Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]#[N:14])=[O:4].[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[F:1][C:2]([F:22])([C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]1[NH:25][N:24]=[N:23][N:14]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccccc1NC(=O)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1Cc1nnn[nH]1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 130 °C
Yield: 18.9 %

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[2-(cyanomethyl)phenyl]butanamide (15 g), sodium azide (14.85 g), ammonium chloride (12.22 g) and dimethylformamide (200 mL) was heated in a 130° C. oil bath under a nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature, water (100 mL) was added and the product was extracted with ethylacetate (3×200 mL). The combined extracts were dried over Na2SO4, filtered and concentrated with a rotary evaporator. The brown residue was purified by high pressure liquid chromatography to give a white solid. The solid was triturated with diethyl ether to give 3.2 g of the title compound, m.p. 117°-178° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].C(=O)C1C=CC=CC=1>[OH-].[Na+]>[CH3:6][C:7]1[CH:14]=[C:13]([O:15][CH2:1][CH:3]2[O:5][CH2:4]2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: Cc1cc(O)ccc1C=O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O=Cc1ccccc1
Product: Cc1cc(OCC2CO2)ccc1C=O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To epichlorohydrin (20 g., 0.216 mole) heated at 55° C. is added dropwise a solution of 2-methyl-4-hydroxybenzaldehyde (9.0 g., 0.066 mole) in 2.5 N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55° C. and then at room temperature overnight. The oil is distilled to give 8.3 g. of 2-methyl-4-82,3-epoxypropyl)benzaldehyde, m.p. 160°-170° C. at 1 mm. Hg.
Reaction SMILES: [CH3:1][C@H:2]([O:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[CH2:20][N:21]2[CH:25]=[CH:24][CH:23]=[C:22]2[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:27])[CH:15]=[CH:16][CH:17]=1)[C:3](N1CCOCC1)=[O:4].[OH-:35].[Li+]>O1CCCC1.CO>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]([C:22]2[N:21]([CH2:20]/[CH:19]=[CH:18]/[C:14]3[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=3)[O:11][C@@H:2]([CH3:1])[C:3]([OH:4])=[O:35])[CH:25]=[CH:24][CH:23]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: [OH-]
Reactant: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)N3CCOCC3)c2)cc1
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)O)c2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of (4-methylphenyl)(1-allyl-1H-pyrrol-1-yl)methanone (47.31 g, 210 mmol) in dimethylformamide (650 ml) were added 4-[(2S)-2-(3-iodophenoxy)propanoyl]morpholine (72.24 g, 200 mmol), sodium hydrogencarbonate (33.60 g, 400 mmol), benzyltriethylammonium chloride (45.56 g, 200 mmol) and palladium acetate (2.245 g, 10.0 mmol), and the mixture was stirred for 6 hours at 50–55° C. After the mixture was allowed to cool to room temperature, thereto was added water (1 L) and the mixture was extracted with toluene/ethyl acetate (1/2) twice (1 L and 0.5 L). The organic layer was washed with an aqueous 10% potassium hydrogensulfate solution three times and then water and an aqueous saturated sodium chloride solution. The organic layer was dried over magnesium sulfate. After addition of charcoal, the organic layer was filtered with Celite. The solvent was removed under reduced pressure to give {1-[(2E)-3-(3-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}phenyl)prop-2-enyl]-1H-pyrrol-2-yl}(4-methylphenyl)methanone (about 10 g). To a solution of {1-[(2E)-3-(3-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}phenyl)prop-2-enyl]-1H-pyrrol-2-yl}(4-methylphenyl)methanone (about 100 g) in tetrahydrofuran (350 ml) and methanol (350 ml) was added an aqueous 2N lithium hydroxide solution (500 ml) and the mixture was stirred for 5 hours at 70° C. The reaction mixture was concentrated, followed by addition of water. The mixture was acidified (pH 2–3) with 1N hydrochloric acid. The solution was extracted with toluene/ethyl acetate (1/2)(1 L×2) and dried over anhydrous magnesium sulfate. The solvent was removed and the residue was dried to give (2S)-2-(3-{(1E)-3-[2-(4-methylbenzoyl)-1H-pyrrol-1-yl]prop-1-enyl}phenoxy)propionic acid (about 90 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1.FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:28])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4cccc(Cl)c4)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-chloro-3-isocyanato-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 393 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.67 (s, 2H) 7.01-7.06 (m, 1H) 7.29-7.34 (m, 2H) 7.48 (d, J=8.48 Hz, 2H) 7.63 (d, J=8.48 Hz, 2H) 7.73 (s, 1H) 7.95 (s, 1H) 8.87 (s, 1 H) 8.97 (br.s, 2H).
Reaction SMILES: [C:1]1([N:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[C:13]2=[O:30])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.Cl>[OH-].[OH-].[Pd+2].CCO>[C:1]1([N:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:18][CH2:17][CH2:16][C:15]3[C:19]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]2[OH:30])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc2c1CCCC(COC(=O)N(c1ccccc1)c1ccccc1)C2=O
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc2c1CCCC(COC(=O)N(c1ccccc1)c1ccccc1)C2O
Reaction time: 5 h
Yield: 21.9 %

