Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:12]Br)[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4].[CH2:14]([NH:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:14]([N:21]1[CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][CH:2]1[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: CCCCCCOC(=O)C(Br)CBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
A solution of 48.5 g (154 mmoles) of n-hexyl 2,3-dibromopropionate (II, Z=O(CH2)5CH3) in 100 ml of dry benzene stirred at 40° C. is added dropwise to a warm solution (80° C.) of 37 g (154 mmoles) of N,N'-dibenzylethylenediamine and 55 ml of triethylamine in 100 ml benzene. The mixture was stirred for 3 hours at 80° C. After cooling and filtration of the triethylammonium chloride, the solution was evaporated off and the crude residue treated with diethyl ether and washed with water. The organic layer was dried (MgSO4), evaporated and chromatographed on a silica gel column using diethyl ether/petroleum ether (10:90, in vol.) as eluent, yielding 52.5 g (86.5%) of the title compound as an oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:28])[NH:26][NH2:27])=[CH:18][C:17]=2[O:16]1>>[CH2:15]1[O:23][C:22]2[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:28])[NH:26][N:27]=[C:9]3[C:10](=[O:11])[C:4]4[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=4)[C:7]3=[O:8])=[CH:18][C:17]=2[O:16]1
Reactant: NNC(=O)Nc1ccc2c(c1)OCO2
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccc2c(c1)OCO2

Procedure:
ninhydrin, 4-(3,4-methylenedioxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[F:36][C:37]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:36][C:37]1([F:42])[CH2:41][CH2:40][N:39]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:34])([F:33])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:38]1
Reactant: FC1(F)CCNC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: Cl
Product: CC(C(=O)N1CCC(F)(F)C1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 3,3-difluoropyrrolidine hydrochloride (Matrix and Cat. No. 008716). LCMS (M+H)+: m/z=563.3.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=O)(C)(C)C.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>C(#N)C>[NH2:8][C@@H:9]([C:13]([CH3:14])([CH3:15])[CH3:16])[C:10]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1)=[O:12]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[C@H](N)C(=O)Nc1ccccn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3,3-dimethylbutanoic acid (1.00 g, 4.32 mmol), pyridine-2-amine (1.506 g, 16.00 mmol), DIEA (8.36 mL, 48 mmol), and HATU (7.87 g, 20.80 mmol) were taken up in ACN (5 mL) and heated at 120° C. for 30 minutes under microwave irradiation. ACN was removed under reduced pressure and the residue was dissolved in water and extracted with EtOAc (2×50 mL). The organic extracts were concentrated under reduced pressure and purified by preparative HPLC. Hydrogen chloride (4 M in THF, 4 mL, 16 mmol) was added to the resulting solid and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. The residue was dissolved in water and extracted with EtOAc (2×50 mL). The aqueous layer was basified with 30% NaOH solution. The resulting solid precipitate was removed by filtration. The filtrate was extracted with DCM (2×50 mL). The DCM layer was dried and concentrated to give the title compound (83 mg) as a brown liquid. LCMS m/z=208.2 [M+H]+.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C.O>[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: O=C1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(C=C2Cc3ccccc3C2=O)cc1
Reaction time: 0.33 h

