Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:4]=1
Reactant: COC(=O)c1ccc(OC)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 107.8 %

Procedure:
To a solution of methyl 4-methoxy-2-(4-fluorophenyl)benzoate (9.8 g; 0.029 mol) in methanol (75 ml) was added 2N aqueous sodium hydroxide solution (45 ml) and the mixture heated at reflux for 1.5 h. The reaction was cooled to ambient temperature, filtered and the filtrate concentrated in vacuo to remove the methanol. The residual aqueous phase was washed with diethyl ether, acidified to pH 1 with concentrated HCl and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and the solvent removed in vacuo to give 4-methoxy-2-(4-fluorophenyl)benzoic acid as a white solid (7.7 g), which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[Li].C(N(CC)CC)C>C(O)(C)(C)C>[NH2:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: NCc1ccccc1CC(=O)O
Agent: [Li]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: NCC1=C(CC(=O)O)CC=CC1

Procedure:
The procedure used by Welch, Dolfini and Giarrusso in U.S. Pat. 3,720,665 (Example 1) to make D-2-amino-2-(1,4-cyclohexadienyl)acetic acid was adapted. A solution of 830 ml. of distilled liquid ammonia was dried with 40 mg. of lithium under an argon atmosphere. To this stirred solution was added 11.0 g. (0.07 mole) of 2 -aminomethylphenylacetic acid and 340 ml. of tert. butyl alcohol. A total of 1.6 g. (0.225 mole) of lithium was added to the vigorously stirred solution over a period of 2 hours. The grey mixture was then treated with 35 g. (0.215 mole) of triethylamine (TEA) hydrochloride and stirred overnight at room temperature for 18 hours. The tert. butyl alcohol was removed at 40° (15 mm.) to yield a white residue which was dried in vacuo over P2O5 overnight. The solid was dissolved in 30 ml. of 1:1 methanol-water and added with stirring to 3.5 l. of 1:1 chloroform-acetone at 5°. the mixture was stirred for 20 min. and the amino acid α-(2-aminomethyl-1,4-cyclohexadienyl)acetic acid, was collected and dried for 16 hours in vacuo over P2O5 to yield 6.3 g. (58%) of white crystals, m.p. 190° decomp. The IR and NMR spectra were consistent for the structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[CH:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.28) (5.7 g, 16.34 mmol) and commercially available 3-nitrophenylboronic acid (3.274 g, 19.61 mmol) according to the general procedure VI. Obtained as a white solid (6.6 g, 92%). MS (ISP) 436.2 [(M+H)+]; mp 164° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15]C)[CH:11]=2)[CH:6]=1.O>Br.C(O)(=O)C>[CH3:17][C:4]([CH3:18])([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)[C:3]([OH:19])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccc2cc(OC)ccc2c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C(=O)O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of α-methyl-6-methoxy-2-naphthaleneacetic acid methyl ester (12.2 g, 50 mmol) in tetrahydrofuran (100 ml) at -70° C. is added a solution of lithium diisopropylamide in cyclohexane (50 ml, 1.5 equiv). After 20 min, methyl iodide (4.0 ml, 1.3 equiv) is added followed by hexamethylphosphoramide (20 ml). After allowing the reaction mixture to warm to room temperature and stir 16 hours, the reaction is quenched by addition of acetic acid (4.3 ml, 75 mmol). The solvent is then removed and the residue is partitioned between ethyl acetate and water. The organic layer is washed with water 3 times and finally with brine. After drying over magnesium sulfate, the organic extract is evaporated to afford a crude solid. Recrystallization of this solid from hexane affords 8.56 g (66%) of α,α-dimethyl-6-methoxy-2-naphthaleneacetic acid methyl ester as white crystals, m.p. 97°-98° C. A solution of this ester (7.4 g, 28.6 mmol) in 48% HBr (50 ml) and acetic acid (50 ml) is refluxed for 3 hours. After the reaction mixture is cooled to room temperature, 0.8 L of water is added and the reaction mixture is extracted with ethyl acetate 5 times. The combined organic extract is washed sequentially with saturated sodium bicarbonate solution and water. After drying over magnesium sulfate, the organic extract is evaporated to afford 6.1 g (93%) of α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid as white crystals, m.p. 208°-210° C. The title compound is prepared according to the method of Example 7 using α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid. A white solid is obtained having a melting point of 207°-209° C.
Reaction SMILES: Cl.[NH2:2]O.C([O-])(=O)C.[Na+].[Cl:9][C:10]1[C:11]([N:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[C:12]([C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH:13]=[CH:14][C:15]=1[Cl:16].O>C(O)C>[Cl:9][C:10]1[C:11]([N:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[C:12]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:17]([C:18]1[CH:24]=[N:2][O:20][C:19]=1[CH:21]1[CH2:23][CH2:22]1)=[O:28]
Reactant: CCOC=C(C(=O)c1ccc(Cl)c(Cl)c1N(CC)C(=O)OC)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(C(=O)OC)c1c(C(=O)c2cnoc2C2CC2)ccc(Cl)c1Cl
Yield: 40.9 %

