Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:34]3[C:29](=[N:30][CH:31]=[N:32][C:33]=3[NH2:35])[N:28]([C@H:36]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH2:38][CH2:37]3)[N:27]=2)=[CH:22][C:21]=1[O:49][CH3:50]>ClCCl.CN(C=O)C.N1C=CC=CC=1>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([C@H:36]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:38][CH2:37]3)[N:27]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([NH:19][C:6]([C:5]4[O:1][C:2]5[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=5[CH:4]=4)=[O:8])=[C:21]([O:49][CH3:50])[CH:22]=3)[C:34]=12
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2o1
Reaction time: 8 h

Procedure:
To benzo[b]furan-2-carboxylic acid (0.743 g, 4.58 mmol) in dichloromethane (14 mL) was added oxalyl chloride (4 mL, 45.8 mmol) and DMF (1 drop). The reaction mixture was stirred overnight. Solvent was evaporated and the residue was dissolved in Dichloromethane (5 mL). Half of the dichloromethane solution (2.5 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.50 g, 1.145 mmol) in pyridine (6 mL) at 0° C. After 30 minutes, the solid as collected by filtration. Water was then added to the solid and the pH of the solution was adjusted to 10 with sodium hydroxide (1.0N). The aqueous was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)benzo[b]furan-2-carboxamide (0.497 g, 75%). 1H NMR (DMSO-d6) δ 1.49 (m, 2H), 2.01 (m, 6H), 2.15 (s, 3H), 2.40 (m, 3H), 2.51 (m, 4H), 4.00 (s, 3H), 4.66 (m, 1H), 7.31 (m, 1H), 7.39 (m, 2H), 7.54 (m, 1H), 7.81 (m, 3H), 8.24 (m, 1H), 9.50 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].[CH3:29][S:30][C:31]1[CH:38]=[CH:37][C:34](CBr)=[CH:33][CH:32]=1>>[CH3:29][S:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@H:15]4[CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:12])=[O:13])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:33][CH:32]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: CSc1ccc(CN2C(=O)C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4COc4ccccc4)ccc32)cc1
Yield: 64 %

Procedure:
(S)-1-(4-Methylthiobenzyl)-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (11d) was prepared according to the same procedure for compound 11a, except using 4-methylthiobenzyl bromide, and purified with hexanesether (1:2) to afford 152 mg (64%) of 11d as a yellow solid, mp 175.4-176.8° C. 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.99 (d, J=10.5 Hz, 1H), 7.27 (m, 6H), 6.96 (t, J=7.2 Hz, 1H), 6.86 (t, J=8.1 Hz, 3H), 4.90 (s, 2H), 4.19 (d, J=8.7 Hz, 1H), 3.96 (m, 2H), 3.53 (m, 1H), 3.25 (m, 1H), 2.50 (s, 3H), 2.05 (m, 2H), 1.82 (m, 2H). Anal. Calcd for C27H26N2O5S2: C, 62.05, H, 5.01; N, 5.36. Found: C, 61.81, H, 4.95; N, 5.34.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][P:37]([O-:41])[O:38][CH2:39][CH3:40])[CH3:35].CN1CCOCC1>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:33])[CH:10]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[C:11]1[CH:12]=[CH:13][C:14]([P:37]([O:38][CH2:39][CH3:40])([O:36][CH2:34][CH3:35])=[O:41])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCOP([O-])OCC
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Temperature: 75 °C
Yield: 93.1 %

Procedure:
To a solution of tert-butoxycarbonylamino-(4-trifluoromethane-sulfonyloxy-phenyl)-acetic acid benzyl ester (2.2 g, 4.50 mmol) in acetonitrile (10 mL) was added diethylphosphite (643 μL, 5.00 mmol) followed by N-methylmorpholine (691 μL, 6.30 mmol). The mixture was purged with nitrogen and tetrakis-triphenylphosphine palladium (260 mg, 0.23 mmol, 15 mol %) was added. The reaction mixture was heated to 75° C. overnight then cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was poured into a separatory funnel containing ethyl acetate (100 mL) and washed with 0.2M aqueous hydrochloric acid (2×), water (2×), brine and dried over sodium sulfate. The solvent was removed in vacuo, and the product was chromatographed over silica gel gradient eluted between 10 to 75% ethyl acetate in hexanes to afforded tert-butoxycarbonylamino-[4-(diethoxy-phosphoryl)-phenyl]-acetic acid benzyl ester (2.0 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([C:14]#[C:15][Si](C)(C)C)[CH:11]=[CH:10][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([C:12]1[CH:11]=[CH:10][C:3]([CH2:4][N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)=[C:2]([CH3:1])[CH:13]=1)#[CH:15]
Reactant: Cc1cc(C#C[Si](C)(C)C)ccc1Cn1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(Cn2ccnc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; 1-(2-methyl-4-trimethylsilanylethynyl-benzyl)-1H-imidazole (Intermediate 140, 140.0 mg, 0.53 mmols) in methanol (5 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (105 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][Si](C(C)(C)C)(C)C)[CH2:16][CH2:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)(=O)C.O1CCCC1.[OH-].[Na+]>O>[O:1]=[C:2]([N:14]1[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCC(=O)N1CCC(O)CC1
Temperature: 75 °C

