Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[CH2:25]([NH:31][CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>ClCCl>[CH2:25]([N:31]([CH3:32])[C:9]([C:7]1[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(=O)c1ccc(C(=O)O)o1
Reactant: CCCCCCNC
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCCN(C)C(=O)c1ccc(C(C)=O)o1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 4.6 g. (0.03 mole) of 5-acetylfuran-2-carboxylic acid in 150 ml. of dichloromethane was added 3.3 g. (0.033 mole) of N-methylmorpholine. The resulting solution was cooled to -20° C., and 3.6 g. (0.033 mole) of ethyl chloroformate was added dropwise, with stirring. Stirring was continued for 1 hour at -15° C. and then 3.8 g. (0.033 mole) of n-hexylmethylamine was added dropwise at -20° C. The resulting mixture was stirred for 1.5 hours while being allowed to warm to room temperature. The reaction mixture was then washed with water, dried (Na2SO4) and evaporated in vacuo to give 7.5 g. of an oil. This oil was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate, to give 5.6 g. of the title amide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:17]([CH:26]=O)=[N:16][CH:15]=2)([CH3:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH2:31].CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1COCC1>[Cl:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH:31][CH2:26][C:17]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:14]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH3:12])[CH3:13])=[CH:15][N:16]=1
Reactant: COc1ccc(C(C)(C)c2cnc(C=O)n2-c2ccc(F)cc2)cc1OC
Reactant: Nc1c(F)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)c2cnc(CNc3c(F)cccc3Cl)n2-c2ccc(F)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
A solution of 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-carbaldehyde (280 mg, 0.76 mmol), 2-chloro-6-fluoroaniline (332 mg, 2.28 mmol), TsOH (72 mg, 0.38 mmol) in THF (8 mL) was heated at reflux for 15 h over molecular sieves (4A). The solution was cooled to 0° C., and NaBH4 (57 mg, 1.5 2 mmol) was added in several portions. The resulting mixture was stirring for 1 h, and filtered through Celite™ to remove molecular sieves. The filtrate was quenched with H2O (5 mL), 2N NaOH (5 mL) and extracted with DCM (2×10 mL). The organic layers were dried over MgSO4 and concentrated to give a residue, which was purified by flash chromatography to provide the title compound as a white solid (157 mg, 0.315 mmol, 42%). 1H NMR (400 MHz, CDCl3) δ1.49 (s, 6H), 3.72 (s, 3H), 3.85 (s, 3H), 4.13 (d, 2H), 4.65 (br, 1H), 6.45 (dd, 1H), 6.48 (m, 2H), 6.51 (d, 1H), 6.60 (m, 1H), 6.64 (d, 1H), 6.76 (dd, 1H), 6.80 (t, 2H), 7.00 (dt, 1H), 7.13 (s, 1H). MS (EI) m/z 498 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[N:19]=[C:18]([Cl:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc2ccccc2c(=O)[nH]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 25 g of 2-(1-methyl-5-nitro-2-imidazolyl)-4-quinazolinone and 26.2 g of phosphorus pentachloride in 150 ml of phosphorus oxychloride is boiled for 3 hours and then evaporated in vacuo (12 Torr). The residue is taken up in methylene chloride and stirred with water for one hour at room temperature. The mixture is made alkaline with sodium bicarbonate and extracted by dropwise addition of methylene chloride. The mixture is dried with magnesium sulphate and treated with animal charcoal, filtered and evaporated in vacuo (12 Torr) at 30° C. The residue is mixed with ether, filtered and washed pure with ether to obtain the heading compound, m.p. 178°-181° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][CH:14]([NH2:23])[CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23][CH:14]([CH3:13])[CH:15]([OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)#[N:2]
Reactant: CC(N)C(O)c1ccccc1
Reactant: COC(=NC#N)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(N=C(NC#N)c1ccccn1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.24 g, 1.5 mmol) was dissolved in methanol (5 ml), DL-phenylpropanolamine hydrochloride (0.31 g, 1.7 mmol, supplied by Tokyo Chemical Industry Co. Ltd.) and triethylamine (0.17 g, 1.7 mmol) were added, and the resulting mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was extracted with ethyl acetate (30 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.23 g, 0.8 mmol, yield: 54%) as colorless crystals.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br-].CP(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:29]1[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1>C(OCC)C>[CH2:1]=[C:29]1[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)[O-]
