Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O)(C)C.C(N=C=NC(C)C)(C)C.[CH3:22][CH2:23][C@@:24]1([OH:47])[C:29](=[O:30])[O:28][CH2:27][C:26]2[C:31]([N:33]3[C:45](=[CH:46][C:25]1=2)[C:44]1[N:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]2)=[CH:36][C:35]=1[CH2:34]3)=[O:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CS(C)=O>[CH3:22][CH2:23][C@@:24]1([OH:47])[C:29](=[O:30])[O:28][CH2:27][C:26]2[C:31]([N:33]3[C:45](=[CH:46][C:25]1=2)[C:44]1[N:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]2)=[CH:36][C:35]=1[CH2:34]3)=[O:32].[NH2:8][CH2:9][C:10]([O-:12])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: NCC(=O)[O-]
Temperature: 25 °C

Procedure:
All chemicals, unless otherwise indicated, were purchased from Sigma Chemical Co. (St. Louis, Mo.) or Fisher Scientific (Houston, Tex.) and used as received. t-boc-glycine (0.31 g, 1.71 mmol; Bachem, Bioscience Inc., King of Prussia, Pa.) was dissolved in 20 mL of anhydrous methylene chloride at room temperature. To this solution was added 1,3-diisopropylcarbodiimide (DIPC, 267.7 mL, 1.71 mmol), 4-dimethylamino-pyridine (DMAP, 0.14 g, 1.14 mmol) and camptothecin (CPT, 0.20149 g, 0.57 mmol) at 0° C. While CPT (Sigma Chemical Co., St. Louis, Mo.) was dissolved in dimethyl sulfoxide (DMSO) because of its low solubility, the concentration of DMSO in working solutions was less than 1.0%; a concentration which did not have a significant effect on cells. The reaction mixture was allowed to warm to room temperature and incubated overnight. The product was washed with 0.1 N HCl, dried and evaporated under reduced pressure to yield the sold product. The product was recrystallized from methanol to give CPT-glycinate. The t-boc protection group was removed by dissolving the CPT-glycinate in a mixture of methylene chloride and trifluoracetic acid (TFA) (50:50) and stirring at room temperature for 3 hours. Solvent was evaporated under reduced pressure and precipitated using ether to give CPT-glycinate-TFA salt. CPT-glycinate-TFA salt (34.0 mg or 50 mg) and PEG-NHS (100 mg; MW ˜3400; Shearwater Corporation, Huntsville, Ala.) were added to methylene chloride (5 ml) and DIEA (50 ml) was added to adjust the pH to basic. The reaction was stirred for 3 hours at room temperature. The product was recrystallized from cold ether and dried under vacuum overnight.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(C(F)(F)F)cc3)CCC2)cc1
Yield: 80.6 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 240 mg (0.89 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 360 mg (1.8 mmol) of 4-trifluoromethylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with hexane gave 240 mg (81%) of 1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 60.0°-61.5° C.; NMR (CDCl3) d 2.06 (m, J=7 Hz, 2H), 2.46 (s, 3H), 2.89 (t, J=7 Hz, 4H), 7.06 (d, J=6 Hz, 2H), 7.10 (d, J=Hz, 2H), 7.27 (d, J=8 Hz, 2H), 7.46 (d, J=8 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5]2.C(N(C(C)C)CC)(C)C.CN1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>[Pd]>[O:15]=[C:7]1[CH:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5][C:4]2[C:9](=[C:10]([N:12]3[CH2:38][CH2:37][CH2:36][C:35]3=[O:39])[CH:11]=[CH:2][CH:3]=2)[NH:8]1
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)cc([N+](=O)[O-])c2NC1=O
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1Cc2cccc(N3CCCC3=O)c2NC1=O
Temperature: 53 °C
Reaction time: 4 h

