Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=O)/[CH:2]=[CH:3]/[CH3:4].S(Cl)(Cl)=O.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([Cl:20])[CH:13]=1>CC(N(C)C)=O.[Cl-].[Na+].O>[Cl:20][C:14]1[CH:13]=[C:12]([NH:11][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: C/C=C/C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: C/C=C/C(=O)Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A solution of crotonic acid (8.24 mL, 98.31 mmol) and thionyl chloride (7.18 mL, 98.31 mmol) in DMA (150 mL) was stirred at 0° C. for 1 hr. To the reaction mixture was added 4-amino-2-chlorobenzonitrile (15 g, 98.31 mmol), and the mixture was stirred at room temperature for additional 14 hr. To the reaction solution was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and 1N hydrochloric acid, and dried, and the solvent was evaporated under reduced pressure to give (E)-N-(3-chloro-4-cyanophenyl)but-2-enamide (21.69 g, 98.31 mmol, quantitative) as a brownish-red powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2.C(O)(=O)C>O>[F:16][C:3]1[C:2]([N:1]2[C:20](=[O:21])[C:19]3[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=3[C:17]2=[O:22])=[CH:15][C:6]2[N:7]([CH2:12][C:13]#[CH:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21

Procedure:
A mixture of 6-amino-7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.31 g), 3,4,5,6-tetrahydrophthalic anhydride (0.28 g) and acetic acid (3 ml) was heated under reflux for 2 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, neutralized with sodium bicarbonate solution, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and hexane (1:2) as an eluent to give 2-[7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.12 ). m.p., 196.0° C.
Reaction SMILES: [C:1]([NH:4][C:5]([CH3:24])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[C:13]([N+:21]([O-])=O)[CH:12]=1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].[H][H].C=O.[C:29]([O-])(=O)C.[Na+]>[Ni]>[C:1]([NH:4][C:5]([CH3:24])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH:21][CH3:29])[CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C(C)(Cc1ccc(NC(C)=O)c([N+](=O)[O-])c1)NC(C)=O
Agent: [Ni]
Agent: C=O
Agent: [Na+]
Product: CNc1cc(CC(C)(NC(C)=O)C(=O)O)ccc1N

Procedure:
Methyl 2-acetamido-2-methyl-3-(3-nitro-4-acetamidophenyl)propionate is treated with hydrogen, formaldehyde, sodium acetate and Raney nickel following the procedure of part B of Example 4 to produce 2-acetamido-2-methyl-3(3-methylamino-4-aminophenyl)propionic acid. This product is hydrolyzed with 10% HCl and cyclized with phosgene by the procedure of part B of Example 4 to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:21]2[C:20]3[C:15](=[CH:16][C:17]([C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:12]([C:31]([NH2:33])=[O:32])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68]O>O1CCOCC1.C1COCC1>[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][O:8][C:7]1[C:2]([F:1])=[C:3]([C:9]2[C:21]3[C:20]4[C:15](=[CH:16][C:17]([C:22]([N:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)=[O:23])=[CH:18][CH:19]=4)[NH:14][C:13]=3[C:12]([C:31]([NH2:33])=[O:32])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCO
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc(O)c4F)c23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(-c2ccc(C(N)=O)c3[nH]c4cc(C(=O)N5CCN(C)CC5)ccc4c23)c1F
Temperature: 95 °C

Procedure:
A mixture of 4-(2-fluoro-3-hydroxyphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Intermediate 84-1, 20 mg, 0.045 mmol) and polymer-supported triphenylphosphine (2.63 mmol/g, 0.358 mmol) in 1,4-dioxane was treated at 0° C. with a solution of diethyl azodicarboxylate (19.5 mg, 0.157 mmol) in THF (0.5 mL), followed after 5 min by a solution of 2-(dimethylamino)ethanol (10 mg, 0.112 mmol) in THF (0.5 mL). The mixture was heated in a sealed tube by microwave irradiation at 90-100° C. for 30 min. The resulting mixture was filtered, the solids were washed with methanol, and the filtrates were concentrated and purified by preparative HPLC to provide 4-(3-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide. Mass spectrum m/z 518.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)=[O:7])[CH3:4].[C:21]([O:25][C:26]([N:28]1[CH2:32][C@H:31]([CH3:33])OS1(=O)=O)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([C@H:31]([CH3:33])[CH2:32][NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([F:20])([F:18])[F:19])[CH:11]=2)=[O:7])[CH3:4]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2n1[C@H](C)CNC(=O)OC(C)(C)C
