Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+]>C(O)C.ClCCl.[Pd]>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12](=[O:26])[NH:13][C:14](=[O:25])[C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:27](=[O:29])[CH3:28])[CH:17]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1NC(=O)C(c2cccc([N+](=O)[O-])c2)=C1Nc1ccc2c(c1)CCC2
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C2=C(Nc3ccc4c(c3)CCC4)C(=O)NC2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(Indan-5-ylamino)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (Table A, Example A359; 0.3 g, 0.9 mmol) and 10% Pd/C (60 mg) in ethanol (25 mL) was hydrogenated at atmospheric temperature and pressure for 2 hours. The reaction mixture was filtered through Kieselguhr and the filtrate concentrated in vacuo to give an orange solid. The crude product was taken up in dichloromethane (5 mL) and treated with acetic anhydride (85 μL, 0.9 mmol) and stirred for 3 hours at ambient temperature. The reaction mixture was poured onto saturated aqueous sodium bicarbonate solution (10 mL) and extracted into ethyl acetate (3×10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography on silica gel using dichloromethane-methanol gave the desired compound as an orange powder.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C>CO.[OH-].[Na+]>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([C:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:4]([OH:35])=[O:3])(=[O:25])=[O:26])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)(CCCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(CCCc2ccccc2)(CCCc2ccccc2)C(=O)O)cc1

Procedure:
2-(4-Methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid ethyl ester (2.0 g, 4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.18 g, 63%. Waxy solid; MS: 449.2 (M+H−H2O)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]1[NH2:18].Cl.[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:12]2[C:13](=[C:21]([CH3:20])[CH:22]=[C:23]([CH3:24])[N:18]=2)[C:14]([C:16]#[N:17])=[CH:15]1
Reactant: CC(=O)CC(C)=O
Reactant: CC(C)c1ccc(-n2cc(C#N)cc2N)c(Br)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Reaction time: 4 h

Procedure:
Part C: A mixture of 18.51 g (0.0609 mole) of 1-(2-bromo-4-isopropylphenyl)-2-amino-4-cyano-pyrrole, 300 mL of ethanol, 0.6 mL of conc. hydrochloric acid, and 10 mL (9.75 g, 0.0974 mole) of 2,4-pentanedione was refluxed with stirring under a nitrogen atmosphere for 4 hrs. The mixture was allowed to cool and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with 10% sodium bicarbonate solution, then with brine. The solution was dried with anhydrous sodium sulfate and evaporated to give 21.76 g of dark, tarry residue. The residue was chromatographed on silica gel by eluting in step gradients of 0, 10, 15, 20, 25; and 30% ethyl acetate in hexane. The initial fraction is 17.6 g (78%) 1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole; m.p. 105.8°. Mass spec: (m+H)+=368.0749; calculated, 368.0762 (79Br). Rf =0.45 on silica gel thin layer chromatography with 70:30 hexane-ethyl acetate.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH2:18][OH:19])=[CH:12][CH:11]=1.N1C=CN=C1>ClCCl.Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[CH2:18][O:19][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC/C=C/c1ccc(Br)cc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC/C=C/c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
tert-Butyl chlorodimethylsilane (1.33 g, 19.5 mmol) was added to a stirred solution of (E)-3-(4-bromo-phenyl)-prop-2-en-1-ol (3.20 g, 15.0 mmol), and imidazole (2.72 g, 18.0 mmol) in dry dichloromethane (75 ml) and the resulting mixture stirred at room temperature for 18 h, a colourless precipitate being formed. The mixture was diluted with dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The aqueous layer was separated, further extracted with dichloromethane (2×100ml) and the combined organic layers washed with brine, dried (MgSO4) and evaporated. The product was purified by column chromatography on silica gel (1% diethyl ether in n-heptane eluent) to give the colourless solid, (E)-[3-(4-bromo-phenyl)-allyloxy]-tert-butyldimethylsilane (4.39 g, 89%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:18][N:17]3[C:19]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[C:20]([CH3:25])[C:21]4[CH:22]=[CH:23][CH:24]=[C:15]([C:16]=43)[O:14]2)(=O)=O)=CC=1.[C-:35]#[N:36].[K+]>CS(C)=O>[C:35]([CH2:11][CH2:12][CH:13]1[CH2:18][N:17]2[C:19]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[C:20]([CH3:25])[C:21]3[CH:22]=[CH:23][CH:24]=[C:15]([C:16]=32)[O:14]1)#[N:36]
Reactant: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCOS(=O)(=O)c2ccc(C)cc2)O4)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCC#N)O4)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
13.7 9 of 2,3-dihydro-2-[2-(p-toluenesulfonyloxy)ethyl]-5-(4-methoxyphenyl)-6-methylpyrrolo[1,2,3-de]-1,4-benzoxazine (preparation see Example 1F)) were dissolved in 50 ml of hot dimethyl sulfoxide under a nitrogen atmosphere. 2.2 g of potassium cyanide were added to the reaction mixture heated at 80° C. and the mixture was stirred for a further 6 hours. For work-up, the reaction mixture was poured into ice-water after cooling. The resulting brown solid was filtered out and dissolved in dichloromethane. The organic solution was washed with water, dried and evaporated. The crude product remaining as a residue was purified by column chromatography using dichloromethane as an eluent. 9.1 g of 2,3-dihydro-2-(2-cyanoethyl)-5-(4-methoxyphenyl)-6-methyl-pyrrolo[1,2,3-de]-1,4-benzoxazine were obtained as a white solid having a melting point of 113° to 14° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@@H:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]([CH:38]=O)[CH3:37].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>[CH3:35][N:36]([CH2:38][C:2]1[CH:10]=[C:9]([C:2]2[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]3[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=3[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:37]
Reactant: CN(C)C=O
Reactant: CC[C@@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
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: [Cs+]
Solvent: O
Product: CC[C@@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3cccc(CN(C)C)c3)cc21