Procedure:
tert-Butyl 6-bromo-8-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (200 g) was suspended in N-methylpyrrolidone (520 mL), and diisopropylethylamine (136.6 g) and 10% Pd—C (water content: 52.5%) (12.6 g) were added thereto. The reactor was washed with N-methylpyrrolidone (200 mL), and the wash liquid was combined with the mixture. The resultant mixture was purged with hydrogen three times, and the mixture was stirred vigorously for four hours while maintaining the internal temperature at 50-56° C. (formation of Compound A). The resultant mixture was cooled to 25° C., and the mixture was filtered through Celite. The filtered solid was washed with N-methylpyrrolidone (20 mL) three times. The filtrate was cooled to 8° C., and 4-chlorobutyryl chloride (80.3 g) was added dropwise thereto, followed by stirring at 14-17° C. for 20 minutes (formation of Compound B). To the resultant mixture was added dropwise 25% aqueous sodium hydroxide solution (265.2 g) over 12 minutes, and the mixture was stirred for 1.5 hours (formation of Compound C). Water (720 mL) was added to the resultant mixture, and stirring was continued for one hour. The formed precipitates were recovered through vacuum filtration, and the thus-recovered residue was washed three times with water (200 mL), whereby the title compound (154 g) (water content: 14%) was yielded as a powdery compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][Br:32])=[CH:29][CH:30]=3)[CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCCCCCCCBr
Reactant: Oc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Product: BrCCCCCCCCCCOc1ccc(C2c3ccc(OCc4ccccc4)cc3OCC2c2ccccc2)cc1

Procedure:
From (+,-) cis 7-Benzyloxy-4-(4-hydroxy-phenyl)-3-phenyl-chroman (2 g, 4.9 mmol) and 1,10-Dibromodecane (7.4 g, 24.5 mmol). The product was purified by flash chromatography using petrol ether-ethyl acetate-toluene-methylene chloride 10+0.5+0.5+0.1 as eluent.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1(C)C=CC=CC=1.O>[CH2:39]([O:12][C:11](=[O:13])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[NH2:1])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: CCCCCCCCCCCCCCO
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 80 %

Procedure:
9.1 g (0.05 mole) of L-tyrosine was used, 11.4 g (0.06 mole) of p-toluenesulfonic acid hydrate was used, and 11.79 g (0.055 mole) of myristyl alcohol was used as an alcohol. After 200 ml of toluene was added thereto as a solvent, these materials were stirred and mixed well. The resulting reaction mixture was heated at the reflux temperature of toluene to carry out the esterification reaction. In this case, water was formed with the progress of the esterification reaction and released in the form of an azeotropic mixture with toluene, which was continuously removed from the reaction system. Thus, the reaction was completed in about 7-15 hours. After being cooled to room temperature, the reaction mixture was poured into a separating funnel and treated with 200 ml of a mixture of 0.2N NaOH and 3M NaCl solutions. This treatment was repeated three times. Thereafter, the toluene layer was isolated and washed thoroughly with water. After washing with water, the toluene layer was isolated and dried overnight over anhydrous sodium sulfate. After drying, the toluene layer was filtered and the resulting toluene solution was evaporated to remove the solvent. Thus, there was obtained 15.1 g (80% yield) of purified free L-tyrosine myristyl ester in the form of an oily material.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[Si](C)(C)C.[CH3:17][CH2:18]O>>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:17][CH3:18])=[O:8]
Reactant: CCO
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: C[Si](C)(C)Cl
Product: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reaction time: 72 h

Procedure:
To a solution of 5,6-dichloronicotinic acid (20.01 g, 104 mmol) in EtOH (500 mL) at 20° C. was added chlorotrimethylsilane (132 mL, 1042 mmol). The reaction was stirred for 72 hours. The reaction mixture was then concentrated and diluted with EtOAc (500 mL), and washed with saturated NaHCO3 (2×100 mL) and brine (100 mL). The organic was then dried (Na2SO4) and concentrated under reduced pressure to give final crude product (21.25 g). LCMS m/z 220.1 (M+H)+, Rt 0.94 min.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[N+:16]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[CH:13][C:12]=1[OH:15])([O-:18])=[O:17]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Yield: 70.5 %

