Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23](SC)[CH:22]([N:26]=[N+:27]=[N-:28])[C:21]1=[O:29])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30]Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[CH:23]([Cl:30])[CH:22]([N:26]=[N+:27]=[N-:28])[C:21]1=[O:29])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1SC)OCCC(=O)OCc1ccccc1
Reactant: ClCl
Solvent: ClCCl
Product: CCOP(=O)(CN1C(=O)C(N=[N+]=[N-])C1Cl)OCCC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
The product of Step E can also be prepared by dissolving 1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-(methylthio)-2-azetidinone (0.44 g.) in methylene chloride (10 ml.) and treating with chlorine (0.110 g.) in methylene chloride (2.0 ml.). The mixture is allowed to stand for 10 minutes at room temperature. The solvent is removed under reduced pressure to afford the 1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-chloro-2-azetidinone as described in Step E.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:55]([C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=1)(=[O:57])[NH2:56]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:62]4[CH:61]=[CH:60][CH:59]=[C:58]([C:55](=[O:57])[NH2:56])[CH:63]=4)=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(Br)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(-c4cccc(C(N)=O)c4)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Yield: 32 %

Procedure:
Aryl halide 5 was coupled to 3-carbamoylphenylboronic acid on a 0.1 mmol scale via General Procedure H to give 38 (38 mg, 32%): δH (400 MHz, CDCl3) 2.39 (s, 3H, CH3), 2.83 (s, 3H, CH3), 3.69 (s, 2H, CH2), 4.84 (s, 2H, CH2), 5.03 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.63 (s, 1H, CH), 6.70 (d, J=8.8 Hz, 1H, CH), 7.19 (d, J=8.0 Hz, 2H, CH), 7.30-7.36 (m, 10H, CH), 7.38-7.41 (m, 3H, CH), 7.54 (d, J=8.0 Hz, 2H, CH), 7.62 (d, J=8.0 Hz, 2H, CH), 7.67 (q, J=7.2 Hz, 4H, CH), 7.79 (t, 2H, J=7.6 Hz, CH), 7.85 (d, J=8.0 Hz, 1H, CH), 8.12 (s, 1H, CH). LRMS (ES+) Calcd for [C51H45N3O7S+Na] 866.29 found 866.51.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:41])[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37](=[O:40])[CH:38]=[CH2:39])([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.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]>[C:23]([O:27][C:28](=[O:41])[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37](=[O:40])/[CH:38]=[CH:39]/[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[C:9](=[O:10])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Br)cc1
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(O)C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Yield: 48.8 %

Procedure:
A mixture of 2-(4-Bromo-phenyl)-2-hydroxy-N-(4-trifluoromethyl-phenyl)-acetamide (8.0 g, 21.4 mmol), (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester (6.2 g, 23.6 mmol), tri-o-tolyl-phosphine (1.0 g, 3.3 mmol), triethylamine (12 mL, 86 mmol), and Pd2(dba)3 (1.5 g, 1.6 mmol) in DMF (160 mL) was heated at 90 degrees Celcius overnight under nitrogen atmosphere. The mixture was poured into saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by flash column chromatography (ethyl acetate/petroleum ether 1:2) to obtain a white solid (5.8 g, 49%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)=[O:3].CN(C)CC[OH:25]>O1CCCC1>[C:2]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=1)([OH:25])=[O:3]
Reactant: O=C(Cl)c1ccc2c(=O)c3cccc(Cl)c3ccc2c1
Reactant: CN(C)CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(=O)c3cccc(Cl)c3ccc2c1
Reaction time: 16 h

Procedure:
1.0 G. of 2-chlorocarbonyl-9-chloro-5-oxo-5H-dibenzo[a,d]cycloheptene, as prepared in Example VIII, is dissolved in 10 ml. of anhydrous tetrahydrofuran with stirring, and treated with 2 ml. of dimethylethanolamine. After the solution is stirred for 16 hours, it is evaporated. The residue is partitioned between ether and dilute hydrochloric acid. The aqueous layer is basified with aqueous ammonia and extracted with ethyl acetate. This solution is evaporated and the residue chromatographed on silica gel, eluting with 10:90:1 methanol:chloroform:triethylamine, to afford the β-N,N-dimethylaminoethyl ester of 2-carboxy-9-chloro-5-oxo-5H-dibenzo[a,d]cycloheptene as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10](OCC)=[O:11])=[C:6]([N+:17]([O-])=O)[CH:5]=1)(=[O:3])[CH3:2].COC1C=CC2OCC(=O)NC=2C=1>C(O)(=O)C.[Fe]>[C:1]([C:4]1[CH:16]=[CH:15][C:7]2[O:8][CH2:9][C:10](=[O:11])[NH:17][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: COc1ccc2c(c1)NC(=O)CO2
Solvent: CC(=O)O
Product: CC(=O)c1ccc2c(c1)NC(=O)CO2
Yield: 51 %

