Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC([C:23]([NH2:25])=[O:24])=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.[C:32]([O:36][C:37](=[O:69])[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:58](=[O:59])[C:57]4[C:52](=[CH:53][C:54](Br)=[C:55]([O:60][CH3:61])[CH:56]=4)[O:51][C:50]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:69])[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:58](=[O:59])[C:57]4[C:52](=[CH:53][C:54]([C:23](=[O:24])[NH2:25])=[C:55]([O:60][CH3:61])[CH:56]=4)[O:51][C:50]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: NC(=O)c1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1
Reactant: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1Br
Product: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1C(N)=O
Yield: 27 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-4-oxo-2-phenyl-4H-chromene-7-carboxylic acid amide, {1-[4-(7-bromo-6-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a colourless oil (22 mg, 27%). LCMS (Method B): RT=4.17 min, [M+H]+=541.
Reaction SMILES: C(OC([O:6][C:7]([CH3:22])([CH:20]=[CH2:21])[C:8]#[C:9][C:10]1(O)[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH:12]=[C:11]1[CH3:18])C)C.[C:23]([OH:26])(=[O:25])[CH3:24]>CCCCCC>[CH3:18][C:11]1[CH:12]([O:26][C:23](=[O:25])[CH3:24])[CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[C:10]=1[C:9]#[C:8][C:7]([CH3:22])([OH:6])[CH:20]=[CH2:21]
Reactant: CC(=O)O
Reactant: C=CC(C)(C#CC1(O)C(C)=CCCC1(C)C)OC(C)OCC
Solvent: CCCCCC
Product: C=CC(C)(O)C#CC1=C(C)C(OC(C)=O)CCC1(C)C

Procedure:
The compound 1-ethoxy-[1-(2,6,6-trimethyl-1-hydroxy-2-cyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-oxy]ethane (9.5 g) in acetic acid (40 ml) was heated at 55° for 11/2 hr and then taken to dryness "in vacuo" (45° at 0.5 mmHg), dissolved in hexane, and chromatographed on silica gel (400 g). Elution with hexane-ether mixtures (4:1 parts vy volume and 3:1 parts by volume 500 ml cuts, 2 liters) yielded 1-(2,6,6-trimethyl-3-acetoxycyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-ol (4.3 g) bp 165° (0.09 mmHg).
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([N+:10]([O-])=O)=[N:8][CH:9]=1.[CH2:15]([OH:17])C>O.[Fe]>[Br:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([NH:10][CH:15]=[O:17])=[N:8][CH:9]=1
Reactant: COc1cc(Br)cnc1[N+](=O)[O-]
Reactant: CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1cc(Br)cnc1NC=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Iron (67.3 g) and ammonium chloride (129 g) were added to a solution of 5-bromo-3-methoxy-2-nitropyridine (56.0 g, CAS: 152684-26-9) in ethanol (500 mL) and water (200 mL). The reaction solution was stirred at 80 to 90° C. for one hour and then left to cool to room temperature. The reaction solution was filtered through celite and washed with ethanol. Then, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with THF (84 mL). The THF solution was added dropwise to a mixed solution of formic acid (78.1 mL) and acetic anhydride (78.3 mL) at room temperature. Then, the reaction solution was stirred for one hour. Ice water (500 mL) was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were washed with water and then air-dried. The crystals were recrystallized from toluene to obtain 34.1 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH2:15]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22](O)=[N:21][C:20]=1[CH3:26])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:21][C:20]=1[CH3:26])[CH3:16]
Reactant: CCOC(=O)c1ccc(O)nc1C
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1C
Yield: 55 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (313 mg, 1.66 mmol) was converted using 6-hydroxy-2-methyl-nicotinic acid ethyl ester instead of 2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO2, heptane:ethyl acetate=60:40 to 10:90, 322 mg, 55%) which was obtained as a colourless oil. MS: m/e=353.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].I[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)=[O:19])=[CH:13][CH:12]=1>CS(C)=O.[NH4+].[Cl-].[Cu]>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]2[CH:21]=[C:20]([C:18]([NH:17][C:14]3[CH:15]=[CH:16][C:11]([C:5]([F:7])([F:6])[C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH:12][CH:13]=3)=[O:19])[CH:29]=[CH:28][C:27]1=2
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(I)cc3)ccc21
