Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]([CH3:38])[CH2:26][CH2:27][N:28]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH:29]=[O:30]>>[CH3:24][N:25]([CH3:38])[CH2:26][CH2:27][N:28]([C:31]1[CH:32]=[CH:33][C:34]([NH:35]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:36][CH:37]=1)[CH:29]=[O:30]
Reactant: CN(C)CCN(C=O)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Product: CN(C)CCN(C=O)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-(2-dimethylaminoethyl)-N-formyl-amino)-aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=1.[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[N:11][N:10]([CH3:26])[N:9]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:24])([F:25])[F:23])=[CH:16][N:15]=1
Reactant: O=C([O-])[O-]
Reactant: CNc1nc(Nc2ccc(-c3nn[nH]n3)cc2Cl)ncc1C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CNc1nc(Nc2ccc(-c3nnn(C)n3)cc2Cl)ncc1C(F)(F)F
Temperature: 40 °C
Yield: 68.5 %

Procedure:
A mixture of N2-(2-chloro-4-(2H-tetrazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (80 mg, 0.22 mmol), K2CO3 (45 mg, 0.32 mmol) and methyl iodide (15 uL, 0.24 mmol) in acetone (2 mL) was heated at 40° C. for 1 h. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and the crude residue purified via silica gel column chromatography (0-100% ethyl acetate/isohexane) to give N2-(2-chloro-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (58 mg, 70%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=385 at 4.31 min. 1H NMR (400 MHz, CDCl3): δ 8.76 (d, J=8.7, 1H); 8.23-8.19 (m, 2H); 8.05 (dd, J=8.7, 2.0, 1H); 7.72 (s, 1H); 5.29 (s, 1H); 4.40 (s, 3H); 3.12 (d, J=4.7, 3H).
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)[CH2:24][C:23]2=[O:39]>>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([CH:25]2[CH2:24][CH:23]([OH:39])[C:22]3[C:27](=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=3)[O:26]2)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: O=C1CC(c2ccc([N+](=O)[O-])cc2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: O=[N+]([O-])c1ccc(C2CC(O)c3cc(O)ccc3O2)cc1

Procedure:
2-(4-Nitrophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) staring from 6-hydroxy-2-(4-nitrophenyl)-chroman-4-one. 1H NMR (300 MHz, d6-DMSO) δ: 8.86 (s, 1H), 8.26 (d, 2H, J 6.9 Hz), 7.74 (d, 2H, J 6.9 Hz), 6.89 (d, 1H J 2.8 Hz), 6.65 (d, 1H, J 8.6 Hz), 6.56 (dd, 1H, J 8.6, 2.8 Hz), 5.46 (d, 1H, J 6.9 Hz), 5.32 (d, 1H, J 10.5 Hz), 4.86-4.94 (m, 1H), 2.31-2.38 (m, 1H), 1.78-1.89 (m, 1H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[O:19][CH:20]=[C:21]([CH2:23][CH2:24][OH:25])[N:22]=1.O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:36]1([CH2:35][CH2:34][CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:25][CH2:24][CH2:23][C:21]3[N:22]=[C:18]([C:14]4[S:13][CH:17]=[CH:16][CH:15]=4)[O:19][CH:20]=3)=[CH:28][CH:29]=2)[CH:40]=[CH:39][N:38]=[CH:37]1
Reactant: OCCc1coc(-c2cccs2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1csc(-c2nc(CCOc3ccc(CCCn4ccnc4)cc3)co2)c1
Yield: 54.9 %

Procedure:
Diethyl azodicarboxylate (1.20 g) was added dropwise to a stirred mixture of 2-(2-thienyl-4-oxazolyl)ethanol (700 mg). 1-[3-(4-hydroxyphenyl)propyl]imidazole (670 mg), triphenylphosphine (1.73 g), and tetrahydrofuran (50 ml) at room temperature. After refluxing for 3 h, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (100:1, v/v) 4-[2-[4-[3-(1-imidazolyl)propyl]phenoxy]ethyl]-2-(2-thienyl)oxazole (690 mg, 55%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 77-78° C.
Reaction SMILES: [C:1]([O:14]CC)(=[O:13])[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1.C(O)C.[OH-].[K+]>O>[C:5]([O:7][CH2:8][CH3:9])(=[O:6])[C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([C:1]([OH:14])=[O:13])[CH:3]=1
Reactant: CCOC(=O)c1cccc(C(=O)OCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 55 g. of this diethyl isophthalate in 140 ml. of ethanol was saponified by the addition of 15 g. of potassium hydroxide in 15 ml. of water. The resulting gel was refluxed 30 minutes, cooled and extracted with ether to remove unreacted diester. The water layer was acidified and the crude acid product precipitated. Ethyl hydrogen isophthalate having a melting point of 131° to 132° C. was obtained in a 16.5 g. yield after recrystallization from benzene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:29])[CH:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(O)(=O)C.O>[CH2:11]([O:13][C:14](=[O:29])[CH:15]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:12]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Temperature: 80 °C

