Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([CH:26]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[CH2:29][NH:28][C:27]1=O)[CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[CH2:23]([CH:26]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[CH2:29][NH:28][C:27]1=[S:10])[CH:24]=[CH2:25]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=CCC1CCC(c2cccc(F)c2F)CNC1=O
Solvent: Cc1ccccc1
Product: C=CCC1CCC(c2cccc(F)c2F)CNC1=S
Temperature: 45 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (649 mg, 1.61 mmol) was added to a suspension 3-allyl-6-(2,3-difluorophenyl)azepan-2-one (426 mg, 1.61 mmol) in toluene (10 mL). After 3 h, the reaction mixture was heated to 45° C. After 30 min, the mixture was concentrated in a cold water bath. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (257 mg). MS 282.1 (M+1).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][OH:22])[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: OCCNCCO
Product: O=C(c1ccccc1)c1ccc(N(CCO)CCO)cc1
Temperature: 155 °C
Yield: 61.7 %

Procedure:
A 100 mL two-neck flask was charged with 4-fluorobenzophenone (15.0 g; 74.9 mmol) and diethanolamine (55.1 g; 524 mmol). The flask was flushed with nitrogen, fitted with a reflux condenser and heated to 155° C. for 48 h under a gentle stream of nitrogen. Complete conversion of the starting 4-fluorobenzophenone was confirmed by TLC. After cooling to ambient temperature, the dark viscous reaction mixture was poured into water (2000 mL). The resulting suspension was thoroughly extracted with diethyl ether (6×250 mL). The aqueous phase was discarded and the organic phase was extracted with hydrochloric acid (2M, 5×200 mL). The pH of the strongly acidic aqueous phase was adjusted to 12-13 by slow addition of 35% aq. ammonia to reprecipitate the product. The aqueous phase was then reextracted with dichloromethane (3×300 mL). The crude organic extract was purified by passing through a short silica gel column (eluent: ethyl acetate). The eluted yellow solution was evaporated and the oily residue dried in vacuo to provide {4-[bis(2-hydroxyethyl)amino]phenyl}(phenyl)methanone (yellow-brown solid; 13.176 g; 62% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N+:9]([O-])=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[CH:12]=2.CS([Cl:29])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[Cl:29][C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[N:14]=[CH:15]2
Reactant: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cc2c(Cl)nc(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A mixture of 3-(2-chlorophenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (200 mg, 0.6 mmol) and methanesulfonyl chloride (0.47 mL, 5.9 mmol) in N,N-dimethylformamide (2.5 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL) and then saturated sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-60% ethyl acetate in heptane) to provide the title compound as an off-white solid (170 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.97 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.75 (dd, J=7.4, 2.0 Hz, 1H), 7.52 (m, 1H), 7.46-7.33 (m, 2H), 1.70-1.60 (m, 1H), 1.25-1.18 (m, 2H), 1.02-0.94 (m, 2H). LCMS (Method E): RT=5.562 min, M+H+=358.0.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[O:10][CH:9]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6])[CH:2]=[CH2:3].[Cl:22]C1C=CC(CO)=CC=1>>[CH2:1]([O:4][C:5]([NH:7][C@H:8]1[CH2:12][C:11](=[O:13])[O:10][CH:9]1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: OCc1ccc(Cl)cc1
Reactant: C=CCOC(=O)N[C@H]1CC(=O)OC1OCc1ccccc1
Product: C=CCOC(=O)N[C@H]1CC(=O)OC1OCc1ccc(Cl)cc1

