Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](NCC(OCC1C=CC=CC=1)=O)=[O:19].[NH:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41].C(N1CCOCC1)C.Cl>CN(C)C=O>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41])=[O:19]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)NCC(=O)OCc2ccccc2)c2ccccc2)=C(C)C1=O
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)N2CCC[C@H]2C(=O)O)c2ccccc2)=C(C)C1=O
Reaction time: 15 h
Yield: 70.9 %

Procedure:
To a mixture of benzyl 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoylglycinate (0.95, 2.0 mmoles) and L-proline (0.24 g, 2.1 mmoles) was added a solution of N-ethylmorpholine (0.48 g, 4.2 mmoles), in dimethylformamide (10 ml) at room temperature. After 15 hours, 1N hydrochloric acid (5 ml) was added to the reaction mixture. The product was extracted with ethylacetate. The extract was worked up in the usual manner. The crude product was chromatographed on a reversed phase ODS column (YMC-Gel ODS, 60/200 mesh, Yamamura Chemical Co. Kyoto) with methanol-H2O (9:1) as eluant to give 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoyl-L-proline (0.64 g, 71%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15]1>>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[C:7]2[C:6](=[O:13])[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:9][CH2:8]2)=[CH:15]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1ccc2c(c1)C(=O)CCO2
Product: COc1ccc2c(c1)C(=O)C(=Cc1c[nH]c3ccccc13)CO2

Procedure:
By the method of Example 1, 6-methoxy-4-chromanone (10.0 g) and 3-indolecarbaldehyde were converted to present title product recrystallized from CH3OH/CH2Cl2, 16.7 g (98%), m.p. 217-219° C.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.C(Cl)Cl.O=C1CCC(=O)N1[O:24][C:25](=O)[CH:26]=[CH:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:25](=[O:24])[CH:26]=[CH:27][CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(C=CC=Cc1ccccc1)ON1C(=O)CCC1=O
Reactant: NCCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=CC=Cc1ccccc1)NCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a suspension of 3-bromopropylamine hydrobromide (1.09 g, 5.0 mmol) in anhydrous methylene chloride triethylamine (0.61 g, 6.0 mmol) was added and the mixture was stirred at ambient temperature for 30 min. The mixture was cooled in the ice bath and a solution of 5-phenyl-penta-2,4-dienoic acid 2,5-dioxo-pyrrolidin-1-yl ester (10) (1.35 g, 5.0 mol) in methylene chloride (20 ml) was added. The reaction mixture was stirred at ice bath temperature for 1.5 hours and at ambient temperature for 2 hours. The solvent was removed and the residue was suspended in water. The precipitate was filtered and washed with water and hexane to give the title compound 11 (1.0 g, 68%). 1H NMR (CDCl3, HMDSO) δ: 1.92-2.32 (2H, m); 3.31-3.67 (4H, m); 6.00 (1H, d, J=15.0 Hz); 6.07 (1H, br s); 6.78-6.96 (2H, m); 7.22-7.61 (6H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[CH:16]=1)[C:11](O)=[O:12])#[N:2].[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:43])[NH:35][CH:36]1[CH2:37][CH2:38][CH:39]([NH:42][C:11](=[O:12])[C:10]2[CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=[C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][CH:28]=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:9]=2)[CH2:40][CH2:41]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: N#Cc1ccc(Oc2cc(OCc3cccc(C#N)c3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3cccc(C#N)c3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 74 %

Procedure:
Following the procedure of Example 5(c) 3-(3-cyano benzyloxy)-5-(4-cyano phenoxy)benzoic acid 0.46 g (1.24 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.265 g, 1.24 mmol) were used to afford 0.52 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 5.25 (2H, s), 6.74 (1H, d), 7.02 (1H, s), 7.32 (2H, d), 7.22 (1H, s), 7.44 (1H, s), 7.64 (1H, m), 7.84 (4H, m), 7.95 (1H, s), 8.3 (1H, d).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:17]([OH:19])=O)[S:6][C:7]=1[S:8][C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[CH:11][C:10]=1[Cl:16])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>>[C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:17]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[O:19])[S:6][C:7]=1[S:8][C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[CH:11][C:10]=1[Cl:16])#[N:2]
Reactant: N#Cc1c(Sc2c(Cl)cncc2Cl)sc(C(=O)O)c1-c1ccccc1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2sc(Sc3c(Cl)cncc3Cl)c(C#N)c2-c2ccccc2)CC1