Temperature: 5 °C
Yield: 87.9 %

Procedure:
Sodium hydride (0.75 g, 17 mmol) was suspended in N,N-dimethylformamide (15 mL) and a solution of 6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (3.6 g, 14 mmol) in N,N-dimethylformamide (15 mL) was added with cooling at 5° C. After 1 h (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (4.0 g, 17 mmol) was added and the solution was allowed to reach room temperature over the weekend. The solution was partitioned between ice water (600 mL) and diethylether (2-×250 mL). The organic layer was washed with ice water and brine, dried (MgSO4), and evaporated. Chromatography on silica gel with n-hexane/diethylether (4:1) yielded the title product as yellow oil (5.1 g, 88%). ISP-MS: m/e=415.3 (M+H+), αD20=−29.6
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:24](Cl)(=[O:26])=[O:25])([O-:16])=[O:15]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:24]([CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15])(=[O:25])=[O:26]
Reactant: O=[N+]([O-])c1ccccc1CS(=O)(=O)Cl
Reactant: NCCOCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1CS(=O)(=O)NCCOCCO
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(2-aminoethoxy)ethanol (0.557 g), 5.31 mmol) and potassium carbonate (1.17 g, 8.48 mmol) in toluene (50 ml) and water (4 ml) at room temperature, was added 2-nitro-alpha-toluenesulfonyl chloride (1.00 g, 4.24 mmol) in one portion and the reaction was left to stir overnight. The reaction was diluted with ethyl acetate and water. The organic layer was separated before being washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude material was purified by column chromatography eluting with ethyl acetate:hexane to afford N-[2-(2-hydroxyethoxy)ethyl]-1-(2-nitrophenyl)methanesulfonamide as product (0.155 g, 12%); Rf (ethyl acetate:hexane 2:1) 0.11; δH (400 MHz, CDCl3) 8.02 (1H, d), 7.67 (2H, m), 7.53 (1H, dt), 5.15 (1H, brs), 4.86 (2H, s), 3.71 (2H, s), 3.56 (4H, m), 3.19 (2H, m) and 2.36 (1H, s); LCMS Rt=2.60 min, m/z (APCI) 305 (MH+).
Reaction SMILES: C([C:5]1([C:18]([NH2:20])=[O:19])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][NH:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(C)(C)C.[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:33]1[O:35][CH2:34]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:33]([OH:35])[CH2:34][N:6]1[CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:5]1[C:18]([NH:20][C:9]([CH3:17])([CH3:10])[CH3:8])=[O:19])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)C1(C(N)=O)NCCc2c1[nH]c1ccccc21
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Solvent: CO
Product: CC(C)(C)NC(=O)C1c2[nH]c3ccccc3c2CCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
A solution of 0.60 g of tert.butyl 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide and 0.66 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane in 20 ml of methanol was heated at reflux under argon for 16 hours and then evaporated to give a clear oil. The two diastereomeric products were separated by flash chromatography on silica gel using n-hexane/ethyl acetate (3:1) for the elution. There were obtained 268 mg of isomer A of 2-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide, MS: m/e 569 [M+H]+ and 65 mg of isomer B of the same compound; MS: m/e 569 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[NH:10][NH2:11])=[CH:4][CH:3]=1.[F:13][C:14]([F:27])([F:26])[C:15]1[O:20][C:19](=O)[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[N:16]=1>N1C=CC=CC=1.ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:10][N:11]2[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:16]=[C:15]2[C:14]([F:13])([F:26])[F:27])=[O:12])=[CH:6][CH:7]=1
Reactant: O=c1oc(C(F)(F)F)nc2ccccc12
