Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13]Br)([CH3:3])[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>C(#N)C>[CH:1]([O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13][NH:19][CH:16]1[CH2:18][CH2:17]1)([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)OC(=O)c1ccc(Br)cc1CBr
Solvent: CC#N
Product: CC(C)OC(=O)c1ccc(Br)cc1CNC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
A stirred, cooled (ice bath) solution of 4-bromo-2-bromomethyl-benzoic acid isopropyl ester (Intermediate 118, 5.1 g, 15.17 mmol) in acetonitrile (25 mL) was treated with cyclopropyl amine (2 mL, 28.9 mmol). The reaction mixture was allowed to warm to ambient temperature. After 2 h, the volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) using 4-20% ethyl acetate in hexane as the eluent to afforded the title product (1.33 g, 28%).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][C:18]=1[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:28][CH2:27][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][C:17]=3[Cl:16])[NH:23][C:22](=[O:26])[CH2:21]4)[CH2:3][CH2:2]2)=[N:8]1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Temperature: 90 °C
Yield: 74.9 %

Procedure:
In a 50 ml 3 necked round bottom flask there were placed 1 gram (4.56 mmol) of 3-piperazinylbenzo[d]isothiazole; 2.5 grams (10.86 mmol) of 6-chloro-5-(2-chloroethyl)indolin-2-one; 50 mg of potassium iodide; 1.64 grams (11.88 mmol) of potassium carbonate. The contents of the flask were heated to 90° C. The reaction was monitored by HPLC. After completion of the reaction, 50 ml of DM water was added to the reaction mixture and stirred. The product was filtered off and washed with water and dried to obtain 1.41 grams (75%) of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one. The crude product was purified by IPA and/or THF. The product matched the spectra of a standard NMR and showed the correct retention time by HPLC with 98.0% assay. The melting point of the compound was found to be 218° C.-220° C., and was found to conform with the melting point of 218° C.-220° C. as disclosed in U.S. Pat. No. 5,206,366.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a heterogeneous solution of 33 (1.6 g, 8.1 mmol) in 16.2 mL of dry THF under a N2 atmosphere was added 0.211 g (8.80 mmol) of 95% NaH. Once the bubbling subsided, 4-fluorobenzylbromide (1.2 mL, 9.7 mmol) was added dropwise to the solution. After 1 hour, when the reaction was complete as judged by TLC, the reaction was quenched by addition of water and the organic layer was diluted with EtOAc. The organic layer was washed with water and the solvent removed in vacuo. The product was purified by column chromatography using 1:1 EtOAc-Hex solvent system to provide 2.3 g (93%) of the product 34 as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 9H), 3.24 (t, 2H, J=5 Hz), 3.60 (t, 2H, J=5 Hz), 4.16 (s, 2H), 4.59 (s, 2H), 7.03 (t, 2H, J=9 Hz), 7.26 (dd, 2H, J=5.8 Hz); 19F NMR (282.6 MHz, CDCl3) δ 62.2.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][C:6]([S:9][CH3:10])=[N:7][N:8]=1)#[N:2].C(O)(=O)C.[N:15]([O-])=[O:16].[Na+]>O>[CH3:10][S:9][C:6]1[S:5][C:4]([C:3](=[N:15][OH:16])[C:1]#[N:2])=[N:8][N:7]=1
Reactant: CSc1nnc(CC#N)s1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1nnc(C(C#N)=NO)s1
Reaction time: 1 h

Procedure:
17.1 g (0.1 mol) of 2-cyanomethyl-5-methylthio-1,3,4-thiadiazole are initially introduced into 75 ml of glacial acetic acid. A solution of 7.8 g (0.11 mol) of NaNO2 in 20 ml of water is added dropwise and the mixture is stirred for 1 hour. 200 ml of water are then added to the solution and the mixture is filtered. The residue is washed with water: 19 g (95% of theory) of end product, melting point >200° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](F)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:29]#[N:30].[Na+].CO>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:29]#[N:30])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3ccccc23)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C#N)c3ccccc23)CC1
Temperature: 100 °C