Procedure:
1-Indanone (4.17 g, 0.032 mol) was dissolved in ethanol (20 ml), and was added to sodium hydroxide (0.44 g, 0.011 mol) dissolved in water (8 ml) and ethanol (3 ml) and was left to stir for 20 min. 4-(Hexyloxy)benzaldehyde (6.4 ml, 0.031 mol), dissolved in ethanol (35 ml), was added to the mixture and was stirred for 4 hours. The product was isolated by vacuum filtration and was washed with cold ethanol (2×20 ml) and was dried in a vacuum oven. Yield=8.47 g, 85%. 1H NMR and 13C NMR gave expected signals.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8])[CH2:2][CH3:3].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:8][CH2:7][C:6]([O:9][C:17](=[O:18])[NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N:5][O:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCONC(=O)CCl
Reactant: O=C=Nc1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CCCON=C(CCl)OC(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
N-Propoxychloroacetamide (15.1 grams; 0.1 mole), benzene (80 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. Phenylisocyanate (12.1 grams; 0.12 mole) dissolved in benzene (25 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 20 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-phenylcarbamoyloxy)-2-propoxyiminoethane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Oc1ccc(F)cc1F
Reactant: NS(=O)(=O)c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzenesulfonamide (400 mg, 1.6 mmol) and 2,4-difluorophenol (228 mg, 1.76 mmol) in DMSO (16 ml) was treated with cesium carbonate (1 g, 3.2 mmol). The resulting mixture was heated to 120° C. for 20 min by microwave irriadation (normal). The mixture was treated with water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan solid. The solid was purified by silica gel chromatography (12 g ISCO, 30% EtOAc in hexanes 30 ml/min) to give the title compound (340 mg, 58%) as a tan solid LCMS (M−H)−=362.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[C:4]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH:3]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:32]2[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]2)=[O:17])[CH2:12][CH2:13]1)=[O:27]
Reactant: OC1CCNCC1
Reactant: O=C(O)CC1CCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)ccc1N1CCC(CC(=O)N2CCC(O)CC2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
A mixture of 0.100 g (0.246 mmol) of {1-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid, 0.124 g (1.23 mmol) of 4-hydroxypiperdine, 0.10 g (0.32 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.10 mL (0.74 mmol) of triethylamine in N,N-dimethylformamide (3 mL) are stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to provide 0.040 g (33%) of the title compound (278) as a colorless solid. [M+H]+=490.2.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33]>C(#N)C.CCOC(C)=O>[C:32]([O:35][CH2:36][C:37]([NH:14][C:13]1[C:12]2[C:7](=[N:8][C:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:10]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH:11]=2)[N:6]([CH3:30])[C:5](=[O:31])[C:4]=1[C:1](=[O:3])[CH3:2])=[O:38])(=[O:34])[CH3:33]
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 90 °C

Procedure:
To the product of Example 2 (120 mg) in acetonitrile (2 mL) was added acetoxyacetyl chloride (0.2 mL). The reaction was heated to 90° C. in a CEM microwave reactor for a total of 34 minutes. The reaction was diluted with EtOAc and was washed with saturated aqueous NaHCO3 solution. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-60% EtOAc in hexane affording the title compound. HPLC/MS: 572.1 (M+1), 574.1 (M+3); Rt=4.06 min.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[NH:6][C:5]1=[O:30])[CH2:2][CH3:3].[F:31][CH:32]([F:37])C(OCl)=O.[Na].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[F:31][CH:32]([F:37])[O:30][C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[N:6]=1
Reactant: CCCn1c(=O)[nH]c2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: O=C(OCl)C(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(OC(F)F)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (100 mg, 0.24 mmol), Sodium chloro difluoroacetate (47 mg, 0.31 mmol), Cs2CO3 (117 mg, 0.36 mmol) and DMF (2 ml) were stirred at 60° C. for 18 hours. Reaction mixture was cooled and diluted with water (10 ml), solid materials were filtered off and it was purified by preparative HPLC to obtain 2-Difluoromethoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one as off white solid (1 mg, 10%) and
Reaction SMILES: [C:1](=[C:4](Cl)[F:5])([F:3])[F:2].[Li]C(CC)C.[Si:12](OCC)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>CCOCC>[C:1](=[C:4]([Si:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[F:5])([F:3])[F:2]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: FC(F)=C(F)Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)C(F)=C(F)F
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
200 ml of freshly distilled dry Et2O is added to a 500 ml vessel (under an argon atmosphere). The vessel is cooled down to −80° C. and 15 g (0.129 mol) of CF2═CFCl gas is bubbled to Et2O. 100 ml (0.13 mol) of sec-BuLi is added dropwise during three hours. The temperature of the solution is kept below −60° C. all the time. The solution is stirred for 15 minutes and 29 ml (27.08 g, 0.130 mol) of Si(OEt)4 is added in small portions. The solution is stirred for over night allowing it to warm up to room temperature. Formed red solution is filtered and evaporated to dryness to result crude trifluorovinyltriethoxysilane, CF2═CFSi(OEt)3.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:20][C@H:21]([CH3:41])[CH2:22][O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[Si:24]([O:23][CH2:22][CH:21]([CH3:41])[CH2:20][C@H:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([C:37]([CH3:38])([CH3:39])[CH3:40])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)[C@@H](CC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 52.2 %

