Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>O1CCOCC1>[Br:8][C:7]1[C:2]([N:9]([C:18](=[O:20])[CH3:19])[NH2:10])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: NN
Reactant: Brc1cccnc1Br
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)N(N)c1ncccc1Br
Temperature: 85 °C
Yield: 28.8 %

Procedure:
To a solution of 0.800 g (3.38 mmol) of 2,3-dibromopyridine in 10 mL of anhydrous 1,4-dioxane was added 0.325 g (10.1 mmol) of anhydrous hydrazine and the resulting mixture was heated to 85° C. for 8 h. The reaction mixture was cooled to ambient temperature then evaporated to dryness in vacuo. The crude residue was dissolved in anhydrous dichloromethane and cooled to −78° C. in a dry ice acetone bath under an atmosphere of nitrogen. Next, 1.0 mL (6.8 mmol) of triethylamine was added followed by 0.210 g (2.72 mmol) of acetyl chloride. The resulting mixture was allowed to warm to ambient temperature over 20 min then all volatiles were removed in vacuo. The residue was suspended in 20 mL of water and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (0.18 g, 23%). LC-MS: m/z (ES) 230, 232 (MH)+and 188, 190 (MH-COCH3)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5]Cl.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16].C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: COC(CCCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 91.3 %

Procedure:
A mixture of 3-methoxy-3-phenyl-1-chloropropane (23.1 mg, 0.126 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90° C. for 72 hrs. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave N-{3-[1-(3-methoxy-3-phenylpropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (45.4 mg, 91.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.45 (S, 1H), 7.34–7.25 (m, 5H), 7.25 (m, 2H), 6.96 (d, 1H, J=7.4 Hz), 4.20 (apparent dd, 1H, J=5.9, 7.6 Hz), 3.2 (s, 3H), 3.04 (d, 1H, J=10.1 Hz), 2.99 (d, 1H, J=10.1 Hz), 2.49 (apparent sept, partially hidden, 4H, J=6.6 Hz), 2.3–2.1 (m, 4H), 1.82 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 395.4 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[N:13]=2)[CH:10]=1)=O.C([Sn](CCCC)(CCCC)[CH:28]=[CH:29][O:30]CC)CCC>>[CH2:29]([O:30][CH:2]=[CH:3][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[N:13]=2)[CH:10]=1)[CH3:28]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: O=C(CBr)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Product: CCOC=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1

Procedure:
This product is obtained under conditions similar to those described in the first step of preparation of Intermediate 9, replacing the tributyl(1-ethoxyvinyl)tin with tributyl(2-ethoxyvinyl)tin.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].CC(O)=O.O(CCCC)CCCC>O.[Fe]>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCCCOCCCC
Solvent: O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCc1ccccc1
Temperature: 80 °C
Yield: 86.8 %

Procedure:
A stirred mixture of 6-methoxy-4-methyl-5-(5-phenylpentoxy)-8-nitroquinoline (9.0 g, 0.024 mole), degreased 40 mesh Fe filings (22.5 g), H2O (90 ml), HOAc (18 ml) and Bu2O (18 ml) was heated at 80° C. for 1 h, cooled, diluted with H2O and filtered. The dark solid was thoroughly extracted with warm Et2O (total, Ca. 500 ml) and the extract was dried (Na2SO4), treated with charcoal and concentrated. The resulting dark brown oil was crystallized from pet ether to give 7.3 g (87%) of 8-Amino-6-methoxy-4-methyl-5-(5-phenylpentoxy) quinoline as yellow green crystals, mp 65°-66° C. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:38](Cl)(=[O:40])[CH3:39]>N1C=CC=CC=1.ClCCl>[C:9]([OH:40])(=[O:8])[CH3:14].[NH2:24][C:22]1[C:23]2[C:15]([C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[C:2]([NH:1][C:38](=[O:40])[CH3:39])[CH:3]=3)=[CH:16][N:17]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH2:27][CH2:26]3)[C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: CC(=O)Cl
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(Oc5ccccc5)c(N)c4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1Oc1ccccc1
Product: CC(=O)O
Temperature: 0 °C

