Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=O.C(O)C.[CH2:15]([NH2:18])[CH2:16][NH2:17].[ClH:19]>CO>[ClH:19].[NH:17]1[CH:4]2[C:3]3[C:2]([C:1](=[O:11])[N:18]2[CH2:15][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NCCN
Reactant: O=Cc1ccccc1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: O=C1c2ccccc2C2NCCN12

Procedure:
A solution of 7.5 g. of phthalaldehydic acid in 30 ml. of ethanol and 34 ml. of ethylenediamine was refluxed for 16 hours. The solution was concentrated in vacuo and the residue was dissolved in methylene chloride. The solution was washed with water, dried and concentrated. The residue was distilled in a bulb tube at 0.3 mm at a bath temperature of 150°-180°. A colorless oil was obtained which was dissolved in methanol and on addition of ethereal hydrogen chloride gave white prisms of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one hydrochloride, m.p. 222°-224° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C@@H:7]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[C@@H:8]([NH:10][CH:11]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.CCOCC.[Cu]I>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C@@H:7]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[C@@H:8]([NH:10][CH:11]([C:17]2[CH:22]=[CH:21][C:20]([N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)=[CH:19][CH:18]=2)[C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(c1ccc(Br)cc1)C(C)(C)C#N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: C[C@H](NC(c1ccc(-n2cncn2)cc1)C(C)(C)C#N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 195 °C

Procedure:
To a solution of 22.5 mg (0.043 mmol) of 3-(1(S)-(4-chlorobenzyl)-2(S)-((1-(4-bromophenyl)-2-cyano-2-methylpropyl)amino)propyl)benzonitrile in 0.5 mL of N-methyl-pyrrolidone, 12 mg (0.173 mmol) of 1,2,4-triazole, 2.3 mg of CuI and 24 mg of K2CO3 were added. The mixture was heated in a microwave reactor at 195° C. for 4 hr. The reaction was diluted with ether, washed with water, brine, dried and concentrated. The residue was purified by prep TLC using 50% EtOAc-hexane to isolate the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][CH:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][C:5]2=O>C(O)(=O)C.[Pd]>[OH:1][C:2]1[C:3]([CH3:20])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][CH:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C1CC(=O)c2c(C)c(O)c(C)c(C)c2O1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 1 h

Procedure:
14 g of ethyl 6-hydroxy-5,7,8-trimethyl-4-oxo-2H-chromene-2-carboxylate [prepared as described in J. Med. Chem., 18, 934 (1975)] were dissolved in 320 ml of acetic acid, and the resulting solution was catalytically reduced for 1 hour at 60°-65° C., under a hydrogen pressure of 3 atmospheres and in the presence of 3.5 g of 10% w/w palladium-on-carbon. The catalyst was filtered off, and the filtrate was poured into water. The white crystals which separated were collected by filtration, to give the title compound, melting at 108°-109° C.
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][C:5]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.[C:46]([O-])([O-:48])=[O:47].[Na+].[Na+]>O1CCOCC1.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>[F:45][C:33]([F:32])([F:44])[C:46]([OH:48])=[O:47].[F:32][C:33]([F:44])([F:45])[O:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:3]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:4][C:5]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:37][CH:36]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(Br)cn3)cccc2s1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(-c4ccc(OC(F)(F)F)cc4)cn3)cccc2s1
Product: O=C(O)C(F)(F)F

