Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[O:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:13]([OH:12])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(F)c1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)(CC(=O)c1cccc(F)c1F)C(=O)OCC

Procedure:
2′,3′-Difluoroacetophenone (10.23 g, 65.6 mmol) and diethyl ketomalonate (15 mL, 98.4 mmol) were stirred at 140° C. for 48 hours. The crude mixture was diluted with toluene and purified by chromatography on silica gel, eluting with 20% v/v ethyl acetate in hexane to afford the title compound as an oil.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[CH:11]=[C:10]3[N:13]([CH3:20])[C:14](=[O:19])[CH:15]=[C:16]([O:17]C)[C:9]3=[CH:8][C:7]=2[NH:6][CH2:5][CH2:4]1)[CH3:2].Cl.C([O-])(=O)C.[Na+]>>[CH2:1]([CH:3]1[C:12]2[CH:11]=[C:10]3[N:13]([CH3:20])[C:14](=[O:19])[CH:15]=[C:16]([OH:17])[C:9]3=[CH:8][C:7]=2[NH:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCNc2cc3c(OC)cc(=O)n(C)c3cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCC1CCNc2cc3c(O)cc(=O)n(C)c3cc21

Procedure:
0.5 g (1.8 mmol) of 9-ethyl-4-methoxy-1-methyl-6,7,8,9-tetrahydropyrido[2,3-g]quinol-2-one in 5 ml of 10% strength hydrochloric acid is heated to reflux for 2 h. The suspension is neutralized to pH 5 using 10% strength sodium acetate solution. The precipitate is filtered off with suction and dried in a desiccator.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:5]=[C:4]2[NH:29][CH:30]=[N:31][C:3]=12.[CH3:32][NH2:33]>>[CH3:32][NH:33][C:7]([C:6]1[C:11]([NH:10][C:9]([C:12]2[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:16]=2)=[O:8])=[C:2]([Cl:1])[C:3]2[N:31]=[CH:30][NH:29][C:4]=2[CH:5]=1)=[O:28]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nc[nH]c3cc12
Reactant: CN
Product: CNC(=O)c1cc2[nH]cnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Yield: 26 %

Procedure:
See example H3 using 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1H-7-oxa-1,3,5-triaza-cyclopenta[b]naphthalen-8-one as starting material and 3 equivalents of methylamine (40% in H2O). A white solid is obtained within 26% yield. m.p.: 190-192° C.; LC/MS: 498/500 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[N+:11]([O-])([O-:13])=[O:12].[K+].C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c(cc1Br)CCN2
Temperature: 5 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
To a solution of 5-bromo-2,3-dihydro-1H-indole (45 g, 0.227 mol) in H2SO4 (98%, 200 mL) was slowly added KNO3 (23.5 g, 0.23 mol) at 0° C. After addition, the mixture was stirred at 0-10° C. for 4 h, carefully poured into ice, basified with Na2CO3 to pH 8 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-bromo-6-nitro-2,3-dihydro-1H-indole (42 g, 76%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[SH:7].Cl.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[N:24]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]2[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]=[C:20]2[NH:19][CH:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][S:7][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:18][CH2:17]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Reactant: Sc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(Cn2c(NC3CCN(CCSc4ncccn4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.8 %

Procedure:
A mixture of 1.12 parts of 2-pyrimidinethiol, 4.6 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine dihydrochloride, 4 parts of potassium carbonate and 80 parts of 2-propanone was stirred for 3 days at room temperature. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'oxybispropane, yielding 1.7 parts (35.8%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyrimidinylthio)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 146.1°-147.7° C. (compound 91).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)(=[O:13])[CH3:12]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of 5-aminoindane (2.0 g, 15.0 mmol) in 5 mL of anhydrous pyridine at 0° C. was added acetic anhydride (2.1 mL, 22.5 mmol) and the solution was stirred at rt for 3 h. The solution was then added to 50 mL of water and the resulting solid filtered and washed with water, then dried under vacuum to yield the title compound (2.23 g, 78%). 1H NMR (CDCl3): 7.44 (s, 1H), 7.2 (bs, 1H), 7.12 (s, 2H), 2.88 (q, 4H), 2.18 (s, 3H), 2.09 (p, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][C:12]3=[N:13][O:14][N:15]=[C:11]3[CH:10]=2)O1.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH:25]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:24][CH2:23]2.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:13]1[O:14][N:15]=[C:11]2[CH:10]=[C:9]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[CH:25]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:24][CH2:23]4)[CH:17]=[CH:16][C:12]=12
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCc2cc(Oc3ccc4nonc4c3)ccc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (0.313 mmol, 77 mg), N-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (0.157 mmol, 40 mg), copper (II)acetate (0.157 mmol, 28.5 mg), triethylamine (0.783 mmol, 0.110 mL, 79 mg) and 4A molecular sieves (100 mg) in DCM (1 mL) was stirred at room temperature for 60 h. The reaction mixture was filtered through dicalite and the pad washed with MeOH before the filtrate was concentrated to dryness. The residue was purified by prep HPLC to give a brown film (32. mg, 5.5%). MS (ESI): m/z [M+H]+ 374.0
Reaction SMILES: [CH:1](=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[OH:14]O>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(O)C>[CH3:2][CH:1]1[O:14][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: OO
Reactant: CC=C(C(=O)OCC)C(=O)OCC
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)OC1C
Temperature: 80 °C
Yield: 74.1 %