Procedure:
was synthesized from allyloxycarbonylamino-β-tert-butyl aspartate by the methods employed by Chapman (Bioorg. & Med. Chem. Lett., 2, pp.6.15-6.18 (1992)) to prepare (3S,2RS)3-allyloxycarbonylamino-2-benzyloxy-5-oxotetrahydrofuran using 4-chlorobenzyl alcohol instead of benzyl alcohol to afford 1.84 g of 2101a as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccccc1
Yield: 82 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and benzoyl chloride to afford the title compound as an off-white solid (37 mg, 82%). 1H-NMR (□, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=6.0 Hz), 6.90 (d, 1H, Harom, J=8.0 Hz), 7.42 (ps t, 1H, Harom, J=8.0 Hz), 7.51-7.68 (m, 5H, Harom), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 7.93 (d, 2H, Harom, J=7.5 Hz), 10.35 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.40 (s, 1H, NHPy2). 13C-NMR (□, ppm, DMSO-d6): 106.56, 110.71, 114.34, 116.20, 127.64, 128.37, 129.32, 130.13, 131.69, 134.68, 140.88, 141.26, 144.65, 147.10, 154.19, 154.69, 165.72. HRMS (EI): m/z [M+H] calcd for C19H15N4O3: 347.1144; found: 347.1140.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=O)[CH2:14][CH2:13]1)=[CH:5][NH:6]2.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1.[Mg]>C(OCC)C.CCCCCC>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:31][CH:30]=3)([C:29]3[CH:30]=[CH:31][C:26]([O:25][C:24]([F:34])([F:33])[F:23])=[CH:27][CH:28]=3)[OH:20])[CH2:16][CH2:17]1)=[CH:5][NH:6]2
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(Cc2c[nH]c3cccc(F)c23)CC1
Agent: [Mg]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCN(Cc2c[nH]c3cccc(F)c23)CC1
Yield: 9.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step B of Example 3, with 0.5 gram (0.0016 mole) of ethyl N-(4-fluoroindol-3-ylmethyl)piperidin-4-ylcarboxylate, 2.0 grams (0.0082 mole) of 4-trifluoromethoxyphenyl bromide, and 0.2 gram (0.0086 gram-atom) of magnesium turnings in about 10 mL of diethyl ether as reagents. The crude reaction product was taken up in hexane. The hexane-insoluble material was collected by filtration and purified by preparative thin layer chromatography with 1:3 ethyl acetate:hexane as an eluant, yielding about 0.09 gram of N-(4-fluoroindol-3-ylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine, mp 76°-88° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CN(C)C=O>[CH2:7]([N:29]1[CH2:30][CH2:31][CH2:32][N:26]([C:18]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[F:16])[CH2:27][CH2:28]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCNCC2)c(F)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 579.2 %

Procedure:
Potassium carbonate (0.526 g, 3.80 mmol) and benzyl bromide (0.155 ml, 0.130 mmol) were added to a solution of 1-(2-fluoro-4-nitrophenyl)-[1,4]diazepane hydrochloride (compound of Reference Example 55; 0.300 g, 1.08 mmol) in anhydrous N,N-dimethylformamide (6 ml), and the mixture was stirred at 80° C. for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (methanol ethyl acetate=1:1) to give the title compound (0.248 g, 69%) as a brown liquid.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([NH2:14])[CH:10]([CH3:15])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[C:16]1([CH:9]2[CH:10]([CH3:15])[CH:11]([NH:14][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:12]([CH3:13])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1C(c2ccccc2)NC(c2ccccc2)C(C)C1N
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a stirred 0° C. solution of 12.7 g (45.3 mmol) of 2,6-diphenyl-3,5-dimethyl-4-aminopiperidine and 5.1 g (50 mmol) of triethylamine in 150 ml of methylene chloride is added dropwise a solution of 9.9 g (45.3 mmol) of lauroyl chloride. After stirring for 30 minutes at 0° C., the reaction mixture is washed with water (2×200 ml) followed by a saturated aqueous sodium bicarbonate solution (300 ml). The organic phase is separated, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid is recrystallized from ethanol to give 15.4 g (73% yield) of the title compound as a white solid melting at 112°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)F)c(F)c1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (0.17 g, a white solid) from 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.15 g, 0.65 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: C[C:2]1([CH2:13][OH:14])[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][NH:3]1>C(Cl)Cl.O=[Mn]=O>[CH3:8][C:7]1[C:2]([CH:13]=[O:14])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:10])[F:11])[CH:6]=1
Reactant: CC1=CC(C(F)(F)F)=CNC1(C)CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cnc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A suspension of (2,3-dimethyl-5-trifluoromethyl-pyridin-2-yl)-methanol (0.300 g, 1.57 mmol)) and activated MnO2 (1.36 g, 15.6 mmol) in CH2Cl2 (10 mL) was stirred at room temperature overnight. After that period of time the suspension was filtered through a celite cake. the solvent was removed from the filtrate, and the residue was purified on silica gel column (CH2Cl2) to afford 3-methyl-5-trifluoromethyl-pyridine-2-carbaldehyde as a pale yellow liquid (0.180 g, 61%). 1H NMR (CD3Cl) δ 2.73 (s, 3H), 7.87 (s, 1H), 8.90 (s, 1H), 10.23 (s, 1H). 2.49 (s, 6H), 2.89-2.94 (m, 4H), 4.51 (s, 2H), 4.55 (s, 2H), 7.84 (dd, 1H, J=5.7, 8.1 Hz), 8.34 (d, 1H, J=8.1 Hz), 8.53 (s, 1H), 8.60 (d, 1H, J=5.7 Hz), 8.94 (s, 1H); 13C NMR (D2O) δ 17.48, 17.65, 22.50, 24.82, 39.49, 54.45, 55.28, 55.42, 126.63, 137.69, 138.39, 138.48, 139.41, 143.21, 143.25 148.63, 148.74, 154.80; 19F NMR (D2O) δ 13.32. ES-MS m/z 367 (M+H). Anal. Calcd. for C19H25F3N4.4.4HBr.3.5H2O.0.9C4H10O: C, 31.85; H, 5.37; N, 6.57; Br, 41.26. Found: C, 31.85; H, 5.13; N, 6.55; Br, 41.18.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:35])=O)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:9]/[C:10](=[N:19]\[OH:20])/[C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=2)=[C:4]([CH3:36])[CH:3]=1.[NH2:37][CH2:38][C:39]1[NH:43][N:42]=[N:41][N:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH:40]1[C:39]([CH2:38][NH:37][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:25]=[CH:26][C:21]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:36])[CH2:9]/[C:10](=[N:19]\[OH:20])/[C:11]4[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=4)=[CH:22][CH:23]=3)=[CH:28][CH:29]=2)=[O:35])=[N:43][N:42]=[N:41]1
Reactant: NCc1nnn[nH]1
Reactant: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)NCc3nnn[nH]3)cc2)cc1