Procedure:
This material was prepared analogous to Example 146 by using N-{4-[5-bromo-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide, (Example 145(b)), (0.1 g, 0.2 mmol), 4-(trifluoromethoxy)phenyl boronic acid (53 mg, 0.26 mmol, Aldrich), Pd(PPh3)4 (23 mg, 0.02 mmol, Aldrich) and aq. Na2CO3 (32 mg in 0.4 mL of water) in dioxane (2 mL). Purification by silica gel chromatography (1:2 of EtOAc/hexanes), followed by preparative HPLC separation gave the title compound as a white solid. MS (ESI, pos. ion) m/z: 590 (M+1). Mp: 212.9–222.3° C.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@:29]([OH:44])([C@H:36]([S:38][CH:39]([CH2:42]O)[CH2:40][OH:41])[CH3:37])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[O:41][CH2:40][C@H:39]([S:38][C@H:36]([CH3:37])[C@:29]([C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[F:21])([OH:44])[CH2:30][N:31]4[CH:35]=[N:34][CH:33]=[N:32]4)[CH2:42][O:17]3)=[CH:12][CH:11]=2)=[CH:19][CH:20]=1)#[N:2]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: N#Cc1ccc(CNC(=O)c2ccc(C=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)NCc3ccc(C#N)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 1(2), a reaction was carried out using N-(4-cyanobenzyl)-4-formylbenzamide, obtained in Example 26(1) (200 mg, 0.76 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (237 mg, 0.66 mmol) and p-toluenesulfonic acid monohydrate (151 mg, 0.79 mmol) and the reaction mixture was treated using a similar procedure to that described in Example 1(2) to afford the trans isomer of the title compound (137 mg, yield 34%) as a white solid and the cis isomer (82 mg, yield 21%) as a white solid. The trans isomer was recrystallized from tetrahydrofuran-hexane to give white powdery crystals and the cis isomer was recrystallized from ethyl acetate to give white powdery cryatals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:19](N(OC)C)=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH2:1]([O:8][CH2:9][CH:10]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:19]=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC(C=O)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
A cold (10° C.) solution of O-benzyl-N1-methoxy-N1-methyl-N2-(tert-butoxycarbonyl)serinamide (6.27 g, 18.5 mmol) in diethyl ether (312 mL) was treated in portions with LAH (780 mg, 20.6 mmol). The reaction was stirred under inert atmosphere for 30 min and quenched at 0° C. by the addition of a solution of KHSO4 (16 g) in water (75 mL). The mixture was diluted with 1 M aqueous HCl (60 mL), and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to a yellow oil. Purification by silica gel chromatography (10% to 50% EtOAc/hexanes) afforded the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.64 (s, 1H), 7.38-7.26 (m, 5H), 5.42 (d, J=5.0 Hz, 1H), 4.51 (dd, J=12.0, 19.5 Hz, 2H), 4.32 (d, J=4.01-3.99 (m, 1H), 3.73-3.70 (m, 1H), 1.46 (s, 9H). ES MS (M+1−100, for loss of BOC group)=180.1.
Reaction SMILES: Br[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N:13]3[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]3)=[C:8]([F:12])[CH:9]=2)[NH:4][C:3]1=[O:23].C(N(CC)CC)C>O1CCCC1.O>[F:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N:13]1[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]1)[NH:4][C:3](=[O:23])[CH:2]=[CH:11]2
Reactant: Cc1nn(-c2cc3c(cc2F)CC(Br)C(=O)N3)c(=O)n1C(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nn(-c2cc3[nH]c(=O)ccc3cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
A solution of 7.0 g (0.018 mole) of 1-[3-bromo-6-fluoro-3,4-dihydroquinolin-2(1H)-one-7-yl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 60 mL of tetrahydrofuran was stirred, and 4.0 g (0.040 mole) of triethylamine was added. Upon completion of addition the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give a residual solid. The solid was slurried in water and collected by filtration. The dried solid was slurried in 100 mL of hot ethyl acetate. The mixture was cooled, and the solid was collected by filtration to yield 3.6 g of 1-[6-fluoroquinolin-2(1H)-one-7-yl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one; m.p. 215°-217° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH:38]([CH3:40])[CH3:37])[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(C(C)C)C3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.250 g, 0.518 mmol) in dichloroethane (5 mL) was treated with acetone (1.96 g, 33.15 mmol) and sodium triacetoxy borohydride (0.220 g, 1.04 mmol). The reaction mixture was stirred at room temperature for 18 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (15 min), 15% methanol in dichloromethane (15 min), 20% methanol in dichloromethane (20 min) and 50% methanol in dichloromethane (5 min) as the eluent. The column afforded 0.123 g (44%) of pure N2-{4-[4-amino-1-(1-isopropyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.449 (s, 1H), 8.265 (s, 1H), 8.127-8.1068 (d, 1H, J=8.08 Hz), 7.7196-7.6999 (d, 1H, J=7.88 Hz), 7.6013-7.5803 (d, 1H, J=8.4 Hz), 7.351-7.299 (m, 4H), 7.173-7.135 (m, 1H), 5.394 (m, 1H), 4.042 (s, 3H), 3.961 (s, 3H), 2.793 (m, 3H), 2.337 (m, 3H), 1.068 (br.s, 6H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.38 min (100%), MH+ 525.3.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>C(OCC)(=O)C>[CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: C=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCOC(C)=O
Product: C=C1CCN(c2ccc(N)cc2)CC1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
To a solution of 4-methylene-1-(4-nitrophenyl)-piperidine (230 mg, 1.05 mmol) in ethyl acetate (5 mL) was added stannous chloride dihydrate (1.19 g, 5.2 mmol). The mixture was heated to 60° C. and maintained for 4 hrs. The mixture was evaporated to dryness then sodium hydroxide solution was added to give a final pH of 8. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water, then brine, and then dried. Concentration under reduced pressure afforded 4-methylene-1-(4-aminophenyl)-piperidine (150 mg, 75%) as a semisolid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[C:13]=[O:14]>C(#N)C>[Cl:8][C:6]1[C:5]([CH3:9])=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13]([NH:12][S:15]([C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[O:14])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(Cl)c1C
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)c(C)c(OC)n1
Reaction time: 3 h