Agent: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of potassium tert-butoxide (15.5 g, 137 mmol) and methyltriphenylphosphine bromide (49 g, 137 mmol) in diethyl ether (300 mL) was stirred at room temperature for 1 hour, followed by the addition of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (10 g, 58 mmol in 100 mL diethyl ether). The mixture was stirred at 35° C. for 2 hours and then allowed to cool to room temperature. The mixture was filtered through a pad of celite, washing with diethyl ether. The filtrate was partitioned with water and washed twice with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil which was purified by column chromatography. Eluting with 10% ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 9.80 g, 58 mmol (100%) of 1,1-dimethylethyl 3-methylideneazetidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, DMSO): 5.05-4.85 (m, 2H), 4.95-4.63 (m, 4H), 1.45 (s, 9H). GC-MS for C9H15NO2: 169.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([CH2:31][NH2:32])=[C:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:19]=[CH:18]C=CC=3)=[C:8]2[S:7][CH2:6]1)=[O:4].COC([C@H]1N2C(=O)C(C#N)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3C=CC=CC=3)=C2SC1)=O.COC(C1N2C(=O)C(C#N)=C(CC3C4C(=CC=CC=4)C=CC=3)C(C3CC3)=C2SC1)=O>>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:33])[C:11]([CH2:31][NH2:32])=[C:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([CH:14]3[CH2:18][CH2:19]3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(CN)c(=O)n21
Agent: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Agent: COC(=O)[C@@H]1CSc2c(-c3ccccc3)c(Cc3cccc4ccccc34)c(C#N)c(=O)n21
Product: COC(=O)[C@@H]1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(CN)c(=O)n21
Yield: 73 %

Procedure:
By following the procedure described for the preparation of 7a from 6a, 6b (46 mg, 0.11 mmol) gave 7b as a yellow solid (33 mg, 73%): [α]D−64 (c 0.25, CHCl3); IR λ 2952, 1747, 1631, 1569, 1504, 1259, 1214 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.2, 1H), 7.94-7.27 (m, 5H), 6.81 (d, J=6.8, 1H), 5.67 (d, J=7.3, 1H), 4.77-100 MHz, CDCl3) δ 168.3, 161.1, 155.6 149.5, 133.7, 133.7, 131.6, 128.7, 127.3, 126.4, 126.0, 125.5, 123.8, 123.4, 116.9, 115.7, 63.4, 53.5, 37.6, 32.6, 31.6, 11.8, 7.2, 7.1; HRMS (FAB+) calcd for C24H25N2O3S 421.1586, obsd 421.1593.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[O:32][C:31]([Si](C(C)C)(C(C)C)C(C)C)=[N:30][CH:29]=2)O1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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>[O:32]1[C:28]([C:2]2[C:3]3[N:4]([C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[CH:29][N:30]=[CH:31]1
Reactant: CCOC(=O)c1cnc2c(Br)cc(C(F)(F)F)cn12
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
A mixture of ethyl 8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (500 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (573 mg), tetrakis(triphenylphosphine)palladium(0) (171 mg), potassium carbonate (410 mg), DME (12 mL) and water (3 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (6 mL), and 1N hydrochloric acid (2 mL) was added thereto. The mixture was stirred at room temperature for 2 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (0.13 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]=[O:18].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O1CCCC1.Cl.O>O1CCCC1>[CH:19]1([CH:17]([C:3]2[S:4][C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=3)=[CH:6][C:2]=2[CH3:1])[OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: Br[Mg]C1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (0.8 g) in tetrahydrofuran (20 mL) was added dropwise 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min. The reaction mixture was treated with 1N hydrochloric acid and poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (0.5 g, 51%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[I:17]N1C(C)(C)C(=O)N(I)C1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([I:17])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Agent: O=S(=O)(O)O
Product: Cc1c(I)cc(Cl)cc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 158.9 %

Procedure:
To a solution of 5-chloro-2-methylbenzoic acid (10.0 g, 58.6 mmol) in sulfuric acid (75 mL, 1407 mmol) was added portionwise 1,3-diiodo-5,5-dimethylimidazolidine -2,4-dione (12.0 g, 31.6 mmol). The reaction turned very dark and quickly formed a thick suspension. The reaction was stirred for 2 h, at which time it was poured into ice water (˜500 mL) and stirred for 30 min to break up the solids. The precipitate was filtered off, washed with water, and dried under vacuum to give 5-chloro-3-iodo-2-methylbenzoic acid (17.3 g, 50.2 mmol, 86% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.48 (br. s., 1H), 8.11 (d, J=2.27 Hz, 1H), 7.73 (d, J=2.27 Hz, 1H), 2.54 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36](=[O:52])[CH2:37][N:38]=[C:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:34])([CH3:33])[CH3:32].[OH-].[Na+].O>C(#N)C>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C:15]([CH:37]([N:38]=[C:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:52])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(=O)CC(c2cc(Cl)cc(Cl)c2)(C(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
