Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]([F:15])([F:14])[F:13])#[N:2].[Br:16]Br>C(O)(=O)C>[Br:16][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([C:12]([F:15])([F:13])[F:14])=[C:3]2[C:1]#[N:2]
Reactant: BrBr
Reactant: N#Cc1c(C(F)(F)F)[nH]c2ccccc12
Solvent: CC(=O)O
Product: N#Cc1c(C(F)(F)F)[nH]c2ccc(Br)cc12
Yield: 65 %

Procedure:
A solution of 3-cyano-2-(trifluoromethyl)indole (1.05 g, 5.0 mmole) in acetic acid is treated with Br2 (0.6 mL, 6.0 mmole) at room temperature, and stirred until reaction is complete by TLC. The reaction mixture is worked up as described in Example 22 to afford the title product as a white solid after chromatography (silica gel and 4:1 hexanes:ethyl acetate) and crystallization, 0.95 g (65% yield), mp 188°-191.5° C., identified by IR, 1HNMR, 19FNMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH:22]2[CH2:24][CH2:23]2)[C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([C:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])([CH3:29])[CH3:28])#[N:26].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([N:8]([CH:22]3[CH2:24][CH2:23]3)[C:4]3[CH:3]=[C:2]([NH:1][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][CH:38]=[C:30]([C:27]([C:25]#[N:26])([CH3:28])[CH3:29])[CH:31]=4)[CH:7]=[CH:6][CH:5]=3)[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc2cnc(N(c3cccc(N)c3)C3CC3)nc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(c3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)C3CC3)nc2s1
Yield: 58.7 %

Procedure:
A solution of N-{5-[(3-aminophenyl)(cyclopropyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 353 μmol), 3-(1-cyano-1-methylethyl)benzoic acid (80 mg, 424 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (201 mg, 530 μmol) in pyridine (3 mL) was stirred at 60° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→95/5), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (106 mg, 59%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1)=[O:7])[CH3:2].[CH2:17]([NH2:20])[C:18]#[CH:19].C(=O)([O-])[O-].[K+].[K+].[F-].[K+]>CS(C)=O.O>[CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:20][CH2:17][C:18]#[CH:19])=[CH:10][CH:9]=1)=[O:7])[CH3:2]
Reactant: CCN(CC)CCC(=O)c1ccc(F)cc1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCNc1ccc(C(=O)CCN(CC)CC)cc1

Procedure:
3-(Diethylamino)-1-[4-fluorophenyl]-1-propanone (Pharmazie, 35, H.7 (1980)), 5 g (0.022 mol), is treated with a mixture of propargylamine, 2.47 g (0.045 mol), potassium carbonate, 3.09 g, and potassium fluoride, 1.3 g (0.022 mol), in dimethylsulfoxide between 50° and 100° C. until TLC shows formation of the aminated product is complete. The reaction is poured into water and the solid is collected. Chromatography of the crude material over silica gel affords the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:25][CH:26]=1
Reactant: Ic1ccc(N(Cc2ccccn2)c2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccccn2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 90.3 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (124 mg) was reacted with N-(4-iodophenyl)-N-((pyridin-2-yl)methyl)pyrimidin-2-amine (159 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyridin-2-ylmethyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (208 mg). Column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=1/1→1/2) was used for purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([S:12]C(=O)N(C)C)[CH:5]=1.CO[Na]>C1COCC1.Cl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([SH:12])[CH:5]=1
Reactant: COC(=O)c1ccc(OC)c(SC(=O)N(C)C)c1
Agent: CO[Na]
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(S)c1
Temperature: 25 °C
Yield: 107.5 %

Procedure:
To a stirred solution of 3-dimethylcarbamoylthio-4-methoxybenzoic acid methyl ester (530 mg, 1.97 mmol) in THF (10 mL), was added MeONa (10 mL, 0.5 M solution in MeOH). The resulting mixture was heated to reflux for 3 h and then cooled to room temperature. The reaction mixture was diluted with 1N HCl aqueous solution (100 mL), extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo to afford 3-mercapto-4-methoxybenzoic acid methyl ester (0.42 g). The product was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][CH:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11].[N+]([O-])(O)=O.C[C:31]1C=C(C)[N:33](C(N)=N)[N:32]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[NH2:33][N:32]=[CH:31][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][CH:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CCOC(=O)CC(NC(=O)NCCCCCCCN)c1cccnc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=[N+]([O-])O
Product: CCOC(=O)CC(NC(=O)NCCCCCCCNC=NN)c1cccnc1
Yield: 74.3 %

