Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([N:18]1[CH2:24][CH2:23][C:22]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[O:21][CH2:20][C:19]1=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.C1COCC1>[CH2:11]([N:18]1[CH2:24][CH2:23][C:22]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[O:21][CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(OCC2(c3ccc(Cl)c(Cl)c3)CCN(Cc3ccccc3)C(=O)CO2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(OCC2(c3ccc(Cl)c(Cl)c3)CCN(Cc3ccccc3)CCO2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a solution of lithium aluminum hydride (934 mg) in diethyl ether (30 mL) was added aluminum chloride (1.09 g), and the mixture was stirred at 0° C. for 10 min. To the reaction mixture was added dropwise a solution of (7RS)-4-benzyl-7-(3,4-dichlorophenyl)-7-[(4-methoxyphenoxy)methyl]-1,4-oxazepan-3-one (6.02 g) in THF (30 mL), and the mixture was stirred at 0° C. for 15 min, and stirred while warming to room temperature for 2 hr. To the reaction mixture was added ice, and the precipitate was filtered off through celite. The filtrate was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.46 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH:5]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]2[C:24]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[S:22][N:21]=2)[C:9]1=[O:31])[CH2:6][CH3:7].[Li+].[OH-]>O1CCOCC1.C1COCC1.O>[CH3:30][C:25]1[C:24]2[C:20]([CH2:19][N:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:17](=[O:18])[N:8]([CH:5]([CH2:6][CH3:7])[CH2:4][C:3]([OH:32])=[O:2])[C:9]3=[O:31])=[N:21][S:22][C:23]=2[CH:28]=[C:27]([CH3:29])[CH:26]=1
Reactant: CCC(CC(=O)OC)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCC(CC(=O)O)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-pentanoic acid methyl ester (65 mg, 0.14 mmol) in 1,4-dioxane (10 mL), THF (5 mL) and water (2 mL) is added LiOH (7 mg, 0.29 mmol) at room temperature. The solution is stirred at room temperature for 8 hours. The solution is concentrated and water is added to the residue. The solution is acidified by 12N HCl in an ice-bath. The precipitated solid filtration to afford the title compound.: LCMS (ESMS): m/z 438.09 (M+H+).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[O:16]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17]1>>[O:16]1[CH:20]=[CH:19][C:18]2[CH:21]=[C:2]3[C:1](=[O:13])[O:14][C:5](=[O:7])[C:4]4=[CH:9][CH:10]=[CH:11][C:12]([C:17]1=2)=[C:3]34
Reactant: O=Cc1ccoc1
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Product: O=C1OC(=O)c2cc3ccoc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and 3-furaldehyde:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:13]=2)[O:9][N:8]=1.[I:24]N1C(=O)CCC1=O>C(#N)C>[I:24][C:11]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][O:9][C:10]=1[C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(-c2noc(-c3cc(-c4ccccn4)no3)n2)cc1
Solvent: CC#N
Product: Cc1ccc(-c2noc(-c3onc(-c4ccccn4)c3I)n2)cc1
Yield: 378 %

Procedure:
A solution of 5-(3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (1.0 g, 3.29 mmol), 1-iodopyrrolidine-2,5-dione (1.11 g, 4.76 mmol), and PdOAc2 (0.148 g, 0.657 mmol) in acetonitrile (14 mL) was heated to 120° C. via microwave for 40 minutes. The reaction was repeated 4 additional times on a similar scale, and the contents of each reaction tube were combined, concentrated, and purified by flash silica gel chromatography (eluting with Hexanes/EtOAc—4/1) to yield 5-(4-iodo-3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (5.35 g, 76% yield). The compound had an HPLC retention time=3.81 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=431+. 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (s, 3H), 7.36 (d, J=8.03 Hz, 2H), 7.46-7.52 (m, 1H), 7.90 (td, J=7.72, 1.63 Hz, 1H), 8.01 (d, J=7.78 Hz, 1H), 8.12 (d, J=8.28 Hz, 2H), and 8.86 (d, J=4.27 Hz, 1H).
Reaction SMILES: [CH2:1](I)[CH3:2].[N+:4]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)([O-:6])=[O:5].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][N:13]([CH2:1][CH3:2])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:25][CH:26]=1)([O-:6])=[O:5]
Reactant: O=[N+]([O-])c1ccc(CCNCCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl iodide (0.37 g) was added dropwise to the product of part (A) (0.75 g) and potassium carbonate (0.33 g) in acetonitrile (20 ml) and the reaction mixture was heated under reflux for 18 hours. The reaction mixture was then evaporated to dryness and the residue taken up in methylene chloride, washed twice with aqueous sodium carbonate, twice with brine, then dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%). The product-containing fractions were combined and evaporated to dryness to give the title compound as an oil, yield 0.47 g.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].N[C@@H:14](C1CCCC1)[C:15](O)=O>>[CH:7]1([C@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:10]([OH:12])=[O:11])[CH2:9][CH2:15][CH2:14][CH2:8]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: N[C@H](C(=O)O)C1CCCC1
Product: COC(=O)N[C@H](C(=O)O)C1CCCC1

