Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[CH2:15]([OH:17])C.C=O.C1CCN2C(=NCCC2)CC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][C:3]=1[CH:12]([CH2:15][OH:17])[C:13]#[N:14]
Reactant: CCO
Reactant: N#CCc1cc(OC(F)F)ccc1Cl
Agent: C=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: N#CC(CO)c1cc(OC(F)F)ccc1Cl
Reaction time: 0.83 h
Yield: 65 %

Procedure:
A 25 mL flask with a stir bar was charged with 3.0 g (13.8 mmol) of 2-(2-chloro-5-(difluoromethoxy)phenyl)ethanenitrile, 12 mL of ethanol and 1.34 mL of 37% formaldehyde solution. The mixture was stirred and a mixture of 115 μL of 40% Triton B in methanol and 38 μL of DBU was added. After a very mild exotherm, all solids dissolved. After 50 minutes at ambient temperature, the reaction was quenched by the addition of 0.5 mL of 3 N HCL. The mixture was filtered to remove floc, diluted with 2 volumes of water and extracted with butyl chloride. The extracts were water washed and stripped to an oil. This was chromatographed on 35 g of silica gel eluting with 5%→60% EtOAc in hexane to recover 2.2 g (65% yield.) of the desired product, Rf 0.18 (silica gel, EtOAc:hexane=1:4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][C:7]=1[F:8].[C:19](Cl)(=[O:21])[CH3:20]>N1C=CC=CC=1.O1CCCC1.O>[C:16]([C:15]1[CH:18]=[C:11]([C:10]#[C:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=2)[CH:12]=[N:13][CH:14]=1)#[N:17]
Reactant: CC(=O)Cl
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(N)c2)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Dissolve 5-(3-amino-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in EXAMPLE 160), (0.2 g, 0.8 mmol) in anhydrous pyridine. A solution of acetyl chloride (0.07 g, 0.88 mmol) in tetrahydrofuran is added to the reaction and stirred overnight at room temperature. Concentrate and dissolve the crude reaction in ethyl acetate and water. Wash the organic layer with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter, concentrate and purify (silica gel chromatography, eluting with 95:5 to 80:20 dichloromethane:ethyl acetate), to give the title compound as a white solid (180 mg, 81%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][F:25])[CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[N:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([O:26][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]5[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][F:25])[CH2:19][CH2:18]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:35][N:34]=2)[CH:30]=[CH:31]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(CCF)CC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCN1CCN(CCF)CC1
Temperature: 85 °C
Yield: 56.1 %

Procedure:
4-Chloro-7-{2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy}-6-methoxyquinazoline (172 mg, 0.47 mmol) was dissolved in dimethylacetamide (5 ml). 5-Hydroxy-7-azaindole (69 mg, 0.51 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (71 mg, 0.51 mmol) were added and the mixture heated to 85° C. for 4 hours. The reaction mixture was cooled, filtered and concentrated. The resulting residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (94/6). The fractions containing the expected product were evaporated under vacuum and the residue was suspended in acetone, filtered and dried under vacuum to give 4-(7-azaindol-5-yloxy)-7-(2-[4-(2-fluoroethyl)piperazin-1-yl]ethoxy)-6-methoxyquinazoline (123 mg, 56%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CN(C=O)C.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:4][CH2:3][CH2:2][N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][CH2:6][O:7][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCCNCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COCCN(CCOCc2ccccc2)Cc2ccccc2)cc1
Reaction time: 8 h

Procedure:
Diethanolamine (42.0 g., 0.4 mole) is stirred under nitrogen in 800 ml. of dry DMF at 0° C. and 50% NaH in mineral oil (57.6 g., 1.2 mole) is added in small portions. After the sodium hydride has reacted, benzyl bromide (205.3 g., 1.2 mole) is added dropwise. The mixture is allowed to come to room temperature while stirring overnight. The reaction mixture is poured into water and is extracted with ether. The ether solution is extracted with dilute HCl. The acid extract is basified with NaOH and extracted with ether. Crude product is recovered by drying, filtering and evaporating the ether. The residual liquid (138.4 g.) is subjected to distillation at 290° C. and 0.01 mm. to remove volatile impurities. This gives 114.4 g. of amber oil.
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([F:23])[CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][Mg+].[Br-]>C1COCC1.CCOCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]([C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:12]=2)([OH:14])[CH3:36])=[CH:16][C:17]=1[F:23])#[N:22]
Reactant: C[Mg+]
Reactant: N#Cc1ccc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 1 h

