Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].[N+]([C:15]1[CH:16]=[C:17]([CH3:22])[N+:18]([O-:21])=[CH:19][CH:20]=1)([O-])=O>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[CH:16]=2)=[CH:4][C:3]=1[F:9]
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: Oc1ccc(Br)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Br)c(F)c2)cc[n+]1[O-]
Temperature: 180 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4-bromo-3-fluorophenol (6 g, 31.41 mmol) in DMF (20 ml) was added NaH (0.81 g, 56 mmol, 60% in mineral oil) at room temperature. The resulting reaction mixture was stirred for 10 min., then, 4-nitro-2-picoline N-oxide (5.6 g, 36.12 mmol) was added. The resulting solution was subjected to microwave heating at 180° C. for 1 h. The mixture was cooled to room temperature and diluted with EtOAc and H2O. Layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue thus obtained was purified by column chromatography (silica gel; DCM/MeOH(NH3) up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound D14 (3.61 g, 39%) as dark orange solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(C=CC(O)=CC=1)O.[C:18]([OH:22])(=[O:21])[CH:19]=[CH2:20].[OH-].[Na+]>CC(C)=O.CO>[CH2:1]([NH:9][CH2:20][CH2:19][C:18]([OH:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: C=CC(=O)O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCCCCNCCC(=O)O
Temperature: 25 °C
Yield: 78 %

Procedure:
To a mixture of n-octylamine (516 g, 4.0 mols), hydroquinone (200 mg) and methanol (400 ml), acrylic acid (144 g, 2.0 mols) was added dropwise with stirring while cooling with ice. After addition, the mixture was refluxed while heating for 4 hours. After cooled to room temperature, NaOH (80 g, 2.0 mols) was added. The reaction mixture was despersed in 6 liters of acetone, and filtration and drying were carried out to obtain the Na salt of N-n-octyl-β-alanine as white crystals having a melting point (dec.) of 242° C. (349 g Yield: 78%).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH2:25][C:26]2=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32]([O:35][CH2:36][CH3:37])(=[O:34])[CH3:33].O>C(COC)OC>[Si:3]([O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][CH:25]=[C:26]2[CH2:33][C:32]([O:35][CH2:36][CH3:37])=[O:34])([C:16]([CH3:19])([CH3:17])[CH3:18])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)CC1=CCCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of diethyiphosphoric acid ethyl ester (19 g) in dimethoxyethane (200 ml) was added NaH (3.4 g, 60%) in oil) at 0° C. under N2. After being stirred for 30 minutes, 5-t-butyidiphenylsilyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene (20 g) was added to the mixture. After being stirred for 12 hours at 80° C., the solution was poured hnto a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was dissolved into a mixture of toluene (100 ml and 1,8-diazabicyclo[5.4.0]-7-undecene (17 ml) and the mixture was stirred for 3 days at 100° C. The solution was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 5-t-butyldiphenylsilyloxy-1-ethoxycarbonylmethyl-3,4-dihydronaphthalene (20.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:24]=[CH:23][C:17](C(OCC)=O)=[CH:16][C:15]=3[CH3:25])=[CH:7][C:6]=2[C:5]2[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:4]=2[N:3]=1.[CH3:31][Mg]I.CC[O:36][CH2:37][CH3:38]>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:24]=[CH:23][C:17]([C:37]([OH:36])([CH3:38])[CH3:31])=[CH:16][C:15]=3[CH3:25])=[CH:7][C:6]=2[C:5]2[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:4]=2[N:3]=1
Reactant: C[Mg]I
Reactant: CCOCC