Procedure:
A mixture of 50 grams (0.27 mole) of diethyl ethylidenemalonate, 455 grams (4.02 moles) of 30% hydrogen peroxide, 17.6 gram (0.053 mole) of sodium tungstate dihydrate and 400 milliliters of ethanol was stirred and heated at 80° C. for one hour, cooled to room temperature and stirred for an additional hour. Ethanol was removed under reduced pressure and the produce extracted into dichloromethane (3×200 milliliters), the extract then water-washed, dried (MgSO4), filtered and solvent removed to give the crude product. Vacuum distillation gave 40.45 grams (0.20 mole) of diethyl 3-methyloxirane-2,2-dicarboxylate having a boiling point of 120° C. at 4millimeters of Hg.
Reaction SMILES: [CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[N:11]=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5]1)[C:2]#[CH:3].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[N:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]1[S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23])[C:2]#[CH:3]
Reactant: C#CC[C@H]1Nc2cccnc2NC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: C#CC[C@@H]1C(=O)Nc2ncccc2N1S(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of (R)-2-(prop-2-ynyl)-1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-one (150 mg, 0.8 mmol) (300 mg of crude from last step) and 4-methylbenzene-1-sulfonyl chloride (229 mg, 1.20 mmol) in pyridine (3 mL) was stirred at room temperature for 3 h. The reaction mixture was treated with 10 % HCl (5 mL) and extracted with ethyl acetate, dried over Na2SO4 and evaporated. Flash chromatography (SiO2, DCM to DCM/ethyl acetate=4:1 to 3:1 to 2:1 to 1:1) gave the title compound as a white solid.
Reaction SMILES: [Na].[Br-].[N+](C1C=CC(C[N+:11]2[CH:32]=[CH:31][C:14]3=[C:15]([C:27]([O:29][CH3:30])=[O:28])[C:16]4[NH:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=5[C:24]=4[C:25]([CH3:26])=[C:13]3[CH:12]=2)=CC=1)([O-])=O.N(C1C=CC(N(C)C)=CC=1)=O.C(Cl)(Cl)Cl>CO>[C:27]([C:15]1[C:16]2[NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]=2[C:25]([CH3:26])=[C:13]2[CH:12]=[N:11][CH:32]=[CH:31][C:14]=12)([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1c2cc[n+](Cc3ccc([N+](=O)[O-])cc3)cc2c(C)c2c1[nH]c1ccccc12
Agent: CN(C)c1ccc(N=O)cc1
Agent: [Br-]
Agent: [Na]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c2ccncc2c(C)c2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 200 mg (13 mmol) of metallic sodium in 600 mL of dry MeOH there were added 2.70 g (5.3 mmol) of the quaternary salt 22, 1.06 g (6.3 mmol) of p-nitrosodimethylaniline, and 300 mL of dry CHCl3. The suspension was stirred overnight at room temperature in a nitrogen atmosphere and then evaporated to dryness. The residue was suspended in a solution of 30 mL of CHCl3 and 5 mL of MeOH and flash chromatographed on a column of 40 g of silica gel with ether-triethylamine (20:1) as the eluant. The purest fraction was set aside and the less pure material was rechromatographed. The process was repeated, and the purest fractions which showed essentially only one spot on TLC were combined; wt 715 mg (47%). After crystallization from EtOAc-CH2Cl2 (5:1), the yellow needles melted at 203°-204° C. dec: NMR (Me2SO-d6) 11.56 (s, 1 H), 9.73 (s, 1 H), 8.87 (d, 1 H), 8.53 (d, 1 H), 8.38 (d, 1 H), 7.80 (d, 1 H), 7.60-7.52 (m, 1 H), 7.30-7.29 (m, 1 H), 4.10 (s, 3 H), 3.33 (s, 3 H); IR (KBr) 3300, 2950, 1675, 1600, 1465 cm-1.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].Cl[CH2:9][CH:10]=O.C(=O)=O>N1C=CC=CC=1>[CH3:2][C:1]1[O:3][CH:9]=[CH:10][C:4]=1[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)CC(C)=O
Reactant: O=CCCl
Agent: O=C=O
Solvent: c1ccncc1
Product: CC(=O)c1ccoc1C
Reaction time: 4.5 h