Procedure:
A mixture of trans-5-(3-amino-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (120 mg, 0.241 mmol) in pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0° C. then treatd with acetyl chloride (25 mg, 0.3 mmol). The mixture was warmed to ambient temperature for one hour then the solvents were removed under reduced pressure and the residue purified by preparative RP-HPLC to give trans-N1-(5-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-phenoxyphenyl)acetamide acetate (45 mg, 35%): 1H NMR (DMSO-d6, 400 MHz) δ 9.67 (bs, 1H), 8.11(s, 1H), 8.00(s, 1H), 7.40(t, 3H), 7.17(m, 2H), 7.05(d, 2H), 6.95(d, 1H), 6.30(bs, 2H), 4.55(m, 1H), 2.2-2.6(m, 9H), 2.14(s, 3H), 2.04(s, 3H), 1.8-2.0(m, 6H), 1.89(s, 3H), 1.44(m, 2H); MS MH+540.5; RP-HPLC (Hypersil HS, 5 μm, 1000 A, 4.6×250 mm; 5%-50% acetonitrile—0.05 M ammonium acetate over 25 min, 1 ml/min) tr 20.37 min.
Reaction SMILES: [I-].[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH:16]=[C:15]([CH3:17])[S:14]/[C:13]/3=[N:18]\[C:19]([N:21]3[CH:25]=[CH:24][N+](C)=C3)=[O:20])=[CH:11][C:5]=2[O:4]1.[CH:28](N(C(C)C)CC)(C)C.CC(N)C>C(#N)C>[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH:16]=[C:15]([CH3:17])[S:14]/[C:13]/3=[N:18]\[C:19]([NH:21][CH:25]([CH3:28])[CH3:24])=[O:20])=[CH:11][C:5]=2[O:4]1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Solvent: CC#N
Solvent: CC(C)N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)/c(=N/C(=O)NC(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial, a solution of (Z)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-methylthiazol-2(3H)-ylidenecarbamoyl)-3-methyl-1H-imidazol-3-ium iodide (Example 40B, 48 mg, 0.09 mmol) dissolved in acetonitrile (0.5 mL) was added followed by the addition of diisopropylethylamine (21 μL, 0.12 mmol) dissolved in acetonitrile (0.5 mL). Then, to the solution was added propan-2-amine (5.9 mg, 0.10 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method) to supply the titled compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.07 (6 H) 2.22 (3 H) 3.65-3.83 (1 H) 6.99 (1 H) 7.32 (1 H) 7.43 (1 H) 7.61 (1 H); MS (ESI) m/z 356 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 114.4 %

Procedure:
To a suspension of 6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (655 mg, 1.6 mmol) and (1R,2R)-2-aminocyclohexanol (558 mg, 4.8 mmol) in anhydrous DMA (3.0 mL) was added DIEA (842 μL, 4.8 mmol). The mixture was heated in a sealed tube at 110° C. for 18 h. The mixture was cooled to rt and added dropwise to a stirred solution of water causing a precipitate to form. After stirring for 10 min, the solid was collected by filtration to afford (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (837 mg) as a tan solid. The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.85 (d, J=1.7 Hz, 1H), 7.65 (s, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.26-7.39 (m, 2H), 7.19 (m, 1H), 5.47 (s, 2H), 4.74 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.32 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.13-1.32 (m, 4H); LCMS (ESI) m/z 457, 459 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)(O)[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[CH2:36]([O:35][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:11][CH2:12]2)[CH2:5][CH2:6]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 8 h

Procedure:
Forty-one (41) mg of 1-[1-(piperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.di-trifluoroacetate was dissolved in 5 ml of dichloromethane, and to which 25 mg of diisopropylethylamine and 11 mg of ethyl chloroformate were added, followed by stirring overnight. The reaction mixture was distributed between chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1). Thus 22 mg of the title compound was obtained as a colorless, amorphous substance.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:24])([CH3:23])[CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:24][C:8]([NH2:7])([CH3:23])[CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12]1
Reactant: Cc1cc(-c2ccccc2)nn1CCC(C)(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccccc2)nn1CCC(C)(C)N
Yield: 91.2 %