Procedure:
Ethyl (4-acetyl-2-nitrophenoxy)acetate (Intermediate 90) was reacted with iron in acetic acid as described for Intermediate 48. The crude product was obtained as an off white solid after work up. Recrystallization with ethyl acetate/methanol afforded the product as a colorless solid in 51% yield.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].[CH3:34][S:35]([OH:38])(=[O:37])=[O:36].CCOCC>O1CCCC1>[S:35]([OH:38])(=[O:37])(=[O:36])[CH3:34].[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][NH2:26])=[CH:19][CH:18]=1)(=[O:15])=[O:16])=[O:6])#[N:2]
Reactant: CC(C)(C)OC(=O)NCCSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-N-cyanomethyl-2-[4-(tert-butoxycarbonylaminoethylsulfanyl)-benzenesulfonylmethyl]cyclohexanecarboxamide (0.35 g, 0.706 mmol) in tetrahydrofuran (2 mL) at room temperature was added dry methanesulfonic acid (0.183 mL, 2.82 mmol). The reaction mixture was stirred overnight at room temperature. Ether (200 mL) was added. The supernatant was decanted. The residue was triturated twice with ether (50 mL each) and was then precipitated from methanol/ether, giving the title compound as its mesylate salt. MS [ESI, (M−H)−] m/z=394 amu.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][S:9]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])(=[O:11])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].COC1C=CC(O)=CC=1.CCOC(C)=O>C(O)(C(F)(F)F)=O>[C:1]([O:6][CH2:7][CH2:8][S:9]([CH2:12][C:13]([OH:15])=[O:14])(=[O:11])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCS(=O)(=O)CC(=O)OC(C)(C)C
Agent: COc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OCCS(=O)(=O)CC(=O)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
Pure 7 (1.2 g, 3.9 mmol) was dissolved in TFA (15 mL) under nitrogen. A trace amount of MEHQ was added to the mixture and the reaction was stirred for 3 hours at 55° C. Completion of the reaction was confirmed by TLC (EtOAc/Hex/TFA: 60:40:0.1% (v/v), Rf: 0.38). The reaction mixture was purified on a silica gel column (EtOAc/Hex, 3/2). 0.6 g (65% yield) 8 was obtained as yellow oil.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([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.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH:25]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([F:30])=[C:22]([F:21])[CH:23]=2)[CH2:16][CH2:15]1)([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: O=Cc1ccc(F)c(F)c1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1F
Yield: 80.3 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.1 g, 0.38 mmol) was reacted with 3,4-difluorobenzaldehyde (0.055 g, 0.38 mmol) in the presence of glacial acetic acid (0.023 g, 0.38 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.03 g, 0.45 mmol) in methanol (5 ml) (Procedure D) to give compound 16j (0.12 g, 80%).
Reaction SMILES: [N:1]1([C:7]([CH:9]2[CH2:12][C:11](=[O:13])[CH2:10]2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[N:1]1([CH2:7][C@@H:9]2[CH2:12][C@H:11]([OH:13])[CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1CC(C(=O)N2CCOCC2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O[C@H]1C[C@@H](CN2CCOCC2)C1

