Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([S-:6])=[S:5])[CH3:2].[K+].[PH:8](=[O:11])([OH:10])[OH:9].[CH2:12]([C:14]([CH2:42][CH3:43])([CH:16](Br)[C:17]1[N:21]=[CH:20][N:19]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)[CH3:15])[CH3:13].O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[PH:8](=[O:9])([OH:11])[OH:10].[CH2:42]([C:14]([CH2:12][CH3:13])([CH:16]([S:5][C:4]([O:3][CH2:1][CH3:2])=[S:6])[C:17]1[N:21]=[CH:20][N:19]([C:22]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)[CH3:15])[CH3:43]
Reactant: CCOC(=S)[S-]
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=[PH](O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=S)SC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(C)(CC)CC
Reaction time: 48 h
Yield: 80.2 %

Procedure:
A stirred solution of 18-Crown-6 (0.03 g) in dry tetrahydrofuran (25 ml) was treated successively with potassium ethylxanthate (0.44 g) and diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 29). The mixture was allowed to stand for two days, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3(ethoxythiocarbonylthio)-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.86 g) as a colourless gum. NMR(CDCl3): δ 1.25(6H,m), 1.4(3H,t), 1.7-1.9(2H,m), 2.3-2.4(2H,m), 4.0(4H,m), 4.6(2H,m), 5.05(1H,t), 7.1(6H,m), 7.3(9H,m), 7.9(1H,S). M/S: M+ 609.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:16][O:17][CH3:18])[C:13](Cl)=[O:14])[N:8]=1.Cl.[NH2:20][CH:21]1[C:46](=[O:47])[N:23]2[C:24]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:25]([CH2:28][Cl:29])[CH2:26][S:27][C@H:22]12.C(=O)([O-])O.[Na+]>O>[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:16][O:17][CH3:18])[C:13]([NH:20][CH:21]2[C:46](=[O:47])[N:23]3[C:24]([C:30]([O:32][CH:33]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:31])=[C:25]([CH2:28][Cl:29])[CH2:26][S:27][C@H:22]23)=[O:14])[N:8]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CON=C(C(=O)Cl)c1nsc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Temperature: -15 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a mixed solution of dichlorometahne (1000 ml) and tetrahydrofuran (200 ml) were added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl chloride (syn isomer) (64 g) and benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (100 g) at -15° C. The mixture was stirred at -15° C. for one hour. The reaction mixture was poured into ice-cooled water, and neutralized with sodium hydrogencarbonate. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (130.5 g)
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH:8]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[C:33]=1[S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[C:33]=1[S:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH2:8])=[CH:29][CH:30]=1)(=[O:41])=[O:42]
Reactant: Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc(C[C@H](N)C(=O)O)cc2)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin (3.0 g, 2.28 mmol) obtained from Example 62 was suspended in pyridine (15 mL), the slurry was cooled to 0° C. and 2,4,6-trimethylphenylsulfonyl chloride (2.49 g, 11.4 mmol) was added. The resulting mixture was agitated for 2 hr. The mixture was filtered and washed with dichloromethane and methanol. The coupling procedure was repeated. The resulting resin was treated with 25% piperidine in N-methylpyrrolidinone (2×15 min) and was washed with dichloromethane and methanol to give 4-[[(2,4,6-trimethylphenyl)sulfonyl]amino]-L-phenylalanine on Wang resin.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20](C)=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.Cl.Cl.CN(C)CCO[C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>>[NH2:7][CH:6]1[CH2:8][C:40]2[CH:41]=[C:42]([NH:43][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:22]=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:20]=[CH:19][CH:18]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:44]=[CH:45][C:46]=2[CH2:4][CH2:5]1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: Cc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Agent: Cl
Product: NC1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 39.8 %