Procedure:
Ethyl β-[[[[7-aminoheptyl]amino]carbonyl]amino]-3-pyridinepropanoate (1.2 g; 3 mmoles), 3,5-dimethylpyrazole-1-carboxamidine nitrate (2.6 g; 13.3 mmoles) and diisopropylethylamine (3.74 g; 28.7 mmoles) were stirred in dioxane (25 ml) and water (10 ml) for 22 hrs. The mixture was taken down to dryness under reduced pressure and the residue was purified by HPLC using a linear gradient of 5-45% acetonitrile/water/trifluoroacetic acid. The desired fractions were collected and lyophilized to give 875 mg of clear oily material. FAB-MS: MH+ =393.2. Elemental analysis: C19H32N6O3 ·CF3COOH·4H2O
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:26]([C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1>C(O)(=O)C.O=[Pt]=O>[N:31]1[CH:32]=[C:27]([C:26]2[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[N:8][CH:9]=[C:10]([CH:25]=2)[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=2)=[O:12])[CH:28]=[N:29][CH:30]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C2=CCOCC2)c(-c2cncnc2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(C2CCOCC2)c(-c2cncnc2)c1
Reaction time: 67 h

Procedure:
A solution of 6-(3,6-dihydro-2h-pyran-4-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 44, 80 mg, 0.180 mmol) in acetic acid (5 mL) was hydrogenated in the presence of PtO2 (16 mg) at RT and atmospheric pressure for 67 h. The RM was filtered through Celite® and the solvent was evaporated off under reduced pressure to give the crude product which was purified by reverse phase chromatography (MPLC, Lichroprep® 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 5% to 39% MeCN+0.1% formic acid). Fractions containing the pure product were combined, basified with NaHCO3 and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative TLC (Silica gel 60 F 254, 0.5 mm, eluent was DCM/MeOH 19:1). The product was dissolved with MeCN, filtered and the filtrate was evaporated off under reduced pressure to afford the title compound as white crystalline solid. HPLC (Condition 3) tR=5.09 min, UPLC-MS (Condition 2) m/z=444.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.65 (m, 2H) 1.85-2.02 (m, 2H) 2.88-3.03 (m, 1H) 3.19-3.28 (m, 2H) 3.80-3.93 (m, 2H) 7.37 (d, J=8.99 Hz, 2H) 7.86 (m, J=9.00 Hz, 2H) 8.23 (d, J=1.96 Hz, 1H) 8.96 (s, 2H) 9.15 (d, J=1.95 Hz, 1H) 9.30 (s, 1H) 10.56 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:4]=1[CH:5]=[O:6].F[B-](F)(F)F.[O:23]=[N+:24]=[O:25].O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:10]([N+:24]([O-:25])=[O:23])=[CH:9][C:8]([C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(C2(C)CCOCC2)cc1C=O
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C=O)cc(C2(C)CCOCC2)cc1[N+](=O)[O-]
Temperature: -40 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of the crude product containing 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzaldehyde (0.719 g) in ethyl acetate (10.0 mL) was cooled to −40° C., and nitronium tetrafluoroborate (0.597 g, 4.49 mmol) was added thereto. The resulting mixture was stirred for 2 hours while raising the temperature to −10° C. Water was added to the reaction solution and the resulting solution was diluted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure, and the obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=90/10-30/70) to obtain 0.644 g of the captioned compound (92% yield in 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:21]=[CH:20][C:19]=1[NH2:33].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:33][C:19]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][C:18]=2[O:17][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1cc(OCCN2CCCCC2)ccc1N
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OCCN3CCCCC3)cc2OC)c1C(=O)OC
Yield: 78 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 2-methoxy-4-(2-piperidin-1-yl-ethoxy)-phenylamine (0.78 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 20 hours. The reaction mixture was cooled, diluted with CH2Cl2 (15 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (25 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 1.1 g of the product at 95:5 methylene chloride-methanol, in 78% yield; 1H NMR (DMSO-d6) δ 1.47-1.49 (m, 2H), 1.57-1.64 (m, 4H), 2.50-2.53 (m, 4H), 2.78 (t, J=6.2 Hz, 2H), 3.81 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 4.10 (t, J=6.2 Hz, 2H), 6.46 (dd, J=8.7 Hz, J=2.7 Hz, 1H), 6.56 (d, J=2.7 Hz, 1H), 6.98 (dd, J=7.2 Hz, J=1.2 Hz, 1H), 7.09-7.16 (m, 2H), 7.21-7.23 (m, 1H), 7.92 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][C:24]([NH2:26])=[O:25])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.[CH:27]([NH2:30])([CH3:29])[CH3:28]>O1CCOCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH2:23][C:24]([NH2:26])=[O:25])[N:10]=2)[CH:5]=[N:6][C:7]=1[NH:30][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)N
