Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=1Cl)=[CH:6]OCC)[CH3:2].[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[H-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:20])[C:11]2[C:12](=[CH:13][C:14]([Cl:18])=[C:15]([F:17])[CH:16]=2)[N:25]([C:24]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=2[F:22])[CH:6]=1)=[O:21])[CH3:2]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O

Procedure:
A solution of 2 g 2-(2,4-dichloro-5-fluoro-benzoyl)-3-ethoxy-acrylic acid ethyl ester (5.97 mmol) and 0.6 ml of 2,4-difluoroaniline (5.97 mmol) in 15 ml of ethanol was stirred at reflux for 25 hrs. The reaction was monitored by TLC. The ethanol was evaporated and the residual ethanol was distilled from an azeotrope with 20 ml heptane and 20 ml ethyl acetate. The yellow oil was dissolved in 20 ml of THF, reacted with 315 mg of a 50% NaH suspension in oil (6.56 mmol) and stirred at reflux for 20 hrs. The solution was diluted with ethyl acetate, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[O:33]1[C:37](=[O:38])[CH2:36][CH2:35][C:34]1=[O:39].CN(C=O)C.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][O:20][C:37](=[O:38])[CH2:36][CH2:35][C:34]([OH:39])=[O:33])[O:16][N:15]=2)=[N:10][CH:9]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 150 mg, 0.342 mmol), dihydrofuran-2,5-dione (83 mg, 0.83 mmol), and 4-dimethylaminopyridine (10.5 mg, 0.09 mmol) were added to DMF (2.5 ml) and pyridine (0.5 ml). The reaction was allowed to stir overnight at room temperature followed by addition to Et2O (100 ml). The precipitate was collected by filtration and washed with additional Et2O (2×20 ml). The precipitate was then suspended in CH2Cl2 (20 ml) and the precipitate was collected by filtration and then washed with additional CH2Cl2 (2×20 ml) to yield the product as a white solid (131 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[C:15](=[O:18])[NH:16][CH3:17])[CH:6]=[CH:7][C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[C:15](=[O:18])[NH:16][CH3:17])[CH:6]=[CH:7][C:8]([OH:10])=[O:9]
Reactant: CNC(=O)c1ccc(C=CC(=O)OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)c1ccc(C=CC(=O)O)cc1OC
Temperature: 50 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To a solution of methyl 3-methoxy-4-methylcarbamoyl-cinnamate (300 mg) in methanol was added 1N sodium hydroxide solution (1.5 ml) at ambient temperature, and the mixture was stirred at 50° C. for 5 hours. The solvent was distilled off, and the residue was dissolved in water. The solution was washed with diethyl ether, and adjusted to pH 4 with 1N hydrochloric acid. The resulting precipitates were collected by filtration and washed with water to give 3-methoxy-4-methylcarbamoylcinnamic acid (250 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])[C:7]=2[OH:24])[N:14]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2-c2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3-chloro-7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M−1)−.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[CH:11][C:10]=1[C:33]1[N:37]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[N:36]=[N:35][N:34]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:42][O:41][CH2:40][CH2:39][CH2:38][N:37]1[C:33]([C:10]2[CH:11]=[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])=[N:34][N:35]=[N:36]1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(F)(F)F)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(F)(F)F)c2)c(O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
5% Pd/C was wetted carefully with MeOH under N2, then 5-(4,6-bis-benzyloxy-3′-trifluoromethyl-biphenyl-3-yl)-1-(3-methoxy-propyl)-1H-tetrazole (90 mg, 0.16 mmol) solution in methanol was added. The reaction system was vacuumed and filled with hydrogen three times. The reaction was stirred under hydrogen at r.t. overnight. After filtering the catalyst over celite, the filtrate was concentrated to give 5-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-3′-trifluoromethyl-biphenyl-2,4-diol (50 mg, 82%). M.p.: 144-182° C.; 400 MHz 1H NMR (CDCl3) δ: 10.82 (s, 1H), 7.62 (s, 1H), 7.72-7.58 (m, 4H), 6.76 (s, 1H), 5.70 (s, 1H), 4.74 (t, J=7.6 Hz, 2H), 3.41 (t, J=6.8 Hz, 2H), 3.10 (s, 3H), 2.31-2.23 (m, 2H); LCMS: 395 [M+H].