Procedure:
To a solution of ethyl {[6-(N,N -diphenylcarbamoyloxy)methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]oxy}acetate (100 mg) in a mixed solvent of THF and EtOH (1:4, 5 ml) were added 20% Pd(OH)2 on carbon and catalytic amount of concentrated hydrochloric acid. The mixture was hydrogenated for 5 hours at 3 atm. After removal of the catalyst by filtration, the filtrate was evaporated. The residue was dissolved in EtOAc, washed with saturated sodium hydrogencarbonate solution, water, and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 2:1) to give ethyl {[(5SR,6RS)-6-(N,N-diphenylcarbamoyloxy) methyl-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]oxy}acetate (22.0 mg) as an amorphous solid.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[O:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[N:26]=1>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: COc1ccc(-c2noc(Cl)n2)cc1
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2noc(N3CCC(N(C(=O)c4ccc(-c5cnco5)cc4)C4CC4)CC3)n2)cc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 5-chloro-3-(4-methoxy-phenyl)-[1,2,4]oxadiazole following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 6): tR=1.92 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[NH:6])[NH2:5].C(N(CC)CC)C.[CH3:18][CH:19]([C:25](=O)[CH3:26])[C:20](OCC)=[O:21]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[N:5]=[C:20]([OH:21])[C:19]([CH3:18])=[C:25]([CH3:26])[N:6]=1
Reactant: N=C(N)c1ccccc1Cl
Reactant: CCOC(=O)C(C)C(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(-c2ccccc2Cl)nc(O)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To 2-chlorobenzimidamide (34.07 g, 220 mmol) and triethylamine (44.50 g, 440 mmol) in ethanol (750 mL) was added ethyl 2-methyl-3-oxobutanoate (38.13 g, 264 mmol). The reaction was heated at 90° C. for 4 h. A further portion (6.36 g) of the ester was added and the reaction was stirred for 3 h. The reaction was concentrated to around 500 mL and stood overnight. Precipitation of the desired pyrimidinol (22.7 g) occurred. The mother liquors were concentrated and DCM and 1M HCl were added. The aqueous layer was extracted 7 times with DCM to give further crops of the desired product (total: 28.9 g, 56%) on concentration as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(OCC)C>CO.O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:16][O:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H](CBr)c1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: c1ccc(COc2ccc([C@@H]3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
6.0 g of (R)-1-(4-benzyloxyphenyl)-2-bromoethanol was dissolved in a mixed solvent of 50 ml of methanol and 25 ml of tetrahydrofuran. Thereto was added a solution of 1.5 g of potassium hydroxide dissolved in 5 ml of water, with ice cooling. The resulting mixture was stirred for 5 minutes at the same temperature and further for 10 minutes at room temperature. The reaction mixture was added to a mixture of 100 ml of diethyl ether and 100 ml of ice water. The organic layer was separated. The aqueous layer was extracted with 50 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3.7 g of (R)-2-(4-benzyloxyphenyl)oxirane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH:9]=2)=[O:5])[CH3:2].[C:31]1([Mg]Cl)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:30])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: Cl[Mg]c1ccccc1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1(O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
6-(2-Morpholine-4-ylethoxy)-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1.5 g, 3.68 mmol) obtained in Step 1 was dissolved in THF, and phenylmagnesium chloride (3.865 mL, 5.89 mmol) was added thereto, followed by stirring for 2 hrs at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 788 mg of the titled compound (yield: 44%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11]C(=O)OC(C)(C)C)[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O.C(=O)(O)[O-]>ClCCl>[N:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([I:10])[CH:9]=1)[NH2:11])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(I)cc(N=[N+]=[N-])c1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1cc(N)cc(I)c1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Step A-4. To a stirred solution of 3-azido-5-iodophenylcarbamic acid, 1,1-dimethylethyl ester (A-3, 4.03 g, 11.2 mmol) in dichloromethane (13 mL) is added trifluoroacetic acid (13 mL). The reaction mixture is stirred at 20°-25° C. for 30 minutes and then carefully poured into a stirred mixture of saturated aqueous bicarbonate (300 mL) and dichloromethane (300 mL). The phases are separated and the organics are dried (MgSO4), filtered and concentrated. The residue is purified by medium pressure liquid chromatography using 20% ethyl acetate in hexane as the eluent to afford 2.43 g of 3-azido-5-iodoaniline (A-4) which is used immediately in the next reaction, CHART B, Step B-1. A small analytical sample is recrystallized from ethyl acetate in hexane. Mp=89°-91° C. IR (mull) 3402, 3299, 2954, 2925, 2869, 2135, 2119, 1596, 1581, 1572, 1570, 1463, 1149, 1304, 1246, 987, 842, 826 cm-1 ; 1H NMR (CDCl3) δ6.79 (t, 1 H, J=2 Hz), 6.75 (t, 1 H, J=3 Hz), 6.23 (t, 1 H, J=2 Hz), 3.75 (bs, 2 H); 13C NMR(CDCl3) δ148.5, 141.9, 120.3, 117.7, 104.6, 94.9; Mass Spec (70eV, EI) m/z 260 (parent), 232, 205, 165, 127, 116, 105 (base), 78, 66, 541, 37; Exact mass calculated for C6H5IN4 : 259.9561. Found: 259.9573. Analysis calculated for C6H5IN4 ; C, 27.71; H, 1.90; N, 21.55; Found C, 27.67; H, 1.90; N, 21.66.
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:21])[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=O.[C:22]([SiH2:26][O:27][C:28]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:39][C:40]([NH2:42])=[O:41])=[C:36]([CH3:38])[N:37]=2)[CH:34]=1)([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>O1CCCC1.CCOC(C)=O>[C:22]([SiH2:26][O:27][C:28]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([C:39]3[C:40](=[O:41])[NH:42][C:9](=[O:21])[C:10]=3[C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)=[C:36]([CH3:38])[N:37]=2)[CH:34]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn2c1CC(N)=O
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn2c1C1=C(c2c[nH]c3ccccc23)C(=O)NC1=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 1.90 ml, 1.90 mmol, 3.0 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of (1H-Indol-3-yl)-oxo-acetic acid methyl ester (192 mg, 0.93 mmol, 1.5 equiv) and of 2-[6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyridin-3-yl]-acetamide (300 mg, 0.62 mmol) in anhydrous tetrahydrofuran (5.0 ml, dried over molecular sieves). The reaction mixture is stirred for 30 minutes at 0° C., 30 minutes at room temperature and 1 hour at 45° C. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of hexane/EtOAc 50:50 to 20:80) affords the title compound (180 mg, 45%). MS (ES+): 611 (M+H)+.
Reaction SMILES: C(S)=C.[C:4]1(=[O:10])[O:9][C:7](=[O:8])[CH:6]=[CH:5]1.[NH2:11][C:12]1[CH:20]=[CH:19][C:15](C(O)=O)=[CH:14][CH:13]=1>>[C:4]([OH:9])(=[O:10])[CH2:5][CH2:6][C:7]([NH:11][C:12]1[CH:20]=[CH:19][CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: C=CS
Product: O=C(O)CCC(=O)Nc1ccccc1

