Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:15]=[C:16]([OH:18])[CH:17]=1>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:28][CH3:29])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:41])([CH3:42])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[CH:15]=[C:16]([OH:18])[CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Trifluoroacetic acid (0.12 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-5-hydroxy-2′-methyl-biphenyl-3-yl]-acetic acid methyl ester (Example 165-(2); 15.9 mg, 0.0247 mmol) in dichloromethane (0.60 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (11.5 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[C:16]([CH3:24])[CH:15]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[C:16]([CH3:24])[CH:15]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C2(c3cccc(Br)c3)COC(N)=N2)ccc1OC(F)F
Solvent: ClCCl
Product: Cc1cc([C@]2(c3cccc(Br)c3)COC(N)=N2)ccc1OC(F)F
Yield: 51 %

Procedure:
A solution of 1.95 g of (RS)-4-(3-bromo-phenyl)-4-(4-difluoromethoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (Building Block S) in dichloromethane was divided in 200 mg aliquots which were separated on chiral HPLC (Chiralpak AD) using a 92:8-mixture of heptane and isopropanol as the eluent. The fractions showing e.e. values in the range of 99.7% to 98.4% of the first eluting enantiomer were combined to give 994 mg of the (S)-(+)-4-(3-bromo-phenyl)-4-(4-difluoromethoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine as a colourless oil which crystallised on standing. The later eluting enantiomer (R)-(−)-4-(3-bromo-phenyl)-4-(4-difluoromethoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine was isolated to give 628 mg (96.8% e.e.) as a colourless oil which crystallised on standing. In addition, a fraction (137 mg) consisting of both isomers was also obtained.
Reaction SMILES: [N:1]([C:4]1[C:5]([F:15])=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)=[C:2]=[O:3].C([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1)=O)C>C(N(CC)CC)C.O1CCOCC1>[F:15][C:5]1[C:4]([N:1]2[C:19](=[O:18])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][N:22]3[C:2]2=[O:3])=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: O=C=Nc1cc2c(cc1F)OCC(=O)N2
Reactant: CCOC(=O)N1CCCCN1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1COc2cc(F)c(-n3c(=O)n4n(c3=O)CCCC4)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A mixture composed of 6-isocyanato-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.14 g), 1-ethoxycarbonylhexahydropyridazine (1.62 g) and dioxane (30 ml) is treated with a few drops of triethylamine, stirred at an ambient temperature for 2 hours, and left overnight. The reaction mixture is made free from dioxane by evaporation in vacuo, mixed with methanol (30 ml) containing a catalytic amount of sodium, and refluxed for 2 hours. After removal of methanol by evaporation in vacuo, the resultant solid is collected, and washed with water to obtain an end product 2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-hexahydro-1H-(1,2,4)-triazolo (1,2-a) pyridazine-1,3-dione (2.45 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@@H:16]([CH:33]([CH3:35])[CH3:34])[C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][CH:20]1[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:31]([NH:30][C:28]([CH:20]1[N:19]([C:17](=[O:18])[C@@H:16]([NH:15][C:10](=[O:12])[C@@H:9]([N:8]([CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:13])[CH:33]([CH3:34])[CH3:35])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21]1)=[O:29])[CH3:32]
Reactant: CCNC(=O)C1Cc2cccnc2N1C(=O)[C@@H](N)C(C)C
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)C1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (40.9 mg, 201 μmol, Eq: 1.5) and 1-((S)-2-amino-3-methylbutanoyl)-N-ethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (39 mg, 134 μmol, Eq: 1.00) in DMF (1 mL) was added HATU (76.6 mg, 201 μmol, Eq: 1.5) followed by triethylamine (30 μL, 215 μmol, Eq: 1.6) and the resulting solution was stirred at rt for 2 h. The reaction was poured into saturated aqueous NaHCO3 (10 mL) and the mixture was extracted with EtOAc (10 mL). The EtOAc layer was concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 12 g, 0% to 100% EtOAc in hexanes) to give tert-butyl (2S)-1-((2S)-1-(2-(ethylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (50 mg), m/z=476 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[CH2:29][CH2:30][CH2:31][OH:32])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:38][CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[CH2:29][CH2:30][CH2:31][O:32][CH2:38][CH3:39])=[CH:33][CH:34]=1
Reactant: CCI
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(CCCO)n2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCCc1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-(3-hydroxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.204 mmol) in DMF (3 mL) was added sodium hydride (24.5 mg, 0.612 mmol, 60% dispersion in mineral oil) at 0° C. The mixture was stirred at room temperature for 30 min. Iodoethane (63.6 mg, 0.408 mmol) was added to the reaction and it was stirred at room temperature for 16 h. The reaction was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (2:1 to 1:1) to give 7-(4-chlorobenzyl)-8-(3-ethoxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (96 mg, 90.6% yield) as a yellow solid. LCMS retention time 1.870 min; LCMS MH+ 519.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]([O:9][CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=[O:8].[CH3:24][C:25](=[CH2:27])[CH3:26]>O1CCOCC1>[NH2:18][C@@H:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([O:23][C:25]([CH3:27])([CH3:26])[CH3:24])=[O:22])=[C:11]([CH2:10][O:9][C:7](=[O:8])[CH3:6])[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Dry dioxane was freed from peroxide by passage through a column of neutral activated alumina. To 100 ml of this solvent was added, in turn, with ice-cooling 10 ml of concentrated H2SO4, 10.9 g of 7-ACA and 50 ml of liquid isobutylene. The mixture was sealed in a pressure bottle, stirred at 30° C. for 2 hours, poured into excess of ice-cold aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate. The combined ethyl acetate extract was washed with brine and dried over sodium sulfate. Evaporation of the filtrate under reduced pressure gave a light brown foam, 8.3 g (63%) of t-butyl 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([NH2:11])[CH3:10].[BH4-].[Na+].O>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:11][CH2:9][CH3:10])=[CH:3][CH:2]=1
Reactant: CCN
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNCc1ccncc1

