Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([NH2:9])=[C:7]([NH2:10])[NH:6][C:5](=[O:11])[N:4]=1.[CH3:12][C:13]([CH:15]=O)=O>O>[NH2:2][C:3]1[C:8]2[C:7](=[N:10][C:13]([CH3:15])=[CH:12][N:9]=2)[NH:6][C:5](=[O:11])[N:4]=1
Reactant: Nc1nc(=O)[nH]c(N)c1N
Reactant: CC(=O)C=O
Agent: Cl
Solvent: O
Product: Cc1cnc2c(N)nc(=O)[nH]c2n1

Procedure:
In 50 mL of H2O is dissolved 1.77 g (0.01 mole) of 4,5,6-triaminopyrimidine-2-one hydrochloride (19). The pH of the solution is adjusted to 5 and then, 4 mL of 40% aqueous methylglyoxal (FLUKA, A G, Switzerland) is added and the solution is heated under reflux for 30 minutes. The resulting precipitate is collected and purified by recrystallization from a large amount of H2O to give 20.
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33].Cl>CN(C)C=O.O>[C:19]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:15][C:14]3[N:13]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(C(=O)O)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid in 100 cm3 of dimethylformamide is added dropwise to a suspension of 1.45 g of sodium hydride (at 60% in oil) in 25 cm3 of dimethylformamide cooled to a temperature in the region of 0° C. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is cooled to a temperature in the region of 0° C. and 4.18 cm3 of (2-chloromethoxyethyl)trimethylsilane are added dropwise. The mixture is stirred for about 20 hours at a temperature in the region of 20° C. After cooling this mixture to a temperature in the region of 0° C., 100 cm3 of water and 16 cm3 of aqueous 1N hydrochloric acid solution are added. The mixture is extracted three times with 100 cm3 of ethyl acetate. The combined organic phases are washed with three times 100 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (98/2 by volume)], 1.8 g of 6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole-3-carboxylic acid are thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[O:22]1[C:26]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])=[CH:25][N:24]=[CH:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>C(#N)C.O>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[C:5]([O:20][CH3:21])=[CH:4][N:3]=[C:2]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:27]([C:26]5[O:22][CH:23]=[N:24][CH:25]=5)[CH:28]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: COc1cnc(Cl)nc1-c1cnn(C(CC#N)C2CC2)c1
Reactant: Nc1cccc(-c2cnco2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc(Nc2cccc(-c3cnco3)c2)nc1-c1cnn(C(CC#N)C2CC2)c1

Procedure:
A mixture of 3-[4-(2-chloro-5-methoxypyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopropylpropanenitrile (20 mg, 0.00008 mol), 3-(1,3-oxazol-5-yl)aniline (18.1 mg, 0.000113 mol), and p-toluenesulfonic acid (11 mg, 0.000064 mol) in dry 1,4-dioxane (0.5 mL, 0.006 mol) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC at pH 10 to give the desired product as a racemic mixture (free base). LCMS (M+H) 428.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]2)=[CH:28][CH:27]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]2[CH2:32][CH2:33][N:34]([C:37]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:38])[CH2:35][CH2:36]2)=[CH:28][CH:27]=1
Reactant: O=C(Cl)N1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@](O)(COC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methyl)propyl-4-nitroimidazole prepared in Example 10 (2.28 g, 9.66 mmol), N,N-diisopropylethylamine (2.81 ml, 16.10 mmol) and 4-dimethylaminopyridine (0.20 g, 1.61 mmol) were added to a suspension of 4-(4-chlorobenzyl)piperazine-1-carbonylchloride (2.20 g, 8.05 mmol) in toluene (30 ml) followed by stirring 100° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-chlorobenzyl)piperazine-1-carboxylate (1.82 g, yield 48%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH:29]1[CH:30]=[CH:31][C:32]2[N:37](O)N=[N:35][C:33]=2[CH:34]=1.C1(N)C=CC=CC=1N>CN(C=O)C.CCOC(C)=O>[NH2:35][C:33]1[CH:34]=[CH:29][CH:30]=[CH:31][C:32]=1[NH:37][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: Nc1ccccc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Nc1ccccc1NC(=O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(dibenzylamino)benzoic