Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClC(Cl)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[O:10][C:13](=[O:14])[N:12]([CH3:16])[CH3:11])#[N:7]
Reactant: N#Cc1ccc(F)cc1O
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CN(C)C(=O)Oc1cc(F)ccc1C#N
Yield: 67 %

Procedure:
Under N2, a stirred solution of intermediate 129, 4-fluoro-2-hydroxybenzonitrile (685 mg, 5.00 mmol), dimethylcarbamoyl chloride, and triethylamine (606 mg, 6 mmol) in dichloroethane (10 mL) was heated at reflux for 20 hrs. The cooled mixture was diluted with dichloroethane (10 mL) washed with water, and brine. The organic layer was separated, dried (Na2SO4), concentrated, and the residue purified by column chromatography (SiO2, 5% ethyl acetate-CH2Cl2) to provide 700 mg (Yield 67%) of the title compound as a white crystalline solid: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.03 (3H, s, NMe), 3.15 (3H, s, NMe), 6.99 (1H, dt, J=2.5 Hz, 8.5 Hz, Ar—H), 7.23 (1H, dd, J=2.5 Hz, 9.5 Hz, Ar—H), 7.61 (1H, dd, J=9 Hz, 6 Hz, Ar—H); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 36.76, 37.06, 102.84, 102.86, 111.59, 111.79, 113.24, 113.42, 114.99, 134.36, 134.45, 152.54, 155.06, 155.16, 164.26, 166.31. HRMS (ESI) calcd for C10H10N2O2F (M+H) 209.0726, found 209.0722.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[C:17]4[C:20]5[C:25]([C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=6[C:16]4=[CH:15][C:14]=3[C:13]3[CH:12]=[C:11](B4OC(C)(C)C(C)(C)O4)[CH:10]=[CH:9][C:8]2=3)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N+:48]([O-:50])=[O:49].C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[N+:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:11]1[CH:10]=[CH:9][C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:19]3[CH:18]=[C:17]4[C:20]5[C:25]([C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=6[C:16]4=[CH:15][C:14]=3[C:13]=2[CH:12]=1)=[CH:24][CH:23]=[CH:22][CH:21]=5)([O-:50])=[O:49]
Reactant: CC1(C)OB(c2ccc3c(c2)c2cc4c5ccccc5c5ccccc5c4cc2n3-c2ccccc2)OC1(C)C
Reactant: O=[N+]([O-])c1ccccc1Br
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1-c1ccc2c(c1)c1cc3c4ccccc4c4ccccc4c3cc1n2-c1ccccc1
Temperature: 90 °C
Yield: 68.6 %

