Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (500 mg, 1.72 mmol) in pyridine (5 mL) were successively added 4-(dimethylamino)pyridine (21.0 mg, 172 μmol) and 4-methoxybenzoyl chloride (17) (587 mg, 3.44 mmol) at room temperature, and the mixture was heated with stirring at 50° C. for 17 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residual pyridine was azeotropically removed with toluene (×3). The residue was purified by column chromatography (silica gel 50 g, dichloromethane/ethyl acetate=9/1). The residue was further recrystallized from ethyl acetate to give Compound 11x (592 mg, 1.39 mmol, 80.8%) as a colorless solid. Rf=0.63 (dichloromethane/ethyl acetate=9/1); 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 3.85 (s, 3H), 4.17 (s, 2H), 7.04-7.11 (m, 4H), 7.14-7.26 (m, 5H), 7.93-7.98 (AA′BB′, 2H), 8.05-8.11 (AA′BB′, 2H), 8.96 (s, 1H), 10.63 (s, 1H); 13C NMR (67.8 MHz, DMSO+CDCl3) 40.3, 54.7, 54.8, 112.9 (2C), 113.7 (2C), 125.4, 125.7, 127.4 (2C), 127.7 (2C), 128.0, 128.5 (2C), 129.4 (2C), 136.2, 137.6, 143.6, 148.2, 150.4, 160.1, 162.0, 165.5; IR (KBr, cm−1) 700, 743, 843, 1030, 1159, 1177, 1258, 1290, 1452, 1485, 1514, 1535, 1580, 1609, 1643, 3242; Anal. Calcd. For C26H23N3O3: C, 73.39; H, 5.45; N, 9.88. Found: C, 73.48; H, 5.40; N, 9.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.C([O:18][CH:19](OCC)[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)C.Cl>CO>[CH:19]([C:20]1[CH:21]=[CH:22][C:23]([CH2:26][N:27]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:24][CH:25]=1)=[O:18]
Reactant: CCOC(OCC)c1ccc(CNc2ccc(C(C)C)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(C=O)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 47.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and {[4-(diethoxymethyl)phenyl]-methyl}(4-isopropylphenyl)amine (0.65 g) as starting materials. The obtained residue was dissolved in a mixed solvent (15 mL) of methanol:1 mol/L-hydrochloric acid (1:2) and heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N-[(4-formylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CO>[C:16]1([CH:22]2[CH2:23][CH2:24][N:25]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:26][CH2:27]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)CNS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reaction time: 21 h

Procedure:
A stirred mixture of (4-fluoro-benzenesulfonyl-amino)-acetic acid (0.0895 g, 0.000384 mol), 4-phenyl-piperidine (0.618 g, 0.000383 mol), and potassium carbonate (0.109 g, 0.000789 mol) in dry dimethyl sulfoxide (0.10 mL) in a tightly capped vial was placed in a hot sand bath (115° C.). After 21 hours, the reaction mixture was cooled and partitioned between ethyl acetate and water. The mixture was acidified with 1M hydrochloric acid (3.2 mL, 0.0032 mol) and the layers were separated. The aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (MgSO4), and rotary evaporated to give a glass. The glass was dissolved in methanol, silica gel was added (4.2 g, 230-400 mesh), and the mixture was rotary evaporated to dryness. The resulting powder was poured onto a column of silica gel (14 g, 230-400 mesh), and eluted with a mixture of hexanes-ethyl acetate-acetic acid (15:15:1, 11×15 mL). Fractions containing product were combined and rotary evaporated. The residue was crystallized from methanol-water (1:1) after a hot filtration to give the title compound as a pale yellow solid; yield 0.070 g (49%), mp=154.5-155.5° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][O:7][C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])=[O:3].CN(C)C.[CH2:17]([OH:20])[C:18]#[CH:19]>C(Cl)Cl>[C:8]([O:7][CH2:6][CH2:5][O:4][C:2]([O:20][CH2:17][C:18]#[CH:19])=[O:3])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C#CCO
Reactant: C=C(C)C(=O)OCCOC(=O)Cl
Agent: CN(C)C
Solvent: ClCCl
Product: C#CCOC(=O)OCCOC(=O)C(=C)C