Procedure:
Prepared according to the procedure described for step A of example 44 from 4-cyano-5-((3,5-dichloropyridin-4-yl)thio)-3-phenylthiophene-2-carboxylic acid from above and 1-methylpiperidin-4-amine (0.11 g, 1.0 mmol). The title product was obtained as a white solid (29.5 mg, 6.0% yield). MS m/z: 503.04, 505.04 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:30])=[C:11]([C:23](=[O:29])[CH:24](OCC)O)[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.[CH3:31][C:32]([NH2:44])([CH3:43])[CH2:33][C:34]1[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=1[CH3:42].[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[CH3:43][C:32]([NH:44][CH2:24][CH:23]([C:11]1[C:10]([CH3:30])=[C:9]([OH:8])[C:14]([OH:15])=[CH:13][CH:12]=1)[OH:29])([CH3:31])[CH2:33][C:34]1[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=1[CH3:42]
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1C
Reactant: Cc1cc(C)c(CC(C)(C)N)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CC(C)(C)NCC(O)c2ccc(O)c(O)c2C)c(C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
350 mg (0.86 mmol) of 1-(3,4-bis-benzyloxy-2-methylphenyl)-2-ethoxy-2-hydroxyethanone and 198 mg (1.03 mmol) of 1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamine were dissolved in 3 mL of ethanol and heated to 80° C. for 30 minutes in the presence of some molecular sieve. After cooling to ambient temperature, 33 mg (0.86 mmol) sodium borohydride was added and the mixture was stirred for 1 hour. The reaction mixture was combined with ethyl acetate and washed with sodium hydrogen carbonate solution. Then the organic phase was freed from solvent and chromatographed. In order to cleave the benzyl protecting groups, the ethanolamine-thus-obtained (364 mg) was dissolved in methanol, combined with 150 mg of Pearlman's catalyst, and hydrogenated at ambient temperature and under normal pressure. The reaction mixture was filtered through CELITE® filter agent and evaporated down. Chromatographic purification of the residue with dichloromethane and methanol as eluent yielded the target compound as a beige solid. Yield: 179 mg (29%); mass spectrometry: [M+H]+=391.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[CH2:49][C:50]([CH3:53])([OH:52])[CH3:51])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:49][C:50]([OH:52])([CH3:53])[CH3:51])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(C)(O)CCn1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 825 mg, 2.50 mmol) was suspended in methylene chloride (12.5 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (1.25 mL, 2.5 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (582 μL, 5.00 mmol) was added. The reaction continued to stir at 0° C. for 10 min. 4-(3-Amino-pyrazol-1-yl)-2-methyl-butan-2-ol (424 mg, 2.50 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to the reaction. The reaction continued to stir at 0° C. for 10 min. The reaction was diluted with methylene chloride (50 mL), washed with water (15 mL), saturated aqueous brine solution (10 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 35% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-3-methyl-butyl)-1H-pyrazol-3-yl]-propionamide (653 mg, 54%) as a white foamy solid: ESI-LRMS m/e calcd for C23H32ClN3O4S [M+] 481.18, found 482.35 [M+H+], 464.22 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.23 (m, 2H, CH2), 1.29 (s, 6H, 2×CH3), 1.46-1.94 (m, 8H, 4×CH2), 1.94-2.04 (m, 2 H, CH2), 2.18-2.29 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.55 (t, J=7.5 Hz, 1H, CH), 3.00-4.25 (m, 2H, NCH2), 6.65 (d, J=2.3 Hz, 1H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.47 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.61 (d, Jm=1.7 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 8.12 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[C:22]([CH3:23])=[CH:21][C:5]2[N:6]([CH2:10][C:11]3[C:12]4[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:30]([O:32][CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:31].CO>C(OCC)(=O)C>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][CH:33]([N:8]1[C:4]2[CH:3]=[C:2]([CH3:1])[C:22]([CH3:23])=[CH:21][C:5]=2[N:6]([CH2:10][C:11]2[C:12]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=3[S:14][CH:15]=2)[C:7]1=[O:9])[O:32][CH2:30][CH3:31])[CH3:39]
Reactant: Cc1cc2[nH]c(=O)n(Cc3csc4cccc(C)c34)c2cc1C
Reactant: CCOC=CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CC(OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 130 °C
Yield: 31.1 %

