Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[Se]=[O:12]>O1CCOCC1>[F:1][CH:2]([F:10])[C:3]1[C:4]([CH:9]=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[Se]
Reactant: Cc1ncccc1C(F)F
Solvent: C1COCCO1
Product: O=Cc1ncccc1C(F)F
Yield: 9.1 %

Procedure:
A mixture of 3-(difluoromethyl)-2-methylpyridine (110 mg, 0.768 mmol) and selenium oxide (102 mg, 0.922 mmol) in 1,4-dioxane (3 mL) was warmed at reflux for twelve hours. The reaction mixture was then concentrated and purified with flash chromatography (12+S Biotage, heptane/ethyl acetate=1:0 to 1:1), to give 3-(difluoromethyl)picolinaldehyde as an oil (11 mg). 1H NMR (400 MHz, CDCl3) δ 10.1 (s, 1H), 8.90 (d, 1H), 8.22 (d, 1H), 7.64 (m, 1H), 7.59 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH:34]([N:37]([CH:41]([CH3:43])[CH3:42])[CH2:38][CH2:39]Cl)([CH3:36])[CH3:35].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:39][CH2:38][N:37]([CH:41]([CH3:43])[CH3:42])[CH:34]([CH3:36])[CH3:35])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21)C(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 2-(diisoproplyamino)ethyl chloride hydrochloride (0.50 g) are added. The reaction mixture is heated to 90° C. for 2 h, then allowed to stir at room temperature overnight. A drop of water is added and the mixture is heated for 20 h. An additional equivalent of 2-(diisoproplyamino)ethyl chloride hydrochloride (0.25 g, 1.25 mmol) is added and the mixture is heated at 100° C. for 5 h, and then stirred at room temperature overnight. Water is added and an oily solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-2% MeOH/CHCl3) gave 0.45 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.22 g of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][C@@H:8]([NH:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH3:4][C:2]([Si:5]([CH3:28])([CH3:29])[O:6][CH2:7][C@@H:8]([NH:18][C:19]1[C:24]([NH:25][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(N)c(N[C@@H](COCc2ccccc2)CO[Si](C)(C)C(C)(C)C)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(OC)nc1N[C@@H](COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of N2-((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)-6-(methyloxy)-2,3-pyridinediamine (673.1 g, 1.612 mol) in DMF (10 L) was added K2CO3 (490.1 g, 3.546 mol). Ethyl bromoacetate (196.6 ml, 1.77 mol) was added to the mixture over 15 min and the reaction mixture was stirred at room temperature. After 3 h, the reaction was quenched in H2O (10 L) then partitioned with EtOAc (10 L). The layers were separated and the aqueous was extracted with EtOAc (7 L). The organic phases were combined, washed with H2O (7 L) and brine (7 L), dried over MgSO4 (1 kg), filtered and evaporated. The resulting dark oil (853 g) was purified by column chromatography (9 kg silica, mixtures of heptane and EtOAc as eluent) to give ethyl N-[2-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)amino]-6-(methyloxy)-3-pyridinyl]glycinate (672.0 g, 83%) as a dark oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[N:31]=[C:32]([CH3:35])[S:33][CH:34]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: Cc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(CN2C[C@@H](C)n3c(cc4cc(OC5CCN(C(C)C)CC5)ccc43)C2=O)cs1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride (2.4 equivalents) and 4-(chloromethyl)-2-methyl-1,3-thiazole, to give the desired product as a light yellow foam (61%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([C:26](=O)[CH3:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+]>CO.C(#N)C>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([CH:26]([NH2:35])[CH3:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloroquinolin-7-yl]ethanone (275 mg, 0.656 mmol) and ammonium acetate (506 mg, 6.56 mmol) in methanol (3.7 mL) and acetonitrile (3.7 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (82.5 mg, 1.31 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C22H35ClN3OSi (M+H)+: m/z=421.2; Found: 421.1.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:23][CH:24]([C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH2:28])[CH3:25]>>[CH3:35][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:26]([CH:24]([CH3:25])[CH3:23])[C:27]=1[NH:28][C:20](=[O:22])[CH2:19][CH2:18][C:15]1[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=1)[CH3:34]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CCCCCCCCCCCCn1nnc(CCC(=O)O)n1
Product: CCCCCCCCCCCCn1nnc(CCC(=O)Nc2c(C(C)C)cccc2C(C)C)n1