Reactant: NC(=O)Cn1ccc2c(-c3noc(-c4cnc(Cl)c(Cl)c4)n3)cccc21
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(C)Nc1ncc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1Cl
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a mixed solution of 2-{4-[5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (100 mg) in dioxane (2 ml) and NMP (2 ml) was added isopropylamine (2200, followed by stirring at 150° C. for 1 hour in a microwave reaction vessel. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (n-hexane:EtOAc=40:60 to 0:100), and the obtained residue was suspended in diisopropyl ether under heating, and collected by filtration to obtain 2-(4-{5-[5-chloro-6-(isopropylamino)pyridin-3-yl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (62 mg) as white powders.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51]1>CN(C=O)C>[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51]1
Reactant: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(c4)OCO5)c3)c(=O)oc12
Temperature: 25 °C
Yield: 79.1 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Benzo[1,3]dioxol-5-yl-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 77% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:22])([CH3:21])[C:19]#[N:20].[CH:23]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=2)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:25][CH2:24]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[C:19]([C:18]([CH3:22])([CH3:21])[CH2:17][C:11]1[CH:12]=[C:13]([O:16][CH2:39][C:35]2[CH:34]=[C:33]([CH:26]([CH:23]3[CH2:24][CH2:25]3)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:38]=[CH:37][CH:36]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])#[N:20]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C#N)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C#N)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 3-(2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl)-2,2-dimethylpropanenitrile (136 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (136 mg) and tributylphosphine (0.22 mL) in toluene (5.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (225 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (203 mg) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[O:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Na+].C(Cl)Cl.Cl>C1COCC1.CCO>[CH2:37]([N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)=[O:27])[CH3:38]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccc(O)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccc(O)cc1
Reaction time: 2.5 h

Procedure:
{2′-[1-Ethyl-3-(4-hydroxy-benzyl)-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}acetic acid ethyl ester (0.535 g, 0.98 mmol) in THF (5 mL) and EtOH (4 mL) was treated with 1N aqueous NaOH (3 mL), and the reaction was stirred for 2.5 hours. Analytical LCMS indicated that starting material was still present, so additional 1N aqueous NaOH was added, and the reaction was heated with a heat gun. Once no starting material was seen by analytical LCMS, the mixture was worked-up with CH2Cl2 and 1N aqueous HCl, and the organic layer was dried over MgSO4, filtered, and concentrated to give the title compound. M+H is 517.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][C:17]([O:19]C)=O)[CH2:4][CH2:3]1.[OH-].[Na+]>CO.CO.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:15][CH2:16][C:17]2=[O:19])[CH2:4][CH2:3]1
Reactant: COC(=O)CCc1ccccc1NC1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 3-(2-(1-methylpiperidin-4-ylamino)phenyl)propanoate (1.1 g, 3.98 mmol) in 20 mL MeOH/5 mL H2O was treated with 1N NaOH (8.8 mL, 8.76 mmol) and stirred at room temperature for 2 hours. The mixture was concentrated and made acidic with 6N HCl. Approximately half of this mixture was diluted with 1N HCl (15 mL) and heated at 110° C. overnight. After cooling, the mixture was concentrated on the rotoevaporator then made basic with saturated Na2CO3. This solution was extracted with 2×100 mL CH2Cl2. The combined organic fractions were dried over MgSO4, filtered and concentrated to give a light brown residue, which was subjected to flash chromatography on silica gel using 5%, 2M NH3 in MeOH/CH2Cl2. A light yellow solid was obtained (320 mg, 78.2%). 1H-NMR (CDCl3) δ 7.24-7.16 (m, 3H), 7.02-6.97 (m, 1H), 4.47-4.34 (m, 1H), 2.99-2.95 (m, 2H), 2.83-2.70 (m, 2H), 2.68-2.55 (m, 4H), 2.33 (s, 3H), 2.13-2.06 (m, 2H), 1.72-1.69 (m, 2H). MS (ESI): 245.2 (M+1, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([C:9]([C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=2)=[O:11])[CH2:26][CH2:27]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Product: CC(=O)Nc1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)cc1
Yield: 99.7 %

