Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:12]3=[N:11][C:4]=1[CH:5]=[N+:6]2[O-:24]
Reactant: c1ccc2c(c1)ncc1nc3n(c12)OCCCC3
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc2nc3n(c2c2ccccc21)OCCCC3
Reaction time: 0.67 h
Yield: 89.6 %

Procedure:
A solution of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinoline (0.1449 g, 0.605 mmol) in 6 mL of dichloromethane was treated with 3-chloroperoxybenzoic acid (0.30 g, 57-86% purity). After stirring for 40 minutes, the reaction mixture was diluted with dichloromethane, washed successively with dilute aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.1384 g of 8,9,10,11-tetrahydro[1,2]oxazepino[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide as a tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1
Reactant: CN(C)CCCCl
Reactant: Oc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: CN(C)CCCOc1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
A 5.46 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was reacted with 3-dimethylaminopropyl chloride by the procedure of Example 255, giving 2.9 g of the desired product, mp 85°-87° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:41])([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.CO.[BH3-][C:47]#N.[Na+]>CC(O)C.CC(O)=O>[CH3:41][C:10]1([N:12]([CH3:47])[C:13]2[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:25][C:24]3[O:23][CH2:22][C:21]4=[N:20][N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[C:18](=[O:39])[CH:17]([CH3:40])[N:16]4[C:15]=3[CH:14]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1
Reactant: [BH3-]C#N
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(N(C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 110 °C
Reaction time: 48 h
Yield: 52.7 %

Procedure:
A mixture of 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Example #100, Step A, 0.250 g, 0.417 mmol) and paraformaldehyde (neat, 0.250 g, 8.34 mmol) in iPrOH (5 mL) and AcOH (0.5 ml) was stirred at 110° C. for 2 days. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. Then, MeOH (5 mL), AcOH (2.5 mL) and NaBH3CN (0.524 g, 8.34 mmol) were added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (0.135 g, 53%). 1H NMR (CDCl3, 400 MHz): δ 7.25 (s, 1H), 6.72 (s, 1H), 5.10 (m, 2H), 4.65 (m, 1H), 4.66 (q, J=13.2 Hz, 2H), 4.03 (d, J=8.8 Hz, 1H), 3.90 (d, J=12.4 Hz, 1H), 3.66 (t, 2H), 3.58 (t, 2H), 2.68 (s, 3H), 1.48 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 0.99 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3>C(OC(=O)C)(=O)C.C(Cl)(=O)C>[C:10]([O:17][C:16]1[CH2:18][CH2:19][C@H:20]2[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[O:11][C:16](=[O:17])[CH3:15])[CH:15]=1)(=[O:11])[CH3:9]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](OC(C)=O)CC[C@@H]34)[C@H]2CC1

Procedure:
The compound 19-nortestosterone, 400 g, is refluxed under nitrogen in a mixture of 1500 ml of acetic anhydride and 1500 ml of acetyl chloride for a period of 3 hours. The volatile solvents are distilled at atmospheric pressure and the final traces of solvent removed under reduced pressure. The solid residue which remains is triturated with ice water, filtered, washed with cold aqueous sodium bicarbonate solution, rinsed with water and dried. Two recrystallizations of this residue from acetone yield 370 g of 3,17β-diacetoxyestr-3,5-diene which melts at 165°-71° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(NCC)C.C1COCC1>[CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:20][N:6]([CH2:7][CH3:8])[CH2:5][CH3:1])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCCCc1nc(-c2ccc(OC[C@H](O)CN(CC)CC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (100 mg, 2.1 mmol, from intermediate A2) in 1 mL of diethylamine and 2 mL of THF was stirred at 76° C. for 1 h in a microwave reactor. Upon completion (determined by LC/MS), the reaction was evaporated in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 96% EtOAc/(2M NH3/MeOH) as an eluent to afford (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:32][CH:33]([NH:40]S(C(C)(C)C)=O)[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCl>[NH2:40][CH:33]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)[CH2:32][NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(CC(NS(=O)C(C)(C)C)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: NC(CNC1CCN(C(=O)OCc2ccccc2)CC1)c1ccncc1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of benzyl 4-((tert-butoxycarbonyl){2-[(tert-butylsulfinyl)amino]-2-pyridin-4-ylethyl}amino)piperidine-1-carboxylate (230 mg, 0.412 mmol) in dichloromethane (10 mL). After 1 h, the reaction was concentrated, dissolved in methanol (5 μL), and treated with 4 N HCl in dioxane (4.12 mmol). After 1 h, the reaction was concentrated to give the title compound. MS 355.2 (M+1)
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].O>C1(C)C=CC=CC=1>[C:4]1([CH:3]=[CH:2][CH:1]=[N:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:18]=[CH:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCCCCCCN
Reactant: O=CC=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C(=Cc1ccccc1)C=NCCCCCCN=CC=Cc1ccccc1
Yield: 97 %

