Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:27])[N:14]([CH3:26])[C:15]([CH2:24][OH:25])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:35][S:36]([O:25][CH2:24][C:15]1[N:14]([CH3:26])[C:13](=[O:27])[C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=[CH:10][C:11]=2[C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(CO)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(COS(C)(=O)=O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A suspension of 1-benzyl-4-(4-chlorophenyl)-5-(hydroxymethyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (4 g, 10.6 mmol) in Dichloromethane (DCM) (50 mL) was treated with Et3N (4.38 mL, 31.5 mmol) and MsCl (1.839 mL, 23.60 mmol) at 0° C. and then stirred for 30 min. The mixture was diluted with Dichloromethane, washed with 0.1N HCl and NaHCO3, dried over Na2SO4, filtered and concentrated to afford (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate as a pale yellow solid (4.8 g, 10.5 mmol, 95% yield) which was used for in next step without any further purification. A solution of (1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl methanesulfonate (4.8 g, 10.5 mmol) in N,N-Dimethylformamide (DMF) (30 mL) was treated with KCN (6.15 g, 94 mmol) and the resultant was stirred at ambient temperature overnight. The mixture was quenched with water and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetonitrile (2.7 g, 7.0 mmol, 67% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.47-7.52 (m, 2H) 7.31-7.35 (m, 3H) 7.27-7.30 (m, 4H) 7.04-7.09 (m, 1H) 5.94-5.98 (m, 1H) 5.83-5.88 (s, 2H) 3.81 (s, 3H) 3.64 (s, 2H); LCMS (m/z) ES+=388 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:15]=2)=[O:10])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1.[CH3:35][Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:18][C:17]([CH3:20])([CH2:19][CH3:35])[CH2:16][C:14]1[N:15]=[C:11]([C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[CH:3][CH:4]=2)[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(Br)cc1
Reactant: C[Sn](C)C
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1

Procedure:
Palladium tetrakis(triphenylphosphine) (107 mg, 0.09 mmol) was added to a degassed, ambient temperature solution of 2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (intermediate 7) (410 mg, 0.9 mmol), 2-bromo-5-fluoropyridine (163 mg, 0.9 mmol) and hexamethylditin (304 mg, 0.9 mmol) in 1,4-dioxane (20 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH:13]N)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1>C(O)(=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:7](=[C:8]([C:9]([OH:11])=[O:10])[CH:12]=1)[NH:13][C:16]1[CH2:17][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20][C:21]2=1
Reactant: NNc1ccc(Br)cc1C(=O)O
Reactant: CCOC(=O)C1CCCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(Br)cc23)C1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A cream colored suspension of 5-bromo-2-hydrazinylbenzoic acid dihydrochloride (6 g, 19.74 mmol) and ethyl 3-oxocyclohexanecarboxylate (3.70 g, 21.71 mmol) in glacial acetic acid, (˜0.4M) (45 mL) was heated at reflux for 4h. The reaction mixture turned in to dark yellow suspension. The reaction mixture was cooled to room temperature and it was concentrated to afford a dark yellow solid. The solid was then suspended in ethyl acetate (˜50 ml) and the solid was filtered, washed with water and ethyl acetate to give 4.14 g of 6-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid. MS (ESI) m/z 366.3 (M+H). 1H NMR (DMSO-d6) δ ppm 13.4-12.3 (b, 1H), 10.99 (s, 1H), 7.79 (d, 1H, J=1.9 Hz) 7.69 (d, 1H, J=1.8 Hz), 4.08-4.17 (m, 2H), 3.05 (dd, 1H, J=16.5, 5.0), 2.97-2.84 (m, 2H), 2.76-2.69 (m, 1H), 2.67-2.59 (m, 1H), 2.19-2.12 (m, 1H), 1.88-1.78 (m, 1H), 1.21 (t, 3H, J=7.2).
