Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:38]=[C:37]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:34][C:35]3[CH:36]=[C:37]([C:45]([CH3:47])([CH3:46])[CH3:48])[CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)C2)c1
Yield: 88.3 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (84 mg, 0.19 mmol) in CH3CN (5 ml) was added 1-Bromomethyl-3,5-di-tert-butyl-benzene (80.0 mg, 0.28 mmol), and diisopropylethylamine (66 μl, 0.38 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (109 mg, 85%). Calcd for C41H54F3NO2 (M+H) 649.87, Found 650.5
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(CCO)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH2:20][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCCC1CCCCC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OCCC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 0.25 h

Procedure:
A mixture of 6.93 g (0.02 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate 1.4 g of tetraethyl orthotitanate and 24 g of 2-cyclohexyl-ethanol is heated to 140° for 2.5 hours, evaporated in vacuo, the residue is taken up in chloroform and the solution is poured into about 20 percent hydrochloric acid. The mixture is stirred for 15 minutes, the chloroform phase is separated, washed successively with 2N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. After chromatography on a silica gel column while eluting with ethyl acetate and subsequent crystallization from ethyl acetate/hexane, there is obtained 2-cyclohexylethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 131°-132°.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([NH2:11])=O)([O-:3])=[O:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:9]([C:5]1[S:6][CH:7]=[CH:8][C:4]=1[N+:1]([O-:3])=[O:2])#[N:11]
Reactant: NC(=O)c1sccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1sccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
The amide 30 (15.5 g, 90 mmol), prepared as described above, was dissolved in dichloromethane (700 ml). Triethylamine (27.2 g, 37.6 ml, 270 mmol) was added and the solution cooled to 0° C. After dropwise addition of neat trifluoroacetic anhydride (24.6 g, 16.5 ml, 117 mmol), the reaction was allowed to warm to room temperature and stirred for 1 h. The solution was concentrated in vacuo, the residue taken into ethyl acetate and then washed successively with hydrochloric acid (1N, 2×), water (1×), saturated aqueous sodium hydrogencarbonate (2×) and brine. Drying over sodium sulfate and removal of solvent gave a dark solid, which was purified by flash chromatography (400 g of silica gel, petroleum ether:ethyl acetate 7:3+1% MeOH as eluent) yielding 2-cyano-3-nitrothiophene 31 (13.4 g, 96.5%). 1H NMR (CDCl3): δ 7.75 (1H, d, J 5.5), 7.68 (1H, d, J 5.5). An analytical sample was obtained by recrystallization from dichloromethane/n-pentane, m.p. 87–88° C.; elemental analysis, calc. for C5H2N2O2S: C, 38.96; H, 1.31; N, 18.17; S, 20.80. Found: C, 38.92; H, 1.20; N, 18.03; S, 21.31.
Reaction SMILES: [CH:1]12[CH2:13][CH:4]([C:5]3[C:6]([OH:12])=[CH:7][CH:8]=[C:9]([OH:11])[C:10]=31)[CH2:3][CH2:2]2.B(F)(F)F.[CH3:18]COCC.[CH3:23][C:24]1([CH:30]=[CH2:31])[O:28][C:27](=[O:29])[CH2:26][CH2:25]1.O>O1CCOCC1>[CH3:18][O:28][C:27](=[O:29])[CH2:26][CH2:25][C:24]1([CH3:23])[CH2:30][CH2:31][C:7]2[C:6](=[C:5]3[CH:4]4[CH2:13][CH:1]([CH2:2][CH2:3]4)[C:10]3=[C:9]([OH:11])[CH:8]=2)[O:12]1
Reactant: C=CC1(C)CCC(=O)O1
Reactant: Oc1ccc(O)c2c1C1CCC2C1
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1,4-methano-naphthalene-5,8-diol (1.34 g, 7.94 mmol), 1.0 mL (3.97 mmol) of BF3.Et2O and 25 mL of dioxane was heated up to 110° C. under a nitrogen atmosphere. A solution of 5-methyl-5-vinyl-dihydro-furan-2-one (1.12 mg, 8.6 mmol) in 24 ml of dioxane was added slowly to the mixture. The addition was completed after two hours and the mixture was continued to reflex for additional 3 hours. After cooling down to room temperature, the mixture was poured to water, extracted with ethyl acetate, washed with water and dried over MgSO4. After the removal of solvents, the residue was mixed with methanol/HCl and let stand overnight at room temperature. Then the solvents were removed and the residue was purified via flash column chromatography on silica gel (1:3 EtOAc/Hex) twice to give 1.30 g of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.29 (s, 1H), 4.70 (s, 1H), 3.68 (s, 3H), 3.52-3.46 (d, 2H), 2.69-2.55 (m, 2H), 2.52-2.47 (m, 2H), 2.00-1.64 (m, 8H), 1.43-1.15 (m, 5H). MS (ESI): 317 (M+H, 70%), 339 (M+Na+, 100%).