Procedure:
To 1.0 g of 2-amino-4-chloro-6-methoxy-5-methylpyrimidine in 35 ml of anhydrous acetonitrile, with stirring at ambient temperature, was added 1.5 g of methyl 2-(isocyanatosulfonyl)benzoate. The mixture was stirred for 3 hours, heated to 50° and allowed to cool. The solid precipitate thus obtained was filtered off and washed with 1-chlorobutane. It melted at 204°-205° and showed infrared absorption peaks at 1740, 1710, 1650 and 1510 cm-1, consistent for the above-named product.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25]([O:27]C)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].Cl>CO.O>[OH:24][CH:21]1[CH2:20][CH2:19][N:18]([C:16]([N:14]2[CH2:15][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:29])[F:30])=[CH:5][CH:6]=3)[CH2:11][CH:12]([C:25]([OH:27])=[O:26])[CH2:13]2)=[O:17])[CH2:23][CH2:22]1
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
828 mg (1.92 mmol) of methyl 5-(4-(trifluoromethoxy)phenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylate were dissolved in 70 ml of methanol, 2159 mg (19.24 mmol) of potassium tert-butoxide were added and the mixture was stirred at 60° C. overnight. For work-up, the reaction solution was diluted with water and acidified with 1N hydrochloric acid (pH 1). The mixture was extracted with ethyl acetate. The combined organic phases were dried with sodium sulphate and concentrated under reduced pressure. Yield: 749 mg (94% of theory)
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH2:33][CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[CH2:33]([C:27]1[N:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[N:22]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH2:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:20][CH3:21])[CH2:18][CH3:19])[N:28]=1)[CH3:34]
Reactant: CCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Reactant: CCc1ncc2c(N)cccc2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: CCc1ncc2c(N=CC(O)(CC(CC)c3cccc(F)c3OC)C(F)(F)F)cccc2n1

Procedure:
In the same way as in Example 31, 112 mg (0.37 mmol) of (4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 60 mg (0.37 mmol) of 5-amino-2-ethylquinazoline and 0.2 ml of titanium tetraethoxide are reacted to give 1-[(2-ethylquinazolin-5-yl)imino]-4-(3-fluoro-2-methoxyphenyl)-2-(trifluoromethyl)hexan-2-ol. 280 mg of crude imine are cyclized in the same way as in Example 31 at −20° C. with 2.4 ml (2.4 mmol) of 1 M boron tribromide solution to give the desired product. Purification by chromatography on silica gel (ethyl acetate) gives 4 mg of desired product and 11 mg of the 8α compound (Example 49).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[C:24]([F:27])([F:26])[F:25])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([O:30]C)=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[C:24]([F:27])([F:26])[F:25])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([OH:30])=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC[C@@H]3C(F)(F)F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC[C@@H]3C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[(2R)-2-(trifluoromethyl)piperidin-1-yl]quinoxaline-6-carboxylate (15 mg, crude) in methanol (15 mL) was added sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted pH to 6 with HCl (1N), then extracted with dichloromethane (4×10 mL) and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. Purification via Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.05% NH3 and CH3CN (10% CH3CN up to 45% in 7 min); Detector, UV 220 nm] afforded 2-(4-fluorophenyl)-3-[(2R)-2-(trifluoromethyl)piperidin-1-yl]quinoxaline-6-carboxylic acid as a yellow solid (9 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][N:20]([S:35]([C:32]2[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:39])[F:40])=[CH:34][CH:33]=2)(=[O:37])=[O:36])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reaction time: 18 h
Yield: 42.2 %

