Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].Br[C:9]1[N:18]=[C:17]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:20])[C:16]([OH:30])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2>N1C=CC=CC=1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:19]([C:17]2[C:16]([OH:30])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([N:1]3[CH2:6][CH2:5][CH2:4][NH:3][C:2]3=[O:7])[N:18]=2)=[O:20])=[CH:28][CH:27]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: O=C1NCCCN1
Solvent: c1ccncc1
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CCCNC2=O)c2cccnc2c1O
Temperature: 25 °C

Procedure:
To a mixture of tetrahydro-2-pyrimidone (0.040 g, 0.4 mmol), 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.050 g, 0.13 mmol), and Cu2O (0.0095 g, 0.07 mmol) under an atmosphere of argon was added pyridine (1.0 mL) and the suspension was stirred at reflux for 16 hr. Cu2O (0.005 g, 0.04 mmol) was added and the reaction heated at 115 C for a further 16 hr. The reaction was allowed to cool to room temperature and the solvent evaporated in vacuo. The residue was treated with DMF (2 mL) and filtered to remove the solids. TFA (0.5 mL) was added to the filtrate which was purified by reverse phase HPLC. (Waters PrePak 500 cartridge C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 75 mL/min over 45 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:14]([Li])CCC.CI.[Cl-].[NH4+]>CCOCC>[CH3:13][O:12][C:3]1[C:2]([CH3:14])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: COc1ncc(C(F)(F)F)cc1Br
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: COc1ncc(C(F)(F)F)cc1C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.12 g (0.020 mol) of 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine in 60 ml of ether was cooled to -70° C. and blanketed with nitrogen. A solution containing 0.021 mole of butyl lithium (8.4 ml of 2.5 M) was added slowly with stirring keeping the temperature below about -65° C. and the mixture allowed to react for another 30 min. Methyl iodide (0.62 ml, 0.01 mol) was added to the mixture and stirring continued at -70° C. for about 30 min. The mixture was allowed to warm to about 20° C. and was then poured onto a mixture of ice and saturated aqueous ammonium chloride. The organic layer that formed was recovered. The aqueous layer was extracted with ether and the extract added to the organic layer. The combined organic materials were dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled to obtain 2.1 g (54 percent of theory) of the title compound as a colorless oil boiling at 67°-69° C. at 24 mm pressure. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[NH2:35])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH:35][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:3]4[CH:4]=[CH:5][C:6]([C:8]5[N:12]=[C:11]([CH3:13])[O:10][N:9]=5)=[CH:7][C:2]=4[CH3:1])=[CH:15][CH:16]=3)=[O:21])[CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Reactant: COc1ccc(N)cc1OCCN1CCOCC1
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN1CCOCC1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxdiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 3-(2-morpholin-4-ylethoxy)-4-methoxyaniline (D13) using a similar procedure to Example 1 (58%) mp 58°-63° C.
Reaction SMILES: [NH2:1][C:2]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:3]2[C:4](=O)[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:1][C:2]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:3]2[CH2:4][N:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1
Reactant: NC12C=CC(CC1)C1C(=O)N(Cc3ccccc3)C(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NC12C=CC(CC1)C1CN(Cc3ccccc3)CC12

Procedure:
19.3 g (68.2 mmol) of 1-amino-4-benzyl-4-azatricyclo[5.2.2.02,6 ]undec-8-ene-3,5-dione are reduced with 8 g of LiAlH4 as described under Z 1-B and the mixture is worked up accordingly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N+:10]([C:13]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16])([O-:12])=[O:11]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:13]=2[N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Yield: 74.1 %