Reactant: CCOC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)(C)O)cc3C)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoate (from Example 74) (1.0 eq.) in DCM at 0° C. was added 3.0 M methyl magnesium iodide (10 eq.) in ether and warmed to room temperature overnight. The reaction was cooled to 0° C. and quenched with water. After stirring for 15 min, the reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution and added EA. The two phases were separated, and the aqueous layer was extracted three times with EA. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH in DCM to give a 2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)propan-2-ol. 1H NMR (Acetone-d6): δ 8.72-8.75 (m, 2H), 8.23 (d, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 7.25 (d, 1H), 7.12-7.14 (m, 2H), 6.6 (br, 2H), 3.91 (s, 1H), 3.07-3.18 (m, 4H), 2.44 (s, 3H), 2.31 (s, 3H), 1.48 (s, 6H). LRMS [M+H]=386.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C@@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([NH2:23])[CH3:22])[CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[F:37])[CH:29]=[CH:30][C:31](O)=[O:32].C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C@@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([NH:23][C:31](=[O:32])[CH:30]=[CH:29][C:28]3[CH:34]=[CH:35][C:36]([F:37])=[C:26]([F:25])[CH:27]=3)[CH3:22])[CH:16]=2)[CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Reactant: CC(N)c1cccc(N2CCO[C@@H](CNC(=O)OC(C)(C)C)C2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(NC(=O)C=Cc1ccc(F)c(F)c1)c1cccc(N2CCO[C@@H](CNC(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mixture of (S)-{4-[3-(1-amino-ethyl)-phenyl]-morpholin-2-ylmethyl}-carbamic acid tert-butyl ester, Preparation 28 (20 mg, 0.06 mmol), 3,4-difluorocinnamic acid (12.1 mg, 0.07 mmol), EDC (23 mg, 0.12 mmol), DMAP (7.3 mg, 0.06 mmol), triethylamine (0.03 ml, 0.24 mmol) in dichloromethane (0.6 ml) was stirred at room temperature overnight. The reaction mixture was purified by filtering through 2 g silica-gel syringe with 80% ethyl acetate/hexanes. The filtrate was concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH2:13][NH:14][C:15]3[C:20]([F:21])=[C:19]([O:22][CH3:23])[CH:18]=[C:17]([O:24][CH3:25])[C:16]=3[F:26])=[CH:11][N:10]=[C:9]([S:27][CH3:28])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>O1CCCC1>[CH:1]1([N:6]2[C:7]3=[N:8][C:9]([S:27][CH3:28])=[N:10][CH:11]=[C:12]3[CH2:13][N:14]([C:15]3[C:16]([F:26])=[C:17]([O:24][CH3:25])[CH:18]=[C:19]([O:22][CH3:23])[C:20]=3[F:21])[C:31]2=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(OC)c(F)c(NCc2cnc(SC)nc2NC2CCCC2)c1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(N2Cc3cnc(SC)nc3N(C3CCCC3)C2=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 16.33 g (0.0398 mol) of cyclopentyl-(5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-amine in 288 mL of anhydrous tetrahydrofuran was cooled to 0° C. using an ice/acetone bath. The reaction mixture was treated with 3.98 g (0.0995 mol) of sodium hydride and continued stirring at 0° C. for 30 minutes. After 30 minutes, 19.35 g (0.019 mol) 1,1′-carbonyldiimidazole was added and continued to stir at 0° C. for an additional 30 minutes. After 1 hour, the ice bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture heated at reflux overnight under nitrogen atmosphere. Evaporated the tetrahydrofuran and partitioned the residue between dichloromethane and water. The aqueous layer was extracted one time with 500 mL dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered and evaporated. There was a portion of the crude material that did not dissolve in the eluent. Filtered the solid and dried in the housevac oven overnight to give the title compound, 6.80 g of crop 1. The remaining crude material was purified using medium pressure-chromatography, eluting with a gradient of 2:1 hexanes/ethyl acetate to 1:1 hexanes/ethyl acetate to give the title compound as a white solid, 8.74 g of crop 2. Combined the crops to give a total of 15.54 g (90%) of the title compound. MS (APCI) (m+1)/z 437.1.