Procedure:
Hydroxylamine hydrochloride (0.53 g) and sodium acetate (0.63 g) were added to a stirred solution of 1-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione (2.88 g) in ethanol. After 0.5 hours water was added, and the mixture extracted (dichloromethane), dried (magnesium sulphate) and evaporated to dryness. Purification by chromatography gave 4-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole (compound number 2, 1.09 g), m.p. 76°-78° C. as a white solid.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C-:10]#[N:11].[K+].CS(C)=O>O>[C:10](#[N:11])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC#CCBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC#CCC#N

Procedure:
A mixture of 5 g. of 1-bromo-2-octyne, 7 g. of potassium cyanide and 35 ml. of dimethylsulfoxide is stirred and heated under nitrogen for about 2.5 hrs. at reflux temperature. The mixture is then poured into water and extracted with ether. The ether extract is washed with water, than with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure leaving a residue comprising 3-nonynenitrile. The thus obtained residue is mixed with 45 ml. of 25% hydrogen chloride in methanol containing 0.5 ml. of water while cooling in an ice bath. The ice is allowed to melt and the mixture is stirred for about 18 hrs., then is poured into water and extracted with ether. The ether extract is washed with water, aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over sulfate, and evaporated under reduced pressure leaving a residue comprising methyl 3-nonynoate. A mixture of the thus obtained methyl 3-nonynoate, 500 mg. of 5% palladium-barium sulfate catalyst and 40 ml. of pyridine is shaken under hydrogen for about 2 hrs., until the uptake of hydrogen practically ceases. The mixture is then filtered, diluted with water, and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate, then is dried over sodium sulfate and evaporated to leave a residue comprising methyl 3-nonenoate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:42]([CH3:44])[CH3:43])[CH:29]([O:34][Si](C(C)(C)C)(C)C)[C:30]([F:33])([F:32])[F:31])=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:42]([CH3:43])[CH3:44])[CH:29]([OH:34])[C:30]([F:32])([F:31])[F:33])=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Reaction time: 4.5 h
Yield: 100.4 %