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[S:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:22]2[CH2:32][CH:33]=[CH:34][CH:35]=[C:21]2[S:20][CH2:19]1)([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: CCOC(=O)CN1C(=O)C(N)CSc2ccccc21
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CCCCc2ccccc2)OCC)CSC2=CC=CCC21
Reaction time: 0.33 h

Procedure:
A mixture of crude chloro (4-phenylbutyl)phosphinic acid, ethyl ester (2.44 mmole), dry tetrahydrofuran (10 ml.), and (±)-3-amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester (0.65 g., 2.05 mmole) at 0° (ice bath) in an argon atmosphere is treated dropwise with triethylamine (0.86 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over 1 minute. After standing at 0° for 20 minutes the ice bath is removed and the reaction mixture is stirred for 16 hours. The reaction mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate and brine, dried (MgSO4), and evaporated. The residue (1.2 g.) is chromatographed on silica (60 g.) eluting with acetone/hexane (1:1) to give 0.8 g. of (±)-dihydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester as an oil after evaporation. TLC (acetone/hexane; 2:1) two spots at Rf =0.59,0.65(isomers at phosphorus).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:19][CH:20]([N-:22]C(C)C)C.BrCC#N>C1COCC1>[C:20]([CH2:19][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1)#[N:22]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
To a solution of commercially available 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (200 g, 0.82 mol) in anhydrous THF (2 L) was added LDA (2M in THF, 575 mL, 1.15 mol) drop-wise at −65° C. under N2. The mixture was stirred at −65° C. for 1.5 h. To the mixture was added bromoacetonitrile (148 g, 1.23 mol) in anhydrous THF (500 mL) at −65° C. The mixture was stirred at −65° C. for 1 h, then warmed up to room temperature and stirred overnight. The reaction was quenched with water (800 mL) at 0° C. and the combined reaction mixture was concentrated in vacuum to give a crude product, which was extracted with ethyl acetate (1 L three times). The combined organic phases were washed with brine (1 L) and dried over Na2SO4. The organic layer was filtered and the filtrate was concentrated under vacuum to give a crude product, which was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (from petroleum ether to 2/1) to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 3.900-3.750 (m, 5H), 3.120-3.000 (m, 2H), 2.612-2.562 (m, 2H), 2.190-2.111 (m, 2H), 1.590-1.502 (m, 2H), 1.402 (s, 9H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[O-:28][C:29]#[N:30].[K+]>O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:29]([NH2:30])=[O:28])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#C[O-]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 11 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.63 mmol) and acetic acid (108 μL, 1.89 mmol) in water (12 mL) was added portionwise potassium cyanate (153 mg, 1.89 mmol). After stirring overnight, the reaction mixture was quenched with a 0.1N aqueous solution of NaOH. The organic layer was separated and the aqueous layer extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) followed by DCM:MeOH (90:10) and DCM:MeOH:NH3 (90:5:5) to give the title compound (25 mg, 11%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.92-6.90 (d, 2H), 4.24 (s, 2H), 4.17 (t, 1H), 4.03 (t, 2H), 3.84-3.79 (m, 2H), 3.61-3.55 (m, 2H), 3.36-3.35 (d, 2H), 2.63 (t, 2H), 2.53 (m, 4H), 2.07-1.97 (m, 4H), 1.88-1.79 (m, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=1)[C:9]([CH3:29])([CH3:28])[CH2:8]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:15][C:13]1[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]2[C:12]=1[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:17]=1)[C:9]([CH3:28])([CH3:29])[CH2:8]2
Reactant: COC(=O)c1cc(Cl)c2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)cc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
To a stirred mixture solution of 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (700 mg, 1.8 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (630 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:9]=[C:13]=[O:14])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(CBr)cc1
