Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH2:19]>C(O)C.O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12]([NH:19][CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1cc(Br)nc(Br)c1
Reactant: CN
Solvent: CCO
Solvent: C1COCCO1
Product: CNc1cc(S(=O)(=O)c2ccccc2)cc(Br)n1
Yield: 61 %

Procedure:
0.42 g (0.00112 mol) of 4-benzenesulphonyl-2,6-dibromopyridine and 1.4 ml of 8M methylamine in ethanol were stirred at room temperature in a mixture of 11 ml of ethanol and 11 ml of dioxane for 48 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:10. The product-containing fractions were suspended in 25 ml of diethyl ether, treated in an ultrasound bath and diluted with 45 ml of hexane. The suspension was suction filtered and the filter material was dried in a high vacuum. There was obtained 0.224 g (61%) of (4-benzenesulphonyl-6-bromopyridin-2-yl)-methylamine as white crystals; m.p.: 145-148° C.
Reaction SMILES: [K].[O-]CCCC.Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH2:24]([O:26][CH2:27][CH2:28][OH:29])[CH3:25]>>[CH2:24]([O:26][CH2:27][CH2:28][O:29][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1)[CH3:25]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCOCCO
Agent: CCCC[O-]
Agent: [K]
Product: CCOCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 85 °C

Procedure:
To a stirred solution of potassium t.butoxide (9.3 g, 82.8 mmol) in 1-ethoxy-2-ethanol (70 ml) was added 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7 g, 27.6 mmol). The mixture was heated to 80-90° C. for 2 h. Then most of the solvent was removed by evaporation under reduced pressure. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, concentrated to give a light brown solid, which was washed with petroleum ether, dried in vacuo (7.8 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[N:16]([CH2:17][CH2:18][OH:19])[C:15]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=1)(O)[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:10])[C:12]2=[N:13][C:14]3[C:15](=[C:20]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH:21]=[CH:22][CH:23]=3)[N:16]2[CH2:17][CH2:18][O:19]1
Reactant: CCN(CC)c1cccc2nc(C(C)(O)c3ccc(Cl)cc3Cl)n(CCO)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc3n(c12)CCOC3(C)c1ccc(Cl)cc1Cl
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-(2,4-dichlorophenyl)-1-[7-(diethylamino)-1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]ethanol (Reference example 210, 63.8 mg, 0.151 mmol) and triphenylphosphine (59.4 mg, 0.227 mmol) in tetrahydrofuran (4 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 103 μL, 0.227 mmol) at room temperature. After 2.5 h, the reaction mixture was concentrated in vacuo, and purified by column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give a colorless amorphous (53.3 mg, 0.132 mmol, 87%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][N:36]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(c2nc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cs2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 28.2 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(2-piperidin-4-yl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.17 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (15 μL, 0.19 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile to provide 28 mg (28%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 8.38 (s, 1 H), 8.10 (s, 1 H), 7.83 (d, 1 H), 7.67 (s, 1 H), 7.27-7.40 (m, 5H), 7.17-7.24 (m, 2 H), 5.66 (s, 2 H), 3.59-3.69 (m, 2 H), 3.16-3.28 (m, 1 H), 2.85-2.95 (m, 5H), 2.20 (d, 2 H), 1.78 (q, 2 H); ES-MS m/z 585.21 [M+H]+, HPLC RT (min) 2.97.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:17])[C:5]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([C:15]#N)[CH:9]=[N:8][C:6]=2[N:7]=1.C(O)=[O:19]>[Ni]>[NH2:1][C:2]1[N:3]=[C:4]([NH2:17])[C:5]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([CH:15]=[O:19])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCCc1c(C#N)cnc2nc(N)nc(N)c12
Reactant: O=CO
Agent: [Ni]
Product: CCCc1c(C=O)cnc2nc(N)nc(N)c12
Reaction time: 8 h
Yield: 8 %