Procedure:
(S)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using (S)-2-amino-2-cyclopentylacetic acid instead of L-Valine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH2:23])C1C=CC=CC=1>CO.S1C=CC=C1.[Pd]>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH2:23])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: NC1CCN(CCc2ccccc2)CC1
Reaction time: 72 h

Procedure:
Following the procedure of Lobbezoo, J. Med. Chem. 24:777 (1981). N-(β-phenylethyl)-4-piperidinone (15.0 g, 74.0 mmol) dissolved in 200 ml of methanol containing 1 ml of a 4% thiophene in methanol solution is treated with benzyl amine (10.0 g, 93.0 mmol) and 2 g of 10% palladium-on-carbon in a Parr flask and hydrogenated for 18 hours (initial pressure, 26.5 psi, final pressure 22.0 psi). The catalyst is filtered and replaced with 2.0 g of fresh 10% palladium-on-carbon. The catalyst is filtered and replaced again with 4.8 g of fresh 10% palladium-on-carbon. The hydrogenation is followed over 3 days, at which point, hydrogen uptake ceases (initial pressure, 35 psi, final pressure, 29 psi). The catalyst is filtered through Celite and is washed with methanol. GLC analysis (2 ft SE-30, 100 C, 1 minute, programmed 20 C/minute rise to 250 C) indicated that 7% unreacted benzyl amine remained). This material nevertheless was used for subsequent experiments.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].O>CN(C)C=O>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:44])[CH3:43])[CH:7]=[CH:6][CH:5]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a suspension of 2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (150 mg, 0.33 mmol) in dimethylformamide (10 mL) was added triethylamine (51 δL, 0.36 mmol). The reaction mixture was cooled to 0° C. and flushed with nitrogen, then acetyl chloride (26 μL, 0.36 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. Water was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was purified by flash chromatography (95:5 chloroform:methanol) to give N-(3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)acetamide (151 mg, 92%) as a tan solid. 1H NMR (CDCl3): δ 8.19 (s, 1H), 7.95 (d, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.63 (s, 1H), 7.36–7.25 (m, 3H), 6.28 (d, 1H), 6.00 (m, 2H), 5.17 (d, 1H), 4.32 (m, 1H), 3.96 (m, 1H), 2.11 (s, 3H), 2.11–2.02 (m, 4H), 1.76–1.48 (m, 12H); MS m/z 496 (M+1).
Reaction SMILES: [C:1]([S:4][C@H:5]([CH2:12][O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6]CC(OC)=O)(=[O:3])[CH3:2].CC(C[Al]CC(C)C)C.N1C=CC=CC=1.[C:46](O)(=[O:48])[CH3:47].C([O-])(O)=O.[Na+]>CCCCCC.C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.O>[C:46]([O:3][CH:1]1[S:4][C@H:5]([CH2:12][O:13][Si:14]([C:27]([CH3:30])([CH3:28])[CH3:29])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:2]1)(=[O:48])[CH3:47]
Reactant: CC(=O)O
Reactant: COC(=O)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)SC(C)=O
Agent: CC(C)C[Al]CC(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1

Procedure:
A solution of 9 (1 g, 2.25 mmol) in 14 mL dry hexane and 2 mL toluene was cooled to -78° C. under nitrogen. A 1.5 M toluene solution of Dibal-H (3.0 mL, 4.5 mmol) was added over a 2 minute period with stirring continued for an addition 30 minutes. The reaction was quenched with 1.2 mL methanol and allowed to reach 25° C. Then 2.5 mL of saturated NaHCO3 solution was added followed by 1.5 mL ethyl acetate. The mixture was dried with MgSO4. The solids were removed by filtration and washed with ethyl acetate. After removal of solvent in vacuo the residue was redissolved in 20 mL dichloromethane and treated with DMAP (10 mg), pyridine (0.9 mL, 10 mmol) and acetic acid (0.47 mL, 5 mmol) with stirring under nitrogen overnight. The reaction mixture was shaken with 50 mL water, than 50 mL of 1% NaHCO3. After drying (MgSO4), the solvent was removed in vacuo and the residue purified by flash chromatography with 8:1 hexane/ethyl acetate: yield 0.78 g (83%) of a viscous oil; FAB MS 357 (M-t-butyl)+ ; 1H NMR (CDCl3) δ 7.68 (m, 4, ArH), 7.4 (m, 6, ArH), 6.0 (m, 1, ArH), 3.75 (m, 1, H-5), 3.5 (m, 1, H-4), 3.5 (m, 1, H-5), 2.15 (m, 2, CH2), 2.0 (2s, 3, aromatic acetyls), 1.9 (m, 2, CH2), 1.05 (s, 9, t-butyl).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]2[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[N+:31](CCCC)(CCCC)(CCCC)CCCC.[F-].C([O-])(=O)C.[Na+].NOS(O)(=O)=O>C1COCC1.O.C(OCC)(=O)C>[CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[N:16]=[C:15]2[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7].[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:15]2[N:14]([C:11]3[CH:12]=[CH:13][C:8]([S:5]([NH2:31])(=[O:7])=[O:6])=[CH:9][CH:10]=3)[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=2)[CH:24]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)CCS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Agent: NOS(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 173.5 %

