Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[C:13]([C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:24][C:23]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])=[CH:7][CH:6]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)#[N:14]
Reactant: Cc1cccc(Cl)c1C=O
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(Cl)c1CNc1ccc(-n2nc(-c3cccnc3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-cyanopyrazole (130 mg, 0.5 mmol) and 2-chloro-6-methylbenzaldehyde (0.9 g) in acetic acid (4 mL) and MeOH (7 mL) at room temperature was added sodium cyanoborohydride (79 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated under a stream of nitrogen, diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, water and dried (MgSO4). The residue obtained on concentration was chromatographed on silica gel (eluant, gradient of 15-25% EtOAc in CH2Cl2) to provide the title compound (152 mg, 76%). NMR (CDCl3, 400 MHz): 9.2 (s, 1H); 8.7(br, 1H); 8.4(br, 1H); 7.6-7.5 (overlapping m, 3H), 7.4-7.1(overlapping m, 5H), 6.8 (d, 2H), 4.5 (s, 2H), 2.5 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]([NH2:19])=[S:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[S:18][CH:21]=[C:22]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:19]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)CCc1ccccc1
Reactant: NC(=S)Nc1cc(OCc2ccccc2)c(Br)cn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Brc1cnc(Nc2nc(CCc3ccccc3)cs2)cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A flask was charged with 1-(4-(benzyloxy)-5-bromopyridin-2-yl)thiourea (2.34 g, 6.92 mmol), 1-bromo-4-phenylbutan-2-one (1.65 g, 7.26 mmol), and triethylamine (1.93 ml, 13.8 mmol). Ethanol (100 mL) was added and the reaction was stirred at 75° C. for 8 hours. The reaction was cooled and filtered, and the collected solids were washed with water to give the desired product (2.54 g, 77.9% yield) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30]>C1COCC1>[CH3:15][C:14]([CH3:16])([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCOC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mixture of diisopropylamine (8.00 mL, 57.1 mmol) in THF (300 mL) cooled to 0° C., n-BuLi (24.60 mL, 61.5 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h. Then the mixture was cooled to −30° C. and a solution of ethyl isobutyrate (6.12 g, 52.7 mmol) in THF (2 mL) was added. The mixture was stirred at −30° C. for 1 h. To the mixture was added a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (10.5 g, 43.9 mmol) in THF (5 mL) at −30° C. The whole mixture was stirred at −30° C. for 3 h and then stirred at 25° C. for 12 h. The mixture was quenched with aqueous NH4Cl and extracted with EA. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=200:1). All fractions found to contain product by TLC (PE/EA=10:1, Rf=0.6) were combined and concentrated to yield a light yellow solid of ethyl 2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate (10 g, 35.3 mmol, 80% yield): 1H NMR (400 MHz, CDCl3) δ: 7.62 (d, J=8.0 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.14 (s, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.18 (s, 6H); ES-LCMS m/z 275 (M+H).
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([F:41])=[C:22]([C:24]34[CH2:32][O:31][CH2:30][CH:29]3[CH2:28][S:27][C:26]([NH:33]C(=O)OC(C)(C)C)=[N:25]4)[CH:23]=2)=[O:16])=[N:13][CH:14]=1>>[ClH:1].[NH2:33][C:26]1[S:27][CH2:28][C@@H:29]2[CH2:30][O:31][CH2:32][C@:24]2([C:22]2[CH:23]=[C:18]([NH:17][C:15](=[O:16])[C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][N:13]=3)[CH:19]=[CH:20][C:21]=2[F:41])[N:25]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)COCC2CS1
Agent: Cl
Solvent: C1COCCO1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)COC[C@H]2CS1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 4M hydrogen chloride in dioxane (834.8 μL; 3.3 mmol) is added to tert-butyl 7a-(5-(5-fluoropicolinamido)-2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylcarbamate (91 mg; 167.0 μmol) and stirred at ambient temperature. After 2 days, the reaction mixture is concentrated in vacuo. The residue is dissolved in minimal dichloromethane and methanol. Ether and hexane are added. The product is precipitated as the salt which is separated from the mother liquor by centrifugation and placed under vacuum to remove any solvent present to give the title compound (58 mg; 125 mmol). LC-ES/MS m/e 391 (M+1); TR=1.675.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(Cl)nc1N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.7 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (5.0 g, 30.7 mmol) in EtOH (100 mL) were added 4-piperidinol (3.1 g, 30.7 mmol) and Na2CO3 (16.3 g, 153.4 mmol). The reaction mixture was stirred at rt for 72 h, after which the reaction mixture was filtered through Celite®. The filtrate was then concentrated under reduced pressure, the residue dissolved in EtOAc, and the organic solution washed with water and brine after which it was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (1:1 EtOAc/hexanes to 100% EtOAc) to give the product (4.8 g, 90%) as a white waxy solid. 1H NMR (400 MHz, CDCl3) δ 1.62-1.70 (m, 2H), 1.70 (d, 1H), 1.98-2.03 (m, 2H), 2.21 (s, 3H), 3.22-3.28 (m, 2H), 3.87-3.92 (m, 2H), 3.97-3.98 (m, 1H), 7.92 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][N:9]2[CH:20]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:40]([F:43])([F:42])[F:41])=[C:35]([CH:39]=1)[C:36](Cl)=[O:37]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:36](=[O:37])[C:35]4[CH:39]=[C:31]([F:30])[CH:32]=[CH:33][C:34]=4[C:40]([F:43])([F:41])[F:42])[CH2:16][CH2:15]3)=[N:10][N:9]2[CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2nc(N3CCNCC3)ccc2n1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 6-piperazin-1-ylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (1.016 g, 3.69 mmol) and diisopropylethylamine (1.29 mL, 7.38 mmol) in anhydrous dichloromethane (20 mL) was added 5-fluoro-2-trifluoromethylbenzoyl chloride dropwise at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, then diluted with dichloromethane and washed with water. The organic layer was dried and concentrated in vacuo. The title compound was obtained in 82% yield (1.365 g) after purification by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C(Cl)[Cl:26]>O>[Cl:26][C:10]1[N:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:12][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: ClCCl
Solvent: O
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Cl
Yield: 20 %

