Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH:7]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([NH:12][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=C1CC(=O)O1
Reactant: NC1CCCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCC1
Temperature: 20 °C
Reaction time: 6 h
Yield: 63.3 %

Procedure:
84 g of diketene were added over 10 minutes at 10° C. to a mixture of 85 g of cyclopentylamine and 500 ml of tetrahydrofuran and after stirring the mixture for 6 hours at 20° C., the mixture was evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and was cooled and vacuum filtered to obtain 107 g of N-cyclopentyl-acetylacetamide melting at 52° C. 56 g of the latter product and 1.6 g of p-toluene sulfonic acid were added to a mixture of 40 g of methyl orthoformate and 80 ml of methanol and the mixture was held at 50° C. for 8 hours and 72 hours at 25° C. 4 ml of quinoline were added and the mixture was evaporated to dryness under reduced pressure. The residue was added to toluene and the mixture was heated at 145° C. for 4 hours while distilling a toluene-methanol azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with an 8-2 methylene chloride-acetone mixture and was crystallized from isopropyl ether to obtain 40 g of N-cyclopentyl-3-methoxy-crotonamide melting at 94° C. The RMN spectra showed the product to be the E isomer.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25]>>[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CS(=O)(=O)N1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(methylsulfonyl)piperazine (1.2 equiv) to give 200 (M+1 460.0)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(OC([NH:23][C@H:24]([C:32](O)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[NH2:23][C@@H:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)=[O:33]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)aniline (0.20 g, 0.87 mmol), N-(tert-butoxycarbonyl)-L-phenylalanine (254.8 mg, 0.96 mmol), phosphorus trichloride (40 μL, 0.46 mmol) and toluene (4 mL) was stirred at 80° C. for 1.5 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by isopropyl ether/n-hexane to give the title compound (333.7 mg, 92.9%) as an yellow white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([CH3:11])=[CH:4][CH:3]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:15])=[O:9])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1nc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-3-methylpyridine-2-carboxylic acid (3.69 g, 21.51 mmol) was taken up in THF (100 mL)/MeOH (25 mL). A solution of TMS-diazomethane (21.5 mL, 43.0 mmol) was added and the resulting solution stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (2-20% EtOAc/hexanes) to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[O:54])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccccn4)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccn4)cc2)CCN3CCC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.40 g) was dissolved in methylene chloride (12 ml), m-chloroperbenzoic acid (111 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 193) (181 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1>[C].[Pd].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propenoate (700 mg), 5% palladium-carbon (1.00 g) and tetrahydrofuran (15 ml) was stirred for one hour at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (618 mg, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:7, volume ratio).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:13]=1)#[CH:11].CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10]#[C:11][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C#Cc1ccc(CCCCCC)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A mixture of 4-bromobenzaldehyde (5.00 g, 27.0 mmol), 1-ethynyl-4-hexylbenzene (6.29 g, 33.4 mmol), Et3N (4.70 mL, 33.4 mmol), bis(triphenylphosphine)palladium chloride (950 mg, 1.35 mmol) and triphenylphosphine (180 mg, 0.68 mmol) in anhydrous THF (100 mL) was stirred at rt for 30 min under inert atmosphere. Then copper(I) bromide (82 mg, 0.43 mmol) was added and the resulting mixture was stirred overnight at rt. The solvent was evaporated off. The residue was dissolved in Et2O (100 mL), washed with water (50 mL), dried over MgSO4 and the solvent was removed under reduced pressure. The resulting brown solid was triturated in hexane (25 mL), filtered off and washed with hexane to give the title compound as a beige solid (7.73 g, 91%). HPLC (Condition A), Rt: 5.88 min (HPLC purity: 91.9%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1>O1CCCC1.C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3cccc(Cl)n3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 89 %

Procedure:
Ethyl 7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at 50° C. for 50 min. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The obtained crystals were collected by filtration, and washed successively with water and diethyl ether to give the title compound (840 mg, yield 90%) as a white solid. The obtained crystals were recrystallized from N,N-dimethylformamide-water to give colorless crystals. melting point 249-250° C. (decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:17](Cl)(=[O:19])=[O:18])[C:11]=2[CH:10]=[CH:9][N:8]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:17]([C:12]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:19]
Reactant: NCCCCN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCCCCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 62 %