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(CBr)cc1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-(bromomethyl)benzamide (0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 g of the desired product.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.C(OC([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:15][CH2:14]1)=O)(C)(C)C.[CH3:24]O>>[ClH:3].[NH:13]1[CH2:14][CH2:15][CH:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)CCC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (2.23 mL, 30.6 mmol) was added dropwise to 25 mL of anhydrous methanol. The resulting anhydrous methanolic HCl solution was added to commercially available 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoic acid (1.97 g, 7.66 mmol) and the resulting mixture was stirred overnight at rt. The solvent was removed under reduced pressure to afford methyl 3-piperidin-4-ylpropanoate hydrochloride. ESI-MS calc. for C9H17NO2: 171; Found: 172 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:59])=[N:52][C:53]([CH3:58])=[CH:54][C:55]=1[O:56][CH3:57]>ClCCl.O>[OH:59][C:51]1[C:50]([CH2:49][NH:48][C:8]([C:6]2[CH:5]=[CH:4][N:3]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:2](=[O:1])[CH:7]=2)=[O:10])=[C:55]([O:56][CH3:57])[CH:54]=[C:53]([CH3:58])[N:52]=1
Reactant: COc1cc(C)nc(O)c1CN
Reactant: CC(c1ccccc1)n1ccc(C(=O)O)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C)nc(O)c1CNC(=O)c1ccn(C(C)c2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.2 %

Procedure:
To a solution of 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid (97 mg, 0.40 mmol) in dichloromethane (15 mL) were added 1-Hydroxybenzotriazole (73 mg, 0.54 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mg, 0.54 mmol) and triethylamine (111 mg, 1.1 mmol). The resultant solution was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (60 mg, 0.36 mmol) was added to the solution, and it was stirred at room temperature for 16 hours. Water (20 mL) was added to the mixture. It was extracted with dichloromethane (50 mL). The organic layer was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford N-((2-hydroxy-4-methoxy-6-methylpyridin-3-yl)methyl)-2-oxo-1-(1-phenylethyl)-1,2-dihydro pyridine-4-carboxamide (40 mg, 28% yield) as a white solid. 1H NMR (300 MHz, CD3OD): δ 7.56 (d, J=7.2 Hz, 1H), 7.31-7.39 (m, 5H), 6.86 (d, J=1.8 Hz, 1H), 6.60 (br, 1H), 6.25-6.30 (m, 2H), 4.41 (s, 2H), 3.91 (s, 3H), 2.31 (s, 3H), 1.76 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[N:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=[C:9](O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=[N:11][C:10]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccccc2)nnc1N1CCN(c2ncccn2)CC1
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc(-c2ccccc2)nnc1N1CCN(c2ncccn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
6-phenyl-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazin-4-ol (22.0 g, 66 mmol) was suspended in 75 ml phosphorus oxychloride and heated with stirring at 100° C. for 3 h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over fitter funnel to provide white solid (21.3 g, 60.3 mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+). 1H NMR (CDCl3): d 8377 (d, J=4.5, 2H), 8.036 (d, J=7.5, 2H), 7.833 (s, 1H), 7.508 (m, 3H), 6.564 (t, J=4.5, 1H), 4.073 (t, J=4.5, 4H), 3.672 (t, J=4.5, 4H).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:14]([N:6]1[C:5]2=[CH:4][N:3]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:2]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7]1=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: Nc1ccccc1
Reactant: COc1ccc(Cn2cc3c(c2Cl)c(=O)n(C)c(=O)n3CC(C)C)cc1
Product: COc1ccc(Cn2cc3c(c2Nc2ccccc2)c(=O)n(C)c(=O)n3CC(C)C)cc1
Temperature: 180 °C
Yield: 120.2 %

Procedure:
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (14 mg, 0.025 mmol) is placed in a Biotage microwave tube, and then aniline (0.5 mL, 5.4 mmol) is added. The mixture was heated at 180° C. for 4 h. The mixture is purified by a semi-preparative HPLC to give 13 mg of pure product (yield: 81%). MS (ESI) m/z 433.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:29])[C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][S:31]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)(=[O:33])=[O:32]>>[ClH:1].[CH3:30][S:31]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:2]2[N:7]=[C:6]([N:8]([CH3:29])[C:9]3[CH:28]=[CH:27][C:12]4[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:40][CH:41]=1)(=[O:32])=[O:33]
Reactant: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: CS(=O)(=O)CCc1ccc(N)cc1
Product: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5ccc(CCS(C)(=O)=O)cc5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-methoxy-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (82 mg, 0.20 mmol) and 4-(2-Methanesulfonyl-ethyl)-phenylamine (40 mg, 0.20 mmol) as a white solid (57 mg, 47%). 1H NMR (300 MHz, d6-DMSO) δ 9.28 (s, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.34-7.38 (m, 3H), 7.13-7.18 (m, 3H), 6.94 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 5.66 (d, J=6.0 Hz, 1H), 4.57 (d, J=5.4 Hz, 2H), 3.72 (s, 3H), 3.62 (s, 3H), 3.43 (s, 3H), 3.35-3.43 (m, 2H), 2.96 (s, 3H), 2.90-2.96 (m, 2H). MS (ESI) m/z=572 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: c1cc2nc(N3CCN(C4CC4)CC3)sc2cc1CN1CCCCC1
Temperature: 63 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (500 mg, 1.7 mmol) in MeOH (14 mL) and THF (28 mL) was added piperidine (290 mg, 3.4 mmol), acetic acid (22 mg, 0.4 mmol) and NaCNBH3 (158 mg, 2.7 mmol). The mixture was stirred at 63° C. overnight. The reaction mixture was concentrated under reduced pressure and CH2Cl2 (15 mL) was added to the residue. The mixture was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 332 mg (28%) of 2-(4-cyclopropylpiperazin-1-yl)-6-(piperidin-1-ylmethyl)benzothiazole as a trifluoroacetate salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]1[CH2:15][N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[CH:17]=[CH:18][C:11]2=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O.C(OCC)(=O)C>CS(C)=O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]1[CH2:15][N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:31])[CH3:32])[C:24](=[O:29])[C:25]([F:28])([F:26])[F:27])=[O:21])[CH:17]=[CH:18][C:11]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2c3c([nH]c12)CN(CC(=O)NC(C(C)C)C(O)C(F)(F)F)C=C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc2c3c([nH]c12)CN(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)C=C3
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 2-(8-ethoxycarbonyl-1,2-dihydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.57 g) in dimethyl sulfoxide (6 mL) and toluene (6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g) and dichloroacetic acid (0.43 mL) and the resulting solution allowed to stir for 2 hours. The reaction mixture was poured into ethyl acetate, washed (1N hydrochloric acid, H2O), dried, and evaporated. The resulting material was purified by chromatography, with methanol:dichloromethane (3:97) as the eluent. The resulting solid was recrystallized from ethyl acetate to give the title compound (0.41 g); mp 218°-219° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:23]=[C:17]3[N:16]=2)=[CH:11][N:10]([CH3:31])[N:9]=1)=[O:7])C.O.Cl>C1COCC1.CO>[CH3:31][N:10]1[CH:11]=[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:23]=[C:17]3[N:16]=2)[C:8]([C:6]([OH:7])=[O:5])=[N:9]1
Reactant: CCOC(=O)c1nn(C)cc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1cc(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
NaOH (3N, 1.5 ml) was added to a solution of 1-methyl-4-(2-phenyl-imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-1H-pyrazole-3-carboxylic acid ethyl ester (390 mg, 1.5 mmol) in a mixture of THF (5 ml) and methanol (5 ml), and the mixture was stirred for 3 h at RT. Water (10 ml) was added, and the mixture was acidified (pH=3) by addition of HCl. The mixture was stirred for 30 min and filtered. The obtained precipitate was washed with a small amount of water, and was dried under vacuum. The thus obtained title compound (240 mg, 45%) was pure enough to be used in the next step. MS (m/e)=363.3 [M+H+].