Procedure:
To a solution of ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (270 mg, 0.75 mmol) in CH2Cl2 (5 mL) was added SO2Cl2 (1.6 mL, 20 mmol). The mixture was heated at reflux overnight, and diluted with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography over silica gel (33% EtOAc in hexane) to give ethyl 5-chloro-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (60 mg) in 20% yield as a white solid: LC-MS m/z 395.0 (MH+), retention time 3.45 min (method 1). This intermediate, which is an example of Formula X in Scheme 2, was converted into 5-chloro-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-piperidinyl)-1H-imidazole-4-carboxamide (Table entry 21).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-]>CO.C(O)(=O)C.[Pd]>[NH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(N)C1
Yield: 69.4 %

Procedure:
A solution of the title compound of Example 3 (37.1 g, 164 mmol) in a mixture of MeOH (100 mL) and acetic acid (25 mL) was added 10% Pd-C (3.7 g) and the reaction mixture was hydrogenated (50 psi) for 24 h at rt in a Parr apparatus. Analysis of the reaction by TLC (solvent system A) and IR (to look for presence or absence of N3 str peak at 2100 cm-1) indicated the reaction to be complete. The solution was filtered through celite to remove catalyst and the filtrate was evaporated in vacuo to give the crude product as an oily residue. The residue was dissolved in 500 mL of 10% aqueous acetic acid and the solution was extracted with Et2O (3×200 mL). The combined ethereal extract was discarded and the aqueous solution was basified by addition of excess concentrated aqueous NH3 solution. The basified mixture was extracted with Et2O (3×200 mL) and the combined organic extract was dried (Na2SO4) and evaporated to give the title compound (22.8 g, 69%) as a pale yellow oil. The fumarate salt crystallized from 2-propanol: mp 197°-198° C., 1H-NMR (CDCl3) ∂ 3.93 (br s, 1H), 3.82 (dm, Jgem =13 Hz, 1H), 1.46 (s, 9H), 1.29-1.41 (complex m, 3H), 1.24 (m, 1H); CIMS (MH+ calcd for C10H20N2O2): 201. Found (MH+): 201; Anal. (calc'd for C10H20N2O2.0.5C4H4O4): C, H, N.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(N)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-amino-2-oxindole to give 0.3 g of 5-Amino-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>>[CH3:26][O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[CH2:16][N:10]1[C:9](=[O:27])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCCC(=O)O)ncc3c2=O)c(OC)c1
Yield: 48.2 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.068 mmol), β-alanine (801 mg, 9.0 mmol) and NaOMe solution (13.5 mL, 6.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl to pH about 1, and the resulting precipitate was isolated by filtration. The crude solid was further purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH) to give 14 mg of the title compound as a light yellow solid. MS: (+) m/z 428.31 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[N:21]=4)=[O:19])=[CH:14][CH:13]=3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:2]1.C(N(CC)CC)C.N1([C:41](=[O:43])[CH3:42])C=CN=C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[C:5]([CH:3]3[CH2:4][N:1]([C:41](=[O:43])[CH3:42])[CH2:2]3)=[N:10][CH:9]=[CH:8][N:7]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: O=C(c1ccc(Oc2nccnc2C2CNC2)cc1)c1nc2ccccc2[nH]1
Reactant: CC(=O)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 36 %