Procedure:
To a solution of compound 24 (0.099 g, 0.27 mmol) in CH2Cl2 (3 mL) was added 4-(trifluoromethyl)benzenesulfonyl chloride (0.093 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). The reaction mixture was stirred for 18 hrs, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was then concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white solid. The solid was triturated with diisopropyl ether/hexanes and vacuum filtered to afford compound 60 as a white powder. (0.065 g, 42.2% yield, 95.7% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.23 (d, J=2 Hz, 1H), 7.86 (m, 4H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J=9 Hz, 1H), 6.68 (s, 2H), 3.48 (m, 4H), 3.15 (m, 4H), 2.35 (s, 6H); MS (ESI, EI+): m/z=580 (MH+).
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[C:9](=[CH:12][C:13]([OH:15])=O)[S:8][CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]2=[O:38])[CH2:24][CH2:23]1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:6]1[C:10](=[O:11])[C:9](=[CH:12][C:13]([N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH2:26][CH2:27]2)=[O:15])[S:8][CH:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCN1C(=O)C(=CC(=O)O)SC1c1ccccc1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)CCN1C(=O)C(=CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)SC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-ylidene)acetic acid (11 mg, 0.036 mmol), 3,4-Dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one.TFA (18 mg, 0.054 mmol) and DiPEA (22 ul, 0.14 mmol) in DMF (0.2 ml) was added HATU (16 mg, 0.043 mmol) and the reaction mixture was stirred at RT for 16 hours. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound.
Reaction SMILES: C(O)C.[Si]([O:21][CH2:22][CH2:23][C:24]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:28]([C:29]2[S:30][C:31]3[CH2:32][N:33]([CH3:38])[CH2:34][CH2:35][C:36]=3[N:37]=2)[N:27]=[C:26]([C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=2[F:46])[S:25]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[F:46][C:40]1[CH:41]=[CH:42][C:43]([F:45])=[CH:44][C:39]=1[C:26]1[S:25][C:24]([CH2:23][CH2:22][OH:21])([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:28]([C:29]2[S:30][C:31]3[CH2:32][N:33]([CH3:38])[CH2:34][CH2:35][C:36]=3[N:37]=2)[N:27]=1
Reactant: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Solvent: CCO
Solvent: CC#N
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO)c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Preparation of 245-(2,5-difluorophenyl)-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethanol: To a solution of 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.070 g, 0.098 mmol) in 2 mL of anhydrous acetonitrile was added HF-TEA (0.160 mL, 0.99 mmol). The solution was stirred at room temperature for 16 hours then slowly quenched with saturated NaHCO3 (20 mL). The mixture was extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-1% MeOH/DCM) and the residue was dissolved in 2 mL of methanol and treated with 1N HCl/MeOH (2 mL). After stirring for 10 minutes, the solution was concentrated in vacuo. The residue was triturated with diethyl ether, filtered, washed with ether and dried in vacuo to afford the desired product as a yellow powder, 0.023 g, 42%. MS ESI (+) m/z 473 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 1H), 7.44 (d, 2H, J=7.5 Hz), 7.32 (m, 2H), 7.26 (m, 1H), 7.07 (m, 2H), 4.10 (m, 1H), 3.96 (m, 1H), 3.65 (m, 1H), 3.54 (q, 2H, J=30.2, 14.3 Hz), 2.83 (m, 1H), 2.72 (m, 2H), 2.57 (m, 2H), 2.48 (s, 3H) ppm.