Procedure:
[1,1-Dimethyl-3-(5-methyl-3-phenyl-pyrazol-1-yl)-propyl]-carbamic acid tert-butyl ester (540 mg) was treated with TFA/CH2Cl2 3:1 (20 ml) at 0° C. for 2 hours. The resulting mixture was concentrated in vacuo and the residue was diluted with ethyl acetate. The organic layer was washed with a mixture of brine/sat. Na2CO3 and brine, dried and evaporated to give a crude oil. This was purified by flash chromatography (5% to 40% gradient of MeOH in CH2Cl2, 0.5% NH4OH content) to give the title compound (349 mg) as a yellow gum.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.CN(C)C=O.[H-].[Na+]>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1oc(-n2ccnc2)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a mixed solution of methyl 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (3.0 g), imidazole (0.82 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.5 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into iced water, and the precipitated crystals were collected by filtration to give methyl 3-[4-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-5-oxazolyl]propionate (1.6 g, yield 80%) as crystals. Recrystallization from methanol gave colorless prism crystals. melting point: 95–96° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:13](N(CC)CC)C.C[Si](C=[N+]=[N-])(C)C>ClCCl.CO.C(#N)C>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: COc1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Yield: 73 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (3.0 g, 17 mmol) and triethyl amine (3.14 mL, 22 mmol) in dichloromethane/methanol/acetonitrile (10:1:10, 168 mL) was treated with (trimethylsilyl)diazomethane (2M solution in hexanes, 10.25 mL, 20.5 mmol). It was stirred over night at room temperature, the solvent was removed under reduced pressure and chromatography on silica gel with hexanes/acetone (1:1) gave 2.2 g (67%) of the product as a colorless solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:26]([NH:28][CH:29]3[CH2:31][CH2:30]3)=[O:27])[CH:19]=2)[C:14]1=[O:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrC1C=C2C(=CC=1)[C:44](=[O:48])NC=C2>CN(C=O)C>[CH2:6]([N:13]1[CH:22]=[C:21]([CH:44]=[O:48])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:26]([NH:28][CH:29]3[CH2:31][CH2:30]3)=[O:27])[CH:19]=2)[C:14]1=[O:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)ccc2c1
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C=O)c2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
DMF (5 mL) was cooled in an ice bath and phosphorus oxychloride (0.11 mL) added. The solution was stirred for 10 minutes. 3-(2-Benzyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide, Example 1 (0.4 g) was then added in one portion and the mixture heated at 80° C. for 6 hours. The mixture was allowed to cool then poured onto ice and stirred for 10 minutes. This was then extracted with ethyl acetate. The organics were combined and evaporated under reduced pressure. The residue was purified (SiO2, 1:1 isohexane/ethyl acetate) to give the sub titled compound (0.15 g).
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:29][C:30]([NH:15][C:14]2[N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:22]=[C:10]3[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 406 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and phenylacetyl chloride.
Reaction SMILES: ClC1C=C2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.C1([NH2:63])CC1>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:63])=[O:50])=[C:33]2[S:53]([NH:7][CH:8]1[CH2:9][CH2:10]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: NC1CC1
Agent: CN
Agent: Cl
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)NC1CC1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with cyclopropylamine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 458.16 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[S:2].[C:13]([O:17][C:18]1C=C([CH:22]=[C:23]([F:25])[CH:24]=1)N)([CH3:16])([CH3:15])[CH3:14]>ClCCl.O>[C:13]([O:17][C:18]1[CH:11]=[C:12]([N:8]=[C:1]=[S:2])[CH:22]=[C:23]([F:25])[CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)Oc1cc(N)cc(F)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Oc1cc(F)cc(N=C=S)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
1,1′-Thiocarbonyldiimidazole (423 g, 2.37 mol) was dissolved in dichloromethane (3200 ml). The mixture was stirred under N2 atmosphere while a solution of 3-tert-butoxy-5-fluoroaniline (435 g, 2.37 mol) in dichloromethane (800 ml) was added slowly within 2 h. Then the mixture was kept stirring at 20° C. for 16 h. The mixture was diluted with water (3000 ml). The separated dichloromethane phase was washed again with water (3000 ml) before dried with anhydrous Na2SO4 for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum to remove solvent to give 1-tert-butoxy-3-fluoro-5-isothiocyanato-benzene (499 g). 1H-NMR (400 MHz, CDCl3): 6.63-6.68 (m, 3H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH2:4][CH2:3]1
Reactant: N#CCCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CN1CCN(CCCC#N)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 25 mL flask was placed 1-methyl-piperazine (0.52 g, 5.1 mmol), 4-bromobutyronitrile (0.78 g, 5.3 mmol) and potassium carbonate (0.71 g, 5.3 mmol) suspended in acetonitrile (5 mL). The reaction mixture was stirred at rt for 4 h., followed by addition of H2O (20 mL) and extraction with ethyl acetate (3×25 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO4) and evaporated to dryness to produce 0.72 g of crude 14 which was used without further purification in the synthesis of compound 15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]([CH3:36])[CH3:35]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1
Reactant: CC(C)CBr
Reactant: O=C(Nc1ccn(Cc2c(O)cccc2Cl)n1)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)COc1cccc(Cl)c1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a solution of N-{1-[(2-chloro-6-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for as preparation see Intermediate 11)(37 mg, 0.102 mmol) in DMF (1 ml) was added potassium carbonate (18 mg, 0.13 mmol) and then 1-bromo-2-methylpropane (0.014 ml, 0.132 mmol, Aldrich). The suspension was stirred at ambient temperature overnight. A further amount of potassium carbonate (7 mg, 0.05 mmol) and then 1-bromo-2-methylpropane (0.014 ml, 0.132 mmol, Aldrich) was added to the suspension. The suspension was stirred at ambient temperature for a further 4 h. The suspension was diluted with methanol (0.5 ml) and then filtered through a cotton wool plug. The filtrate was purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid) (Method A). The solvent was evaporated in vacuo to give the title compound as a colourless gum (4 mg); LCMS: (System 1) MH+=420, tRET=3.63 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:5](O)=[O:6].C([N:20](CC)CC)C.ClC(OCC(C)C)=O.N>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:5]([NH2:20])=[O:6]
Reactant: CN1CCN(c2ccc(C(=O)O)cc2F)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(N)=O)cc2F)CC1
Reaction time: 3 h
Yield: 12 %

Procedure:
To 3-fluoro-4-(4-methylpiperazin-1-yl)benzoic acid (250 mg, 1.05 mmol) in THF (10 ml) was added triethylamine (221 μl, 1.58 mmol) and isobutyl chloroformate (145 μl, 1.10 mmol). The mixture was stirred at 0° C. for 1 hour, at which time concentrated aqueous ammonia (3 ml) was added. The reaction mixture was stirred for 3 hours then the volume was reduced in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated to afford (30.0 mg, 12%) of 3-fluoro-4-(4-methylpiperazin-1-yl)benzamide, which was used without further purification. MS (EI) for C12H16FN3O: 238 (MH+).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCC=O
Product: CCCCN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared from butanal and piperazine-1-carboxylic acid tert-butyl ester.