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 58 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
Under a nitrogen atmosphere ethylbromodifluoroacetate (0.244 mL, 1.90 mmol) was added to a suspension of 5,6,7,8-tetrahydro-N-(4-iodophenyl)-5,5,8,8-tetramethylnaphthalene-2-carboxamide 22 (826 mg, 1.90 mmol), powder copper (99.999%, 588 mg) in anhydrous DMSO (16.7 mL). The reaction mixture was stirred at 58° C. for 18 h. After cooling, the mixture was poured in aqueous NH4Cl 5% (150 mL). This mixture was extracted with EtOAc (5×150 mL). The organic layer was washed with aqueous NH4Cl 5% (3×100 mL), brine (3×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography using as eluent cyclohexane:EtOAc=95:5. Ethyl 2-(4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)phenyl)-2,2-difluoroacetate 23 was obtained (0.61 g, 74.6% yield) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[C:19](=[O:24])[NH:20][CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:17][C:18]1[C:19]([O:24][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc[nH]c1=O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccnc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 60.4 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 3-methyl-2-pyridone (20 mg, 0.18 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(3-methyl-pyridin-2-yloxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (20 mg, 60%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 7.99 (br. s., 1H), 7.86 (d, J=8.5 Hz, 2H), 7.68 (d, J=6.9 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.29 (dd, J=14.0, 6.2 Hz, 2H), 7.18 (d, J=6.6 Hz, 1H), 5.98-6.24 (m, 2H), 5.15 (s, 2H), 1.99 (s, 3H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([N:16]1[C:20]([C:21](SC)=[O:22])=[C:19]([CH:25]=O)[N:18]=[C:17]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:13]#[C:14][CH3:15].[CH2:40]([O:47][C:48]([NH:50][CH:51](P(OC)(OC)=O)[C:52]([O:54][CH3:55])=[O:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH3:55][O:54][C:52]([C:51]1[N:50]([C:48]([O:47][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:49])[C:21](=[O:22])[C:20]2[N:16]([CH2:12][C:13]#[C:14][CH3:15])[C:17]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:29][CH2:28]3)=[N:18][C:19]=2[CH:25]=1)=[O:53]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)SC
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(C(=O)OC)n(C(=O)OCc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.079 g of 1,8-diazabicyclo[5.4.0]-7-undecene and then 5 ml of dichloromethane containing 0.194 g of t-butyl 4-[1-(2-butynyl)-4-formyl-5-methylsulfanylcarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate were added to a 2 ml dichloromethane solution of 0.174 g of methyl benzyloxycarbonylamino-(dimethoxyphosphoryl)-acetate, and the mixture was stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.147 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:2).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:21])[CH3:20].O>CN(C)C(=O)C>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:19](=[O:21])[CH3:20])=[N:9][C:8]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccccc2)s1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2cccnc2)c(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
To a solution of [5-phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]amine (1.10 g, 4.34 mmol) in N,N-dimethylacetamide (20 mL) was added acetyl chloride (680 mg, 8.68 mmol) and stirred at 80° C. for 3 h. Water was added to the reaction mixture and extracted with ethyl acetate twice. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethyl ether to give the title compound (750 mg, yield 59%).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCC(=O)OC(C)(C)C)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCC(=O)O)ccc12

Procedure:
1 g (2.36 mmol) of 18 are dissolved in 20 ml of dichloromethane and stirred at room temperature for 20 hours with 2 ml of trifluoroacetic acid. The solution is subsequently evaporated, and the residue is purified by preparative HPLC on RP-18, giving ethyl 3-phenyl-3-(6-carboxymethoxyindol-3-yl)-propionate trifluoroacetate.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.Cl[C:15]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([N+:28]([O-:30])=[O:29])=[CH:17][N:16]=1.O>CN(C=O)C>[N+:28]([C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][C:15]([O:3][C:4]2[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=2)=[N:16][CH:17]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1ccccc1
