Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)(=O)C>[O:26]=[C:24]([NH:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1)[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Temperature: 23 °C

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (50 mg, 0.164 mmol) and acetic anhydride (0.5 mL) were warmed to 60° C. for 1 h. After cooling to 23° C., the reaction was diluted with ethyl acetate (50 mL), washed with NaOH (1N, 50 mL), and dried (Na2SO4). Concentration in vacuo afforded 6-(1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (57): Mass Spectrum (CI) 347 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH3:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[Br:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH3:15])[CH:9]=3)[CH:5]=[C:4]([CH3:16])[N:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidine (example A.47) (3.84 g, 15.2 mmol) and commercially available 3-bromo-benzene-boronic acid (3.2 g, 15.9 mmol) according to the general procedure IVb. Obtained as a white solid (2.87 g, 51%). MS (ISP) 375.1 [(M+H)+]; mp 108° C.
Reaction SMILES: [OH-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[O:18])=[C:15]([OH:38])[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]>CO.O1CCOCC1>[C:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])=[C:15]([OH:38])[CH:14]=2)[CH2:10][CH2:11]1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCN(C(C)=O)CC2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N1CCC(Oc2ccc(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c(O)c2)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.082 mL) was added to a solution mixture of the obtained methyl 2-(4-((1-acetylpiperidin-4-yl)oxy)-2-hydroxybenzamido)-4-phenylbenzoate (0.016 g) in methanol (0.5 mL) and dioxane (0.5 mL), followed by stirring at 60° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then methanol (1 mL), dioxane (1 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.082 mL) were added to the reaction mixture, followed by stirring at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Water was added to the obtained residue, followed by adjusting the pH to 3 with 6 mol/L hydrochloric acid. The solid substance was collected from the reaction mixture by filtration to obtain 0.014 g of 2-(4-((1-acetylpiperidin-4-yl)oxy)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]([F:26])[C:10]([NH:13][C@@H:14]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[N:11][CH:12]=1)[CH3:2].Cl>CCO.O1CCOCC1>[F:26][C:9]1[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:27])[CH:12]=[N:11][C:10]=1[NH:13][C@@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(F)c1
Temperature: 24 °C
Reaction time: 3.5 h
Yield: 83.1 %

Procedure:
To an ice-cooled solution of tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-3-fluoro-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (11.6 g) in EtOH (70 ml) was added solution of 4N HCl in dioxane (76.4 ml). The mixture was stirred at 24° C. for 3.5 hr, and evaporated under reduced pressure. The residue was poured into a mixture of water and CH2Cl2. The pH of the aqueous layer was adjusted to ca.9 with NaHCO3. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give ethyl (2E)-3-{5-fluoro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate (7.1 g, 83%) as colorless powder.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[NH2:5][C:6]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][NH:10][CH2:11]2.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:5][C:6]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][N:10]([CH:1]([CH3:3])[CH3:2])[CH2:11]2
Reactant: Nc1c2c(cc3ccccc13)CNCC2
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N1CCc2c(cc3ccccc3c2N)C1
Reaction time: 6 h

Procedure:
A solution of 5.2 g of isopropyl bromide in 10 ml of ethanol is added dropwise at room temperature to a mixture of 8.0 g of 5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinoline [see Example 4]and 4.5 g of anhydrous sodium carbonate in 30 ml of ethanol. The reaction mixture is then boiled for 6 hours. The solvent is removed by evaporation, and the residue is treated with water. The resulting mixture is extracted with methylene chloride. The organic phase is washed with water, dried over potassium carbonate and evaporated. The title compound is obtained as a residue which is recrystallized from hexane/isopropanol (M.Pt. 112° - 113°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[S:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20](O)=[O:21])[N:14]=[C:13]([C:23]2[C:24](=[O:31])[O:25][C:26]([CH3:30])=[CH:27][C:28]=2[OH:29])[CH2:12]1.CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:72]([O:76][C:77](=[O:81])[CH:78]([NH2:80])[CH3:79])([CH3:75])([CH3:74])[CH3:73]>CN(C=O)C>[C:72]([O:76][C:77](=[O:81])[CH:78]([NH:80][C:20]([CH:15]1[N:14]=[C:13]([C:23]2[C:24](=[O:31])[O:25][C:26]([CH3:30])=[CH:27][C:28]=2[OH:29])[CH2:12][CH:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[S:17][C:16]1([CH3:18])[CH3:19])=[O:21])[CH3:79])([CH3:75])([CH3:74])[CH3:73]
Reactant: CC(N)C(=O)OC(C)(C)C
Reactant: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NC(C(=O)O)C(C)(C)S2)c(OC)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NC(C(=O)NC(C)C(=O)OC(C)(C)C)C(C)(C)S2)c(OC)c1
Yield: 46.7 %