Reactant: NNC(=O)Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1)Nn1c(C(F)(F)F)nc2ccccc2c1=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
4-(p-Chlorophenyl)semicarbazide (1.49 g, 8.03 mmol) is added to a solution of 2-(trifluoromethyl)-4H-3,1-benzoxazin-4-one (1.72 g, 8.00 mmol) in pyridine (27 mL) at 100° C. The reaction mixture is stirred for 15 hours at 100° C., cooled to room temperature and concentrated in vacuo to obtain a solid. The solid is diluted with dichloromethane and the mixture is washed sequentially with 10% hydrochloric acid and water and concentrated in vacuo to obtain a tan solid. The tan solid is washed with dichloromethane and filtered. The filtrate is concentrated in vacuo to obtain a brown foam. The foam is diluted with ether and the mixture is washed sequentially with 10% hydrochloric acid, water and saturated sodium hydrogen carbonate solution, dried over anhydrous MgSO4, decolorized with carbon and concentrated in vacuo to obtain a cream colored foam. Flash chromatography of the cream colored foam using silica gel and a 3:1 dichloromethane/hexanes solution gives the title product as a white solid, 0.36 g, which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]([CH2:9][C:10]1[C:11]([Cl:16])=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:18][CH2:19][OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1cccnc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: OCCN(Cc1ccccc1)Cc1cccnc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of the compound (11.8 g) obtained in step 1 in THF (30 mL) was added 1M BH3.THF complex/THF solution (134 mL) at 0° C., and the mixture was stirred at 90° C. for 1 hr. After the reaction mixture was cooled to 10° C., MeOH (20 mL) was added, and the mixture was concentrated under reduced pressure. The residue was suspended in 6N hydrochloric acid (43 mL), and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was cooled to 10° C., and made basic with aqueous sodium hydroxide solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give 2-{benzyl[(2-chloropyridin-3-yl)methyl]amino}ethanol (6.92 g, 86%) as a colorless oil.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH:23](N1CCOCC1)=[O:24].Cl>C1COCC1.C1CCCCC1>[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH:10]=[CH:11][C:12]=1[CH:23]=[O:24]
Reactant: Fc1cccc(-c2ccc3ccccc3c2)c1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc3ccccc3c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A 86.86 ml cyclohexane solution of sec-butyl lithium in a concentration of 1.01M was dropped into a 300 ml THF solution of 15.00 g (=67.49 mmol) of 2-(3-fluorophenyl)naphthalene at −70° C. After the dropping was finished, the reaction solution was stirred at the same temperature for 1 hour, added with a 150 ml THF solution of 10.88 g (=94.49 mmol) of 4-formylmorpholine through dropping and then slowly heated to room temperature. After being stirred for 18 hours, 25 ml of 6N HCl(aq) was dropped into the reaction solution, and then the reaction mixture was extracted thrice with toluene. The extract was washed with water and an aqueous solution of NaHCO3, and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellow solid of 16.83 g was purified with silica gel chromatography using toluene as the eluent to obtain a yellowish solid of 13.26 g, which was further recrystallized with toluene to obtain 10.09 g of 2-fluoro-4-naphthalene-2-yl-benzaldehyde as yellowish crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([N:6]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][N:8]=[C:7]1[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])(=[O:5])=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:47][CH2:46]C1>>[CH3:25][N:2]([CH3:1])[S:3]([N:6]1[C:10]([CH:46]=[O:47])=[CH:9][N:8]=[C:7]1[Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:19])[CH3:20])(=[O:5])=[O:4].