Procedure:
To a mixture of 5,6-Dimethyl-1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.31 mmol) and K2CO3 (86 mg, 0.62 mmol) in a microwave vial was added Ethyl 3-ethoxyacrylate (0.45 g, 3.1 mmol). The reaction mixture was heated to 130° C. for 20 min in a microwave. The reaction mixture was then diluted with ethyl acetate (since there was some insoluble material left, MeOH was added to the solution mixture to solubilize the material). This organic phase was washed with water (×2). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexane:ethyl acetate as an eluent to afford 45 mg of the desired product as an oily foam. LCMS (ESMS): m/z 467.32 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:18]=[CH:17][C:11]([C:12](=[CH2:16])[C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=1)(O)=[O:6]>>[Cl:3][C:5]([C:8]1[CH:18]=[CH:17][C:11]([C:12](=[CH2:16])[C:13]([NH2:15])=[O:14])=[CH:10][CH:9]=1)=[O:6]
Reactant: C=C(C(N)=O)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: C=C(C(N)=O)c1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 50 cc. of thionyl chloride and 0.05 moles of p-carboxyatropamide is heated at reflux on the steam-bath for 1/2 hour. The reaction is concentrated in vacuo to give p-chlorocarbonylatropamide suitable for use in the following step.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]=2[CH2:24][CH3:25])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:28])=O.C(=O)([O-])O.[Na+].O>C1(C)C=CC=CC=1>[Cl:28][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[O:11][C:10]=1[CH2:24][CH3:25]
Reactant: O=S(Cl)Cl
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl {2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (705 mg) in toluene (10 mL) was added thionyl chloride (290 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled, neutralized with saturated aqueous sodium hydrogen carbonate, and poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (742 mg, 100%) as a yellow solid.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>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:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: c1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1=CC=CC=CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Ethyl diazoacetate (43.4 g, 0.38 mol) was added slowly (syringe pump) over a period of 7 hours to a mixture of benzene (594.32 g, 7.61 mol) and tetrakis (perfluorobenzoato) dirhodium (II)(0.84 g, 00.16 mol). After stirring at room temperature for 16 hours, the solvent was removed and the oily residue distilled in vacuo to give 50.44 g (81%) of ethyl 1,3,5-cycloheptatriene-1-carboxylate: bp 90°-96° C. 2.4-3.0 mm Hg).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][CH:29]=[C:6]2[C:7]([N:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][CH:29]=[C:6]2[C:7]([N:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: CCOc1cc(C(CC(=O)OC)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Yield: 55.4 %

Procedure:
To a solution of methyl 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate (2.5 g, 5.8 mmol) in 25 mL of ethyl acetate was added 0.25 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford a yellow solid. The crude product was purified by flash column chromatography (silica gel, 7% ethyl acetate/methylene chloride). The resulting solid was recrystallized (60 mL ethyl acetate/20 mL hexane) and was then dried in vacuo (60° C.,<1 mm) to afford 1.28 g (55%) of methyl 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate as a yellow solid: mp 134-136° C.; 1H NMR (CDCl3)δ 7.40-7.26 (m, 1H); 7.16-7.01 (m, 3H), 6.86-6.72 (m, 2H), 5.71 (dd, J=6, 9.8 Hz, 1H), 5.28 (br s, 2H), 4.10 (q, J=7 Hz, 2H), 3.83 (s, 3H), 3.73 (dd, J=9).8, 16.5 Hz, 1H), 3.64 (s, 3H), 3.24 (dd, J=6, 16.5 Hz, 1H), 1.44 (t, J=7 Hz, 3H); 13C NMR (CDCl3)δ 171.1, 169.8, 168.3, 148.9, 148.1, 145.3, 134.9, 132.3, 131.3, 120.9, 120.0, 112.5, 112.4, 111.1, 110.8, 64.2, 55.8, 51.8, 50.2, 36.0, 14.6; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 50/50, acetonitrile/0.1% aqueous phosphoric acid) 5 min, 100%; Anal. Calcd. for C21H22N2O6. Theoretical: C, 63.31, H, 5.57, N, 7.03. Found: C, 63.11; H, 5.50; N, 6.99.
Reaction SMILES: Br[Si](C)(C)C.C(O[C:9](=[P:40]([OH:42])=[O:41])[C:10]1[N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[C:13]2=[N:12][N:11]=1)=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[C:17]([N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:16]=3)C.CN(C)C=[O:46]>>[CH3:33][C:31]1[N:30]=[C:29]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:28]([C:17]2[CH:16]=[C:15]3[C:20]([NH:21][C:22](=[O:23])[C:13]4[N:14]3[C:10]([CH2:9][P:40]([OH:41])([OH:42])=[O:46])=[N:11][N:12]=4)=[CH:19][C:18]=2[C:24]([F:25])([F:27])[F:26])[CH:32]=1
Reactant: CN(C)C=O
Reactant: CCOC(c1nnc2c(=O)[nH]c3cc(C(F)(F)F)c(-n4cc(C)nc4-c4ccccc4)cc3n12)=[P+]([O-])O
Agent: C[Si](C)(C)Br
Product: Cc1cn(-c2cc3c(cc2C(F)(F)F)[nH]c(=O)c2nnc(CP(=O)(O)O)n23)c(-c2ccccc2)n1