Procedure:
To 100.12 g acetylacetone, 44 g dolomite powder and 4 ml pyridine (5 mol%) are added as described in example 1, whereafter 174.4 g 45% aqueous chloracetaldehyde solution is added, with stirring. Stirring is continued at 70° C. for 4.5 hours, and then another hour at 75° C. The CO2 -volume generated is 10.8 liter at room temperature. Workup occurs as in example 1. A fraction is collected at temperatures from 59°-61° C. at 11 torr; it amounts to 93.56 corresponding to 75.5% of the theoretical.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](Cl)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[C:4]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)=[O:21])=[CH:16][CH:15]=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Yield: 80.8 %

Procedure:
(2-(4-(3-Chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy)propionic acid chloride hydrochloride (0.8 g) and 4-aminobenzene sulfonamide (0.5 g) were dissolved in dry tetrahydrofuran (20 ml), and the solution was stirred, with an addition of triethylamine (0.6 ml) at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure, the residue was dissolved in methylene chloride and washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous sodium chloride After drying over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under a reduced pressure was purified by medium pressure column chromatography by using silica gel, to obtain the title compound (0.8 g).
Reaction SMILES: [CH3:1][C@@:2]1([C:17]([O:19][CH3:20])=[O:18])[CH2:6][C:5]([CH3:8])([CH3:7])[C:4](=O)[N:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Li+].[B-](CC)(CC)CC.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C1COCC1>[CH3:1][C@@:2]1([C:17]([O:19][CH3:20])=[O:18])[CH2:6][C:5]([CH3:7])([CH3:8])[CH2:4][N:3]1[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11]
Reactant: COC(=O)[C@]1(C)CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Agent: CC[B-](CC)CC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a stirred solution of (S)-1-tert-butyl 2-methyl 2,4,4-trimethyl-5-oxopyrrolidine-1,2-dicarboxylate 106C (13.96 g, 48.9 mmol) in THF (100 mL) was added Super-hydride (lithium triethylboro-hydride) (58.7 mL, 58.7 mmol) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 2 h and quenched with saturated NaHCO3 at −78° C. The reaction mixture was warmed to 0° C. and hydrogen peroxide (15 ml) was added drop-wise at 0° C. The mixture was stirred at 0° C. for 30 min and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4. After concentration, the crude product was used for the next step without purification. To a stirred solution of the crude product obtained above in CH2Cl2, was added half of triethylsilane (17.19 mL., 108 mmol) and half of BF3.OEt2 (13.64 mL., 108 mmol) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 h, then the remaining triethylsilane (17.19 mL., 108 mmol) and BF3.OEt2 (13.64 mL, 108 mmol) were added. The reaction mixture was stirred at −78° C. for 2 h and quenched with saturated NaHCO3 solution. The reaction mixture was extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over Na2SO4. The crude product was purified by Biotage (0-30% EtOAc/Hexane, 1.5 L) to give (S)-1-tert-butyl 2-methyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylate 106D (10 g, 75%) as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[N:29][NH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@H]1CCCC[C@@H]1NC>O1CCOCC1.[Cu]I>[Cl:26][C:27]1[CH:28]=[N:29][N:30]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH:31]=1
Reactant: Clc1cn[nH]c1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N3CCc4ccc(-n5cc(Cl)cn5)cc4C3)nc(N)n2)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (20 mg, 0.05 mmol, Example 1), 4-chloro-1H-pyrazole (6.1 mg, 0.060 mmol, Astatech, Cat. No. 64527) in 1,4-dioxane (1 mL), potassium carbonate (14 mg, 0.10 mmol), (1S,2S)-N,N′-dimethylcyclohexane-1,2-diamine (1.4 mg, 0.0099 mmol, Aldrich, Cat. No. 633089), and Copper(I) iodide (0.94 mg, 0.0050 mmol, Aldrich, Cat. No. 215554) were added. The mixture was degassed with nitrogen and heated at 120° C. overnight. The reaction mixture was concentrated. The residue was dissolved in MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS(M+H)+: m/z=425.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]([C:14]([NH2:16])=[O:15])[C:11]([NH2:13])=[O:12].Br.Br.[O:19]1[CH2:25][CH2:24]NN[CH2:21][CH2:20]1.C(N(CC)CC)C.Cl>C1(C)C(C)=CC=CC=1>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:10]1[C:11](=[O:12])[N:13]2[CH2:21][CH2:20][O:19][CH2:25][CH2:24][N:16]2[C:14]1=[O:15]
Reactant: Cc1cc(C)c(C(C(N)=O)C(N)=O)c(C)c1
Reactant: C1COCCNN1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Cc1cc(C)c(C2C(=O)N3CCOCCN3C2=O)c(C)c1
Temperature: 22 °C