Procedure:
A solution of intermediate 39, 3-(Morpholin-4-ylcarbonyl)cyclobutanone (1.1 g, 6.1 mmol) in absolute THF (10 mL) was added dropwise to a solution of LiAlH4 (0.46 g, 12 mmol) in absolute THF (10 mL) in argon under stirring. The mixture was refluxed under stirring for 1 h, cooled, and 10 N NaOH (0.5 mL) and water (2.5 mL) were added. The organic layer was decanted, and the water layer was extracted with THF (2×5 mL). The organic layers were evaporated to give the title compound as colorless oil in ˜100% (1.1 g) yield. 1H-NMR (400 MHz)-data (dmso-d6): 4.8-4.95 (d, 1H, J=6.4 Hz, OH), 3.8 (ddddd, 4H, J=5.3 Hz, CHOH), 3.48-3.58 (m, 4H, CH2OCH2), 2.22-2.35 (m, 8H, (CH2)3N, cyclobutylCHH), 1.77-1.90 (m (ttt), 1H, CHCH2N), 1.36-1.47 (m, 2H, cyclobutylCHH).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: FC(F)(F)c1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncccc5C(F)(F)F)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromo-3-trifluoromethyl pyridine (338 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (535 mg, 93%) as a black oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([N:16]([CH3:22])[CH2:17][C:18](OC)=[O:19])=[O:15])=[CH:4][CH:3]=1.[Na].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[C:18](=[O:19])[CH2:17][N:16]([CH3:22])[C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)CN(C)C(=O)Cc1ccccc1Oc1ccc(Cl)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CC(=O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
27.8 g (79.9 mmol) of methyl N-{2-[2-(4-chlorophenoxy)phenyl]-1-oxoethyl}-N-methylglycinate (compound IIIb) was dissolved in 150 mL of toluene. 11.5 g of sodium tert-butoxyde were added, and the resulting mixture was stirred overnight at room temperature. 350 mL of water were added, and the resulting mixture was extracted three times with 150 mL of ethyl acetate. The combined organic phases were washed with 200 mL of water. The aqueous phases were combined and pH was adjusted to 1 with HCl 2 M. The solvent was removed by filtration, and the solid was recrystallized twice with methanol, to obtain 5.4 g of 3-[2-(4-chlorophenoxy)phenyl]-1-methylpyrrolidine-2,4-dione (compound IVb) as a solid. Yield: 21.4%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8](=[CH2:19])[CH2:9][CH:10]([C:15](OC)=[O:16])[C:11](OC)=[O:12].O.[OH-].[Na+]>C1COCC1>[CH3:19][C:8](=[CH2:7])[CH2:9][CH:10]([CH2:15][OH:16])[CH2:11][OH:12]
Reactant: C=C(C)CC(C(=O)OC)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CC(CO)CO
Yield: 52.8 %

Procedure:
To a solution of lithium aluminum hydride (9.20 g) in THF (250 mL) was slowly added a solution of dimethyl 2-(2-methylallyl)malonate (13.0 g) in THF (20 mL) at 0° C. The reaction mixture was heated under reflux for 2 hr. Water (60 mL) and 15% aqueous sodium hydroxide solution (72 mL) were added to the reaction mixture, and the mixture was filtered and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (4.80 g) as a yellow oil.
Reaction SMILES: ClC([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:12]([NH:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:45])C(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1>O1CCCC1.O1CCOCC1>[C:27]1([C:26]([NH:25][CH:12]2[CH:13]([S:14][CH2:15][C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[NH:10][C:11]2=[O:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C1NC(SCC#Cc2ccc(F)cc2)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1-(1-Chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin -2-one (570mg) was dissolved in a 1:1 mixture of dry tetrahydrofuran and dioxan (20ml) under nitrogen. Triphenylphosphine (495mg) and dry pyridine (150mg) were added and the mixture heated at 49° for 16 hours. The reaction mixture was filtered the filtrate evaporated. The residue was triturated with toluene and the soluble portion re-evaporated. Chromatography on silica afforded 1-(1-t-butoxycarbonyl)-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio) azetidin-2-one, as a white solid (418mg).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[N:5][C:6]2[N:7]([CH2:9][C:10]([C:13]([F:16])([F:15])[F:14])(O)[N:11]=2)[CH:8]=1>C(O)C>[Br:2][C:3]1[CH:4]=[N:5][C:6]2[N:7]([CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:11]=2)[CH:8]=1
Reactant: OC1(C(F)(F)F)CN2C=C(Br)C=NC2=N1
Agent: Br
Solvent: CCO
Product: FC(F)(F)c1cn2cc(Br)cnc2n1
Yield: 76.4 %

Procedure:
A mixture of 0.97 g of resulting 6-bromo-2-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-2-ol hydrobromide and 10 ml of ethanol was stirred under heat-reflux for 5 hours. The cooled reaction mixture was concentrated under reduced pressure, then water was added, and the mixture was extracted with ethyl acetate. The resulting matter was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.54 g of 6-bromo-2-trifluoromethyl-imidazo[1,2-a]pyrimidine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[Cl:22])[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30].CNCCNC.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[Cu]I>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([N:27]2[CH2:28][CH2:29][O:25][C:26]2=[O:30])=[CH:20][C:15]=1[CH:10]1[CH2:9][C:8]([CH3:24])([CH3:23])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=2)[NH:11]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Br)ccc1Cl)N2
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC1(C)CC(c2cc(N3CCOC3=O)ccc2Cl)Nc2ccc(C(=O)O)cc21
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A mixture solution of 2-(5-bromo-2-chloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.39 g, 3.53 mmol), oxazolidin-2-one (323 mg, 3.7 mmol), copper(I) iodide (135 mg, 0.71 mmol), N,N′-dimethyl-ethane-1,2-diamine (0.152 mL, 1.41 mmol), and potassium carbonate (1.46 g, 10.6 mmol) in acetonitrile (30 mL) was stirred at 90° C. for 72 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (200 mL×2), washed with saturated aqueous ammonium chloride solution (50 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 2-[2-chloro-5-(2-oxo-oxazolidin-3-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.7 g, 49%) as a white solid: MS (ESI) M+1=401.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].C(=O)(O)[O-].[Na+].Cl[CH2:16][C:17](Cl)=[O:18].[OH-].[Na+].Cl(O)(=O)=O>O1CCCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17](=[O:18])[CH2:16][O:9][C:3]=2[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+2]([O-])O
Solvent: C1CCOC1
Product: O=C1COc2cc(O)ccc2N1
Reaction time: 0.17 h
Yield: 42.4 %