Procedure:
Cinnamaldehyde (198.2 g, 1.5 mole) is carefully added to a solution of 1,6-hexanediamine (87.2 g, 0.75 mole) in toluene (400 ml). Slight exotherm to 60° C. is observed. The resulting solution is heated at reflux until water (27 ml, 1.5 mole) is evolved. Evaporation of the solution gives 250.7 g of a brown viscous oil. 1H NMR: δ 1.0-2.85 (broad bands 8H); δ 3.6 (triplet 4 H); δ 6.82-8.22 (broad multiplete 16 H). Elemental analysis: Theory for C24H28N2 : C,83.72; H,8.14; N,8.14%. Found: C,83.61; H,8.35; N,8.05%.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17](O)=O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C(Cl)[Cl:26].C[Si](Cl)(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[CH2:1]([N:3]([CH2:23][CH3:24])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[CH2:17][Cl:26])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: ClCCl
Reactant: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(CCl)c(=O)[nH]2)cc1

Procedure:
From 6.0 g. of 6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 175 ml. of methylene chloride, 2.4 ml. of triethylamine, 2.2 ml. of trimethylsilyl chloride and 2.5 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([Cl:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:24][N:25]([CH2:27][C:28](Cl)=[O:29])[CH3:26].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:22][C:21]1[C:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[CH2:27][N:25]([CH3:26])[CH3:24])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CN(C)CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a suspension of 4-amino-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (2 g; 4.5 mmol; 1 eq) in DCM (100 mL) is added dimethylaminoacetyl chloride hydrochloride (710 mg; 4.5 mmol; 1 eq) and N-ethyldiisopropylamine (2.3 mL; 13.5 mmol; 3 eq) and the reaction mixture is stirred at room temperature overnight. To complete the reaction, dimethylaminoacetyl chloride hydrochloride (1.06 g; 6.74 mmol; 1.5 eq) is added and the reaction mixture is allowed to stir another 2 days. The precipitate formed is filtered off and the filtrate is treated with a solution of citric acid. The precipitate in the organic phase is filtered and the aqueous phase is basified with Na2CO3. The product is extracted with DCM and the organic phase is concentrated to near dryness to afford 1.5 g (80%) of the title compound as a yellow powder. HPLC (max plot) 85%; Rt 2.37 min. UPLC/MS (ES+) 420.2, (ES−) 418.3.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][Cl:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[Cl:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][Cl:15])[S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: ClCCNCCCl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 743.4 %

Procedure:
Triethylamine (3.1 mL, 22.2 mmol) was added dropwise to a suspension of N,N-bis(2-chloroethyl)amine hydrochloride (2.0 g, 11.2 mmol) in dichloromethane and the mixture was stirred at room temperature for 20 minutes. The mixture was then cooled in an ice bath and methanesulfonyl chloride (1.41 g, 1.1 mmol) was added dropwise. The cooling bath was removed and the mixture was stirred for 4 hours at room temperature. Water was added to the reaction mixture and the organic layer was washed with 2M aqueous hydrochloric acid, water, dried (MgSO4) and evaporated to give the title compound (1.80 g, 73%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:14])[CH2:2][CH3:3].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[CH:25]=O>O1CCCC1>[CH2:1]([O:4][C:5](=[O:15])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:25][C:17]2[O:16][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH:18]=2)=[CH:9][C:8]=1[CH3:14])[CH2:2][CH3:3]
Reactant: O=Cc1cc2ccccc2o1
Reactant: CCCOC(=O)Nc1ccc(N)cc1C
Solvent: C1CCOC1
Product: CCCOC(=O)Nc1ccc(NCc2cc3ccccc3o2)cc1C
Reaction time: 1 h
Yield: 43 %

