Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]([C:18]1[N:19](CC2C=CC=CC=2)[CH:20]=[CH:21][N:22]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C>[Pd].C(O)C>[C:12]1([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:18]2[NH:22][CH:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC(c1ccccc1)(c1ccccc1)c1nccn1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(C(c2ccccc2)c2ncc[nH]2)cc1

Procedure:
A slurry of (1-benzyl-1H-imidazol-2-yl)(diphenyl)methyl acetate (1-3, 13.1 g, 34.0 mmol, 1 equiv) and 10% palladium on carbon (6.03 g, 56.4 mmol, 1.66 equiv) in ethanol (250 mL) was stirred under hydrogen (balloon) for 24 h. The reaction mixture was filtered through a pad of celite and washed thoroughly with ethyl acetate. The combined filtrate was concentrated to dryness, and the residue was suspended in saturated aqueous sodium bicarbonate solution. The product was filtered, washed with water (2×100 mL) followed by a 1:1 mixture of ethyl ether and hexanes (2×50 mL) and air dried to yield 2-(diphenylmethyl)-1H-imidazole (1-4) as a white solid. 1H NMR (300 MHz, DMSO) δ 11.8 (br s, 1H), 7.29 (d, 6H, J=4.3 Hz), 7.21 (m, 4H), 7.03 (br s, 1H), 6.85 (br s, 1H), 5.51 (s, 2H), 1.84 (s, 3H). LRMS m/z (M+H) 235.0 found, 335.1 required.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:23]#N)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[CH2:5][CH2:4]1.[H-].S(=O)(O)[O-:29].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)([CH:23]=[O:29])[CH2:5][CH2:4]1
Reactant: COc1ccc(C2(C#N)CCC(OC)(OC)CC2)cc1OC1CCCC1
Reactant: O=S([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C2(C=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one dimethyl ketal (0.57 g, 1.6 mmol) in toluene (20 mL) at room temperature under an argon atmosphere was treated with a solution of dissobutylaluminium hydride (1.5M in toluene, 2.7 mL, 4 mmol). After 2 h, a solution of saturated aqueous sodium bisulfite was added and the mixture was extracted twice with ethyl acetate. The organic extract was washed with 5% aqueous sodium carbonate,was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (0.55 g, 96%).
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].FC(F)(F)C(O)=O.[CH3:16][S:17]([C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[N:30]=[CH:29][N:28]=[C:27]3[N:31]([CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[N:32]=[CH:33][C:26]=23)=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]2[N:30]=[CH:29][N:28]=[C:27]3[N:31]([CH:34]4[CH2:35][CH2:36][N:37]([S:5]([CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:7])=[O:6])[CH2:38][CH2:39]4)[N:32]=[CH:33][C:26]=23)=[CH:40][CH:41]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CS(=O)(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
Isobutanesulfonyl chloride (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 23 mg, 0.15 mmol) was added dropwise to a stirred solution of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 60 mg, 0.12 mmol) and diisopropylethylamine (0.11 mL, 0.62 mmol) in dichloromethane (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h and then washed with water. The organic layers was dried (sodium sulfate), filtered, evaporated, triturated with ether and purified by HPLC to give to give 4-(4-methanesulfonyl-phenoxy)-1-[1-(2-methyl-propane-1-sulfonyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (26 mg, 43%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:31])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:27](=[CH:28][CH:29]=1)[O:26][C:11]1([CH2:14][N:13]([CH2:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH3:25])[CH:17]=3)[CH2:12]1)[CH2:10][C:9]2=[O:30].[OH-].[Na+]>>[CH3:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][N:13]2[CH2:14][C:11]3([CH2:10][C:9](=[O:30])[C:8]4[C:27](=[CH:28][CH:29]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:31])=[O:2])[CH:7]=4)[O:26]3)[CH2:12]2)=[CH:17]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3cn(C)c4ccccc34)C1)O2
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)O)ccc4O3)C2)c2ccccc21
Yield: 84.4 %

Procedure:
(E)-3-[1′-(1-Methyl-1H-Indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (220 mg, 0.53 mmol) was hydrolyzed with 1 M NaOH (0.68 ml) following the procedure described in Example 30, Step A, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (180 mg) as a brown solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[O:14][CH2:15][C:16](=[O:23])[C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[C:26]([CH:33]=O)=[CH:25]1.N1CCCCC1>C(O)C>[NH:24]1[C:32]2=[N:31][CH:30]=[CH:29][CH:28]=[C:27]2[C:26]([CH:33]=[C:15]2[O:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:12][CH2:11]3)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:25]1
Reactant: CCOC(=O)C1=C(N2CCC(N3CCOCC3)CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(N2CCC(N3CCOCC3)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 12.8 %