Procedure:
In a manner similar to Example 34, 2-dodecyl-2H-tetrazole-5-propanoic acid was condensed with 2,6-bis(1-methylethyl)aniline to give the title compound, mp 41°-43° C.
Reaction SMILES: N#N.[NH2:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].C[O-].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1.CO>[C:17]([NH:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:8][CH3:9])[O:10][CH3:11])(=[O:20])[CH:18]=[CH2:19]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: C=CC(=O)Cl
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CC(=O)NCCC[Si](OC)(OC)OC
Temperature: 0 °C

Procedure:
A one liter, three-necked flask equipped with a thermometer, stirring paddle, air tight stirring sleeve, N2 inlet and dropping funnel was charged with aminopropyltrimethoxysilane (100.0 g, 0.558 moles), toluene (160.1 g), sodium methoxide (33.16 g, 0.614 moles) and methanol (10.11 g). The mixture was stirred under N , atmosphere and cooled to 0° C using a dry ice/isopropanol bath. To this, 55.37 g (0.614 moles) of acrylyl chloride dissolved in 100 g of toluene was added gradually over a period of 30 minutes. The mixture was agitated for another 30 minutes. By-product sodium chloride was removed by filtration and the solvent was removed under reduced pressure to obtain acrylamidopropyltrimethoxysilane in essentially quantitative yield. Sodium nitrite (0.001 g) was added as an inhibitor.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=3)[C:9](SC(C)(C)C)=[C:8]2[CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1.[CH2:32](S)C.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([O:27][CH3:32])=[O:26])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Reactant: CCS
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A suspension of 1.0 g of 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid (from Example 1 Step B) in 50 mL of CH2Cl2 was treated with 1.3 mL of ethanethiol and 3.47 g of AlCl3 at 0° C. under argon. After 40 min the mixture was poured onto 50 mL 1N HCl, extracted with 3×50 mL of CH2Cl2 washed with 2×50 mL of H2O, dried with MgSO4 and the solvent removed. The residue was dissolved in 10 mL ether and ethereal diazomethane added until all the acid was consumed. The excess solvent was removed and the residue chromatographed on silica gel to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]([CH2:9]Br)=[C:4]([CH2:7]Br)[CH2:5]Br.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[H-].[Na+]>CN(C)C=O>[C:12]1([CH3:11])[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:7][C:4]3[CH2:5][N:21]([S:18]([C:15]4[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=4)(=[O:19])=[O:20])[CH2:9][C:3]=3[CH2:2]2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: BrCC(CBr)=C(CBr)CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC3=C(C2)CN(S(=O)(=O)c2ccc(C)cc2)C3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.1 %

