Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].O[CH2:12][C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38]C)=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[C:16]([CH:40]([CH3:42])[CH3:41])[O:15][N:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+].Cl>ClCCl.O1CCCC1.O.CO>[CH3:42][CH:40]([C:16]1[O:15][N:14]=[C:13]([CH2:12][O:10][C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])[C:17]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([C:36]([OH:38])=[O:37])[CH:30]=[CH:29]3)=[CH:22][CH:21]=1)[CH3:41]
Reactant: Oc1c(F)cc(F)cc1F
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CO)noc4C(C)C)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)c1onc(COc2c(F)cc(F)cc2F)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C
Yield: 36.5 %

Procedure:
To a solution of 2,4,6-trifluorophenol (18 mg, 0.12 mmol), methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinoline carboxylate (52 mg, 0.12 mmol) and triphenylphosphine (35 mg, 0.13 mmol) in dichloromethane (2 mL) was added diisopropyl azodicarboxylate (0.024 mL, 0.13 mmol) slowly. The solution was heated in a microwave reactor at 100° C. for 10 minutes. The solution was adsorbed onto silica gel and purification was done by chromatography (0-70% ethyl acetate in hexanes) to afford a solid which was dissolved in 2:1 tetrahydrofuran:methanol (1.5 mL). Then 1 N sodium hydroxide (0.19 mmol, 0.19 mmol) was added. The solution was subjected to microwave radiation at 120° C. for 500 seconds. The solution was concentrated then diluted with water before the addition of 1 N hydrochloric acid (0.19 mmol, 0.19 mmol). The resulting solid was extracted with ethyl acetate twice and the combined organic layers were dried over magnesium sulfate and concentrated. The resulting solid was washed with methanol and dried to afford 6-(4-{[(5-(1-methylethyl)-3-{[(2,4,6-trifluorophenyl)oxy]methyl}-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylic acid (24 mg, 35%). 1H-NMR (400 MHz, DMSO-d6) δ 8.44-8.06 (m, 5H), 7.69 (d, J=9 Hz, 2H), 7.11 (d, J=9 Hz, 2H), 6.65 (t, J=9 Hz, 2H), 5.23 (s, 2H), 5.12 (s, 2H), 3.29 (septet, J=7 Hz, 1H), 1.37 (d, J=7 Hz, 6H). HRMS (ESI) C30H23F3N2O5 calculated: 549.1632 (M+H)+, found: 549.1631 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([O:4][C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([O:13][CH2:14][C:15]([O:17]CC2C=CC=CC=2)=[O:16])[C:9]1=[O:25])=[O:6])[CH3:3]>C(O)C.[Pd]>[CH3:26][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([O:13][CH2:14][C:15]([OH:17])=[O:16])[C:9]1=[O:25])=[O:6])[CH3:3]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)O
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
(3S-trans)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-4-methyl-1-[[(phenylmethoxy)carbonyl]methoxy]-2-azetidinone (0.73 g, 2.0 mmol) was dissolved in 12 ml of absolute ethanol and 0.36 g of 10% palladium on charcoal was added under argon. Hydrogenolysis (1 atmosphere, 20° C.) was completed in 30 minutes. The reaction mixture was filtered and the volatiles were removed to yield 0.55 g of crude (3S-trans)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-4-methyl-1-(carboxymethoxy)-2-azetidinone.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:23][CH2:24][C:25](OCC)=[O:26])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[BH4-].[Na+]>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:23][CH2:24][CH2:25][OH:26])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1
Reactant: CCOC(=O)COC(c1cccc(F)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCO)c2cccc(F)c2F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.1 %