Procedure:
A mixture of 0.1 M solution of (4-amino-2-methylphenyl)-carbamic acid propyl ester (0.35 mL, 0.035 mmol) and 0.1 M solution of benzofuran-2-carbaldehyde (0.35 mL) in tetrahydrofuran (THF) was kept at 55° C. for 60 minutes. Volatiles were removed in vacuo. To the obtained residue 0.2 M sodium cyanoborohydride (NaBH3CN) (0.5 mL) in methanol and acetic acid (0.03 mL) were added. After sonication for 60 minutes the reaction mixture was evaporated in vacuo and the title compound was separated by preparative LC/MS to give 5.1 mg of colorless solid. Yield 43%. LC/MS (m/z) 339.2 ([M+H]+); RT=2.92, (UV, ELSD) 94%, 94%.
Reaction SMILES: [NH2-].[Na+].N.[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:14]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([CH3:4])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: ClCc1ccccc1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
To a stirred mixture of sodium amide (prepared from 0.9 g 39.13 mmoles of sodium) and ca 100 ml of liquid ammonia was added a solution of 5.08 g (38.73 mmoles) of 5-methylindole in 100 ml of ether during 5 minutes. The mixture was stirred for 1.5 hours. Then a solution of 5.15 g (40.68 mmoles) of benzyl chloride in 100 ml of ether was added during 10 minutes. The mixture was stirred for two hours. The ammonia was allowed to evaporate overnight. The inside of the flask was washed down with MeOH. Then 150 ml of H2O was added. The layers were separated. The aqueous layer was extracted with 100 ml of ether. The combined ether phases were washed with 50 ml of brine and dried over MgSO4. Evaporation of the solvent left 9.41 g of oil. The oil was chromatographed on a 700 g column of silica gel. The column was eluted with 30% CH 2 Cl2 -Skellysolve B and 200 ml fractions were collected. The fractions were assayed by silica gel tlc (2×8") (25% CH2Cl2 -Skellysolve B). Fractions 12-17 were combined giving 4.52 g (53%) of 1-benzyl-5-methylindole as a yellow-green oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][C:14]=1[CH:19]=O>C(O)(=O)C.CCO>[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][C:14]=1[CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c(C=NNC(=O)c2ccc(O)cc2)[nH]1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 3,5-dimethyl-pyrrole-2-carboxaldehyde (0.25 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give grey solid 0.44 g, in 86% yield, mp: 261.2° C. 1H NMR (CD3OD) δ 8.12 (s, 1H), 7.79 (d, 2H), 6.88 (d, 2H), 5723 (s, 1H), 2.24 (s, 3H), 2.13 (s, 3H). 13C NMR (CD3OD) δ 166.5, 162.5, 139.4, 134.1, 130.5, 127.1, 124.9, 124.1, 116.3, 110.7, 12.9, 10.7. Anal. Calcd for C14H15N3O2: C, 65.35; H, 5.88; N, 16.33. Found: C, 65.52; H, 5.79; N, 16.30.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[C:14]([NH:16][OH:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C([O:29]C1C=CC(CC(N)=O)=CC=1)C>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[C:14]([NH:16][OH:17])=[O:15])=[O:29])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2ccc(OCC)cc2)cc1
Reactant: CCOc1ccc(CC(N)=O)cc1
Product: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2ccc(OCC)cc2)cc1
Yield: 73 %

Procedure:
Starting from 2-{[4-(2-butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-(4-ethoxyphenyl)acetamide (808 mg, 2.27 mmol) and following the procedure as outlined in Example 7, 640 mg of 2-{[4-(2-Butynyloxy)phenyl]sulfinyl}-N-hydroxy-2-(4-ethoxyphenyl acetamide was isolated as a brown powder. Yield: 73%; MS: 388.2 (M+H)+. Mp: 192-193.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[NH2:19])[CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:23](OC(Cl)(Cl)Cl)=[O:24]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([N:9]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[NH:19][C:23]1=[O:24])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCC[C@H](NC(=O)c1ccc(OC)cc1N)C(=O)OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[C@@H](C(=O)OC)n1c(=O)[nH]c2cc(OC)ccc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 209.4 %