Procedure:
3-[1-[4-[[2(Trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol -2-yl]pyridine was prepared from Example 30 with a method similar to that described in Example 48, Step 1. To a solution of 3-[1-[4-[[2-(trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (0.200 g, 0.46 mmol) in 1.0 mL of dry THF was added n-Bu4NF (1.38 mL of 1.0H THF solution, 1.38 mmol). The mixture was heated to reflux for 1 hour and cooled to room temperature. A solution of sodium acetate (0.17 g, 2.1 mmol) in 3 mL of water and hydroxylamine-O-sulfonic acid (0.26 g, 2.3 mmol) were added sequentially and the mixture was stirred for 1 hour. Water (7 mL) and ethyl acetate (7 mL) were added. The organic phase was separated and washed with saturated NaHCO3 solution, water, brine, dried over HgSO4 and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate/acetone, 95:5) to give 0.147 g of 4-[2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide as a colorless solid (87%): mp(DSC) 213°-215 ° C. Anal. Calc'd. for C15H11F3N4O2S: C, 48.91; H, 3.01; N, 15.21; S, 8.71. Found: C, 48.58; H, 2.99; N, 14.87; S, 8.85.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[CH:5][C:4]=1[CH3:21])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH2:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([NH:11][C:12]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[O:20])=[CH:5][C:4]=1[CH3:21])[CH3:2]
Reactant: CCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C
Yield: 65 %

Procedure:
Phenyl N-(6-ethyl-2-methoxy-5-methylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[N:47]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:34].C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:50]2[CH2:51][CH2:52][CH2:53][N:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)[CH2:48][CH2:49]2)([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccncc3)C2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccncc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.90 g, 1.65 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.49 g, 0.83 mmol), and N,N-diisopropylethylamine (2.1 mL, 11.6 mmol) in acetronitrile (14 mL). Heat to reflux. After 48 hour, add sodium carbonate and stir. After 1 hour, dilute the reaction mixture with dichloromethane, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia and then 50% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give a residue. Dissolve the residue in dichloromethane, extract with a saturated aqueous sodium bicarbonate solution, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.39 (silica gel, 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:25][C@H:24]2[CH:23]=[CH:22][CH:21]([CH3:26])[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:27])[C@H:16]([NH:28]C(=O)OC(C)(C)C)[C:15](=[O:36])[N:14]2[CH2:37][C@H:38]([O:40][C:41]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:44]([O:51][CH3:52])=[CH:43][N:42]=4)[CH2:39][C@H:13]2[C:12](=[O:53])[NH:11]3)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[ClH:54]>O1CCOCC1>[ClH:54].[NH2:28][C@@H:16]1[C:15](=[O:36])[N:14]2[CH2:37][C@H:38]([O:40][C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:44]([O:51][CH3:52])=[CH:43][N:42]=3)[CH2:39][C@H:13]2[C:12](=[O:53])[NH:11][C@:10]2([C:8]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:5])=[O:6])=[O:9])[CH2:25][C@H:24]2[CH:23]=[CH:22][CH:21]([CH3:26])[CH2:20][CH2:19][CH2:18][C@H:17]1[CH3:27]
Reactant: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4/C=C\C(C)CCC[C@@H](C)[C@H](N)C(=O)N3C2)c2ccccc12
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4/C=C\C(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)NS(=O)(=O)C5CC5)C[C@H]4C=CC(C)CCC[C@@H](C)[C@H](N)C(=O)N3C2)c2ccccc12

