Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]([OH:12])CO)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)NCC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a stirred solution of (2,3-dihydroxy-propyl)-carbamic acid tert-butyl ester (0.955 g, 5.00 mmol) in water (12 mL) was added sodium periodate (2.35 g, 11.0 mmol). The mixture was stirred at room temperature for 1 h and then extracted with dichloromethane (3×10 mL). The extracts were dried over Na2SO4 and concentrated to give (2-oxo-ethyl)-carbamic acid tert-butyl ester as a colorless liquid (778 mg, 98%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 4.07 (d, J=4.5 Hz, 2H), 5.20 (brs, 1H), 9.65 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2([CH3:20])OCC[O:16]2)[C:8]1=[O:21])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH3:20])[C:8]1=[O:21])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCC2(C)OCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCC(C)=O)C1=O

Procedure:
A solution of 2-6 (450 mg, 1.10 mmol), p-TSA (50 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 2-7 as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:21](OCC)=[O:22].CC[O-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21][OH:22])[C:14](=[O:20])[CH2:15]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A solution of 0.27 g (0.9 mmol) of 9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one in 2.0 mL of THF was stirred at rt and 0.70 mL (8.7 mmol) of ethyl formate was added followed by 1.0 mL of EtOH and 0.78 mL of a 21 wt % solution of NaOEt in EtOH. The reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was concentrated by rotary evaporation, quenched with sat. aq. NH4Cl and extracted with CHCl3. The organic layer was dried over MgSO4, filtered and concentrated to afford 0.25 g (86%) of 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one as an orange solid. 1H NMR (300 MHz, CDCl3) δ 14.11 (s, 1H), 8.24 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 4.85 (s, 1H), 4.32 (m, 1H), 2.58 (dd, J=19.8, 7.7 Hz, 1H), 2.17 (d, J=19.8 Hz, 1H), 2.00-1.76 (m, 2H), 1.61 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].C[Al](C)C.C(O[C:18](=O)[CH:19]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:18]([CH:19]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(OC1CCN(C)CC1)c1ccccc1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCC(OC(c2ccccc2)c2nc3cc(Cl)c(Cl)cc3[nH]2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A round-bottom flask is charged with 4,5-dichlorobenzene-1,2-diamine (354 mg) and toluene (2 mL); a solution of trimethylaluminum 2M in toluene (1 mL) is added dropwise. The reaction mixture is heated at 60° C. for one hour. A solution of (1-methyl-piperidin-4-yloxy)phenylacetic acid ethyl ester in toluene (1 mL) is added dropwise and heating is pursued for one hour. The reaction mixture is cooled to room-temperature and a solution of sodium hydroxide is added dropwise to pH 10. The slurry is filtered on celite, cake washed with water (4×5 mL) and ethyl acetate (4×5 mL). After decantation, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is diluted with glacial acetic acid (3 mL) and the reaction mixture is heated at reflux for one hour. Acetic acid is removed on a rotary evaporator and the residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0 to 95/5/0.5 to give 5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazole melting at 221° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCNCC1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCOCCN1CCCCCC1
Yield: 65 %

Procedure:
[2-(2-methoxyethoxy)ethyl]azepane was obtained using procedure 1a, from azepane (10.3 g, 0.103 mol) in methanol (50 cm3), 1-bromo-2-(2-methoxy-ethoxy)ethane (10.0 g, 0.103 mol) and potassium carbonate (16.0 g). After distillation in vacuo (66-68° C., 1.0 mmHg), [2-(2-methoxyethoxy)ethyl]azepane was obtained as a colourless liquid in ca. 65% yield. δH (500.13 MHz, CDCl3) 3.59 (6H, m), 3.38 (3H, s), 2.73 (2H, t), 2.68 (4H, m), 1.59 (8H, br m). ESI-MS: m/z=202 [M+H]+ (100). Calcd. for C11H23NO2: 202.1807; found: 202.1802.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C1(P(CCC)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C([SiH](CCCCCCCC)CCCCCCCC)CCCCCCC.CN([CH:69]=[O:70])C>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:1]1[C:5]2[CH:6]=[C:7]([CH:69]=[O:70])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CN(C)C=O
Reactant: O=S(=O)(Oc1ccc2ccoc2c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCC[SiH](CCCCCCCC)CCCCCCCC
Solvent: O
Solvent: CCN(CC)CC
Product: O=Cc1ccc2ccoc2c1
Temperature: 70 °C