Procedure:
Mix 1-oxododecyl-4-(O-tert-butyldimethylsilyloxy)piperidine (3.5 mmol) with a solution of acetic acid (9 mL), tetrahydrofuran (6 mL) and water (6 mL). Heat at 75° C. overnight. Cool to room temperature and make basic with 10% sodium hydroxide and extract into methylene chloride. Wash with water, then with brine and dry (Na2SO4). Evaporate the solvent in vacuo and purify by flash chromatography (5% methanol/methylene chloride) to give the title compound. 587E-115
Reaction SMILES: F[C:2]1C=[CH:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.BrC1C=CC(F)=C[N:19]=1>>[N:6]1[CH:7]=[CH:2][N:19]=[CH:4][C:5]=1[N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: Fc1ccc(Br)nc1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Product: c1cnc(-n2cnc3cnccc32)cn1

Procedure:
Intermediate 4 was prepared in a manner analogous to Intermediate 1, substituting 2-bromopyrazine for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C10H7N5, 198.07; m/z found 199.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37]2)(=[O:33])=[O:32].N1CCCCC1>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])/[C:37]/2=[CH:17]\[C:14]1[NH:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=2[C:15]=1[CH3:16])(=[O:32])=[O:33]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 79.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (60 mg, 0.21 mmol) and 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (67 mg, 0.19 mmol) were dissolved in 3 ml of ethanol, and added with 52 μl of piperidine the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-oxoindolin-3-ylidene)methyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydro pyrrolo[3,2-c]azepin-4(1H)-one 70 (95 mg, yield 79%) as an orange solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Br:18])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2([CH3:17])[CH3:16])(=O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:18][C:6]1[CH:7]=[C:8]2[C:13](=[C:4]([CH2:1][CH3:2])[CH:5]=1)[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]2([CH3:16])[CH3:17]
Reactant: CC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred, cooled (ice bath) solution of 8-acetyl-6-bromo-2,2,4,4-tetramethyl chroman (Intermediate 45, 0.95 g, 3.1 mmol) in trifluoroacetic acid (10 mL) was treated with triethylsilane (10 mL) and the resulting reaction mixture was allowed to warm to ambient temperature and stirred overnight. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with hexane (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent to afford the title compound as a clear oil, contaminated with a small amount to triethylsilane (0.51 g, 56%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([N:8]2[C:7]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)=[O:20])=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9]2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(C#N)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CN)cc2)n1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
To a solution of 1-[5-tert-butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (4.0 g, 8.8 mmol) in anhydrous THF (20 mL) was added a solution of lithium aluminum hydride in THF (1M, 9.7 mL, 9.7 mmol) with stirring at 0° C. under nitrogen, and then the reaction mixture was stirred at room temperature for 5 h. The excess lithium aluminum hydride was quenched by dropwise addition of EtOAc (5 mL) followed by EtOH (5 mL) and then 10% aqueous KHSO4 solution (5 mL). The reaction mixture was stirred at room temperature for an additional 10 min, and was then filtered through a pad of Celite® filter agent. The Celite® was washed with EtOH (50 mL) and the filtrate was concentrated at reduced pressure. The residue was purified by MPLC (80:20 CH2Cl2/MeOH) to give 3.2 g (79%) of the desired product. 1H-NMR (DMSO-d6) δ 9.38 (s, 1H), 8.41 (dd, J=1.5, 4.8 Hz, 2H), 7.49 to 7.46 (m, 6H), 7.07 (d, J=6.9 Hz, 2H), 6.85 (dd, J=1.8, 4.8 Hz, 2H), 6.32 (s, 1H), 3.82 (s, 2H), 1.26 (s, 9H); MS LC-MS [M+H]+=457, RT=1.96 min.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18].[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C1C=CC=CC=1>[Cl:18][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2c(O)ccnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1cnn2c(Cl)ccnc12
Temperature: 80 °C
Yield: 25.1 %