Procedure:
To a solution of (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (4 g, 9.7 mmol) in MeOH (80 mL) was added NaBH4 (2.9 g, 77.4 mmol) in portions while the temperature was lower than 40° C. After addition, the mixture was stirred at rt for 2-3 hrs. The solvent was removed in vacuo to give a residue, which was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and evaporated to give (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (3.5 g, 97%). 1H NMR (CDCl3, 400 MHz) δ 7.12 (m, 3H), 4.52 (q, 1H), 4.11 (m, 1H), 3.69 (m, 3H), 3.41 (m, 3H), 2.65 (m, 1H), 2.02 (m, 1H), 1.65 (m, 1H), 1.42 (d, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH2:4][OH:5].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl.O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])=[CH:6][C:3]=1[CH2:4][O:5][CH2:27][O:28][CH3:29]
Reactant: COCCl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CO)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCOCc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 2-bromo-5-tert-butyldimethylsiloxybenzylalcohol (36.9 g, 116 mmol) and diisopropylethylamine (26.0 mL, 150 mmol) in dichloromethane (300 mL) was added chloromethyl methyl ether (11.0 mL, 145 mmol), and the mixture was stirred at room temperature for overnight. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (96:4 hexane/ethyl acetate) to give 1-bromo-4-tert-butyldimethylsiloxy-2-methoxymethoxymethylbenzene (39.3 g, 94%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[ClH:11].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=O)[CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.CO>C(O)(=O)C>[ClH:11].[ClH:11].[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: O=Cc1cccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Reactant: C1COCCN1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3cccc(CN4CCOCC4)c3)cc2s1
Reaction time: 18 h

Procedure:
290 mg (3.32 mmol) of morpholine and 31 mg (0.50 mmol) of sodium cyanoborohydride are successively added to a solution of 80 mg (0.17 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride (Example 33A) in 1.0 ml of a 6:1 mixture of methanol and acetic acid. After 18 h at. 80° C., purification is carried out by preparative HPLC.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[CH:14][C:15]([OH:17])=[O:16])=[CH:4][CH:5]=1)=[O:8]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
A solution of methyl p-formylbenzoate (12.33 g), malonic acid (16 g) and piperidine (1 ml) in pyridine (100 ml) is refluxed for two hours. The reaction mixture is poured into ice-water, and the precipitated white powder is collected by filtration, and washed with water, and dried to give 4-methoxycarbonyl cinnamic acid (14.7 g).
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([Si:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH:18]=[CH2:19])[CH:16]=[CH2:17])[CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH:27]([O:29]C)Cl.CC(C)([O-])C.[Li+].[OH-].[Na+].OO.C12C(=O)C(CCC1)CCC2>O.C(O)C.CCCCCC.O1CCCC1.CO.CCCCCC>[CH2:10]([Si:15]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19][C:27](=[O:29])[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=C[Si](C=C)(CCCCC)c1ccccc1
Reactant: COC(Cl)Cl
Agent: B1C2CCCC1CCC2
Agent: CC(C)(C)[O-]
Agent: O=C1C2CCCC1CCC2
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of 15.9 g of 9-borabicyclo [3.3.1] nonan, 14.8 g of n-pentylphenyldivinylsilane and 150 ml of n-hexane was refluxed for 2 hours and then cooled with ice water. 7.0 ml of borane-dimethylsufide was added to the mixture, which was then heated again and refluxed for 2 hours. After cooling, 16 ml of methanol was added at room temperature and the mixture was stirred for 2 hours at 0° C. 25.0 g of dichloromethylmethyl ether was then dripped into the mixture, followed by also dripping a hexane-tetrahydrofuran (1:1) solution of 1.33M lithium t-butoxide into the mixture. After stirring at room temperature for 2 hours, 80 ml of ethanol, 10 ml of water and 10.0 g of sodium hydroxide were added. Then 80 ml of an aqueous solution of 30% hydrogen peroxide was slowly added. After stirring at room temperature for 2 hours, the organic layer was dried/concentrated to obtain a mixture of the target product and bicyclo [3.3.1] nonan-9-one. They were separated by means of silica-gel chromatography to obtain 15.2 g (yield 91%) of the target product. The target product thus obtained exhibited the same spectra as those of Example 7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](Cl)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:14]([CH3:13])[C@H:15]2[CH2:34][N:19]3[C:20]4[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)Cc1ccc(F)c(F)c1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1ccc(F)c(F)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from (3,4-difluorophenyl)acetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 413.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:25]=[CH:24][C:16]3[C:17]([CH3:23])([CH3:22])[O:18][C:19](=[O:21])[NH:20][C:15]=3[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:26]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:25]=[CH:24][C:16]3[C:17]([CH3:22])([CH3:23])[O:18][C:19](=[O:21])[NH:20][C:15]=3[CH:14]=2)=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccccc3)ccc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2cc(OCCCCS(=O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 2 from 7-(4-phenylmercapto-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[O:25])[CH:18]=2)=[CH:14][C:13]=1[Cl:41].N1C=CC=CC=1.O1CCCC1>C(OCC)(=O)C.O>[Cl:41][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][C:12]=1[NH:11][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:28][CH2:27]2)=[O:25])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(N)c(Cl)c3)ccn2)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccn2)CC1
Temperature: 25 °C

