Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+]([O-])=O)=[N:13][O:14][CH3:15])[CH2:9][N+:8]([O-:19])=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1.C(O)C.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([CH:12]=[N:13][O:14][CH3:15])[CH2:9][N+:8]([O-:19])=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1
Reactant: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1)[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CON=CC1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.5 g of 7-chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine 4-oxide, 10 ml of ethanol, 5 ml of tetrahydrofuran and 0.4 g of sodium borohydride was stirred at ambient temperature for 1 hr. After partitioning between methylene chloride and aqueous sodium bicarbonate solution, the organic phase was dried and evaporated. Chromatography of the residue over 7 g of silica gel yielded 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-methoxy-1H-1,4-benzodiazepine-2-methanimine 4-oxide as light yellow resin.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CO.ClCCl>[CH2:22]([NH:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 22.5 °C
Reaction time: 40 h
Yield: 50.9 %

Procedure:
To (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (2.36 g, 7.58 mmol) in a mixture of Methanol (15.00 ml) and Dichloromethane (15 ml) was added BENZALDEHYDE (0.845 ml, 8.34 mmol). To the resulting clear solution SODIUM CYANOBOROHYDRIDE (0.702 g, 10.61 mmol) was added in portions at 20-25° C. to avoid intensive foaming and the solution was stirred at 20-25° C. for 40 h. The solution was quenched at 20-25° C. with 1N HCl (12 ml), neutralised with 3N NaOH (12 ml), the mixture was extracted with DCM (100 ml). The organic phase was washed with brine, dried (MgSO4), evaporated to dryness. The residue was purified on a column with EA-MeOH 9:1 as eluent, fractions collected, concentrated to approx 20 ml, cooled in ice. The precipitate collected, washed with Ethyl Acetate-Petroleum Ether 1:1, dried on air to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (1.55 g, 3.86 mmol, 50.9% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:48][CH2:49][C:50]([NH:52]O)=[NH:51]>CN(C=O)C.CCOC(C)=O>[Cl:48][CH2:49][C:50]1[N:52]=[C:24]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=2)[CH2:7]3)[O:25][N:51]=1
Reactant: N=C(CCl)NO
Reactant: Cc1cc(C(=O)O)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nc(CCl)no2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 135 °C
Yield: 29.4 %

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid (80.0 mg, 0.49 mmol), EDCI (104.0 mg, 0.54 mmol), HOBT (73.0 mg, 0.54 mmol) and 2-chloro-N-hydroxyacetamidine (59.0 mg, 0.54 mmol) were mixed in DMF (4.0 mL) over the weekend. The reaction mixture was diluted with EtOAc and washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product was subjected to column chromatography (100% EtOAc). The product was heated to 135° C. in DMF for 1.5 hours. The reaction mixture was cooled and diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product was purified by column chromatography to yield the title compound as a brown oil (63.0 mg, 33%). 1H NMR (300 MHz, CDCl3): δ 8.01 (d, 2H), 7.37 (d, 2H), 7.21 (d, 2H), 4.81 (s, 2H), 4.69 (s, 2H), 4.34 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][N:17]([C:12]1[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)[CH:32]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(Nc5cccnc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N-Methyl-N-(3-{2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 3-(4-methylpiperazin-1-yl)aniline (45.0 mg, 0.235 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.017 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11-8.06 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.28-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.78-6.73 (m, 1H), 6.57 (d, J=8.0 Hz, 1H), 3.32 (s, 3H), 3.29-3.24 (m, 4H), 3.09 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=518 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[CH:20]1[C:30]2[CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[CH2:26][NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[CH:20]1[C:30]2[CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[CH2:26][N:25]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.7 %

Procedure:
To a solution of 0.27 g (1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 2 ml of tetrahydrofuran is added 0.20 g (1 mmol) of 6,11-dihydro-5H-dibenz[b,e]azepine and 0.20 g of triethylamine. The mixture is stirred at room temperature for 3 hours and the solvent removed under vacuum. To the residue is added 1N HCl and the mixture extracted with ethyl acetate (20 ml) and the extract washed with saturated NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated. The residue is triturated with ether-hexane and filtered to give 0.47 g of a white solid: Mass Spectrum; EI 433(M+1); EI-high resolution 432.1842.
Reaction SMILES: [SH:1][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][S:6][CH2:5][CH2:4]1.[C:10]1(=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]1=[O:20]>>[S:6]1[CH2:7][CH2:8][C:3]2([O:9][C:13]3[C:14]4[C:19]([C:10](=[O:21])[C:11](=[O:20])[C:12]=3[S:1][CH2:2]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:4][CH2:5]1
Reactant: OC1(CS)CCSCC1
Reactant: O=C1C=Cc2ccccc2C1=O
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCSCC1)O2

