Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCC(C)C)nc1Cl
Yield: 86.7 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-isobutoxypiperidine-1-carboxylate obtained in Example (117d) (1.26 g, 4.6 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 1.02 g, 5 mmol), WSC hydrochloride (2.88 g, 15 mmol), HOBt (1.01 g, 7.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 1.71 g of the title compound as a colorless solid (87%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16](B4OC(C)(C)C(C)(C)O4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31].Br[C:37]1[CH:38]=[C:39]2[CH:45]=[N:44][NH:43][C:40]2=[N:41][CH:42]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>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.C(#N)C>[F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:37]4[CH:38]=[C:39]5[CH:45]=[N:44][NH:43][C:40]5=[N:41][CH:42]=4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31]
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
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: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnc5[nH]ncc5c4)cc23)c1F
Temperature: 145 °C

Procedure:
In a microwave vial, propane-1-sulfonic acid {2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (30, 0.050 g, 0.099 mmol) is combined with 5-bromo-1H-pyrazolo[3,4-b]pyridine (31, 0.030 g, 0.15 mmol), 1 mL of tetrahydrofuran, 1 mL of acetonitrile, tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), and potassium carbonate (0.400 mL, 1.00 M in water). The reaction is heated at 145° C. for 45 minutes in a microwave, then extracted with ethyl acetate, and the organic layer is washed with water and brine. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of methanol:dichloromethane. Appropriate fractions are combined, concentrated under vacuum and the resulting solid is further washed with a mixture of ethyl acetate:hexane to provide the desired compound. MS (ESI) [M−H+]−=495.05.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH2:10][O:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][CH:12]([OH:15])[CH2:13][CH3:14]>CN(C=O)C.[H-].[Na+]>[CH:12]([O:15][CH2:10][CH:8]([OH:9])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH2:13][CH3:14])[CH3:11]
Reactant: CCC(C)O
Reactant: C1CCC(C[C@H]2CO2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)OCC(O)CC1CCCCC1
Yield: 55.2 %

Procedure:
The product from Example 1308C (420 mg, 3.0 mmol) in DMF (3.0 mL), 2-butanol (1.1 mL, 12.0 mmol) in DMF (6.0 mL) and NaH, 60% dispersion in mineral oil, (240 mg, 6.0 mmol) in DMF (12 mL) were allowed to react in a manner similar to that described in Example 1308D. The residue was chromatographed (silica gel; EtOAc/hexanes, 1:12) to afford a clear oil (355 mg, 55%). MS (CI/NH3) m/z: (M+NH4)+ 232.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:3]=1[F:23].O1CCCC1>CO>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:3]=1[F:23]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1C
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1C
Yield: 96.4 %