Procedure:
A solution 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.96 g) in dry tetrahydrofuran (8 mL) was treated with tetrabutylammonium fluoride (1M in tetrahydrofuran; 1.62 mL) and the mixture was stirred for 4.5 h. The reaction mixture was diluted with ethyl acetate (75 mL), washed with water (twice) and brine, dried and evaporated to yield a yellow foam. Purification by flash chromatography, eluting with ethyl acetate:chloroform (first 5:95, then 10:90), and overnight drying under vacuum gave 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide as a white solid (0.793 g); TLC: Rf =0.19, chloroform:ethyl acetate (20:1); 300 MHz NMR: 0.81 (d,3, J=6.7), 0.88 (d,3, J=6.7), 1.67-1.84 (m,1), 3.82 (t,1, J=8.8), 4.0-4.17 (m,1), 4.34 (d,1, J= 15), 4.50 (m,1), 5.18 (s,2), 6.20 (d,1, J=7.7), 6.49 (d,1, J=7), 7.31-7.47 (m,10), 7.86 (d,1, J=9.7), 7.91 (d,1 J=7.7), 8.53 (s,1); MS: m/z=532(M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:49][CH3:50])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([O:44]COC)([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[F:52]>ClCCl>[CH3:8][O:9][C:10](=[O:53])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:49][CH3:50])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([OH:44])([C:40]([F:41])([F:43])[F:42])[C:36]([F:38])([F:37])[F:39])=[C:29]([CH3:48])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][C:13]=1[F:52]
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
Dichloromethane (1.5 mL) and trifluoroacetic acid (0.153 mL) were added to (4′-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 78-(1); 41 mg, 0.063 mmol), and the mixture was stirred at room temperature for one day. The reaction solution was directly concentrated under reduced pressure and azeotropically distilled with toluene. The residue was purified by preparative TLC (hexane/ethyl acetate=5/1) to give the title compound (30.1 mg, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.ClCCl.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(OCC)C>[CH3:28][S:29]([O:15][C@H:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:17]=[CH:16][C:5]=3[N:6]=2)[CH2:10]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 20 mL scintillation vial equipped with a magnetic stirbar was added (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-ol (Reference Example 7, 1.15 g, 3.67 mmol). Dichloromethane (10 mL) was then added to the reaction vial to give a solution. To this stirred solution was added 2.5 equivalents of triethylamine (1.279 mL, 9.18 mmol). The reaction vial was capped with a septum and vented to a bubbler. The vial was placed in an ice water bath. To this stirred, 0° C. solution was added dropwise 2.0 equivalents of methanesulfonyl chloride (0.572 mL, 7.34 mmol). The reaction mixture was stirred for 10 minutes at 0° C., then the ice bath was removed and stirring was continued at room temperature overnight. The reaction mixture was washed with water, then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give an oil that was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF10-4g [2 connected in series], 100% dichloromethane). Fractions containing product were combined and concentrated under reduced pressure to give a solid that was treated with diethyl ether. This suspension was filtered to collect (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate. 1H NMR (300 MHz, CDCl3) δ ppm 1.68-1.81 (m, 1H), 1.94-2.16 (m, 3H), 3.06 (s, 3H), 3.51-3.68 (m, 2H), 3.85-3.90 (m, 2H), 4.86-4.93 (m, 1H), 7.37-7.39 (m, 2H), 7.69-7.71 (m, 1H); MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7]([Cl:24])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(F)ccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cc(F)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-acetoxy-4-fluorobenzoic acid (852 mg, 4.9 mmol) in dry dichloromethane (40 mL) under dry nitrogen were added sequentially dry DMF (8 drops), dry pyridine (0.5 mL) and oxalyl chloride (0.5 mL). After stirring 1.5 h at room temperature, the reaction mixture was evaporated to dryness to afford 2-acetoxy-4-fluoro-benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 93.6 %

Procedure:
Substantially the same procedure as in Reference Example 5 was repeated using 4,4'-dichlorobenzhydrol (14.7 g, 58.1 mmol) and ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) to give 21.0 g (yield: 94%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].B(O)(O)[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCO.O.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>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOC(=O)c1nc(-c2ccc(C)cc2)c2ccccc2c1OCc1ccccc1
Reaction time: 4 h
Yield: 105.8 %