Procedure:
15.70 g (0.147 mol) of 4-pyridine-formaldehyde was dissolved in 200 mL of ethanol, added under stirring in cold-water-bath with 21 g (0.296 mol) of 65-70% ethylamine aqueous solution, reacted for 0.5 h, monitored with TLC until the reaction was almost completed. Added carefully with 5.6 g (0.148 mol) of sodium borohydride in several batches, small amount in each batch, after the end of addition, added with 30 mL of water, reacted overnight (20 h), the reaction was completed according to TLC monitoring. Evaporated to remove solvent, added with water, extracted with dichloromethane, washed with water and saturated saline in order, dried with anhydrous sodium sulfate, evaporated to remove solvent to obtain yellow thick liquid, 30 g, crude yield 73.4%. 1H NMR(CDCl3, 400 MHz)δ: 1.14(t, 3H, J=7.00 Hz), 2.66(q, 2H, J=7.00 Hz), 3.81(s, 2H), 7.26-7.27(m, 2H), 8.52-8.54(m, 2H).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[H-].[Na+]>CN(C)C=O>[N:30]1([CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:10][CH2:9]2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](COC/C=C/Cn2ccnc2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 25.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide (example 19.1) was reacted with imidazole in N,N-dimethylformamide in the presence of sodium hydride to yield trans-N-[4-(4-imidazol-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as yellowish solid, MS: 486 (MH+).
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C:23]([CH2:29][OH:30])=[CH:24]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([Zn]CC)C.ICI.C(OCC)(=O)C>C1C=CC=CC=1.O>[Si:1]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C:23]1([CH2:29][OH:30])[CH2:31][CH:24]12)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC(CO)=C2)(c1ccccc1)c1ccccc1
Reactant: CC[Zn]CC
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1cccc2c1CCC1(CO)CC21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-t-butyldiphenylsilyloxy-2-hydroxymethyl-3,4-dihydronaphthalene (1.0 g) in benzene (10 ml) were added diethylzinc (7.2 ml, 1M solution in hexane) and diiodomethane (1.2 ml) at 0° C. under N2. After being stirred for 4 hours at room temperature, the solution was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 5-t-butyldiphenylsilyloxy-1,2-methylene-2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]([CH2:21][CH2:22][OH:23])[CH2:19][OH:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@H:18]2[CH2:21][CH2:22][O:23][C:19]2=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C(CO)CCO)cc1OC
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1ccc([C@H]2CCOC2=O)cc1OC

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. 2-(3,4-dimethoxyphenyl)-1,4-butanediol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (2R)-2-(3,4-dimethoxyphenyl)butyrolactone as a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[NH:5]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[NH2:5]
Reactant: COC(=O)[C@H](CSc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)CSc1ccc([N+](=O)[O-])cc1

Procedure:
Crude II from Step B is taken up in 2 ml anisole and then treated at 0° C. for 11 minutes with 10 ml of TFA. The TFA and anisole are pumped off at 0.1 Torr at 30° C. and the residue partitioned between chloroform and aqueous 1 N HCl. The aqueous layer is made to pH 9.0 with NaOH and extracted with CH2Cl2, providing a solution of compound 3·III.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH:8]=[C:7]2[O:17]C)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1.O>[CH:1]1([CH2:4][CH2:5][C:6]2([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[CH:8][C:7]2=[O:17])[CH2:3][CH2:2]1
Reactant: COC1=CC(=O)c2ccccc2C1(C)CCC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(CCC2CC2)C(=O)C=C(O)c2ccccc21
Temperature: 95 °C
Yield: 63.9 %