Procedure:
To a stirred suspension ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.95 g, 4.6 mmol) in POCl3 (8.0 mL, 86 mmol) was added dimethyl aniline (0.8 μL, 0.006 mmol) and the mixture was heated at 80° C. for 2 hours. The mixture was slowly poured onto ice, and the pH was carefully adjusted to ˜7 with 1N NaOH, then to pH 10 with solid Na2CO3. The mixture was then extracted with dichloromethane (3×). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness. Trituration of the solids with hexanes gave ethyl 7-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (260 mg, 25%) as a tan solid. ESI-MS m/z calc. 225.0, found 226.5 (M+1)+; Retention time: 0.87 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(F)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-(3,4-difluorophenyl)-boronic acid, (CAN 168267-41-2) as starting materials.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:32][CH2:33][O:34]C)[CH:4]=[CH:5]2.O.[C:37](O)(=O)C>>[C:33]([O:32][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1)[CH2:11][CH2:10][C@@H:9]35)(=[O:34])[CH3:37]
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OCc4ccc(C(=O)OC)cc4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(CO[C@H]2CC[C@H]3[C@H]4Cc5ccc(OC(C)=O)c6c5[C@@]3(CCN4C)[C@H]2O6)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinane (1.40 g, 2.92 mmol) is dissolved with water (35 ml) and glacial acetic acid (35 ml) and then stirred for 4 hours at 100° C. The volatile components are eliminated using the Rotavapor. The residue thus obtained is purified by flash chromatography (100 g of silica gel; mobile phase: methylene chloride/methanol= 4:1). The product is dissolved in a mixture of water and glacial acetic acid and lyophilised. Yield: 1.225 g 4,5α-epoxy-17-methyl-6α-((4-(methyloxycarbonyl)-phenyl)-methoxy)-morphinan-3-ol acetate (84.7%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH2:34])=[CH:30][N:29]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:34][C:31]3[CH:30]=[N:29][C:28]([O:27][CH3:26])=[N:33][CH:32]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: COc1ncc(N)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ncc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Temperature: 150 °C
Yield: 59.8 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), 2-methoxypyrimidin-5-amine (65.9 mg, 526 μmol), xantphos (60.9 mg, 105 μmol), Pd2(dba)3 (32.1 mg, 35.1 μmol) and cesium carbonate (229 mg, 702 μmol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 40-80% ethyl acetate in hexanes) to give N-tert-butyl-2-(2-methoxypyrimidin-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (99 mg, 210 μmol, 60%) as a yellow solid. (EI/CI) m/z: 484.3 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:36][CH:35]2[O:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]3[O:60][CH2:59][CH2:58][N:57]([CH2:61][CH2:62][CH2:63][O:64][CH3:65])[C:56]=3[CH:66]=2)=[CH:30][CH:29]=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:36][CH:35]2[O:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]3[O:60][CH2:59][CH2:58][N:57]([CH2:61][CH2:62][CH2:63][O:64][CH3:65])[C:56]=3[CH:66]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN)cc3)cc21
Reactant: O=C(O)Cc1ccccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNC(=O)Cc4ccccc4F)cc3)cc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.135 g of 2-fluorophenyl acetic acid is dissolved in 5 ml of dichloromethane. 0.127 g of carbonyldiimidazole is added and the reaction solution is stirred at 20° C. over 1 hour. A solution of 0.472 g of benzyl 4-[4-(2-aminoethoxy]phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benz[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 184) in 4 ml of dichloromethane is added dropwise and the solution is subsequently stirred at 20° C. over 1 hour. The reaction solution is diluted with 10 ml of dichloromethane and subsequently washed with 10 ml each of 1M NaOH and water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a light yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (4:1 EtOAc-heptane); Rt=5.14.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:20][CH:19]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(Cn2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The purpose of this example is to demonstrate one method for the preparation of a benzimidazole derivative of Formula IV. To a stirred, room temperature, solution of benzimidazole (11.8 g, 1.00×10-1 mole) and dry DMF (100 ml) was added portion-wise sodium hydride (4.4 g, 1.1×10-1 mole, 60% oil dispersion). After ca. 30 minutes, 4-fluorobenzyl chloride (14.6 g, 1.01×10-1 mole) Was added. The reaction was stirred at room temperature for ca. 17 hours and was then poured into a separatory funnel containing water and a 2:1 mixture of ethyl acetate:toluene. The two phases were mixed and the aqueous layer was separated. The organic layer was washed two times with H2O and once with saturated aqueous NaCl before being dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil which was purified by flash chromatography (20% acetone/ethyl acetate). The resulting oil was kugelrohr distilled (230°-245° C./0.3 mm) affording 1 [(4-fluorophenyl)methyl]-1H-benzimidazole as an oil which solidified giving a colorless solid: 17.4 g (77%), m.p. 60°-62° C.
Reaction SMILES: I[CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[CH2:18][CH2:17]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].[C:52]([CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])#[N:53]>C1C=CC=CC=1>[C:52]([CH:54]([CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[CH2:18][CH2:17]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2)[C:55]([O:57][CH2:58][CH3:59])=[O:56])#[N:53]
Reactant: CCOC(=O)CC#N
Reactant: IC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A mixture of (3S)-3-(iodomethyl)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (287 mg, 0.57 mmol, 1.00 equiv), 18-Crown-6 (190 mg, 0.72 mmol, 1.25 equiv), potassium carbonate (141 mg, 1.02 mmol, 1.78 equiv) and ethyl 2-cyanoacetate (678 mg, 5.99 mmol, 10.43 equiv) in benzene (20 mL) was stirred overnight at 80° C. under nitrogen. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by a silica gel column with DCM/MeOH (30:1-10:1) to provide 230 mg (83%) of ethyl 2-cyano-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanoate as a light yellow solid. MS (ES): m/z 485 [M+H]+.