Procedure:
A flask use in Example 1 was charged with 19.3 g of 2-methacryloyloxyethyl chloroformate and 11.5 g of trimethylamine in 50.0 g of methylene chloride. To the flask was added 7.0 g of propargyl alcohol dropwise over one hour. The mixture was allowed to react for 6 hours at 30° C. After the reaction, the mixture was processed as in Example 1 to give 2-propargyloxycarbonyloxyethyl methacrylate as colorless liquid. Yield, 53.6% of theory. The product was identified to be the same as the product of Example 1 by the IR spectrum and 1H--NMR.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].C(OCC)C>O1CCOCC1>[ClH:30].[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[CH2:20][N:19]1[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccco2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1coc(Cn2c(N3CCCNCC3)nc3ccccc32)c1
Reaction time: 1 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane (0.6 g, 1.5 mmol) and dioxane (10 mL). Add a solution of hydrochloric acid in dioxane (6 mL, 4 M). After 1 hour, add diethyl ether (50 mL) to give a solid. Collect the solid by filtration and dry to give 4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane hydrochloric acid salt: 219-221° C.
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:11]([CH3:18])[C:12](=O)[C:13]([F:16])([F:15])[F:14]>>[CH3:18][C:11]1[S:9][C:7]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:8][C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CC(Br)C(=O)C(F)(F)F
Reactant: NC(=S)N1CCNCC1
Product: Cc1sc(N2CCNCC2)nc1C(F)(F)F
Yield: 25 %

Procedure:
Prepared in analogy to example 49 (a) from 1-piperazinecarbothioamide and 3-bromo-1,1,1-trifluoro-2-butanone. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 25%). MS (m/e): 252.1 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.C.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]([OH:29])([C:27]#[CH:28])[CH3:26].N1CCCCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:28]#[C:27][C:25]([OH:29])([C:21]4[S:20][CH:24]=[CH:23][N:22]=4)[CH3:26])[CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(=O)[nH]c3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2[nH]c(=O)n(-c3ccnc(N)n3)c2c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromo-2,3-dihydro-1H-1,3-benzodiazol-2-one (230 mg, 0.751 mmol) in EtOAc was added charcoal (5 mol %). The mixture was stirred at RT for 20 min then filtered and concentrated in vacuo. To the residue in a sealed tube was added 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (230 mg, 1.50 mmol), piperidine (2 mL), tetrakis(triphenylphosphine)palladium (43.4 mg, 0.038 mmol) and copper(I) iodide (14.3 mg, 0.075 mmol). The reaction mixture was then heated at 75° C. for 18 hr then partitioned between EtOAc (15 mL) and water (2 mL). The organic layer was concentrated in vacuo and the residue purified by reverse phase preparative HPLC to afford the title compound: 1H NMR (500 MHz, DMSO) δ 1.90 (3 H, s), 6.92 (2H, s), 6.95 (1H, s), 7.04 (1H, d, J=8.04 Hz), 7.21 (1H, dd, J=8.04, 1.42 Hz), 7.40 (1H, d, J=5.52 Hz), 7.68 (1H, d, J=3.31 Hz), 7.77 (1H, d, J=3.15 Hz), 8.26-8.36 (2H, m), 11.57 (1H, br. s.); LC-MS: m/z=+379.0 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[Br:12][CH2:13][CH2:14][CH2:15]Br>CN(C=O)C>[Br:12][CH2:13][CH2:14][CH2:15][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: BrCCCBr
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: BrCCCn1cnc2ccccc21
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of benzimidazol (355 mg, 3.00 mmol) in dry DMF (10 mL) was added NaH (83 mg, 3.3 mmol) at 20° C. under N2 atmosphere. The reaction mixture was stirred for 30 min, and then 1,3-dibromopropane (1.82 g, 9.00 mmol) was added and stirres for additional 15 h at 20° C. The reaction was quenched by addition H2O, and the product was extracted with EtOAc. The organic solution was then washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. 1-(3-Bromo-1-propyl)benzimidazole (530 mg, 74%) was isolated by flash chromatography on a silica gel column by elution with EtOAc/Hexanes a pale yellow oil. 1H NMR (CDCl3, 300 MHz) δ2.40 (qu, 2H, J=6.6 Hz), 3.33 (t, 2H, J=6.2 Hz), 4.42 (t, 2H, J=6.6 Hz), 7.12-7.20 (m, 1H), 7.27-7.48 (m, 2H), 7.43-7.49 (m, 1H), 7.78-7.86 (m, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][CH2:11][O:13]2)=[CH:4][CH:3]=1
Reactant: OC(CCCCl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Brc1ccc(C2CCCO2)cc1
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a solution of 1-(4-bromophenyl)-4-chlorobutan-1-ol (1.0 g, 3.8 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (110 mg, 4.56 mmol) at 0° C. After being stirred for 2 hours, the reaction mixture was quenched with water, brought to pH=6 with 1M HCl aqueous, and extracted with ethyl acetate. The organic was washed with brine, dried over sodium sulfate, filtered and concentrated to give the target compound (910 mg, 100%) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)C.[OH-].[Na+]>CO>[Cl:15][C:11]1[CH:10]=[C:9]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:23])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Yield: 92.7 %