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[F:12][C:13]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=1[NH2:15].[OH-].[Na+].Cl>CC(C)=O.O>[F:12][C:13]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=1[NH:15][C:10]([NH2:9])=[S:11]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(F)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(F)c(NC(N)=S)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzoyl isothiocyanate (20.20 g, 123.9 mmol) in acetone (350 mL) at 60° C. was added a solution of 2-fluoro-5-methoxyaniline (15.90 g, 112.6 mmol) in acetone (60 mL). The reaction mixture was refluxed for 2 hours and cooled to room temperature. The solution was concentrated to a volume of approximately 100 mL and then poured into ice water (900 mL). The resulting precipitate was collected, washed with water and hexanes, and dried at 40° C. under vacuum. It was then added into a solution of sodium hydroxide (15.00 g, 375.0 mmol) in water (300 mL) at 80° C. Heating was continued for 2 hours. After the reaction had cooled to room temperature, the pH was adjusted to 10 with concentrated hydrochloric acid. The precipitate was collected by filtration and washed with saturated aqueous sodium bicarbonate solution (2×250 mL), water (2×250 mL) and hexanes (2×250 mL) to afford the title compound as a white solid. Yield: 17.40 g, 86.9 mmol, 77%. 1H NMR (300 MHz, CDCl3) δ 3.86 (s, 3H), 6.13 (br s, 1H), 6.82 (m, 1H), 6.90 (m, 1H), 7.13 (m, 1H), 7.63 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccnc3)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and pyridine-3-sulfonyl chloride (102 mg, 0.63 mmol) were dissolved in pyridine (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford pyridine-3-sulfonic acid [3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (73 mg, yield: 39%) as yellow solid. MS (ESI+APCI) M+1=357.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:10]2([CH2:13][CH:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:10]2([CH2:13][CH:12]([N:14]3[CH2:15][CH2:16][CH:17]([C:20](=[O:21])[NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:19]3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)C1CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
1-[6-(tert-Butoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid was dissolved in DMF (2 mL) and t-butylamine (0.087 g, 1.20 mmol), HATU (0.227 g, 0.60 mmol) and DIPEA (0.193 g, 1.50 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give tert-butyl-2-[4-(tert-butylcarbamoyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.071 g, 60.5%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5](C(O)C(O)=O)=[CH:4][CH:3]=1.CN(C(C1C=CC=CC=1)C#N)C.[OH:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30](O)[C:31]#[N:32])=[CH:28][CH:27]=1.C1(O)C=CC=CC=1.S(=O)(=O)(O)O>>[OH:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]([C:5]2[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=2)[C:31]#[N:32])=[CH:28][CH:27]=1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Reactant: N#CC(O)c1ccc(O)cc1
Agent: CN(C)C(C#N)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: Oc1ccccc1
Product: N#CC(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
The afore-mentioned process can not advantageously be employed to prepare cyanobisphenols wherein R1 is hydrogen. When R1 and all R2 are hydrogen, the following procedure is effective to prepare the cyanobisphenol. 4-Hydroxybenzaldehyde is reacted with sodium cyanide in the presence of sodium bisulfite to yield 4-hydroxymandelonitrile, a cyanohydrin which has the following formula. ##STR13## The reaction and conditions are described in Landenberg et al., "Synthesis of 3-Hydroxy-2(3)-Benzofuranone and of 4-Hydroxymandelic Acid", 58 J. Amer Chem Soc. 1292 (1936) and in Taylor, et al, "a-N,N-Dimethylaminophenylacetonitrile", 5 Organic Synthesis 437 (1962). 4-Hydroxymandelonitrile is then reacted with excess phenol in the presence of sulfuric acid at a temperature of about 55° C. to 60° C. to yield bis-(4-hydroxyphenyl)acetonitrile: ##STR14## A description of the reaction and its conditions is found in Schraufstatter, "Darstellung und Reaktionen von 4,4'-Dihydroxydiphenylacetonitril", 295 Arch. Pharm. 269 (1962).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[O:11][CH2:12][CH2:13][OH:14]>C(OCC)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[O:11][CH2:12][CH2:13][O:14][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: COc1cccc(OCCO)c1
Reactant: NS(=O)(=O)Cl
Solvent: CCOCC
Product: COc1cccc(OCCOS(N)(=O)=O)c1

Procedure:
The title compound was prepared by procedures of Example 4 from sulfamoyl chloride and 2-(3-methoxyphenoxy)ethanol through the first evaporation step to give a brown, viscous, oily residue. The oil was dissolved in 300 ml of ethyl ether. The organic solution was washed with two 300 ml portions of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to give a viscous, oily residue for the second time. The oil was purified by chromatography using silica gel and methylene chloride-acetone in 90:1 ratio as eluting agent. Fractions containing the title compound were combined and solvents evaporated under reduced pressure to give a viscous oil which solidified on standing. The solid was recrystallized from ethyl-petroleum ether (30°-60° C.) to give the title compound as white solid, mp 78°-82° C., in 46% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH2:12]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:13]#[CH:14].C(N(CC)CC)C>CN(C=O)C.C(OCC)C.[Cu]I.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>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:12][C:13]#[C:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: C#CCOC1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1OCc2cc(C#CCOC3CCCCO3)ccc21
Temperature: 65 °C

Procedure:
To a mixture of 5-bromophthalide (2.00 g, 9.39 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (5.3 ml, 37.6 mmol), copper(I) iodide (0.645 g, 3.39 mmol), triethylamine (1.90 g, 18.8 mmol) in DMF (20 ml), was added tetrakis(triphenylphosphine)palladium (1.30 g, 1.13 mmol). The mixture was heated at 65° C. under argon for 16 hours, cooled to room temperature and diluted with diethyl ether (250 ml). The filtrate was washed with brine (4×100 ml), dried over anhydrous Na2SO4, and concentrated to give a dark-reddish residue. Purification of the residue mixture by silica gel column chromatography, eluted with a gradient of EtOAc, led to 5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-3H-isobenzofuran-1-one as a white solid (2.23 g, 87%).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[C:13]([O:24][CH:25]([CH3:27])[CH3:26])(=[O:23])[CH:14]([CH2:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[OH:15].C(O)(=O)[C@@H](CC(O)=O)O.C(I)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)P(N(C)C)(N(C)C)=O.C1COCC1>[CH2:1]([C:14]([CH2:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])([OH:15])[C:13]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CC(C)OC(=O)CC(O)C(=O)OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(O)C[C@@H](O)C(=O)O
Agent: [Li]CCCC
Solvent: CCI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(O)(CC(=O)OC(C)C)C(=O)OC(C)C
Temperature: -50 °C
Yield: 98.4 %

Procedure:
To a stirred solution of diisopropylamine (19.69 ml., 140 mmole) in 200 ml. of dry THF maintained under nitrogen at 0° C. was added with stirring n-butyl lithium (86.68 ml., 134.37 mmole). After 10 minutes the solution was cooled to about -50° C. and a solution of diisopropyl malate (13.95 g., 63.99 mmole) prepared with D-malic acid in dry hexamethylphosphoramide, HMPA (11.45 ml., 63.99 mmole) was added. The resulting red solution was allowed to warm to a temperature of about -10° C., and after a few minutes the mixture was cooled to about -20° C. and ethyl iodide (6.14 ml., 76.88 mmole) was added. The reaction mixture was allowed to warm to room temperature over one hour and was then heated for 45 minutes at 45° C. The reaction mixture was allowed to cool to room temperature, was neutralized with 1M citric acid, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness to yield 15.5 g. (62.99 mmole, 98.5% yield) of diisopropyl ethylmalate as an oil. The product was obtained as a mixture of the diastereoisomers represented by the following formulas ##STR90##
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:47]([CH3:48])=[CH:46][C:39]([O:40][CH2:41][C:42]([CH3:45])([OH:44])[CH3:43])=[CH:38][C:37]=1[CH3:49]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:47]([CH3:48])=[CH:46][C:39]([O:40][CH2:41][C:42]([OH:44])([CH3:43])[CH3:45])=[CH:38][C:37]=2[CH3:49])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCC(C)(C)O)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 1-(4-bromo-3,5-dimethylphenoxy)-2-methylpropan-2-ol following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.77 min; Mass spectrum (ESI+): m/z=535 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:9]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([CH3:38])[CH:32]=1)([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[C:14]([CH3:30])[CH:13]=1)[CH2:10][CH3:11])[CH3:8].[CH3:39][O:40][CH2:41]Cl.[Cl-].[NH4+]>CN(C)C=O>[CH2:7]([C:9]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([CH3:38])[CH:32]=1)([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([O:29][CH2:39][O:40][CH3:41])([C:25]([F:26])([F:27])[F:28])[C:21]([F:24])([F:23])[F:22])=[C:14]([CH3:30])[CH:13]=1)[CH2:10][CH3:11])[CH3:8]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
Potassium carbonate (1.8 g, 13.6 mmol) was added to a solution of 4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenol (Example 25-(1); 2.50 g, 5.45 mmol) in N,N-dimethylformamide (36 mL), and the mixture was stirred for 20 minutes. Then, methoxymethyl chloride (0.50 mL, 6.54 mmol) was added, and the mixture was stirred for one hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate/hexane) to give the title compound (1.46 g, 66%).