Procedure:
To a solution of (S)-2-(2-amino-4-methoxy-benzoylamino)-hexanoic acid methyl ester (1.0 g, 3.50 mmol) in THF (30 mL) is added trichloromethyl chloroformate (325 mg, 1.64 mmol). The mixture is stirred at 90° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated to give (S)-2-(7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-hexanoic acid methyl ester (1.1 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.[CH2:15]([O:22][C:23]1[C:28]([CH2:29][CH3:30])=[CH:27][C:26](B(O)O)=[C:25]([O:34][CH3:35])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:22][C:23]1[C:28]([CH2:29][CH3:30])=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]3[CH3:14])[N:3]=2)=[C:25]([O:34][CH3:35])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCc1cc(B(O)O)c(OC)cc1OCc1ccccc1
Reactant: Cc1ccc(C)n1-c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1cc(-c2cccc(-n3c(C)ccc3C)n2)c(OC)cc1OCc1ccccc1
Yield: 73.1 %

Procedure:
Under a nitrogen atmosphere, 5.00 g (19.91 mmol) of 2-bromo-6-(2,5-dimethylpyrrol-1-yl)pyridine, 5.98 g (20.91 mmol) of 4-benzyloxy-5-ethyl-2-methoxy-phenylboronic acid (5), 8.44 g (79.64 mmol) of sodium carbonate and 1.15 g (0.996 mmol) of tetrakis(triphenylphosphine)palladium(0) were combined in 90 mL of ethanol and 10 mL of water. The solution was allowed to reflux for 64 hours, and then the reaction mixture was concentrated in vacuo. The resultant yellow residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted again with ethyl acetate (200 mL). The combined organic extracts were washed with brine (1×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield crude product as a yellow oil which crystallized upon standing. Recrystallization of this solid from absolute ethanol afforded 6.00 g (73%) of 2-(4-benzyloxy-5-ethyl-2-methoxy-phenyl)-6-(2,5-dimethyl-pyrrol-1-yl)-pyridine (6) as a tan solid.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]=[CH:34][N:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:32]=1)(=[O:3])[CH3:2].[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]=[CH:34][N:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:32]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1cnc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1cnc(/C=C2\CNCCC2SC(C)=O)n1
Yield: 54 %

Procedure:
Following a procedure similar to that described in Example 132-(f), (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,4-triazol-3-yl]methylidene}-1-(triphenylmethyl)piperidine obtained in Example 166-(c) was treated with trifluoroacetic acid in dichloromethane and the crude product was purified by silica gel chromatography using dichloromethane and methanol (20:1 to 10:1) as an eluent to afford the title compound (860 mg, yield: 54%) as a yellow amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH:20]=[CH2:21])=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][C:14]=3[C:22]([F:24])([F:25])[F:23])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21

Procedure:
A mixture of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (27 mg, 0.07 mmol) and palladium on carbon (10 mg, 10 wt %; Aldrich) in methanol (1 mL) was subjected to 1 atmosphere of hydrogen for 50 min. The reaction was then filtered, concentrated, and the resulting residue was purified by radial chromatography (30% ethyl acetate in hexanes) to give the desired product as a clear residue (25 mg, 91%).
Reaction SMILES: [C:1](=[N:14][CH2:15][C:16]1[C:17]([Cl:32])=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=[CH:19]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[CH3:35]C(C)([O-])C.[K+]>C1COCC1.CCOC(C)=O>[C:1](=[N:14][CH:15]([C:16]1[C:17]([Cl:32])=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:20]=[CH:19]2)[CH3:35])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN=C(c3ccccc3)c3ccccc3)ccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CC(N=C(c1ccccc1)c1ccccc1)c1ccc2c(ccn2C(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a stirred solution of 322 (1.22 g, 2.74 mmol) and iodomethane (0.17 mL, 2.74 mmol) in anhydrous THF (22.3 mL) at 0° C. was added dropwise a solution of potassium tert-butoxide (358.4 mg, 3.098 mmol) dissolved in THF (˜0.50 mL) over 5 min. The reaction mixture was stirred at RT under N2 for 3 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford 1.19 g (94.6%) of tert-butyl 5-[1-(benzhydrylideneamino)ethyl]-4-chloro-1H-indole-1-carboxylate (324) as a foam: MS (ESI) m/z=459.1 [M+1]+.