Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([CH3:40])[C:38]=1O)[C:34]#[N:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]3)[CH2:14][O:15][C:38]3[C:37]([CH3:40])=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=3[CH3:30])[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: Cc1cc(C#N)cc(C)c1OCC(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-ethanol, 3,5-dimethyl-4-hydroxybenzonitrile (commercially available), tri-n-butylposphine and N′N′N′N-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of a gradient of heptane:ethyl acetate (100:0 to 60:40). Light yellow solid (27%). MS (Turbo Spray): m/z=556.178 [M+H].
Reaction SMILES: O.[O:2]=[C:3]1[CH:11]([Br:12])[CH2:10][CH2:9][C:8]2[N:7]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:6]=[CH:5][C:4]1=2.[Cl:22][CH2:23][CH:24](O)[CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:22][CH2:23][CH:24]1[CH2:25][O:26][C:3]2([CH:11]([Br:12])[CH2:10][CH2:9][C:8]3[N:7]([S:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH:6]=[CH:5][C:4]2=3)[O:2]1
Reactant: O=C1c2ccn(S(=O)(=O)c3ccccc3)c2CCC1Br
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c1CCC(Br)C21OCC(CCl)O1
Yield: 97 %

Procedure:
In a three necked flask equipped with a thermometer, a stirrer and a reflux condenser having Widmer-type water trap filled with Molecular Sieves are placed 4-oxo-5-bromo-1-benzenesulfonyl-4,5,6,7-tetrahydroindole (100 parts), 3-chloro-1,2-propanediol (311 parts), p-toluenesulfonic acid monohydrate (3 parts) and toluene (4500 parts), and the mixture is refluxed for 7 hours 20 minutes while drying the refluxing azeotropic mixture. After cooling, the reaction mixture is adjusted to pH 9 with 2.5N aqueous sodium hydroxide with stirring, and the formed toluene layer is separated. The water layer is washed with benzene (200 parts). Toluene layer and benzene washing are combined, washed twice with water (500 parts) and dried over anhydrous sodium sulfate (500 parts). The drying agent is filtered off, and the filtrate is concentrated under reduced pressure. The obtained residue (143 parts) is dissolved in benzene (300 parts), stirred with active charcoal (50 parts) for 30 minutes and filtered through a filter-bed of siliceous earth. The filtrate is concentrated under reduced pressure, and stirring of resulted residue with a small amount of ether and hexane affords amorphous powder. This is collected by filtration, washed with a mixture of ether and hexane, and dried to give 4'-chloromethyl-5-bromo-1-benzenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]-dioxolane diastereomer mixture (122 parts) in 97% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:34][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56](Br)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:60][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>O.CCOC(C)=O.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:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:22]4[CH:21]=[CH:20][C:19]([C:16]5[NH:15][C:14]([CH:13]6[CH:12]7[CH2:34][CH:9]([CH2:10][CH2:11]7)[N:8]6[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:18][CH:17]=5)=[CH:24][CH:23]=4)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:60][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
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: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 80 °C
Yield: 6.1 %

Procedure:
To the solution of 3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (560 mg, 1.22 mmol) and 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (535 mg, 1.28 mmol) in 1,2-dimethoxyether (11 ml) and water (3.5 ml) was added sodium bicarbonate (343 mg, 4 mmol), followed by Pd(PPh3)4 (55 mg). The mixture was heated at 80° C. for 7 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/MeOH) gave 4,4′-bis-[2-(2-tert-butoxycarbonyl-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-imidazol-4-yl]-biphenyl (50 mg). m/z: 677.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(O[I:16](OC(=O)C)([O-])(=O)=O)(=O)C.C([N+](CC)(CC)CC)C>ClCCl>[OH:1][C:2]1[C:9]([I:16])=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(=O)O[I+2]([O-])([O-])([O-])OC(C)=O
Reactant: COc1ccc(O)c(C=O)c1
Agent: CC[N+](CC)(CC)CC
Solvent: ClCCl
Product: COc1cc(I)c(O)c(C=O)c1
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To a solution of 2-hydroxy-5-methoxy-benzaldehyde (15.97 g, 104.9 mmole) in 375 mL dichloromethane at −15° C. was added tetraethylammonium diacetoxyiodate (48.06 g, 128.1 mmole) over 15 minutes. After stirring overnight, an additional amount of tetraethylammonium diacetoxyiodate (46.93 g, 125.1 mmole) was added over 15 minutes. The reaction was stirred for an additional 12 hours, concentrated, and added to 2N HCl. The mixture was extracted into ethyl acetate and the combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated in vacuo and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 3.47 g (11.9%) of iodide as a yellow solid: Mp=103–105° C.; 1H NMR (DMSO-d6) δ 11.3 (s, 1H), 9.73 (s, 1H), 7.60 (d, 1 H, J=3.0 Hz,), 7.07 (d, 1 H, J=3.1 Hz), 3.83 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH3:16])[CH3:15])[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:15][N:14]([CH3:16])[CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CN(C)C1CCCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C1CCCNC1