Procedure:
(R)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (100 mg, 0.23 mmol), N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine, HCl (100 mg, 0.34 mmol) and Palladium Tetrakis (26 mg, 0.023 mmol) in DMF/water (3 mL:1 mL) were stirred for 10 min under nitrogen. Cesium carbonate (220 mg, 0.68 mmol) was added and the insoluble mixture was irradiated (microwave) at 150° C. for 15 min. The contents were evaporated, dissolved in DCM/MeOH (1:1), and pre-absorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 80:20:2 in DCM). The isolated product was first treated with EtOAc along with some hexanes. The product was then dissolved in MeOH and purified by reversed-phase HPLC (30×100 Varian Polaris C18 column, eluent: 10-80% gradient of MeCN in water with 0.1% TFA). The product fractions were combined, most of the solvent was evaporated, and a sat. solution of NaHCO3 was added. Solids that crashed out were filtered, air-dried for 15 min, and dried in vacuum-oven overnight. The solid product was collected as 85 mg (75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1H) 8.21 (t, J=5.05 Hz, 1H) 7.77 (d, J=1.26 Hz, 1H) 7.60-7.66 (m, 2H) 7.41 (t, J=7.58 Hz, 1H) 7.30 (s, 1H) 7.25 (d, J=7.58 Hz, 1H) 7.22 (d, J=1.52 Hz, 1H) 5.87 (s, 1H) 4.60-4.68 (m, 1H) 4.36 (s, 1H) 4.35 (s, 1H) 3.49 (br. s., 2H) 2.24 (s, 3H) 2.19 (d, J=8.84 Hz, 9H) 2.11 (s, 3H) 1.77-1.88 (m, 2H) 1.41 (d, J=6.57 Hz, 3H) 0.74 (t, J=7.33 Hz, 3H); LCMS: 499.4 (MH+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CC#N>[N:11]1([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCNC1
Reactant: Clc1nc2ccccc2o1
Solvent: CC#N
Product: c1ccc2oc(N3CCCNCC3)nc2c1
Yield: 38.7 %