Procedure:
A mixture of 250 g (1.79 mol) of m-nitrophenol, 602 g (1.79 mol) of Alphabromo-myristic acid ethyl ester, 248 g (1.79 mol) of potassium carbonate, and 1350 ml of dimethylformamide is heated to 80° C. for 3 h with stirring. The mixture is then poured out slowly into a mixture of 2300 ml of water and 250 ml of acetic acid. The product is extracted with dichloromethane. The solvent is removed by evaporation.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(NO)C1CCOCC1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(C3CCOCC3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-tetrahydro-pyran-4-carboxamidine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.10 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17](F)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:27])[C:12]([C:24]([OH:26])=[O:25])=[CH:13][N:14]2[CH:21]1[CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1>N1C=CC=CC=1>[CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([CH3:28])[CH2:34]2)[CH:16]=[C:15]2[C:10]=1[C:11](=[O:27])[C:12]([C:24]([OH:26])=[O:25])=[CH:13][N:14]2[CH:21]1[CH2:23][CH2:22]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CC1CN(c2cc3c(c(NCc4ccccc4)c2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Yield: 79.5 %

Procedure:
A mixture of 3.0 g of 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 2.5 g of 2-methylpiperazine and 30 ml of pyridine was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the solution was acidified with acetic acid and treated with activated charcoal. It was then neutralized with aqueous ammonia. The crystals which precipitated were collected by filtration to give 2.9 g of 5-benzylamino-1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 129°-130° C.
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])O.[NH3:15]>>[NH2:5][CH:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:12]([OH:13])[CH:14]=1)[C:2]([NH2:15])=[O:1]
Reactant: N
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Product: NC(=O)C(N)Cc1ccc(O)c(O)c1

Procedure:
Hence, in one exemplary particular, L-DOPA is converted to an ester thereof (e.g., a methyl ester), and is thereafter reacted with an aqueous solution of ammonia, to thereby produce L-Dopamide (2-amino-3-(3,4-dihydroxyphenyl)propaneamide).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([OH:19])[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[CH:16][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of 1,5-dimethyltetrazole (0.98 g, 10.0 mmoles) in tetrahydrofuran (20 mL) at -30° C. was added n-butyl lithium (4.7 mL of 2.14M solution, 10.0 mmoles). After stirring for 0.25 hour, the solution was cooled to -50° C. and 4,4'-difluorobenzophenone (1.74 g, 8.0 mmoles) was added. After stirring for 1 hour at -50° C. and 1 hour at -10° C., the reaction was quenched with 1N hydrochloric acid. The mixture was extracted with methylene chloride, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 40% (v/v) ethyl acetate in hexane to give 2.0 g of the title compound; m.p.=116°-118° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])CC2C=CC(OC)=CC=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([N:35]2[CH2:40][C@@H:39]3[CH2:41][C@H:36]2[CH2:37][N:38]3[CH3:42])[C:33]=1[Cl:34])[C:29]#[N:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:34][C:33]1[C:32]([N:35]2[CH2:40][C@@H:39]3[CH2:41][C@H:36]2[CH2:37][N:38]3[CH3:42])=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[NH:25][C:2]1[N:7]=[C:6]([NH:8][CH2:18][CH3:19])[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1
Reactant: CN1C[C@@H]2C[C@H]1CN2c1cc(C#N)cc(N)c1Cl
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CCNc1nc(Nc2cc(C#N)cc(N3C[C@@H]4C[C@H]3CN4C)c2Cl)nn2c(C#N)cnc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 191.1 %

