Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:18][O:19][CH2:20][C:21]#[N:22])[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[O:9][C:8]2[C:3]1=[CH:4][C:5]([I:17])=[CH:6][CH:7]=2.C[Al](C)C>CC1OCCC1>[Br:16][C:13]1[CH:14]=[C:15]2[C:2]3([N:1]=[C:21]([NH2:22])[CH2:20][O:19][CH2:18]3)[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([I:17])[CH:4]=3)[O:9][C:10]2=[N:11][CH:12]=1
Reactant: N#CCOCC1(N)c2cc(I)ccc2Oc2ncc(Br)cc21
Agent: C[Al](C)C
Solvent: CC1CCCO1
Product: NC1=NC2(COC1)c1cc(I)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A solution of 2-((5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)methoxy)acetonitrile (5.58 g, 11.82 mmol) in 100 mL 2-MeTHF under nitrogen atmosphere was treated with trimethylaluminum [2N in heptane (7.98 mL, 15.96 mmol)]. After stirring for 10 minutes at RT, the reaction mixture was heated to 80° C. for 90 minutes. The reaction mixture was cooled to RT and quenched with MeOH. The reaction mixture was treated with saturated Rochelle's salt solution and vigorously stirred for an additional hour. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. Purification of the crude residue by column chromatography [0-80% (90:10:1 DCM/MeOH/NH4OH)/DCM] gave 3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (Intermediate 2, 2.97 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=[O:20])[CH:15]=3)[CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.Br>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=[O:20])[CH:15]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2cc(-c3ccc(O)cc3)ccc2c1
Reaction time: 10 h
Yield: 82.3 %

Procedure:
Into a four-necked flask equipped with a stirring rod, dropping funnel, reflux condenser and thermometer was charged 0.63 g (0.0023 mol) of 2-(4'-methoxyphenyl)naphthalene-6-carboxylic acid of Example 9. To the compound were added 50 ml of acetic acid, 30 ml of acetic anhydride and 15 ml of 48% hydrobromic acid. The reaction was continued for 10 hours while the mixture was being heated with stirring, thereby obtaining clear solution. When 50 ml of water was added to the reaction solution, white precipitate was obtained. The precipitate was separated from the mixture by filtration, and then dried to obtain 0.5 g of 2-(4'-hydroxyphenyl)naphthalene-6-carboxylic acid. The yield of the product was 82 mol % on the basis of 2-(4'-methoxyphenyl)naphthalene-6-carboxylic acid used. The purity of the produce was 98%.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1.CN(C(ON1N=N[C:41]2[CH:42]=CC=N[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)C=C.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([O:22][CH2:42][CH:41]=[CH2:40])=[O:21])=[CH:18][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2ccc(-c3ncnc4c3c(C(=O)O)cn4COCC[Si](C)(C)C)cc2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: C=CCO
Product: C=CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3ccc4cn(C)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-(2-Methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (50 mg, 0.12 mmol), HATU (90 mg, 0.24 mmol), and allyl alcohol (0.016 mL, 0.24 mmol) were sequentially added to DMSO (1.0 mL) followed by the addition of Hunig's base (0.10 mL, 0.59 mmol). The reaction was stirred for 17 hours at room temperature at which point an additional amount of HATU (90 mg, 0.24 mmol), Hunig's base (0.10 mL, 0.59 mmol) and allyl alcohol (0.016 mL, 0.24 mmol) were added. The reaction was stirred at room temperature for 17 hours and then extracted with EtOAc (×3) from a saturated sodium bicarbonate solution. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give prop-2-en-1-yl 4-(2-methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calcd for C24H30N5O3Si [M+H]+: 464, found 464.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>>[Br:13][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(=O)oc2c1
Reactant: O=C1CCC(=O)N1Br
Product: O=c1ccc2ccc(CBr)cc2o1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
To a solution of 7-methylcoumarin (50 g) in acetonitorile (1.2 L) were added N-bromosuccinimide (56 g) α,α′-azobisisobutyronitrile (510 mg) and the mixture was stirred at 78° C. for 30 minutes. The reaction solution was concentrated and then added water (1 L). The appeared crystal was filtrated to give the title compound (76 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1C=CC=C[CH:19]=1.[CH2:24](I)[CH3:25]>ClCCl>[CH2:18]([N:1]([CH2:24][CH3:25])[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1)[CH3:19]
Reactant: CCI
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN(CC)c1ccc(CCO)cc1
Temperature: 120 °C