Procedure:
Using the procedure described in Example 93, Part A, 4-methoxyaniline (43.76 mmol) and 2,4-dinitrobenzoyl chloride (48.14 mmol) yielded 10.29 g (74%) of the title compound.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH2:31][CH3:32])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[Si]([O:40][CH2:41][CH:42]=O)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:30][CH2:31][CH3:32])=[C:7]([CH:5]4[CH2:6][N:3]([CH2:42][CH2:41][OH:40])[CH2:4]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH:27]([F:29])[F:28])[C:20]=12
Reactant: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(CCO)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1 step 8, with 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (racemic) and {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde as starting materials. After reductive amination, tetrabutylammonium fluoride was added to remove the tert-butyl(dimethyl)silyl group. The product was isolated as a racemic mixture. LCMS calculated for C21H25ClF3N6O2 (M+H)+: m/z=485.2; Found: 485.2. 1H NMR (300 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.38 (m, 2H), 6.29 (m, 1H), 3.78-3.67 (m, 4H), 3.53 (m, 1H), 3.12 (m, 2H), 2.99-2.87 (m, 2H), 2.34 (m, 2H), 1.68 (d, 3H), 1.22 (m, 3H) ppm.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:22]([C:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]3)=[O:32])=[N:21]2)=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:22]([C:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][N:34]3[C:8](=[O:10])[CH3:9])=[O:32])=[N:21]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCCCN3)cc2-c2ccccn2)cn1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)N3CCCCN3C(C)=O)cc2-c2ccccn2)cn1
Reaction time: 0.33 h

Procedure:
Triethylamine (0.210 mL), acetyl chloride (0.0807 mL) and 4-dimethylaminopyridine (13.5 mg) were added to 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexahydropyridazine (0.275 g) obtained in Example 162 in methylene chloride (6.0 mL) at room temperature, followed by stirring for 20 minutes. The mixture was partitioned between water and chloroform. The organic layer was washed with saturated brine, and then dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an amorphous product (0.149 g, 59%).
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:3].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24](Cl)=[O:25])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>O1CCCC1>[CH3:3][CH:2]([NH:1][C:24](=[O:25])[CH:23]=[CH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC(C)N
Reactant: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)NC(=O)C=Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
To a stirred solution of 31.0 g. of 2-aminoundecane in 100 ml. of tetrahydrofuran, was added a solution of 19.0 g. 3-(3-nitrophenyl)propenoyl chloride in 100 ml. of tetrahydrofuran, dropwise, during 75 minutes, at ca. 5° C. After the addition, the mixture was allowed to warm to room temperature, and stirring was continued for 45 minutes. The solvent was removed by evaporation in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was removed, washed successively with 1 N hydrochloric acid and water, and dried. Evaporation of the solvent in vacuo, followed by recrystallization of the residue from hexane, afforded 26 g. (83% yield) of the title product, m.p. 81°-83° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][C:10]=1[CH3:27])#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][N:42]=[C:41]([CH3:44])[N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[C:10]([CH3:27])[CH:11]=4)=[C:22]([CH2:23][CH2:24][CH3:25])[N:43]4[N:42]=[C:41]([CH3:44])[N:40]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: Cc1n[nH]c(NC2CCC3(CC2)OCCO3)n1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(C)c1)C(=O)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-3-oxohexanoate (3.00 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-3-methyl-1H-1,2,4-triazol-5-amine (1.00 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL) and N,N-diethylaniline (10 mL) was stirred at 180° C. overnight, allowed to cool and poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a brown oil (1.20 g, 53%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][CH2:7][C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][N:9]=1>>[Br:6][CH2:7][C:8]1[C:12]2[CH:13]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:15]=[CH:16][C:11]=2[O:10][N:9]=1
Reactant: BrCc1noc2ccccc12
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc2onc(CBr)c2c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 80.2 %

