Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:9])=[CH:3][C:4](=[O:8])[CH:5]([CH3:7])[CH3:6].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C(O)(C)C>[Cl:1][C:2]([Cl:9])=[CH:3][CH:4]([OH:8])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C(=O)C=C(Cl)Cl
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: CC(C)C(O)C=C(Cl)Cl
Yield: 81.8 %

Procedure:
A mixture of 33.4 gm (0.18 mole) of 1,1-dichloro-4-methyl-1-penten-3-one, 40.9 gm (0.20 mole) of aluminum isopropoxide, and 200 ml of isopropanol was heated at reflux for 2 hours. The by-product, acetone, was distilled periodically from the reaction mixture by alternating between reflux and distillation. When the vapor temperature of the distillate reached 82°, the heating was stopped. To the reaction mixture was then added a cold solution of 70 ml of concentrated hydrochloric acid in 350 ml of water. The aqueous mixture was extracted several times with carbon tetrachloride. The combined extracts were dried over magnesium sulfate and filtered. The carbon tetrachloride was evaporated, and the residue was distilled to give 24.9 gm (82% yield) of 1,1-dichloro-3-hydroxy-4-methyl-1-pentene; b.p., 72°/5mm.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([NH:9][C:10]3[C:15]([S:16]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2].[C:23](Br)(=[O:25])[CH3:24]>ClCCCl>[C:1]([O:4][C:5]1[CH:18]=[C:17]2[C:8]([N:9]([C:23](=[O:25])[CH3:24])[C:10]3[C:15]([S:16]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]2[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)Br
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Solvent: ClCCCl
Product: CC(=O)Oc1cc2c(c3ccccc13)N(C(C)=O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-acetoxy-12H-benzo[a]phenothiazine (3.0 g) and powdered 4 Angstrom molecular sieves (7.5 g) in 1,2-dichloroethane (75 ml) there was added slowly acetyl bromide (1.05 ml). The mixture was stirred at room temperature for 1 hour, then filtered. The filtrate was evaporated down to an oil which was triturated with a mixture of ether and hexane to afford solid title product (3 g), m.p. 141°-142° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C1COCC1.C(OCC)C>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])/[CH:3]=[CH:2]\[CH2:1][OH:4])[CH2:21][CH2:22][CH3:23]
Reactant: C#CCO
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 18 h

Procedure:
Propargyl alcohol (5 mL) was added to a solution of lithium aluminium hydride (1M in THF, 43 mL) in THF (70 mL) at −78° C. The resultant mixture was warmed to room temperature and stirred for 18 hours. It was re-cooled to −78° C. and a solution of tri-n-butyl tin chloride (8.32 mL) in diethyl ether (50 mL) was added and the mixture was stirred for 3 hours whilst gradually warming to room temperature. The reaction mixture was cooled to −5° C. and quenched by addition of water and 15% aqueous sodium hydroxide solution then warmed to room temperature. Ethyl acetate was added and the mixture was stirred for 1 hour. The mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on a silica column which had been pre-washed with 20% triethylamine in acetonitrile. The column was eluted with a mixture of ethyl acetate and pentane with a gradient of 0-10% to give (Z)-3-tributylstannanyl-prop-2-en-1-ol (5.06 g) as a clear oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([NH:9]C=O)[N:6]=[C:5]([C:12](=[N:36][O:37][CH3:38])[C:13]([NH:15][CH:16]2[C:34](=[O:35])[N:18]3[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH:23]([S:25][C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH3:24])[CH2:21][S:22][C@H:17]23)=[O:14])[CH:4]=1.C(OCC)C>CO>[ClH:2].[NH2:9][C:7]1[N:6]=[C:5]([C:12](=[N:36][O:37][CH3:38])[C:13]([NH:15][CH:16]2[C:34](=[O:35])[N:18]3[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH:23]([S:25][C:26]4[NH:27][N:28]=[N:29][N:30]=4)[CH3:24])[CH2:21][S:22][C@H:17]23)=[O:14])[CH:4]=[C:3]([Cl:2])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cc(Cl)nc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 156 %