Reactant: CC(=O)Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccccc3)c([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 16.24 g, 406 mmol) was suspended in DMF (800 mL) and solid N-(3-hydroxyphenyl)acetamide (61.0 g, 406 mol) was added portionwise over 1 h (warming and frothing occurs). After the final addition the product from Step 4 (101.2 g, 406 mmol) was added as a solid, portionwise, over 10 min and the resulting mixture was heated to 60° C. overnight. Water (800 mL) was carefully added dropwise to the still warm reaction mixture over 1 h to give a fine yellow precipitate. The mixture was then cooled to 0° C., filtered and the resulting solid was washed with cold H2O and hexane to give the title compound (143.3 g, 97%) as a yellow solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 10.06 (s, 1H), 9.80 (s, 1H), 8.91 (s, 1H), 7.44-7.49 (m, 3H), 7.37 (dd, 2H, 1.26 Hz, 8.6 Hz), 7.29-7.33 (m, 3H), 6.76-6.80 (m, 1H), 6.22 (s, 1H), 2.04 (s, 3H). MS (ES+) m/e 365 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]([CH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]1)[C:6]1[C:7]([CH:12]=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:4]>CCO.O>[CH2:3]([N:5]([CH2:14][C@H:15]1[CH2:16][CH2:17][C@H:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20]1)[C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:4]
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (62.3 mg, 1.65 mmol) was added to a stirred solution of ethyl (trans-4-{[ethyl(2-formylpyridin-3-yl)amino]methyl}cyclohexyl)acetate (136.9 mg, 0.412 mmol) in EtOH (10 mL) at room temperature. The reaction was stirred at room temperature for 1 h, then diluted with water and most of the EtOH was removed in vacuo. The resulting aqueous slurry was extracted with EtOAc (3×20 mL) and the combined extracts were washed with brine (5 mL), dried (Na2SO4) and concentrated in vacuo to afford ethyl [trans-4-({ethyl[2-(hydroxymethyl)pyridin-3-yl]amino}methyl)cyclohexyl]acetate. LCMS calc.=335.2; found=335.3 (M+1)+.
Reaction SMILES: [N:1]([CH:4]([CH2:8][CH2:9][C:10]#[N:11])[C:5](O)=[O:6])=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N:1]([CH:4]([CH2:8][CH2:9][C:10]#[N:11])[C:5]([Cl:15])=[O:6])=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CCCC(N=[N+]=[N-])C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCCC(N=[N+]=[N-])C(=O)Cl
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of 2-azido-4-cyanobutyric acid (0.76 g, 4.94 mmol) in dry methylene chloride (20 ml) was added oxalyl chloride (0.65 g, 5.1 mmol) and a drop (~15 mg) of DMF. The reaction mixture was stirred at room temperature until the evolution of gas ceased (15 min) and then refluxed for 10 min. Removal of the solvent in vacuo gave 0.84 g (99%) of the title compound as a syrup; ir (neat) νmax : 2250, 2110, 1780 cm-1.
Reaction SMILES: [ClH:1].Cl.Cl.C([O:11][C:12]([C:14]1([C:17](=[O:49])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]4[CH2:40][CH2:39][CH:38]([N:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)[CH2:37][CH2:36]4)=[O:34])[CH:27]=3)=[CH:21][C:20]=2[F:48])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>O.C(O)C.[Pd]>[ClH:1].[ClH:1].[ClH:1].[F:48][C:20]1[CH:21]=[C:22]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)=[O:34])[CH:27]=2)[CH:23]=[CH:24][C:19]=1[NH:18][C:17]([C:14]1([C:12]([OH:13])=[O:11])[CH2:16][CH2:15]1)=[O:49]
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)O)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 291 %

Procedure:
1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester trihydrochloride (5 g) was dissolved in a mixed solvent of water (10 ml) and ethanol (20 ml), and palladium on carbon (250 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (0.2 MPa) for 7 hours and 50 minutes. The reaction mixture was filtered, and the residue was washed with a mixed solvent of water (6 ml) and ethanol (10 ml). Ethanol (50 ml) was added to the filtrate, which was azeotropically distilled off and concentrated, and water (0.6 g) and ethanol (8.3 ml) were added. 2-Propanol (10 ml) was added to the solution, followed by stirring at room temperature for 5 minutes. 1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride (150 mg) was added, followed by stirring for 13 hours and 45 minutes. 