Procedure:
A solution tert-butyl diethylphosphonoacetate (64 g) in THF (100 mL) was added dropwise to a suspension of sodium hydride (containing 40% mineral oil, 13.2 g) in THF (400 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 75 minutes. A solution of ((R)-3-bromo-2-methylpropoxy)-tert-butyldiphenylsilane (99.4 g) in THF (100 mL) was added dropwise to the reaction mixture, which was then heated under reflux for 23 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 74.6 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=1)[C:6]([NH:8][NH2:9])=O.C(N(CC)CC)C.Cl.Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[CH:42]=[CH:43]/[C:44](=[NH:48])OCC)[CH:33]=[N:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>C(O)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[CH:42]=[CH:43]/[C:44]2[N:48]=[C:6]3[CH:5]([C:10]4[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=4)[CH2:4][CH2:3][N:8]3[N:9]=2)[CH:33]=[N:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1
Reactant: CCOC(=N)/C=C/c1cnc(-n2cnc(C)c2)c(OC)c1
Reactant: NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(/C=C/c2nc3n(n2)CCC3c2cc(F)c(F)c(F)c2)cnc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 25 h

Procedure:
A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride synthesized in Examples 253 and 254 (565 mg) and triethylamine (1.0 mL) in ethanol (10 mL) was added to a solution of ethyl (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidate dihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL) at room temperature. The reaction solution was stirred at 80° C. for 25 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 154 mg of the racemic title compound. The racemic title compound (154 mg) was purified by CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) and then separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=7:3) to obtain the title optically active compound with a retention time of 17 minutes and positive optical rotation (40 mg) and the title optically active compound with a retention time of 23 minutes and negative optical rotation (37 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
A 500 mL round bottom flask was charged with 4-hydroxybenzaldehyde (40 g, 328 mmol) and DMF (250 mL). 4-methoxybenzyl chloride (57.8 mL, 426 mmol) was added, followed by potassium carbonate (90 g, 656 mmol). The reaction mixture was stirred at room temperature for 5 h then poured into ice water (2.5 L). The product was collected by filtration and rinsed with water. After drying thoroughly, 78 g (98%) of aldehyde 12.1 was obtained as a light yellow powder. 1H NMR (400 MHz)(DMSO-d6) δ 9.88 (s, 1H); 7.88 (d, 2H, J=8.7 Hz); 7.42 (d, 2H, J=8.8 Hz); 7.21 (d, 2H, J=8.8 Hz); 6.97 (d, 2H, J=8.6 Hz); 5.16 (s, 2H); 3.77 (s, 3H). MS ESI (pos.) m/e: 243.1 (M+H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[CH:12][C:13]([F:29])=[C:14]([C@:16]2([CH2:27][F:28])[CH2:21][C@@H:20]([C:22]([F:25])([F:24])[F:23])[O:19][C:18]([NH2:26])=[N:17]2)[CH:15]=1.[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1)#[C:31][CH3:32]>O1CCOCC1.O.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:29][C:13]1[CH:12]=[CH:11][C:10]([C:35]2[CH:36]=[N:37][CH:38]=[C:33]([C:30]#[C:31][CH3:32])[CH:34]=2)=[CH:15][C:14]=1[C@:16]1([CH2:27][F:28])[CH2:21][C@@H:20]([C:22]([F:25])([F:24])[F:23])[O:19][C:18]([NH2:26])=[N:17]1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC#Cc1cncc(-c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)c1
Yield: 55.5 %