Procedure:
Raney Ni (1.2 g damp) was added with the aid of 95-97% HCO2H (7 mL) to a solution of 2,4-diamino-5-propylpyrido[2,3-d]pyrimidine-6-carbonitrile (I-4a) (500 mg, 2.19 mmol) in 95-97% HCO2H (5 mL). The stirred mixture was heated at 75°-80° C. for 1.5 h. Raney Ni was removed by filtration, and the filtrate was evaporated. The residue was dissolved in hot H2O (20 mL), and the solution was filtered, then cooled, and treated with concentrated NH4OH to pH 7 to cause solid to precipitate. The mixture was kept at 0°-5° C. overnight before the solid was collected and washed with cold H2O. This crude material was applied to a silica gel column and eluted with CHCl3 --MeOH (7:1). Evaporation of the product fractions afforded the aldehyde compound 2,4-diamino-5-propylpyrido[2,3-d]pyrimidine-6-carboxaldehyde; yield 8% (41 mg).
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCCC5(CC)CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.Cl.Cl.[CH3:40][N:41]([CH3:70])[C:42]([C:44]1[CH:45]=[CH:46][C:47]2[CH:51]=[C:50]([C:52]3[C:57]([CH3:58])=[CH:56][N:55]=[C:54]([NH:59][CH2:60][CH2:61][CH2:62][CH:63]4[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]4)[N:53]=3)[S:49][C:48]=2[CH:69]=1)=[O:43]>>[ClH:24].[ClH:1].[CH3:70][N:41]([CH3:40])[C:42]([C:44]1[CH:45]=[CH:46][C:47]2[CH:51]=[C:50]([C:52]3[C:57]([CH3:58])=[CH:56][N:55]=[C:54]([NH:59][CH2:60][CH2:61][CH2:62][CH:63]4[CH2:64][CH2:65][N:66]([CH3:3])[CH2:67][CH2:68]4)[N:53]=3)[S:49][C:48]=2[CH:69]=1)=[O:43]
Reactant: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Reactant: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C)CC1
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C)CC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-ethyl-1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-6-carboxylic acid dimethylamide di-hydrochloride and isolated as yellow foam. ES+(m/z) 452 [M(free base)+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][CH3:13])[CH:8]=[C:7]([NH2:14])[C:6]=1[NH2:15])[CH3:2].COC(C1C2N=C(N)[NH:26][C:25]=2C=CC=1)=O.BrC#N>CO>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:15]=[C:25]([NH2:26])[NH:14][C:7]=2[CH:8]=[C:9]([S:11][CH2:12][CH3:13])[CH:10]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)c1cc(SCC)cc(N)c1N
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: N#CBr
Solvent: CO
Product: CCOC(=O)c1cc(SCC)cc2[nH]c(N)nc12
Yield: 90 %

Procedure:
0.9 g (3.75 mmol) of 2,3-diamino-5-ethylsulfanyl-benzoic acid ethyl ester was subjected to a similar cyclization condition as illustrated in intermediate A by using 1.2 g (11.3 mmol) of BrCN in methanol to produce 0.9 g (3.4 mmol, 90%) of 2-amino-6-ethylsulfanyl-1H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 266 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][CH2:29]SC)[N:9]=2)[CH:7]=1.BrCC[N:39]1[CH:43]=[C:42](NC(C2C=NN3C=CC=NC=23)=O)[C:41]([C:56]2C=C(Cl)C=CC=2OC(F)F)=N1.N1C=CC=CC=1CN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][C:29]3[CH:56]=[CH:41][CH:42]=[CH:43][N:39]=3)[N:9]=2)[CH:7]=1
Reactant: CSCCNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: NCc1ccccn1
Product: O=C(Nc1cn(CCNCc2ccccn2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12

Procedure:
Using synthetic method analogous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and pyridin-2-ylmethanamine. LCMS (Method 20) [M+H]+=539.2, RT=2.53 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68 (dd, 1H, J=1.6, 4.0 Hz), 8.67 (s, 1H), 8.49 (d, 1H, J=4.0 Hz), 8.37 (s, 1H), 7.72 (dd, 1H, J=1.6, 7.6 Hz), 7.70-7.61 (m, 2H), 7.46-7.06 (m, 5H), 4.27 (t, 2H, J=6.0 Hz), 3.83 (s, 2H), 2.98 (t, 2H, J=6.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:20])=[O:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([NH:20][C:34]([NH:33][S:30]([C:27]4[CH:28]=[CH:29][C:24]([CH3:36])=[CH:25][CH:26]=4)(=[O:32])=[O:31])=[O:35])=[O:19])=[CH:15][CH:16]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(N)=O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(=O)NC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 91.7 %