Procedure:
A solution of triflate 20-3 (0.798 g, 3.0 mmol), Pd(OAc)2 (13.5 mg, 0.060 mmol), and diphenylphosphinopropane (24 mg, 0.060 mmol) in DMF (15 mL) was heated to 70° C. with a gentle flow of CO (g) passing through it. Triethylamine (1.66 mL, 12 mmol) was added followed by trioctylsilane (2.70 mL, 6.0 mmol). The solution was maintained at 70° C. for 2 h, and cooled to room temperature. The solution was diluted with water (10 mL). The mixture was extracted with Et2O (2×30 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (5% acetone/hexanes) to give the desired aldehyde 20-4.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH2:23][CH2:24][CH3:25])[CH2:8]1)=[O:5])[CH3:2].[OH-].[K+].[CH2:30](I)[CH2:31][CH3:32].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH2:30][CH2:31][CH3:32])[CH:13]=3)[N:9]([CH2:23][CH2:24][CH3:25])[CH2:8]1)=[O:5])[CH3:27]
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CCCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4c3c(cn4CCC)C[C@H]21

Procedure:
Under nitrogen, 2 g of 1,1-diethyl-3-(6-n-propyl-8α-ergolinyl)urea, 2.7 g of pulverized KOH, 217 mg of tetrabutylammonium hydrogen sulfate, and 5.5 ml of n-propyl iodide are stirred in 100 ml of absolute tetrahydrofuran for 5 hours at room temperature. After adding 50 ml of H2O, the mixture is extracted with ethyl acetate, rinsed, and dried, thus obtaining 1.8 g (80% of theory) as an oil [α]D =+2.6° (c=0.5 CHCl3)
Reaction SMILES: C(NC1N=C(NC)N=C2C=1N=CN2CC1C=CC=CC=1Cl)(=O)C.[C:24]([NH:27][C:28]1[N:36]=[C:35]([NH:37][CH3:38])[N:34]=[C:33]2[C:29]=1[N:30]=[CH:31][N:32]2[CH2:39][C:40]1[C:45](F)=[CH:44][CH:43]=[CH:42][C:41]=1[F:47])(=[O:26])[CH3:25]>>[C:24]([NH:27][C:28]1[N:36]=[C:35]([NH:37][CH3:38])[N:34]=[C:33]2[C:29]=1[N:30]=[CH:31][N:32]2[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[F:47])(=[O:26])[CH3:25]
Reactant: CNc1nc(NC(C)=O)c2ncn(Cc3c(F)cccc3F)c2n1
Agent: CNc1nc(NC(C)=O)c2ncn(Cc3ccccc3Cl)c2n1
Product: CNc1nc(NC(C)=O)c2ncn(Cc3ccccc3F)c2n1

Procedure:
6-(N-acetylamino)-9-(2-chlorobenzyl)-2-(N-methylamino)-9H-purine and 6-(N-acetylamino)-9-(2,6-difluorobenzyl)-2-(N-methylamino)-9H-purine.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].Br[C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].Cl>C(OCC)C.O.C(C(C)=O)C>[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15]
Reactant: CC(C)(Br)C(=O)O
Reactant: Cc1cccc(O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(OC(C)(C)C(=O)O)c1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
Sodium hydroxide (82.0 g, 2.05 mol) was added to a solution of methyl ethyl ketone (400 mL) containing 2,3-dimethylphenol (50.0 g, 410 mmol), and the mixture was stirred at 50° C. for 1 hour. After that, a solution of methyl ethyl ketone (200 mL) containing 2-bromo-2-methylpropionic acid (103 g, 615 mmol) was added thereto, and the mixture was stirred at 50° C. for 4 hours. After cooled to room temperature, the reaction solution was distributed by adding water and diethyl ether. 6N hydrochloric acid was added to the aqueous layer to be acidic, and then extraction was performed using ethyl acetate. The extract was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 50/50) to give 38.3 g of the title compound (yield: 45%).
Reaction SMILES: Br[CH:2]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].N1C=CN=N1.O>CN(C)C=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]([S:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:5])=[O:6])=[CH:2][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:15]=1
Reactant: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Agent: c1c[nH]nn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)C=C(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Yield: 73 %

