Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Br:12])[CH:3]=1.[F:13][C:14]([F:35])([F:34])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([C:15]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:14]([F:35])([F:13])[F:34])=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)=[O:8])=[C:4]([Br:12])[CH:3]=1
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1cc(Br)c(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cc(Br)c(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 1 h
Yield: 57.8 %

Procedure:
4-Amino-2-bromo-5-fluorobenzoic acid (2.045 mmol, 0.479 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.7 g) and triethylamine (6.14 mmol, 0.853 mL, 0.621 g) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour. The reaction mixture was diluted with dichloromethane and saturated sodium hydrogen carbonate solution and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (660 mg). MS (ESI) m/z 558.5 [M+H]+
Reaction SMILES: [CH2:1]([C:7]1[C:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:27][C:26]2[C:9](=[CH:10][C:11]3[C:12](=[O:36])[C:13]4[C:22]([C:23](=[O:35])[C:24]=3[CH:25]=2)=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=4)[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([BH-](CC)CC)C.[Li+].Cl>C1COCC1>[CH2:29]([C:28]1[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][C:9]2[C:26](=[CH:25][C:24]3[CH:23]([OH:35])[C:22]4[C:13]([CH:12]([OH:36])[C:11]=3[CH:10]=2)=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=4)[CH:27]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCc1cc2cc3c(cc2cc1CCCCCC)C(=O)c1cc2ccccc2cc1C3=O
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCc1cc2cc3c(cc2cc1CCCCCC)C(O)c1cc2ccccc2cc1C3O

Procedure:
A solution of 334 mg of 2,3-di(n-hexyl)-6,13-pentacenequinone dissolved in 50 mL of THF was added to 11 mL of a 1 mol/1000 mL THF solution of lithium triethylborohydride, and the mixture was heated for 20 hours under reflux in a nitrogen atmosphere. The resulting solution was neutralized with diluted aqueous hydrochloric acid, and the organic phase was separated, concentrated and dried under a vacuum to produce 2,3-di(n-hexyl)-6,13-dihydro-6,13-dihydroxypentacene almost stoichiometrically.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:15][O:16][CH3:17]>CN(C)C=O>[CH3:15][O:16][CH2:17][O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Oc1cccc2c1CCCC2
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g 5,6,7,8-tetrahydro-naphthalen-1-ol was dissolved in 20 ml of N,N-dimethylform-amide. To this solution was added slowly 0.256 g of 95% NaH, followed by addition of 0.768 ml of chloromethoxymethane. The reaction was flushed with nitrogen and left stirring overnight at room temperature. The reaction mixture was then diluted with 50 ml of water and extracted with 50 ml of diethyl ether. The organic layer was washed with 50 ml of water, dried over magnesium sulphate and concentrated in vacuo to afford a crude oil. This was purified by flash chromatography (silica, heptanes/dichloro-methane) to afford 1.0 g of 5-methoxymethoxy-1,2,3,4-tetrahydro-naphthalene.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18](O)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(S(F)(F)([F:37])(CC)N)C>C(Cl)Cl>[CH2:1]([N:13]1[N:17]=[N:16][C:15]([C:18]([F:37])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCS(N)(F)(F)(F)CC
Reactant: CCCCCCCCCCCCn1nnc(C(O)(C(=O)OCC)c2ccccc2)n1
Solvent: ClCCl
Product: CCCCCCCCCCCCn1nnc(C(F)(C(=O)OCC)c2ccccc2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A solution of 2-dodecyl-α-hydroxy-α-phenyl-2H-tetrazole-5-acetic acid, ethyl ester (0.45 g, 1.08 mole) in CH2Cl2 (2 mL) was added dropwise to a -78° C. solution of diethyl amino sulfur trifluoride (DAST, J. Org. Chem. 1975;(40):574:578, 0.15 mL, 1.1 mole) in CH2Cl2 (1 mL) under dry nitrogen. The mixture was stirred for 60 minutes at -78° C. before the cooling bath was removed and the solution allowed to warm to room temperature, where it was stirred an additional 3 hours. The mixture was poured into ice water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with brine (50 mL) and dried. Filtration and concentration produced an oil which was flash chromatographed (silica gel, 7:1 hexane-ethyl acetate) to afford 0.3 g (66%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9](=[O:11])[CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:27]1([CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[O:11][C:36](=[O:37])[C:35]([S:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:39]([OH:40])[CH:10]=1
Reactant: CC(=O)c1c(C)cccc1C
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cc(O)c(SCc2ccccc2)c(=O)o1