Procedure:
To 20 g (0.1 mole) of 4-phenylmethoxy-phenol in 200 ml acetic acid were added, dropwise at room temperature, 7.26 ml of nitric acid (d=1.4, 0.105 mole). 2 Hours after completion of the addition the reaction medium was poured onto cold water and extracted twice with 250 ml of methylene chloride. The organic phase was washed twice with 200 ml of water and dried over sodium sulfate. Then the solvent was evaporated and the residue flash chromatographed using ethyl acetate/heptane 30/70 as eluting solvent to give 17.3 g (Yield=70.6%) of 2-nitro-4-phenylmethoxy-phenol.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:23]>C1(OC)C=CC=CC=1.ClCCl.O1CCOCC1>[ClH:23].[NH2:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH2:10]1
Reactant: CC1=CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC1=CCC(N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butoxycarbonylamino-4-methylcyclohex-3-ene (0.4 g) in a mixture of anisole (0.4 ml) and dichloromethane (0.8 ml) was added trifluoroacetic acid (1.2 ml) at 0° C. and the mixture was allowed to stir at 0° C. for 1 hour. Evaporation gave a residue, which was taken up into a solution of hydrogen chloride in dioxane (4N, 2 ml). Evaporation under reduced pressure and trituration with diisopropyl ether gave l-amino-4-methylcyclohex-3-ene hydrochloride, which was used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.CN(C)C=O.[Br:25][C:26]1[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[O:3]1[C:4]2[CH:9]=[C:8]([C:10]3([C:13]([NH:32][C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([Br:25])[N:31]=4)=[O:15])[CH2:11][CH2:12]3)[CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1cccc(Br)n1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.2 g, 5.8 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (2.5 mL) and N,N-dimethylformamide (0.3 mL) were added and the solution was allowed to stir at 60° C. for 30 minutes. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in 5 mL of anhydrous pyridine. This solution was then slowly added to a solution of 6-bromopyridin-2-amine (1.0 g, 5.8 mmol) suspended in 10 mL of anhydrous pyridine. The resulting mixture was allowed to stir for 15 hours at 110° C. The mixture was then evaporated to dryness, suspended in 50 mL of dichloromethane, and washed with three 20 mL portions of 1N NaOH. The organic layer was dried over sodium sulfate, evaporated to near dryness, and then purified by silica gel column chromatography utilizing dichloromethane containing 2.5% triethylamine as the eluent to yield the pure product. ESI-MS m/z calc. 361.2. found 362.1 (M+1)+; Retention time 3.43 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.17 (m, 2H), 1.42-1.55 (m, 2H), 6.06 (s, 2H), 6.92-7.02 (m, 2H), 7.09 (d, J=1.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 8.78 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2

Procedure:
2-({1-[1-(4-Fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine (298 mg, 0.88 mmol) was dissolved in dichloromethane (10 mL) and N,N-dimethylpyridin-4-amine (118 mg, 0.97 mmol) was added. After dropwise addition of a solution of propane-1-sulfonyl chloride (138 mg, 0.97 mmol) in dichloromethane (2 mL) stirring was continued over night. The reaction mixture was diluted with dichloromethane (20 mL), washed with an aqueous ammonium chloride solution (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, ethyl acetate:dichloromethane=1:10). Yield: 200 mg (0.45 mmol, 51%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:48][O:47][CH2:46]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:46][O:47][CH2:48]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1COC1
Yield: 73.5 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amide (362) (290 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammoniumfluorid (1M in tetrahydrofuran, 1.3 mL, 13 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 1.5 h (silica TLC, ethyl acetate:hexane=1:1/SiO2/UV, Rf=0.3.) The tetrahydrofuran was removed in vacuum and the crude mass was diluted with ethyl acetate (50 mL) and washed with water (25 mL) and brine (25 mL). The organic phase was thereafter dried and concentrated in vacuum to get a crude mass which was purified by CombiFlash using a gradient eluent mixture of ethyl acetate and hexane to obtain pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-oxetan-3-yl-amide (363) (175 mg, 73%) as a white solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=1.O.NN.Cl>C(O)C>[CH3:26][S:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][NH2:3])=[CH:17][CH:18]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(OCCCN)cc1
Reaction time: 1 h

Procedure:
A suspension of 5.5 g of N-[4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propoxy]phenyl]methanesulfonamide in 200 ml of ethanol is treated with 1.5 ml of hydrazine hydrate and the mixture stirred and refluxed for 6 hours. A precipitate forms in 1 hour. After 6 hours, 5 ml of HCl is added and the mixture refluxed for 1 hour and allowed to stand at room temperature for 18 hours. The precipitate is collected, stirred with 50 ml of hot water and the insolubles washed with 50 ml of water. The combined water washes are evaporated in vacuo to a dry residue. The residue is dissolved in 100 ml of saturated sodium bicarbonate, treated with activated carbon, filtered and the filtrate acidified with acetic acid and concentrated in vacuo to 100 ml. The precipitate is collected, washed with 25 ml of cold water and dried to give a solid, m.p. 200° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C(=CC=[C:40]([O:43]C)C=3)CC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:43][CH3:40])[CH:18]=3)[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCc3ccc(OC)cc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCc3ccc(OC)cc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.27-1.31, 1.86, 2.58, 2.75, 2.83, 2.85, 2.97, 3.80, 4.54, 5.67, 6.83-6.88, 7.20; HRMS (FAB) calcd for C18H22BrN3O+H 376.1025, found 376.1020. Anal. Calcd for C18H22BrN3O: C, 57.45; H, 5.89; N, 11.17; Br, 21.23. Found: C, 56.15; H, 5.65; N, 10.83.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH2:12][C:13](=S)[C:14]([OH:16])=[O:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20]>[O-]CC.[Na+]>[OH:20][N:19]=[C:13]([CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(O)C(=S)Cc1cc(-c2ccccc2)cs1
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C(Cc1cc(-c2ccccc2)cs1)=NO
Yield: 90 %