Procedure:
(E)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid ethyl ester (10.5 g) in methanol (30 mL) was treated with 2N sodium hydroxide solution (20 mL) and the mixture was heated at reflux for 15 minutes. The crude solid, obtained from the usual work up, was crystallized from dichloromethane-hexane to furnish 8.95 g of (E)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid, mp 167°-168° C. Recrystallization from ether-hexane gave the analytical specimen, mp 167°-168° C. Anal. Calculated for C17H12Cl2O2 : C, 63.97; H, 3.79; Cl, 22.21 Found: C, 63.93; H, 3.77; Cl, 22.25.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([NH:10]C(=O)C(C)(C)C)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([C:4]2[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Nc1cccc(C2CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1cccc(C2CC2)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a solution of N-(6-cyclopropylpyridin-2-yl)pivalamide (4.25 gm, 19.49 mmol) in dioxane (34 ml) was added 9N HCl (34 ml). The mixture was stirred for 18 hours at 90° C. After cooling to 25° C., the pH of the reaction was adjusted with to achieve pH-9. The solution was diluted with ethyl acetate (200 ml) quantity and washed with saturated sodium bicarbonate. Next, the organic portion was dried over sodium sulfate and concentrated to get 2 gm (77.5% yield) clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:13].[Cl:14][C:15]1[CH:16]=[C:17]([NH:25][C:26](OC2C=CC=CC=2)=[O:27])[C:18](=[CH:23][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([S:9]([NH:12][C:26]([NH:25][C:17]2[CH:16]=[C:15]([Cl:14])[CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[O:27])(=[O:11])=[O:10])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1c(Cl)cc(S(N)(=O)=O)cc1Cl
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1cc(Cl)c(N)c(Cl)c1
Yield: 45.4 %

Procedure:
1.06 g (4.40 mmol) of 4-amino-3,5-dichlorobenzenesulfonamide and 1.34 g (4.40 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as Example 1 to obtain 905 mg (yield 44%) of methyl 2-{[(4-amino-3,5-dichlorobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (5 ppm, DMSO-d6): 3.87 (3H, s), 6.59 (2H, br), 7.–22 (1H, dd), 7.72 (2H, s), 7.93 (1H, d), 8.24 (1H, d), 10.17 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[NH2:17][C:18]([NH2:20])=[S:19].O>C(O)C>[NH2:20][C:18]1[S:19][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:3]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][CH:2]=2)[N:17]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1Cl
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1ccc(F)cc1
Yield: 75.8 %

Procedure:
A mixture of 10.5 g (0.05 mole) of ethyl p-fluorobenzoylacetate, 6.7 g (0.05 mole) of sulfuryl chloride and 30 ml. of chloroform was held at reflux for 18 hours and cooled. The chloroform solution was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 10.8 g (88%) of ethyl 2-chloro-(p-fluoro)-benzoylacetate as an oil. A mixture of 10.8 g (0.441 mole) of ethyl 2-chloro-(p-fluoro)-benzoylacetate, 3.36 g (0.0441 mole) of thiourea, 20 ml. of water and 10 ml. of ethanol was held at reflux for 3 hours. Ethanol was removed under reduced pressure. The residue was made basic with saturated sodium bicarbonate. The solid was filtered, washed with water and recrystallized from ethanol to give 8.9 g (76%) of ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate as white prisms, m.p. 205°-208° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21](O)=[O:22])=[CH:10][CH:9]=2)=[O:4].O.Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH2:21][OH:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(CO)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a solution of 2-benzyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid 3-methyl ester (300 mg) in THF (3 ml) was added dropwise a solution (1M, 1.5 ml) of borane complex in THF under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 4 hrs. To the reaction mixture was further added dropwise a solution (1M, 3 ml) of borane complex in THF at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added water and 10% hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (280 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12](O)=[O:13])=[CH:8][O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([Cl:18])=[O:13])=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1coc2cc(O)ccc2c1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1coc2cc(O)ccc2c1=O

