Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccccc2)CCN(C)C1
Reaction time: 8 h
Yield: 3.1 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 5 mmol) was dissolved in NMP (1 mL). KOH (280 mg, 5 mmol) was then added to it, followed by addition of 2-bromoacetophenone (208 mg, 1 mmol). The reaction was kept overnight at RT and was monitored by TLC and LC/MS. The reaction was quenched by adding water, and the compound extracted using EtOAc, which was washed with water (2-3×). The organic layer was dried over sodium sulfate and then concentrated to yield 10 mg of dark brown crude oil, which was then purified by column chromatography using 100-200 mesh silica in 5% MeOH:DCM. 1HNMR (CD3OD, TFA salt) d (ppm): 8.15 (m, 1H), 7.70 (m, 1H), 7.60 (m, 2H), 7.28 (d, 1H), 7.20 (m, 1H), 7.0 (m, 1H), 5.80 (m, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 4.20 (m, 1H), 3.80 (m, 1H), 3.60 (m, 2H), 3.10 (s, 1H), 2.40 (s, 3H), 2.30 (m, 1H), 2.0 (m, 1H), 1.80 (m, 1H).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1>C(#N)C>[S:1]([O:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: OCCc1ccccc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Product: NS(=O)(=O)OCCc1ccccc1
Yield: 68 %

Procedure:
The sulfamoyl chloride in acetonitrile solution prepared in (a) was reacted as in Example 12 with 12.2 g (0.1 mole) of β-phenethyl alcohol using 40.4 g (0.4 mole) triethylamine in 100 ml additional acetonitrile followed by using extracting, washing and concentration procedures of Example 12 through the first evaporation. The crude oily residue was purified by chromatography (10×80 cm glass column; 700 g silica gel; eluents methylene chloride followed by 10:1 methylene chloride/acetone). Fractions containing the title compound were combined and solvents evaporated under reduced pressure to give 13.6 g (68% yield) of title compound as light-yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C(C)C
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (1.25 g) and 37% formalin (0.83 mL) in the same manner as in Example 1 was dissolved in chloroform (7 mL), and triethylamine (1.25 mL) and 3-cyano-5-isopropyl-4-methoxybenzoyl chloride (710 mg) were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (1.02 g) as a yellow oily substance.
Reaction SMILES: [C:1]1([CH:7]([NH2:15])[CH2:8][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.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)Cl.O>[C:23]([NH:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NC(Cc1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To a stirred two phase solution of 1,2-diphenylethylamine (30.0 g, 0.15 mol) in 300 ml of methylene chloride and 500 ml of water was added sodium carbonate (23.9 g, 0.225 mol) and the solution was cooled to 10° C. under nitrogen. Ethyl chloroformate (21.5 ml, 0.225 mol) was added dropwise over a 1 hour period. The reaction was warmed to ambient temperature and stirred at that temperature for 3 hours. The phases were separated and the aqueous phase was extracted with methylene chloride (75 ml). The combined methylene chloride extracts were washed with 1N HCl (200 ml), dried and evaporated to a white solid, 40.3 g. Recrystallization from cyclohexane gave N-carboethoxy-1,2-diphenylethylamine, mp 74°-75° C.