Procedure:
In 200 ml of chloroform was dissolved 8.8 g of 1,4-diaminobutane, and to the solution was added dropwise 100 ml of a chloroform solution containing 4.55 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and then the reaction solution ws extracted with a 10% aqueous hydrochloric acid solution. The pH of the aqueous layer was adjusted to 10 with a 10% aqueous sodium hydroxide solution, and the aqueous layer was extracted with chloroform. The chloroform layer extracted was washed with water and dried with anhydrous potassium carbonate. Then the chloroform was distilled from the chloroform layer, and the residue obtained was subjected to a column chromatography [silica gel: 200 g; developing solvent: 2% methanol/chloroform (volume ratio)] to give 3.46 g of N-(4-aminobutyl)-5-isoquinolinesulfonamide, i.e., Compound (3) as an oily substance in a yield of 62%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][O:20]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]([CH2:18][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([OH:20])[CH3:21])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(c2cccnc2)CO1
Reactant: CN1CCc2[nH]c3c(Cl)cccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cccc(Cl)c3n2CC(C)(O)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
6-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.5 mmol) was dissolved in 15 mL DMF and stirred for 5 min at RT. Sodium hydride (540 mg, 13.5 mmol) was added portionwise at RT under nitrogen. 3-(2-Methyl-oxiranyl)-pyridine (800 mg, 5.9 mmol) was diluted in 5 mL DMF and added dropwise at the same temperature and stirred for 16 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water (30 mL) and filtered. The residue was crystallized in EtOH (1 mL) and ether (40 mL) and purified by reverse phase chromatography to obtain 620 mg of 1-(6-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.77 (s, 1H), 8.5 (d, 1H), 8.45 (s, 1H), 7.71 b (s, 1H), 7.17 b (s, 1H), 7.06 (d, 1H), 6.97 (t, 1H), 5.12 b (s, 1H), 4.3 b (s, 1H), 3.78 (m, 1H), 3.62 (m, 1H), 3.14 (m, 1H), 2.63 (m, 2H), 2.57 (s, 3H), 2.5 b (s, 2H), 1.53 (s, 3H). Separation by chiral HPLC provided enantiomers 57a and 57b.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:43])[C@H:35]([NH2:42])[CH2:36][C:37]1[CH:41]=[CH:40][S:39][CH:38]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:42][C@H:35]([CH2:36][C:37]4[CH:41]=[CH:40][S:39][CH:38]=4)[C:34]([OH:33])=[O:43])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](N)Cc1ccsc1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@H](Cc4ccsc4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 94.9 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2R)-amino-3-thiophen-3-yl-propionic acid methyl ester HCl (28.1 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 63.4 mg of the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C1COCC1>[O-:24][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc[n+]([O-])c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To a mixture of 4-(3-pyridyl)toluene (35 g, 0.207 mol) in pyridine (400 ml) and water (400 ml) was added KMnO4 (163 g, 1.03 mol) in portions and refiuxed for 12 h. The reaction mixture was filtered through celite and acidified with cone. HCl. The product was washed with water and dried to give 4-(3pyridyl)benzoic acid (32 g, 76%) as a white solid. To a mixture of 4-(3-pyridyl)benzoic acid (22 g, 0.11 mol) in THF (2.51), mCPBA (152 g 0.44 mol, 50%) was added and stirred at RT for 12 h. The solid was filtered, and washed with TBF to give 4-(1-oxido-3-pyridinyl)benzoic acid (20 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:18]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1

Procedure:
Ethyl 2-{4-[(7-chloroquinolin-3-yl)oxy]phenoxy}-2-methylpropionate (15) was prepared from 4-[(7-chloroquinolin-3-yl)oxy]phenol and ethyl 2-bromo-2-methylpropionate following essentially the same procedure as that described in Example 1 part (c). The product, a pale yellow oil was characterised by proton magnetic resonance spectroscopy. Pmr spectrum (CDCl3 ; δ in ppm): 8.65 (1H, d); 7.95 (1H, bs); 7.35 (3H, m); 6.9 (4H, s); 4.2 (2H, q); 1.6 (6H, s); 1.2 (3H, t).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl.O>[OH-].[Na+]>[CH2:16]([O:15][C:13]([NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC1CCC(C(=O)O)CC1)OCc1ccccc1
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a solution of trans-4-aminocyclohexane carboxylic acid hydrochloride (5.0 g, 34.92 mmol) in aqueous 2.0N NaOH (35 mL) is added benzyl chloroformate (5.0 mL, 34.92 mmol). The mixture stirs for 1.5 h. Then the suspension is acidified with 12N HCl (aq) to pH=1. H2O is added (100 mL) and the precipitate is filtered off. The filter cake is dried to afford 8.2 g of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid. LC/MS: [M+H]30 =278, Rt=0.85 min (method 6)
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4]>C1COCC1.CO.[Ni]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)c1ccc(N)cc1