Procedure:
The crude 4-(mercaptomethyl)tetrahydro-2H-thiopyran-4-ol was then reacted with naphthalene-1,2-dione as outlined in procedure F [both step (i) and (ii)] to afford crude 2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-thiopyran]-5,6-dione. The crude 2′,3′,5′,6′-tetrahydrospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-thiopyran]-5,6-dione was purified by flash column chromatography (SiO2, 25% EtOAc in hexanes) to afford the product as a purple solid. M.p.=221-223° C., 400 MHz 1H NMR (CDCl3) δ 8.05 (dd, d, J=7.4 Hz, 1.1 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.67 (dt, J=6.2 Hz, 1.1 Hz, 1H), 7.50 (dt, J=6.2 Hz, 1.1 Hz, 1H), 3.10-3.03 (m, 1H), 2.64-2.60 (m2, 2H), 2.47-2.43 (m, 2H), 1.99-1.92 (m, 2H); LCMS: 319 [M+H].
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:20])[F:19])[N:14]([C:21]3[N:26]=[C:25](Cl)[N:24]=[C:23]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:22]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C1COCC1>[Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:20])[F:19])[N:14]([C:21]3[N:22]=[C:23]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:24]=[C:25]([N:37]4[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]4)[N:26]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O[Si](C)(C)C(C)(C)C)cccc43)n2)CC1

Procedure:
Reaction of 4-(tert-butyldimethylsilyloxy)-1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole with 2.2 equivalents of tert-butyl 1-piperazinecarboxylate in THF at room temperature gave a quantitative yield of tert-butyl 4-[4-[4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate as an oil: 1H NMR (CDCl3) 7.91 (d, J=8.2 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 3.85 (m, 8H), 3.77 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H), 1.05 (s, 9H), 0.30 (s, 6H); MS (APCI+) 648.7 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31].C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[O:31])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: O=C(O)c1ccccn1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(N)c2cc(C(=O)Nc3ccc(CNC(=O)c4ccccn4)cc3)ccc2n1
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of 27 mg (0.05 mmol) 4-amino-N-[4-(aminomethyl)phenyl]-2-methyl-6-quinolinecarboxamide, 7 mg (0.1 mmol) 2-pyridinecarboxylic acid, and 0.028 ml (0.2 mmol) triethylamine in 2 ml DMF was added 36 mg (0.75 mmol) PyBrop and stirred at room temparature for 1 d. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 7.4 mg (23%) of the title compound. MS 412.3 (M+1)+, 1H-NMR (DMSO-d6) δ 2.60 (s, 3H), 4.47 (d, 2H), 6.64 (s, 1H), 7.33 (d, 2H), 7.60 (m, 1H), 7.70 (d, 2H), 7.86 (d, 1H), 8.00 (t, 1H), 8.04 (t, 1H), 8.35 (d, 1H), 8.65 (m, 1H), 8.94 (s, 1H), 8.98 (br. 2H), 9.32 (t, 1H).
Reaction SMILES: C(OC([NH:8][N:9]([C:13]([C:15]1[S:16][C:17]2[CH2:18][CH2:19][O:20][C:21]3[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=3[C:23]=2[N:24]=1)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:30].O1CCOCC1>CO>[ClH:30].[CH:10]([N:9]([C:13]([C:15]1[S:16][C:17]2[CH2:18][CH2:19][O:20][C:21]3[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:22]=3[C:23]=2[N:24]=1)=[O:14])[NH2:8])([CH3:12])[CH3:11]
Reactant: CC(C)N(NC(=O)OC(C)(C)C)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)N(N)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
A suspension of N′-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (6.14 g, 12.7 mmol) in methanol (49 mL) was treated with 4N HCl in dioxan (12.7 mL, 51.0 mmol) and stirred at RT for 0.75 h before being warmed to 50° C. and stirred for 3 h. The reaction mixture was concentrated in vacuo and the resultant solid was triturated with diethyl ether to give the title compound as a yellow brown solid (5.14 g, 12.3 mmol, 96%). LCMS: RT=4.79 min, [M+H]+=382/384.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:15][C:16](=[O:37])[CH:17]([S:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][S:27][CH:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][O:10][C:9](=[O:11])[CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:23][CH:24]=2)[C:16]([OH:37])=[O:15])=[CH:31][CH:32]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Reactant: CN1CCN(CC(=O)O)CC1
Product: CN1CCN(CC(=O)OCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)CC1