Procedure:
A mixture of 1-benzyl-3-dimethylaminopiperidine and 0.5 g. of 10 percent palladium on carbon in 100 ml. of methanol was heated to ca. 56°C. and shaken under ca. 40 psi of hydrogen until uptake ceased. The catalyst was filtered, and the solvent distilled at atmospheric pressure. Distillation of the residue afforded 3-dimethylaminopiperidine, b.p. 87°-89°C./28 mm.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([CH3:13])=[C:5]([C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])[CH:6]=[O:7].Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22]>CO.C1(C)C=CC=CC=1>[CH3:13][C:4]1[C:3]([O:2][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])=[C:10]([CH3:11])[CH:9]=[C:8]([CH3:12])[C:5]=1[CH:6]=[O:7]
Reactant: Cc1cc(C)c(C=O)c(C)c1O
Reactant: O=C1NCCN1CCCl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(C)c(OCCN2CCNC2=O)c(C)c1C=O

Procedure:
To a solution of sodium (1.63 g, 0.071 mol) in methanol (60 mL) is added dropwise 3-hydroxy-2,4,6-trimethylbenzaldehyde (11.90 g, 0.073 mol) in anhydrous toluene (300 mL). The mixture is heated under reflux and then the methanol is distilled off (volume of azeotropic mixture collected 80-90 mL). After returning to 80-90° C., (2-chloroethyl)imidazolidin-2-one (10.45 g, 0.070 mol) is added all at once to the reaction medium. After heating for 7 hours under reflux, the solvents are evaporated under reduced pressure (Tbath 50° C., 25 mbar). Dichloromethane (150 mL) and water (30 mL) are added to the mixture obtained. The organic phase is then washed twice with water (20 mL). After drying over Na2SO4, the dichloromethane is evaporated under reduced pressure (Tbath 35° C., 33 mbar). Petroleum ether (3 times 50 mL) and water (50 mL) are added to the mixture obtained (24 g) and the precipitate obtained is filtered and washed on the filter with water (15 mL) and petroleum ether (twice 15 mL).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 108.2 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (50 g, 0.2 mol), triethylamine (50.5 g, 0.5 mol) in DCM was added methanesulfonyl chloride (28 g, 0.25 mol) in portions and the reaction mixture was stirred at 0° C. for 20 min and at RT for 1.5 h, and washed with citric acid solution and water. The organic layer was dried over sodium sulfate and concentrated to give the title intermediate (70 g, 97% yield). 1H NMR (CDCl3, 400 MHz) δ (ppm) 5.23 (m, 1H), 4.44 (m, 1H), 3.75 (m, 5H), 3.04 (s, 3H), 2.64 (m, 1H), 2.26 (m, 1H), 1.43 (m, 9H).
Reaction SMILES: CN1CCOCC1.Cl[C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([S:15]([O:18][C:19]2[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([CH3:25])[CH:24]=2)(=[O:17])=[O:16])[CH:14]=1>[Pd].CO>[CH3:28][O:27][C:12]1[CH:11]=[CH:10][CH:9]=[CH:14][C:13]=1[S:15]([O:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[C:23]([CH3:25])[CH:24]=1)(=[O:16])=[O:17]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: [Pd]
Solvent: CN1CCOCC1
Solvent: CO
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Yield: 63 %