Procedure:
Using 4-(acetylamino)benzoic acid (179 mg) and 1-(2,4-dimethylphenyl)piperazine (190 mg) and by the reaction and treatment in the same manner as in Example 93, the title compound (350 mg) was obtained.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]([S@@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>O1CCOCC1.[Cl-].[Na+].O>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:21][S@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[S@](=O)N=C(c1ccccc1)c1ccccc1
Temperature: 105 °C
Reaction time: 0.17 h

Procedure:
In a flame dried flask under N2, benzophenone (0.514 g, 2.82 mmol) was dissolved in anhydrous dioxane (5 mL). Ti(IV) ethoxide (1.479 mL, 7.05 mmol) was added followed by (S)-(−)-2-methyl-2-propanesulfinamide (0.376 g, 3.10 mmol). The rxn was heated to 105° C. After 4.5 hr the reaction was cooled to RT and brine (15 mL) was added. A precipitate formed and the reaction was rapidly stirred for 10 min. The suspension was filtered through celite and the filter cake was washed with brine and ethyl acetate. The layers of the filtrate were separated. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow oil. The oil was purified by flash column chromatography (90:10 hexanes/ethyl acetate). The fractions were combined and concentrated in vacuo to afford (S)-N-(diphenylmethylene)-2-methylpropane-2-sulfinamide as a light yellow oil. 1H NMR (CDCl3) δ 7.51-7.43 (broad m, 10H), 1.30 (s, 9H). [M+H]+=286.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]([SH:9])[N:4]=[N:5][C:6]=1[NH:7][NH2:8].[C:10]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O)(=O)[CH3:11].Cl>C(O)C>[NH2:1][CH:2]1[C:6]([N:7]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[C:10]([CH3:11])=[N:8]2)=[N:5][NH:4][N:3]1[SH:9]
Reactant: NNc1nnn(S)c1N
Reactant: CC(=O)C1CCCCC1=O
Agent: Cl
Solvent: CCO
Product: Cc1nn(C2=NNN(S)C2N)c2c1CCCC2
Yield: 9.5 %

Procedure:
4-Amino-5-hydrazino-3-mercapto-1,2,3-triazole (7.3 g, 0.05 mol), 7.0 g (0.05 mol) acetyl cyclohexanone, 1.25 ml concentrated hydrochloric acid, and 350 ml ethanol are refluxed for 3 hours, evaporated to dryness, and recrystallized from ethyl acetate to give 1.2 g of white crystals, m.p. 201°-2°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][OH:15].C(OCC)(OCC)OCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>[CH2:1]([O:8][CH2:9][C:10]1([CH3:11])[O:15][CH2:14][CH2:13][O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: CC(=O)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(OCC)OCC
Product: CC1(COCc2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 61.5 h
Yield: 90.5 %

Procedure:
A mixture of 1-benzyloxy-2-propanone (4.94 g, 30.1 mmol), ethylene glycol (20 ml, 359 mmol), triethyl orthoformate (5 ml, 30.1 mmol), and p-toluenesulfonic acid monohydrate (130 mg, 0.683 mmol) was stirred at room temperature for 61.5 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (20 ml) was added and the mixture was extracted twice with chloroform (50 ml) and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 4/1 gradient). Desired fractions were concentrated to obtain the title compound (5.67 g, 90.5% yield) as a colorless oil.