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][S:12]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[CH:19][CH:18]=1)(=[O:14])=[O:13])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.O1CCCC1>[C:4]([O:8][C:9]([NH:11][S:12]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[CH:21][CH:22]=1)(=[O:14])=[O:13])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
Lithium hydroxide monohydrate (826 mg, 19.68 mmol) in water (10 mL) was added to a solution of ethyl 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoate (3.8 g, 9.84 mmol) in tetrahydrofuran (30 mL) at 0° C. and stirred at room temperature for 18 h. The volatiles were evaporated; the residue diluted with water (50 mL) and extracted with diethyl ether (2×20 mL). The aqueous layer was acidified (pH ˜5) with acetic acid at 0° C., precipitated solid was filtered and dried under reduced pressure to afford 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoic acid (2.3 g, 56%) as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][C:12]1[C:13](=[O:21])[CH2:14][C@@H:15]([O:17]C(=O)C)[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C1C=CC=CC=1.C(OC(CC1C(=O)C[C@@H](OC(=O)C)C=1)=O)C>C(O)C>[CH2:1]([O:8][C:9]([CH2:11][C:12]1[C:13](=[O:21])[CH2:14][C@@H:15]([OH:17])[CH:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[C@H]1C=C(CC(=O)OCc2ccccc2)C(=O)C1
Agent: CCOC(=O)CC1=C[C@H](OC(C)=O)CC1=O
Solvent: OCc1ccccc1
Solvent: CCO
Product: O=C(CC1=C[C@H](O)CC1=O)OCc1ccccc1

Procedure:
Example 34: Example 34 was conducted according the procedure of Example 32 except that the starting material was (R)-2-benzoxycarbonylmethyl-4-acetyloxy-2-cyclopenten-1-one (4 g, 97% e.e.) and benzyl alcohol were used instead of (R)-2-ethoxycarbonylmethyl-4-acetoxy-2-cyclopenten-1-one and ethanol. The titled compound was obtained with high optical purity (3.4 g, 99% e.e.).
Reaction SMILES: C1(/C=[CH:8]/[C:9]2[N:10]=[CH:11][C:12]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:13]=3[N:14]=2)C=CC=CC=1.CSC.CN(C=[O:27])C>CO>[O:19]=[C:16]1[NH:15][C:13]2[N:14]=[C:9]([CH:8]=[O:27])[N:10]=[CH:11][C:12]=2[CH2:18][CH2:17]1
Reactant: CN(C)C=O
Reactant: O=C1CCc2cnc(/C=C/c3ccccc3)nc2N1
Solvent: CO
Solvent: CSC
Product: O=Cc1ncc2c(n1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a round bottom flask was added 2-[(E)-2-phenylethenyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (600 mg, 2.39 mmol) in DMF (10 mL) and methanol (10 mL). Ozone was bubbled through the solution at room temperature for 20 minutes and the excess ozone was purged with a stream of nitrogen. Dimethyl sulfide (1.77 mL, 23.9 mmol) was added and the reaction was stirred at room temperature for 24 h. The solvent was evaporated and the resulting solid was dissolved in 20% MeOH-DCM. The crude product was added to a silica gel column and was eluted with 0-20% MeOH-DCM. The collected fractions gave the title compound (400 mg, 95% yield).
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:30][CH2:31][N:32]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:33][CH2:34]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:37])=[O:36])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-phenethyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.244 mmol) was alkylated using (S)-2-methyloxirane (26 mg, 0.488 mmol), DIPEA (171 μL, 0.977 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=661.7 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].O[N:21]1[C:25]2C=[CH:27][CH:28]=[CH:29][C:24]=2N=N1.CCN=C=NCCCN(C)C.N1CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:21]2[CH2:27][CH2:28][CH2:29][CH2:24][CH2:25]2)=[O:13])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCCCC2)cc1[N+](=O)[O-]

Procedure:
2-Nitro-terephthalic acid 1-tert-butyl ester (500 mg, 1.88 mmol) in DCM (18 mL), was treated with 1-hydroxybenzotriazole (0.39 g, 2.43 mmol), EDCI (0.47 g, 2.43 mmol) and piperidine (0.24 mL, 2.43 mmol). After 3 hours the reaction was diluted with DCM (50 mL) and washed with aqueous NaHCO3 (30 mL), water (30 mL) and finally with brine. After drying over sodium sulphate and evaporation of the solvent the title compound was obtained as a colourless oil in quantitative yield. The crude was employed in the following reaction without any further purification.