[C:12]1([S:11][C:10]2[NH:6][CH:7]=[N:8][CH:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)S(=O)(=O)n1c(Sc2ccccc2)cnc1[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Product: c1ccc(Sc2cnc[nH]2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-(N,N-dimethylsulfamoyl)imidazole (1.5 g, 8.6 mmol) was taken up in 28 mL of THF. The solution was cooled to −78° C. and n-BuLi (5.4 mL, 8.6 mmol) added dropwise via syringe. After stirring at −78° C. for 1 h TBSCl (1.3 g, 8.56 mmol) in 10 mL of THF was added. The bath was removed and the reaction allowed to warm-up to rt. The reaction mixture was stirred overnight. The reaction mixture was cooled to −20° C. and n-BuLi (5.4 mL, 8.6 mmol) added. After 45 min phenyldisulfide (1.9 g, 8.6 mmol) in 8 mL of THF was added. The reaction mixture was stirred at rt for 48 h. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was collected and washed with water and then brine. The solution was dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (2.5% EtOAc/hexane) afforded 2.8 g (7.0 mmol) of 2-(t-butyldimethylsilyl)-5-phenylsulfanylimidazole-1-sulfonic acid dimethylamide (1) as a yellow color oil. The compound (1) (2.8 g, 7.0 mmol) was dissolved in THF and the solution cooled to 0° C. TBAF (7.0 mL, 7.0 mmol) was added dropwise to the solution. The reaction mixture was stirred overnight at rt. The next day the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine. The solution was dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (50% EtOAc/hexane) afforded 474 mg of 5-phenylsulfanylimidazole-1-sulfonic acid dimethylamide (2) and 290 mg of 5-phenylsulfanyl-1H-imidazole (3) (H). The 478 mg of (2) was added to 2N HCl and the solution heated at reflux for 2 h. The reaction mixture was made basic with 2N NaOH and extracted with ethyl acetate. The organic layer was washed with water followed by brine. The solution was dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (EtOAc) afforded (3) as a white crystalline solid. A combined total of 360 mg (2.0 mmol) of (3) is recovered.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:12][CH:13]=2)[S:6][CH:7]=1)[CH3:2].[CH3:19][O:20][C:21](=[O:34])[C@H:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29](O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=4)=[CH:13][N:12]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH3:23]
Reactant: CCc1csc(-c2ccc(OCCCO)nc2)n1
Reactant: COC(=O)[C@@H](C)n1ccc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1csc(-c2ccc(OCCCOc3ccc4c(ccn4[C@H](C)C(=O)OC)c3)nc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
A solution of 3-[5-(4-ethyl-thiazol-2-yl)-pyridin-2-yloxy]-propan-1-ol (Example 73, 7.0 g, 0.025 mol), (R-2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester (Example 8, 4.961 g, 0.023 mol), and triphenylphosphine (7.716 g, 0.029 mol) in dichloromethane (60 mL) was treated with a solution of 1,1′-(azodicarbonyl)-dipiperidine (7.423 g, 0.029 mol) in dichloromethane (45 mL) slowly over 25 minutes while maintaining the temperature around 25° C. The resulting suspension was stirred at rt for 18 h. Upon completion, the solvent was removed under vacuum and the crude product was purified by silica gel chromatography using a gradient of 5-35% ethyl acetate/hexanes to give 7.3 g (69%) of the title compound as a beige solid. The product was characterized as in Example 69.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([O:15]S(C)(=O)=O)[CH2:10]2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2].O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][C:28]=1[Br:38].[H-].[Na+].C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C1COCC1>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][C:28]=3[Br:38])[CH2:10]2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2]
Reactant: CCCc1c(O[C@@H]2CCC[C@H](OS(C)(=O)=O)C2)ccc(C(C)=O)c1O
Reactant: COC(=O)Cc1ccc(O)c(Br)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCc1c(O[C@H]2CCC[C@H](Oc3ccc(CC(=O)OC)cc3Br)C2)ccc(C(C)=O)c1O

Procedure:
To a solution of the title compound of Step C of this example (500 mg; 1.35 mmole) in toluene (30 ml) and THF (1.5 ml) was added successively 4-hydroxy-3-bromophenylacetic acid, methyl ester (1 g, 4 mmoles), sodium hydride (169 mg; 7 mmoles) and 15-crown-5 (10 mg). The reaction mixture was refluxed for 10 hours under nitrogen. It was then worked-up as in Step B of Example 8 to yield the title compound of this step.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:23])([CH3:22])[CH2:8][CH:9]2[NH:12][C:13]([NH:15]C2C=CC=CC=2)=[O:14])=[CH:5][CH:4]=1)#[N:2].[CH2:24](N=C=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:23])([CH3:22])[CH2:8][CH:9]2[NH:12][C:13]([NH:15][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1(C)CC(NC(=O)Nc2ccccc2)c2cc(C#N)ccc21
Reactant: O=C=NCc1ccccc1
Solvent: CCO
Product: CC1(C)CC(NC(=O)NCc2ccccc2)c2cc(C#N)ccc21
Yield: 126.7 %

Procedure:
A solution of 3-amino-5-cyano-1,1-dimethylindane (0.40 g, 2.15 mmol, prepared according to part F of Example 6) and benzyl isocyanate (0.29 g, 2.15 mmole) in ethanol (3.5 ml) under argon was heated at reflux for three hours. The solvent was recovered under vacuum to obtain 0.87 g of yellow gum. The crude product was chromatographed on silica eluting with 1:1 ethyl acetate/hexane to obtain an amorphous white solid (0.44 g). The chromatogrpahy isolate was further purified by crystallization from isopropyl ether to afford the title compound as a pure white solid (0.40 g), m.p. 130°-132° C. 1H NMR δ 7.71 (d, J=8.21 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J=7.63 Hz, 1H), 7.31 (m, 5H), 6.44 (m, 2H), 5.22 (m, 1H), 4.28 (d, J=5.86, 2H), 2.30 (dd, J=7.04, 12.90 Hz, 1H), 1.71 (dd, J=9.38, 12.31 Hz, 1H), 1.35 (s, 3H), 1.17 (s, 3H); 13C NMR δ 157.97, 156.88, 145.38, 140.75, 131.88, 128.19, 127.59, 126.98, 126.58, 123.50, 119.06, 109.33, 52.06, 48.74, 42.98, 42.00, 28.64, 28.21.
Reaction SMILES: [CH:1]1([CH2:9][NH2:10])[CH2:6][CH2:5][CH:4]([CH2:7][NH2:8])[CH2:3][CH2:2]1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.[OH-].[NH4+:17].C(Cl)C(O)C.N>CO>[NH2:17][CH2:11][CH:13]([OH:15])[CH2:14][NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][CH:1]([CH2:9][NH2:10])[CH2:2][CH2:3]1
Reactant: ClCC1CO1
Reactant: [NH4+]
Reactant: NCC1CCC(CN)CC1
Agent: CC(O)CCl
Agent: N
Agent: [OH-]
Solvent: CO
Product: NCC(O)CNCC1CCC(CN)CC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
1,4-Cyclohexanebis(methylamine) (14.2 g., 0.1 mole) is dissolved in 50 ml. of anhydrous methyl alcohol and the solution cooled to +5° C. in an ice bath. Epichlorohydrin (9.3 g., 0.1 mole) is added in a 2-minute period and the temperature maintained at +5° C. for 2 hours; reaction is allowed to continue at 10°-15° C. until thin layer chromatography of an aliquot (silica gel plate with development using a solution of 1 volume concentrated aqueous ammonium hydroxide in 4 volumes of methyl alcohol) indicated nearly complete conversion of the starting diamine to the propylene chlorohydrin. The solution is then added to 100 ml. of dry methyl alcohol previously saturated at 0° C. with dry ammonia gas by continuous dropwise flow at +5° C. with good agitation and external cooling. After stirring 2 hours at +5° C., it is allowed to warm to 20° C. and mixed overnight. The reaction is competed by heating at 45°-55° C. for 6 hours. The solvent and ammonia was removed by stripping and the product purified using fractional distillation under reduced pressure.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]#[N:12].[CH3:13][O:14]CCl>[N+](C)([O-])=O.ClCCl.ClCCl>[C:11]([C:7]1[N:6]([CH3:5])[CH:10]=[C:9]([CH:13]=[O:14])[CH:8]=1)#[N:12]
Reactant: Cn1cccc1C#N
Reactant: COCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: Cn1cc(C=O)cc1C#N
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Aluminum trichloride (24.24 g, 180.86 mmol) was dissolved in nitromethane/dichloromethane (1/1, 320 ml) and, after cooling to -20° C., 1-methylpyrrole-2-carbonitrile (8 g, 75.36 mmol) was added. Then α,α-dichlorodimethyl ether (10.4 g, 90.43 mmol) dissolved in dichloromethane (42 ml) was added dropwise. After the mixture had been stirred at 0° C. for 4 h, it was poured onto ice (200 g). The aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution until neutral. After drying over sodium sulfate, the solvent was removed in a rotary evaporator. The crude product was employed without further purification in the following reactions. Yield: 9.2 g (91%).