Procedure:
In a 40 mL vial at room temperature, 2-chlorobenzo[d]oxazole (760 mg, 5 mmol) was added to a solution of homopiperazine (2 g, 20 mmol) in CH3CN. The reaction mixture gradually turned into a suspension. Upon standing for additional half an hour, solid was filtered off and the collected filtrate was directly subjected to chromatography (Isco, gradient elution, CH2Cl2 to 9:1 CH2Cl2/MeOH). 420 mg of the desired product was isolated (MS, M++H=218.1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:54])[N:5]1[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:39][CH3:40])=[N:14][C:13]3[N:41]([S:44]([C:47]4[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=4)(=[O:46])=[O:45])[CH:42]=[CH:43][C:12]=3[C:6]1=[N:7]2.[NH4+:55].[OH-]>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:7][C:6]2[C:12]3[CH:43]=[CH:42][N:41]([S:44]([C:47]4[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=4)(=[O:45])=[O:46])[C:13]=3[N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:33][CH2:34]5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:39][CH3:40])[N:5]=2)[C:3]=1[C:4]([NH2:55])=[O:54]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Yield: 60.4 %

Procedure:
A solution of 8-fluoro-5-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (4.5 g, 5.81 mmol) and 30% aqueous NH4OH (75 mL, 5.81 mmol) and tetrahydrofuran (75 mL) was stirred at rt overnight in a 200 mL rb flask. The solution was extracted with ethyl acetate (250 mL) and brine (50 mL). The organic layers were dried over MgSO4, filtered, concentrated onto Celite and purified on SiO2 (1-10% MeOH in CH2Cl2 and 0.1% NH4OH) to afford 2-fluoro-6-({2-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (2.78 g, 3.51 mmol, 60% yield) as a mixture with several other products. The desired product was the predominant component. The product weight was 2.78 grams. ESIMS (M+H)+=792.42 (100%). This material was used without further purification in the next step.
Reaction SMILES: [CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(O)C.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][CH2:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCc1ccc(CCC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Yield: 93.1 %

Procedure:
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane (216 mg; synthesized in example 2(1)) and palladium-carbon (50 mg; content 5) were suspended in a mixed solvent (6 ml) of ethanol, ethanol and ethyl acetate (1:1:1). In an atmosphere of hydrogen, the suspension was stirred for 90 min at room temperature. After stirring, the suspension was filtered through celite. The filtrate was condenced under reduced pressure. Thre residue was purified by column chromatography on silica gel (methylene chloride:methanol=19:1) to give the title compound (202 mg) having the following physical data:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:19])=[C:6]([Br:18])[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:18][C:6]1[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=[C:4]([C:1]2([CH3:2])[O:22][CH2:21][CH2:20][O:3]2)[C:5]=1[CH3:19]
Reactant: OCCO
Reactant: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Br)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C2(C)OCCO2)nn(-c2ccc(F)cc2)c(=O)c1Br
Yield: 89.4 %

Procedure:
A suspension of 6-acetyl-4-bromo-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (3.2 g), ethylene glycol (3.1 g) and p-toluenesulfonic acid (0.2 g) in toluene (35 ml) was heated under reflux for 10 hours with removing water formed. After cooling on standing, the reaction mixture was extracted with ethyl acetate. After washing with a saturated aqueous sodium hydrogen carbonate solution and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), and the resulting crude crystals were washed with hexane to obtain 4-bromo-2-(4-fluorophenyl)-5-methyl-6-(2-methyl-1,3-dioxolan-2-yl)-3(2H)-pyridazinone (3.25 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(Cc2ccccc2)n1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 4 h with 3.4 g of benzylhydrazine hydrochloride and 5.9 ml of triethylamine in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-benzyl-1H-[1,2,4]triazole remains as colorless crystals of m.p. 166-168° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=1)([CH3:21])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)cn1
Product: COc1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 62 using (4-isopropylphenyl)[(2-methoxy-5-pyridyl)methyl]amine (0.50 g) and 2,6-diisopropylphenyl isocyanate (0.63 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-[(2-methoxy-5-pyridyl)methyl]urea (0.57 g) was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:15])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)OCC(C)(C)C(=O)Cl