Procedure:
7-(2,4-Dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepine-3-carboxylic acid (0.03 g), prepared as in Example 2, was dissolved in DMF (2 mL) and 2-amino-propionic acid tert-butyl ester (0.012 g), N-methylmorpholine (0.2 ml) and PyBOP (0.034 g) were added to the solution at room temperature. The mixture was stirred while the progress of the reaction was followed by analytical HPLC and when complete (16 hours) the solvent was removed in vacuo. Purification of product by preparative HPLC (RPC18 column, 2-70% acetonitrile/water containing 0.1% HCl) provided 2-({1-[7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepin-3-yl]-methanoyl }-amino)-propionic acid tert-butyl ester (18 mg) as an off-white powder. LCMS: M+ 575.0.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH2:28][CH3:29])[C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=2)=[CH:8][CH:7]=1.CO>S(=O)(=O)(O)O.O>[CH2:28]([N:19]([CH2:18][C:14]1[CH:13]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=2)[CH:17]=[CH:16][CH:15]=1)[C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:29]
Reactant: CCN(Cc1cccc(-c2ccc(C3OCCO3)cc2)c1)C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: CCN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
400 mg (1 mmol) of N-(4′-[1,3]dioxolan-2-yl-biphenyl-3-ylmethyl)-N-ethylbenzamide, 5 ml of methanol, 2 g of silica and a few drops of sulfuric acid are introduced into a round-bottomed flask. The mixture is stirred at room temperature for 24 hours. The reaction medium is poured into water and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. 320 mg (91%) of the desired product are obtained.
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[C:27]([C:29]1[CH:38]=[C:37]2[C:32]([C:33]([CH3:41])([CH3:40])[CH2:34][CH2:35][C:36]2=[O:39])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:40][C:33]1([CH3:41])[C:32]2[CH:31]=[CH:30][C:29]([C:27]#[C:28][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:38][C:37]=2[C:36](=[O:39])[CH2:35][CH2:34]1
Reactant: C#Cc1ccc2c(c1)C(=O)CCC2(C)C
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl )ethynyl]benzoate (Compound 1), 4 g (21.7 mmol) of 7-ethynyl-3,4-dihydro-4,4 -dimethylnaphthalen-1(2H)-one (Compound L) was converted into the title compound using 6 g (21.7 mmol) of ethyl 4-iodobenzoate, 5 g (7.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.4 g (7.2 mmol) of cuprous iodide.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([CH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)=[O:16].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>O1CCCC1>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][C:17]1([C:15]([O:14][CH3:13])=[O:16])[C:25]2[C:20](=[CH:21][C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:38]
Reactant: COC(=O)C1CCc2cc(C3CCCCC3)ccc21
Reactant: CCOC(=O)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C(=O)OC)CCc2cc(C3CCCCC3)ccc21
Temperature: -20 °C

Procedure:
23.6 ml of butyl-lithium (20% strength in hexane) are slowly added dropwise to a solution of 7.6 g of diisopropylamine (absolute) in 80 ml of absolute tetrahydrofurane at -10° to -15°C under a dry nitrogen atmosphere, whilst stirring, and 15 minutes after completion of the addition a solution of 15.5 g of 5-cyclohexyl-1-indanecarboxylic acid methyl ester in 40 ml of absolute tetrahydrofurane is added. The reaction solution is cooled to -20°C and a solution of 16.5 g of ethyl bromoacetate in 40 ml of absolute tetrahydrofurane is rapidly added dropwise. In the course thereof, the temperature rises to 0°C. The reaction solution is partitioned between three times 200 ml of methylene chloride and three times 200 ml of 2 N hydrochloric acid. The combined organic phases are washed with water, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum yields 1-methoxycarbonyl-5-cyclohexyl-1-indaneacetic acid ethyl ester in the fraction boiling at 140°-142°C/0.04 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.N>O.S(C1C=CC(C)=CC=1)(O)(=O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Ethyl acetate (300 ml) was added to 6-chloropurine (25 g, 162 mmol) and tosylic acid monohydrate (460 mg, 2.43 mmol) and the resulting mixture was heated at 60° C. Dihydropyrane (16 ml, 178 mmol) was added and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled to room temperature followed by the addition of 28% aqueous ammonia solution (15 ml) and the organic layer was fractionated, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (35 g, 91%) as a pale yellow solid.
Reaction SMILES: CO.[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C@@H:5]([CH2:7][CH3:8])[CH3:6].[O:12]=[CH:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22]O)[OH:21])[OH:19])[OH:17])[OH:15]>N1C=CC=CC=1>[CH2:22]([NH:3][C@@H:4]([C:9]([OH:11])=[O:10])[C@@H:5]([CH2:7][CH3:8])[CH3:6])[C:20]1([O:12][CH2:13][C@@H:14]([OH:15])[C@@H:16]([OH:17])[C@@H:18]1[OH:19])[OH:21]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC[C@@H](C)[C@@H](N)C(=O)O
Solvent: CO
Solvent: c1ccncc1
Product: CC[C@@H](C)[C@@H](NCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O)C(=O)O
Yield: 49.2 %