Procedure:
The title compound was prepared starting from N-methyl piperazino acetic acid and 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2-trichloro-ethyl ester in the same manner as described for example 7 (yield: 7.9 mg, 26%). 1H-NMR (300 MHz, CDCl3): δ 2.28-2.54 (m, 4H), 2.42 (s, 3H), 2.63-2.88 (m, 4H), 2.88-3.29 (m, 10H), 3.60-3.67 (m, 1H), 5.00-5.21 (m, 2H), 6.91-7.00 (m, 2H), 7.13-7.20 (m, 2H), 7.22-7.33 (m, 4H); Mass Spectrum: M+H+475.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15](O)[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15]([Cl:32])[N:14]3[N:18]=[CH:19][CH:20]=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1CCC(c2cc(O)n3nccc3n2)CC1
Solvent: CN(C)c1ccccc1
Product: COC(=O)C1CCC(c2cc(Cl)n3nccc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
4-(7-Hydroxy-pyrazolo[1,5-a]pyrimidin-5-yl)-cyclohexanecarboxylic acid methyl ester (10.6 g), N,N-dimethylaniline (15.0 ml) and POCl3 (120 mL) were mixed and stirred at room temperature for 18 hours. The solution is reduced in vacuo and cooled to 0° C. in ice bath. The reaction is then quenched with sat. NaHCO3(aq) and extracted with DCM (100 mL×3). The combined organics are dried with Na2SO4 and the solvent removed in vacuo. The resulting oil was purified via silica gel column on 20% to 100% ethyl acetate in hexanes gradient to yield the titled compound (2.5 g, 32% over three steps). LC-MS: 294 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23].C(OC(C)C)(=O)C>C(#N)C>[O:23]=[C:22]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC#N
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 100 mL round bottom flask was charged with acetonitrile (20 mL, HPLC grade) and tert-butyl 4[(2-aminopyridin-3-yl)amino]piperidine-1-carboxylate (11, 1.89 g, 6.47 mmol) was added. Upon completion of addition, acetonitrile (5 mL) was added and the resulting suspension was stirred at room temperature for 30 minutes. Carbonyl diimidazole (1.57 g, 97.1 mmol) was then added over period of 10 minutes. The reaction mixture was heated to 50° C. and stirred overnight. The resulting solution was cooled to room temperature and concentrated under reduced pressure to give a brown solid. This solid was then mixed with 20 mL of isopropyl acetate and 20 mL of ice cold water. The resulting thick slurry was stirred overnight at room temperature. The brown solids were collected by vacuum filtration, washed with cold water (3×25 mL) and isopropyl acetate (3×25 mL) to give a light gray solid, which was dried to constant weight to give 1.73 g (84% yield) of tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate. This material was submitted to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 11.56 (broad s, 1H), 7.89 (d, 1H), 7.54 (d, 1H), 6.98 (dd, 1H), 4.34 (m, 1H), 4.08 (broad m, 2H), 2.85 (broad m, 2H), 2.13 (m, 2H), 1.72 9 (d, 2H), 1.43 (s, 9H). MS (EI) for C16H22N4O3: 319 (MH+)
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([CH2:20][NH2:21])[OH:19]>C(O)C>[C:1]([NH:3][C:4]([NH:21][CH2:20][CH2:18][OH:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: NCCO
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CCO
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCO

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.7 g) (British Specification No. 1397436) and ethanolamine (1.34 g) in ethanol (50 ml) was heated under reflux for 19 hours. Concentration followed by chromatographic purification on a column of silica gel with chloroform-methanol (10:1) as eluant and final recrystallisation from isopropyl alcohol--acetonitrile gave the title compound, m.p. 146°-7°. (Found: C, 46.8; H, 6.5; N, 29.6; S, 11.2%. C11H18N6OS requires: C, 46.8; H, 6.4; N, 29.8; S, 11.4%).
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=1)N.C(O)(C(F)(F)F)=O>C(OCC)(=O)C>[N:24]1([C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:16]3[C:4](=[O:15])[C:5]([N:10]4[CH:14]=[CH:13][N:12]=[N:11]4)=[CH:6][NH:7]3)[CH:19]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: NNc1cc(N2CCOCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Temperature: 5 °C
Yield: 61.5 %