Procedure:
In accordance with the procedure described in Example 5-a), 7-hydroxychromone-3-carboxylic acid (206 mg, 1 mmol) was treated with thionyl chloride (0.3 ml, 4.1 mmol) to obtain 7-hydroxychromone-3-carbonyl chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)=[CH:12]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[NH:25][CH:24]=[CH:23][N:22]=3)=[CH:12]2)=[CH:26][CH:27]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Cn2cc(Cc3ncc[nH]3)c3ccccc32)cc1
Yield: 53.9 %

Procedure:
1-(4-Ethoxycarbonylbenzyl)-3-(1-imidazolylmethyl)indole (1.53 g) was dissolved in ethanol (25 ml) and a solution of sodium hydroxide (0.2 g) in water (5 ml) was added. The solution was heated under reflux for 2 hours and then evaporated. The residue was taken up in water and the solution was just acidified with acetic acid. A gummy precipitate was formed which solidified on scratching. The solid was filtered off, washed with water and crystallised from ethanol to give 1-(4-carboxybenzyl)-3-(1-imidazolylmethyl)indole (0.76 g), m.p. 234°-235° C. Found: C, 72.32; H, 4.96; N, 12.67. C20H17N3O2 requires: C, 72.49; H, 5.17; N, 12.68.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([CH3:28])=[C:21]([CH:9]([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:10][CH2:11][NH:12][CH3:13])[CH:26]=1
Reactant: COC(=O)NCCOC(CCN(C)C(=O)OC(C)(C)C)c1cc(Cl)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCC(OCCNC(=O)OC)c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 143.8 %

Procedure:
tert-butyl 3-(2-(methoxycarbonyl)aminoethoxy)-3-(2-methyl-5-chlorophenyl)propyl(methyl)carbamate (110 mg) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to afford methyl 2-(1-(5-chloro-2-methylphenyl)-3-(methylamino)propoxy)ethylcarbamate (120 mg, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:12][CH2:11][CH2:10][C:9]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]=[CH:6][C:5]1=2.C([O-])([O-])=O.[K+].[K+].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CN(C=O)C.C(OCC)(=O)C>[N:25]1([CH2:2][CH2:3][CH:4]2[CH2:12][CH2:11][CH2:10][C:9]3[N:8]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:7]=[CH:6][C:5]2=3)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: ClCCC1CCCc2c1cnn2-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(-n2ncc3c2CCCC3CCN2CCOCC2)cc1
Yield: 75.9 %

Procedure:
A mixture of 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazole (423 mg, 1.62 mmol), K2CO3 (336 mg, 2.43 mmol), morpholin (0.42 mL, 4.87 mmol) and a catalytic amount of KI in 20 mL of DMF is heated to reflux during 18 hours. The solvent is eliminated at reduced pressure, the crude is diluted with ethyl acetate, washed with water, and the organic phase is evaporated at reduced pressure. The resultant crude is purified by chromatography on silica-gel to obtain 4,5,6,7-tetrahydro-4-(2-(morpholin-4-yl)ethyl)-1-phenyl-1H-indazole (384 mg, 1.23 mmol, 76%, oil)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:22][CH:19]3[CH2:21][CH2:20]3)[C:10]=2[N:11]=1
Reactant: NC1CC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(NC3CC3)c2n1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclopropanamine (0.038 ml, 0.550 mmol), PdCl2(dppf)-CH2Cl2Adduct (4.08 mg, 5.00 μmol) and sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give 6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine (0.060 g, 54%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 0.76-0.79 (2H, m), 0.99-1.03 (2H, m), 3.02-3.06 (1H, m), 7.12 (1H, brs), 7.61-7.63 (1H, m), 8.04-8.07 (1H, m), 8.73 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(CNC(=O)C2CC2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(CNC(=O)C2CC2)ccc1Cl
Yield: 52.6 %

Procedure:
To a solution of methyl 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoate (10.0 g, 30 mmol) in THF: methanol (10:20 mL) was added aqueous solution of NaOH (6.0 g, 140 mmol). The reaction mixture was refluxed for 3-5 h. The reaction mixture was concentrated, diluted with water and acidified with dilute HCl. The reaction mixture was extracted with 10% MeOH:DCM and concentrated to afford 4.0 g of desired product. 1H NMR (300 MHz, DMSO de): δ 0.67 (m, 4H), 1.59 (m, 1H), 4.28 (d, J=6.0 Hz, 2H), 7.37-7.50 (m, 2H), 7.65 (s, 1H), 8.64 (m, 1H), 13.40 (br s, 1H).