Procedure:
A mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetamide (step 5, 105 mg, 0.30 mmol), p-toluenesulfonyl isocyanate (0.07 mL, 0.45 mmol), toluene (10 mL) and THF (5 mL) was heated at reflux temperature. After 6 h, an additional 0.1 mL of p-toluenesulfonyl isocyanate was added and the mixture was heated for 3 h. The mixture was cooled and left at room temperature for 2 days. The mixture was concentrated and the residue was purified by preparative TLC (ethyl acetate) to afford 150 mg (92%) of the title compound as colorless amorphous solids: 1H-NMR (CDCl3) δ 9.78 (1H, s), 7.95 (2H, d, J=8.3 Hz), 7.84 (1H, s), 7.54 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.0 Hz), 7.32 (2H, d, J=8.4 Hz), 7.18 (1H, s), 3.78 (2H, s), 2.77 (2H, q, J=7.5 Hz), 2.41 (3H, s), 1.35 (3H, t, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:10][C@H:9]2[CH3:33])[CH:5]=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].Cl.O>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:33])[CH:5]=[CH:4][C:3]=1[C:34]([F:37])([F:35])[F:36]
Reactant: C[C@@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1c1ccc(C(F)(F)F)c(Cl)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@@H]1CNCCN1c1ccc(C(F)(F)F)c(Cl)n1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
A suspension of 1-(6-chloro-5-trifluoromethyl-pyridin-2-yl)-2-(R)-methyl-4-trityl-piperazine (from Step 1 above; 5.70 g, 10.9 mmol) in EtOH (70 mL) was heated to 80° C. Aqueous HCl (4 M; 6 mL) was added and the mixture was heated in an open vessel for one hour. To the clear solution was water added (100 mL) and the precipitate was filtered off. The solvent from the filtrate was evaporated down to about 10 mL, the crystals were filtered off and the evaporation continued down to 3 mL and another portion of slightly pinkish crystals were filtered off. The combined crystal fractions were taken up between alkaline water (NaOH)/CHCl3. The aqueous phase was washed twice with CHCl3 and the combined, dried (MgSO4), organic phases were evaporated at reduced pressure to give a light yellow oil (1.75 g, 69%). A NOE between the methylene protons at C-2 in the piperazine ring and the C3-hydrogen in the pyridine ring was observed. Purity 99% (HPLC). Fragmenting MS analysis supports the stated structure. HRMS m/z calcd for C11H13ClF3N3 (M)+ 279.0750. found 279.0744.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][N+:15]([CH3:18])=[CH:16]Cl.[Cl-]>>[CH3:14][N:15]([CH3:18])[CH:16]=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH:11]=[O:13]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Product: CN(C)C=C(C=O)c1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitrophenylacetic acid is treated with Vilsmeier reagent to give 3-(dimethylamino)-2-(4-nitrophenyl)-2-propenal. This product is treated with cyanoacetamide and sodium methoxide to give 1,2-dihydro-5-(4-nitrophenyl)-2-oxo-3-pyridinecarbonitrile. The preceding product is hydrolyzed with 1:1 concentrated hydrochloric acid-acetic acid to give 1,2-dihydro-5-(4-nitrophenyl)-2-oxo-3-pyridinecarboxylic acid. The above product is boiled with quinoline to give 5-(4-nitrophenyl)-2(1H)-pyridone. When the preceding product is treated with phosphorus oxychloride, 2-chloro-5-(4-nitrophenyl)pyridine is obtained. This product is treated with hydrazine to give 2-hydrazino-5-(4-nitrophenyl)pyridine. The above product is treated with ethyl orthoacetate to give the product of the Example.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[NH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.Cl>O>[C:10]1([C:8]2[CH:7]=[N:6][C:2](=[O:1])[N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCC(=O)c1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C1N=CC(c2ccccc2)=N1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Potassium cyanate (2.00 g, 24.7 mmol) was added in portions, over 15 min, to a stirred solution of 2-aminoacetophenone hydrochloride (3.85 g, 22.4 mmol) in water (130 mL) at 70° C., while the pH of the solution was maintained at pH 1 to 3 by addition of conc. hydrochloric acid. The reaction mixture was stirred at 70° C. for 4 h, then allowed to cool to ambient temperature and stood for 18 h. The title compound was isolated by filtration. MS: m/z=161 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:16][NH2:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:17][CH3:16])=[O:11])[CH2:7]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 48 h
Yield: 35.1 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1 -azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40 % aqueous monomethylamine. After stirring for 48 hr, the reaction mixture was diluted with 100 ml of water and the solid which formed was collected by filtration (6.0 g). Recrystallization from benzene yielded 2.0 g (35.1%) of tan crystals, m.p. 134°-135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[CH2:4][C:5]#[N:6].[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH:21]=O)=[CH:16][N:15]=1.N>C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]1[C:5]([NH2:6])=[N:20][C:18]2[N:19]=[C:14]([NH2:13])[N:15]=[CH:16][C:17]=2[CH:21]=1
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: Nc1ncc(C=O)c(N)n1
Agent: C
Agent: N
Product: Cc1cc(C)c(-c2cc3cnc(N)nc3nc2N)c(C)c1