Reaction SMILES: [CH3:1][O:2][C:3]([O:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[CH2:4][CH2:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1.[CH:34](N(C(C)C)CC)([CH3:36])[CH3:35].ICCC>C(O)(C)C.C(OCC)(=O)C>[CH2:35]([N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])([O:32][CH3:33])[C:28]([F:30])([F:31])[F:29])=[CH:27][CH:26]=1)[CH2:34][CH3:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCCCCCCCCCNCCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Solvent: CC(C)O
Solvent: CCCI
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN(CCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A solution of N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]dodecylamine (500 mg, 1.05 mmol), diisopropyl ethylamine (0.35 ml, 2.1 mmol) and 1-iodopropane (0.26 ml, 2.66 mmol) in isopropanol was heated to reflux for 21 h. After cooling to r.t., the mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed on silica gel (dichloromethane/methanol 98:2 to 95:5) to afford the title compound (0.526 g, 73%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:26]=2)[C:22]([NH:24][NH2:25])=[O:23])=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:36](=O)[C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])[O-].[K+].[K+].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:10][C:11]([C:17]2[CH:26]=[C:21]([C:22]4[O:23][C:36]([C:37]([O:39][CH3:40])=[O:38])=[N:25][N:24]=4)[CH:20]=[N:19][CH:18]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Reactant: COC(=O)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1nnc(-c2cncc(-c3nc(NCc4ccccn4)c4c(-c5ccccc5)cccc4n3)c2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
To a solution of 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinohydrazide (from Example 185, 0.30 g, 0.66 mmol) in DCM at 0° C. was added methyl 2-chloro-2-oxoacetate (0.062 mL, 0.66 mmol) and potassium carbonate (0.273 g, 1.90 mmol). Upon completion of addition, the mixture was stirred at RT for 16 h. After this time, water was added and the mixture was extracted into DCM, dried and concentrated. The resulting residue was dissolved in DCM. Triflic anhydride (0.187 mL, 1.1 mmol) and pyridine (0.149 mL, 1.8 mmol) were added and the resulting mixture was stirred at RT for 16 h. At the conclusion of this period, the reaction mixture was quenched with water and extracted with DCM (100 mL). The DCM layer was washed with water and brine. Chromatographic purification provided methyl 5-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate (270 mg, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.81 (s, 1H), 9.17 (s, 1H), 9.09 (s, 1H), 8.24 (d, J=4.4 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.75-7.72 (t, J=7.6 Hz, 3H), 7.59-7.51 (m, 5H), 7.34 (d, J=7.2 Hz, 2H), 7.24 (t, J=6.4 Hz, 1H), 6.98 (t, J=3.2 Hz, 1H), 4.77 (d, J=4.0 Hz, 2H). LCMS Method Q: retention time 1.39 min; [M+1]=514.5; HPLC Method B: purity 98.1%, retention time=8.74 min.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([CH3:14])[C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)c(F)c(F)c1C(=O)Cl
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of 8.2 g (39.4 mmol) of 2,3,4,5-tetrafluoro-6-methylbenzoic acid, 6.0 g (47.2 mmol) of oxalyl chloride, and 100 ml of dichloromethane was treated with three drops of DMF. The solution was stirred for three hours, then concentrated to give 8.8 g of the title compound as a yellow liquid. The product was used as is in the next step.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(Nc2ccccc2)c2ccccc2c1O

