Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C(OC(=O)[NH:38][CH2:39][CH2:40][NH2:41])(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:38][CH2:39][CH2:40][NH:41][C:18]([C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:21]=[C:22]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:23]=[CH:24][C:2]=2[Cl:1])[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCNC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to the method described for Example 3 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and tert-butyl(2-aminoethyl)carbamate. The residue was dissolved in DCM (10 mL) and treated with 4M HCl in dioxane (5 mL) with stirring at room temperature for 4 hours. The reaction was concentrated in vacuo and eluted through an SCX-2 column using MeOH followed by 7N NH3 in MeOH; followed by reverse phase chromatography eluting with 5-95% MeCN (with 0.1% NH3) in water (with 0.1% NH3); followed by silica gel column chromatography eluting with 1-5% 7N NH3/MeOH in DCM and finally trituration with TBME.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[N:16]([C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-phenylindole (27) (25 gm, 0.129 mol) in acetic acid (250 mL) was cooled to 180C and a solution of sodium nitrite (8 g, 0.115 mol) in water (10 mL) was added dropwise while keeping the temperature of the reaction at ca. 20° C. The resulting reaction was stirred for 30 min at room temperature then diluted with ice water (250 mL). The reaction mixture was was filtered and the solid was washed with water then recrystallized using methanol to provide Compound 28. Yield=27.5 gm (96.4%). ES-MS: 223.22 (M++1); NMR (DMSO-d6): 7.0 (m, 1H), 7.1 (m, 1H), 7.22 (m, 1H), 7.32 (m, 2H), 7.40 (m, 1H), 7.48 (m, 2H), 7.60 (m, 1H).
Reaction SMILES: C[N:2]([C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:31])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])([OH:22])[CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:10][CH:9]=1)[NH:3][C:4]([NH2:6])=[S:5].[CH3:33][O-].[Na+]>C(O)C>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C@:15]([OH:22])([C@H:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:6]([CH3:33])[C:4]([SH:5])=[N:3][N:2]=2)=[CH:13][CH:12]=1)[CH3:31])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: CC(c1ccc(C(=O)N(C)NC(N)=S)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](c1ccc(-c2nnc(S)n2C)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A solution of N-methyl-4-{2-[2,4-difluorophenyl]-2-hydroxy-1-[1,2,4-triazol-1-yl]but-3-yl}benzoylthiosemicarbazide (2.1 g, 4.5 mmol) in ethanol (50 ml) was heated under reflux and treated with sodium methoxide solution (30%, 5.5 mmol) in portions over 24 hours. The mixture was reduced in volume to 20 ml under reduced pressure and partitioned between ethyl acetate (100 ml) and water (50 ml). The aqueous layer was further extracted with ethyl acetate (3×50 ml) and the organic extracts combined, washed with brine (50 ml), dried (Na2SO4) and evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10]([OH:17])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[CH:14]=[CH:15][S:16][C:11]3=[C:10]([O:17][CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: ClCc1ccccn1
Reactant: Oc1cc(-c2ccc(F)cc2)nc2ccsc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc(OCc3ccccn3)c3sccc3n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-(4-fluorophenyl)-thieno[3,2-b]pyridin-7-ol (30 mg, 0.09 mmol), 2-picolyl chloride hydrochloride salt (30 mg) and potassium carbonate (100 mg) in DMF (2 mL) is heated at 100° C. for 2 hours. The reaction solution is cooled to room temperature, quenched with aqueous sodium bicarbonate solution and extracted several times with ethyl acetate. The combined ethyl acetate layers are dried over Na2SO4, filtered and concentrated. The residue is purified by preparative thin layer chromatography to give 5-(4-Fluorophenyl)-7-[(2-pyridyl)-methyloxy]-thieno[3,2-b]pyridine as white solid (compound 1).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC1C=CC(S(OC[C@@H:24]2[O:26][CH2:25]2)(=O)=O)=CC=1.O1CCC[CH2:28]1>>[CH2:5]([N:4]([CH3:28])[CH2:3][C@H:25]1[CH2:24][O:26]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNCc1ccccc1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1ccccc1)C[C@H]1CO1
Reaction time: 1 h
Yield: 64 %