Procedure:
To a solution of (4-(3-(azetidin-3-yl)pyrazin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone in DMF (1.0 mL) is added triethylamine (104 μL, 0.743 mmol) and 1-(1H-imidazol-1-yl)ethanone (60.0 mg, 0.545 mmol). The reaction was stirred at rt 7 h. The reaction mixture was added to saturated NaHCO3 (5 mL) and extracted with Teac (3×5 mL). The combined organic layers were washed with water (5 mL), saturated NaCl (5 mL), dried (MgSO4) and concentrated. Purification by RPHPLC gives 1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidin-1-yl)ethanone (55.4 mg, 36.0% over 3 steps) as a white solid. MS (ESI, pos. ion) m/z: 414.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=1.C[O-].[Na+]>CO>[Br:12][C:13]1[CH:14]=[C:15](/[CH:18]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[S:16][CH:17]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cc(Br)cs1)c1ccc(Cl)cc1F
Yield: 63.2 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (4.05 g, 24 mmol) was reacted with 4-bromo-2-thiophenecarboxaldehyde (Aldrich) (6.08 g, 29 mmol), methanolic solution (25 wt %) of sodium methoxide (6 mL, 26 mmol) in methanol (90 mL) at 50° C. for 3 h to give (Z)-3-(4-bromo-thiophen-2-yl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a light yellow solid (5.2 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Clc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.031 g, 0.09 mmol) and EtOH (3.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (2 to 13%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.014 g, 30%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.62 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.61 (s, 2H) (NCH2-pyridyl and C6H4CH2N), 3.71 (br s, 4H, piperazine N(CH2)2), 7.39 (dd, J=5.30, 8.2 Hz, pyridine 5-H), 7.47 (d, J=8.2 Hz, 2H) and 8.12 (d, J=8.7 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.78 (d, J=6.9 Hz, 1H, pyridine 4-H), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.50, 4.6 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.5 Hz, 1H, pyridine 2-H), 13.42 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([F:27])[C:7]3[NH:11][C:10](=[O:12])[N:9]([CH:13]4[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]4)[C:8]=3[CH:26]=2)[CH2:3][CH2:2]1.[ClH:28]>ClCCl.O1CCOCC1>[ClH:28].[CH:1]1([C:4]2[CH:5]=[C:6]([F:27])[C:7]3[NH:11][C:10](=[O:12])[N:9]([CH:13]4[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]4)[C:8]=3[CH:26]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c(F)cc(C4CC4)cc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1[nH]c2c(F)cc(C3CC3)cc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1-Dimethylethyl 4-(6-cyclopropyl-4-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D28, 0.28 mmol, 107 mg) was dissolved in 1 ml of dichloromethane and treated with HCl (1 ml of a 4M solution in 1,4-dioxane) at room temperature and the mixture stirred at room temperature for 3 hours. The solvent was evaporated to afford the title compound, 100 mg, 0.32 mmol, complete conversion, M++H=276.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[O:11])=[CH:8][N:9]=1)(=O)C.Cl.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:4][C:5]1[S:6][C:7]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[O:11])=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(S(=O)c2ccc(N)cc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(S(=O)c2cnc(N)s2)cc1
Yield: 105.8 %