Procedure:
The title compound was prepared by Method A using 2',6'-dimethyl acetophenone (0.785 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 140°-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.15 (s, 6 H), 3.99 (s, 2 H), 6.12 (s, 1 H), 7.22 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Cc1ccc(F)nc1
Product: Cc1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)nc1

Procedure:
The title compound, MS: m/e=308.2 (M+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-fluoro-5-methylpyridine.
Reaction SMILES: C1(C2N=C(/C=C/[C:12]3[CH:13]=[C:14]([CH:18]=[O:19])[CH:15]=[CH:16][CH:17]=3)SC=2)CCC1.CC(C)([O-:23])C.[K+].C(O)(C)(C)C>C(O)(=O)C>[C:18]([OH:19])(=[O:23])[C:14]1[CH:13]=[CH:12][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture composed of 3.15 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzenecarboxaldehyde, 1.44 g of potassium tert-butoxide and 100 ml of tert-butanol was heated to reflux for 2 hr while exposed to air. The mixture was then diluted with 100 ml of ice water. This mixture was then acidified with acetic acid and extracted with methylene chloride. The combined extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo to yield (E)-3-[2-(4-cyclobutyl)-2-thiazolyl)ethenyl]benzoic acid; m.p. 172°-175° C. from ethyl acetate.
Reaction SMILES: CS(C)=O.[CH2:5]1[O:13][C:12]2[C:7](=[C:8]([CH2:14][C:15]#[N:16])[CH:9]=[CH:10][CH:11]=2)[O:6]1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Na+]>O>[CH2:5]1[O:13][C:12]2[C:7](=[C:8]([CH:14]([C:15]#[N:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=[CH:10][CH:11]=2)[O:6]1
Reactant: N#CCc1cccc2c1OCO2
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(C#N)c1cccc2c1OCO2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Into 5 ml of dimethylsulfoxide, was added 0.26 g (1.6 mmol) of 2,3-methylenedioxyphenylacetonitrile, then, 0.24 g (1.6 mmol) of n-pentyl bromide and a 50% aqueous solution of sodium hydroxide were added dropwise thereinto simultaneously under cooling with ice. After 30-minute stirring at room temperature, the mixutre was added with water and extracted with ether. The ether extract was dried over magnesium chloride and then the solvent was evaporated off to obtain 0.30 g of oily 1-(2,3-methylenedioxyphenyl)hexane carbonitrile.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:6][CH:5]=[N:4]1)[CH3:2].C1C(=O)N([Cl:25])C(=O)C1>C1COCC1>[Cl:25][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[O:11][C:12]=1[CH3:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1nccc1-c1cc(C(=O)OC)oc1C
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1cc(C(=O)OC)oc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A mixture of methyl 4-(1-ethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylate (950 mg, 4.06 mmol) and NCS (650 mg, 4.87 mmol) in THF (10 mL) was heated at 70° C. in a sealed tube. After 2 h, the reaction mixture was concentrated and purified via column chromatography (silica, 10-20% EtOAc/Hexane) affording the title compound (970 mg, 89%) as a white solid: LC-MS (ES) m/z 269 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:15][C:16]1[N:21]=[C:20]([C:22](O)=[O:23])[CH:19]=[C:18]([CH3:25])[N:17]=1>>[CH3:15][C:16]1[N:21]=[C:20]([C:22]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]3[CH3:11])=[CH:4][CH:3]=2)=[O:23])[CH:19]=[C:18]([CH3:25])[N:17]=1
Reactant: Cc1cc(C(=O)O)nc(C)n1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Product: Cc1cc(C(=O)Nc2ccc3c(c2)N(C)C(=O)C3(C)C)nc(C)n1

Procedure:
Prepared in analogy to example 1b from 6-amino-1,3,3-trimethylindolin-2-one and 2,6-dimethylpyrimidine-4-carboxylic acid. The title compound was obtained as white foam.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:25](=[O:26])[CH:24]=[C:23]3[C:18]([C:19]4[CH:29]=[CH:28][S:27][C:20]=4[CH2:21][CH2:22]3)=[N:17]2)=[CH:12][CH:11]=1>C(Cl)Cl>[C:5]([C:28]1[S:27][C:20]2[CH2:21][CH2:22][C:23]3[C:18]([C:19]=2[CH:29]=1)=[N:17][N:16]([C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][CH:14]=1)[C:25](=[O:26])[CH:24]=3)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(-n2nc3c(cc2=O)CCc2sccc2-3)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)CCc1cc(=O)n(-c3ccc(C)cc3)nc1-2
Reaction time: 0.17 h