Reaction SMILES: [OH:1][C:2]1[C:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([CH3:10])[O:9][C:5]2=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[N:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30](S(C)(=O)=O)[N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:35][O:34][C:32]1[N:33]=[C:28]([O:27][CH3:26])[N:29]=[C:30]([O:1][C:2]2[C:15]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]3[C:7]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([CH3:10])[O:9][C:5]3=[CH:4][CH:3]=2)[N:31]=1
Reactant: COc1nc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1c(C)oc2ccc(O)c(C(=O)OCc3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)oc2ccc(Oc3nc(OC)nc(OC)n3)c(C(=O)OCc3ccccc3)c12
Temperature: 70 °C
Reaction time: 2 h
Yield: 109.7 %

Procedure:
A mixture comprising 2 g of benzyl 5-hydroxy-2-methyl-3-methoxycarbonylbenzofuran-4-carboxylate, 1 g of 4,6-dimethoxy-2-methylsulfonyl-1,3,5-triazine and 1 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was heated and stirred at 70° C. for two hours. The mixture was returned to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the obtained solid was thoroughly washed with ethanol to obtain 2.4 g (yield: 86%) of the desired compound.
Reaction SMILES: Br[C:2]1[N:18]([CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]2)[C:5]2[C:6]([O:11][CH:12]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH3:13])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=2[N:3]=1.[C:27]1([C@@H:33]2[CH2:38][O:37][CH2:36][CH2:35][NH:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[F-].[Cs+]>CS(C)=O.O>[Cl:10][C:8]1[N:7]=[C:6]([O:11][CH:12]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH3:13])[C:5]2[N:18]([CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]3)[C:2]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][C@H:33]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:3][C:4]=2[CH:9]=1
Reactant: CC(Oc1nc(Cl)cc2nc(Br)n(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Reactant: c1ccc([C@@H]2COCCN2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1nc(Cl)cc2nc(N3CCOC[C@H]3c3ccccc3)n(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Temperature: 125 °C

Procedure:
To a solution of 2-bromo-6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (1.5 g, 3.40 mmol) in DMSO (15 mL), in a microwave tube was added (R)-3-phenylmorpholine (797 mg, 4.77 mmol) and cesium fluoride (3.6 g, 23.8 mmol). The reaction was heated at 125° C. in a microwave for 45 mins. The reaction was then diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 8-10% EtOAc/petroleum ether) to yield (3R)-4-(6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-phenylmorpholine. MS ES/APCl calc'd. for C30H39ClN4O2 [M+H]+ 523. found 523.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:17][O:18][CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22]Cl.C(N(CC)CC)C.S(=O)(=O)(O)O>ClCCl>[CH3:17][O:18][CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCCN(CCC#N)SCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(CCC#N)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 19.9 g (0.09 mole) quantity of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was poured into 100 ml of a dichloromethane solution containing 19.45 g (0.1 mole) of N-(2-methoxyethyl)-N-cyanoethylaminosulfenyl-chloride. The mixture was agitated by a stirrer and 18 g (0.18 mole) of triethylamine was added dropwise thereto at less than 10° C. over a period of 30 minutes. Thereafter the mixture was stirred at the same temperature for 2 hours. A 5% aqueous solution of sulfuric acid was added to the mixture until a pH of 6 was achieved. The dichloromethane solution was washed with a 5% aqueous solution of sodium hydrogencarbonate and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated at reduced pressure, giving 31.8 g of a yellowish brown oily product in a yield of 84.0%.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:17]([CH2:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][CH2:14][C:13]1=[O:27]>CO.C(Cl)Cl>[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC(=O)CCC1CCCC(=O)N1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCC(O)CCC1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