Procedure:
4-Benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (207 mg, 0.5 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) were dissolved in THF (3 ml) and the solution was stirred for 10 min before a solution of p-tolylboronic acid (68 mg, 0.5 mmol) in EtOH (0.5 ml) and a solution of Na2CO3 (106 mg, 1 mmol) in water (0.5 ml) were added. The resulting mixture was refluxed with stirring for 4 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (2 ml) and the mixture was extracted with EtOAc (10 ml). The organic phase was dried over MgSO4 and evaporated in vacuo to give a yellowish oil (225 mg). Purification by flash column chromatography on silica gel using hexanes:EtOAc=94:6 as the eluent gave the title compound as a colorless oil; MS-(+)-ion: M+1=426.2.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[NH2:15][C:16]1[N:42]=[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:41])=[C:29]([NH:31][C:32]([C:34]4[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[CH:35]=4)=[O:33])[CH:30]=3)=[CH:23][N:18]2[N:17]=1>O1CCCC1.CN(C)C=O.O>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([NH:15][C:16]1[N:42]=[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:41])=[C:29]([NH:31][C:32]([C:34]4[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[CH:35]=4)=[O:33])[CH:30]=3)=[CH:23][N:18]2[N:17]=1)=[O:6]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)nn4c3)ccc2F)n(C)n1
Reactant: O=C(O)C1CC1(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5(F)F)nn4c3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of 2,2-difluorocyclopropanecarboxylic acid (104 mg, 0.850 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (74.3 μL, 0.850 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (3 mL). N-{5-[(2-Amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (65.0 mg, 0.170 mmol) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=80/20→0/100) and recrystallized from ethyl acetate to give the title compound (22.0 mg, 27%) as a white solid.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[C:6]([C:14]1[C:15]([NH:21][C:22](=[O:25])[CH2:23]I)=[CH:16][N:17]([CH3:20])[C:18]=1[CH3:19])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O.C(O)C>[C:6]([C:14]1[C:15]([NH:21][C:22](=[O:25])[CH2:23][NH:4][OH:1])=[CH:16][N:17]([CH3:20])[C:18]=1[CH3:19])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: NO
Reactant: Cc1c(C(=O)c2ccccc2)c(NC(=O)CI)cn1C
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)c2ccccc2)c(NC(=O)CNO)cn1C
Reaction time: 48 h

Procedure:
Sodium hydroxide (64 g) was added to a solution of hydroxylamine hydrochloride (111 g) in water (370 ml) and the obtained solution was diluted with ethanol (3500 ml). N-(4-benzoyl-1,5-dimethyl(1H)pyrrol-3-yl)-2-iodoacetamide (124.5 g) was then added and the obtained suspension was stirred under nitrogen stream for about 48 hours. The reaction mixture was filtered in order to remove the salts and the filtrate was concentrated to dryness at the pump. The residue was washed with a small amount of water and crystallized from ethyl acetate yielding 82.5 g of the compound of the title. M.p. 140°-42° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[NH:7][C:8]([C:12](=[O:18])[C:13]([CH3:17])([CH3:16])[CH2:14][CH3:15])=[N:9]2)=[CH:4][CH:3]=1.O[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]([C:8]1[NH:7][C:6](=[O:19])[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:3][CH:4]=2)[N:9]=1)=[O:18]
Reactant: CCC(C)(C)C(=O)c1nc2cc(O)ccc2c(=O)[nH]1
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)c1nc2cc(OCCCN3CCOCC3)ccc2c(=O)[nH]1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
7-hydroxy-3-methylpivaloyl-3,4-dihydroquinazolin-4-one (750mg, 2.7 mmol) was suspended in methylene chloride (40 ml) and 4-(3-hydroxypropyl)morpholine (490 mg, 3.4 mmol) and triphenylphosphine (890 mg, 3.4 mmol) were added at 5° C. The mixture was stirred for 5 minutes at 5° C. and diethyl azodicarboxylate (590 mg, 3.4 mmol) was added over 5 minutes. The reaction mixture was stirred at 5° C. for 30 minutes then at ambient temperature for 1 hour. The reaction mixture was purified directly by column chromatography eluting with methylene chloride, then ethyl acetate, then acetonitrile/ethyl acetate (1/5), and finally acetonitrile/ethyl acetate/aqueous ammonia (50/50/0.5). The purified product was triturated with ether/isohexane and collected by filtration to give 3-methylpivaloyl-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (745 mg, 68%).
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[F:28][C:29]([F:35])([F:34])[CH2:30][CH2:31][CH:32]=O>CC#N>[F:28][C:29]([F:35])([F:34])[CH2:30][CH2:31]/[CH:32]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=CCCC(F)(F)F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)/C=C/CCC(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a suspension of lithium chloride (0.504 g, 11.9 mmol) in MeCN (20 mL) were added ethyl 2-(diethoxyphosphoryl)acetate (available from Aldrich) (1.91 mL, 9.52 mmol) and DBU (1.42 mL, 9.52 mmol) at room temperature. The mixture was cooled to 0° C., and 4,4,4-trifluorobutanal (available from Matrix Scientific) (1.00 g, 7.93 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford (E)-ethyl 6,6,6-trifluorohex-2-enoate 68.B (6:1 E/Z) as a colorless liquid (1.13 g, 73%).