Procedure:
To a suspension of 6.4 g of aluminum chloride in methylene chloride was added 2.3 ml of acetyl chloride under ice-cooling and the mixture was stirred for 10 minutes. A solution of 4.7 g of 5,6-dihydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one in methylene chloride was added thereto, the mixture was stirred at room temperature for 30 minutes and then refluxed for an hour. The mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel (SiO2 :100 g) column using chloroform as an eluent. The resulting solid was recrystallized from a mixed solvent of chloroform and methanol to give 3.7 g of 8-acetyl-5,6-dihydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one as a white powder, melting at 240°-242° C.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)=O)=CC=1.[OH:34][CH2:35][C:36]1[CH:37]=[C:38](O)[CH:39]=[CH:40][CH:41]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:35][OH:34])[CH:41]=2)=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19]1(=[O:27])=[O:28])([CH3:30])([CH3:32])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(CO)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 0 %

Procedure:
A mixture of 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate (0.120 g, 0.244 mmol), 3-(hydroxymethyl)phenol (0.030 mg, 0.244 mmol) and K2CO3 (0.168 mg, 1.218 mmol) in MeCN (2 ml) was heated in the microwave reactor at 120° C. for 25 mins. The reaction mixture was filtered, evaporated and the residue was purified twice by silica gel column chromatography (Horizons Biotage) using 50% EtOAc in hexane and then 0-10% EtOAc in DCM as eluent to give the title compound (0.049 mg, 45%). 1H NMR (500 MHz CDCl3): δ 7.54-7.7.46 (m, 2H), 7.45-7.40 (m, 3H), 7.30-7.24 (m, 1H), 6.96 (d, 1H), 6.91 (s, 1H), 6.78 (d, 1H), 5.73 (t, 1H), 4.69 (s, 2H), 3.92 (t, 2H), 3.11-3.06 (m, 2H), 1.88-1.80 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 158.8, 142.9, 135.4, 131.8, 129.9, 129.8, 128.8, 125.3, 119.8, 113.9, 112.9, 107.2, 66.0, 65.4, 61.7, 42.4, 28.9, 27.8; Mass Spectrum M+H+ 445.
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:2]1=2.O.[OH-].[Li+]>CO.O>[C:18]([O:17][C:15]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:2]1=2)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1cnc2c(c1)N(C(=O)OC(C)(C)C)CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ncc(C(=O)O)cc21
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a suspension of 1-tert-butyl 7-methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1,7-dicarboxylate (1.25 g, 4.25 mmol) in methanol (20 mL) and water (5 mL) was added lithium hydroxide monohydrate (1.27 g, 30.3 mmol). The reaction was warmed to 40° C. and stirred at that temperature for 18 h. The reaction mixture was concentrated in vacuo to provide 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylic acid. The yield was assumed to be 100% for calculation purposes in subsequent reactions. LCMS (+ESI) m/z=281.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[CH2:18]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.S(Cl)([Cl:29])=O>ClCCl>[C:4]([Si:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[CH2:18][Cl:29])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(F)(F)F)sc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(F)(F)F)sc1CCl
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of [3-(tert-butyldimethylsilanyloxy)-5-trifluoromethylthiophen-2-yl]methanol in anhydrous dichloromethane (100 mL) was added triethylamine (4.05 g, 40.0 mmol) followed by thionyl chloride (2.38 g, 20.0 mmol) at 0° C. The reaction mixture was stirred for 30 min and quenched with water (50.0 mL). After separation, the organic layer was washed with water (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with hexane to afford the title compound (2.31 g, 70%) as a yellow oil, which was directly used.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10](OCC)[CH:11]=C=O)=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1.Cl.O1CCOCC1.[C:34](=[O:37])(O)[O-:35].[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:34]([OH:35])=[O:37])[CH3:11])=[CH:4][C:3]=1[N:17]1[C:25](=[O:26])[N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:18]1
Reactant: O=C([O-])O
Reactant: CCOC(C=C=O)Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl)C(=O)O