Procedure:
N-{5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-methylphenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mmol) and 3-{[2-(dimethylamino)ethyl]oxy}-aniline dihydrochloride (112 mg, 0.44 mmol) were coupled according to the procedure of Example 56, Step H to give 25 mg of the title compound (19%). 1H NMR (400 MHz, d6-DMSO) δ 9.63 (s, 1H), 9.53 (s, 1H), 8.81 (d, J=7.2 Hz, 1H), 8.49 (d, J=9.2 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H), 7.72 (s, 1H), 7.52 (s, 1H), 7.47-7.43 (m, 1H), 7.36 (d, J=4.8 Hz, 1H), 7.30-7.25 (m, 3H), 7.14-7.08 (m, 2H), 6.97-6.95 (m, 2H), 6.52-6.50 (m, 2H), 3.97 (m, 2H), 3.90 (s, 2H), 2.58 (t, J=5.6 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 6H) ppm. ES-LC/MS m/z=604 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:27])[N:13]([CH3:26])[C:14]([C:23](O)=[O:24])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:9]3[CH2:28][O:29][CH2:30][CH2:31][C:8]2=3)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:37])=O>O1CCCC1.CN(C=O)C>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:11]3[C:12](=[O:27])[N:13]([CH3:26])[C:14]([C:23]([Cl:37])=[O:24])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:9]3[CH2:28][O:29][CH2:30][CH2:31][C:8]2=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C(=O)Cl)n(C)c(=O)c3c2c2c(n3Cc3ccc(F)cc3)CCOC2)cc1
Reaction time: 0.25 h
Yield: 93 %

Procedure:
A solution of methyl 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylate (0.4 g, 0.869 mmol) in Tetrahydrofuran (THF) (2.77 ml)/Methanol (2.77 ml) was treated with 2M LiOH (3.04 ml, 6.08 mmol) and heated to reflux (80° C. bath). After 18 h, the reaction mixture was cooled to ambient temperature and poured into 1M HCl. The layers were partitioned and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylic acid as a beige solid. A solution of 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carboxylic acid in THF (10 mL) was treated with oxalyl chloride (0.110 ml, 1.303 mmol) and 1 drop of DMF. After 15 min, the reaction mixture was concentrated in vacuo to afford 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carbonyl chloride (375 mg, 0.807 mmol, 93% yield). An ice cold solution of 5-(4-fluorobenzyl)-7-methyl-6-oxo-9-(p-tolyl)-1,3,4,5,6,7-hexahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridine-8-carbonyl chloride (375 mg, 0.807 mmol, 93% yield) in 1,2-DME (10 mL) was treated with NaBH4 (0.161 g, 4.34 mmol) and then warmed to ambient temperature. After 1 h, the reaction mixture was cooled to 0° C. and quenched with MeOH (1 mL) and 1M HCl (˜20 mL). EtOAc was added and the layers were partitioned and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated to afford 5-(4-fluorobenzyl)-8-(hydroxymethyl)-7-methyl-9-(p-tolyl)-3,4,5,7-tetrahydropyrano[3′,4′:4,5]pyrrolo[2,3-c]pyridin-6(1H)-one (333 mg, 0.770 mmol, 89% yield) as a white solid. The residue was used without further purification. LCMS (m/z) ES+=433 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:29][O:30][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:11]3=[O:28].Cl.[NH2:32][OH:33].C(N(CC)CC)C>C(O)C>[OH:33][N:32]=[C:8]([C:7]1[C:2]([OH:1])=[CH:3][C:4]2[O:30][CH2:29][C:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:11]3=[O:28])[C:5]=2[CH:6]=1)[NH2:9]
Reactant: NO
Reactant: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C#N)cc43)c3ccccc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C(N)=NO)cc43)c3ccccc32)cc1
Yield: 99.3 %

Procedure:
To a stirred solution of 6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.84 g, 2.10 mmol) and hydroxylamine hydrochloride (0.20 g, 2.9 mmol) in ethanol (50 mL) was added triethylamine (0.40 mL, 2.9 mmol). The reaction mixture was stirred at reflux for 18 h and concentrated in vacuo. The residue was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford N′,6-dihydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carboximidamide (0.90 g, 99%): MS (ES+) m/z 431.9 (M+1).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C[Si](C)(C)N[Si](C)(C)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH:24][C:4]2[C:5]3[CH:10]=[N:9][CH:8]=[CH:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Oc1ncnc2ccncc12
Reactant: CC(C)(C)c1ccc(CCN)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(C)(C)c1ccc(CCNc2ncnc3ccncc23)cc1

