Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:23][N:13]([N:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=[C:2]1[CH3:1])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: CI
Reactant: Cc1nc(-c2cccnc2)cn1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccnc2)cn1N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
To a solution of tert-butyl 2-methyl-4-(pyridin-3-yl)-1H-imidazol-1-ylcarbamate (2.0 g, 7.3 mmol) in dry DMF (15 mL) at 0° C. was added sodium hydride (0.35 g, 8.7 mmol, 60% dispersion in oil). The reaction was stirred at 0° C. for 30 minutes and then methyl iodide (1.55 g, 10.9 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 3 hours before it was warmed to ambient temperature. The reaction was extracted with ethyl acetate (15 mL×2). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.18 g, 56.2%) as an orange oil, which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3): δ 8.96 (s, 1H), 8.49 (s, 1H), 8.16-8.13 (m, 1H), 7.38-7.36 (m, 2H), 3.36 (s, 3H), 2.35 (s, 3H), 1.44 (s, 9H); ESIMS m/z 289 [(M+H)]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23](O)[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CS(C)=O>[N:29]([CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[C:24]([F:27])([F:26])[F:25])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 110 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.44 mmol) in tetrahydrofuran (4.0 mL) were added thionyl chloride (0.065 mL, 0.891 mmol) and 1 drop of N,N-dimethylformamide at room temperature. After stirring at room temperature for 2 hr, aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated an vacuo to give 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.43 mmol, 93%) as pale yellow solid. A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (68.6 mg, 0.146 mmol) and sodium azide (19 mg, 0.292 mmol) in dimethylsulfoxide (5.0 mL) was stirred at 110° C. for 20 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (68.2 mg, 0.143 mmol, 98%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.C1CCCCC1.CN(C)[CH:38]=[O:39].[NH4+].[Cl-]>O1CCCC1>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:38]=[O:39])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCN(CCc1ccc(Br)cc1)C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCCCCCN(CCc1ccc(C=O)cc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of [2-(4-bromo-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester (20 g, 50.2 mmol) dissolved in tetrahydrofuran (200 mL) under a nitrogen atmosphere at −78° C. was added 1.3 M sec-BuLi in cyclohexane (100.5 mmol, 77.3 mL) dropwise. The solution was allowed to stir at −78° C. for 30 minutes. Anhydrous N,N-dimethylformamide (150.6 mmol, 11.6 mL) was added in one portion and the solution was allowed to warm to room temperature. After stirring for 30 minutes the mixture was poured over saturated NH4Cl solution and extracted with diethyl ether (3×). The organic layers were combined, washed with water (1×), saturated brine (2×), dried over Na2SO4 and concentrated to a crude yellow oil. The oil was purified by chromatography on silica gel (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate in hexanes to give impure [2-(4-formyl-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester as a clear oil used directly in the following procedure. (11.62 g crude).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[N:15]=2)[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[F:25][C:22]([F:23])([F:24])[C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]3)[NH:12][CH:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylcarboxylic acid methyl ester (13.4 mmol) in 50 ml of THF was added LiOH (80.3 mmol) in 30 ml of H2O. The mixture was stirred at 60° C. for 2 hours, then concentrated, diluted with H2O and washed with ether. The aqueous layer was acidified to pH 5-6, extracted with EtOAc, dried over Na2SO4, and concentrated to give trans-4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexyl-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:14])(=[O:15])[N:10]([CH3:27])[CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)NC3)c(F)c2)C(=O)O1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)N(C)C3)c(F)c2)C(=O)O1
Yield: 75.1 %

Procedure:
N-[[(5S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (200 mg, 0.52 mmol), powdered potassium carbonate (85 mg, 0.62 mmol) and methyl iodide (88 mg, 0.62 mmol) were stirred under nitrogen in dry DMF (1 mL) for 24 hours. After evaporation of the solvent, the residue is partitioned between chloroform (65 mL) and water (15 mL). The chloroform is dried (MgSO4), filtered and evaporated. The residue is chromatographed over silica gel, eluting with 2-6% methanol-chloroform. The product is obtained as a white foam (156 mg, 75%). HRMS (FAB) calc'd for M+H=400.1342; Found: 400.1343.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]S(C1C=CC(C)=CC=1)(=O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([NH:8][CH2:9][CH2:10][S:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)CCNC(=O)OC(C)(C)C)cc1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSCc1ccccc1
Reaction time: 18 h