Procedure:
16 g (84.1 mmol) of 2-methyl-2-(4-nitro-phenyl)-propionitrile (Example 1d) and 4.16 g of Raney-Ni are shacked in 160 ml of THF-MeOH (1:1) under 1.1 bar of H2 for 12 h at rt. After completion of the reaction, the catalyst is filtered-off and the filtrate is evaporated to dryness. The residue is purified by flash chromatography on silica gel (hexane-EtOAc 3:1 to 1:2) to provide the title compound as an oil. ES-MS: 161 (M+H)+; analytical HPLC: tret=2.13 minutes (Grad 1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:21][CH:22]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)(=[O:36])[CH3:35]
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)C2

Procedure:
A stirred solution of 0.954 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide in 25 ml of methylene chloride and 5 ml of acetic anhydride is heated at reflux for 24 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with ethyl acetate-hexane (7:3) to give 0.800 g of a white solid; mass spectrum (M+H)519.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:5]2[N:6]=[CH:7][C:8]([C:10](N)=[O:11])=[CH:9][N:4]2[N:3]=1.[OH-:14].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:13]=[C:5]2[N:6]=[CH:7][C:8]([C:10]([OH:14])=[O:11])=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2ncc(C(N)=O)cn2n1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2ncc(C(=O)O)cn2n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid amide (475 mg) was dissolved in ethanol (5 ml), and 5 N sodium hydroxide solution (2 ml) was added thereto and stirred for 1 hour at 70° C. The reaction mixture was cooled to room temperature, water was added thereto, and the reaction mixture was washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (300 mg, Y.:63%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=O)[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].CO.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: N#Cc1c(F)cccc1C(=O)c1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)S(=O)N=C(c1ccnc(Cl)c1)c1cccc(F)c1C#N
Yield: 47.8 %

Procedure:
Ti(OEt)4 (15 mL) was added to a solution of 2-(2-chloro-pyridine-4-carbonyl)-6-fluoro-benzonitrile (3.6 g, 13.81 mmol) and 2-methyl-propane-2-sulfinic acid amide (2.5 g, 20.72 mmol) in dry THF (100 mL) at room temperature. The resulting mixture was stirred to reflux for 40 hours and then treated with CH3OH (50 mL) and saturated sodium bicarbonate solution (10 mL). The resulting suspension was filtered through a pad of Celite® and the solids were washed with THF (50 mL) and CH3OH (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using a gradient of 25-50% EtOAc in hexane to afford the title compound (2.4 g, 48%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:24]=[CH:23][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20]CC(C)(C)[O:17]3)=[C:12]([Br:25])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=[O:33])=CC=1>CC(C)=O.O>[C:1]1([S:7]([C:10]2[CH:24]=[CH:23][C:13]([O:14][CH2:15][C@H:16]([OH:17])[CH2:20][OH:33])=[C:12]([Br:25])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)CC[C@@H](COc2ccc(S(=O)(=O)c3ccccc3)cc2Br)O1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(OC[C@H](O)CO)c(Br)c1

Procedure:
A solution of 4-(S)-(4-benzenesulfonyl-2-bromo-phenoxymethyl)-2,2-dimethyl-[3,3]dioxolan (1.07 g, 0.0025 mol) and pyridinum toluene-4-sulfonate (0.38 g, 0.0015 mol) in acetone (20 mL) and water (5 mL) was heated under reflux for 12 hours. The solvent was removed under reduced pressure. The oily residue was dissolved in ethyl acetate (100 mL), washed with cold 10% aqueous hydrochloric acid, saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. Recrystallization of the residue (diethyl ether-hexane) gave 3-(4-benzenesulfonyl-2-bromo-phenoxy)-propane 1-2-(R)-diol as white crystals. Mp. 104.6-105.9° C.