Procedure:
After adding 0.21 ml of phenyl chloroformate to a solution of 660 mg of t-butyl 4-({[4-(4-amino-3-chlorophenoxy)-2-pyridyl]amino}carbonyl)-1-piperidine carboxylate, 0.14 ml of pyridine and 10 ml of tetrahydrofuran while stirring at room temperature, the mixture was further stirred for 13 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate and the organic layer was washed with water, after which silica gel was added and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate) to obtain 500 mg of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[OH-].[Na+].[H][H]>O.N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: [H][H]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC1Cc2cc3c(cc2C(c2ccc(N)cc2)=NN1)OCO3
Reaction time: 5 h

Procedure:
A mixture of 8.80 g (0.03 moles) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine, 5.675 g (0.15 moles) of sodium borohydride and 80 ml of pyridine is stirred on a water bath heated to boiling, for 5 hours. When the reaction mixture is cool, 90 ml of water is added to it, then, under ice-cooling, 260 ml of an aqueous hydrochloric acid solution containing 110 ml of concentrated hydrochloric acid are added, and thereafter 115 ml of 40% aqueous sodium hydroxide solution are dropped to the reaction mixture. On adding the water, hydrogen evolution occurs, on adding the base the aimed compound separates in the form of an oil containing pyridine. The mixture is then extracted with benzene, the benzene phase is shaken with water, dried, clarified with activated charcoal and evaporated under reduced pressure. The residue is taken up in 50 ml of water, the crude product is filtered off, washed 5 times with 10 ml of water, dried at 50°-60° C., recrystallized from 16 ml of 50% aqueous ethanol and finally the crystal water is removed at 100°-105° C. under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([OH:21])(=O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18](=[O:21])(=[O:19])[NH:31][CH2:30][CH2:29][O:28][CH3:27])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccccc1Cl
Reactant: COCCN
Product: CCOC(=O)c1cnc2c(S(=O)(=O)NCCOC)cnn2c1Nc1ccccc1Cl
Yield: 100.3 %

Procedure:
Using 7-(2-chlorophenylamino)-6-(ethoxycarbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.400 g, 1.008 mmol) obtained in Example 6 step 2 and 2-methoxyethylamine (0.303 g, 4.032 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.459 g, 100%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>ClCCl.C(OCC)(=O)C>[CH2:47]([NH:54][C:15]([C:11]1[S:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:13][C:12]=1[CH3:14])=[O:17])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)NCc1ccccc1
Yield: 50.1 %

Procedure:
To a stirred solution of 2-(tert-butoxycarbonylamino)-4-methylthiazole-5-carboxylic acid (2.97 g, 11.50 mmol) and diisopropylamine (8.5 mL, 48.70 mmol) in dichloromethane (40 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.25 g, 11.50 mmol) and 1-hydroxybenzotriazole (2.02 g, 14.80 mmol). After 30 min benzylamine (1.7 mL, 15.60 mmol) was added. The resultant mixture was stirred at ambient temperature over 8 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford 2-(tert-butoxycarbonylamino)-4-methylthiazole-5-carboxylic acid benzylamide (2.00 g, 50% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[N:7]2.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:15])[CH:8]=[N:7]2
Reactant: O=c1cnc2cccc(Br)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cnc2cccc(Br)c2n1
Temperature: 50 °C