Procedure:
4-Methylmorpholine (3.2 mL, 29.1 mmol) was added to a mixture of 3-(5-chloro-2- methoxyphenylsulfonyloxy)-5-methylphenol (8.82 g, 26.8 mmol, as prepared in the preceding step) and 10% palladium on carbon (2.23 g) in deoxygenated methanol (15 mL). The mixture was hydrogenated (atmospheric pressure) at ambient temperature for 3 h then filtered through Celite with methanol. Solvent was removed in vacuo and the crude product was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound (4.97 g, 63%) as a colorless syrup. 1H-NMR (300 MHz, DMSO-d,) δ 9.71 (s, 1 H), 7.76 (ddd, 1 H, J=1.7, 7.4, 8.4 Hz), 7.69 (dd, 1 H, J=1.7, 7.9 Hz), 7.38 (d, 1 H, J=8.4 Hz), 7.09 (dt, 1 H, J=1.0, 7.9 Hz), 6.48 (br s, 1 H), 6.33 (br s, 1 H), 6.26 (t, 1 H, J=2.2 Hz), 4.00 (s, 3 H), 2.15 (s, 3 H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C14H14O5S: 317.0 (M+Na). Found: 316.9
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:30][CH3:31])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCI
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC(F)F
Temperature: 70 °C
Yield: 23.2 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and ethyl iodide (153 mg, 0.98 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 23%).
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=O)C.[NH3:29]>C(O)C>[C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)(=[O:3])[NH2:29]
Reactant: N
Reactant: CCOC(=O)Cc1ccc(OCC(O)CNC(C)CCc2ccccc2)cc1
Solvent: CCO
Product: CC(CCc1ccccc1)NCC(O)COc1ccc(CC(N)=O)cc1
Reaction time: 240 h
Yield: 57 %

Procedure:
In this example, 1.7 g of 1-(4-ethoxycarbonylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol (Compound 14) is dissolved in 100 ml of ethanol and the solution is poured into a pressure tube. Then, 100 ml of liquid ammonia is added thereto. The tube is sealed and is allowed to stand for 10 days at room temperature. After completion of the reaction, ethanol is distilled away from the solution under reduced pressure. The residue is recrystallized from methylisobutylketone to obtain 0.9 g of 1-(4-carbamoylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol. (Yield: 57%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][CH2:18][CH2:19][OH:20].[OH-].[Na+]>C(O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2ccc(CCCO)cc2)cc1
Reaction time: 40 h

Procedure:
4'-Cyano-4-hydroxybiphenyl (6 g, 0.02 mol) and 3-bromo-1-propanol (5.6 g, 0.04 mol) were dissolved in ethanol (300 ml), followed by gradually dropwise adding an aqueous solution of sodium hydroxide (10 g) in water (20 ml) over 30 minutes, continuing, as it was, stirring for 40 hours, thereafter distilling off ethanol (about 200 ml) under reduced pressure, then adding water (500 ml), extracting the resulting deposited crystals three times with toluene (100 ml), removing insoluble matter by filtration, washing the toluene layer twice with a 2N aqueous solution of NaOH, further 3 times with water, drying over anhydrous sodium sulfate, completely distilling off toluene and recrystallizing the residual crystals from methanol to prepare 3-(4'-cyano-4-biphenylyl)-1-propanol. Yield: 2 g (28%). This product exhibited liquid crystal phases and its C-N point was 109.0°~110.7° C. and its N-I point was 113.6° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32](Cl)=[O:33].CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32]([C:28]2[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=2)=[O:33])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: Cn1ccnc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 22.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), 1-methyl-1H-imidazole-2-carbonyl chloride (0.026 g, 0.283 mmol), dry THF (5 mL), DIPEA (2 mL). The obtained crude was purified by column chromatography using 2% ammonia in 20% MeOH:DCM as mobile phase to afford 0.020 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 3.50 (s, 3H), 4.41 (d, J=18.0 Hz, 1H), 6.99 (s, 1H), 7.43 (br, 2H), 7.67 (d, 1H), 7.78 (s, 1H), 8.28 (d, J=4.5 Hz, 2H), 8.30 (s, 1H), 9.08 (t, 1H); MS (m/z): 477.10 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
A mixture of 4-fluorobenzenethiol (1.0 g), potassium carbonate (2.4 g) and N,N-dimethylformamide (25 mL) was treated with 4-bromobenzaldehyde (0.73 g), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrated concentrated under reduced pressure. The residue was purified by crystallisation from a mixture of diethyl ether and cyclohexane to afford the title compound as a white solid (0.89 g).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=1[I:29]>O1CCCC1>[I:29][C:21]1[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=1[O:3][CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=[N+]([O-])c1ccc(F)c(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc([N+](=O)[O-])cc2I)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
A solution of sodium hydride (0.16 g, 3.9 mmol) in tetrahydrofuran (10 mL) at 0° C. was treated with a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (0.82 mL, 3.7 mmol) in tetrahydrofuran (5 mL) and stirred at 0° C. for 30 minutes. The reaction mixture was treated with a solution of 1-fluoro-2-iodo-4-nitrobenzene (1.0 g, 3.7 mmol) in tetrahydrofuran (5 mL) and heated at 70° C. for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude brown oil. Purification by flash column chromatography gave the desired product (1.4 g, 81%) as a yellow oil. LCMS for C18H251N2O5Na (M+Na)+: m/z=499.0.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.F[C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39])[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C(#N)C>[OH:34][C:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][C:23]2[CH:35]=[CH:36][C:37]([N+:38]([O-:40])=[O:39])=[C:21]([NH:1][C@@H:2]3[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]3)[CH:22]=2)[CH2:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@@H](C(=O)O)CC3)c2)CC1
Temperature: 75 °C
Reaction time: 48 h
Yield: 143.2 %