Procedure:
N-Boc-2-Tosyl-ethylamine (100 mg, 0.32 mmol) was added to a mixture of benzylmercaptan (45 mL, 0.38 mmol) and Cs2CO3 (68 mg, 0.21 mmol) in 1.6 mL of dry DMF. The reaction was stirred for 18 hours after which time the reaction mixture was poured onto water. The aqueous layer was extracted three times with AcOEt. The combined organic layers were washed with water, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated. The residue was purified using SiO2 with AcOEt/Petroleum ether 5:95 to 15:75. A yellow oil was obtained (72 mg, 83%). NMR 1H (ppm, CDCl3): 7.31-7.25 (m, 5H), 4.79 (br. s., 1H), 3.70 (s, 2H), 3.25 (m, 2H), 2.55-2.53 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)O1.Br[C:32]1[CH:33]=[C:34]([O:38][CH2:39][CH2:40][NH:41][C:42](=[O:46])[CH2:43][O:44][CH3:45])[CH:35]=[N:36][CH:37]=1>[Pd].C1COCC1>[C:25]([NH:24][C:22]1[S:23][C:19]2[CH:18]=[C:17]([C:32]3[CH:33]=[C:34]([O:38][CH2:39][CH2:40][NH:41][C:42](=[O:46])[CH2:43][O:44][CH3:45])[CH:35]=[N:36][CH:37]=3)[CH:29]=[CH:28][C:20]=2[N:21]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: COCC(=O)NCCOc1cncc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(=O)NCCOc1cncc(-c2ccc3nc(NC(C)=O)sc3c2)c1
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A Biotage high recovery microwave vessel was charged with sodium carbonate hydrate (0.048 g, 0.38 mmol), 0.15 mL water and a stirbar. The slurry was sonicated and stirred for 10 minutes. An inert atmosphere inlet was placed over the vessel and the remaining reagents were added under a flow of nitrogen. To the vessel was added N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.043 g, 0.14 mmol), 100 mg Pd FibreCat® palladium catalyst, and N-(2-(5-bromopyridin-3-yloxy)ethyl)-2-methoxyacetamide (0.0247 g, 0.085 mmol) dissolved in 1 mL THF. The vessel was sealed, and irritated using a Biotage personal chemistry microwave reactor to 130° C. for 25 minutes. The cooled reaction was diluted with 5 mL THF, and filtered through a 0.22 μm PTFE membrane. The catalyst was washed with THF (2×5 mL), and the combined filtrates were concentrated in vacuo. The residue was sonicated in 2 mL water, and filtered. The precipitate was then dissolved in 3 mL MeOH, filtered, and concentrated in vacuo. The crude was purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 10% B; 5.0→35 min@20 mL/min, linear gradient to 40% B; 35→45@20 mL/min, isocratic at 40% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 10% B; 60 min end; A=10.7 mM NH4HCO3 in water, pH adjusted to 8.6 with concentrated NH4OH; B acetonitrile). A band that eluted from 24.2 to 26.0 minutes was isolated. The solvent was removed in vacuo to afford N-(2-(5-(2-(N-actyl)aminobenzo[d]thiazol-6-yl)pyridin-3-yloxy)ethyl)-2-methoxyacetamide. (0.0090 g, 26% yield). 1H NMR (400 MHz, DMF) δ ppm 2.34 (s, 3H) 3.37 (s, 3H) 3.70 (q, J=5.84 Hz, 2H) 3.89 (s, 2H) 4.35 (t, J=5.97 Hz, 2H) 7.81 (dd, J=2.54, 1.96 Hz, 1H) 7.83 (s, 1H) 7.85 (s, 1H) 7.86-7.90 (m, J=8.41, 1.86 Hz, 1H) 8.32 (d, J=2.25 Hz, 1H) 8.47 (d, J=1.47 Hz, 1H) 8.62 (br. s., 1H) 12.35 (br. s., 1H). 13C NMR (101 MHz, DMF) δ ppm 22.46 (s, 1 C) 38.02 (s, 1 C) 58.54 (s, 1 C) 66.92 (s, 1 C) 71.91 (s, 1 C) 118.91 (s, 1 C) 120.35 (s, 1 C) 121.07 (s, 1 C) 125.49 (s, 1 C) 132.82 (s, 1 C) 133.22 (s, 1 C) 136.79 (s, 1 C) 137.04 (s, 1 C) 140.37 (s, 1 C) 149.26 (s, 1 C) 155.35 (s, 1 C) 159.21 (s, 1 C) 169.69 (s, 1 C) 169.72 (s, 1 C). HPLC-MS: retention time=1.12 min (99.3%@215 nm; 98.1% @254 nm; m/z=401.1, calculated for C19H20N4O4S+H+=401.1).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=O)(O)=[O:28]>C(O)CO>[C:38]1([C:36]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27](=[O:28])[N:1]([C:3]3[CH:8]=[C:7]([C:9]4[C:18]5[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=5)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=4)[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOc1cc2cc(CO)cc(-c3ccnc(NN)c3)c2cc1OCC
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: OCCO
Product: CCOc1cc2cc(CO)cc(-c3ccnc(-n4nc(-c5ccccc5)c5ccccc5c4=O)c3)c2cc1OCC
Yield: 75.7 %