Procedure:
In a four-aperture flask, 9.6 g (70 mmol) of p-aminophenethyl alcohol, 38.7 g (280 mmol) of potassium carbonate, and 100 mL of monochlorobenzene were poured, and the mixture was heated at 120° C. under an argon atmosphere with stirring. Then, 32.8 g (210 mmol) of ethyl iodide was delivered by drops into the mixture for 5 hours. Upon completion of the dripping, the mixture was further heated with stirring for 5 hours. The reaction solution was cooled to the room temperature and then diluted with dichloromethane, followed by washing with water three times. The dichloromethane solution was dried with anhydrous magnesium sulfate, the solvent was distilled away to purify the dichloromethane solution by silica gel chromatography using a mixture solvent of toluene/ethyl acetate (2/1) as an eluent to thereby synthesize 12.1 g (yield: 89% by mass) of p-diethylaminophenethyl alcohol.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:13][CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:24][C:25]1[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:26]=1[NH2:27].[C:36](O[Na])([CH3:39])([CH3:38])[CH3:37]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:36]([CH:13]1[CH2:12][CH:11]([C:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:31][C:25]=4[F:24])[C:3]=3[NH:10][CH:9]=2)[CH2:16][CH2:15][N:14]1[C:17]([OH:19])=[O:18])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)O[Na]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(Cl)ncnc23)CC1
Reactant: CS(=O)(=O)c1ccc(N)c(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)C1CC(c2c[nH]c3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc23)CCN1C(=O)O
Yield: 6.7 %

Procedure:
tert-Butyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (54.8 mg, 0.163 mmol) was dissolved in 1,4-dioxane (0.5 mL), 2-fluoro-4-methylsulfonylaniline (32.0 mg, 0.169 mmol), tert-butoxysodium (15.9 mg, 0.109 mmol) and bis(tri-tert-butyl-phosphine)palladium (0) (5.8 mg, 0.011 mmol) were added, and the mixture was irradiated with microwave in a sealed tube at 130° C. for 3 hours. The reaction liquid was filtered, the filtrate was concentrated under a reduced pressure, and the obtained residue was purified by using silica gel chromatography (ethyl acetate:hexane=3:1) to give the titled compound (3.6 mg, 6.5%) as a white amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21]CC)=[O:20])[O:16]2)=[CH:11][CH:10]=1.I[CH3:35]>>[Cl:1][C:2]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:31])([F:33])[F:32])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH3:35])([C:19]([OH:21])=[O:20])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(OCC(F)(F)F)cc3Cl)cc2O1
Reactant: CI
Product: CC1(C(=O)O)CCc2ccc(OCCCOc3ccc(OCC(F)(F)F)cc3Cl)cc2O1

Procedure:
The title compound was prepared from ethyl 7-(3-(2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy)propoxy)-chromane-2-carboxylate (Example 5, Step D) following the procedure described in Example 1, Step C employing iodomethane instead of iodoethane followed by hydrolysis as described in Example 5, Step E.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 20 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (100 mg, 0.4 mmol) in pyridine (2 ml) was added benzoyl chloride (55 mg, 0.4 mmol) and the mixture stirred overnight at 20° C. To this mixture 2N HCl to pH 1 (20 ml) was added then the mixture was extracted twice with EtOAc (20 ml), washed with saturated NaHCO3 solution, dried with Na2SO4 and the solvent evaporated. The crude product was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/MeOH (98:2), the product fractions were pooled and the solvent evaporated, to afford the title compound as a white solid (97 mg, 69% yield), MS: m/e=360 (M+).
Reaction SMILES: [C-:1]#[N:2].[Na+].O.[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29]>C(#N)C>[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26]([O:16][CH:15]([C:1]#[N:2])[C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([O:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:13]=2)=[O:27])[C:24]1([CH3:30])[CH3:29]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a stirred solution of sodium cyanide (0.74 g, 0.015 mold) in a 1:1 by volume mixture of water and acetonitrile (20 ml) at room temperature was added all at once 3-phenoxybenzaldehyde (1.98 g, 0.01 mole) in the same solvent system (5 ml) followed by a dropwise addition over 10 minutes of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (2.73 g, 0.012 mole). Stirring was continued at room temperature for 2 hours, after which the mixture was extracted thrice with methylene chloride (30 ml each). The combined organic layers were washed once with aqueous 2 N NaOH (25 ml), then thrice with water (25 ml each) to a final wash pH of about 6, dried over Na2SO4, and concentrated to give α-cyano-3-phenoxybenzyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (3.76 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[C:9](O)=[C:8]([F:11])[C:7]([Br:12])=[C:6]([CH3:13])[C:3]=1C#N.C(=S)(OCC)[S-].[K+].[CH3:21][N:22](C)[CH:23]=[O:24].S(Cl)([Cl:28])=O>N1C=CC=CC=1>[Br:12][C:7]1[C:8]([F:11])=[C:9]2[O:24][C:23]([Cl:28])=[N:22][C:21]2=[C:3]([C:2]#[N:1])[C:6]=1[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Reactant: CN(C)C=O
Agent: CCOC(=S)[S-]
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1c(Br)c(F)c2oc(Cl)nc2c1C#N
Temperature: 70 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
2-Amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (1.54 g, 6.28 mmol) was dissolved in pyridine (80 ml), then potassium O-ethyl dithiocarbonate (3.10 g, 19.3 mmol) was added, followed by heating under reflux for 3 hours. The solvent was evaporated away under reduced pressure, then ethyl acetate and diluted hydrochloric acid were added for liquid-liquid separation of the organic layer. After washing with water and saturated brine and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. Again using 2-amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (1.45 g, 5.92 mmol), pyridine (75 ml) and potassium O-ethyl dithiocarbonate (2.90 g, 18.1 mmol), the same reaction was carried out, and the resulting residues were combined, dissolved in thionyl chloride (70 ml). N,N-dimethylformamide (0.70 ml) was added, followed by stirring at an external temperature of about 70° C. for 1 hour, then the reaction liquid was concentrated under reduced pressure. Dichloromethane and aqueous sodium hydrogencarbonate solution were added, and the organic layer was separated. After extraction with dichloromethane, the organic layers were combined, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain the entitled compound (1.93 g, 55%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][CH2:32]Cl.Cl.[OH:35][CH:36]1[CH2:39][NH:38][CH2:37]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:31][CH2:32][N:38]5[CH2:39][CH:36]([OH:35])[CH2:37]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OC1CNC1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: ClCCBr
Agent: Cl
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CC(O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-3-[2-(3-hydroxyazetidin-1-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1), 1-bromo-2-chloroethane and 3-hydroxyazetidine hydrochloride following General Procedure G.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 26.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(4-chlorophenyl)methyl](4-isopropylphenyl) amine (1.5 g) as starting materials, N-[(4-chlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained. melting point: 87-88° C.
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].F[B-](F)(F)F.CO[N+:12]1[N:13]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:14]=[C:15]([CH3:17])[CH:16]=1>CO.O>[CH3:2][O:3][C:16]1[C:15]([CH3:17])=[N:14][N:13]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=2)[N:12]=1
Reactant: C[O-]
Reactant: CO[n+]1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 23 °C
Reaction time: 6 h