Reaction SMILES: [K].[N:2]([C@@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C@H:6]1[OH:16])=[N+:3]=[N-:4].N([C@H:20]1[C@H](O)CCN(C(OCC)=O)C1)=[N+]=[N-].IC>O.CN(C)C=O.CC(O)(C)C>[N:2]([C@@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C@H:6]1[O:16][CH3:20])=[N+:3]=[N-:4]
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](N=[N+]=[N-])C1
Reactant: CCOC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Agent: [K]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](OC)C1
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a stirred solution of 20.6 parts of 2-methyl-2-propanol, potassium salt in 54 parts of N,N-dimethylformamide was added dropwise a solution of 30.3 parts of a mixture of ethyl trans-4-azido-3-hydroxy-1-piperidinecarboxylate and ethyl trans-3-azido-4-hydroxy-1-piperidinecarboxylate in 45 parts of N,N-dimethylformamide at a temperature below 20° C. (ice bath). Upon completion, stirring was continued for 1 hour at room temperature. 25.9 parts of iodomethane were added dropwise at a temperature <10° C. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into 400 parts of water. The product was extracted with trichloromethane. The extract was washed with a sodium chloride solution, dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The desired fractions were collected and the eluent was evaporated, yielding 15.6 parts (48.8%) of ethyl trans-4-azido-3-methoxy-1-piperidinecarboxylate as a residue (interm. 4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[Cl:19]C(Cl)Cl>>[ClH:19].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Agent: O=[N+]([O-])c1ccncc1NCc1ccc(F)cc1
Product: Cl
Reaction time: 1 h

Procedure:
To a stirred and cooled (0° C.) solution of 8.7 parts of N-[(4-fluorophenyl)methyl]-4-nitro-3-pyridinamine, 1-oxide and 150 parts of trichloromethane was added dropwise a solution of 10.2 parts of phosphor trichloride in 75 parts of trichloromethane. Upon completion, the mixture was allowed to reach room temperature and stirring was continued for 1 hour at reflux temperature. The reaction mixture was cooled and the solvent was evaporated. The residue was stirred in trichloromethane. The product was filtered off and dried, yielding 9 parts of N-[(4-fluorophenyl)methyl]-4-nitro-3-pyridinamine monohydrochloride (16).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Cl:15][C:11]1[CH:10]=[C:9]([CH3:16])[C:8]2[C:13](=[CH:14][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=3)([C:3]#[N:4])[CH3:17])[N:7]=2)[CH:12]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: Cc1cc(Cl)cc2cn(CC(C)(N)C#N)nc12
Product: Cc1cc(Cl)cc2cn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5-chloro-7-methyl-2H-indazol-2-yl)propionitrile (58 mg, described in Example 101) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (77 mg, 73%). MS (ES): M/Z [M+H]=453. 1H NMR: (400 MHz, DMSO-d6): 1.69 (s, 3H), 2.38 (s, 3H), 5.05 (d, 1H), 5.21 (d, 1H), 7.03 (s, 1H), 7.66 (s, 1H), 7.87 (d, 2H), 7.94 (d, 2H), 8.37 (s, 1H) and 8.97 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).