Procedure:
To a suspension of cis-4-aminocyclohexanecarboxylic acid (0.199 g, 1.392 mmol) and DIPEA (0.553 mL, 3.16 mmol) in ACN (5 mL) was added 2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol (0.375 g, 1.265 mmol). The reaction was stirred at 75° C. After 48 hours, the reaction mixture was concentrated, diluted with water (10 mL), and extracted with DCM and EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide cis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylic acid as an orange powder (0.76 g, 143% yield).
Reaction SMILES: [CH2:1]([C:3]1([CH3:30])[N:22]([CH2:23][CH2:24][OH:25])[C:21]([CH2:27][CH3:28])([CH3:26])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]1[CH3:29])[CH3:2].C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[C:38]([O:25][CH2:24][CH2:23][N:22]1[C:21]([CH2:27][CH3:28])([CH3:26])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]([CH3:29])[C:3]1([CH2:1][CH3:2])[CH3:30])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCCCCCCCN1C(=O)NC2(CC(C)(CC)N(CCO)C(C)(CC)C2C)C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCN1C(=O)NC2(CC(C)(CC)N(CCOC(=O)c3ccccc3)C(C)(CC)C2C)C1=O
Yield: 49.9 %

Procedure:
To a solution of 2.5 g of the oily product obtained in Example 6 in 30 ml of benzene were added 1.2 g of triethylamine; 0.8 g of benzoyl chloride was then added dropwise with ice-cooling. The mixture was refluxed by heating for 2 hours and, after cooling, an aqueous solution of potassium carbonate was added. The mixture was extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulphate and then concentrated by evaporation under reduced pressure. The resulting oily product was first purified by column chromatography on silica gel (eluent: a 10 : 0.5 by volume mixture of hexane and triethylamine) and then by recrystallization from diethyl ether, giving 1.5 g of Compound 130 as crystals melting at 123° - 124.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:18]([O:20][CH3:21])=[O:19])=[C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH2:31][SH:32]>CS(C)=O>[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH2:31][S:32][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:18]([O:20][CH3:21])=[O:19])=[C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2nc(Cl)ccc12
Reactant: SCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1c(C(=O)OC)sc2nc(SCc3ccc(Cl)cc3Cl)ccc12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 6-chloro-3-(2-ethoxy-2-oxoethoxy)thieno[2,3-b]pyridine-2-carboxylate (126.4 mg) and DMSO (3.8 mL) were added K2CO3 (63.6 mg) and 2,4-dichlorobenzyl mercaptan (0.065 mL). The mixture was stirred at 80° C. for 3 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (73.9 mg).