Procedure:
A mixture of 11.5 g (22.1 mmol) of 10-phenyl-13-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)-10H-phenanthro[9,10-b]carbazole, 5.4 g (26.5 mmol) of 1-bromo-2-nitrobenzene, 0.44 g (0.4 mmol) of tetrakis(triphenylphosphine)palladium, 30 ml of 2M Na2CO3, 40 ml of EtOH and 80 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. overnight. After finishing the reaction, the mixture was allowed to cool to room temperature. The solution was extracted with 250 ml of ethyl acetate and 500 ml of water. The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (Hx-EA) to give product 7.8 g (69%).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].CC(C)([O-])C.[K+].[F:38][C:39]([F:62])([F:61])[CH2:40][CH2:41][CH:42]([C:45]1[CH:46]=[N:47][C:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)=[CH:49][CH:50]=1)[CH:43]=O>C1(C)C=CC=CC=1>[CH3:2][O:3][C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:43]/[CH:42]([C:45]2[CH:46]=[N:47][C:48]([C:51]3[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:58])[F:59])=[CH:53][CH:52]=3)=[CH:49][CH:50]=2)[CH2:41][CH2:40][C:39]([F:38])([F:62])[F:61])=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(/C=C/C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
(4-Methoxycarbonyl-benzyl)-triphenyl-phosphonium chloride (6.7 g, 15 mmol) is suspended in anhydrous toluene (25 mL) and potassium tert-butoxide (1.7 g, 15 mmol) is added at room temperature in one portion. The mixture is allowed to stir under nitrogen for 1 h. Meanwhile, 5,5,5-trifluoro-2-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-pentanal (3.61 g, 10.0 mmol) is dissolved in another portion of the toluene (25 mL), and kept at room temperature. The mixture is then cooled to 0° C. with ice water, and then the ketone is transferred by cannula. The reaction is allowed to stir at 0° C. for 10 min, then the ice bath is removed. The reaction is allowed to warm to room temperature and monitored by HPLC. Upon complete conversion, the reaction is carefully quenched with saturated ammonium chloride solution, and diluted with ethyl acetate, then extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The cis and trans 4-{6,6,6-Trifluoro-3-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-hex-1-enyl}-benzoic acid methyl ester (2.0 g, 4.1 mmol) are isolated as pure regioisomers (1:1) after column chromatography, 31% total yield.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C(N(CC)CC)C>[C:2]1([C:1]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)c2ccccc2)CC1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3ccccc3)o2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a mixture of tert-butyl 4-[(2-benzoylhydrazino)carbonyl]piperidine-1-carboxylate (3.00 g) and THF (60 mL) were added triethylamine (7.2 mL) and toluenesulfonyl chloride (4.94 g), followed by stirring at 50° C. overnight. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain tert-butyl 4-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (2.84 g) as a colorless oily sub stance.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=[O:17]>C(O)(=O)C>[OH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][N:19]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:17]
Reactant: NNC(=O)c1ccccc1O
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccccc1O
Temperature: 100 °C
Yield: 84 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 344 mg of the title compound (84%) as a yellow solid in 98.5% purity by HPLC (Rt: 4.61, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C(N(CCCC)CCCC)CCC.I[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH2:26][C:27]([C:34]1[CH:43]=[CH:42][C:41]2[C:40]([CH3:45])([CH3:44])[CH2:39][CH2:38][C:37]([CH3:47])([CH3:46])[C:36]=2[CH:35]=1)=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:44][C:40]1([CH3:45])[CH2:39][CH2:38][C:37]([CH3:46])([CH3:47])[C:36]2[CH:35]=[C:34]([C:27]3([CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH3:33])[C:15]4[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=4[O:25][CH2:26]3)[CH:43]=[CH:42][C:41]1=2
Reactant: CCCCCC=C(COc1cc(C(=O)OC)ccc1I)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: CCCC=CCC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)COc2cc(C(=O)OC)ccc21
Temperature: 80 °C

Procedure:
A mixture of tributylamine (0.28 ml, 1.16 mmol), palladium diacetate (24 mg, 0.1 mmol) and methyl 4-iodo-3-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-octenyloxy]benzoate (610 mg, 1.06 mmol) in acetonitrile (15 ml) is heated at 80° C. for 24 h. The reaction medium is concentrated on a rotary evaporator under vacuum at 40° C. and then treated with 20 ml of water and ethyl ether. After separation of the phases by settling, the organic phase is washed twice with 20 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[CH3:29][N:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[CH3:31]>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:35]5[CH:36]=[CH:37][C:32]([N:30]([CH3:31])[CH3:29])=[CH:33][CH:34]=5)=[CH:3][C:4]([C:25]([F:28])([F:27])[F:26])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(N(C)C)cc3)c2[nH]1

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 4-(N,N-dimethylamino)phenylboronic acid (41 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 515 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2>>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 78 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 8 (49 mg, yield 78%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH:22]([F:24])[F:23])[CH:12]=2)([C:9]#[CH:10])[CH2:5][CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[F:23][CH:22]([F:24])[O:21][C:13]1[CH:12]=[C:11]([C:6]2([C:9]#[CH:10])[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]2)[CH:16]=[CH:15][C:14]=1[O:17][CH:18]([F:19])[F:20]
Reactant: C#CC1(c2ccc(OC(F)F)c(OC(F)F)c2)CCC(OC)(OC)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: C#CC1(c2ccc(OC(F)F)c(OC(F)F)c2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A mixture of 4-(3,4-bisdifluoromethoxyphenyl)-4-ethynylcyclohexan-1-one dimethyl ketal (0.2 g, 0.53 mmol) and p-toluenesulfonic acid (catalytic amount) in acetone (10 mL) was stirred under an argon atmosphere at room temperature for 0.5 h. The mixture was concentrated, was diluted with methylene chloride and was washed with water. The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo to provide an oil (0.17 g, 98%). Analysis Calc. for C16H14F4O3 : C 58.19, H 4.27; found: C 58.30, H 4.40.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.NC1CCC([OH:30])C1>>[CH3:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][CH:4]([OH:30])[CH2:5]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: NC1CCC(O)C1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccccn2)nc(NC2CCC(O)C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 3-aminocyclopentanol hydrochloride instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.50-1.58 (m, 1H), 1.70-1.78 (m, 3H), 1.96 (bs, 4H), 2.34 (s, 3H), 3.32 (s, 3H), 4.20-4.32 (m, 2H), 7.69-7.75 (m, 1H), 7.79-7.85 (m, 1H), 8.20-8.29 (m, 1H), 8.69 (bs, 1H); MS (ESI) m/z 314.8 (M+1)+.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])([O-])=O.[N:14]([Si](C)(C)C)=[N+:15]=[N-].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C1COCC1>[NH:1]1[CH:4]=[C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[N:15]=[N:14]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cccc(/C=C/[N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2c[nH]nn2)c1