Procedure:
To a solution of 4-cyano-3-fluorophenyl 1-(triphenylmethyl)imidazol-4-yl ketone from Step E (7.0 g, 15.3 mmol) in dry THF (280 mL), under argon, at −78° C., was added MeMgBr (5.3 mL of a 3.0 M solution in Et2O, 15.9 mmol), dropwise. After 1 hr, the reaction mixture was quenched with sat. aq. NH4Cl (100 mL) and extracted with CH2Cl2 (2×150 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane—30% to 50% EtOAc, to yield the titled product as pale solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].CO>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:18]([CH3:23])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)C(CC(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)O

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoate (0.4 mmol) was dissolved in 5 mL of DMSO, 10 mL of 1 NaOH and 5 mL of MeOH and heated at 100° C. overnight. The reaction was quenched with sat. KH2PO4 and extracted with 2× EtOAc. The EtOAc extracts were dried over MgSO4, filtered, and concentrated by rotary evaporator to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoic acid. MS found: (M+H)+=369.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19].[Na].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:6][C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1)=[O:22])=[O:5]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1
Temperature: 100 °C

Procedure:
9.5 g of 2,6-dichlorobenzamide and 10.34 g of 3,4-dichlorophenylisocyanate in 25 ml of pyridine to which 1 g of sodium has been added are heated on a steam bath (100° C.+) for 24 hours. The reaction mixture is poured on ice which contains concentrated hydrochloride acid and the solid precipitate is thoroughly washed with successively water and alcohol. The substance is recrystallized from acetonitrile. Melting point 232° C.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 11.3 %

Procedure:
Using cyclohexyl{3-methoxy-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.75 g) synthesized in Example 62(2) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.50 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.13 g, 12%) was obtained as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:14][N:15]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCCCCC>[C:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:14][N:15]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(O)c3ccccc3)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCCCCC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(=O)c3ccccc3)cc21
Temperature: 23 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl)-1H-indazol-6-yl }-methanol (68 mg, 0.15 mmol) in dichloromethane (3 mL) at 23° C. under n atmosphere of argon was added periodinane (Dess-Martin reagent) (190 mg, 0.45 mol). The resulting mixture was stirred at 23° C. for 1 hour. The solution was then diluted with hexane (3 mL) then filtered through Celite and concentrated under reduced pressure to a solid. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 9:1) to give phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanone (54 mg, 79% yield). Rfsm=0.41, Rfp=0.63 (7:3 hexane:EtOAc); FTIR (thin film) 3059, 2952, 2894, 1659, 1474, 1448, 1307, 1249, 1078, 836, 649 cm−1. MS (ESI) [M+H]/z Calc'd 455, found 455.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]1.[CH2:13]([N:16]=[C:17]=[O:18])[CH:14]=[CH2:15]>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:13]([NH:16][C:17]([O:12][N:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH2:3]1)=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCN=C=O
Reactant: ON=C1CCOc2ccccc21
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCNC(=O)ON=C1CCOc2ccccc21
Yield: 72.6 %