Procedure:
Chlorosulfonic acid (1.5 ml, 22 mmol) was slowly added to 3-Bromomethyl-benzo[d]isoxazole (1.0 g, 4.7 mmol) at RT under argon. The reaction was heated at 90° C. for 12 h and then left at RT for 6 h. The resulting viscous oil was quenched over ice, extracted with EtOAc, dried over MgSO4 and concentrated in vacuo to a brown oil (1.17 g, 80% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].O.Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>CC#N>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[C:9]([Cl:14])[CH:8]=1)[CH3:2]
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cl)c1)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(Cl)c1)OC
Temperature: 85 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
3-(3 Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (0.020 g, 0.077 mmol) was dissolved in CH3CN (3 mL) and 4-(3-bromo-propoxy)-biphenyl (Example 132, Step D), (0.025 g 0.085 mmol) and K2CO3 (0.032 g, 0.23 mmol) were added. The mixture was heated to 85° C. and stirred for 5 hours. After cooling, water (2 mL) was added. The mixture was extracted in EtOAc (3×10 mL), washed with H2O (2×5 mL) and brine (2×5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate 9:1) to produce 3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionic acid ethyl ester (0.017 mg, 48%). 1H-NMR (200.15 MHz, CDCl3): δ 7.57–7.24 (m, 9H), 7.02–6.89 (m, 3H), 4.28–4.12 (m, 5H), 3.89 (dd, 1H, J=7.24, 5.62), 3.62 (t, 1H, J=6.44), 3.36 (s, 3H), 2.93 (dd, 2H, J=6.31, 2.42), 2.32 (qn, 2H, J=5.10), 1.25 (t, 3H, J=7.2).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1.C(N(CC)CC)C>>[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[C:6](=[O:8])[C:5]5[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=5)=[CH:29][CH:30]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1ccc(C(=O)O)cn1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(C)c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)cn1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that commercially available 6-methylnicotinic acid was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 0.54 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 1.2 equivalents of triethylamine were added as the final reagent to the reaction mixture. The product was purified by chromatography using silica gel eluted with 95:5 chloroform/methanol followed by crystallization from acetonitrile. MS, m/z(M+)=553.2365.
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>C(O)(C)C>[OH:23][CH:20]([CH2:21][OH:22])[CH2:19][NH:18][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1nccnc1Cl
Reactant: NCC(O)CO
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1nccnc1NCC(O)CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g (0.0094 mol) 3 and 1.01 g (0.01 mol) triethylamine in 25 ml isopropanol is added 0.91 g (0.01 mol) 3-amino-1,2-propanediol (10). The reaction mixture becomes reddish and is stirred at room temperature for 16 hours. The solvent is then removed on the rotary evaporator and the residue is purified by flash chromatography on silica gel to afford pure 11 as a yellow solid, m.p. 100°-102°.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1.[F:20][C:21]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[F:20][C:21]1[CH:29]=[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:27]=[CH:26][C:22]=1[C:23]([O:17][C:14]1[CH:13]=[N:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:18][CH3:19])=[CH:6][CH:7]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: CCC(C)COc1ccc(-c2cnc(O)cn2)cc1
Reactant: CCCCCCCCc1ccc(C(=O)Cl)c(F)c1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(C(=O)Oc2cnc(-c3ccc(OCC(C)CC)cc3)cn2)c(F)c1
Reaction time: 8 h

Procedure:
8.0 mmol of 5-[4-(2-methylbutoxy)-phenyl]-2-pyrazinol (known from Japanese Preliminary Published Application 92,276/'85) are added with stirring to a mixture of 7.0 mmol of 2-fluoro-4-octylbenzoyl chloride and 5 ml of pyridine and left to stand overnight. This gives optically active (S) 2-(2-fluoro-4-octylbenzoyloxy)-5-[4-(2-methylbutoxy)-phenyl]-pyrazine after extraction with toluene (30 ml) and water (20 ml), working up of the toluene phase and subsequent distillation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:15])[CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:14][CH2:13][CH2:12][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:15]
Reactant: COc1ccc(C(O)CC#N)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(O)CCN)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile (1.25 g, 6.02 mM) in dried tetrahydrofuran (25 ml) was dropped into a solution of lithium aluminum hydride (0.55 g, 14.48 mM) in dried tetrahydrofuran (40 ml) at 0° C. This was gradually warmed to room temperature and stirred for 1 hour. Next, the reaction solution was again cooled to 0° C., water was carefully added to it, then the mixture was stirred at room temperature for 30 minutes. Next, the solution was filtered through Celite, the filtrate was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product of 3-amino-1-(3,4-dimethoxyphenyl)-1-propanol (1.27 g). The crude product obtained here had a sufficient purity even without purification, so could be used as it was for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][Cl:13])=[C:6]([O:14][CH3:15])[CH:5]=1.C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:10][CH2:11][CH2:12][Cl:13])=[CH:8][C:9]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OCCCl)c(OC)c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 85 %