Procedure:
A mixture of 2-acetylamino-5-(4-aminophenylsulfinyl)thiazole (5.0 g) in a mixture of aqueous 6N-hydrochloric acid (10 ml) and acetic acid (35 ml) was refluxed for 3.5 hours with stirring. The reaction mixture was diluted with water and adjusted to pH 8 using aqueous sodium carbonate under ice cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(4-aminophenylsulfinyl)thiazole (4.5 g, yield: 100%).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][C:2]1=[C:6]([C:13](C(OOCC)=O)=[O:14])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1>>[S:3]1[CH2:4][CH2:5][S:1][C:2]1=[C:6]([C:13](=[O:14])[NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCCS1
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)C(C(=O)OC(C)C)=C2SCCS2)n1

Procedure:
Following the procedure of Example 22, the titled compound was prepared as a white solid (41%) from isopropyl 2-(1,3-dithiolan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate and 2-amino-4-methylthiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.[CH3:37][O:38][C:39]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)=[O:40]>ClCCl>[CH3:37][O:38][C:39](=[O:40])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=4[Cl:1])=[N:6][CH:7]=[CH:8][CH:9]=3)=[O:12])[CH2:14][CH2:15]2)(=[O:50])=[O:51])=[CH:45][CH:44]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(S(=O)(=O)N2CCN(C(=O)c3cccnc3Oc3cc(Cl)ccc3Cl)c3ccccc32)cc1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (80 mg, 0.2 mmol, 1.0 equiv; Example 122) in anhydrous dichloromethane (2 mL) was added N-ethyldiisopropylamine (51.3 mg, 69 μL, 0.4 mmol, 2.0 equiv; [CAS RN 7087-68-5]) and methyl 3-(4-chlorosulphonyl)phenylproprionate (57.8 mg, 0.22 mmol, 1.1 equiv; [CAS RN 374537-95-8]) and the reaction mixture stirred at rt over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 44 mg (35%) of the title compound as a light off-white powder. MS (ISP): 626.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:30])[N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[BrH:31].C(O)(=O)C>C(O)C>[BrH:31].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:30])[N:8]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH:20]=[C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c2cc(O)ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1

Procedure:
A mixture of 7-methoxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.2 g), 47% hydrobromic acid (2.6 ml) and acetic acid (6 ml) was refluxed for 28 hours. After cooling, the reaction mixture was diluted with ethanol and the precipitated crystals were collected. Recrystallization from ethanol afforded 7-hydroxy-3-[4-(4 -phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione hydrobromide (0.1 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: C1=CC2(CCNCC2)c2ccccc21
Yield: 99 %

Procedure:
A solution of 1'-(tert-butyloxycarbonyl)spiro[indene-1,4'-piperidine] (3.0 g, 0.011 mol) in ethyl acetate (150 ml) was stirred at 0° C., and treated with hydrogen chloride for 30 minutes. The mixture was then evaporated to dryness, ethyl acetate (100 ml) was added, then removed in vacuo three times. The residue was stirred with anhydrous ether (200 ml), and the solid filtered off, to give spiro[indene-1,4'-piperidine] hydrochloride (2.3 g, 99%) as a pale yellow solid. The product was not purified further.