Procedure:
A solution of tert-butyl (2R,6S,7R,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(4-methoxyisoquinolin-1-yloxy)-7,11-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (500 mg, 0.66 mmole) in dioxane.HCl was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to get crude compound (350 mg, 77%). The crude compound was washed with diethyl ether and taken to the next step without further purification. MS: MS m/z 652.2 (M+−1).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:11])[CH2:4][S:3]1(=[O:13])=[O:12].[I:14]I>C(Cl)(Cl)Cl>[I:14][C:9]1[S:8][C:7]2[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[CH2:4][C:5](=[O:11])[C:6]=2[CH:10]=1
Reactant: CN1c2sccc2C(=O)CS1(=O)=O
Reactant: II
Solvent: ClC(Cl)Cl
Product: CN1c2sc(I)cc2C(=O)CS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a stirring solution of 1-methyl-1H-thieno[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide (Preparation 33, 1.0 g) in CHCl3 (100 ml) at ambient temperature is added HgO (1.19 g) and iodine (1.17 g). The resulting mixture is stirred overnight at ambient temperature and the solids removed by filtration through diatomaceous earth. The solvent is removed in vacuo and the residue purified via flash column chromatography (4/1, hexanes/EtOAc) to afford 0.68 g (43%) of the title compound as a tan solid. Physical characteristics: 1H NMR (CDCl3) δ 3.40, 4.20, 7.53; IR (diffuse reflectance) 2986, 1675, 1664, 1505, 1478, 1405, 1338, 1327, 1275, 1245, 1177, 1158, 1129, 818, 781 cm−1; MS (EI) m/z 343 (M+). Anal. Found: C, 24.65; H, 1.82; N, 4.08.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])[C:6](=[O:25])[N:5]([CH3:26])[C:4]=2[N:3]=1.[CH2:27]([SH:30])[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])[C:6](=[O:25])[N:5]([CH3:26])[C:4]=3[N:3]=[C:2]2[S:30][CH2:27][CH2:28][CH3:29])=[CH:13][CH:14]=1
Reactant: CCCS
Reactant: CC(O)CCn1c(=O)c2c(nc(Br)n2Cc2ccc(Cl)cc2)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2c(c(=O)n(CCC(C)O)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (100 mg, 0.23 mmol, example 97, step 1) in DMF (5 mL) was added propane-1-thiol (20.7 mg, 0.27 mmol) followed by potassium carbonate (93.9 mg, 0.68 mmol). The reaction was stirred at 60° C. for 3 h. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product (80 mg, 80.9% yield) as yellow oil. LCMS MH+ 437.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:15])[CH2:12][CH2:13]Cl)=[CH:10][C:5]=2[O:4][C:3]1=[O:16].C([O-])(=O)C.[K+]>CN(C)C=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:15])[CH:12]=[CH2:13])=[CH:10][C:5]=2[O:4][C:3]1=[O:16]
Reactant: Cn1c(=O)oc2cc(C(=O)CCCl)ccc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)c1ccc2c(c1)oc(=O)n2C
Reaction time: 0.83 h

Procedure:
In a 150-ml ground-necked flask equipped with a reflux condenser, 5 g (0.02 mol) of 3-methyl-6-( 3-chloropropionyl)benzoxazolinone, described in Patent Application FR 89/02554, are dissolved in 70 ml of dimethylformamide. 2.04 g of potassium acetate are introduced. The mixture is heated with magnetic stirring to 75°-80° C. for 50 min. After cooling, the reaction mixture is poured into ice-cold water. The resulting mixture is stirred for 0.5 h. The precipitate obtained is drained, washed with water, dried and recrystallized in toluene.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][N:9]([CH2:16][C:17]2[CH:36]=[CH:35][C:20](/[CH:21]=[CH:22]/[C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Bi](Cl)(Cl)Cl.[BH4-].[Na+].CO>C(O)C>[NH2:1][C:4]1[CH:38]=[CH:37][C:7]([CH2:8][N:9]([CH2:16][C:17]2[CH:36]=[CH:35][C:20](/[CH:21]=[CH:22]/[C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[CH:19][CH:18]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Agent: Cl[Bi](Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc(N)cc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a solution of the product of Example 149E (0.8 g, 1.56 mmol) dissolved in ethanol (20 mL) was cooled in an ice bath to 0° C., then bismuth(III) chloride (1.47 g, 4.67 mmol) was added followed by the portionwise addition of sodium borohydride (943 mg, 24.92 mmol) and warming the solution to room temperature for 20 minutes. The methanol was added and the solid removed by filtration, the filtrate concentrated to an oil, which was redissolved with dichloromethane and extracted with aqueous sodium bicarbonate. The organic solution was then dried, filtered, and concentrated to afford the title compound. m/z 484 (M+H)+.