Procedure:
Sodium hydride (60%, 88 mg) was suspended in tetrahydrofuran (5 ml) at room temperature under nitrogen atmosphere, and N-methylbenzylamine (0.284 ml) was added dropwise while stirring. After 1 hour, (2R)-glycidyl tosylate (457 mg) was added thereto and the reaction mixture was stirred overnight at room temperature, then at 50° C. for 7.5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was the purified by silica gel column chromatography (eluent; ethyl acetate) to provide the titled compound (225 mg, 64%) as a colorless oil.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]([CH3:10])=[O:9].[H][H].O=O>C(O)(=O)C>[CH:1]1([OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=[O:9])[CH2:10][CH2:6][CH2:1][CH2:2][CH2:7]1
Reactant: CC(C)=O
Reactant: C1CCCCC1
Reactant: [H][H]
Agent: O=O
Solvent: CC(=O)O
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
After adding Fe2O3 (1 g), Pd/silica (Pd content 1.3%, 1 g) and cyclohexane (5 g) to the mixture of acetone (20 ml) and acetic acid (1 ml), it was stirred in a flow of hydrogen and oxygen gases at the respective rate of 20 ml/min. As the result of reaction for 3 hours at 30° C. under atmospheric pressure, 3.13 mole % of cyclohexanol and 0.41 mole % cyclohexanone with the total yield of 3.54 mole % were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[C:5]([NH:7][N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=1)[CH:9]([CH3:11])[CH3:10])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:42][CH2:43][O:44][CH3:45]>CC(C)=O>[CH:9]([N:8]([C:12](=[O:31])/[CH:13]=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:16]=1)[NH:7][C:5](=[O:6])[C:4]1[CH:32]=[CH:33][CH:34]=[C:2]([O:1][CH2:42][CH2:43][O:44][CH3:45])[CH:3]=1)([CH3:11])[CH3:10]
Reactant: COCCBr
Reactant: CC(C)N(NC(=O)c1cccc(O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1cccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)c1
Temperature: 60 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(2-(3-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100.0 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in acetone (5.0 ml), 1-bromo-2-methoxyethane (0.024 ml, 0.26 mmol) was added drop-wise. The reaction mixture was refluxed at 60° C. for 48 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (CHCl3:methanol=60:1) so that ivory solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(3-(2-methoxyethoxy)benzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (62.4 mg, 55.5%).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[C:37]([NH:44][CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:50][C:49]1[CH:51]=[CH:52][C:46]([CH2:45][NH:44][C:37](=[O:38])[O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[CH:47][CH:48]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (29.9 mg, 0.108 mmol) in dry dichloromethane (3 mL) was added triethylamine (0.038 mL, 0.271 mmol), 2-chloro-1-methylpyridinium iodide (41.0 mg, 0.160 mmol), and 4-(N—BOC-aminomethyl)aniline (30.6 mg, 0.138 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 60° C. for 2 hours. LC/MS showed no starting material remaining. The reaction mixture was concentrated and purified by HPLC on a Waters Sunfire column to afford the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:24]([CH:25]=O)=[CH:23][C:11]3[C:12]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=4)=[N:13][O:14][C:10]=3[C:9]=2[F:27])[CH2:5][C@@H:4]([CH3:28])[O:3]1.[NH:29]1[C:34](=[O:35])[NH:33][C:32](=[O:36])N[C:30]1=[O:37].[CH3:38]CO>>[F:27][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=3)[C:11]=2[CH:23]=[C:24]2[C:8]=1[N:6]1[CH2:7][C@@H:2]([CH3:1])[O:3][C@@H:4]([CH3:28])[C@@H:5]1[C:38]1([C:32](=[O:36])[NH:33][C:34](=[O:35])[NH:29][C:30]1=[O:37])[CH2:25]2
Reactant: CCO
Reactant: O=c1[nH]c(=O)[nH]c(=O)[nH]1
Reactant: CSc1nccc(-c2noc3c(F)c(N4C[C@@H](C)O[C@H](C)C4)c(C=O)cc23)n1
Product: CSc1nccc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1

Procedure:
In a microwave reactor, 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(2-(methylthio)pyrimidin-4-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 437, 719 mg, 1.79 mmol) and 1,3,5-triazinane-2,4,6-trione (242 mg, 1.88 mmol) in EtOH (10 ml) were heated at 140° C. for 1 hour. The solution was concentrated to dryness to afford 916 mg of desired product, used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7](F)=[CH:8][CH:9]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:8][CH:9]=1
Reactant: C1COCCN1
Reactant: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(F)ccc21
Solvent: CN1CCCC1=O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(N3CCOCC3)ccc21
Yield: 41.5 %