Procedure:
A solution containing 6.52 g (0.04 mole) of 4-chromanone oxime and 75 ml benzene was stirred and refluxed for 0.50 hrs. using a Dean-Stark apparatus. The solution was cooled to 60° and 6 drops triethylamine and 3.32 g (0.04 mole) allyl isocyanate in 10 ml benzene was added. The solution was stirred and refluxed for 4 hrs., concentrated to dryness, and the residue was recrystallized from 20 ml toluene to give 7.15 g (73%) of the product, m.p. 83°-86°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](OC)=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:13]OC.C([Li])CCC.CO[B:23]([O:26]C)[O:24]C.[O:28]1[CH2:32]CC[CH2:29]1>>[CH3:11][O:10][C:4]1[C:5]([CH2:29][O:28][CH3:32])=[C:6]([B:23]([OH:24])[OH:26])[CH:7]=[CH:2][C:3]=1[O:12][CH3:13]
Reactant: C1CCOC1
Reactant: COB(OC)OC
Reactant: COCOc1c(Br)ccc(OC)c1OC
Agent: [Li]CCCC
Product: COCc1c(B(O)O)ccc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 1-bromo-3,4-dimethoxy-2-methoxymethoxy-benzene (1 g, 3.62 mmol) in tetrahydrofuran (15 mL) at −78° C., was added n-butyllithium (5.5 mL, 7.24 mmol) and stirred for 20 min to this trimethylborate (3.76 g, 36.23 mmol) was added and the resultant reaction mixture was stirred for 30 min at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3,4-dimethoxy-2-(methoxymethyl)phenylboronic acid as a solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][N:20]([CH3:28])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[N:22]=2)=[CH:17][CH:16]=1.[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH3:28])[C:21]2[N:22]=[C:23]([F:27])[C:24]([B:31]([OH:36])[OH:32])=[CH:25][CH:26]=2)=[CH:29][CH:30]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(CN(C)c2cccc(F)n2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN(C)c2ccc(B(O)O)c(F)n2)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
In a microwave tube was placed 2,6-difluoropyridine (0.183 mL, 2.00 mmol) and (4-methoxyphenyl)-N-methylmethanamine (0.604 g, 4.00 mmol) in 2 mL of water. The mixture was heated at 150° C. for 20 min. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layer were dried over anhydrous sodium sulfate, filtered and concentrated to give 470 mg of a crude yellow oil, which was purified by column chromatography (3/1 hexanes/ethyl acetate) to give 400 mg of N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine as a clear, colorless oil. To a solution of diisopropylamine (1.92 mL, 13.6 mmol) in 25 mL of THF at 0° C. was added butyllithium (1.6 M in hexanes, 8.93 mL, 14.3 mmol). The mixture stirred for 30 minutes and was then cooled to −60° C. and N-(4-methoxybenzyl)-6-fluoro-N-methylpyridin-2-amine (1.760 g, 7.15 mmol) was added dropwise in 10 mL of THF. The reaction stirred for 1 h at −60° C. and then triisopropyl borate (2.88 mL, 12.5 mmol) was added and the reaction allowed to warm up to RT and stirred for 1 h. Ammonium chloride (sat.) was added and the reaction was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2.13 g of a crude yellow foam, which was purified by column chromatography (3/1 hexanes/ethyl acetate to 1/1 ethyl acetate/hexanes) to give 750 mg of a off-white solid. ES+=291.2 (M+H)
Reaction SMILES: [C:1]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9](OC)=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[CH3:18][NH:19][O:20][CH3:21].[Li]CCCC>>[C:1]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([N:19]([CH3:18])[O:20][CH3:21])=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CNOC
Reactant: CCCCC#Cc1ccccc1C(=O)OC
Agent: Cl
Agent: [Li]CCCC
Product: CCCCC#Cc1ccccc1C(=O)N(C)OC
Yield: 77 %

Procedure:
Treatment of methyl 2-(1-hexyn-1-yl)benzoate (157) (2.29 g, 10.6 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 2.0 g (77%) of the title compound (158) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.92 (t, J=7.2 Hz, 3H), 1.40-1.60 (m, 4H), 2.39 (t, J=7.0 Hz, 2H), 3.32 (br s, 3H), 3.50 (br s, 3H), 7.26-7.35 (m, 3H), 7.37-7.45 (m, 1H). LCMS (APCI): m/z 246 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][O:37][CH2:38][CH2:39]Br>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:39][CH2:38][O:37][CH3:36])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1
Reactant: COCCBr
Product: COCCN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 145) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: FC1C(F)=CC(F)=C(F)C=1.[F:11][C:12]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:13]=1[C:14]#[N:15].C(C1(C(F)=C(F)C=C(F)C1F)C=O)#N>>[F:11][C:12]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:13]=1[CH2:14][NH2:15]
Reactant: N#Cc1c(F)c(F)cc(F)c1F
Agent: Fc1cc(F)c(F)cc1F
Agent: N#CC1(C=O)C(F)=C(F)C=C(F)C1F
Product: NCc1c(F)c(F)cc(F)c1F