Procedure:
To a stirred solution of ethyl 2-(4-morpholinopiperidin-1-yl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.31 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.045 g, 0.31 mmol) in ethanol (10 mL), piperidine (0.020 mL, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound (0.018 g, y. 13%) as solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[Li][CH2:9][CH2:10][CH2:11]C.BrCC=C>C1COCC1>[CH2:11]([CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][C:2]1=[O:7])[CH:10]=[CH2:9]
Reactant: [Li]CCCC
Reactant: O=C1CCCCN1
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1CCCNC1=O
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of piperidin-2-one (0.5 g, 5.0 mmol, 1 equiv) in dry THF (10.0 mL) was added nBuLi (4.2 ml, 10.5 mmol, 2.1 equiv) dropwise at 0° C. The mixture was then cooled to −75° C. and excess 3-bromoprop-1-ene was added to the mixture. The reaction mixture was kept at −78° C. for 1 h, quenched with NH4Cl solution and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was directly used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:54][C:55]([NH2:59])([CH3:58])[CH2:56][NH2:57]>CN(C=O)C>[NH2:59][C:55]([CH3:58])([CH3:54])[CH2:56][NH:57][C:17]([C:13]1[N:8]2[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:20]=3[F:24])[C:7]2=[N:15][C:14]=1[CH3:16])=[O:18]
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)(N)CN
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(C)N)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (0.30 mmol), 145 mg of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.45 mmol) and 122 mg of 4-methylmorpholine (1.20 mmol) were initially charged in 1.9 ml of DMF. 53 mg of 2-methylpropane-1,2-diamine (0.60 mmol) were then added, and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 94 mg of the title compound (78% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(-c2ccc(Br)cc2)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 4-bromothiobenzamide (7.62 g), 35.2 mmole), ethyl 4-chloroacetoacetate (5.82 g, 35.2 mmole) and dimethylformamide (23 ml) was stirred under nitrogen and heated in an oil-bath at 115°-120° C. for 11/2 hours. Thin layer chromatography showed the presence of unreacted thioamide. More ethyl chloroacetoacetate (2.91 g, 17.6 mmole) was added and heating was continued for 11/2 hours, by which time no unreacted thioamide remained. The mixture was cooled and poured into ice-water (125 ml) and extracted with ether (2×100 ml). The extract was washed with water (2×100 ml), dried (MgSO4) and evaporated to a semi-solid which contained the desired ester and the corresponding acid. The mixture was dissolved in ethanol (100 ml) saturated with hydrogen chloride and the solution was allowed to stand at room temperature for 1 day. The solution was evaporated to dryness and the ester was used without further purification for preparing the amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])=[CH:9][PH:10](=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+].[CH:30](OCC)([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])=[CH:9][P:10]([CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CCO[PH](=O)C=C(C)c1ccc(Cl)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(OCC)P(=O)(C=C(C)c1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of 1.68 g of ethyl 2-(4-chlorophenyl)prop-1-enylphosphinate in 20 ml of triethyl orthoformate is treated with 0.1 g of boron trifluoride diethyl etherate and the resulting solution stirred for 7 days at room temperature. The reaction mixture is then treated with 20 ml 10% aqueous sodium hydrogen carbonate solution and extracted twice with dichloromethane. The organic layer is removed, dried and concentrated to give an oil. Chromatography on silica gel gives ethyl 2-(4-chlorophenyl)prop-1-enyl-(diethoxymethyl)phosphinate as a colourless oil. 1H-NMR (CDCl3): δ(ppm)=7.38 (4H, m; Ph), 5.51 (1H, d, CH), 4.62 (1H, d, CH--P), 4.05 (2H, q, CH2OP), 3.88-3.56 (CH, m, 2×CH2OC), 2.07 (2H, d, d, CH2P), 1.28-1.14 (9H, m, 3×CH3).
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([C:15]([CH3:19])([CH3:18])[CH:16]=O)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:2])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: [Li]CCCC
Reactant: COc1ccc(C(C)(C)C=O)cc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC(C)(C)c1ccc(OC)c(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (7.71 g, 0.0215 mol) in dry THF (100 mL) was cooled to 0° C. under argon. n-BuLi (2.5M, 8 mL, 0.020 mol) was added slowly. The resulting clear orange solution of the ylide was stirred for another 15 min at 0° C. 2-(3-Bromo-4-methoxy-phenyl)-2-methyl-propionaldehyde (3.7 g, 0.014 mol) was dissolved in dry THF (50 mL) and added to ylide-solution. The mixture was stirred for 3 h/25° C. and the resulting suspension was quenched with MeOH (10 mL). The solvent was removed under reduced pressure and the crude product was purified by flash chromatography using n-heptane as eluent. Yield: 3.1 g (84%). GCMS: >99%
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]([C:19]1[N:20]=[C:21]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[S:22][C:23]=1[C:24]([OH:26])=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[ClH:18].[NH2:8][CH2:9][CH2:10][CH:11]([C:19]1[N:20]=[C:21]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[S:22][C:23]=1[C:24]([OH:26])=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 215.2 %