Reaction SMILES: C(O[SiH](OCC)OCC)C.[C:11](OCC)(=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:11]([OH:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCC(=O)OCC
Agent: [Ti+4]
Agent: CCO[SiH](OCC)OCC
Agent: CC[O-]
Product: CCCCCCCCCCO
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
A dry Schlenk tube under argon was charged with titanium (IV) ethoxide (32 μL, 0.15 mmol) and triethoxysilane (1.39 mL, 7.5 mmol) and heated to 40° C. After 15 min., ethyl decanoate (696 μL, 3 mmol) was added. After 18 hours, the reaction was determined to be complete by GC analysis. Standard work-up afforded 444 mg (93% yield) of decanol as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:61])[CH2:7][N:8]([CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:9](=[O:52])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:26][C:27]1[N:28]([CH2:32][C:33](=[O:51])[N:34]([CH2:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:29]=[CH:30][N:31]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[NH:62]1CCCCC1>CN(C=O)C>[NH2:62][C@@H:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:26][C:27]1[N:28]([CH2:32][C:33]([N:34]([CH2:43][C:44]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:50])[CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:51])[CH:29]=[CH:30][N:31]=1)[CH2:16][C:12]1[N:11]([CH2:10][C:9](=[O:52])[N:8]([CH2:7][C:6](=[O:61])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH:15]=[CH:14][N:13]=1)[C:23]([OH:25])=[O:24]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCCCC(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Yield: 79 %

Procedure:
A solution of 2-4(9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (190 mg, 0.173 mmol) and piperidine (0.50 mL) in DMF (0.50 mL) was stirred at room temperature for 1 hrs. The solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by Biotage SP4 with a gradient method of 5-50% methanol in DCM to give (S)-2-amino-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (0.120 g, 79%). 1H NMR (400 MHz, DMSO-d6). 6.92 (s, 2H), 6.76 (s, 2H), 5.01 (s, 4H), 4.32 (s, 2H), 4.31 (s, 2H), 3.92 (s, 4H), 3.44 (s, 4H), 3.01-2.99 (m, 1H), 2.30 (t, J=7.2 Hz, 2H), 1.60-1.57 (m, 2H), 1.43 (s, 18H), 1.35 (m, 18H). 1.30-1.12 (m, 4H); MS (ESI), 439.4 (M/2+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:16][CH2:15][CH:14]([O:17][CH3:18])[O:13][CH3:12])=[S:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: COC(CN)OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(NC(=S)NCC(OC)OC)cc1

Procedure:
A solution of 10 g (.06 mole) of p-methoxyphenyl isothiocyanate in 100 ml of CHCl3 was treated with 6.3 g (.06 mole) of aminoacetaldehyde dimethyl acetal. The solvent was evaporated and the residue was recrystallized from ethanol to yield N-(p-methoxyphenyl)-N'-(β,β-dimethoxyethyl)thiourea, 9.2 g (57%). A suspension of this thiourea in a solution of 5 ml of concentrated H2SO4 and 20 ml of H2O was refluxed for 3 hours. The mixture was cooled and a solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-(4-methoxyphenyl)-2-mercaptomidazole, 4.9 g (70%), mp 215-7° . The compound can be deprotected, for example, as illustrated in Example 5 and 6, below, to prepare the phenol, Y is --OH.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C[O-].[Na+].OC1C=CC(NC(=O)N(C)C)=CC=1.[Na].[Cl:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1>CS(C)=O.CO>[Cl:31][C:32]1[N:37]=[C:36]([O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:13])[N:10]([CH3:11])[CH3:12])=[CH:6][CH:7]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CN(C)C(=O)Nc1ccc(Oc2ccnc(Cl)n2)cc1

Procedure:
4-Hydroxyphenyl-N,N-dimethylurea (12.0 grams; 0.066 mole) was mixed with a solution of sodium methylate (prepared by mixing sodium metal (1.53 grams) in 55 milliliters (ml) of methanol) and the resulting sodium 4-hydroxyphenyl-N,N-dimethylurea solution added gradually over a period of about one hour to a solution of 2,4-dichloropyrimidine (9.94 grams; 0.066 mole) in 50 ml. of dimethylsulfoxide. During the addition, the reaction temperature rose from about 55°C. to a temperature from between about 60° to about 65°C. The resulting reaction mixture was maintained at temperatures from between about 60° to about 70°C. for a period of about 30 minutes. The reaction mixture, which was nearly neutral, was poured into about 300 ml. of cold water and the resulting product precipitate recovered by filtration and washed with additional portions of water. The product precipitate was dissolved in acetonitrile and the resulting solution filtered with activated charcoal and then cooled to crystallize the product. The product thus obtained was recrystallized again from methylene chloride and dried. As a result of these operations, the desired title product was obtained as a white solid having a melting point of 192°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.Cl.[CH2:26]([OH:28])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[NH:17])[O:28][CH2:26][CH3:27])=[CH:14][CH:15]=2)=[O:18])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