Procedure:
Conc. hydrochloric acid (242 mg.) was added to a solution of 7-[2-(6-chloro-2-formamidopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.2 g.) in methanol (12 ml.), and the mixture was stirred at ambient temperature for 5 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a foamy residue, which was pulverized with ethyl ether. This powder (1.1 g.) was dissolved in methanol (6 ml.), and to ethyl ether (50 ml.) was added dropwise the methanol solution. The precipitates were collected by filtration and then dried to give 7-[2-(2-amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (0.95 g.).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=O)=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl.CN.C1C=CC2N(O)N=[N:40][C:38]=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[Br:1][C:2]1[C:3]2[N:12]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:40][CH3:38])=[O:30])=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)c2c1c(-c1ccc(CC(=O)O)cc1)nn2-c1c(F)cccc1F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Br)cnc(OC)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of (4-(7-bromo-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetic acid (60 mg), methylamine hydrochloride (12.8 mg), HOBt (25 mg) and triethylamine (26 μL) in DMF (3 mL) was added EDCI hydrochloride (36 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (57 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=3)=[CH:16][CH:15]=2)=[O:13])[C:9]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:8][C:7]=1[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:2][CH2:3][CH3:4]>Cl.CO.O>[CH2:1]([O:5][C:6]1[N:11]=[C:10]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)=[O:13])[C:9]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:8][C:7]=1[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(C(=O)c2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C(=O)OCC)cc1C(=O)OCC
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCOc1nc(C(=O)c2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(C(=O)OCC)cc1C(=O)OCC
Temperature: 20 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
One drop of concentrated hydrochloric acid is added to a solution of 30 mg (0.04 mmol) of the compound from Example 1 in 2 ml of methanol and the mixture is stirred at 20° C. for 3 hours. The reaction mixture is diluted with water and washed three times with ethyl acetate, the combined organic phases are washed with water and sodium chloride solution, dried over sodium sulphate and concentrated and the residue is chromatographed over 25 g of silica gel using methylene chloride/methanol 10:1 to give 15.9 mg of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[N:13][NH:14][C:15](=[O:16])[C:10]=2[CH:9]=[CH:8]1.[H-].[Na+].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[N:13][N:14]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[C:15](=[O:16])[C:10]=2[CH:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]ncc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2c(ccn2COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To 1.5 L of dehydrated N,N-dimethylformamide solution containing 107 g (0.403 mol) of 1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 16-(b) was added 22.2 g (0.509 mol) of sodium hydride (55% dispersed material in mineral oil) by dividing it into several portions under argon atmosphere and under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Then, 85.9 g (0.515 mol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into ice-water, neutralized with a saturated aqueous solution of ammonium chloride, and extracted with toluene. The organic layer after separation was washed successively with water and then a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained concentrate was recrystallized from 400 ml of cyclohexane to obtain 76.2 g of the title compound as a white solid. (Yield: 48%)
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Cl:14][C:15]1[S:19][C:18]([C:20](Cl)=[O:21])=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[S:19][C:18]([C:20]([NH:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[O:21])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g (2.7 mmol) tert. Butyl 3-amino-pyrrolidine-1-carboxylate are dissolved in 7 ml DCM, combined with 1.4 ml (10.1 mmol) TEA and 0.5 g (2.7 mmol) 5-chloro-thiophene-2-carboxylic acid chloride and stirred for one hour at RT. The reaction mixture is diluted with DCM and washed successively with dil. aqueous KHSO4 solution, sat. aqueous NaHCO3 solution and water. The combined organic phases are dried on sodium sulphate and evaporated to dryness i. vac.
Reaction SMILES: [C:1]1([C:7]([S:13][CH:14](O)[C:15]([O:17][CH3:18])=[O:16])(O)[C:8]([O:10]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC)(=O)[C:21](OC)=[O:22].[Na]>>[OH:22][C:21]1[C:8]([OH:10])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(=O)OC
Reactant: COC(=O)C(O)SC(O)(C(=O)OC)c1ccccc1
Agent: [Na]
Product: COC(=O)c1sc(-c2ccccc2)c(O)c1O
Yield: 43.4 %

Procedure:
Prepared by the method described in Example 15 from dimethyl α-phenyl-thiodiglycolate (9.0 g, 35 mmoles), dimethyl oxalate (6.1 g, 52 mmoles) and sodium (2.5 g, 109 mmoles). The product is obtained as a beige powder (3.8 g); mp 143°-144° C.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:6]([NH2:7])=[CH:5][C:4]=1F)#[N:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH:23]([CH3:27])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>CS(C)=O.C(N(C(C)C)CC)(C)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:4]2[C:3]([C:1]#[N:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:6]([CH:5]=2)[NH2:7])[CH:23]([CH3:27])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1cc(N)c([N+](=O)[O-])cc1C#N
Temperature: 140 °C
Reaction time: 12 h
Yield: 76.4 %