2-Propanol (50 ml) was further added, and the mixture was stirred at room temperature for 24 hours and 35 minutes. The crystals were filtered and dried to give the title compound (4.26 g) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:22][C:19]3[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)([CH2:6][CH3:7])[C:4]([OH:3])=[O:23])=[CH:17][CH:18]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: CCC(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the method of Example 46. 1H NMR (400 MHz, CDCl3) δ 8.01 (bs, 1H), 7.31-7.26 (m, 2H), 7.06-6.96 (m, 5H), 6.72 (d, 2H, J=8.8 Hz), 4.08 (t, 2H, J=6.4 Hz), 3.28 (s, 2H), 2.91 (t, 2H, J=6.4 Hz), 2.81 (tt, 1H, J=11.6, 3.6 Hz), 2.26 (s, 3H), 2.18-1.98 (m, 4H), 1.82-1.77 (m, 2H), 1.72-1.67 (m, 1H), 1.58-1.48 (m, 2H), 1.39-1.18 (m, 3H), 0.92 (t, 3H, J=7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:22])=[CH:18][CH:19]=1)#[N:13]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: Nc1ccc2ncccc2c1
Product: N#Cc1ccc(NC(=O)Nc2ccc3ncccc3c2)cc1

Procedure:
Prepared from 6-aminoquinoline and 4-cyanophenyl isocyanate. m/z (ES+) 289 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COC(CBr)OC
Reactant: Cc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccc(C)cc1C=O)OC
Yield: 94.1 %

Procedure:
To a solution of 100 mg (0.73 mmol) of 2-hydroxy-5-methyl-benzaldehyde in DMF (1 ml) were added 109 μl (0.92 mmol) of 2-bromo-1,1-dimethoxy-ethane and 112 mg (0.81 mmol) of potassium carbonate. The reaction mixture was heated to reflux for 90 min. Then water was added at RT and the mixture was extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to yield 2-(2,2-dimethoxy-ethoxy)-5-methyl-benzaldehyde as a yellow oil (154 mg, 93%). 1HNMR (CDCl3, 300 MHz): δ 2.32 (s, 3H), 3.48 (s, 6H), 4.09 (d, J=5.3 Hz, 2H), 4.75 (t, J=5.3 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.4 and 2.3 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H), 10.48 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=2)=[N:10]1.C(=O)([O-])[O-:29].[K+].[K+].OO.O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][NH:14][C:13](=[O:18])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:27])=[O:29])=[CH:21][CH:20]=2)=[N:10]1
Reactant: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3cc[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a solution of (4-(1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (80.0 mg) obtained in Example 39 in DMSO (0.8 mL) was added potassium carbonate (36.6 mg), and then 30% aqueous hydrogen peroxide (0.068 mL) was added thereto. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the white precipitate was collected by filtration, washed with water, and dried in vacuum to give the title compound (7.5 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][S:15][CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1)=[O:19])[CH2:13][CH2:14][S:15][CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CSCCC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSCCC(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 83.8 %

Procedure:
9.5 g of N-benzyloxycarbonyl-DL-methionine, 3.4 g of triethylamine, 150 ml of chloroform, 3.7 g of ethyl chlorocarbonate and 3.4 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 1(i) to obtain 10.3 g (yield: 84%) of 2-(N-benzyloxycarbonyl-DL-methionylamino)-1,3,4-thiadiazole as white crystals having a melting point of 155°-159° C.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[CH2:15]([N:18]=[C:19]=[S:20])[CH:16]=[CH2:17]>CN(C=O)C>[CH2:15]([N:18]1[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[N:3]=[C:19]1[SH:20])[CH:16]=[CH2:17]
Reactant: C=CCN=C=S
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(S)nc(C(F)(F)F)cc1=O
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Sodium hydride (60% in oil, 2.71 q, 60.0 mmol) was added to DMF (40 ml) solution of ethyl 3-amino-4,4,4-trifluorocrotonate spending 30 minutes under ice-cooling, followed by stirring for 20 minutes. Next, allyl isothiocyanate (5.3 ml, 54.0 mmol) was added under ice-cooling, followed by overnight stirring while gradually returning to room temperature. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, water (40 ml) and 2 N hydrochloric acid (1.25 ml) were added to the thus obtained residue. The thus precipitated solid was isolated by filtration, washed with water and hexane and then thoroughly dried to obtain light yellow solid of 3-allyl-2-mercapto-6-trifluoromethyl-4(3H)-pyrimidinone (12.7 g, 89%).