Procedure:
Bromotrimethylsilane (1 ml, 7 mmol) was added dropwise to a stirred solution of 1-(ethoxy-hydroxy-phosphorylmethyl)-8-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (500 mg, 0.94 mmol) in 20 ml of dry N,N-dimethylformamide.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([Si](C)(C)C)=[CH:12][C:13]=1[C:14]([F:18])=[C:15]([Cl:17])[F:16])(=[O:8])=[O:7])(C)(C)C.FC(F)(F)S(O)(=O)=O>O>[Cl:17][C:15]([F:16])=[C:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7])[F:18]
Reactant: CC(C)(C)NS(=O)(=O)c1sc([Si](C)(C)C)cc1C(F)=C(F)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)c1sccc1C(F)=C(F)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A portion (0.74 g) of the N-tert-butyl-3-(2-chloro-1,2-difluoroethenyl)-5-trimethylsilyl-2-thiophenesulfonamide prepared in (1) was treated with 4 ml of trifluoromethanesulfonic acid under stirring at room temperature for 2 hours. After completion of the reaction, the resulting product was poured into water and extracted with methylene chloride. The extracted layer was washed with water and dried. After distilling off methylene chloride under vacuum, the residual crystals were washed with a small amount of toluene and dried to obtain 0.26 g of 3-(2-chloro-1,2-difluoroethenyl)-2-thiophenesulfonamide having a melting point of 112° to 116° C.
Reaction SMILES: [F:1][C:2]([C:5]([CH2:7][CH3:8])=[O:6])([F:4])[F:3].[C:9]([Mg]Br)#[C:10][CH3:11]>C1COCC1>[F:1][C:2]([F:4])([F:3])[C:5]([OH:6])([C:9]#[C:10][CH3:11])[CH2:7][CH3:8]
Reactant: CC#C[Mg]Br
Reactant: CCC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CC#CC(O)(CC)C(F)(F)F
Reaction time: 1 h

Procedure:
To ethyl trifluoromethyl ketone (5.00 g, 40.0 mmol) in THF (20 ml) at room temperature was added 1-propynyl magnesium bromide (0.5 M in THF, 60 mL, 30.0 mmol). The reaction mixture was allowed to stand at rt 1 h, and concentrated in vacuo. The residue was partitioned between Et2O and aq. NH4OAc, the phases were separated, and the organic phase washed with brine, dried over MgSO4, filtered and concentrated (not to complete dryness), to afford a 50 wt. % solution (estimated by 1H NMR) of the title compound (remainder THF and Et2O), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 6.63 (s, 1H), 1.87 (s, 3H), 1.75-1.63 (m, 2H), 1.04 (t, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]=[N+]=[N-])=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CO>C(OCC)(=O)C.[C].[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH2:25])=[CH:22][CH:23]=3)=[N:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CN=[N+]=[N-])cc3)nc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CN)cc3)nc2)CC1
Yield: 68.4 %

Procedure:
To a solution of 1-acetyl-4-(6-{2-[4-(azidomethyl)phenyl]ethyl}pyridin-3-yl)piperazine (226.8 mg, 0.622 mmol) in ethyl acetate (10 ml) was added 10% palladium carbon (45.1 mg, 50% containing water), and the mixture was hydrogenated at room temperature, under atmospheric pressure. Methanol (10 ml) was added to the reaction mixture, and the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was washed with a mixture of ethyl acetate/diisopropyl ether (1:1) and dried under reduced pressure to give 1-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)methanamine (144.0 mg, yield 68.2%) as a white solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)=[N+:2]=[N-:3].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:29][C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCN=[N+]=[N-])cc1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCOc1ccc(Cl)cc1
Temperature: 90 °C
Yield: 56.9 %

Procedure:
7-Azidoheptyltosylate (920 mg, 3.8 mmol) was dissolved in DMF (12 mL). 4-Chlorophenol (650 mg, 5.0 mmol) and K2CO3 (1.7 g, 12.3 mmol) were added and the mixture was heated to 90° C. for 4 h. The mixture was concentrated under reduced pressure, the residue was partitioned between EtOAc (100 mL) and water (25 mL). The organic layer was dried, filtered and concentrated under reduced pressure. Flash chromatography (silica gel, hexanes/EtOAc 95/5) yielded 1-azido-7-(4-chlorophenoxy)-heptane (579 mg, 49%). 1-Azido-7-(4-chlorophenoxy)-heptane (570 mg, 2.1 mmol) was dissolved in EtOH (3 mL). Pd/C (101 mg, 10%) was added and the mixture was stirred under an atmosphere of H2 for 75 min. The reaction mixture was filtered through celite and concentrated under reduced pressure to yield the title compound (453 mg, 89%). The product contained ˜25% of 7-(phenoxy)-heptylamine.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(OC)c2)c(-c2cccnc2F)c1F
Reaction time: 4 h
Yield: 76 %

Procedure:
Tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (551 mg) was dissolved in ethyl acetate (5 mL) and 2-propanol (3 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added at room temperature. The reaction mixture was stirred for 4 hr and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 327 mg, 76%).