Procedure:
1-(2-Hydrazino-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (177 mg), 1-carboxy-2-phenylcarbonylbenzene (191 mg) and ethylene glycol (1 ml) are treated in the same manner as in Example 104-(3) to give 1-{2-(4-phenyl-1(2H)-phthalazinon-2-yl)-4-pyridyl}-3-hydroxymethyl-6,7-diethoxynaphthalene (206 mg), which is listed in Table 14.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-Fluoronitrobenzene (3.0 g, 21.3 mmol) was dissolved in toluene (25 mL). Thiomorpholine (2.4 mL, 23.4 mmol) was added and the mixture stirred overnight at 100° C. At 17 h, the mixture was distributed between ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH2:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C1COCC1>[CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1cc(N)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a stirred mixture of 3-ethyl-1-phenyl-1H-pyrazol-5-amine (1.00 g, 5.34 mmol) and potassium carbonate (1.48 g, 10.68 mmol) in THF (50 mL) at −5° C., was added phenyl chloroformate (1.00 g, 6.41 mmol) dropwise. After stirring for a further 30 min at −5° C., the reaction mixture it was warmed to rt and stirred for a further 15 h. The mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford an oil. Recrystallization from petroleum ether gave phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (1.00 g, 61%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 10.07 (brs, 1H), 6.74-7.59 (m, 10H), 6.30 (s, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z 308 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](I)[CH3:21]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([O:13][CH2:20][CH3:21])=[CH:4][N:3]=1
Reactant: CCI
Reactant: Oc1cnc(Cl)c2cccc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a solution of 1,5-dichloroisoquinolin-4-ol (0.5 g, 2.33 mmol) in acetonitrile (15 ml) was added K2CO3 (0.96 g, 7.01 mmol) followed by ethyl iodide (0.72 g, 4.67 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1,5-dichloro-4-ethoxyisoquinoline (0.3 g, 53%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.26-8.24 (d, J=8 Hz, 1H), 7.86 (s, 1H), 7.78-7.76 (d, J=8 Hz, 1H), 7.55 (t, J=8 Hz, 1H), 4.26-4.21 (m, 2H), 1.57 (t, J=7 Hz, 3H); MS: MS m/z 242.6 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([OH:12])[CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1ccccc1OCc1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)c1ccccc1OCc1ccccc1

Procedure:
2-(benzyloxy)benzaldehyde (5g, 23.6 mmol) was reacted with vinylmagnesium bromide in THF (90 ml) at 0 C. The reaction was quenched with 2 N HCl and the product was extracted in i-PrOAc, dried over Na2SO4 and purified by flash chromatography with EtOAc:toluene 2.5:97.5.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36](Cl)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:20]=[C:21]([F:28])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:28][C:21]1[CH:20]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36]([C:4]3[CH:5]=[CH:6][C:1]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:2][CH:3]=3)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:18]=[C:17]([F:16])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc(-c3ccccc3)cc2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 30.9 %