Procedure:
2-Bromo-1-(4-chlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one (4.44 g) and triazole (2.76 g) were dissolved in dimethylformamide (30 ml), and the solution was refluxed for 2 hours. After cooling, it was poured into 100 ml of water and extracted with 100 ml of chloroform. The chloroform layer was washed for three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized in n-hexane, and the crystals were collected by filtration and dried to give 2.65 g of 1-(4-chlorophenyl)-4,4-dimethyl-1-phenylsulfonyl-1-penten-3-one. m.p. 135°-136° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)=[CH:6][CH:5]=1.[CH3:40]I>O1CCCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([N:29]([CH3:40])[C:30](=[O:39])[O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)=[CH:6][CH:5]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(Br)cc2)N(C)C(=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60 wt % in mineral oil) (69 mg, 1.15 mmol) was added to a 0° C. solution of benzyl {2-(4-bromophenyl)-1-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}carbamate (340 mg, 0.58 mmol) in tetrahydrofuran (6 mL). After stirring at 0° C. for 20 min, methyl iodide (72 μL, 1.15 mmol) was added and the reaction allowed to warm to ambient temperature. The reaction mixture was quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded benzyl {2-(4-bromophenyl)-1-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}methylcarbamate.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:3]=1.Br[C:23]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[N:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Br:1])[C:7]3[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=3[CH:5]=2)[CH:23]=1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Reactant: CSc1nc2c(Br)cc(CNc3ncccc3N)cc2s1
Product: CSc1nc2c(Br)cc(Cn3cnc4cccnc43)cc2s1

Procedure:
6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromo-2-(methylthio)benzo[d]thiazole was synthesized as an orange solid (180 mg) using a procedure analogous to that described in Step 3 of Example 41, substituting N2-((4-bromo-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine from the previous step for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 390, 392 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1.[CH2:31]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]([CH3:31])[CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCN(c2ccncc2)CC1
Reactant: C=O
Product: CN(CC1CCN(c2ccncc2)CC1)c1ccccc1C(=O)Nc1ccc(Cl)cn1

Procedure:
Using a similar procedure to that described in Example 27, N-(5-chloropyridin-2-yl)-2-[1-(4-pyridinyl)piperidin-4-ylmethyl]aminobenzamide (100 mg, 0.237 mmol) and paraformaldehyde (20 mg, 0.238 mmol) afforded, after purification by column chromatography (SiO2: 2 to 4% [2 N ammonia in methanol]:chloroform), 25 mg (24%) of the title compound.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[N:8]=[C:9]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1Cl.CN([CH:33]=[O:34])C>C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[CH:33]=[O:34]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
nBuLi (1.3 mL, 2.05 mmol, 1.57 M in hexane) was added dropwise to a solution of 4,5-dichloro-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (842 mg, 2.05 mmol) in THF (30 mL) at −78° C. under N2. The mixture was stirred for 30 min and DMF (1.0 mL) was then added dropwise. The mixture was stirred for 20 min and then allowed warm up to room temperature and stirred for 20 min. Quenched by aqueous NH4Cl and extracted with EtOAc and the organic layer was dried over sodium sulfate and concentrated.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>C(N(CC)CC)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cccnc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C(#Cc1cccnc1)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.1 %

Procedure:
Add phenylacetylene (0.175 mL, 1.6 mmol), copper (I) iodide (0.028 g, 0.15 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.051 g, 0.07 mmol) to a solution of 3-bromopyridine (0.140 mL, 1.45 mmol) in degassed triethylamine (6 mL) and stir under nitrogen at 80° C. for 16 h. Cool to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:dichlormethane, to give the title compound (91.1 mg, 35%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:13]2[C:9]([S:10][C:11]3[CH2:16][CH2:15][CH2:14][C:12]=32)=[N:8][CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:8]1[CH:7]=[C:6]([CH2:4][OH:3])[N:13]2[C:12]3[CH2:14][CH2:15][CH2:16][C:11]=3[S:10][C:9]=12
Reactant: CCOC(=O)c1cnc2sc3c(n12)CCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc2sc3c(n12)CCC3
Yield: 56 %