Procedure:
To a solution of 8.00 g of 4-cyano-3-fluoro-6-nitroaniline (which was synthesized following J. Med. Chem. 1994, 37, 467) and 17.60 g of 1-tert-butoxycarbonyl-3-methylpiperazine in 25 ml of dimethylsulfoxide, 23 ml of diisopropylethylamine was added and stirred for 3 hours at 140° C. and 12 hours at room temperature. 1N aqueous sodium hydroxide solution was added to the reaction liquid which then was extracted with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was washed with chloroform-methanol, to provide 12.2 g of the title compound as a pale yellow solid.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:16]([NH:26][C:27]([CH3:32])([C:29]([OH:31])=O)[CH3:28])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl.[CH3:34][NH:35][O:36][CH3:37].Cl>C(Cl)Cl>[CH3:37][O:36][N:35]([CH3:34])[C:29](=[O:31])[C:27]([NH:26][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([CH3:28])[CH3:32]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-Methylmorpholine (682 mg, 741 μL, 6.74 mmol) and isobutylchloroformate (460 mg, 441 μL, 3.37 mmol) were added successively to a stirred solution of N-carbobenzyloxy-2-methylalanine (0.64 g, 2.69 mmol) in dry CH2Cl2 at 0° C. under N2. The resulting cloudy mixture was stirred at 0° C. for 90 min. N,O-Dimethylhydroxylamine hydrochloride (316 mg, 3.24 mmol) was added portionwise and the mixture was warmed to room temperature and stirred for 3 h. The mixture was poured into 1N HCl (30 mL) and extracted with CH2Cl2 (3×40 mL). The combined extracts were washed with 1N HCl (30 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-80% EtOAc in hexanes gradient) to afford benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate. Rf=0.47 (50% EtOAc in hexanes). LCMS calc.=303.1; found=303.2 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.82 (s, 1H), 5.09 (s, 2H), 3.60 (s, 3H), 3.18 (s, 3H), 1.60 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:5][C:6]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:8](=[CH:9][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=2)[CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:8](=[CH:9][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:11]=2)[CH:7]=1
Reactant: COC(=O)C(=Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of methyl-2-(tert-butoxycarbonyl)-3-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)acrylate (3.7 g, 8.0 mmol) in methanol (20 mL) was flushed with nitrogen (2×), and treated with palladium (10% on charcoal, 0.37 g). The flask was flushed with hydrogen and was shaken in a parr apparatus overnight at 60 psi. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 2.3 g (63%). 1H-NMR (CDCl3, 500 MHz) δ −0.03 (s, 9H), 0.92-0.97 (m, 2H), 1.41 (s, 9H), 2.59 (s, 3H), 3.00-3.17 (m, 2H), 3.59-3.67 (m, 2H), 3.71 (s, 1H), 4.54-4.64 (m, 1H), 4.92-5.01 (m, 1H), 5.71 (s, 2H), 6.82 (s, 1H), 7.12-7.19 (m, 2H), 8.01 (s, 1H). Mass spec.: 464.29 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](O)[CH2:14][CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[O:7]1[CH2:13][CH2:14][CH2:15][O:16][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(C2OCCCO2)ccc1O
Yield: 85.3 %

Procedure:
A mixture of 8 g of 4-hydroxy-3-nitrobenzaldehyde,16 g of 1,3-propanediol, a catalytic amount of pyridinium p-toluenesulfonic acid and 250 ml of toluene was azeotropically dehydrated with heating under reflux. The reaction mixture was cooled, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from toluene-n-hexane to obtain 9.2 g of 4-(1,3-dioxan-2-yl)-2-nitrophenol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](B3OC(C)(C)C(C)(C)O3)=[CH:7][N:8]2[S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:30]1[O:34][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=[N:32][N:31]=1.Br[C:40]1[N:45]=[C:44]([CH:46]2[CH2:48][CH2:47]2)[CH:43]=[CH:42][N:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH:46]1([C:44]2[CH:43]=[CH:42][N:41]=[C:40]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[C:3]([C:30]5[O:34][C:33]([NH:35][CH:36]([CH3:37])[CH3:38])=[N:32][N:31]=5)[CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=4)(=[O:12])=[O:13])[CH:7]=3)[N:45]=2)[CH2:48][CH2:47]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)c(F)cc32)cc1
Reactant: Brc1nccc(C2CC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)c(F)cc32)cc1
Temperature: 130 °C
Yield: 102.6 %