Procedure:
A mixture consisting of 0.45 g of pyrido-[4,3-d]pyrimidine-4-ol, 0.53 g of 2-[4-(t-butyl)phenyl]ethylamine, about 40 mg of (NH4)2SO4 in 4 mL of hexamethyldisilazane was refluxed for about five hours. The mixture was then cooled and excess disilazane was removed in vacuo. The residue was dissolved in CH2Cl2, and the solution was washed with water and filtered through phase separating paper. Evaporated the CH2Cl2 and adsorbed the residue onto silica gel, which was applied to a thin silica pad and eluted with CH2Cl2 →50% EtOAc/50% CH2Cl2EtOAc. Fractions containing the major product were combined and the product which crystallized was recrystallized from hexane/EtOAc. Yield 0.2 g. M.P. 157-158° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.Cl[C:17]([O:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].C(N1C2C(=CC(Br)=CC=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>>[C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[N:5]([C:17]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:18])[CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: O=C(Cl)OC1CCCC1
Agent: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CCCC2)C[C@@H]1C

Procedure:
Cyclopentyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate was prepared from (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone and cyclopentyl chloroformate according to the procedure outlined above for (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate. MS (ESI, pos. ion) m/z 381, 383 [M+1]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].Br[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:13][CH2:12][CH2:11][N:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1COCCN1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COCCN1CCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
Add NaH (0.47 g, 11.8 mmol) to a solution of morpholin-3-one (Vieles, P.; Seguin, J., Bulletin de la Societe Chimique de France, 1953, 287-9) (1.0 g, 9.9 mmol) in DMF (10 ml) at room temperature. Stir for 30 min, add (2-bromo-ethoxymethyl)-benzene (2.2 g, 10.2 mmol), and stir at room temperature for 18 h. Dilute with water and extract with EtOAc (2×). Combine the organics, dry, and concentrate. Purify by flash chromatography using 0-5% MeOH in CH2Cl2, to give the product as an oil. (1.7 g, 74%). 1H NMR (400 MHz, CDCl3): δ 7.28 (m, 5H), 4.48 (s, 2H), 4.13 (s, 2H), 3.80 (t, 2H, J=5.1 Hz), 3.65 (m, 2H), 3.59 (dd, 2H, J=7.5, 2.6 Hz), 3.48 (t, 2H, J=5.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][NH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: NCc1ccccn1
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][Si:16]([CH3:18])([CH3:17])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-nitrophenol (5.0 g, 35.9 mmol) (Aldrich) in dimethylformamide (50 mL) was added imidazole (3.18 g, 46.7 mmol) (Aldrich) and t-butyldimethylsilyl chloride (6.49 g, 43.1 mmol) (Avocado Research Chemicals Ltd.). The reaction mixture was stirred at room temperature for 1 day. TLC analysis showed starting material was still present. Another portion of t-butyldimethylsilyl chloride (1.0 g, 6.63 mmol) was added and the mixture was stirred at room temperature for another 1 day. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with a mixture of water (100 mL) and aqueous 1N HCl (80 mL). The organic layer was then washed with water, saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate/hexanes (1:9, V/V) to afford 1-nitro-4-(1,1,2,2-tetramethyl-1-silapropoxy)benzene. (Yield 7.8 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([Cl:22])=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.[N:36]1([C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[ClH:22].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[O:50])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-4,5-bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12b) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 794.3 [(M+H)+]
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:23]3[CH:24]=[CH:19][N:20]=[C:21]([NH:25][CH:26]4[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]4)[N:22]=3)=[CH:7][NH:6]2)=[CH:10][CH:11]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2ccc(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(F)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-6-fluoro-1H-indole (prepared by TBDMS protection of 6-fluoro-1H-indole) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 1.04 g (63%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6](N(CC)CC)C.[CH:13]1([N:16]=[C:17]=[S:18])[CH2:15][CH2:14]1.ClC1C=CC(N=C=S)=CC=1.CI>CN(C=O)C>[CH:13]1([NH:16][C:17](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[S:18][CH3:6])[CH2:15][CH2:14]1
Reactant: N#CCC#N
Reactant: CCN(CC)CC
Reactant: S=C=NC1CC1
Agent: S=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CI
Product: CSC(NC1CC1)=C(C#N)C#N
Reaction time: 0.08 h