Procedure:
The copolymer of vinyl mercaptan and maleic anhydride which is further reacted with p-amino benzoic acid to form polymeric succinanilic acid,
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[CH:21]([OH:23])[CH3:22])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:58][C:59]1[C:60]([CH3:71])=[C:61]([CH2:67]C(O)=O)[CH:62]=[CH:63][C:64]=1[C:65]#[N:66]>C(Cl)Cl.C1COCC1.CCOC(C)=O.C1(C)C=CC=CC=1>[C:21]([C@@H:9]1[C@@H:10]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH2:11][CH2:12][N:8]1[C:6](=[O:7])[CH2:67][C:61]1[CH:62]=[CH:63][C:64]([C:65]#[N:66])=[C:59]([Cl:58])[C:60]=1[CH3:71])(=[O:23])[CH3:22]
Reactant: Cc1c(CC(=O)O)ccc(C#N)c1Cl
Reactant: CC(O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)Cc1ccc(C#N)c(Cl)c1C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
To compound 1L (480 mg, 1.4 mmol) was added 7 mL of 10% TFA/CH2Cl2 solution at RT, and stirred at 4 hr. A 7 mL toluene was added to the reaction mixture, and concentracted. It was dissolved in 5 mL of CH2Cl2, a solution of PyBrop (1.2 g, 2.5 mmol) and compound 1G (210 mg, 1 mmol) in 3 mL of THF were added followed by iPr2NET (520 μL, 3 mmol), and the stirring was continued for 3 hr at RT. It was concentracted, dissolved in EtOAc, washed with water, dried over Na2SO4, and concentrated. Purification by flash chromatography (silica gel, 30% EtOAc in hexanes) provided the title compound (220 mg). MS (ES) m/z 435 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:16](=[O:33])[CH:17]=[CH:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2]>O1CCCC1.[Pd]>[C:1]([NH:4][CH:5]([C:16](=[O:33])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1csc2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)NC(Cc1csc2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 59.8 %