Procedure:
3-[(E)-2-Nitroethenyl]benzonitrile (2.79 g, 16.0 mmol) and azidotrimethylsilane (2.76 g, 24.0 mmol) was stirred in anhydrous DMF (100 mL) at 50° C. To this was added tetrabutylammonium fluoride (17.6 mL of a 1.0M solution in THF, 17.6 mmol) via syringe pump over 20 min. The resulting reaction was quenched with MeOH (25 mL) and concentrated in vacuo to a volume of ca. 30 mL. The resulting crude mixture was dissolved in EtOAc (300 mL) and washed with H2O (2×100 mL). The product was then extracted from the EtOAc layer with 1M aqueous NaOH (4×75 mL). The combined basic aqueous portions were treated with 4M HCl to obtain an endpoint of pH=4, and the product was extracted into EtOAc (4×100 mL). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to obtain 3-(1H-1,2,3-triazol-4-yl)benzonitrile as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6](=O)[CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[CH3:2].CS(O)(=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CSc1cccc(OC)c1
Agent: CS(=O)(=O)O
Product: CCOC(=O)Cc1csc2cccc(OC)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
4-(3-methoxy-phenylsulfanyl)-3-oxo-butyric acid ethyl ester (10.9 g, 40.62 mmol) is added to methanesulfonic acid (26.6 mL, 406 mmol). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into ice-water (300 g) and extracted with EtOAc (100 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography eluting with 20% EtOAc/Hexanes. The appropriate fractions are combined and concentrated under reduced pressure to afford the title compound (6.00 g, 59%). ES/MS n/e 251.0 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[CH:22][CH:23]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1ccncc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 4 h
Yield: 89.9 %

Procedure:
In DMF (5 mL), 1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid (P. E. Maligres et al., Tetrahedron, 53:10983 (1997)) (1.00 g, 3.80 mmol), 4-aminopyridine (572 mg, 6.08 mmol), EDC (801 mg, 4.18 mmol), and HOAt (569 mg, 4.18 mmol) were combined and aged under N2 for 4 h. The reaction was partitioned between sat. NaHCO3 and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organics were washed with water and brine then dried over Na2SO4, filtered and concentrated under reduced pressure, affording 1.16 g of benzyl 4-[(4-pyridinylamino)carbonyl]-1-piperidinecarboxylate as a yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@:22]([CH2:27][CH:28]([F:30])[F:29])([OH:26])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].N[C@@H](CC1C=CC(OCCCC)=CC=1)C(OC(C)(C)C)=O.N[C@@H](CC1C=CC(OCCCC)=CC=1)C(OC)=O>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:31]=[CH:32]/[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39](=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C@:22]([CH2:27][CH:28]([F:30])[F:29])([OH:26])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(F)F)C(=O)O)C(=O)OC)cc1
Agent: CCCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Agent: CCCCOc1ccc(C[C@H](N)C(=O)OC)cc1
Product: CCCCCCCC(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)O)[C@@](O)(CC(F)F)C(=O)O