Procedure:
3-(4-Phenylthiophen-2-yl)-2-thioxopropanoic acid (0.9 g, 3.4 mmol), hydroxylamine hydrochloride (740 mg, 10.6 mmol), and an ethanolic solution sodium ethoxide [prepared from 0.4 g of sodium and 30 mL of absolute ethanol] was refluxed for 1.5 h. Solvent was removed under reduced pressure and the residue was diluted with water and acidified with 1.5N HCl to adjust the pH of the solution ˜3. The solid product was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, then removal of the solvent under reduced pressure yielded 2-(hydroxyimino)-3-(4-phenylthiophen-2-yl)propanoic acid (0.8 g, yield 89%) as an off-white solid. 1H NMR (400 MHz, MeOD) δ 7.59-7.57 (m, 2H), 7.37-7.33 (m, 3H), 7.24-7.23 (m, 2H), 3.31 (s, 2H). MS (ESI) m/z: Calculated for C13H11NO3S: 262.05. found: 262.0 (M+H)+.
Reaction SMILES: C(O)(=O)C.[NH2:5][C@:6]([CH3:59])([C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:7][O:8][C@@H:9]1[C@@:16]2([CH3:41])[C@@H:17]3[CH2:18][CH2:19][C@H:20]4[C:29]([C@@:12]3([CH2:13][O:14][CH2:15]2)[CH2:11][C@H:10]1[N:42]1[C:46]([C:47]2[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][CH:48]=2)=[N:45][CH:44]=[N:43]1)=[CH:28][CH2:27][C@:26]1([CH3:30])[C@:21]4([CH3:40])[CH2:22][CH2:23][C@@:24]([C@H:35]([CH3:39])[CH:36]([CH3:38])[CH3:37])([CH3:34])[C@H:25]1[C:31]([OH:33])=[O:32]>CO.[OH-].[OH-].[Pd+2]>[NH2:54][CH2:53][C:50]1[CH:49]=[CH:48][C:47]([C:46]2[N:42]([C@@H:10]3[CH2:11][C@:12]45[C:29]6[C@H:20]([CH2:19][CH2:18][C@H:17]4[C@@:16]([CH3:41])([CH2:15][O:14][CH2:13]5)[C@H:9]3[O:8][CH2:7][C@@:6]([NH2:5])([CH3:59])[C:55]([CH3:56])([CH3:58])[CH3:57])[C@:21]3([CH3:40])[C@:26]([CH3:30])([C@H:25]([C:31]([OH:33])=[O:32])[C@:24]([C@H:35]([CH3:39])[CH:36]([CH3:38])[CH3:37])([CH3:34])[CH2:23][CH2:22]3)[CH2:27][CH:28]=6)[N:43]=[CH:44][N:45]=2)=[CH:52][CH:51]=1
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4-c4ccc(C#N)cc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4-c4ccc(CN)cc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Reaction time: 6 h
Yield: 77.8 %

Procedure:
Palladium hydroxide on carbon (10.6 mg, 0.015 mmol) and acetic acid (17 μl, 0.297 mmol) were added to a stirred solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-14-[5-(4-cyanophenyl)-1H-1,2,4-triazol-1-yl]-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 168, 52.5 mg, 0.060 mmol) in methanol (3.0 ml). The reaction mixture was degassed (3×) and purged with hydrogen before being placed under a hydrogen balloon. After 6 hours, the hydrogen balloon was removed. The reaction mixture was degassed (2×), diluted with methanol, and filtered through a pad of Celite. The filtrate was evaporated under reduced pressure to give a colorless residue. The residue was dissolved in methanol and purified using a single HPLC run on a 30×150 mm Sunfire Prep C18 OBD 10 μm column by eluting with acetonitrile/water+0.1% TFA. The total flow rate was 20 ml/min and the HPLC method employed a 17 minute 20%-100% acetonitrile/water gradient followed by a 2 minute acetonitrile flush. The product fractions were combined, the solvent was evaporated under reduced pressure, and the residue was lyophilized from ethanol and benzene to give the title compound (35.4 mg) as a white solid.