Procedure:
To a solution of 4-{3-[(tert-butoxycarbonyl)amino]-1-(4-chlorophenyl)propyl}-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid (0.304 g, 0.631 mmol) in DCM (5.9 mL) was added a solution of hydrogen chloride in dioxane (4 M, 3.1 mL, 12 mmol) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was then azeotroped with toluene and dried under vacuum to give the product (0.284 g, 108%) which was used directly in the next step. LCMS: (AA) ES+ 382, 384.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:30][CH3:31])=O)C.[N:32]([C:35]1[CH:43]=[CH:42][C:38]2[O:39][CH2:40][O:41][C:37]=2[CH:36]=1)=[C:33]=[O:34]>>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:30][CH3:31])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:32]([C:35]3[CH:43]=[CH:42][C:38]4[O:39][CH2:40][O:41][C:37]=4[CH:36]=3)[C:33]2=[O:34])[CH2:22][CH2:21]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc4c(c3)OCO4)c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c12
Yield: 64.9 %

Procedure:
4-(3-Benzo[1,3]dioxol-5-yl-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (110 mg) was prepared from 4-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.31 mmol) and 5-isocyanato-benzo[1,3]dioxole (0.465 mmol) following general procedure C. LCMS: m/z 547 [M+1]+.
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:14]=2[O:21]C)=[C:11]2[C:6]([C:7]([C:23]([F:26])([F:25])[F:24])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[OH:21])=[C:11]2[C:6]([C:7]([C:23]([F:26])([F:25])[F:24])=[CH:8][CH:9]=[CH:10]2)=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(O)cc1O
Yield: 40.6 %

Procedure:
Prepared according to Method D step C from 2-allyl-3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-2H-indazole (0.05 g, 0.14 mmol), boron tribromide (0.104 mL, 1.1 mmol) and 1.0 mL of cyclohexene to give the product (0.019 g) as a white solid.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:28][C:29]([F:38])([F:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1>O1CCCC1>[F:28][C:29]([F:37])([F:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH3:16])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:31]=1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(OCC(C)Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2(α,α,α-trifluoro-p-tolyloxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.75 g of α,α,α-trifluoro-m-cresol in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)(O)[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:27])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH2:14]3)=[N:9][C:8]2=[O:27])=[CH:28][CH:29]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 19.1 %

Procedure:
To 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one (240 mg, 0.58 mmol) synthesized in Synthesis Example 111, trifluoroacetic acid (2.3 mL) was added and the resultant mixture was stirred at room temperature for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel (amino-type) column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (44 mg, yield: 19%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].P([O-])([O-])([O-])=O.[K+].[S:30]1[C:34]([C:35](=[S:37])[O-:36])=[CH:33][N:32]=[CH:31]1.P(=O)(O)(O)O>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:37][C:35]([C:34]3[S:30][CH:31]=[N:32][CH:33]=3)=[O:36])[CH2:15][S:14][C@H:9]12
Reactant: [O-]C(=S)c1cncs1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: NC1C(=O)N2C(C(=O)O)=C(CSC(=O)c3cncs3)CS[C@H]12
Reaction time: 5 h