Procedure:
1.9 g (8.8 mmol) of the compound from Example 3A and 1.9 g (9.7 mmol) of the compound from Example 16A are initially introduced into 25 ml ethyl acetate and 504 mg (4.4 mmol) TFA are added at RT. The mixture is stirred under reflux for 16 h, then cooled to 5° C. and subsequently stirred for a further 2 h. The solid formed is filtered off, washed with ethyl acetate and dried first in air and thereafter under a high vacuum. 1.7 g of product are obtained.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].[C:20]([CH2:22][C:23]([NH2:25])=[O:24])#[N:21]>CN(C)C=O.C(O)C>[C:20]([C:22]1[C:23](=[O:24])[NH:25][C:5]([CH3:6])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH:3]=1)#[N:21]
Reactant: N#CCC(N)=O
Reactant: COC(=O)Cc1ccc(C(=CN(C)C)C(C)=O)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(CC(=O)O)cc1

Procedure:
11 g 4-dimethylamino-3-(4-methoxycarbonylmethylphenyl)-3-buten-2-one are reacted with cyanacetamide as described in Example 1. The title compound is obtained (m.p. 280°-282°--from dimethylformamide/ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2C=CN=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22]C2N=C(N)[S:26][C:20]=2[CH2:19]1.BrC1C(=O)N(C)C=C(Br)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:26][C:20]3[CH2:19][N:18]([CH3:17])[CH2:23][CH2:22][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccncn2)c1=O
Reactant: CN1CCc2nc(N)sc2C1
Agent: Cn1cc(Br)cc(Br)c1=O
Product: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)sc2C1
Yield: 44 %

Procedure:
Following the procedures described for compound 113a and starting with 115a (4.0 g, 23.5 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (3.0 g, 17.8 mmol) afforded 115b as a yellow solid (2.8 g, 44%). MS: [M+H]+ 357.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][CH:4]=1)#[N:2].C(O)C.[OH-].[Na+]>O>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 82 °C
Yield: 91.9 %

Procedure:
A mixture containing ethyl p-cyanobenzoate (87.5 g, 0.5 mol), ethanol (192.5 g), and water (449.2 g) was placed in a 1 l-flask. The mixture was heated to 82° C. A 20% aqueous solution of sodium hydroxide was added to the mixture so as to adjust the pH of the mixture at 8.0-8.5. Twenty-seven hours after the reaction started, liquid chromatographic analysis revealed that the reaction mixture contained 67.6 g of p-cyanobenzoic acid (yield 92%). The reaction mixture was cooled to 30° C., and hydrochloric acid was added thereto to lower the pH to 3.1. The mixture was heated again to 82° C. to dissolve. The resultant mixture was cooled for crystallization, to thereby obtain 64.2 g of p-cyanobenzoic acid crystal (purity 95.0%, yield 83%).
Reaction SMILES: I[C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1.[CH2:26](N(CC)CC)[CH3:27].C([Si](C)(C)C)#C>C(#N)C.CC(O)=O.CC(O)=O.[Pd]>[C:26]([C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][CH:3]=1)#[CH:27]
Reactant: CCN(CC)CC
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)ccc(OC)c21
Agent: [Pd]
Agent: C#C[Si](C)(C)C
Solvent: CC#N
Solvent: CC(=O)O
Product: C#Cc1ccc(OC)c2c1nc(-c1ccc(C(C)C)cc1)n2CCOC
Temperature: 50 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of 50 mg (0.111 mmol) 4-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole, 0.1 ml (0.77 mmol) triethylamine, 0.1 ml (0.7 mmol) ethinyltrimethylsilane and 5 mg palladium-II-acetate in 1 ml acetonitrile is stirred at 50° C. for 3 hours. Then the reaction mixture is cooled to room temperature and poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 17 mg of the title compound as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][OH:17].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:9])[CH2:7][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCC1CCCCN1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCCCC1CO
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Bromo-acetic acid tert-butyl ester (0.39 g, 2 mmol) was dissolved in DMF (1 mL). A solution of piperidin-2-yl-methanol (0.25 g, 2.2 mmol) in DMF (1 mL) and diisopropylethylamine (0.38 mL, 2.2 mmol) was added. The reaction mixture was stirred at 50° C. for 16 h. The solvent was removed in vacuo. EtOAc (20 mL) and water (7 mL) was added. The two phases were separated. The aqueous phase was extracted twice with EtOAc (20 mL). The combined EtOAc phases were dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The product was isolated as an oil. Yield: 0.37 g, 80%.