Procedure:
A 5 ml microwave vial was loaded with 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (71.8 mg, 0.209 mmol), 3-amino-4-chloro-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzonitrile (50 mg, 0.190 mmol), Pd(OAc)2 (6.41 mg, 0.029 mmol), XANTPHOS (17.62 mg, 0.030 mmol) and Potassium phosphate (145 mg, 0.685 mmol). The vial was evacuated and back-filled with nitrogen 4 times. Toluene (2 ml) was added and the flask was again evacuated and back-filled with nitrogen 4 times, and then heated with stirring to 80° C. for 5 hours. The reaction mixture was cooled to room temperature, filtered through Celite and solids washed with dichloromethane. Evaporation to dryness gave 163 mg crude product 2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, which was used “as is” in the following deprotection reaction.
Reaction SMILES: [CH2:1](O)[CH2:2]O.C(O)COCCO.[C:12]1(=O)O[C:15](=O)[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>O>[CH2:20]1[CH:15]2[CH:2]3[CH:1]=[CH:12][CH:13]([CH:14]2[CH:18]=[CH:19]1)[CH2:21]3
Reactant: OCCO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: OCCOCCO
Solvent: O
Product: C1=CC2C3C=CC(C3)C2C1
Temperature: 120 °C

Procedure:
The reaction product was added by 184 g (2.95 mol) of ethylene glycol (EG), 85 g (0.8 mol) of diethylene glycol (DEG) and 30 g (0.2 mol) of phthalic anhydride (PA), and then esterified by heating to 200° C. with removing water distillated from the reaction product. When the acid value of the esterified product reached 22, it was cooled to 120° C. to obtain a dicyclopentadiene-modified unsaturated polyester (second step).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([NH:45][C:46](=[O:50])[CH2:47][CH2:48][CH3:49])=[N:33][N:34]3COCC[Si](C)(C)C)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([NH:45][C:46](=[O:50])[CH2:47][CH2:48][CH3:49])=[N:33][NH:34]3)=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Temperature: 67 °C

Procedure:
8.6 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 650 mg of N-[6-(4-nitrophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The medium is maintained at 67° C. for 18 hours and is then allowed to return to room temperature to add 75 cm3 of ethyl acetate and 75 cm3 of saturated aqueous sodium hydrogen carbonate solution. The organic phase is washed with 50 cm3 of saturated aqueous sodium chloride solution and then with 50 cm3 of water, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa; 50° C.); the residue is taken up in 10 cm3 of ethyl acetate, filtered off on a sinter funnel and then washed successively with 5 cm3 of ethyl acetate and with 10 cm3 of diisopropyl ether. After drying (90 Pa; 50° C.), 280 mg of N-[6-(4-nitrophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of yellow crystals melting at 250° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([CH2:12][OH:13])[C:8]=2[C:15]([F:17])([F:18])[F:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: OCc1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
To a solution of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (Intermediate 1-5D, 3.0 g, 11.7 mmol) in THF (20 mL) at 0° C. was added N-methylmorpholine (1.92 mL, 17.5 mmol) followed by isobutyl chloroformate (2.30 mL, 17.5 mmol) via syringe over 5 min. The resulting suspension was stirred at 0° C. for 15 min. The suspension was then added to a suspension of sodium borohydride (0.794 g, 21.0 mmol) in THF (40 mL) and methanol (12 mL) at −78° C. via a 10 mL syringe. During the addition, frothing was observed. The reaction mixture was stirred for 60 min. The reaction mixture was slowly warmed to approximately −20° C. and quenched with a 20 mL of a 1:9 mixture of acetic acid in water. The reaction mixture was then stirred at room temperature for 60 min. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate (120 mL), washed with water (20 mL), saturated aqueous solution of sodium bicarbonate (2×20 mL) and brine (20 mL). The organic layer was collected, the aqueous layers were back-extracted with ethyl acetate (100 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate in hexane (1% to load; 5%-9%-12%) afforded (5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)methanol (1.79 g, 7.36 mmol, 63% yield) as a clear, colorless oil. The compound had an HPLC ret. time=2.02 min. (condition A); LC/MS M+1=243.8.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].O>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(-c2ccc(O)cc2)cc1)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=C(Oc1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To an argon-flushed flask containing a suspension 0.486 g (1.68 mmol) of 4'-hydroxy-4-biphenylyl benzoate in 10 ml of acetic acid at 10°-15° C., 0.345 ml of HNO3 (d: 1.41) was added dropwise (about a drop per min). Then the reaction mixture was vigorously stirred at the same temperature for 30 min. Water (40 ml) was added and the mixture was again stirred for 30 min. The yellow precipitate was filtered, washed several times with water, dried and purified by flash chromatography on silica gel using dichloromethane/hexanes [65/35] as eluent to give 4'-hydroxy-3'-nitro-4-biphenylyl benzoate (compound 15, Scheme II) as a yellow solid (0.539 g, 96%). This material was recrystallized from ethanol to give product of mp. 163° C.; . Rf [hexanes/dichloromethane 40/60]: 0.42; 1H NMR (300 MHz, CDCl3): δ 7.25(d, 1H, J=8.7 Hz), 7.33(d, 2H, J=8.7 Hz), 7.50-7.70(m, 5H), 7.84(dd, 1H, J=2.7 Hz, J=8.7 Hz), 8.23(d, 2H, J=7.2 Hz), 8.32(d, 1H, J=2.7 Hz), 10.60(s, 1H); 13C NMR (300 MHz, CDCL3): δ 120.54, 122.45, 122.81, 127.85,, 128.65, 129.33, 130.23, 133.04, 133.78, 136.04, 136.22, 150.91, 154.44, 165.15; IR (CHCL3): 3250(broad), 3020, 1740, 1620, 1540, 1510, 1490, 1325, 1270, 1225, 1220, 1170, 1080, 1065, 1025, 1000, 850 cm-1 ; Mass spectrum, m/z(rel.intensity): 335(M+ 7), 105(100), 77(16) .
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19]C)=[O:18])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:19])=[O:18])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(Cc2ccccc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
In THF (15 ml) was dissolved methyl 1-benzylindole-3-carboxylate (606.1 mg, 2.284 mmol). To the resulting solution was added 0.25N NaOH (8.0 ml) and the mixture was stirred at 70° C. for 18 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue thus obtained was acidified with 1N HCl (5.5 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 1-benzylindole-3-carboxylic acid (100%) as a light pink amorphous substance.
Reaction SMILES: O.[SH-].[Na+].[CH3:4][S:5]([C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[O:10][N:9]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrC[C:29]1[C:30]([C:41]([F:44])([F:43])[F:42])=[N:31][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:33]=1[Cl:34]>CN(C)C=O.O>[Cl:34][C:33]1[N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:31]=[C:30]([C:41]([F:44])([F:43])[F:42])[C:29]=1[CH2:4][S:5][C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[O:10][N:9]=1
Reactant: FC(F)(F)c1nn(-c2ccccc2)c(Cl)c1CBr
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(SCc2c(C(F)(F)F)nn(-c3ccccc3)c2Cl)=NO1
Reaction time: 2 h
Yield: 66 %

