Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([NH:21][C@H:22]([C:44]([O-])=[O:45])[CH2:23][S:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl.[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH2:52].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH:52][C:44](=[O:45])[C@H:22]([CH2:23][S:24][C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:21][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A solution of compound (XX) (19.33 g, 30.0 mmol), glycine methyl ester hydrochloride (see Curtis and Goebel, J. Prakt. Chem., 37:150, (1888)) (3.47 g, 30.0 mmol) and N-hydroxysuccinimide (3.46 g, 30.1 mmol) was cooled to 0° C., then treated with a solution of DCC (6.87 g, 33.4 mmol) in CH2Cl2 (20 ml). The mixture was stirred, cold, for 30 minutes, then at room temperature for 3 hours. The precipitate was filtered off, washed with CH2Cl2, and the combined filtrate and washings were washed with 1M aqueous KHS04, 5% aqueous NaHCO3 and saturated brine, dried (MgSO4) and evaporated. Recrystallization of the resulting solid gave compound (XXI) (12.3 g, 77%), mp 167°-9°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[N:15]=[CH:16][CH:17]=[CH:18][C:11]=3[NH:10][C:9]2=S)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2ncccc2[nH]c(=S)n1-c1ccc(F)cc1
Product: O=c1c2ncccc2nc(Cl)n1-c1ccc(F)cc1
Temperature: 135 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(4-fluorophenyl)-2-thioxo-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one (2.6 g, 9.5 mmol) in 30 mL of POCl3 is heated to 135° C. and stirred for 2 days. After cooling to RT, the excess POCl3 is removed in vacuo, and the residue is azeotroped twice with toluene. The resulting sticky brown oil/solid mix is dissolved in CH2Cl2 and neutralized to pH 7-8 with saturated NaHCO3. The layers are separated, and the CH2Cl2 layer is dried (Na2SO4), filtered, and evaporated to give a brown sticky solid. Purification by column chromatography (gradient from CH2Cl2 to 20% EtOAc/CH2Cl2) affords the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (1H, m), 8.05 (1H, m), 7.74 (1H, m), 7.28 (4H, m).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([NH:20][CH3:21])=[O:19]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][CH:17]([C:18](=[O:19])[NH:20][CH3:21])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: CNC(=O)C(N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: CNC(=O)C(Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-N-methyl-3-phenyl-propionamide to provide the title compound in good yield. LCMS m/z 384 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][N:10]=[C:11]=[S:12].[Cl:13][C:14]1[C:15]([O:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.Cl>CN(C=O)C>[CH:9]([NH:10][C:11]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:15]2[C:14]([Cl:13])=[CH:19][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:17][N:16]=2)=[N:26]1)=[S:12])=[CH2:8]
Reactant: S=C=NCCBr
Reactant: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CNC(=S)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.1 %

Procedure:
Potassium carbonate (0.76 g, 5.5 mmol) and 2-bromoethyl isothiocyanate (0.83 g, 5 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (1.39 g, 5.0 mmol) in DMF (15 ml), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (30 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/20→1/10), to give a white solid of N-vinyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carbothioamide (0.11 g, yield: 5.0%). mp: 90-92° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.87 (d, J=0.8 Hz, 3H), 4.79 (d, J=8.6 Hz, 1H), 5.00 (dd, J=0.9 and 15.7 Hz, 1H), 6.19 (q, J=0.8 Hz, 1H), 7.45 (ddd, J=0.9, 8.6 and 15.7 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 8.36 (m, 1H), 10.15-10.55 (m, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[CH2:10][N:11]2[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14][N:13]([C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)[C:12]2=[O:30])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:37]([O:39]CC)=[CH2:38])CCC.C(=O)([O-])O.[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:37]([C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[CH2:10][N:11]2[C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:14][N:13]([C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[C:12]2=[O:30])=[CH:4][CH:3]=1)(=[O:39])[CH3:38]
Reactant: CC(C)C[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)Nc1ccc(Br)nc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=O)c1ccc(NC(=O)CN2C(=O)N(c3ccc(C(F)(F)F)nc3)C[C@@H]2CC(C)C)cn1
Temperature: 150 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A suspension of N-(6-bromopyridin-3-yl)-2-{(5S)-5-(2-methylpropyl)-2-oxo-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}acetamide (78 mg), tributyl(1-ethoxyvinyl)tin (145 mg), bis(triphenylphosphine)palladium(II) dichloride (22 mg), and copper(I) iodide (6.3 mg) in acetonitrile (1.5 mL) was stirred under irradiation with microwave at 150° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was separated by phase separation cartridge, and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC, 1M HCl (1.5 mL) was added to the resulting product, and the mixture was stirred at room temperature for 10 min. The mixture was made basic with saturated sodium hydrogen carbonate, followed by extraction with chloroform, and the solvent was distilled off under reduced pressure to afford the title compound (60 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][N:13]=1)[CH3:2].CC1(C)C(C)(C)OB([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[C:16]([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)[CH:15]=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OS(=O)(=O)C(F)(F)F)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(N)cc2)ccn1
Yield: 70.1 %