Procedure:
In a similar fashion using route 51 general procedure 118, 12-chloro-9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 503 (100 mg, 0.3 mmol), morpholine (0.052 ml, 0.6 mmol) and NMP (2 ml) gave title compound (50 mg, 41%) after purification by column chromatography using chloroform/MeOH (99.5:0.5) as the eluent.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:12])[C:3]=1[CH3:13].[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].[F-].[Cs+]>O.O1CCOCC1.C(O)C>[OH:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)=[C:3]([CH3:13])[C:4]=1[CH3:12]
Reactant: Cc1c(Br)ccc(OCCO)c1C
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(OCCO)ccc(-c2ccc(C(=O)O)cc2)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 2-(4-bromo-2,3-dimethylphenoxy)ethanol (0.531 g), 4-carboxyphenylboronic acid (0.360 g), tetrakis-(triphenylphosphine)palladium(0) (0.125 g), cesium fluoride (1.645 g), water (2 mL), ethanol (2 mL) and 1,4-dioxane (8 mL) was stirred at 80° C. for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4′-(2-hydroxyethoxy)-2′,3′-dimethylbiphenyl-4-carboxylic acid (0.62 g) as a crude product. A mixture of the crude 4′-(2-hydroxyethoxy)-2′,3′-dimethylbiphenyl-4-carboxylic acid, benzyl bromide (0.445 g), and potassium carbonate (0.450 g) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to afford the title compound (0.033 g).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.CN1C(=O)N(C)CCC1.[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:28]1)=[O:26])[CH3:23].C(Br)C=C>C1COCC1>[CH2:36]([O:35][C:33]([C:29]1([CH2:7][CH:5]=[CH2:6])[CH2:30][CH2:31][CH2:32][CH:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:28]1)=[O:34])[CH3:37]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCCC(C(=O)OCC)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: C=CCBr
Product: C=CCC1(C(=O)OCC)CCCC(C(=O)OCC)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a cooled solution (−78° C.) of N,N-diisopropylamine (272 mL, 1.94 mol) in anhydrous THF (1.4 L) was added n-BuLi (1.6 M in hexane, 1.21 L, 1.94 mol) over the period of one hour and 20 minutes. The mixture was stirred at 0° C. for one hour and again cooled down to −78° C. DMPU (834 mL, 6.92 mol) was added dropwise, followed by the addition of the solution of cyclohexane-1,3-dicarboxylic acid diethyl ester from step 1 (316 g, 1.38 mol) in THF (400 mL). The mixture was stirred at −78° C. for 2.5 hours, and then allyl bromide (132 mL, 1.52 mol) was added. The mixture was warmed up to rt slowly and stirred at rt overnight. The mixture was quenched with ice-cold aqueous HCl (1 N, 1 L), diluted with ethyl acetate (30 mL) and extracted. The organic layer was washed with water (4×1.5 L), brine, dried over Na2SO4 and concentrated under reduced pressure to afford 371 g of the title compound as a thick oil, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:17][C:18](=[O:27])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:16])([CH3:15])[CH3:14].[OH-].[K+]>CS(C)=O>[C:13]([O:17][C:18](=[O:27])[NH:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[CH:24][CH:25]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C=O)cc2[N+](=O)[O-])cc1

Procedure:
A mixture of 4-chloro-3-nitrobenzaldehyde and (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester were reacted together in DMSO with addition of KOH to provide the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48]C(=O)C)=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>O.C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([OH:48])=[C:43]([CH:47]=2)[C:44]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.7 %

Procedure:
4-Nitroaniline (0.414 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.080 g, 0.177 mmol, 18%).
Reaction SMILES: C(O[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1)C.[NH2:14][NH2:15]>C(O)C>[NH:14]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1)[NH2:15]
Reactant: CCOC1=NCCc2ccccc21
Reactant: NN
Solvent: CCO
Product: NNC1=NCCc2ccccc21