Procedure:
4-(4-Fluoro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester 28 (2.00 g, 4.9 mmol) was dissolved in DMF (20 mL). Sodium cyanide (1.2 g, 24.5 mmol) and tetra-n-butylammonium bromide (7.9 g, 24.5 mmol) were added and the reaction was heated to 100° C. overnight. The reaction was diluted with dichloromethane (100 mL) and charged to a separatory funnel. The organic layer was washed three times with water, brine and dried over MgSO4. Filtration and concentration in vacuo afforded a dark colored oil. Flash column chromatography (98:2 dichloromethane:methanol) afforded an oil that was rechromatographed (99:1 dichloromethane:methanol) to afford 29 as an orange solid. Wt.: 640 mg (31%). 1H NMR (300 MHz, CDCl3) δ 8.71 (m, 1H), 8.40 (m, 1H), 8.34 (d, 1H), 8.00 (d, 1H), 7.83 (m, 2H), 4.80 (d, 1H), 3.87 (m, 2H), 3.32 (m, 1H), 2.61 (m, 2H), 1.63 (m, 2H), 1.38 (s, 9H), 1.27 (m, 2H); LC/MS m/z 414 (M−H)−
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1[CH:53]=[CH:52][C:51]([C@H:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:56][C@@H:54]([C:51]4[CH:52]=[CH:53][C:48]([CH3:47])=[CH:49][CH:50]=4)[CH3:55])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1ccc([C@@H](C)N)cc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@H](C)c2ccc(C)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(+)-1-(4-methylphenyl)ethylamine (Lancaster) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1.CC(C)([O-])C.[K+].[C:30](#[N:33])[CH:31]=[CH2:32]>C1C=CC=CC=1>[C:30]([CH2:31][CH2:32][O:21][CH2:14][C@:15]12[CH2:17][CH2:18][C@H:19]3[C@@H:10]([CH2:9][CH2:8][C:7]4[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=[C:3]([O:2][CH3:1])[C:20]=43)[C@@H:11]1[CH2:12][CH2:13][CH2:16]2)#[N:33]
Reactant: C=CC#N
Reactant: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(COCCC#N)CCC[C@H]3[C@@H]1CC2
Reaction time: 5 h

Procedure:
A solution of 1,3-dimethoxy-17β-hydroxyestra-1,3,5(10)-triene (1.5 g, 4.7 mM), potassium t-butoxide (0.053 g, 0.47 mM) and acrylonitrile (0.5 g, 9.4 mM) in 25 ml of anhydrous benzene is refluxed with vigorous stirring for 5 hrs. An additional 0.5 g of acrylonitrile and 0.025 g of potassium t-butoxide are added; the solution is refluxed for 2 hrs and allowed to stir at room temperature for 18 hrs. The resulting suspension is filtered and the filtrate evaporated in vacuo to give an oily residue which is chromatographed on 100 g of neutral silica gel. Elution with chloroform gives an oil which after trituration with hexane gives 17β-(2-cyanoethoxy-1,3-dimethoxyestra-1,3,5(10)-triene, yield 1.06 g (60.6%); m.p. 142°-144° (toluene-hexane).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]([C:14](O)=[O:15])[CH:12]3[CH2:17][CH2:18][CH:9]2[CH2:10][CH2:11]3)=[CH:5][CH:4]=1.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:13]([C:14]([NH:24][C:25]3([C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=4)[CH2:27][CH2:26]3)=[O:15])[CH:12]3[CH2:17][CH2:18][CH:9]2[CH2:10][CH2:11]3)=[CH:19][CH:20]=1
Reactant: O=C(O)C1C2CCC(CC2)N1Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)C3C4CCC(CC4)N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Yield: 34.3 %

Procedure:
The title compound (D156) (12 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (D111) (22.5 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (18 mg). (Reaction time: 2 hrs; 60° C.)
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2cc(CO)ccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCn1ncc2cc(C=O)ccc21
Reaction time: 2 h