Procedure:
In analogy to example 228, (E)-4′-(1-(4-chloro-2-methylphenyl)-3-(hydroxyimino)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)propyl)biphenyl-4-carboxylic acid (example 227) was reacted with 5-aminomethyltetrazole in the presence of HATU to give the title compound as a light yellow foam, MS (ESI+): m/z=582.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH2:15][CH:7]3[C:6]=2[N:24]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1
Reactant: CCOC(=O)C1Oc2ccc(Cl)nc2C2Cc3c(F)cccc3N12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Yield: 84.9 %

Procedure:
To a solution of ethyl 2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (10.22 g, 29.36 mmol) and DDQ (8.67 g, 38.17 mmol) in toluene (80 mL) was stirred at 80° C. for 2 hours. The mixture was then diluted with water (50 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=20:1) to provide ethyl 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (8.64 g, yield: 85%), which was also prepared from 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol and methyl 2,2-dibromoacetate in the presence of base, such as DBU etc. 1H-NMR (CDCl3, 400 MHz) δ 7.33 (d, J=8.4 Hz, 1H), 7.30 (s, 1H), 7.09˜7.18 (m, 3H), 6.78˜6.83 (m, 1H), 6.52 (s, 1H), 3.96˜4.09 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). MS (M+H)+: 347.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:24]1([C:22]([NH:21][NH:20][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)C1CCCC1
Yield: 94.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-N′-(cyclopentylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 191 (0.33 g, 0.84 ml) in methanol (20 mL) was added 10% Pd/C (0.30 g). The mixture was hydrogenated under 15 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered through Celite, and the filtrate was evaporated to give (2S,5R)-N′-(cyclopentylcarbonyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 192 (0.24 g, 98%) as a colorless foam.
Reaction SMILES: [CH3:1][CH:2]([CH:6]=[CH2:7])[C:3]([OH:5])=[O:4].[C:8]1([CH2:14]O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=NC1CCCCC1)=NC1CCCCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][CH:2]([CH:6]=[CH2:7])[C:3]([O:5][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: C=CC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(C)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-methylbut-3-enoic acid (9.5 g, 95 mmol) in DCM (80 mL) was added phenylmethanol (10.26 g, 95 mmol), N,N′-methanediylidenedicyclohexanamine (19.58 g, 95 mmol) and DMAP (1.159 g, 9.49 mmol) (exothermic reaction) and the resulting mixture was stirred at rt over weekend. The reaction mixture was filtered through a pad of CELITE® to remove the solids and the filtrate was collected and concentrated. The filtrate was then concentrated and subjected to silica gel chromatography to yield the desired product as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.C(OC(N1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])=O)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:16]3[C:26](=[O:27])[C:25]4[C:24](=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]3=[O:32])[CH2:11][C:10]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Temperature: 70 °C