Procedure:
The title compound was synthesized by a method similar to that of No. 5509214, (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-(2,2-difluoro-ethyl)-2-hydroxy-12-oxo-nonadec-4-enoic acid, except that tert-butyl (S)-2-amino-3-(4-butoxy-phenyl)-propionate was used instead of No. 5509214, methyl (S)-2-amino-3-(4-butoxy-phenyl)-propionate.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([I:27])C(=O)C1>CC#N.CCOC(C)=O>[I:27][C:9]1[NH:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
The product of Step 1 (700 mg, 2.85 mmol) was dissolved in 10 mL of MeCN, to which was added NIS (770 mg, 3.42 mmol) and catalytic amount of TPA. After stirring at rt overnight, the reaction was diluted with EtOAc, washed with aq NaHCO3, aq Na2S2O3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give 770 mg of 4-(5-iodo-2-phenyl-1H-imidazol-4-yl)benzonitrile. LCMS: [M+1]=372.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:20][C:21]([F:24])([F:23])[F:22])=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:25]Br>C(Cl)(Cl)Cl.BrBr.C(Cl)Cl>[Br:25][C:11]1[C:12]([S:13]([C:16]([F:17])([F:19])[F:18])(=[O:15])=[O:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:10]=1[S:20][C:21]([F:24])([F:22])[F:23]
Reactant: O=S(=O)(c1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(c1c(-c2ccc(Cl)cc2)[nH]c(SC(F)(F)F)c1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]-5-[(trifluoromethyl)thio]pyrrole (0.5 g, 0.00122 mol) in chloroform (10 mL) is cooled with an ice bath, treated with a solution of bromine (0.21 g, 0.00134 mol) in chloroform (5 mL), stirred for two hours, warmed to room temperature, treated with two drops of additional bromine and stirred for one hour. The reaction mixture is diluted with methylene chloride, washed with water, saturated sodium hydrogen carbonate solution, saturated sodium metabisulfite solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a syrup. Flash chromatography of the syrup using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as a white solid (0.25 g, mp 122°-125° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[O:11])[C:5]#[N:6].P([O-])(O)(O)=[O:14].[K+].Cl([O-])=O.[Na+]>CS(C)=O.O>[C:5]([C:4]1[CH:3]=[C:2]([F:1])[C:9]([C:10]([OH:14])=[O:11])=[C:8]([F:12])[CH:7]=1)#[N:6]
Reactant: O=P([O-])(O)O
Reactant: N#Cc1cc(F)c(C=O)c(F)c1
Agent: [K+]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(C(=O)O)c(F)c1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 3,5-difluoro-4-formylbenzonitrile (0.2 g, 1.1 mmol) in dimethylsulfoxide (10 mL), were added a aqueous solution of potassium dihydrogen phosphate (0.41 g, 2.9 mmol in 0.4 mL of water), sodium chlorite (0.216 g, 2.3 mmol in 4 mL of water) in one lot at an ambient temperature. The resulting reaction mixture was stirred for about 1 hour. The reaction mass was diluted with water (100 mL). The aquoeus phase was extracted with ethyl acetate (3×100 mL). The combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-cyano-2,6-difluorobenzoic acid (200 mg, 91.32%).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([NH:25][NH2:26])[CH2:23][CH3:24]>CO>[C:1]1([CH:7]2[N:25]([CH2:22][CH2:23][CH3:24])[N:26]=[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][S:10][CH2:9][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccccc3)CSCC2C1c1ccccc1
Yield: 57.5 %

Procedure:
A mixture of 5.84g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one and 1.48g of n-propyl hydrazine in 100ml of methanol is heated at reflux temperature for 3 hours. Upon cooling, solids are collected and washed with methanol. Recrystallization from methanol gives 4.0g of material, melting point 111°-120°C. Two recrystallizations from acetonitrile yield 2.0g of the title compound, melting point 119.5°-122°C.
Reaction SMILES: [ClH:1].[C:2]1(=O)[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)N.CO>Cl>[ClH:1].[CH3:13][N:14]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]3)[C:2]1=2
Reactant: CN(N)c1ccccc1
Reactant: O=C1CCCC12CCNCC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccccc31)CCC21CCNCC1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 8-azaspiro[4,5]decane-1-one hydrochloride (5.2 g) in 95% ethanolic hydrochloric acid (30 ml) and 1-methyl-1-phenylhydrazine (5 g) was heated overnight on a steam bath, under nitrogen. The reaction mixture was cooled to ambient temperature, methanol was added and the mixture was concentrated in vacuo. The residue was flash chromatographed (silica gel) eluting with 10% methanol/dichloromethane. The appropriate fractions were collected and concentrated to afford 7.4 g (95%) of product, mp>270° C.