Procedure:
30 g of tetrakis (bromomethyl)ethylene and 30 g of p-toluene sulfonamide were dissolved in 400 ml of dimethylformamide. 150 g of potassium carbonate anhydride (or 50% sodium hydride 17 g) was added and then stirred at room temperature for 24 hours. Thereafter, this reaction mixture was distilled under vacuum to remove solvents. By adding 30 ml of water and 100 ml of ethylacetate, 17 g of the title compound was obtained as pale yellow powder (yield 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][CH:16]1[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C:17]1([CH3:32])[CH3:31].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][CH:16]3[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][C:17]3([CH3:32])[CH3:31])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1N
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)OCc2ccccc2)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 63.0 mg, 0.230 mmol) in N,N-dimethylformamide (0.5 mL), was added benzyl 4-amino-3,3-dimethylpyrrolidine-1-carboxylate (Intermediate 11, 57 mg, 0.230 mmol) and N,N-diiospropylethylamine (0.121 mL), and heated at 90° C. for 16 h. The reaction was added water, stirred at rt for a 3 hours and filtered. The solid was rinsed with water and dried under vacuum to give benzyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpyrrolidine-1-carboxylate (72 mg, 64.5% yield) as a yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ 10.83-10.77 (m, 1H), 8.16 (s, 1H), 7.67 (s, 1H), 7.41-7.27 (m, 7H), 7.09-7.04 (m, 1H), 5.18-5.08 (m, 2H), 4.56-4.45 (m, 1H), 4.16-3.95 (m, 1H), 3.42 (d, J=2.2 Hz, 3H), 1.20 (d, J=13.9 Hz, 6H); MS (ES+) m/z: 486.4, 487.9 (M+H); LC retention time: 4.02 min (analytical HPLC Method I).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=1>>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][NH:3][CH2:1][CH3:2]
Reactant: CCN
Reactant: BrCc1cccc(Br)c1
Solvent: CO
Product: CCNCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To 80% ethylamine/MeOH (1.1 g) was added 1-bromo-3-(bromomethyl)benzene (1 g) in five divided portions at room temperature, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to liquid separation with chloroform and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined, dried over Na2SO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica, 3% MeOH/CHCl3) to obtain N-(3-bromobenzyl)ethanamine (610 mg) as a colorless oil.
Reaction SMILES: [F:1][CH2:2][C:3]([O:5]CC)=O.[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH2:14][Mg]Br)=[CH:11][CH:10]=1>O1CCCC1.[Cl-].[NH4+]>[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH2:14][C:3](=[O:5])[CH2:2][F:1])=[CH:11][CH:10]=1
Reactant: CCOC(=O)CF
Reactant: Clc1ccc(CC[Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CF)CCc1ccc(Cl)cc1
Temperature: -50 °C
Reaction time: 5 h
Yield: 18 %

Procedure:
To a stirred solution of ethyl fluoroacetate (0.59 ml; 6.0 mmol) in tetrahydrofuran (6 ml) under nitrogen at −76° C. was added dropwise a 0.5 M solution of 4-chlorophenethylmagnesium bromide in tetrahydrofuran (10 ml; 5.0 mmol). The suspension obtained was stirred at −50° C. during 5 h. The mixture was poured in ammonium chloride sat. solution (20 ml) and extracted with dichloromethane (3×20 ml). Combined organics were dried over sodium sulfate and evaporated. The crude obtained was subject flash chromatography (eluant: c-hexane/ethyl acetate 95:5) to afford 0.13 g (18% of theory) of 4-(4-chloro-phenyl)-1-fluoro-butan-2-one as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH2:5]Br.C[N+]1([O-])CC[O:16]CC1>C(#N)C>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=[O:16]
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1c(Cl)ccc(Cl)c1CBr
Solvent: CC#N
Product: Cc1c(Cl)ccc(Cl)c1C=O
Temperature: 4 °C
Reaction time: 1 h

Procedure:
67.4 g (0.19 mol) of 72.2% pure 3,6-dichloro-2-methylbenzyl bromide is initially charged in 280 ml of acetonitrile. At 0-5° C., a solution of 54.0 g (0.46 mol) of N-methylmorpholine N-oxide and 280 ml of acetonitrile is added over a period of 25 min, and the mixture is stirred at 0-8° C. for 1 h. The precipitate is filtered off with suction and taken up in 280 ml of acetonitrile, and 250 g (0.42 mol) of 20% strength NMO in acetonitrile are then added at 40° C. The reaction mixture is stirred at 40° C. for 1 h and concentrated under reduced pressure, the residue is taken up in 250 ml of methylene chloride and the mixture is washed three times with 250 ml of water, dried over Na2SO4 and concentrated under reduced pressure. This gives 32.9 g of a product which is 92.6% pure.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH:13]2[CH2:16][N:15]([C:17]([C@@H:19]3[CH2:23][C@H:22]([S:24][C:25]4[C@H:26]([CH3:49])[C@@H:27]5[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]5[C:29]=4[C:30]([O:32]CC4C=CC([N+]([O-])=O)=CC=4)=[O:31])[CH2:21][N:20]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:18])[CH2:14]2)=O)=CC=1)([O-])=O.[H][H]>O1CCCC1.O.[Pd]>[NH2:12][CH:13]1[CH2:14][N:15]([C:17]([C@@H:19]2[CH2:23][C@H:22]([S:24][C:25]3[C@H:26]([CH3:49])[C@@H:27]4[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]4[C:29]=3[C:30]([OH:32])=[O:31])[CH2:21][NH:20]2)=[O:18])[CH2:16]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC(N)C4)C3)[C@H](C)[C@H]12
Yield: 54.7 %