Procedure:
A mixture of 1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (810 mg, 2.5 mmol, Example D-28 a) and aniline (3 ml) was stirred in a pressure tube in a microwave oven at 150° C. for 20 min. The reaction was repeated on the same scale. Both reaction mixtures were combined, EtOAc (100 ml) was added and the mixture was washed with H2O (5×30 ml, pH=1-2). The organic phase was dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using hexanes/EtOAc as the eluent to give 770 mg of 4-hydroxy-1-phenylamino-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=337.21.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][C:5]=2[N:4]=[CH:3]1.[OH-].[Na+].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: CCOC(=O)c1ccc2c(c1)ncn2C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CC(C)O
Product: Cn1cnc2cc(C(=O)O)ccc21
Yield: 86.2 %

Procedure:
Ethyl 1-methyl-1H-benzimidazole-5-carboxylate (800 mg, 3.92 mmol) prepared in the Step 1-1-4 was suspended in 2-propanol (10 ml), and a 1 mol/L sodium hydroxide aqueous solution (10 ml) was added thereto. The mixture was heated under reflux for one hour. After being allowed to cool, the mixture was neutralized with 1 mol/L hydrochloric acid. The resulting mixture was then acidified with citric acid, separated by filtration, and washed with a small quantity of water. Then, the resulting product was subjected to through circulation drying overnight to give the title compound (595 mg, 86%) as a gray powder.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[C:26]([Br:32])[C:25]=1[Cl:33]>>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[C:26]([Br:32])[C:25]=1[Cl:33])[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: Clc1c(Br)cc(CBr)cc1Br
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Br)c(Cl)c(Br)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (100 mg, 0.306 mmol; Example 1, Step 2) and 1,3-dibromo-5-(bromomethyl)-2-chlorobenzene (122 mg, 0.337 mmol) following essentially the same procedure described in Step 1 of Example 7-9. The title compound was obtained as a white solid (175 mg) and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[Br:23][C:20]1[CH:21]=[CH:22][C:2]2[N:1]=[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2cc(Br)ccc2N)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccc(Br)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-5-bromoanilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 8-bromo-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [N:1]([CH:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)[CH3:5])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.Cl>C1COCC1>[NH2:1][CH:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:7]1)[CH3:5]
Reactant: CC(N=[N+]=[N-])C1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)C1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 2.5 h

Procedure:
To a solution of 3-(1-azidoethyl)-1-(benzyloxycarbonyl)piperidine (1.95 g, 6.76 mmol) in THF (30.6 mL) was added Ph3P (2.66 g, 10.14 mmol) followed by water (3.4 mL). The mixture was placed in an oil bath at 50° C. for 2.5 h. The reaction mixture was cooled and carefully poured into an Erlenmeyer flask containing 1N HCl. The layers were separated, and the aqueous layer was washed once with EtOAc and the organic layer was discarded. The aqueous layer was then neutralized with saturated aqueous NaHCO3 carefully and was extracted with EtOAc (3×30 mL) and the organic extracts discarded. The aqueous layer was made strongly basic (>pH 12) with SN NaOH, then it was extracted with EtOAc (4×50 mL). The combined organic extracts were washed with brine and dried over Na2SO4. The title compound (950 mg) was used in the next step without purification. Partial 1H NMR (500 MHz, CDCl3): δ 7.3 (m, 5H); 5.12 (s, 2H); 4.1 (brm, 2H); 1.25 (br s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1.[CH3:16][C:17]1([CH3:27])[C:22](=[O:23])[CH2:21][C:20](=[O:24])[C:19]([CH3:26])([CH3:25])[O:18]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[N:3]=[C:2]([CH:21]3[C:20](=[O:24])[C:19]([CH3:25])([CH3:26])[O:18][C:17]([CH3:27])([CH3:16])[C:22]3=[O:23])[C:7]([CH3:8])=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: Cc1cnc(-c2ccc(Cl)cc2)nc1Cl
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: Cc1cnc(-c2ccc(Cl)cc2)nc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A microwave vial is charged with 4-chloro-2-(4-chlorophenyl)-5-methylpyrimidine (239 mg, 1 mmol), 2,2,6,6-tetramethyl-pyran-3,5-dione (170 mg, 1 mmol), palladium acetate (12 mg, 0.05 mmol), X-Phos (48 mg, 0.1 mmol) and potassium phosphate (424 mg, 2 mmol). 1,2-dimethoxyethane (3 ml) is added and the reaction heated to 150° C., with stirring, for 30 minutes. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 4-[2-(4-chlorophenyl)-5-methylpyrimidin-4-yl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(Cl)(=O)C(Cl)=O.[N:21]1C(C)=CC=[CH:23][C:22]=1[CH3:28].C(N)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](=[O:9])[NH:21][CH:22]([CH3:28])[CH3:23])[N:6]=1
Reactant: Cc1cccc(C)n1
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CCOC(=O)c1sc(Cl)nc1C(=O)NC(C)C
Temperature: 45 °C
Yield: 97.2 %