Procedure:
10.8 Parts of 2-[2,4-dichloro-5-(1-ethoxy-carbonylethoxy)-phenyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A]pyridin-3(2H)-one, 20.6 parts of concentrated hydrochloric acid (38%) and 175 parts of dioxane were combined and heated to 80° for 30 hours. After cooling the solution was poured into 750 parts of water. The pH of the solution was raised to 8-9 by addition of solid sodium bicarbonate. The aqueous solution of the product was then extracted three times with 250 parts of methylene chloride. The organic extracts were discarded. The aqueous solution of the product was then acidified to pH 1 by addition at concentrated hydrochloric acid (38%). The aqueous solution of product was extracted three times with 250 parts of methylene chloride. The solution of product was dried with anhydrous sodium sulfate. The solvent was removed on a rotary evaporator at reduced pressure. The glassy residue was triturated with ether. 4.4 Parts of white solid with m.p. 183°-185° were obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:16][C:17]1[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:4]1[C:3]([CH2:2][O:16][C:17]2[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: ClCc1cccnc1-c1ccccc1Cl
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccccc2Cl)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(2-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 1.50 equiv) in CH3CN. (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The residue was purified by prep-HPLC. This resulted in 86.2 mg (11%) of 5-[[2-(2-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a brown oil.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][N+:11]#[C-:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:14]I.[OH-].[Na+].O>ClCCl>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([S:7]([CH:10]([N+:11]#[C-:12])[CH3:14])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of toluene-4-sulfonylmethylisocyanide (15 g), methyl iodide (109 g) benzyl trimethyl ammonium chloride (3.5 g) in dichloromethane (300 mL) was added 5 mol/L aqueous sodium hydroxide solution (307 mL) under ice cooling, and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added water and this mixture was extracted with diethyl ether. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (16 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])([C:12]2[CH:17]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[CH2:9][CH:10]=[CH2:11])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].[CH2:39]([Zn]CC)C.ICI.Cl>C1(C)C=CC=CC=1>[CH:10]1([CH2:9][C@@:8]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:35]([F:38])([F:36])[F:37])[CH:4]=2)[C:12]2[CH:17]=[C:16]([O:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[CH2:39][CH2:11]1
Reactant: C=CC[C@](NC(=O)NCC(F)(F)F)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ICI
Product: O=C(NCC(F)(F)F)N[C@@](CC1CC1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 31.9 %

Procedure:
At 0° C. under argon, to a solution of (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)but-3-enyl)-3-(2,2,2-trifluoroethyl)urea (40 mg, 0.070 mmol), prepared as described in Procedure 6 and 10, in dry toluene (1 mL) was added diethyl Zinc (1.0 M in hexane, 1.2 mL, 1.2 mmol), followed by dropwise addition of diiodomethane (0.2 mL). The reaction mixture was gradually warmed to 110° C., and heated at 110° C. for 1 h. After cooling, 1 N HCl was added and the reaction mixture was stirred at room temperature for 5 min. The reaction mixture was extracted with EtOAc and the organic layer was washed with H2O, sat. NaHCO3, sat. NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5 u column eluting with 50-100% MeOH in H2O with 0.1% TFA, 40 mL/min, monitoring at 220 nm) to give (R)-1-(2-cyclopropyl-1-(4-fluoro-3-(trifluoromethyl)-phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea (Example 317) as white solid (13 mg, yield 32%). LCMS: RT=3.26 min [M+H] 583.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 50-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.55 (d, J=6.6 Hz, 1H), 7.46 (m, 1H), 7.12 (t, J=9.3 Hz, 1H), 6.94-6.85 (m, 3H), 5.84 (tt, J=52.8, 2.8 Hz, 1H), 5.61 (br, s, 1H), 4.78 (br, t, J=6.1 Hz, 1H), 3.69 (m, 2H), 2.31 (m, 2H), 0.36 (m, 3H), 0.00 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([F:33])[CH:27]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:2].[CH:34](=O)[CH2:35][CH3:36]>>[CH2:1]([N:3]([CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([F:33])[CH:27]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH:4]1[CH2:5][CH2:6][N:7]([CH2:34][CH2:35][CH3:36])[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCC=O
Reactant: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(F)c3)n2)c1)C1CCNCC1
Product: CCCN1CCC(N(CC)Cc2cccc(-c3ccnc(NCCc4ccc(O)c(F)c4)n3)c2)CC1

Procedure:
Intermediate 92 was coupled with propionaldehyde following procedure E. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 492. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 7.9 (d, 1H), 7.4-7.3 (m, 2H), 7.2 (t, 1H), 7.0-6.9 (m, 2H), 6.8 (m, 3H), 3.6 (s, 2H), 3.5 (d, 2H), 3.1 (m, 3H), 2.7 (q, 2H), 2.6 (m, 4H), 2.2 (t, 2H), 1.7-1.6 (m, 4H), 1.5-1.4 (m, 2H), 0.94 (t, 3H), 0.80 (t, 3H).