Procedure:
In dichloromethane (10 ml), (1-ethyl-1H-indazol-5-yl)methanol (0.3 g, 1.70 mmol) prepared in Example 4-3 was dissolved, and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.0 g, 2.38 mmol) was added thereto. The mixture was stirred for 2 hours. The mixture was subjected to extraction with chloroform, and the extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1cccc2c1CCN2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4c(C)cccc43)c2cc1OC
Yield: 94 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 94% yield from 4-methyl-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 174°-175° C.; LC-MS: 322 (MH+); anal. RP18-HPLC RT: 4.85 min.).
Reaction SMILES: C(O)C.[Cl-].[NH4+].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=2[CH3:31])=[O:21])[CH2:16][CH2:15]1>[Fe].O>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:8]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=3[CH3:6])[CH2:19][CH2:18]2)=[O:21])=[C:23]([CH3:31])[CH:24]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3C)CC2)c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3C)CC2)c(C)c1
Yield: 118.1 %

Procedure:
2-Methyl-4-nitrobenzoic acid (500 mg), 1-(2,4-dimethylphenyl)piperazine (523 mg) and 1-hydroxybenzotriazole 1 hydrate (373 mg) were dissolved in N,N-dimethylformamide (13 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (531 mg) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg). Then, to a mixed solution of ethanol (11 mL) and water (3 mL) were added ammonium chloride (660 mg) and iron (480 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (833 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:14])=O.[Cl-].[Cl-].[Ca+2]>>[Cl:14][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([N:4]=1)=[N:6][CH:7]=[CH:8][CH:9]=2
Reactant: Cn1c(=O)[nH]c2ncccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Product: Cn1c(Cl)nc2ncccc21

Procedure:
The mixture of 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.1 g) and phosphorus oxychloride (6.87 mL) was stirred at 100° C. under a dry atmosphere (CaCl2 tube) for 5 h. The mixture was neutralized with sat.NaHCO3 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 2-chloro-1-methyl-1H-imidazo[4,5-b]pyridine (600 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.[C:48](O)(=[O:50])[CH3:49].CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1.ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:48](=[O:50])[CH3:49])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: CC(=O)O
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](OC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Temperature: 60 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
A mixture of 8a (0.20 g, 0.51 mmol), diphenyl-2-pyridylphosphine (0.20 g, 0.77 mmol) and acetic acid (0.12 mL, 2.05 mmol) was dissolved in anhydrous THF (15 mL) under an argon atmosphere. To this solution was added di-tert-butylazodicarboxylate (DBAD) (0.18 g, 0.77 mmol) in one portion and the mixture was stirred for 18 hours at 60° C. The solvent was under reduced pressure and the residue was dissolved in dichloromethane (25 mL). The CH2Cl2 portion was washed with 4 M HCl (2×25 mL) and saturated NaCl (25 mL), and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude residue. Flash column chromatography (eluent: n-hexanes/EtOAc, 7:3) gave 0.18 g (80%) of 34 as a white crystalline solid, mp 215-216° C.; 1H NMR (CDCl3): δ 1.10 (3H, s); 1.28 (1H, dd, J=6.0, 14.1); 1.45 (1H, m); 1.46 (3H, s); 1.64 (2H, m); 1.80 (1H, dd, J=3.0, 9.9); 2.10 (1H, m); 2.13 (3H, s); 2.18 (1H, ddd, J=3.3, 3.3, 15.0); 2.34 (1H, ddd, J=3.3, 13.0, 15.6); 2.45 (1H, dd, J=5.1, 13.5); 2.54 (1H, s); 2.90 (1H, dd, J=3.6, 13.2); 3.71 (3H, s); 4.85 (1H, dd, J=3.2, 3.2); 5.54 (1H, dd, J=5.1, 11.7); 6.38 (1H, dd, J=1.4, 1.7); 7.40 (2H, m); 13C NMR (CDCl3): δ 15.4, 16.3, 18.3, 21.2, 31.1, 35.2, 38.8, 43.2, 43.6, 51.1, 51.5, 52.1, 61.9, 72.3, 76.6, 108.5, 125.7, 139.4, 143.9, 169.6, 171.4, 172.4, 204.6; anal. C 63.63%, H 6.59%, O 29.70%, calcd for C25H28N2O7S, C 63.88%, H 6.53%, O 29.60%.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:14])=O.[CH3:15][CH:16]([C:21]1[CH:27]=[C:26]([CH:28]([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=1[NH2:23])[CH2:17][CH:18]([CH3:20])[CH3:19].C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCCC1.C(OCC)(=O)C>[CH3:15][CH:16]([C:21]1[CH:27]=[C:26]([CH:28]([C:29]([F:31])([F:32])[F:30])[C:33]([F:34])([F:35])[F:36])[CH:25]=[CH:24][C:22]=1[NH:23][C:12]([C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1])=[O:14])[CH2:17][CH:18]([CH3:19])[CH3:20]
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Reactant: CC(C)CC(C)c1cc(C(C(F)(F)F)C(F)(F)F)ccc1N
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CC(C)c1cc(C(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1c(C(F)(F)F)nn(C)c1Cl
Yield: 43.3 %