acid (50 mg, 0.16 mmol) in DMF was added EDC (181 mg, 0.95 mmol), HOBt (128 mg, 0.95 mmol) and phenylenediamine (171 mg, 1.58 mmol) were which was allowed to stir at room temperature for 12 hours. The crude reaction mixture was diluted with EtOAc (20 mL) and then washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (20-100% MeCN/H2O with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (20 mL) and washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to gave the desired N-(2-aminophenyl)-4-(dibenzylamino)benzamide: 1H NMR (600 MHz, MeOH-d4) δ 7.83 (d, J=9.0 Hz, 2H), 7.31 (m, 6H), 7.25 (m, 8H), 6.81 (d, J=9.1 Hz, 2H), 4.79 (s, 4H); cal'd 408.2 (MH+), exp 408.2 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:6]1=2.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26]>C(O)C.ClCCl.[Pd]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([NH:15][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[NH:26])=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCSc2ccc([N+](=O)[O-])cc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: ClCCl
Solvent: CCO
Product: CN(C)CCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A suspension of N,N-dimethyl-2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (75 mg, 0.281 mmol) and palladium, 10 wt. % on activated carbon (29.9 mg, 0.028 mmol) in ethanol (5 mL) was stirred at room temperature under an atmosphere of hydrogen (balloon pressure) for 90 minutes. During this time, the yellow color of the reaction dissipated. To this mixture was then added methyl thiophene-2-carbimidothioate hydroiodide (160 mg, 0.561 mmol), and the resulting suspension was stirred overnight at room temperature. The mixture was then diluted with dichloromethane and filtered to remove palladium. The organic filtrate was further diluted with water and saturated sodium carbonate (1:1). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organics were dried, filtered, concentrated, and then chromatographed in 1:19 (2M NH3 in methanol):ethyl acetate, giving the desired product 27 (61 mg, 62.8%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.3 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.37 (brs, 2H), 6.17 (s, 1H), 6.08 (d, J=7.8 Hz, 1H), 3.63-3.58 (m, 2H), 3.39-3.32 (m, 2H), 3.01-2.96 (m, 2H), 2.42 (t, J=6.9 Hz, 2H), 2.10 (s, 6H); ESI-MS (m/z, %): 347 (MH+, 100), 276 (74); ESI-HRMS calculated for C17H23N4S2 (MH+), calculated: 347.1358, observed: 347.1349; HPLC purity: 95% by area.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C[O-].[K+].[H][H]>[Ru]>[CH2:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: [H][H]
Agent: [Ru]
Agent: C[O-]
Agent: [K+]
Product: NC1CCC(CC2CCCCC2)CC1
Temperature: 290 °C

Procedure:
In a steel autoclave fitted with a stirring apparatus and a product draw off system retaining the catalyst in the reactor can be placed 200 parts of 4-aminodiphenylmethane as described in British Patent 764,633 and 100 parts of a finely divided 5% ruthenium on an alumina support and 15 parts of potassium methoxide. The mixture within the autoclave can then be heated to 290°C with stirring and hydrogen added to maintain a pressure of 290 atmospheres for 20 minutes. The resulting mixture can then be freed of catalyst by filtration and distilled to strip off solvent. Final distillation under vacuum can then be used to provide the desired product, 4-aminodicyclohexylmethane, which is a colorless viscose liquid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[CH3:22][C:23]([C:26]1[N:27]=[C:28]([NH2:31])[S:29][CH:30]=1)([CH3:25])[CH3:24]>>[CH3:22][C:23]([C:26]1[N:27]=[C:28]([NH:31][C:18]([C:3]2[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][C:7]=3[C:2]=2[OH:1])=[O:19])[S:29][CH:30]=1)([CH3:25])[CH3:24]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: CC(C)(C)c1csc(N)n1
Product: CN1C(C(=O)Nc2nc(C(C)(C)C)cs2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 33 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 4-(1,1-dimethyl-ethyl)-2-thiazolamine with a yield of 33% of theory.