4-Chloro-3-(pyridin-2-yl)aniline (687 mg, 3.36 mmol) was dissolved in dichloromethane (8.0 ml) and THF (8.0 ml), treated with pyridine (0.33 ml, 4.0 mmol), and cooled to 0° C. 4-Cyanobenzoyl chloride (612 mg, 3.7 mmol) was added and the reaction was stirred for 1.0 hour. The reaction was diluted with dichloromethane and methanol was added to dissolve all solids. The solution was washed with water once, brine once, dried with MgSO4, and evaporated to an orange solid which was purified by silica gel flash column chromatography (50% ethyl acetate/50% hexanes) to afford 908 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide as a yellow solid. N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide (500 mg, 1.5 mmol) was slurried in ethanol (75 ml) and heated until just dissolved. The solution was cooled in an ice bath, and saturated with HCl gas. The solution was heated briefly to 70° C. to dissolve precipitated solids, cooled in an ice bath, and resaturated with HCl gas. The solution was then stored at 0° C. for 18 hours. The solution was saturated again with HCl gas, heated to 70° C. until all solids dissolved, cooled to 0° C., resaturated with HCl gas, and stored at 0° C. for 18 hours. Finally, nitrogen gas was bubbled through the solution for 1.0 hour, and the solution was evaporated to dryness. The residue was dissolved in methanol, treated with MP-carbonate (2.57 g) and stirred 30 min. The solution was filtered to afford a neutral, methanolic solution of ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate, which was diluted with enough methanol to make a 0.075 M solution.
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH:18](Br)[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C.C(OCC)(=O)C>[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[N:2]=[C:1]([SH:3])[S:4][C:18]=2[CH2:17]1)=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=S)[S-]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1Br
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCc2nc(S)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a solution of ammonium dithiocarbamate (0.19 g, 1.7 mmol) in 2 mL of ethanol was added 1-benzyloxycarbonyl-3-bromo-4-piperidone (0.53 g, 1.7 mol). The reaction was stirred at rt overnight. The next morning the reaction was heated at 75° C. for 2 h. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate, water (2X) and then brine. The solvent was removed under reduced pressure and the product subjected to flash chromatography (2:1 hexane/ethyl acetate). Crystallization from ethyl acetate/hexane afforded 0.14 g of 5-benzyloxycarbonyl-2-mercapto-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:30]1[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=1.O.NN>CO.C1COCC1>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2)sc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (200 mg, 0.40 mmol) in MeOH/THF (10 mL, 1:1) at RT was added hydrazine hydrate (0.20 mL, 4.0 mmol). After stirring for 24 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound as a light yellow solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH2:47]SC)[CH:41]=[C:40]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.CO.O[O:58][S:59]([O-:61])=O.[K+].[C:63](=O)(O)[O-].[Na+]>O>[CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH2:47][S:59]([CH3:63])(=[O:61])=[O:58])[CH:41]=[C:40]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2][CH2:3]1
Reactant: O=C([O-])O
Reactant: O=S([O-])OO
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCSC)c1
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl (3-{cyclopropyl{3-(3-methoxypropyl)-5-[3-(methylthio)propoxy]benzyl}amino)-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 75, Step 2 (1 eq.) in a 1:1 (v/v) methanol:water solution (0.05 M) was added Oxone™ (2.5 eq.) and sodium bicarbonate (10 eq.). The reaction mixture was stirred at RT for 1 h. The volatiles were then removed in vacuo and the result residue was extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:2 (v/v) Hex:EtOAc→1:3 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>O1CCCC1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20])=[O:31]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2Cl)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2,4-dichlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 285°-287° C. (d).