Procedure:
Dissolved malononitrile (5.0 g) in DMF (50 mL), added triethylamine (1 eq), and stirred for 5 minutes before adding cyclopropyl isothiocyanate (1 eq) dropwise, then stirred until complete by TLC (absence of 4-chlorophenylisothiocyanate, 3 hrs). Added methyl iodide (1 eq) dropwise, then stirred until intermediate was fully consumed (absent on TLC, 18 hrs); poured into 100 mL ice water, then filtered resulting solution to obtain 2-((cyclopropylamino)(methylthio)methylene)malononitrile as a white powder.
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH3:19])[C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=2)=[C:5]([S:20][CH3:21])[CH:4]=1)#N.[CH3:22][Mg]I.CC[O:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:28]([C:29]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH3:19])[C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=2)=[C:5]([S:20][CH3:21])[CH:4]=1)(=[O:27])[CH3:22]
Reactant: C[Mg]I
Reactant: CCOCC
Reactant: CCN(c1nc(C)cc(C)n1)c1ccc(C#N)cc1SC
Solvent: c1ccccc1
Product: CCN(c1nc(C)cc(C)n1)c1ccc(C(C)=O)cc1SC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To 0.5 g (1.68 mmoles) of the nitrile of Example 52 in 10 mL dry C6H6 was added 1.1 mL (3.3 mmoles) of a 3 M solution CH3MgI in ether and the mixture was stirred at 25° C. for 2 h and at reflux for 1 h. The reaction was quenched with water and 10% HCl and stirred for 20 min before 1 M NaOH was added until the solution was alkaline and the mixture was extracted with 100 mL EtOAc. The organic layer was washed with water, brine, dried and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes to give 370 mg product (70% yield); mp 125-126° C. Elemental analysis for C17H21N3OS: Theory C, 64.73; H, 6.71; N, 13.32; S, 10.16. Found C, 64.53; H, 6.73; N, 13.08; S, 10.19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:24][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: CC(c1ccc(-c2ccccc2Cl)cc1)S(=O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 19.9 gm (0.059 mol) of [1-(2'-chloro-4-biphenylyl)-ethylsulfinyl]-acetic acid and 12.5 gm (0.088 mol) of methyl iodide in 120 ml of dry dimethyl sulfoxide was admixed with 12.2 gm (0.088 mol) of dry potassium carbonate, and the mixture was stirred at room temperature for 19 hours. The crude reaction product was precipitated with water and extracted with ethyl acetate (yield: 23.1 gm). For purification, the obtained crude product was purified by chromatography on 1200 gm of silicagel with cyclohexane ethyl acetate=1/1. The combined fractions with an Rf -value of 0.23 (on carrier 2) were combined and evaporated, leaving 6.2 gm (31.2% of theory) of the title compound; oil, Rf -value: 0.23 on carrier 1 with cyclohexane/ethyl acetate=1/1.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7.18 mL (48.0 mmol) benzyl chloroformate in 50 mL DCM was added dropwise to 12.3 g (45.7 mmol) tert-butyl 4-piperidin-4-yl-piperazine-1-carboxylate and 8.2 mL (50 mmol) N-ethyldiisopropylamine in 200 mL DCM while cooling with ice and the reaction mixture was stirred overnight at RT. It was washed with 200 mL of 15% K2CO3 solution, the organic phase was separated off and dried over Na2SO4. After elimination of the desiccant and solvent the residue was further reacted without any further purification.