Procedure:
To a mixture comprised of methyl 4-amino-3-fluoro-2-(2-methyl-phenylamino)-5-nitrobenzoate (2.52 g, 0.00789 mol), tetrahydrofuran (50 ml), methanol (50 ml) and washed Raney nickel (0.5 g) was initially applied 48.6 psi of hydrogen gas at 30.2° C. in a shaker for 4 hours 48 minutes. The mixture was filtered and the filtrate concentrated in vacuo to afford 2.20 g of a salmon-colored amorphous solid; 96% yield; 1H-NMR (400 MHz; DMSO) δ 7.84 (s, 1H), 7.04 (d, 1H, J=7.1 Hz), 6.98 (d, 1H, J=1.2 Hz), 6.95–6.91 (m, 1H), 6.68–6.64 (m, 1H), 6.40–6.36 (m, 1H), 5.39 (s, 2H), 4.73 (s 2H), 3.66 (s, 3H), 2.21 (s, 3H); 19F-NMR (376 MHz; DMSO) δ −139.66 (s).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CN(C)C=O.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[CH2:25]([O:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cccc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-hydroxy-3-methylbenzoate (25 g, 150.44 mmol, 1.00 equiv), N,N-dimethylformamide (250 mL) and Cs2CO3 (103 g, 316.13 mmol, 2.10 equiv). This was followed by the addition of (bromomethyl)benzene (31 g, 181.25 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 1.2 L of ethyl acetate. The resulting mixture was washed with 3×800 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 40 g (crude) of methyl 2-(benzyloxy)-3-methylbenzoate as brown oil. MS (ESI) m/z 257 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](O)(=[O:18])[C:16]#[CH:17]>ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[C:16]#[CH:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.b. from 4′-chlorobiphenyl-4-ylamine and propynoic acid. Yield: 0.4 g (29.2% of theory); C15H10ClNO (M=255.70); calc.: molecular ion peak (M+H)+: 256/258; found: molecular ion peak (M+H)+: 256/258; Rf value: 0.35 (silica gel, dichloromethane/ethanol 20:1).
Reaction SMILES: [CH:1]1C=CC=C[CH:2]=1.C([Li])CCC.[CH3:12][O:13][CH:14]([O:21][CH3:22])[C:15](=O)[C:16]#[C:17][CH2:18][CH3:19]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCCCCC>[CH3:12][O:13][CH:14]([O:21][CH3:22])[C:15](=[CH:1][CH3:2])[C:16]#[C:17][CH2:18][CH3:19]
Reactant: CCC#CC(=O)C(OC)OC
Reactant: c1ccccc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC=C(C#CCC)C(OC)OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyltriphenylphosphonium bromide (24.8 g) is stirred with 100 ml benzene, and 40 ml (1.6 N) butyl lithium in hexane is added over about 1/2 hour with a water bath used to take up the slight heat of reaction. The mixture (bright orange) is stirred at room temperature for 0.75 hour, and 10.0 g of the 1,1-dimethoxy-3-hexyne-2-one is added dropwise in 1/2 hour.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH3:31])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=4)[NH:23][N:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:41][CH:42]([CH3:46])[C:43](Cl)=[O:44].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH3:31])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:43](=[O:44])[CH:42]([CH3:46])[CH3:41])[CH:28]=4)[NH:23][N:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(Cc1n[nH]c2ccc(O)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(Cc1n[nH]c2ccc(OC(=O)C(C)C)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 3-(2-(9-fluorenylmethoxycarbonylamino)propyl)-1H-indazol-5-ol (0.17 g, 0.41 mmol) and diisopropylehtylamine (0.06 g, 0.50 mmol), in methylene chloride (10 mL) cooled at 0° C. is added 2-methylpropionyl chloride (0.05 g, 0.5 mmol) followed by 4-dimethylaminopyridine (0.05 g, 0.40 mmol). The reaction allowed to warm to room temperature and then is stirred at room temperature. The reaction mixture is added to dilute aqueous sodium bicarbonate and extracted with ether. The combined ether extracts are washed, dried (MgSO4) and concentrated. The residue is purified by chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH:5]([NH:22][C:23]([C:25]1([NH:30][C:31](=[O:40])[CH:32]([S:36][C:37](=[O:39])[CH3:38])[CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[CH:11][CH:12]=1)[CH3:2].[CH3:42][CH2:43][OH:44]>[Pd]>[CH2:1]([O:3][C:4](=[O:41])[CH:5]([NH:22][C:23]([C:25]1([NH:30][C:31](=[O:40])[CH:32]([S:36][C:37](=[O:39])[CH3:38])[CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:43](=[O:44])[CH3:42])[CH:14]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C(Cc1ccc(-c2cccc([N+](=O)[O-])c2)nc1)NC(=O)C1(NC(=O)C(SC(C)=O)C(C)C)CCCC1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(-c2cccc(NC(C)=O)c2)nc1)NC(=O)C1(NC(=O)C(SC(C)=O)C(C)C)CCCC1
Reaction time: 18 h