Sodium borohydride (24 mg, 0.63 mmol), followed by MeOH (2 drops), was added to a solution of 7-[2-oxo-6-(3-oxo-octyl)-piperidin-1-yl]-heptanoic acid methyl ester (23 mg, 0.063 mmol) in CH2Cl2 (1.0 mL) at 0° C. The mixture was allowed to warm to rt. After 4 h at rt, the reaction was quenched with HCl (11.0M aqueous) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 14 mg (61%) of the title compound.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:6]=[C:7]([CH2:21][CH2:22][OH:23])[CH:8]=[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:10]=1[Cl:11].CCN(C(C)C)C(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CCOCC>[CH3:33][S:34]([O:23][CH2:22][CH2:21][C:7]1[CH:8]=[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCO)cc(Cl)c1Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCOS(C)(=O)=O)cc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a dichloromethane (0.11 M) solution of 2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]ethanol (1 eq.) from the previous step was added at 0° C. Hunig's base (1.5 eq.) and methanesulfonyl chloride (1.1 eq.). The resulting suspension was stirred at 0° C. for 30 min and at RT for 15 min. The reaction was then diluted with ether and quenched with 1N aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to give the title compound as a brown oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:10]=2)[NH:5][CH:4]=1)#[CH:2].Cl[C:25](=[N:42][OH:43])[C:26]1[CH:27]=[C:28]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C1COCC1>[CH:21]([S:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:10]=[C:11]3[C:3]([C:1]4[O:43][N:42]=[C:25]([C:26]5[CH:27]=[C:28]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])[CH:29]=[CH:30][CH:31]=5)[CH:2]=4)=[CH:4][NH:5][C:6]3=[N:7][CH:8]=2)=[CH:17][CH:16]=1)(=[O:20])=[O:19])([CH3:23])[CH3:22]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(C(Cl)=NO)c1
Reactant: C#Cc1c[nH]c2ncc(-c3ccc(S(=O)(=O)C(C)C)cc3)nc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1cccc(-c2cc(-c3c[nH]c4ncc(-c5ccc(S(=O)(=O)C(C)C)cc5)nc34)on2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.8 %

Procedure:
To a solution of 7-ethynyl-2-(4-isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (72 mg, 0.2213 mmol) and tert-butyl 1-(3-(chloro(hydroxyimino)methyl)phenyl)ethylcarbamate (66.12 mg, 0.2213 mmol) in THF (2.5 mL) was added triethylamine (26.88 mg, 37.02 μL, 0.2656 mmol) The mixture was stirred at ambient temperature for 45 minutes then heated at 65° C. for 3.5 hours. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residues was dissolved in warm DCM (50 mL) and washed with saturated aqueous NaHCO3(×1), dried (MgSO4), filtered and concentrated in vacuo. The residue triturated from hot MeCN and the precipitate obtained on cooling was isolated by filtration and washed with MeCN to give the sub-title compound as a pale yellow powder (83 mg, 64% Yield). 1H NMR (400 MHz, DMSO) δ 1.28 (d, 6H), 1.41-1.45 (m, 3H), 1.43 (s, 9H), 3.58 (sept, 1H), 4.79 (br t, 1H), 7.52-7.62 (m, 4H), 7.92 (d, 1H), 8.00 (s, 1H), 8.10 (d, 2H), 8.68 (d, 2H), 8.76 (s, 1H), 9.25 (s, 1H) and 13.08 (br s, 1H) ppm; MS (ES) 588.1.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:48])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)[CH2:25][CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C)C)[C:15]=3[Cl:47])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:49]>CO.O1CCOCC1>[ClH:47].[ClH:49].[C:1]12([CH2:11][NH:12][C:13](=[O:48])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:36][CH2:37][CH2:38][OH:39])[C:15]=3[Cl:47])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)[Si](C)(C)OCCCN(CCCNc1nccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl)CCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccnc(NCCCN(CCCO)CCCO)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(1-adamantylmethyl)-2-({3-[bis(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)amino]-propyl}amino)3-chloroisonicotinamide (Example 36(iii)) in methanol (5 ml) was treated with HCl in 1,4-dioxane (3 ml). The mixture was stirred at room temperature for 3 hrs. The solvent was evaporated. The product was purified by reverse phase HPLC, using NH3/H2O/CH3CN as eluant. The resulting oil in methanol was treated with ethereal HCl and the solvent was evaporated to yield the title compound as a white solid (0.14 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:11][C:12]1([F:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:11][C:12]1([F:18])[CH2:17][CH2:16][N:15]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)=[O:7])[CH2:14][CH2:13]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1cccc(I)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(I)c1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-iodobenzoic acid 1 (482 mg, 1.94 mmol) in DMF (6 mL) was added 4,4-difluoropiperidine 2 (259 mg, 2.14 mmol), HATU (886 mg, 2.33 mmol) and diisopropylethylamine (750 mg, 5.81 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N sodium hydroxide solution, 1 N hydrochloric acid, water and brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired 4,4-difluoro-1-[(3-iodophenyl)carbonyl]piperidine compound 77-1 (362 mg, 1.03 mmol).