Procedure:
A solution of 6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (Formula E-4) (5.8 g) in dry THF (125 mL) was treated with LiAlH4 (1.86 g) and reacted for 5.5 hours. After serial quenching with water and 15% sodium hydroxide, the suspension was diluted to 700 mL with chloroform. The filter cake was washed with hot chloroform, the combined filtrate and washes were evaporated to yield pure 6,7-Dihydro-5H-cyclopent[d]imidazo[2,1-b]thiazole-3-methanol (FIG. E-5) (2.67 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=2[N:26]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:24][CH2:25][C:19]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[N:26][C:20]=4[CH2:21][CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc2c(n1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ccc2c(n1)CCN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method of example 2 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. Yield: 0.05 g (60% of theory). ESI-MS: m/z=402 (M+H)+; Rt(HPLC): 1.12 min. (Method J).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.[NH2:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([Cl:35])=[CH:30][N+:29]=1[O-].S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>C(O)(=O)C.C1C=CC=CC=1>[Cl:35][C:31]1[CH:32]=[C:33]([F:34])[C:28]([NH:27][C:24]([C:16]2[C:17]3[O:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][C:13]=3[CH:15]=2)=[O:25])=[N:29][CH:30]=1
Reactant: Nc1c(F)cc(Cl)c[n+]1[O-]
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ncc(Cl)cc3F)c3c(c2[nH]1)CC(C)(C)O3

Procedure:
The title compound was prepared by following the same procedure described for Example-108 by using 2-[(2-Chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8 dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.200 g, 0.536 mmol), 2-amino-5-chloro-3-fluoropyridine 1-oxide (Intermediate-43, 0.104 g, 0.643 mmol), thionyl chloride (2 mL), DIPEA (2 mL), benzene (5.0 mL). To a solution of obtained crude product (0.200 g) in acetic acid (10.0 mL) was added iron powder (0.200 g). The reaction mass was stirred at 80° C. for 2-3 h. Excess of Iron powder was separated. The reaction mass was diluted with water, it was extracted with ethyl acetate. The reaction mass was filtered through celite bed and organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on basic alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.021 g of the desired product. 1HNMR (DMSO-d6): 1HNMR (DMSO-d6): δ 1.52 (s, 6H), 2.23 (s, 3H), 3.10 (s, 2H), 7.23-7.31 (m, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 8.14 (d, J=9.6 Hz, 1H), 8.33 (s, 1H), 9.07 (br s, 1H), 9.84 (s, 1H), 10.92 (brs, 1H); MS [M+H]+: 500.12.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][NH:10][CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH:11]([C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:10][CH2:9][CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C23CCCC2CNCC3)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Cc1ccccc1)C1NCCC2(c3ccccc3)CCCC12
Temperature: 25 °C

Procedure:
To a cold solution (0°-5° C.) of 3.0 g. of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 47 ml. of methanol containing 14 ml. of water and 2.6 g. of potassium carbonate was added 2.6 g. of phenylacetyl chloride in one portion. The reaction mixture was stirred at 0°-5° C. for thirty minutes and then was warmed to 25° C., at which it was stirred for an additional one hour. The reaction mixture was concentrated under reduced pressure, leaving an oily residue. The oil was then dissolved in 500 ml. of diethyl ether and washed with dilute aqueous sodium bicarbonate solution and with water. After drying the ethereal solution, the solvent was evaporated under reduced pressure to afford 4a-phenyl-2-phenylacetyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine formed in the above acylation reaction as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:22]([O:24][C:25]([CH3:27])=[CH2:26])=[O:23]>C1COCC1>[CH3:1][O:2][C:3]1([C:8]([NH:10][C:22](=[O:23])[O:24][C:25]([CH3:27])=[CH2:26])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(C(N)=O)CCCC1
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C1(OC)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
A −78° C. solution of 1-methoxycyclopentanecarboxamide (0.9 g, 6.29 mmol) in THF (40 mL), under Ar, was treated with LiHMDS (1M in THF, 8.17 mL, 8.17 mmol), stirred for 0.5 h, treated with a solution of isopropenyl chloroformate (0.824 mL, 7.54 mmol) in THF (5 mL), stirred at −78° C. for 15 min, warmed to RT and stirred for 1 h. The mixture was treated with satd. NH4Cl, the layers separated and the aqueous layer extracted with EtOAc (1×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford crude prop-1-en-2-yl (1-methoxycyclopentanecarbonyl)carbamate (1.5 g, 105%) which was used without further purification. MS (ESI) m/z: 228.1 (M+H+).