Procedure:
To a solution of Compound [XXXV] (6.03 g, 21.2 mmol, 1.0 eq.) in CHCl3 (100 mL, anhydrous) was added N-ethoxycarbonylphthalimide (5.12 g, 23.3 mmol, 1.1 eq.) and triethylamine (11.8 mL, 84.9 mmol, 4.0 eq.). The mixture was then heated to 70° C. for 24 hours. The reaction was then cooled and concentrated. Methanol was added to the residue, and the mixture concentrated, then methanol was added again, and the resulting solid collected by filtration to provide Compound [XXXVI] as a light tan solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.30-3.39 (m, 2H) 3.44-3.53 (m, 2H) 3.89 (s, 4H) 7.42-7.49 (m, 2H) 7.50-7.58 (m, 2H) 7.69 (dd, J=5.34, 3.10 Hz, 2H) 7.78 (dd, J=5.54, 3.00 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=2)=[O:12])=[C:4]([F:13])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)C=Cc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(C=Cc1ccc(Br)cc1F)Nc1ccc(Cl)cc1
Yield: 81.3 %

Procedure:
A mixture of 3-(4-bromo-2-fluoro-phenyl)-acrylic acid (12.7 g, 52 mmol), 4-chloroaniline (9.9 g, 78 mmol), HOBt (10.5 g, 78 mmol) and EDCI (15.0 g, 78 mmol) in 200 mL of dichloromethane was refluxed overnight, and the resulting mixture was washed with 1M NaOH solution, water and brine, dried over Na2SO4, and concentrated. Recrystallization of the residue from EtOAc/Hexane gave 15 g (82%) of white solid. MS: calc'd 354 (MH+), exp 354 (MH+). 1H NMR (CDCl3, 400 MHz), 7.75 (d, 1H, J=15.6 Hz), 7.60 (d, 2H, J=8.8 Hz), 7.48 (s, 1H), 7.32-7.38 (m, 5H, J=7.6 Hz), 6.70 (d, 1H, J=15.6 Hz).
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].[C:15]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(OC(C)(C)C)=O>C(OCC)(=O)C.CO>[C:26]([O:25][C:23]([O:22][C:15]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.4 h
Yield: 82 %

Procedure:
A solution of 751 grams (4.6 moles) of 4-acetoxystyrene in 3767 grams of ethyl acetate was charged to a 12-liter three-necked flask equipped with a mechanical stirrer, condenser, and ice-bath. A solution of 634 grams (0.8 moles) of potassium hydroxide in 1197 grams of methanol, and 1685 grams (7.6 moles) of molten di-tert-butyl dicarbonate was added in small portions to the stirred reaction mixture, over a period of 1 hour 20 minutes. The reaction temperature was maintained at 25° C. throughout the addition. The contents of the vessel were stirred an additional 1.4 hours at 25° C. The reaction slurry was washed twice with 4-liter portions of deionized water. The organic layer was vacuum stripped at 35° C. and 50 mm Hg until most of the solvent had been removed. The residue was further stripped at 75° C. and 1.5 Mm Hg. The residual oil, 1015 grams (99.5% conversion and 82% yield, based on 4-acetoxystyrene) was vacuum distilled to yield pure 4-tertiary-butoxycarbonyloxystyrene. Yields observed in multiple experiments employing the above procedure are shown below. The method was not yet optimized in terms of all of the variables, which variables may have differed slightly from batch to batch, accounting for the range in yield.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[Cl:11][C:12]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:11][C:12]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:3][C@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:17][CH:16]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a stirred solution of known tert-butyl L-(+)-lactate (0.88 g), 4-(2',4'-dichlorophenoxy)phenol (1.54 g) and triphenylphosphine (1.58 g) in dry tetrahydrofuran (58 ml) on an ice bath, diethylazodicarboxylate (0.95 ml) was added dropwise. After the addition, the ice bath was removed and the mixture was further stirred at room temperature for 25 hours. The reaction mixture was evaporated with a rotary evaporator. The residue thus obtained was purified by silica gel chromatography [silica gel 399 g, eluant:ethyl acetate-hexane (1:30)] to give tert-butyl (2R)-(+)-2-[4'-(2",4"-dichlorophenoxy)phenoxy]propionate as a colorless oily substance (0.98 g). This was left to stand at room temperature under high vacuum (0.25 Torr) for 2 hours and under atmosphere for several days to crystallize. A crystalline substance thus formed was washed with a small amount of hexane and filtered to give colorless crystals.