Procedure:
Compound II (52 mg, 0.109 mmol), Pd(PPh3)4 (12 mg, 0.011 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (48 mg, 0.218 mmol) and potassium carbonate (60 mg, 0.44 mmol) were stirred in toluene (3 mL) and water (1.5 mL) at 120° C. under microwave irradiation (300 W) for 30 min. The reaction mixture was then poured onto brine (50 mL) and extracted with EtOAc (2×20 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 0:100) to furnish III as a brown oil (32 mg, 70%).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1.C(N(CC)CC)C.[CH3:28][S:29]C>O1CCCC1.O>[CH3:28][S:29][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1
Reactant: Brc1cncc(C#Cc2ccccc2)c1
Reactant: CSC
Agent: CC(C)[Mg]Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CSc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.3 %

Procedure:
Add a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (0.96 mL, 1.94 mmol) to a solution of 3-bromo-5-phenylethynylpyridine, (prepared as described in EXAMPLE 9), (500 mg, 1.94 mmol) in anhydrous tetrahydrofuran (2 mL) and stir under nitrogen at room temperature for 2 h. Add triethylamine (0.27 mL, 1.94 mmol) and dimethyl sulfide (0.175 mL, 1.94 mmol). Stir for an additional 2 h, dilute with water, extract with dichloromethane, dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting from 100:0 to 100:50 with hexanes:ethyl acetate, to give the title compound (10.1 mg, 2.3%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li+].[OH-].Cl>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)/C=C/c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of intermediate methyl (2E)-3-(1H-indol-5-yl)acrylate obtained from step 1 (255 mg, 1.27 mmol) in MeOH/H2O 5:1 (10 mL) was added solid LiOH (532 mg, 12.7 mmol) and the reaction mixture was stirred at room temperature overnight. The solution was acidified (pH ˜1) with HCl 1N and then extracted with ethyl acetate. The organic layer was washed with H2O (×3), then dried over sodium sulfate, filtered and evaporated under reduced pressure to give 0.24 g of intermediate E (2E)-3-(1H-indol-5-yl)acrylic acid (94% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][N:15]2[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]2)=[O:13])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][N:15]2[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20]2)=[O:13])=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)NN2CC=CCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(C(=O)O)cc1)NN1CC=CCC1
Yield: 56.6 %

Procedure:
To a solution of N-[[(4-methoxycarbonylphenyl)-carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.21 g) in a mixture of methanol (30 ml) and chloroform (30 ml) was added. 1N sodium hydroxide (10 ml) and the mixture was stirred at ambient temperature for 18 hours. After evaporation of the solvent, the residue was extracted with chloroform (20 ml×3). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (40 g) eluting with chloroform, to give N-[[(4-carboxyphenyl)-carbamoyl]amino]-1,2,3,6-tetrahydropyridine (0.65 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.NO.Cl.CC[N:22](CC)CC>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH2:22])[CH3:15])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(N2CCOCC2)c1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC(N)c1cc(F)cc(N2CCOCC2)c1
Reaction time: 16 h

Procedure:
A mixture of 1-(3-fluoro-5-morpholin-4-yl-phenyl)ethanone (2.23 g), NH2OH.HCl (1.4 g), and Et3N (2.8 mL) in EtOH (20 mL) was refluxed for 3 hours. After concentration, the residue was extracted with CH2Cl2. The organic layer was washed with water, dried over MgSO4 and concentrated in vacuo. A suspension of the resulting residue (2.23 g) and Ra—Ni (1 mL) in a mixture of 3 mL of 30% ammonium hydroxide and 15 mL of MeOH was hydrogenated at 50 psi for 16 hours. The crude reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography (10% ammonium hydroxide in methanol) to give 1.665 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:12]=1)[CH3:2]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2ccc(Cl)cc2)n1
Yield: 28.1 %

Procedure:
A stirred mixture of 8.0 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 3.8 g of p-chloroaniline and 3.2 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate until precipitation resulted. Recrystallization of this material from 95% ethanol afforded 3.0 g of product, mp. 109°-112°C.
Reaction SMILES: [CH:1]1([C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[Mg]>CO.Cl>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)C=C(c1ccc(Cl)cc1)C1CC1
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: COC(=O)CC(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 62.3 %

Procedure:
A mixture of 17.0 grams (0.072 mole) of methyl 3-cyclopropyl-3-(4-chlorophenyl)propenoate and 4.3 grams (0.18 mole) of magnesium in 250 ml of methanol was stirred at ambient temperature for about 3.5 hours. After this time the reaction mixture was carefully diluted with aqueous 3N hydrochloric acid. The mixture was extracted with diethyl ether. The combined ether extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under vacuum, yielding 10.7 grams of methyl 3-cyclopropyl-3-(4-chlorophenyl)propanoate; b.p. 91-97° C./0.10 mm. The spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:17](=[S:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)[C:15](=[O:31])[C:11]32[CH2:14][CH2:13][CH2:12]3)=[CH:6][CH:5]=1.[CH3:33][NH2:34]>>[CH3:33][NH:34][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:17](=[S:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:20]=3)[C:15](=[O:31])[C:11]32[CH2:12][CH2:13][CH2:14]3)=[CH:6][CH:5]=1
Reactant: CN
Reactant: COC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Reaction time: 15 h
Yield: 84 %