Procedure:
To a solution of 4-aminobenzene-1,3-diol (2.5 g, 20 mmol) in tetrahydrofuran (30 mL), sodium bicarbonate (2.52 g, 30 mmol) was added and stirred for 10 minutes. Then 2-chloroacetyl chloride (1.6 mL, 20 mmol) was added to the above mixture. The resulting reaction mixture was stirred at ambient temperature for 18 hours. A precipitate formed and removed by filtration. The filtrate was concentrated to give the oil residue. The resulting residue was treated with 10% NaOH aqueous solution for 30 minutes. The aqueous layer was acidified with 1N hydrogen chloric acid and extracted with ethyl acetate, washed with brine and water. The organic layer was separated, dried (Na2SO4) and concentrated. The crude material was purified by silica gel chromatography using a 90:10 mixture of hexane and ethyl acetate as eluent to afford the title product as a white solid (1.4 g, 42% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.42 (1H, s), 9.23 (1H, s), 6.69 (1H, m), 6.35 (2H, m), 4.47 (2H, s). MS m/z: 164.01 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N:17]1[C:21](=[O:22])[N:20]([CH:23]([F:25])[F:24])[C:19]([CH3:26])=[N:18]1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][CH:34](Br)[C:35]([O:37][CH3:38])=[O:36].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:17]2[C:21](=[O:22])[N:20]([CH:23]([F:24])[F:25])[C:19]([CH3:26])=[N:18]2)=[CH:4][C:5]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:34]([CH3:33])[C:35]([O:37][CH3:38])=[O:36])=[CH:12][CH:11]=1
Reactant: Cc1nn(-c2cc(Sc3ccc(O)cc3)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(Sc2cc(-n3nc(C)n(C(F)F)c3=O)c(Cl)cc2Cl)cc1
Temperature: 0 °C
Yield: 45.7 %

Procedure:
A stirred mixture of 1.5 g (0.0036 mole) of 1-[2,4-dichloro-5-(4-hydroxyphenylthio)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.75 g (0.0054 mole) of potassium carbonate, 0.90 g (0.0054 mole) of methyl DL-2-bromopropionate, and 0.20 g (8×10-4 mole) of 18-crown-6 in 30 mL of N,N-dimethylformamide was heated at 100°-120° C. for approximately 18 hours. The reaction mixture was allowed to cool and was poured into ice-water. This aqueous mixture was extracted with diethyl ether and ethyl acetate. The organic extracts were combined and washed with water. The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a yellow oil. This oil was purified by column chromatography on silica gel, eluting with diethyl ether:petroleum ether (40:60) to yield 0.83 g of methyl 2-[4-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl- 5-oxo-1H-1,2,4-triazol-1-yl)phenylthio]phenoxy]propionate as a solid, m.p. 100°-101° C. The nmr spectrum was consistent with the proposed compound.
Reaction SMILES: [C:1]([O:12][CH:13]1[CH:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][CH:15]([CH3:22])[CH2:14]1)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-])=[O:5].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].OS([O-])(=O)=O.[K+]>>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([O:12][C@H:13]1[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C@@H:15]([CH3:22])[CH2:14]1)=[O:11]
Reactant: CC1CCC(C(C)C)C(OC(=O)c2ccccc2C(=O)[O-])C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)c1ccccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
3.78 g (12.4 mmol) monomenthyl (−)-phthalate (Fluka) was heated at reflux in 19 ml oxalyl chloride (18 eq.) for 1.5 h. The excess oxalyl chloride was distilled under vacuum. 2.75 g crude acid chloride was then diluted in 5 ml THF cooled to −8° under argon, and 0.97 g (3 eq.) NaBH4 was added. The reaction mixture was maintained under stirring at 0° for 10 min and at ambient temperature for 30 min. The mixture was then poured over cold 5% KHSO4 then extracted using diethyl ether. Chromatography of the crude product over silica gel (93:7 toluene/ether) yielded 1.85 g (55%) pure (1R,3R,4S)-3-p-menthanyl 2-hydroxymethylbenzoate in the form of a colourless oil.