Procedure:
A mixture of 2.0 g (ca. 7.64 mmol) 8-Bromo-1H-quinoxalin-2-one and 36 ml of POCl3 is heated to 50° C. for 16 h. After cooling, the excess of POCl3 is evaporated, water is then added and extracted 3× with CH2Cl2. The combined organic layers are successively washed with water, NaHCO3, saturated brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane:CH2Cl2=7:3=>1:1) to afford the title compound as a pale orange solid, MS: 243 (M)+
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[NH:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[C:14](O)=[O:15].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>CC(N(C)C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:19]([NH:20][C:21]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[C:11]([CH3:10])[CH:12]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1cc(C(=O)O)ccc1Nc1nc(-c2ccccc2)c2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2c(C)cccc2C)ccc1Nc1nc(-c2ccccc2)c2ccccc2n1
Yield: 46.9 %

Procedure:
A stirred solution of 2,6-dimethylaniline (130 μL, 1.06 mmol), 3-methyl-4-(4-phenylquinazolin-2-ylamino)benzoic acid (188 mg, 0.53 mmol), HATU (433 mg, 1.13 mmol) and Hunig's base (350 μL, 2.00 mmol) in dimethylacetamide (10 mL) was heated to 70° C. overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and extracted with a 10% aqueous solution of lithium chloride and a 1 N solution of sodium hydroxide. The combined organic phases were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The product was purified by preparative reverse phase HPLC (CH3CN/H2O). Acetonitrile was removed from the isolated pure fractions on a rotary evaporator and the aqueous remainder was lyophilized to give N-(2,6-dimethylphenyl)-3-methyl-4-[(4-phenylquinazolin-2-yl)amino]benzamide as a white solid (114 mg, 47%). 1H NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 9.20 (s, 1H), 8.03 (m, 1H), 7.88 (m, 2H), 7.80 (m, 2H), 7.78 (m, 2H), 7.65 (m, 4H), 7.35 (m, 1H), 7.13 (m, 3H), 2.40 (s, 3H), 2.20 (s, 6H). MS (EI) for C30H26N4O: 459.0 (MH+).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10](=[O:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:6][N:5]=1.Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:9]=[C:8]([CH:10]([OH:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:6][N:5]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccnc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (3.12 g, 22.9 mmol) in diethyl ether (100 ml) was added sodium borohydride (1.74 g, 45.8 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and a solution of ethyl 3-(2-fluoropyridin-4-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (4.78 g, 11.5 mmol) in diethyl ether (30 ml) was added to the filtrate. The mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling to quench the reaction. Then, water (100 ml) was added and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(2-fluoropyridin-4-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate((2RS,3RS) form: (2RS,3SR) form=9:1, 4.05 g, 84%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[C:9]1([CH2:15][CH2:16][CH2:17][Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:8])[CH2:17][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccsc1Br
Reactant: Br[Mg]CCCc1ccccc1
Product: OC(CCCc1ccccc1)c1ccsc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 2-bromo-thiophene-3-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[C:10]([CH3:14])[C:11](O)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>>[C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[C:10]([CH3:14])[C:11]([Cl:19])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=C(C)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C=C(C)C(=O)Cl)cc1
Yield: 87.7 %

Procedure:
Into 20 g of this 4-acetoxy-α-methylcinnamic acid was dropped 100 g of thionyl chloride, reaction was carried out under reflux for 2 hours, unreacted thionyl chloride was removed by distillation and the reaction product was subjected to distillation under a reduced pressure to obtain 19 g of 4-acetoxy-α-methylcinnamic acid chloride. This acid chloride was dissolved in 100 ml of acetone, 11 g of l-2-octanol and 10 g of triethylamine were added to the solution, and the reaction was carried out for 10 hours under reflux. The precipitated triethylamine hydrochloride was removed by filtration, acetone was removed from the filtrate by using an evaporator, and the ether-soluble component was extracted from the residue with diethyl ether. The unreacted acid chloride was removed, and extract was dehydrated on magnesium sulfate overnight, and subsequently, diethyl ether and remaining l-2-octanol were removed by distillation under a reduced pressure. Then, 100 ml of acetone and 100 ml of an aqueous saturated solution of sodium carbonate were added to the residue and reaction was carried out under reflux for 15 hours. The obtained product was hydrolyzed and extracted with ether again. The extract was dehydrated and ether was evaporated to obtain 15 g of 1R-methylheptyl 4-hydroxy-α-methylcinnamate.