Procedure:
To a stirred solution of 8.95 g. (0.0328 moles) of 7-aminocephalosporanic acid and 2.76 g. (0.0328 moles) of sodium bicarbonate in 150 ml. of aqueous phosphate buffer at pH 6.4 was added 6.0 g. (0.0328 moles) of thiazole-5-thiocarboxylic acid potassium salt. The mixture was stirred in a nitrogen atmosphere at 50° for 5 hours keeping the pH at 6.6 with 42% phosphoric acid. The mixture was cooled to 20° and the precipitated solid was removed by filtration, washed with water, acetone and ether and dried in vacuo over phosphorus pentoxide to provide 4.25 g. (36%) of a tan crystalline solid. Infrared and NMR spectra were consistent with the structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[N:60]1([C:66]([O:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[O:67])[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCCCCC.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].CCOC(C)=O>[C:13]([O:12][C:11]([NH:10][C@@H:8]([C:4]1[CH:3]=[C:2]([N:63]2[CH2:62][CH2:61][N:60]([C:66]([O:68][CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[O:67])[CH2:65][CH2:64]2)[CH:7]=[CH:6][CH:5]=1)[CH3:9])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a suspension of Intermediate 33A (50 mg, 0.167 mmol) and Pd2(dba)3 (15.25 mg, 0.017 mmol) in toluene (2 mL) was added xantphos (28.9 mg, 0.050 mmol), benzyl piperazine-1-carboxylate (36.7 mg, 0.167 mmol), followed by sodium tert-butoxide (48.0 mg, 0.500 mmol). The reaction mixture was stirred at 70° C. for 16 h, and then filtered. The filtrate was concentrated and purified on ISCO using a 15 min gradient from 0 to 100% EtOAc in hexane to give Intermediate 33B (70 mg, 0.159 mmol, 96% yield). LC-MS (ESI) m/z 440.1 (M+H), RT=2.27 min (Method B).
Reaction SMILES: C(O)[C@@H]([C@H]([C@@H](CO)O)O)O.[C@@H:11]1([OH:22])[C@@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([OH:19])[C@@H:13]([OH:20])[C@H:12]1[OH:21]>>[CH2:12]([OH:21])[C@@H:13]([C@H:14]([C@H:15]([C@@H:16]([CH2:11][OH:22])[OH:17])[OH:18])[OH:19])[OH:20]
Reactant: O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O
Agent: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO

Procedure:
A total of 500 mg per vial of CPA, taken as the anhydride, was mixed with one of the following excipients: (A) 250 mg per vial maltodextrin, or (B) 500 mg per vial maltodextrin.
Reaction SMILES: O=N.[CH2:3]([N:7]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=1)=[O:10])[CH2:4][CH2:5][CH3:6]>[Pd].CCO>[CH2:22]([N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=1)[OH:10])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN(CCCC)CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: [Pd]
Agent: N=O
Solvent: CCO
Product: CCCCN(CCCC)CC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 18.5 h

Procedure:
A mixture of 0.46 g (1.35 mmol) of the ketoamine free base, N-[4-[2-(Dibutylamino)-1-oxoethyl]phenyl]methanesulfonamide, 0.15 g of 10% palladium on carbon catalyst and 150 ml of absolute EtOH is placed on a Parr hydrogenator and shaken under an hydrogen atmosphere for 18.5 hrs. The catalyst is removed by filtration and the filtrate is concentrated in vacuo. The residue is chromatographed on a 100 ml silica gel column (elution with 3% MeOH:CH2Cl2 containing 0.3% NH4OH) and fractions are collected. The title compound is recrystallized from Et2O:pet. ether.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC.CCOC(C)=O.[I-].[K+]>[N:17]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CCOC(=O)c1ccc(OCCCN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of ethyl 4-(3-chloropropoxy)benzoate (4.73 g) (D. A. Walsh et al J. Med. Chem. 1989, 32(1), 105), piperidine (2.9 ml), sodium carbonate (3.1 g) and potassium iodide (162 mg) in 1-butanol (50 ml) was heated at 105° C. for 16 h. The reaction was cooled to rt, diluted with EtOAc (100 ml), washed with water (3×50 ml), saturated brine (50 ml), dried (MgSO4) and evaporated to give the title compound (D1) (6.88 g). MS electrospray (+ion) 292 (MH+). 1H NMR δ (CDCl3): 7.98 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 4.34 (2H, q, J=7.5 Hz), 4.06 (2H, t, J=6.3 Hz), 2.46 (4H, m), 2.00 (2H, m), 1.50 (6H, m), 1.38 (3H, t, J=7.5 Hz).