Procedure:
A suspension of 2-{[1-(2-acetylthio-3-methyl-butanoylamino)-cyclopentanecarbonyl]-amino}-3-[6-(3-nitro-phenyl)-pyridin-3-yl]-propanoic acid ethyl ester (110 mg) and 25 mg of 10% Pd/C in 10 mL of EtOH is stirred under a H2 atmosphere for 18 h. The catalyst is filtered off, and the reaction mixture is concentrated in vacuo. The residue is purified by chromatography on silica gel (50% EtOAc/hexane) to produce yellow product; 1H NMR (250 MHz, CDCl3) δ8.39 (d, 1H), 7.60 (s, 2H), 7.10-7.36 (m, 3H), 6.71 (d, 1H), 6.34 (d, 1H), 4.76 (app q, 1H), 4.15 (q, 2H), 3.62 (dd, 1H), 3.05-3.25 (m, 2H), 2.35, 2.32 (two s, 3H), 1.55-2.40 (m, 9H), 1.19 (t, 3H), 0.92-1.06 (m, 6H).
Reaction SMILES: [CH2:1]([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]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.Cl.Cl.[NH2:38][O:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43]>C(Cl)Cl>[CH2:1]([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:38][O:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CN(C)CCON
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A solution of the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 in dehydrated methylene chloride (10 mL) was cooled to 0° C. under an argon atmosphere, followed by adding dropwise isobutyl chloroformate (289 μL, 2.20 mmol). Then, triethylamine (293 μL) was added, followed by stirring for 30 minutes. Thereby, a mixed acid anhydride was prepared in the reaction system. To this reaction mixture were gradually added 2-(aminooxy)-N,N-dimethylethanamine dihydrochloride (591 mg) described in Reference Example 18 and triethylamine (930 μL) while washing with dehydrated methylene chloride (7.0 mL), followed by stirring at the same temperature for 1 hour. This reaction mixture was filtered though Kiriyama filter paper. Subsequently, the residue was washed with methanol and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride and water, and the organic layer extracted with methylene chloride was dried over magnesium sulfate, followed by distilling off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (amino silica, chloroform/methanol=10/1) to afford 291.1 mg of the title compound as a colorless oil (yield 40%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=Nc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A mixture of p-azidotoluene (3.9 g), N-bromosuccinimide (5.5 g) and azobisisobutyronitrile (1.0 g) in carbon tetrachloride (30 ml) was heated under reflux in the dark under nitrogen for 18 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was dissolved in ether (50 ml) and filtered. Evaporation of solvent gave an oil (6.5 g) which was chromatographed on silica gel (200 g, Merck 7734). Elution with petroleum ether (b.p.40°-60°) gave the title compound as an oil (2.37 g). I.R. (Neat) 2120 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(F)cc1O
Product: O=C(Nc1ccccc1)Nc1ccc(F)cc1O
Yield: 91 %

Procedure:
N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea was prepared from 2-amino-5-fluoro phenol (200 mg, 1.57 mmol) and phenyl isocyanate according to the procedure in General Method A The product was purified by precipitation from toluene and filtering to afford the titled compound (352 mg, 91%). mp: 195.5°-195.7° C.; 1H NMR (CD3OD/CDCl3): δ7.70 (m, 1H), 7.3 (d, 2H, J=8.25 Hz), 7.15 (t, 2H, J=8.25 Hz), 6.89 (t, 1H, J=8.25 Hz), 6.50-6.38 (m, 2H); EI-MS m/z 246 (M+H)+ ; Anal. (C13H11N2O2F) C, H, N.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:14]([O:13][C:11]([CH2:10][C:2]1[NH:1][C:9]2[C:4]([C:3]=1[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])[CH3:15]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)Cc1cc2ccccc2[nH]1
Product: CCOC(=O)Cc1[nH]c2ccccc2c1C(=O)C(=O)OCC

Procedure:
In step (1) of Reaction Scheme VII, ethyl 1H-indol-2-ylacetate is reacted with ethyl chlorooxoacetate to provide ethyl (2-ethoxycarbonylmethyl-1H-indol-3-yl)oxoacetate. The reaction can be carried out using the general method described in step (1) of Reaction Scheme I. Ethyl 1H-indol-2-ylacetate is known.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=1>>[CH3:37][C:32]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)([CH2:16][C:17]([OH:20])([CH3:18])[CH3:19])[O:12][C:11]3=[O:28])[CH3:9])=[CH:4][CH:3]=2)[CH:35]=[C:34]([CH3:36])[N:33]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine in Step 4. LC-MS Method 2 tR=1.001, m/z=477.1; 1H NMR (CDCl3) 1.05-1.23 (d, 6H), 1.49 (d, 3H), 2.10-2.23 (m, 4H), 2.31-2.42 (m, 1H), 2.56 (s, 6H), 2.89 (m, 1H), 5.67 (m, 1H), 6.92-7.07 (m, 4H), 7.08 (s, 2H), 7.22 (m, 2H), 7.33 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:23][NH:24][CH3:25].[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([N:24]([CH3:25])[CH3:23])=[O:7]
Reactant: CNC
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)N(C)C)c1I