Procedure:
The intermediate 4-(2-chloro-ethoxy)-3-methoxy-benzoic acid methyl ester (2.7 g, 11.03 mmol) was taken in acetic acid (30 mL) and acetic anhydride (6 mL) was added. The solution was cooled to 0° C. and 90% nitric acid (2 mL) was added. The reaction mixture was stirred for 10-15 minutes at ambient temperature, then heated to 50° C. for 2h. Completion of the reaction was monitored by TLC. The reaction mixture was cooled and was poured on to crushed ice. The precipitate formed was filtered and was dried to afford the pure 4-(2-chloro-ethoxy)-5-methoxy-2-nitro-benzoic acid methyl ester (2.73 g, 85%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.35 (s, 1H), 4.42 (t, 2H), 4.10-3.90 (m, 5H), 3.80 (m, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[C:10]1([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[Cl:5][CH2:6][C:7]([C:13]1[CH:14]=[CH:15][C:10]([CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:11][CH:12]=1)=[O:8]
Reactant: CC(=O)NCCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NCCc1ccc(C(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
Aluminium chloride (1.63 g) was dissolved in 1,2-dichloroethane (15 mL). Chloroacetylchloride (0.732 mL) was added to the mixture at 0° C., and stirred additionally for 20 minutes, then N-(2-phenylethyl)acetamide (1 g) in 1,2-dichloroethane (5 mL) was added dropwise. The mixture was stirred for 1 hour at room temperature, and then poured into ice water. The mixture was extracted with chloroform, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The solid was washed with ethyl acetate and ethyl ether, and dried in vacuo to give N-{2-[4-(2-chloroacetyl)phenyl]ethyl}-acetamide as a white powder (1.18 g, 80.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:13]([O-])=O)[CH:9]=2)[N:4]=1.[Cl-].[NH4+]>[Fe].CO>[CH3:1][O:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:13])[CH:9]=2)[N:4]=1
Reactant: COc1cnc2cc([N+](=O)[O-])ccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1cnc2cc(N)ccc2n1
Yield: 124.2 %

Procedure:
Into 20 ml of methanol was dissolved 726 mg of 2-methoxy-6-nitroquinoxaline, and then 1.0 g of iron powder and a saturated ammonium chloride aqueous solution were added thereto, followed by heating under refluxing overnight. Insoluble matter was separated by filtration using celite and then the solvent was removed by evaporation. A sodium bicarbonate aqueous solution was added to the residue, followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 770 mg of the title compound from chloroform-methanol (100:1, v/v).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)[CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cc(C2CCNC2)ccn1
Product: Nc1c(F)c(N2CCC(c3ccncc3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 48 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4 -oxo-3-quinolinecarboxylic acid (1.10 g, 3.7 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example1 provided the title compound (0.75 g, 48%) as a yellow solid, mp 236°-238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH:15]([CH3:18])[CH2:16][CH3:17])=[C:11]([Cl:19])[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-:21].[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([OH:21])([CH:15]([CH3:18])[CH2:16][CH3:17])[C:11]([Cl:19])=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(C)c1c(Cl)[nH]n(-c2cc(Cl)cc(Cl)c2)c1=O
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Product: CCC(C)C1(O)C(=O)N(c2cc(Cl)cc(Cl)c2)N=C1Cl
Yield: 46.3 %

Procedure:
0.7 g of 1-(3,5-dichlorophenyl)-3-chloro-4-(1-methylpropyl)-5-pyrazolone and 0.7 g of potassium carbonate were cooled to -20° C. and 0.7 g of 75% m-chloroperbenzoic acid were added all at once. The procedure of Example 46 was followed to obtain 0.34 g of 1-(3,5-dichlorophenyl)-3-chloro-4-hydroxy-4-(1-methylpropyl)-5-pyrazolone used as is for the next step.