Procedure:
To a stirred solution of 2-chloro-5 (ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (Intermediate 7, 1.0 g, 4.2 mmol) in dry dichloromethane (20 mL) was added oxalyl chloride (0.73 mL, 8.4 mmol) and 2 drops of dry dimethylformamide. The reaction mixture was refluxed to 45° C. for 1½ h. The reaction mixture was cooled to room temperature, and then evaporated to dryness under reduced pressure. The residue was dissolved in dry dichloromethane (20 mL) and cooled to 0° C., then 2,6-lutidine (0.493 mL, 4.237 mmol) was added followed by addition of isopropyl amine (0.360 mL, 4.237 mmol). After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was extracted with ethyl acetate (2×50 mL). The organic layer was washed with 1 N hydrochloric acid (1×50 mL), then dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.13 g (96%) of the title compound as a thick syrup. NMR: 1.26 (d, 6H), 1.38 (t, 3H), 4.24 (m, 1H), 4.40 (q, 2H), 7.51 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[N:19]=[CH:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH:54]4[CH2:57][O:56][CH2:55]4)[CH2:50][C@@H:49]3[CH3:58])=[CH:44][N:43]=2)[C:27]1=[O:59]>>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:22])[N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:47]=[CH:46][C:45]([N:48]7[CH2:53][CH2:52][N:51]([CH:54]8[CH2:55][O:56][CH2:57]8)[CH2:50][C@@H:49]7[CH3:58])=[CH:44][N:43]=6)[C:27](=[O:59])[N:26]([CH3:25])[CH:31]=5)[CH:7]=[CH:6][N:5]=4)[N:19]=[CH:18][C:17]=3[C:16]=2[CH2:15]1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: CC1(C)Cc2sc3c(=O)n(-c4nccc(Cl)c4C=O)ncc3c2C1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CC(C)(C)C6)c3C=O)cn(C)c2=O)nc1

Procedure:
Following the procedure for preparation in Example 191k, and starting with 282i (216 mg, 0.60 mmol), and (5)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 191j (482 mg, 0.90 mmol), 282j was obtained as a yellow solid (407 mg, 48%). MS-ESI: [M+H]+ 678.8
Reaction SMILES: C(O[C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])C1C=CC=CC=1.[CH3:33][S@@:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:35]>>[CH2:24]([NH:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9](=[O:32])[CH2:33][S@@:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:35])=[O:31])=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc([S@](C)=O)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Product: COc1ccc([S@@](=O)CC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1
Yield: 27.6 %

Procedure:
By the same procedure as in Example 15-D) using N-benzylaminocarbonyl-L-prolyl-L-proline benzyl ester (2.00 g) and (S)-(-)-4-methoxyphenyl methyl sulfoxide (780 mg) as obtained in Example 15-C), there was obtained 629 mg of the title compound as colorless needles (See Table 7).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:14])=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:14])=[C:7]([Cl:15])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1c(N)ccc2cn[nH]c12
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)c(Cl)cc2cn[nH]c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
To a mixture of 1.66 g (8.71 mmol) of 6-amino-1H-indazole-7-carboxylic acid methyl ester in 17 mL of N,N-dimethylformamide, is added 1.21 g (8.71 mmol) of N-chlorosuccinimide. The mixture is stirred during 4 hours at 50° C. and then the solvent is evaporated. The residue is precipitated in ethyl acetate and after filtration and washings with ethyl acetate, 927 mg of a pure white solid are obtained. The filtrate is evaporated and submitted to a flash chromatography which gives an additional 723 mg of the compound. In totality, 1.65 g (84%) of a product are obtained as a white solid; LC/MS:226/228 (M+H)+.
Reaction SMILES: [F:1][C:2]1([C:8]([O:10]CC2C=CC=CC=2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>C(O)C.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)C1(F)CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)C1(F)CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
A mixture of the compound (0.18 g) obtained in step 2 and 20% palladium hydroxide (0.02 g) in ethanol/ethyl acetate (2/1 mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 4 hr. The reaction mixture was filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (0.084 g, 78%) as a gray powder.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.O>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1cc2c(Cl)cccc2c(N2CCSCC2)n1
Reactant: C1CNCCN1
Agent: Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: Clc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 97 %

Procedure:
1-Thiomorpholino-3-piperazino-5-chloro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3,5-dichloro-isoquinoline and piperazine by heating in diphenyl ether at 200°C. M.p. of its hydrochloride: 273°-275°C (from water); yield: 97% of theory.