Procedure:
A solution of 1.5 g (0.0068 mol) of 2,4,6-trimethylphenylmalonic acid diamide, 2.16 g (0.0082 mol) of [1,4,5]oxadiazepane dihydrobromide and 2.93 g (0.029 mol) of triethylamine. in 50 ml of xylene is heated for two hours at reflux temperature in a nitrogen atmosphere. The suspension formed is cooled to 22° C., stirred with 1N hydrochloric acid and filtered. The crystalline residue is washed with water and then with diethyl ether and dried in vacuo at 60° C. The desired title compound has a melting point of 248-250° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2csc(N)n2)CC1
Yield: 74.8 %

Procedure:
A solution of Boc-piperazine (4.67 g), 2-amino-4-chloromethylthiazole hydrochloride (WO 0190090; 5.1 g) and potassium carbonate (8.4 g) in DMF (100 ml) was mixed at 65° C. for 12 hours. The precipitated insolubles were filtered off, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column to obtain the title compound as a brown solid (5.6 g, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:30](O)[CH3:31]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:30][CH3:31])=[O:16])=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(CCCc2ccccc2Br)cc1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CCCc2ccccc2Br)cc1
Reaction time: 40 h

Procedure:
To a solution of 4-[3-(2-bromophenyl)propyl]benzoic acid (2.0 g) in a mixture of chloroform (50 ml) and ethanol (50 ml) was added dropwise, with stirring, concentrated sulphuric acid (98% w/v, 5.0 ml) and the resulting solution allowed to stand for 40 hours at 20° C. The solution was poured onto a stirred mixture of chloroform (100 ml) and saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated to give ethyl 4-[3-(2-bromophenyl)propyl)benzoate (2.3 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[H-].[Na+].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)([O-:20])=[O:19].O>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2ncn(Cc3cccc([N+](=O)[O-])c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
An ice-cold solution of 6-(2-furyl)1H-purine-2-amine (201 mg, 1 mmol) in DMF (6 mL) was treated with NaH (44 mg, 1.1 mmol), stirred for 30 min, treated with 3-nitrobenzyl bromide (238 mg, 1.1 mmol), stirred at room temperature for 3 h, treated with water and the resulting solid filtered, suspended in methanol, stilled for 30 min, and filtered to give the title compound (201 mg, 60%) as a yellow solid.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].P(C#N)(OCC)(OCC)=O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:19]([O:20][CH3:21])[CH3:18])=[O:16])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Reactant: CNOC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CON(C)C(=O)c1cc2c(O)cccc2s1
Yield: 89.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 16 using 4-(methoxymethyloxy)benzo(b)thiophene-2-carboxylic acid (4.5 g), N,O-dimethylhydroxylamine hydrochloride (2.1 g) and diethyl cyanophosphate (3.2 g), 4-hydroxy-N-methoxy-N-methylbenzo(b)thiophene-2-carboxamide (4.0 g) was obtained as a brown oil. By the reactions in the same manner as in Starting Material Synthesis Example 1 using the brown oil (2.0 g) and (S)-glycidyl nosylate (2.0 g), the title compound (1.1 g) was obtained as brown crystals.
Reaction SMILES: [ClH:1].Cl.C([O:5][C:6]([C:8]1([CH2:22][O:23][C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:34](=[NH:36])[NH2:35])[CH2:31]3)=[CH:26][CH:25]=2)[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])C.Cl>>[ClH:1].[ClH:1].[C:34]([N:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][C:24]([O:23][CH2:22][C:8]3([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][N:11]([C:14]4[CH:15]=[C:16]([CH3:21])[N:17]=[C:18]([CH3:20])[CH:19]=4)[CH2:12][CH2:13]3)=[CH:25][CH:26]=2)[CH2:31]1)(=[NH:35])[NH2:36]
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=N)N)CC3)CCN(c2cc(C)nc(C)c2)CC1
Agent: Cl
Product: Cc1cc(N2CCC(COc3ccc4c(c3)CN(C(=N)N)CC4)(C(=O)O)CC2)cc(C)n1
Yield: 188.7 %

Procedure:
To 4-(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)-1-(2,6-dimethylpyridin-4-yl)piperidine-4-carboxylic acid ethyl ester dihydrochloride (85 mg) was added 6N hydrochloric acid, and the mixture was stirred under reflux for 3 hours. After completion of the reaction, insoluble material was removed and the solvent was evaporated. The obtained residue was washed with diethyl ether and dried under reduced pressure to give the title compound (76 mg).