Procedure:
A dry mixture of 40 ml of methanol and 10 ml of pyridine was added to 100 mg of dry D-isoleucine together with 300 mg of anhydrous glucose, and reaction and purification were carried out as described in Example 9, but making use of smaller-volume chromatography columns. Crystallization of the final product yielded 110 mg of N-(1-deoxyfructopyranos-1-yl)-D-isoleucine. Melting point 142°-144° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:29]1([CH2:35][S:36][CH:37]([C:41](O)=[O:42])[C:38](O)=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[OH:42][C:41]1[CH:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)[O:3][C:38](=[O:39])[C:37]=1[S:36][CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc2ccccc2c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc3ccccc3c2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 2-acetyl naphthalene (1.97 g, 11.6 mmol), lithium bis(trimethylsilyl)amide (2.13 g, 12.76 mmol), chlorotrimethylsilane (1.61 mL, 12.76 mmol), THF (127 mL), and diethyl ester of [(phenylmethyl)thio]-propanedioic acid (2.90 g, 10.5 mmol). m.p. dec. 203° C.; 1H NMR (250 MHz, DMSO-d6) δ4.04 (s, 2 H), 6.89 (s, 1 H), 7.23 (m, 5 H), 7.61 (m, 2 H), 7.84 (d, 2 H), 8.05 (m, 3 H), 8.43 (s, 1 H), 11.95 (bs, 1 H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1[SH:9].Cl[C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1[S:9][C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
3,5-dichloropyridine-4-thiol sodium salt prepared as in example 17 (0.179 g, 1 mmol), methyl 5-chloro-4-nitro-thiophene-2-carboxylate (221 mg, 1 mmol) was mixed in toluene (5 mL). Then potassium carbonate (0.207 g, 1.5 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 4 hours. After this time, the reaction mixture was filtered and diluted with ethyl acetate. The organic solution was washed with water (2 mL×2), brine (2 mL×2), dried (Na2SO4), and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a 96:4 mixture of hexane and ethyl acetate to afford the title product as a solid (82.5 mg, 23% yield). 1H NMR (300 MHz, d6-DMSO) δ: 9.05 (2H, s), 8.20 (1H, s), 3.82 (3H, s). MS m/z: 365.2 [M+H]+.
Reaction SMILES: CO[C:3](=[O:34])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH2:30][OH:31])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[OH:31][CH2:30][C:22]1[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=[C:20]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:10][CH:9]=2)[C:5]2[NH:4][C:3](=[O:34])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:21]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)c(OC)c(OC)c1
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc(CO)c1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of 114 mg of [2-(3-hydroxymethyl-4,5-dimethoxyphenyl) -2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (22b)) in 2 ml of DMF there were added 25 mg of 2-hydrazinopyrimidine and 35 pd of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(5-hydroxymethyl-3,4-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (51 mg) as a light brown solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][N:35]3[CH2:36][CH2:37][CH2:38][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The product of step iii) (0.1 g) was dissolved in dichloromethane (10 mL) and 1-methyl-1,4-diazepane (0.062 mL) added. The mixture was stirred at room temperature for 5 minutes then sodium triacetoxyborohydride (0.16 g) was added. The mixture was allowed to stand and the solvent allowed to evaporate. Methanol (5 mL) was added and the solution purified directly by HPLC to give the title compound as a solid (30 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[C:27]([C:31](O)=[O:32])=[N:26]2)=[CH:21][CH:20]=1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:31]([C:27]2[C:28]([CH3:30])=[CH:29][N:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[N:26]=2)=[O:32])[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Reactant: Cc1cn(-c2ccc(F)cc2)nc1C(=O)O
Product: Cc1cn(-c2ccc(F)cc2)nc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (0.24 mmol) was used in general procedure 2 with 1-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (0.30 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-1-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carboxamide. MS (Q1) 449.1 (M)+
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([F:16])[F:15])[CH3:11]>[Cu].CS(C)=O>[CH2:10]([O:12][C:13](=[O:18])[C:14]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([F:16])[F:15])[CH3:11]
Reactant: N#Cc1ccc(I)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
According to the Kumadaki method (K. Sato et al., Chem. Pharm. Bull., vol. 47 p. 1013 (1999)) and the above-described scheme, 4-iodobenzonitrile (Compound 1a; 343.5 mg, 1.5 mmol), bromodifluoroacetic acid ethyl ester (304.5 mg, 1.5 mmol), copper powder (190.5 mg, 3.0 mmol) and DMSO (3.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 24 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-cyanophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2a) was obtained with a yield of 60%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:17]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:2][CH2:3]3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1ccc2c(c1)CCc1ccccc1N2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(N2c3ccccc3CCc3ccccc32)CC1
Reaction time: 1 h

Procedure:
60.0 mg (0.216 mmol) of 5-(4-piperidinyl)-10,11-dihydro-5H-dibenzo-[b,f]azepine, 50.0 mg (0.258 mmol) of N-t-butoxycarbonylglycine, 62.1 mg (0.324 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 3 mg (0.03 mmol) of 4-dimethylaminopyridine were dissolved in 1 ml of dichloromethane. 43.7 mg (0.432 mmol) of triethylamine was added to the obtained solution, and they were stirred for 1 hour. The product was purified by the silica gel chromatography (hexane:ethyl acetate=89:11 to 65:35) to obtain the title compound.