Procedure:
A benzene solution (25 ml) of crude 3-acetoxy-2,2-dimethyl propionic acid from Example 3(a) (7.4 g, 46.5 mmol), oxalyl chloride (6.45 g, 51 ml) and DMF (2 drops) was stirred at ambient temperature for 3 hours. The pale yellow solution was distilled to provide the title compound as a colorless liquid, b.p.15 85°-88° C. NMR (CDCl3) δ4.18 (2H, s), 2.08 (3H, s), 1.35 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH:27]=O)=[CH:21]2)[CH3:13].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:27][C:22]1[NH:23][C:24]2[C:20]([CH:21]=1)=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:14]([CH2:12][CH3:13])[CH2:29][CH3:30])=[CH:26][CH:25]=2
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccc(Br)cc43)cc2c1
Temperature: 100 °C
Yield: 66 %

Procedure:
A mixture of 5-bromo-2-oxindole (41 mg, 0.2 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 60 mg (66%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34](Cl)=[O:35]>C1COCC1>[CH3:28][N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:35]
Reactant: CN1CCC[C@@H]1C(=O)Cl
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)[C@H]3CCCN3C)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and (R)-1-methylpyrrolidine-2-carbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (t, J=7.33 Hz, 3H) 1.30-1.40 (m, J=7.45, 7.45, 7.45, 7.45 Hz, 2H) 1.94-2.04 (m, 2H) 2.10-2.23 (m, 3H) 2.60-2.63 (m, 1H) 2.91 (s, 3H) 3.24-3.27 (m, 1H) 4.21-4.30 (m, 1H) 6.79 (s, 1H) 7.57 (t, J=7.71 Hz, 1H) 7.75-7.83 (m, 3H) 7.85-7.90 (m, 3H) 8.09 (d, J=8.08 Hz, 1H) 9.87 (s, 1H) 11.01 (s, 1H); ESI-MS: m/z calc'd for C27H29N5O2S 487.62. found 488.1 (M+H)+.
Reaction SMILES: ClC1C=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17][OH:18])=[N:9]2)=CC=1.CC(C[AlH]CC(C)C)C.ClCCl>C1(C)C=CC=CC=1>[N:9]1[CH:10]=[CH:5][CH:6]=[CH:7][C:8]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18]
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCc1cccc(/C=C/c2ccccn2)c1
Temperature: -70 °C

Procedure:
The methyl benzoate (Example 37b part ii) (2.25 g, 9.4 mmol) was dissolved in dry toluene (60 ml) and cooled to -70° C. under nitrogen. 1M DIBAL in dichloromethane (18.8 ml, 18.8 mmol) was added over 15 minutes and the reaction mixture allowed to warm up to -30° C. for 30 minutes. The reaction was quenched by careful addition of methanol (8 ml), then water, and after filtration through Celite the organic phase was evaporated in vacuo.
Reaction SMILES: CON(C)[C:4](=[O:11])[C@@H:5]([NH:7][C:8](=[O:10])[O-:9])[CH3:6].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.S([O-])(O)(=O)=O.[Na+]>O1CCCC1>[F:13][C:14]([F:24])([F:23])[C:15]1[CH:20]=[CH:19][C:18]([C:4](=[O:11])[C@@H:5]([NH:7][C:8](=[O:10])[O:9][C:15]([CH3:20])([CH3:16])[CH3:14])[CH3:6])=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)[O-]
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of N-{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (9.6 g) in tetrahydrofuran (180 mL) was dropwise added at 0° C. to a solution of 1.48M 4-trifluoromethylphenylmagnesium bromide in tetrahydrofuran (70 mL) which had been prepared in another batch. The mixture was stirred at room temperature for 14 hours, and cooled down to 0° C. After addition of aqueous sodium hydrogen sulfate, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and filtered to remove the sodium sulfate. Evaporation of the organic solvent in vacuo gave t-butyl N-[(1S)-2-(4-trifluoromethylphenyl)-1-methyl-2-oxoethyl]carbamate (13.4 g) as an orange solid.