Procedure:
To a solution of Example 157C (1.06 g, 4.10 mmol) in dioxane (10 mL) was added 1 N NaOH (10 mL, 10 mmol) and the reaction mixture heated at 95° C. for 16 hours. After cooling the solution to room temperature, the reaction mixture was diluted with 50 mL of water, the pH adjusted to 2.0 with 1N HCl, and the aqueous layer extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. The product was purified by flash chromatography on SiO2 eluting with a 10-25% ethyl acetate/hexane gradient yielding the title compound (0.635 g, 64% yield) as a crystalline solid. 1H NMR (300 MHz, DMSO-d6): δ ppm−0.51 (m, 2H) −0.02 (m, 2H) 0.14 (m, 2H) 0.46 (m, 1H) 1.16 (s, 3H) 5.42 (s, 1H) 7.12 (t, J=7.35 Hz, 1H) 7.34 (m, 2H) 7.64 (d, J=7.35 Hz, 1H). MS (ESI+) m/z=243 (M+H)+.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[C:10]([OH:12])=[O:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1NCC2CCCCC21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC3CCCCC3C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.7 %

Procedure:
Octahydroisoindole-1-carboxylic acid (0.125 g; 0.74 mmol) from Example 1, Step A, p-toluenesulfonyl chloride (0.155 g; 0.814 mmol), and sodium carbonate (0.157 g; 1.48 mmol) were dissolved in water (3 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and washed with EtOAc. The water layer was acidified with concentrated. HCl and extracted with CH2Cl2 (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford N-(4-methylbenzenesulfonyl)-octahydroisoindole-1-carboxylic acid (0.15 g).
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][OH:18])=[N:14][CH:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:19]I>C(Cl)Cl>[Si:3]([O:10][CH2:11][C:12]1[S:16][C:15]([CH2:17][O:18][CH3:19])=[N:14][CH:13]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(CO)s1
Agent: N#N
Solvent: ClCCl
Product: COCc1ncc(CO[Si](C)(C)C(C)(C)C)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)methanol (1.21 g, 4.65 mmol) in CH2Cl2 (3.0 mL) was treated with MeI (0.35 mL, 5.57 mmol) followed by Ag2O (1.61 g, 6.97 mmol) and the resulting mixture (protected from light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (4:1 hept-EA)=0.27. LC-MS-conditions 07: tR=0.99 min, [M+H]+=273.95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.Br[CH2:21][CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:21][CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27]
Reactant: COCOCCCBr
Reactant: Clc1cncc(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCCCc1c(Cl)cncc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.3 %

Procedure:
3,5-Dichloropyridine (4.4 g, 30 mmol) is dissolved in THF (100 ml), and thereto is added a solution of n-butyl lithium in hexane (19 ml, 30 mmol) at −70° C., and the mixture is stirred for 15 minutes. 1-Bromo-3-methoxymethoxypropane (6.0 g, 33 mmol) is added to the mixture, and the mixture is warmed to 0° C. over a period of time for one hour. The reaction is quenched with a saturated brine (50 ml), and the mixture is extracted with ethyl acetate (150 ml×2). The organic layer is washed with a saturated brine (100 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give 1-(3,5-dichloropyridin-4-yl)-3-methoxymethoxypropane (1.0 g) as an oil.
Reaction SMILES: [N:1]([CH:4]1[N:10]=[C:9]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:8]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:7]=2[N:6]([CH3:21])[C:5]1=[O:22])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[NH2:1][CH:4]1[N:10]=[C:9]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:8]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:7]=2[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: CN1C(=O)C(N=[N+]=[N-])N=C(c2ccsc2)c2cc(Cl)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN1C(=O)C(N)N=C(c2ccsc2)c2cc(Cl)ccc21

Procedure:
As illustrated in the scheme above and following General Procedure 7, 3-azido-7-chloro-1,3-dihydro-1-methyl-5-(3-thienyl)-2H-1,4-benzodiazepin-2-one (1.60 g, 4.82 mmol) and PS—PPh3 (30.0 g of 1.37 mmol/g, 41.1 mmol) were combined. After workup and purification by “catch and release,” the title compound was obtained as a brown solid (1.35 g, 92%). 1H-NMR (CDCl3): δ 7.56-7.50 (m, 4H), 7.36 (dd, J=3.1 Hz, J=4.9 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 4.46 (s, 1H), 3.43 (s, 3H), 2.35-2.15 (br s, 2H). MS (ESI) (M+H)+=306.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:13])[CH:5]=[CH:4][C:3]1=2.[C:15](Cl)(=[O:17])[CH3:16].N1C=CC=CC=1>ClCCl.Cl>[CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]2[CH:7]=[C:6]([NH:13][C:15](=[O:17])[CH3:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)Cl
Reactant: CC1=CCC(C)(C)c2ccc(N)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)C(C)=CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
General Procedure T A solution of 5,5,8-trimethyl-5,6-dihydro-naphthalen-2-ylamine (Compound 159, 1.47g, 7.9 mmol) in 10 mL of dichloromethane was stirred at 0° C., and acetyl chloride (1.0 mL, 1.39 g, 18 mmol) and then pyridine (1.0 mL, 1.0 g, 12 mmol) were added, and the reaction stirred at 0° C. for 1 h. The reaction mixture was then diluted with 10% HCl and extracted two times with methylene chloride. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvents were removed in vacuo. The residual crude product was purified by silica gel chromatography (30% ethyl acetate in hexanes) to give the title compound as a white solid, which was immediately used in the next step.