Procedure:
A 20 mL microwave vial was charged with 5-(6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (185 mg, 0.342 mmol), Xphos (Strem Chemicals, Newburyport, Mass., 9.8 mg, 0.021 mmol), Pd2(dba)3 (Strem Chemicals, Newburyport, Mass., 9.4 mg, 10.27 μmol), 2-bromo-4-cyclopropylpyrimidine (CombiPhos Catalysts Inc., Princeton, N.J., 82 mg, 0.411 mmol) and potassium phosphate (218 mg, 1.03 mmol) followed by purging with argon. The solids were treated with dioxane (4.0 mL) and water (1.0 mL) and heated in the microwave at 130° C. for 20 min. The reaction mixture was treated with water and extracted with EtOAc, dried over MgSO4, filtered and concentrated. Purification of the crude residue on the ISCO Combiflash Rf (12 g Redisep column, using a gradient of 0-100% EtOAc in hexanes) afforded 5-(3-(4-cyclopropylpyrimidin-2-yl)-6-fluoro-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (186.7 mg, 0.351 mmol, 102% yield) as a viscous yellow oil in ca. 90% purity. MS (ESI, pos. ion) m/z: 533.0 (M+H)+. The material was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]#[N:12])=[CH:4][C:3]=1[N+:13]([O-])=O.[H][H]>CN(C=O)C.[Pt]>[NH2:13][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6]2[N:10]=[CH:9][NH:8][C:7]=2[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c2nc[nH]c12
Reactant: [H][H]
Agent: [Pt]
Solvent: CN(C)C=O
Product: Cc1c(N)cc(C#N)c2nc[nH]c12

Procedure:
A mixture of 7-Methyl-6-nitro-1H-benzimidazole-4-carbonitrile (24) (1.010 g, 5.0 mmol) and Pt/C (5% Pt/C sulfided, 0.502 g, 50 wt %, C5002 Engelhard Industries) in DMF (75 mL) is hydrogenated at about 40 psi hydrogen pressure at about 50° C. over about 24 hours. The catalyst is removed from the reaction mixture by filtration through a Celite pad and the filtrate is concentrated in vacuo. The residue obtained is triturated in acetonitrile, and filtered to provide 6-Amino-7-methyl-1H-benzimidazole-4-carbonitrile (10), as a tan solid (0.768 g, 90% Yield).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])#[N:2].[I-].C[N:15](C)N(C)C>CS(C)=O>[C:1]([C:3]1([NH2:15])[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:4]1[NH2:5])#[N:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N
Reactant: CN(C)N(C)C
Agent: [I-]
Solvent: CS(C)=O
Product: N#CC1(N)C=CC([N+](=O)[O-])=CC1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
To a solution of 2-cyano-5-nitroaniline (435 mg, 2.67 mmol) in dimethylsulfoxide (25 ml) was added tetramethylhydrazine iodide(534 mg, 2.67 mmol) and sodium t-pentoxide (880 mg, 8.01 mmol). The mixture was stirred at room temperature for 12 hrs., the reaction was quenched with 10% HCl. Precipitated solids were filtered and the remaining solution was extracted with ethyl acetate, the solvent was evaporated and chromatography of the resulting solid on silica gel(25%EtOAc/Hexane) gave the desired product (254 mg, 53%). 1H NMR (CD3COCD3): δ7.49 (d, 1H), 7.03 (bs, 2H), 6.80 (d, 1H), 5.78(bs, 2H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:45]([OH:47])=[O:46])[CH2:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[NH:23][C:24]([CH3:44])=[C:25]([C:40]([O:42][CH3:43])=[O:41])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:16])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@H:12]([C:45]([OH:47])=[O:46])[CH2:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[NH:23][C:24]([CH3:44])=[C:25]([C:40]([O:42][CH3:43])=[O:41])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:16]
Reactant: CCOC(=O)C1=C(COCCNC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1=C(COCCNC(=O)CC[C@H](N)C(=O)O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 90.2 %

Procedure:
A solution of 2-[2-(-(S)-4-benzyloxycarbonylamino-4-carboxybutanamido)ethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.97 g) in 10% aqueous ethanol (22 ml) was stirred for 2 hours under an atmosphere of hydrogen [103.4 kPa (15 p.s.i.)] at room temperature in the presence of 5% palladium on carbon (97 mg). The mixture was filtered and evaporated to leave the title compound as an amorphous solid, (0.7 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([NH:9][S:10]([C:13]1[CH:18]=[C:17]([CH2:19][NH2:20])[CH:16]=[CH:15][C:14]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:12])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([NH:9][S:10]([C:13]1[CH:18]=[C:17]([CH2:19][NH:20][C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][C:14]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:12])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(CN)cc1S(=O)(=O)NC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(C)=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
0.63 g (8 mmol) of acetyl chloride dissolved in 10 ml of dichloromethane is added dropwise to a solution, cooled to 0° C., of 2.01 g (6.7 mmol) of N-tert-butyl-5-aminomethyl-2-methoxycarbonylbenzenesulfonamide and 0.93 ml (6.7 mmol) of triethylamine in 30 ml of dichloromethane, and the mixture is then stirred at room temperature for 2 h. The reaction solution is washed with water, dried and evaporated to dryness i.v. 2.1 g (91%) of N-tert-butyl-5-acetamidomethyl-2-methoxycarbonylbenzenesulfonamide are obtained as a viscous oil.