Procedure:
The title compound was prepared according to Example 1, starting from 0.915 g of 2,4,6-trimethyl-benzyl cyanide and 0.76 g of 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 276°-282° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 279 (MH+, 54), 280 (MH+ +1, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:40](=[O:41])[CH2:39][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Reaction time: 22 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.027 ml phenyl-acetyl chloride (0.2 mmol). After 22 h stirring at reflux, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 90 mg of a light brown solid (94%). MS (ISP) 469.3 (M+H)+.
Reaction SMILES: C(O)(=O)C.Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1.O=[C:17]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18]1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:17]3[CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][C:21]=3[C:10]=2[CH:9]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCC(C(=O)O)C1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CC(C(=O)O)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To 250 ml of 80% acetic acid in water were added 4-methoxyphenylhydrazine hydrochloride (21 g, 0.12 mole) and 3-oxocyclopentane carboxylic acid (20 g, 0.15 mole). After stirring at ambient temperature for two hours, the mixture was stirred at 100° C. for three hours. After cooling, the mixture was filtered, and the tan precipitate washed with water, and dried to give 15 g of a solid, mp ~200° C. A sample of this material was recrystallized from ethanol/ether (1:2) to give a tan solid, mp 210° C. (dec.).
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([O:30]C)=[O:29])[CH:22]=4)[NH:17]3)=[CH:12][CH:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[C:25]([CH3:27])([CH3:26])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:28]([OH:30])=[O:29])[CH:22]=4)[NH:17]3)=[CH:14][CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3CCCCC3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)C2CCCCC2)cc1
Yield: 95 %

Procedure:
To a mixture of methyl 2-(4-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (53 mg, 0.11 mmol) in methanol (3 mL) and water (1.5 mL) was added a solution of sodium hydroxide (123 mg, 2.83 mmol.) in water (1.5 mL). The resultant mixture was heated for reflux until the complete of the reaction (monitored by thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 2-(4-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, yellow solid, 50 mg, 95% Yield; MS (ESI+APCI) M+1=429.11.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18].O>C1(C)C=CC=CC=1>[Cl:15][CH2:16][C:17]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CCl)NCCc1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
β-phenylethylamine (0.68 kg) was taken in dry toluene (4.42 L) and sodium bicarbonate (0.612 kg) was added at 30° C. and cooled to 0-5° C. Chloroacetyl chloride was slowly added under nitrogen blanket at 0-10° C., stirred and maintained for 2 hr. After completion of the reaction, water was added slowly and reaction mass was allowed to attain 33±2° C. and the layers were separated. To the aqueous layer toluene was added, stirred and two layers were separated. To the organic layer dil HCl solution (0.653 L DM water+0.272 L con HCl) was added, stirred and two layers were separated. To the organic layer again sodium bicarbonate solution (0.653 L DM water+0.068 kg sodium bicarbonate) was added, stirred and two layers were separated. Water was added to the organic layer, stirred and two layers were separated. From the organic layer toluene was distilled out, methanol was added, heated to 58° C., stirred. To the reaction mass water was added, temperature was maintained at 58° C., stirred for 1-1.5 hr, cool to 30±2° C. for 3 hrs under stirring. Stirring was continued for 3 hrs at 0-5° C. The reaction mass was filtered, washed with water and dried.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Cu]>[C:1]1([O:7][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: [Cu]
Product: c1ccc(Oc2ccccc2)cc1
Yield: 44.7 %

Procedure:
However, the catalyst disclosed in Japanese Patent KOKAI No. 57-11932 is insufficient in the yield of phenol. Actually, the maximum conversion of benzoic acid was 50.5%, and the maximum selectivity to phenol was 88.6%, and therefore, the maximum yield was 44.7%. Besides, when an exothermic reaction is conducted such as the oxidation reaction of benzoic aicd using the catalyst containing a copper compound, hot spots occur in the catalyst layer to progress calcining of the catalyst. As a result, the catalytic activity is degraded sharply. In the manufacturing process disclosed in Japanese Patent KOKOKU No. 59-20384, the yield of phenol is insufficient. That is, the maximum conversion of benzoic acid was 63.7%, and the maximum selectivity to phenol was 82.2%, and therefore, the maximum yield was 52.4%. Moreover, byproducts such as diphenyl oxide are produced abundantly, and therefore, a purification process for the produced phenol is necessary. In the manufacturing process disclosed in Japanese Patent KOKOKU No. 64-934, the maximum conversion of benzoic acid was 75%, and the maximum selectivity to phenol was 89%. Therefore, the maximum yield was 66.8%. Moreover, all of the above conventional processes are inferior in productivity due to low space time yield (the production amount of phenol per unit volume of catalyst per unit time), and therefore, they are disadvantageous in the industrial production of phenol.