Procedure:
3630 mg of 4-nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in Example 121(1)] were dissolved in 190 ml of a 3:2 by volume mixture of tetrahydrofuran and water, and 5500 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated at 30° C. for 1.5 hours in an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration, the filtrate was washed with diethyl ether and the resulting aqueous solution was concentrated to 10 ml by evaporation under reduced pressure. The resulting solution was subjected to reverse phase silica gel column chromatography (Cosmosil 75C18 -prep, 250 ml, manufactured by Nacalai Tesque), eluted with mixtures of acetonitrile and water in proportions of 0:100, 2:98, 4:96, 6:94 by volume, in that order. The fractions containing the title compound were collected, concentrated by evaporation under reduced pressure and freeze-dried, to obtain 901 mg of the title compound as a powder.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:1](=[O:3])[CH3:2])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccccc2O)nc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1cc(C(=O)OCc2ccccc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Acetic anhydride (1 mL) was added to a pyridine (10 mL)) solution of 2-(2-hydroxyphenyl)-4-quinolinecarboxylic acid benzyl ester (1.09 g, 3.07 mmol) obtained above, and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated, and then, the residue was purified by silica gel column chromatography to obtain 2-(2-acetoxyphenyl)-4-quinolinecarboxylic acid benzyl ester (940 mg, 2.34 mmol).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([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.[CH3:36][C:37]1[S:38][C:39]([CH:42]=[O:43])=[CH:40][N:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH:42]([C:39]2[S:38][C:37]([CH3:36])=[N:41][CH:40]=2)[OH:43])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: Cc1ncc(C=O)s1
Product: Cc1ncc(C(O)c2nc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(Cl)c2F)s1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 2-methylthiazole-5-carbaldehyde.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](=O)([O:28]C(C)(C)C)[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>ClCCl>[C:24]([O:23][C:22]([N:12]1[CH2:11][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1)=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 110.3 %

Procedure:
4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (Lancaster, 1.00 g, 4.35 mmol), triethylamine (0.92 g, 9.13 mmol), and di-tert-butyl carbonate (Aldrich, 1.04 g, 4.78 mmol) were combined in dichloromethane (100 mL) and stirred at room temperature for 14 hours. The mixture was washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL), saturated sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated in vacuo to give 4-(4-chlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.41 g, 100%) of as a viscous yellow oil, which was used without further purification. 4-(4-Chlorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (334 mg, 1.14 mmoL) was dissolved in acetone/water (1:1, 10 mL), and N-methylmorpholine-N-oxide (Aldrich, 462 mg, 3.42 mmoL) and a catalytic amount of osmium tetroxide (Aldrich) were added. The mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium sulfite (2 mL) was added, and the mixture was stirred for 30 minutes at room temperature. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated in vacuo to give cis-[rac]-4-(4-chlorophenyl)-3,4-dihydroxypiperidine-1-carboxylic acid tert-butyl ester (364 mg, 1.11 mmol, 97%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH:15]1([CH2:18][NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][NH:19][C:20]([C:21]2[CH:22]=[C:23]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)=[CH:4][C:3]=3[CH3:14])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:37])[CH2:17][CH2:16]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)NCC4CC4)ccc3C)c(C)c2)o1

Procedure:
The title compound was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).