Procedure:
2.1 g of sodium hydrosulfide hydrate (purity: 70%, 26.2 mmoles) was added to a solution of 2.3 g (13.1 mmoles) of 3-methylsulfonyl-5,5-dimethyl-2-isoxazoline dissolved in 20 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 1.8 g (13.1 mmoles) of anhydrous potassium carbonate, 2.0 g (13.1 mmoles) of Rongalit and 3.6 g (10.5 mmoles) of 4-bromomethyl-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 15 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.7 g (yield: 65.5%) of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as white crystals (melting point: 89 to 90° C.).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH:20]N)=O>>[Cl:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]1[NH:20][N:8]=[C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([CH3:2])[CH:4]=2)[N:7]=1
Reactant: Cc1cccc(C(=N)N)c1
Reactant: NNC(=O)c1sccc1Cl
Agent: Cl
Product: Cc1cccc(-c2n[nH]c(-c3sccc3Cl)n2)c1

Procedure:
The title compound was prepared from 3-methyl-benzamidine hydrochloride and 3-chloro-thiophene-2-carboxylic acid hydrazide by a procedure similar to Example 88b as a yellow solid (0.013 g, 5.6%). 1H NMR (CD3OD): 7.75 (s, 1H), 7.69 (d, J=5.7 Hz, 1H), 7.4 (d, J=5.7 Hz, 1H), 7.24 (m, 2H), 6.97 (d, J=6.3 Hz, 1H), 3.10 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[Cl-].[NH4+].C(OCC)(=O)C.[CH2:25]1[CH2:29]OC[CH2:26]1>>[CH:26]1([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[OH:10])[CH2:25][CH2:29]1
Reactant: C1CCOC1
Reactant: COc1cccc(C(=O)c2cccnc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1cccc(C(O)(c2cccnc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3-methoxyphenyl)-(3-pyridinyl)methanone (500 mg) in THF (10 ml) was added 1.1 M cyclopropylmagnesium bromide THF solution (2 ml) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1:2) to give cyclopropyl-(3-methoxyphenyl)-(3-pyridinyl)methanol (470 mg).