Procedure:
A mixture of 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-benzoic acid methyl ester (51b) (0.046 g, 0.1 mmol) and methylamine (1 ml distilled from its 40% aqueous solution) was kept at −20° C. for 15 hours. After evaporation of the methylamine, the mixture was chromatographed (dichloromethane:acetone, 80:20) to yield N-methyl-4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]benzamide (51c) [RD161] (0.041 g, 0.085, 84%), the structure of which is illustrated in Formula 27.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[CH:48]1([CH2:51][C:52]([C:55]2[N:59]=[C:58]([CH3:60])[O:57][N:56]=2)([NH2:54])[CH3:53])[CH2:50][CH2:49]1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:54][C:52]([C:55]3[N:59]=[C:58]([CH3:60])[O:57][N:56]=3)([CH3:53])[CH2:51][CH:48]3[CH2:49][CH2:50]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: CC(CF)Oc1cc(C(=O)O)ncc1C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OC(C)CF)c(C3CC3)cn2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer A) (example 287e, 0.08 g, 334 μmol) in dry DMF (2 ml) was added TBTU (113 mg, 351 μmol) and triethylamine (102 mg, 140 μl, 1.00 mmol). The reaction was stirred at room temperature for 30 minutes followed by addition of 1-cyclopropyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (example 66e, 72.8 mg, 334 μmol). The reaction was then stirred at room temperature overnight. The reaction was diluted with ethyl acetate and extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to give the a mixture of epimers. The epimers were then separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the second epimer collected (23 mg, 17%); MS (ESI, m/z): 403.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:5][NH:6][C:7](=[S:12])[NH:8][NH:9][CH:10]=O.[O-]CC.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:5][N:6]1[CH:10]=[N:9][N:8]=[C:7]1[SH:12]
Reactant: O=CNNC(=S)NCc1cc(F)cc(F)c1
Agent: CC[O-]
Agent: [Na+]
Product: Fc1cc(F)cc(Cn2cnnc2S)c1
Yield: 70.9 %

Procedure:
The crude 4-(3',5'-difluorobenzyl)-1-formyl-3-thiosemicarbazide (3.5 g) was refluxed overnight in a solution of sodium ethoxide (from sodium (0.3 g) in ethanol (25 ml.)). The reaction was filtered, evaporated to dryness, and diluted with water. The aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid, and the precipitate was collected by filtration and recrystallized from ethanol-water to yield 2.3 g (71%) of 4-(3',5'-difluorobenzyl)-1,2,4-triazole-3-thiol after recrystallization from water, m.p.: 129°-130° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Br[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(#N)C>[CH:1]1([NH:4][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: CC#N
Product: CCOC(=O)C(NC1CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
Cyclopropylamine (0.30 mL) was added to an acetonitrile (10 mL) solution of diethyl bromopropanedioate (1.0 g), and the mixture was stirred for 16 hours at room temperature. The precipitated solid was filtered out, and the filtrate was concentrated under reduced pressure. Then, the resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=90/10→70/30) to obtain diethyl (cyclopropylamino)propanedioate (colorless oil) (0.57 g, 63%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([CH3:40])[CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:39])([F:38])[F:37]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccc(S(N)(=O)=O)c4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1 H-imidazol-4-yl}-benzenesulfonamide (0.128 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as an off-white solid (0.077 g, 15%). MS (ISN) 526.4 [(M−H)−]; mp 180° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112 %

Procedure:
To a stirred solution of ethyl 2-(4-(benzyloxy)phenyl)acetate (20 g, 0.07 mol) in EtOH (300 mL) was added a solution of KOH (20.7 g, 0.37 mol) in water (100 mL) at RT. The reaction mixture was then stirred for additional 1 h at RT and then concentrated in vacuo. The residue was acidified to pH˜2 using 2 N HCl and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to afford 2-(4-(benzyloxy)phenyl)acetic acid (19 g, 98%) as a solid.
Reaction SMILES: [Na+].[C:2]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([S:16]([O-:19])(=O)=[O:17])=[CH:13]2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3].P(Cl)(Cl)([Cl:22])=O>CC(N(C)C)=O>[Cl:22][S:16]([C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][C:6]([NH:5][C:2](=[O:4])[CH3:3])=[CH:15]2)=[CH:10][CH:11]=1)(=[O:19])=[O:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3.6 g (12.5 mmol) of compound 130 was added 100 mL of phosphorous oxychloride. Then, 4 mL of dimethylacetamide was added dropwise. The reaction was allowed to stir at ambient temperature for 5 hours and then was poured onto 2 L of ice. After the ice had melted, the solid precipitate was collected by vacuum filtration and was washed with water. After drying in vacuo, this provided 3.4 g of compound 131.