C@:19]23[CH2:54][CH2:53][C@@H:52]([C:55]([CH3:57])=[CH2:56])[C@@H:20]2[C@@H:21]2[C@@:34]([CH3:37])([CH2:35][CH2:36]3)[C@@:33]3([CH3:38])[C@@H:24]([C@:25]4([CH3:51])[C@@H:30]([CH2:31][CH2:32]3)[C:29]([CH3:40])([CH3:39])[C:28]([C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47]C)=[O:46])=[CH:43][CH:42]=3)=[CH:27][CH2:26]4)[CH2:23][CH2:22]2)=[O:17])[C:13]1([CH3:59])[CH3:58])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([NH:18][C@:19]23[CH2:54][CH2:53][C@@H:52]([C:55]([CH3:57])=[CH2:56])[C@@H:20]2[C@@H:21]2[C@@:34]([CH3:37])([CH2:35][CH2:36]3)[C@@:33]3([CH3:38])[C@@H:24]([C@:25]4([CH3:51])[C@@H:30]([CH2:31][CH2:32]3)[C:29]([CH3:40])([CH3:39])[C:28]([C:41]3[CH:50]=[CH:49][C:44]([C:45]([OH:47])=[O:46])=[CH:43][CH:42]=3)=[CH:27][CH2:26]4)[CH2:23][CH2:22]2)=[O:17])[C:13]1([CH3:59])[CH3:58])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)[C@@H]3C[C@H](NC(=O)OCc4ccccc4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)[C@@H]3C[C@H](NC(=O)OCc4ccccc4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 4 h
Yield: 20.8 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1R,3S)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylcyclobutanecarboxamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (135 mg, 0.168 mmol) in THF (5 mL), MeOH (2 mL) was added a solution of lithium hydroxide monohydrate (0.014 mL, 0.504 mmol) in water (1 mL). The reaction mixture was stirred at 75° C. After 4 h, the mixture was concentrated to a white paste. The crude material was dissolved in THF (1.75 mL), MeOH (1 mL) and 1N HCl (0.25 mL) and injected into a reverse phase prep-HPLC using HPLC method 11 and dried in a vacuum oven to give the title compound (30.4 mg, 0.035 mmol, 21.09% yield) as white solid. LCMS: m/e 789.4 (M+H)+, 3.14 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (d, J=8.3 Hz, 2H), 7.41-7.37 (m, 4H), 7.36 (d, J=3.4 Hz, 1H), 7.25 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.6 Hz, 1H), 5.19-5.07 (m, 3H), 4.99 (br. s., 1H), 4.77 (s, 1H), 4.66 (s, 1H), 3.98-3.88 (m, 1H), 2.70-2.55 (m, 3H), 2.47-2.28 (m, 3H), 2.19-2.09 (m, 2H), 1.99-1.87 (m, 1H), 1.76 (d, J=7.8 Hz, 1H), 1.72 (s, 3H), 1.71-1.63 (m, 2H), 1.58 (d, J=8.1 Hz, 3H), 1.50 (br. s., 3H), 1.43 (br. s., 1H), 1.37 (br. s., 3H), 1.33 (d, J=12.2 Hz, 2H), 1.28 (s, 3H), 1.24 (d, J=7.1 Hz, 1H), 1.16 (d, J=12.2 Hz, 2H), 1.09 (s, 3H), 1.02 (s, 6H), 1.01 (br. s., 3H), 0.96 (s, 6H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.Cl.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][NH:28][CH2:29]2>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][N:28]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:29]2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: Clc1cccc2c1CNC2
Agent: Cl
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4cccc(Cl)c4C3)cn2)c1
Yield: 10 %

Procedure:
The title compound was prepared in 10% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-chloroisoindoline hydrogen chloride according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.15 (2H, m), 4.05 (4H, br s), 4.25 (2H, m), 7.19-7.27 (2H, m), 7.59 (1H, dd, J=4.9 Hz), 7.66 (1H, dd, J=6.7 and 3.0 Hz), 7.94 (1H, s), 8.11 (1H, s), 8.28 (1H, s), 8.33 (1H, s), 8.65 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H17ClN4O2, 369. Found, 369.