Reaction SMILES: O.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH:53][C:54]1[CH:55]=[C:56]([C:60]2[N:69]=[C:68]([NH:70][C:71]3[CH:72]=[C:73]4[C:77](=[CH:78][CH:79]=3)[N:76]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[N:75]=[CH:74]4)[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[N:61]=2)[CH:57]=[CH:58][CH:59]=1)=[O:10]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC[C@H]1C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of (S)-1-methylpyrrolidine-2-carboxylic acid monohydrate (14 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (49 μL, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired oil product tert-butyl 5-(2-(3-((S)-1-methylpyrrolidine-2-carboxamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[N:5]([CH3:7])[CH3:6].[CH2:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=O)=[C:14]1[CH3:33])[CH3:12].Cl.[OH-].[Na+].[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[C:37]([NH:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:7])[CH3:6])[CH:8]=[CH:9][C:10]=1[C:22]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([CH2:11][CH3:12])[C:14]=2[CH3:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26](=[O:28])[O:27]1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1cccc(N)c1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3NC(C)=O)OC(=O)c3ccccc32)c2ccccc21
Temperature: 25 °C

Procedure:
A suspension of 1.36 g (0.01 mole) of m-amino-N,N-dimethylaniline in 20 ml of acetic anhydride was heated to 80°-90° C. for approximately thirty minutes and then cooled to room temperature. Three grams (0.01 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A of Example 1, was added and the resulting mixture was heated at 60°-70° C. for approximately thirty minutes. After cooling, the reaction mixture was poured into 100 ml of 10 percent hydrochloric acid and the mixture made alkaline with 10 percent aqueous sodium hydroxide with the addition of ice. The solid which separated was collected by filtration and dried to obtain 3-[2-acetamido-4-dimethylaminophenyl]-3-(1-ethyl-2-methyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =Y1 =H; ##STR30## R=R5 =CH3 ; R6 =CH2CH3) as a pale blue-colored solid melting over the range 180°-195° C. Infrared absorption maxima appeared at 1757 cm-1 (C=O; s )and 1696 cm-1 (C=O; s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH:20]([CH3:22])[CH3:21])[N:14]=2)=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]=1)(=O)=O.[CH3:31][OH:32].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN([CH:65]=[O:66])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:20]([N:15]1[C:16](=[O:19])[CH:17]=[CH:18][C:13]([C:10]2[N:11]=[CH:12][C:7]([C:31]([O:66][CH3:65])=[O:32])=[N:8][C:9]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14]1)([CH3:21])[CH3:22]
Reactant: CO
Reactant: CN(C)C=O
Reactant: CC(C)n1nc(-c2ncc(OS(=O)(=O)C(F)(F)F)nc2-c2ccccc2)ccc1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cnc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)n1

Procedure:
A mixture of 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2-pyrazinyl trifluoromethanesulfonate (1.0 g), MeOH (5.98 ml), palladium acetate (102 mg) and 1,3-bis(diphenylphosphino)propane (187 mg) in DMF (10 ml) was stirred with CO gas bubbling at 20° C. for 30 minutes. Then the reaction mixture was stirred under CO gas at 60° C. for 6 hours. Water and EtOAc were added to the reaction mixture. The organic layer was washed with 1N HCl, aq. NaHCO3 and brine. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain methyl 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2-pyrazinecarboxylate (68 mg) as white powder.
Reaction SMILES: C(OP([C:9]#[N:10])(=O)OCC)C.[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][N:23]=1.[OH:34][C:35]([C:38]1[CH:39]=[C:40](N)[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)([CH3:37])[CH3:36].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:10][CH2:9][C:40]2[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=[C:38]([C:35]([OH:34])([CH3:37])[CH3:36])[CH:39]=2)=[O:17])=[CH:14][C:13]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CC(C)(O)c1cc(N)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCc2cc(C(C)(C)O)cc(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Diethylcyanophosphonate (Aldrich, Buchs, Switzerland; 0.33 mL, 2.0 mmol) is added to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (306 mg, 1.0 mmol), 3-[(1-hydroxy-1-methylethyl)]-5-(1,1,1-trifluoromethyl)benzeneamine (220 mg, 1.0 mmol) and triethylamine (560 μL, 4.0 mmol) in 5 mL N,N-dimethylformamide at 10° C. After stirring for 3 hours at 60° C., the mixture is treated with saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined extracts are dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to afford a crude product which