Procedure:
Sodium metal (0.25 g, 11.0 mmol) was stirred at 23° C. in methanol (10 mL) until a clear solution was obtained. This sodium methoxide solution was added to crude 1-methoxy-4-methyl-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazolium tetrafluoroborate (1:1) (i.e. the product of Step B, 1.1 g, 3.2 mmol). The reaction mixture was stirred at 23° C. for 6 h, during which time a white precipitate formed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL, 10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0 to 10% ethyl acetate in hexanes to afford the title compound (0.82 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=4[Cl:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)cc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-chloro-4-fluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=614.1)=93%.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:12]2[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:32][CH:31]=1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 90.5 %

Procedure:
The title compound (92 mg) was prepared as in Example 177, Steps C and D, using 159 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 156 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C16H20FN3, 273.16; found, m/z 274.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.42-7.35 (m, 2H), 7.33-7.27 (m, 2H), 4.37 (m, 1H), 3.46-3.39 (m, 2H), 3.34-3.28 (m, 2H), 3.23-3.18 (m, 2H), 2.81-2.74 (m, 2H), 1.41 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][NH2:13]>C(Cl)Cl>[CH3:12][NH:13][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])(=[O:10])=[O:9]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 2-methylbenzenesulfonyl chloride (37.4 g, 0.196 mol) in methylene chloride (300 ml) at -5° to 0° under nitrogen was added liquid methylamine (27.5 ml, 0.588 mol) at a rate to maintain an internal temperature less than 10°. The reaction mixture was stirred at 0° for 1/2 hour and then allowed to warm to room temperature. After 11/4 hours, filtration and concentration of the filtrate gave an oil which solidified upon cooling. Washing the solid with n-butyl chloride gave N,2-dimethylbenzenesulfonamide as a light yellow powder (28.4 g, 78%), mp. 62°-64°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[C:19]1([CH3:32])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][CH:27]=[CH:28][C:29](=[O:31])[CH3:30]>>[C:29]([C:28]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:26]([CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:32])[CH:27]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)C=CNCc1ccccc1C
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3C)C=C1C(C)=O)C2=O

Procedure:
The title compound 59 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 60 (110 mg, 0.57 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 59 as a yellow oil. (Yield 100 mg, 59%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:22]([O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: N[C@H](CO)CSCc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N)CSCc1ccc(F)cc1
Reaction time: 8 h
Yield: 104.8 %

Procedure:
2(R)-Amino-3-(4-fluorobenzylsulfanyl)propan-1-ol (16.15 g), 4-dimethylamino-pyridine (554 mg), and triethylamine (16.7 mL) were weighed into a 1000 mL round bottom flask fitted with a stir bar, 250 mL addition funnel, septum, and nitrogen inlet. Methylene chloride (150 mL) was added to give a clear pale amber solution. A solution of tert-butyldimethylsilyl chloride (12.54 g) in CH2Cl2 (100 mL) was added dropwise over 40 min. After stirring overnight, the reaction mixture was poured into water and the organic phase was separated, dried over anhydrous MgSO4 and removed the solvent on rotavap to give 2-(tert-butyldimethylsilanyloxy)-1(R)-(4-fluoro-benzylsulfanylmethyl)ethylamine (25.92 g) as a clear yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:30])=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[O:13].O>O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:30][C:2]([O:4][CH3:5])=[O:3])=[C:11]([CH:29]=1)[C:12]([NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:16]=1)=[O:13]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
Methyl chloroformate(42 μL, 0.54 mmol) was added to a solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt(200 mg, 0.49 mmol) in tetrahydrofuran(5 mL) under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with n-hexane under suspension to give the title compound(171.2 mg, 78.6%) as a white solid.