Procedure:
5-Chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (230 mg, 1 mmol) was dissolved in thionyl chloride (2 ml), and the solution was stirred at reflux temperature for 2 hours. After concentration under reduced pressure, the resulting acid chloride was added to a solution of 2-(1,3-dimethylbutyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (330 mg, 1 mmol) and triethylamine (150 mg, 1.5 mmol) in tetrahydrofuran (10 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 233 mg of the desired compound.
Reaction SMILES: [S:1]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([O:4][CH2:5][C@H:6]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@H:7]([CH3:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])=[O:2].C1C(=O)N([Br:39])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[S:1]([C:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=1)([O:4][CH2:5][C@H:6]([O:17][Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:19])[CH3:20])[C@H:7]([CH3:16])[CH2:8][CH:9]([Br:39])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)CCc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)CC(Br)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.8 %

Procedure:
To a 5 L 3-neck round-bottom flask equipped with a mechanical stirrer, reflux condenser and nitrogen inlet was added CCl4 (1680 mL), tosylate 19 (140 g, 0.30 mol), NBS (65 g, 0.365 mol) and AIBN (16.5 g, 0.10 mol). The mixture was degassed by evacuation under full vacuum with stirring, and backfilling with nitrogen (3×). The reaction mixture was then heated to reflux, whereupon the color became dark brown. After 15 min at vigorous reflux, the reaction mixture became light yellow, and chromatographic analysis indicated the reaction was complete. After cooling to room temperature, the reaction was filtered, and the filtrate was concentrated to dryness. The residue was redissolved in hexanes, filtered again, and concentrated to dryness to afford the title compound (170.3 g) as an amber oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[S:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1NC(=S)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Temperature: 40 °C
Yield: 170.1 %

Procedure:
To a solution of tert-butyl[(3S,5S,6R)-6-methyl-2-oxo-5-phenylpiperidin-3-yl]carbamate (796 mg, 2.62 mmol) in toluene (26.2 mL) was added Lawesson's Reagent (539 mg, 1.33 mmol) and the resulting mixture stirred at 40° C. 16 h. The mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (100% hexanes→60% hexanes/ethyl acetate) gave the title compound (725 mg). MS 343.3 (M+Na).
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[C:12]([O:20][CH3:21])[C:11]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.OS([O-])(=O)=O.[K+]>CO>[CH3:21][O:20][C:12]1[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]([O:9][CH3:8])[C:11]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(OC)c(-c2ccccc2)c(OC)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(OC)c1-c1ccccc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Aqueous 5 N sodium hydroxide solution (44 mL) was added to a THF (150 mL)-MeOH (150 mL) solution of methyl 2,6-dimethoxybiphenyl-4-carboxylate (20.0 g), and stirred at 40° C. for 5 hours. The reaction solution was poured into aqueous 0.5 M KHSO4 solution, and extracted with ethyl acetate. The combined organic layers were washed with aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was recrystallized from hexane/ethyl acetate to obtain the title compound as a colorless crystal.