Procedure:
A solution of 3,4-dihydroisocarbostyril (IV: Y=Y'=Z=Z'=H) (64.3 g.) in dried methylene dichloride was added to a methylene dichloride (250 ml.) solution of triethyloxonium fluoborate, prepared from boron trifluoride etherate (227 g.), epichlorohydrin (74 g.) and absolute ether (600 ml.) After being stirred (for about 16 hr. at 25° C.), the mixture was treated with potassium carbonate solution (50%, 75 ml.) and water (25 ml.), stirred (for 1-1/2 hr.) and filtered. The solid material was washed thoroughly with methylene dichloride and dissolved in hot water. The solution was filtered and extracted three times with chloroform. 1-Ethoxy-3,4-dihydroisoquinoline fluoborate (10.5 g.) obtained in an earlier run was dissolved in potassium carbonate solution and the solution was extracted three times with methylene dichloride. The combined methylene dichloride washing, chloroform extract and methylene dichloride extract were stripped of solvents and distilled under reduced pressure, affording 1-ethoxy-3,4-dihydroisoquinoline (III: Q=C2H5, Y=Y'=Z=Z'=H) (68.4 g., b.p. 110°-137° C./16 mm. Hg), part (10.82 g.) of which was a center cut (b.p. 129°-131° C./16 mm. Hg). B. A solution of 1-ethoxy-3,4-dihydroisoquinoline (2.0 g.) in ethanol (10 ml.) was added dropwise with stirring to a solution (at 80° C.) of hydrazine (95%, 1.83 g.) in ethanol (5 ml.). The solution was concentrated, diluted with chloroform, washed with water, dried and concentrated. The residue (1.6 g.) was crystalized from ether in three crops (0.7 g., 0.5 g., 0.3 g.). Recrystallization of the first crop from ether-pentane afforded 1-hydrazino-3,4-dihydroisoquinoline (V: Y=Y'=Z=Z') (m.p. 55°-57° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].S(=O)(=O)(O)O.O[CH2:16][CH:17]([CH2:19]O)O>[N+](C1C=CC=CC=1)([O-])=O>[F:8][C:4]1[C:3]([OH:9])=[C:2]2[C:7]([CH:16]=[CH:17][CH:19]=[N:1]2)=[CH:6][CH:5]=1
Reactant: OCC(O)CO
Reactant: Nc1cccc(F)c1O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1c(F)ccc2cccnc12
Temperature: 140 °C
Yield: 51.8 %

Procedure:
To a solution of 2-amino-6-fluorophenol (4.0 g, 31.6 mmol) and nitrobenzene (20 mL) in a sealable reaction vessel was added in portions sulfuric acid (4.0 mL). Glycerol (12.0 g, 126 mmol) was added in one portion, and the solution turned to dark brown. The vessel was flushed with nitrogen, sealed and heated to 140° C. for 6 h. The reaction mixture was cooled to rt, diluted with 30 mL ice/water mixture, and washed 3 times with methyl t-butyl ether (removes most of the nitrobenzene). The aqueous phase was neutralized to pH=6-7 by slow addition of 6N NaOH. The resulting black precipitate was collected and the water solution was extracted with ethyl acetate 3 times. The organic extracts were combined with the black precipitate, concentrated in vacuo, and purified on silica gel column with 0-10% MeOH/DCM to give 2.67 g (51.7%) of 7-fluoro-8-quinolinol as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(OCCc2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OCCc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenethyloxy-pyridine.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:20].C([Li])CCC.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([CH3:37])=[CH2:36]>C1COCC1.CCOC(C)=O>[CH3:20][C:3]1[CH:4]=[C:5]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([F:26])=[C:28]([C:35]([CH3:37])=[CH2:36])[CH:29]=1)[OH:32]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Br
Reactant: C=C(C)c1cc(C=O)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3,5-dimethyl-triisopropylsilanoxybenzene (1.29 g, 3.6 mmol, G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607) in THF at −78° C. was added n-butyllithium (1.58 mL, 3.96 mmol, 2.5 M in THF). After 30 min, a solution of 4-fluoro-3-isopropenylbenzaldehyde (500 mg, 3.0 mmol) in THF was added. The reaction mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, diluted with EtOAc and quenched with water. The organic layer was dried over MgSO4, filtered and concentrated to afford crude 1-(2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-1-(4′-fluoro-3′-isopropenylphenyl)methanol as an oil: 1H NMR (200 MHz, CDCl3): δ 7.18 (m, 1 H), 7.02 (m, 1 H), 6.94 (m, 1 H), 6.56 (s, 2 H), 6.22 (s, 1 H), 5.18 (m, 2 H), 2.20 (s, 6 H), 2.08 (s, 3 H), 1.25 (m, 3 H), 1.11 (m, 18).