Procedure:
From the toluene extract, a small amount of a sample was withdrawn, and it was subjected to GC analysis. As a result of the analysis, the tetrafluoroterephthalonitrile as a raw material remained in an amount of 21.0 mol %, and tetrafluoroterephthalaldehyde was obtained in an amount of only 5.0 mol %. The amount of 2,3,5,6-tetrafluorobenzene was 0.65 mol %, the amount of 2,3,5,6-tetrafluorobenzonitrile was 0.53 mol %, and 1-cyano-2,3,5,6-tetrafluorobenzaldehyde wherein a nitrile group on only one side had reacted was obtained in an amount of 63.1 mol %. On the other hand, the aqueous phase was neutralized and then subjected to GC analysis. As a result of the analysis, presence of 2.88 mol % of 2,3,5,6-tetrafluorobenzylamine was confirmed. The results are set forth in Table 2.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:17].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[CH2:23]=O.Cl>O1CCOCC1>[ClH:17].[C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:16])[CH:13]([CH2:23][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH3:15])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(=O)c1cc(-c2ccccc2)no1
Reactant: C1CCNC1
Reactant: C=O
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CN1CCCC1)C(=O)c1cc(-c2ccccc2)no1

Procedure:
In a similar manner to Example 1, 14 g (85.1 mmol) of 3-phenyl-5-butyrylisoxazole, 8.4 g (78.5 mmol) of pyrrolidine hydrochloride, 2.6 g (86.7 mmol) of paraformaldehyde and 20 droplets of concentrated hydrochloric acid were reacted in 20 ml of dioxane so that 3-phenyl-5-{2-(1-pyrrolidinylmethyl)butyvyl} was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:26])[C:9]=2[C@H:27]([OH:33])[C:28]([O:30]CC)=[O:29])=[CH:4][CH:3]=1.[BH4-].[Na+].BrC1C=[C:45]2[C:40]([CH:41]=C(C)C(C(=O)C(OCC)=O)=C2C2C=CC(Cl)=CC=2)=[CH:39]C=1.[CH3:62][C:63]([NH2:67])([C:65]#[CH:66])[CH3:64]>>[NH2:67][C:63]([CH3:64])([CH3:62])[C:65]#[C:66][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[C:10]([CH3:26])[C:9]([C@H:27]([O:33][C:40]([CH3:45])([CH3:41])[CH3:39])[C:28]([OH:30])=[O:29])=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(=O)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(C)(C)N
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc2ccc(C#CC(C)(C)N)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-(7-(3-Amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (98) was prepared by the method of Example 67 using the reduction method of Example 51, step 3, for (S)-ethyl 2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBH4 step, from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. The remainder of the sequence follows the method of Example 67 using 2-methylbut-3-yn-2-amine in Step 7. 1H-NMR: 400 MHz, (CD3OD) δ: 7.81 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.57 (m, 3H), 7.45 (d, J=8 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.62 (s, 3H), 1.68 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M—NH2]calcd for C28H28ClO3: 447.2; found: 446.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[C:21](=[O:23])[N:25]([CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28])[C:15]2=[O:17]
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)c(OC)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c(OC)c1
Yield: 67 %

Procedure:
A mixture of 3-(2,4-dimethoxyphenylamino)phthalic acid (0.75 g, 2.4 mmol) and rac-α-aminoglutarimide hydrochloride (0.40 g, 2.4 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.64 g of the product at 25:75 hexanes-ethyl acetate, in 67% yield: mp 208-210° C.; 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.54-2.64 (m, 2H), 2.83-2.92 (m, 1H), 3.78 (s, 3H), 3.79 (s, 3H), 5.12 (dd, J=12.7 Hz, J=5.4 Hz, 1H), 6.57 (dd, J=8.6 Hz, J=2.6 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.95 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.7, 55.4, 55.7, 99.5, 104.7, 110.4, 112.2, 118.3, 120.1, 125.2, 132.1, 136.1, 144.2, 153.7, 157.9, 167.2, 168.9, 170.1, 172.8; Anal. calcd for C21H19N3O6.0.3H2O: C, 60.81; H, 4.76; N, 10.13. Found: C, 60.87; H, 4.64; N, 10.00.