To a solution of 4-[(E)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (1 g) and (benzhydrylidene-amino)-acetic acid tert-butyl ester (643 mg) in acetonitrile (5 mL) was added a solution of sodium hydroxide (0.6 mL, 32%) at room temperature. The reaction was stirred at ambient temperature for 18 hours, then water was added and the reaction mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 05% ethyl acetate in cyclohexane) to afford 4-[3-[(Benzhydrylidene-amino)-tert-butoxycarbonyl-methyl]-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (1.12 g) as a yellow foam. 19F NMR (376 MHz, CDCl3) δ −60.99 and −61.88 ppm (mixture of 2 diastereoisomers).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CCOC(C)=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of tert-butyl (R)-2-(4-aminophenyl)morpholine-4-carboxylate (3.2 g, CAS 1260220-42-5) in DMF (25 ml) was added NBS (2.05 g) and the mixture was stirred at room temperature for 30 min. The reaction mixture was then poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, gradient: 0% to 70% EtOAc in heptanes) to give tert-butyl (R)-2-(4-amino-3-bromophenyl)morpholine-4-carboxylate (3.71 g, 90%) as an off-white solid. MS (ISP): 359.1 ([{81Br}M+H]+), 357.0 ([{79Br}M+H]+), 303.0 ([{81Br}M+H—C4H8]+), 301.0 ([{79Br}M+H—C4H8]+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].CN(C)CCO.Cl>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:9](=[O:10])([O:5][C@@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: C[C@H](O)C(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of (S)-(−)-1,1,1-trifluoro-2-propanol (1.95 g) in CHCl3 (30 ml) was added 4-nitrophenyl chloroformate (5.16 g) and pyridine (135 g) at room temperature. After 1-hour stirring at 60° C., the resulting mixture was cooled to room temperature. To the resulting mixture was added 2-(dimethylamino)ethanol (1.52 g) and was stirred at room temperature for 1 hour. The mixture was poured into 1 M aqueous solution of HCl and extracted with CHCl3. The extract was washed with water and then dried over Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (eluent:hexane/EtOAc=1/0˜50/50) to give 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][C:2]=1[F:1])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(O)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)OC(C)(C)C)c2)c(F)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 105.8 %

Procedure:
To a solution of ethyl 3-{3-fluoro-4-[(3-hydroxybenzyl)oxy]phenyl}propanoate (0.30 g, 0.94 mmol) and tert-butyl bromoacetate (0.92 g, 4.70 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.52 g, 3.76 mmol), and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was diluted with ethyl acetate, filtered, washed with water, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=6:4) to give the title compound (0.43 g, yield 99%) as an oily matter.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].O>CCCCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cc(C)c(N)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: O
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Yield: 35 %

Procedure:
20 g of 2,6-diacetylpyridine (0.123 mol), 19.08 g of 2-chloro-4,6-dimethylaniline (0.123 mol) and 0.5 g of p-toluenesulfonic acid were heated under reflux on a water separator in 500 ml of heptane for 75 min. The insoluble solid was filtered off. The solvent was distilled off from the filtrate down to 150 ml, and the remaining filtrate was cooled to room temperature, while stirring. 25.3 g of a yellow solid precipitated out. This was filtered off and recrystallized from 60 ml of hot isopropanol. A total of 12.9 g (0.043 mol) of 1-{6-[1-(2-chloro-4,6-dimethylphenylimino)ethyl]-pyridin-2-yl}ethanone were obtained in a yield of 35%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[N:4][C:3]=1[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH:30]1([C:2]2[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[N:4][C:3]=2[NH:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Br)nc2C(N)=O)c1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(C3CC3)nc2C(N)=O)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 181) (50 mg), cyclopropylboronic acid (18 mg), tetrakistriphenylphosphine palladium (24 mg), potassium carbonate (71 mg), dioxane (2.5 mL) and water (0.5 mL) was stirred at 115° C. overnight. After cooling, the reaction liquid was partitioned using chloroform, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying, the organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 10:1:0.1). The resulting residue was solidified with ethyl acetate-hexane to give 6-cyclopropyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (10 mg) as a yellow solid.
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[F:51])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=3)=[CH:53][CH:52]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccccc4F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 55.6 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(2-fluorobenzyl)-1-piperidinecarboxamide (0.21 g, 0.27 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.15 mmol)