is recrystallised from ethylacetate to give the title compound as a crystalline solid, m.p. 253–258° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[N:65]1([CH2:70][CH2:71][C@H:72]2[CH2:77][CH2:76][C@H:75]([NH2:78])[CH2:74][CH2:73]2)[CH2:69][CH2:68][CH2:67][CH2:66]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:78][C@H:75]3[CH2:76][CH2:77][C@H:72]([CH2:71][CH2:70][N:65]4[CH2:69][CH2:68][CH2:67][CH2:66]4)[CH2:73][CH2:74]3)=[O:29])[C:24]3[C:19](=[C:20]([O:30][CH3:31])[CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c1-c1ccccc1N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)C2CC(=O)N[C@H]1CC[C@H](CCN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [5-(3,4-dichloro-benzenesulfonyl)-10-methoxy-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 17/d) (0.163 g, 0.34 mmol), triethylamine (0.3 mL, 2.1 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (0.152 g, 0.4 mmol) in dry dimethyl formamide (10 mL) was stirred at room temperature for five minutes before trans-4-(2-pyrrolidin-1-yl-ethyl)-cyclohexylamine dihydrochloride (Reference Example 4) (0.09 g, 0.34 mmol) was added. The pH of the reaction mixture was adjusted to 8 by addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with saturated sodium hydrogencarbonate solution (30 mL), the precipitated crystals were filtered off, washed with water and dried. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:NH4OH=9:1:0.1 as eluent. The product was crystallized with diethyl ether to yield 0.135 g (60%) of the title compound. MS (EI) 657.2 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH2:16])=[CH:9][CH:8]=1)C.[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH3:25].FC1C(F)=C(F)C(F)=C2C(=O)OC(=O)C=12.[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[N:51]=[C:52]=[O:53]>C(Cl)Cl.N1C=CC=CC=1>[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[NH:51][C:52](=[O:53])[N:16]([CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:17][CH2:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(=O)Cl
Reactant: CCOC(=O)C(Cc1ccc(OCCN)cc1)OCC
Reactant: O=C=Nc1ccc(F)cc1F
Agent: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCN(CCOc1ccc(CC(OCC)C(=O)O)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the compound obtained in Example 1, Step c (42 mg) in methylene chloride (2 ml) was added with pyridine (32 μl) and valeryl chloride (21.4 μl, Tokyo Kasei Kogyo) and stirred at room temperature for 4 hours. The reaction mixture was added with tetrafluorophthalic anhydride (22 mg) and further stirred for 2 hours. The reaction mixture was added with a polyamine resin (100 mg, prepared by the same method as described in Example 3), stirred for 1.5 hours and filtered, and the filtrate was concentrated. The resulting residue was dissolved in THF (1 ml), added with ethyl acetate (200 μl) and borane/dimethyl sulfide complex (36 μl, Tokyo Kasei Kogyo) and stirred at room temperature for 20 hours. The reaction mixture was added with ethanol (0.2 ml) and stirred at room temperature for 1 hour and at 50° C. for 1 hour. The reaction mixture was concentrated, and the resulting residue was dissolved in methylene chloride, washed with 1 N aqueous sodium hydroxide, dried and concentrated. Because a TLC analysis verified that the reaction was incomplete, a THF solution of the residue was prepared again and subjected to the reduction reaction and the post-treatments again. By using the resulting compound, the title compound (5.6 mg) was obtained in the same manner as that of Example 3 except that 2,4-difluorophenyl isocyanate (Aldrich) was used instead of the 2,4-dimethoxyphenyl isocyanate.
Reaction SMILES: C(OC[N:9]1[N:13]=[N:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]C3C=C(C(=O)C)C=CC=3O)=[CH:16][CH:15]=2)=[N:10]1)(=O)C(C)(C)C.N1C=NN=N1.[OH:37][C:38]1C=CC=C[C:39]=1CCCC1C=CC(C([O-])=O)=CC=1.[CH2:56]([O:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1CCCC1C=CC(C(OC)=O)=CC=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[CH2:56]([O:63][C:64]1[CH:65]=[CH:66][C:67]([C:38](=[O:37])[CH3:39])=[CH:68][C:69]=1[CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:12][N:13]=[N:9][N:10]=2)=[CH:19][CH:18]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(=O)c1ccc(O)c(CCc2ccc(-c3nnn(COC(=O)C(C)(C)C)n3)cc2)c1
Reactant: O=C([O-])c1ccc(CCCc2ccccc2O)cc1
Reactant: COC(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Agent: c1nnn[nH]1
Product: CC(=O)c1ccc(OCc2ccccc2)c(CCc2ccc(-c3nnn[nH]3)cc2)c1

Procedure:
2-(Pivaloyloxymethyl)-5-{-4-[2-(2-hydroxy-5-acetylphenyl)ethyl]phenyl}tetrazole was converted to N-2-(pivaloyloxymethyl)-5-{-4--2-(2-benzyloxy-5-acetylphenyl) ethyl]phenyl}tetrazole by the process described in Example 1 for the conversion of 4-[3-(2-hydroxyphenyl)propyl]benzoate to methyl 4-[3-(2-benzyloxyphenyl)propyl]benzoate.