Procedure:
4-Biphenylboronic acid (51.5 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (20 mg, 31%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3].[NH2:22][C:23](=[N:43]O)[C:24]1[CH:33]=[C:32]2[C:27]([CH2:28][CH2:29][N:30]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)=[CH:26][CH:25]=1>CCOC(C)=O>[CH2:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:16][N:22]=[C:23]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][N:30]([CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:43]=2)=[CH:12][C:11]=1[CH2:19][O:20][CH3:21])[CH3:3]
Reactant: CCC1CCCCN1c1ccc(C(=O)O)cc1COC
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC1CCCCN1c1ccc(-c2nc(-c3ccc4c(c3)CN(CCC(=O)OC(C)(C)C)CC4)no2)cc1COC

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 22 (188 mg; 0.6 mmol) and Intermediate 25 (182 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum.
Reaction SMILES: [CH3:1][NH2:2].CO.C([O:7][C:8](=O)[CH2:9][C:10](=[O:16])[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)C>CO>[CH3:1][NH:2][C:8](=[O:7])[CH2:9][C:10](=[O:16])[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)c1cccs1
Reactant: CN
Solvent: CO
Product: CNC(=O)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A 9.8 g (126.26 mmol) portion of 40% methylamine/methanol solution was added to 20 ml of methanol solution containing 5 g (25.25 mmol) of 3-oxo-3-(2-thienyl)propionic acid ethyl ester obtained in Reference Example 1 and stirred at room temperature for 19 hours. After the reaction, the solvent and excess methylamine were evaporated under a reduced pressure to obtain 4.6 g of crystals of N-methyl-3-oxo-3-(2-thienyl)propionamide.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][NH:15][C:7]=12>C1(C)C(C)=CC=CC=1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:8]3=[N:9][C:10]([CH3:12])=[CH:11][C:6]([NH:4][CH2:3][CH2:1][OH:2])=[C:7]3[NH:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(Cl)c2[nH]nc(-c3ccc(Cl)cc3)c2n1
Reactant: NCCO
Solvent: Cc1ccccc1C
Product: Cc1cc(NCCO)c2[nH]nc(-c3ccc(Cl)cc3)c2n1

Procedure:
A mixture of ethanolamine (5 ml) and 7-chloro-5-methyl-3-(4-chlorophenyl)-1H-pyrazolo[4,3-b]pyridine (D16) (0.6 g) were heated under reflux in xylene (10 ml) under nitrogen for 48 h. The mixture was evaporated to dryness in vacuo and dissolved in a mixture of water (40 ml) and methanol (60 ml). The pH of the solution was adjusted to ca. 12 with 10% sodium hydroxide solution and then the solution was evaporated to one third volume in vacuo. The resulting precipitate (0.6 g) was collected, washed with water, and recrystallised from ethyl acetate-methanol (trace) to afford the title compound (0.42 g), m.p. 222°-224° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)[CH:29]=[O:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:31]=[C:28]([CH2:29][OH:30])[CH:27]=[N:26][CH:25]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To a solution of 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinaldehyde (30.0 mg, 0.0740 mmol) in methanol (25 mL) was added NaBH4 (8.40 mg, 0.220 mmol). Reaction mixture was stirred at room temperature for 3 h and diluted with cold water (50 mL). The aqueous solution was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with saturated brain solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 12 g, 40% EtOAc/hexanes) to get (5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)methanol (15.0 mg, 50.0%). LCMS Condition B-12: retention time 2.15 min, [M+1]=406.2. HPLC Condition B-2: retention time 9.20 min, Purity 98.03%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.64 (d, J=5.7 Hz, 2H), 4.82 (d, J=5.7 Hz, 2H), 5.45 (t, J=5.7 Hz, 1H), 6.64 (t, J=5.2 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 7.22-7.55 (m, 10H), 7.90 (d, J=2.7 Hz, 1H), 8.49 (t, J=2.1 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 9.24 (d, J=2.0 Hz, 1H).