Procedure:
The acid chloride (16.23 g.) prepared from 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid and thionyl chloride was interacted with 60 ml. of dimethylamine (40% in water), 20 ml. of 35% aqueous sodium hydroxide and 30 ml. of water. The product was isolated and recrystallized from isopropyl alcohol to give 3-amino-2,4,6-triiodo-5-(N-methylacetamido)N,N-dimethylbenzamide as a pale yellow solid, m.p. 235°-240° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1.[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]([OH:18])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1ccnc(Br)c1
Reactant: O=Cc1cc(F)ccc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccnc(C(O)c2cc(F)ccc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of 2-bromo-4-methylpyridine (334 μl, 3 mmol) under ice cooling and the mixture was stirred at room temperature for 60 minutes. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise to the resulting brown solution. The temperature of the reaction mixture was raised gradually to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. After drying the solvent, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=5:1), whereby the title compound (456 mg, 65%) was obtained as needle crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:14][C:5]1[C:6]2[O:10][C:9]([CH3:11])([CH3:12])[C:8](=[O:13])[C:7]=2[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC1(C)Oc2c([N+](=O)[O-])ccc(Cl)c2C1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Oc2c(N)ccc(Cl)c2C1=O
Yield: 76.8 %

Procedure:
By the method of Example 1, Step E, 4.82 g (0.020 mole) of 4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran-3-one and 5.0 g of powdered iron were reacted in 80 mL of glacial acetic acid and 10 mL of water, yielding 3.25 g of 7-amino-4-chloro-2,3-dihydro-2,2-dimethylbenzofuran-3-one as an oil which subsequently solidified, m.p. 71°-73° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH:3]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[C:17]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[CH:4]([CH:7]=[CH:24][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH:2]1[OH:1]
Reactant: O=CC1CCC(O)C1CCCCCCCO
Reactant: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1CCC(O)C1CCCCCCCO
Yield: 61.6 %

Procedure:
A mixture of 3-hydroxy-2-(7-hydroxyheptyl)cyclopentanecarbaldehyde (4.5 g., 0.02 mole) and hexanoylmethylene triphenylphosphorane (7.5 g., 0.02 mole) in dry tetrahydrofuran (100 ml.) was heated under reflux for 6 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel. Elution with a 3:2 mixture of petrol (b.p. 40°-60°C.) and ethyl acetate gave 2-(7-hydroxyheptyl)-3-(3-oxo-1-octenyl)cyclopentanol (4 g., 63%), λmax 230 mμ, ε 12,900 (ethanol), νmax 1660 cm-1, 1620 cm-1 (liquid film).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].F[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[Cl:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:3]=1
Reactant: Oc1ccncc1Cl
Reactant: Fc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)cc1Cl
Temperature: 150 °C
Reaction time: 2 h

Procedure:
3-Chloropyridin-4-ol (0.259 g), 1-fluoro-3-(trifluoromethyl)benzene (0.126 mL) and potassium carbonate (0.276 g) were suspended in N-methyl-2-pyrrolidone (1.2 mL), and the suspension was stirred at 150° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane→methanol/ethyl acetate) to give the title compound (28.1 mg).
Reaction SMILES: [F:1][C:2]([F:15])([CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=CN=1)[C:3]([NH:5][NH2:6])=[O:4].FC(F)(C(O)C1[S:25]C=CC=1)C(OCC)=O.NN>>[F:1][C:2]([F:15])([CH:7]([OH:14])[C:8]1[S:25][CH:11]=[CH:12][CH:13]=1)[C:3]([NH:5][NH2:6])=[O:4]
Reactant: NNC(=O)C(F)(F)C(O)c1ccccn1
Reactant: CCOC(=O)C(F)(F)C(O)c1cccs1
Agent: NN
Product: NNC(=O)C(F)(F)C(O)c1cccs1

Procedure:
α,α-difluoro-β-hydroxy-2-thiophenepropanoic acid, hydrazide (26) was prepared in the same manner as α,α-difluoro-β-hydroxy-3-(2-pyridinyl)-propanoic acid, hydrazide (10), as described above in Example10, on a 1.4 mmol scale from ethyl α,α-difluoro-β-hydroxy-2-thiophenepropanoate and hydrazine to yield 0.23 g (74%) of product. Analysis calculated for C7H8N2O2F2S (M.W. 222.21): C, 37.84; H, 3.63; N, 12.61. Found: C, 37.72; H, 3.51; N, 12.42.