Procedure:
2-Acetamido-1-(3-benzo[b]thienyl)-5-(3,5-bistrifluoromethylphenyl)-4-penten-3-one (2.0 g) was hydrogenated in tetrahydrofuran (100 ml) using 10% Pd/C (0.5 g) at 50 p.s.i. The product was purified by chromatography on silica using ethyl acetate/petroleum ether (bp 60°-80° C.)(1:1) to yield the title compound as a white solid (1.2 g), mp=83°-84° C.; found: C, 56.41; H, 3.81; N, 2.84; C23H19F6NO2S requires C, 56.67; H, 3.93; N, 2.87%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)#[CH:13]>>[CH3:21][O:20][C:18]1[CH:17]=[N:16][CH:15]=[C:14]([C:12]#[C:13][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[CH:19]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: C#Cc1cncc(OC)c1
Product: COc1cncc(C#Cc2cccc(C(F)(F)F)c2)c1
Yield: 65 %

Procedure:
Prepare essentially as described in PREPARATION 10 using 1-iodo-3-trifluoromethylbenzene (0.430 mL, 3.0 mmol) and 3-ethynyl-5-methoxypyridine, (prepared essentially as described in PREPARATION 10), (415 mg, 3.1 mmol) at room temperature for 16 h to give the title compound (541 mg, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[CH3:18][O:19][CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 31.6 %

Procedure:
A mixture of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (4.5 g, 19.9 mmol), chloromethyl methyl ether (2.3 mL, 30.3 mmol), potassium carbonate (5.5 g, 39.8 mmol) and potassium iodide (0.66 g, 3.98 mmol) in N,N-dimethylformamide (50 mL) was stirred at 70° C. for 20 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:97-1:9) to give the title compound (1.7 g, yield 32%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10](N)=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:16])=[O:11])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1ccc(C(F)(F)Cl)[nH]c1=O
Product: O=C(O)c1ccc(C(F)(F)Cl)[nH]c1=O
Temperature: 0 °C

Procedure:
11.0 g (49.4 mmol) of 6-[chloro(difluoro)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide were heated in 77 ml of 50% strength sulfuric acid. The mixture was then added to ice water, and the precipitate was filtered off with suction and dried. This gave 7.2 g (65% of theory) of a yellowish powder.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([S:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:2]1.[OH-].[Na+]>O1CCOCC1>[O:1]1[CH2:5][CH2:4][CH:3]([S:6]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)(=[O:8])=[O:7])[CH2:2]1
Reactant: COC(=O)c1ccc(S(=O)(=O)C2CCOC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(S(=O)(=O)C2CCOC2)cc1
Temperature: 80 °C
Yield: 84.7 %

Procedure:
To methyl 4-tetrahydrofuran-3-ylsulfonylbenzoate (1.07 g, 3.96 mmol) in dioxane (11 mL) was added 1 M sodium hydroxide (10.5 mL, 10.5 mmol) and the reaction was heated at 80° C. for 10 minutes. The solvent was evaporated under reduced pressure. The residue was dissolved in water (30 mL) and washed with ethyl acetate (3×25 mL). The aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield 4-tetrahydrofuran-3-ylsulfonylbenzoic acid (0.86 g, 85%) as a white solid. ESI-MS m/z calc. 256.0. found 257.3 (M+1)+; Retention time: 0.69 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.59 (s, 1H), 8.19 (d, J=8.3 Hz, 2H), 8.05 (d, J=8.3 Hz, 2H), 4.38-4.15 (m, 1H), 4.06-3.97 (m, 1H), 3.87-3.71 (m, 2H), 3.72-3.54 (m, 1H), 2.20-2.06 (m, 2H).