Procedure:
A mixture of potassium phosphate (0.168 g, 0.792 mmol), (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8a, 0.0985 g, 0.264 mmol), (5-(prop-1-yn-1-yl)pyridin-3-yl)boronic acid (0.106 g, 0.660 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (9.35 mg, 0.013 mmol) in dioxane/water (2.0/0.5 mL) was irradiated at 110° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography: 12 g, 0-100% EtOAc/DCM. The product was obtained as a white solid (0.060 g, 55% yield). MS m/z=410 [M+H]+. Calculated for C20H16F5N3O: 409.4.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-])=O.[Cl:16][CH2:17][C:18](Cl)=O.P(Cl)(Cl)(Cl)=O>[Ni].C(O)C>[Cl:16][CH2:17][C:18]1[O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N:13]=1
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2oc(CCl)nc2c1

Procedure:
Ethyl 4-hydroxy-3-nitrobenzoate (32 g) prepared according to the method described in J. Org. Chem., vol. 26, p. 2223 (1961) was subjected to reduction under increased pressure at 70 atm in the presence of a Raney Nickel catalyst in absolute ethanol (200 ml). The product was then caused to react with chloroacetyl chloride, and was subsequently subjected to ring closure with phosphorous oxychloride to yield 2-chloromethyl-5-ethoxycarbonylbenzoxazole (27.3 g). The chloromethyl compound (10 g) was caused to react with dimethylamine to yield 2-dimethylaminomethyl-5-ethoxycarbonylbenzoxazole (6 g), which was subsequently subjected to reduction with lithium aluminium hydride in anhydrous tetrahydrofuran (60 ml) thereby to obtain 2-dimethylaminomethyl-5-hydroxymethylbenzoxazole (2 g).
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[CH2:5][S:4][C:3]1=[S:8].[O:9]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1>C(O)C>[NH2:1][N:2]1[C:6](=[O:7])[C:5](=[CH:20][C:19]2[CH:22]=[CH:23][C:16]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:17][CH:18]=2)[S:4][C:3]1=[S:8]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: NN1C(=O)CSC1=S
Solvent: C1CCNCC1
Solvent: CCO
Product: NN1C(=O)C(=Cc2ccc(Oc3ccccc3)cc2)SC1=S
Yield: 68.6 %

Procedure:
To a solution of 3-aminorhodanine (1.00 g) in ethanol (20 ml) were added 4-phenoxybenzaldehyde (1.47 g) and piperidine (57 mg), and the mixture was heated with reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to give 3-amino-5-(4-phenoxybenzylidene)-2-thioxothiazolidin-4-one (1.52 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].Cl.[NH2:9][OH:10].CCN(C(C)C)C(C)C>CCO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[N:9][OH:10])[NH2:7]
Reactant: N#Cc1nccs1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=NO)c1nccs1
Yield: 93.1 %

Procedure:
Hydroxylamine hydrochloride (9.03 g, 130 mmol) was added to a solution of 1,3-thiazole-2-carbaldehyde (14.71 g, 130 mmol) and pyridine (10.5 mL, 130 mmol) in DCM (100 mL). The reaction mixture was stirred overnight at room temperature and then washed twice with water. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 15.26 g of 1,3-thiazole-2-carbaldehyde oxime (yield 92%). 1,3-thiazole-2-carbaldehyde oxime (15.23 g, 119 mmol, 1 equiv) was dissolved in 80 mL of dioxane and then TEA (41.4 mL, 2.5 equiv) was added. The reaction mixture was cooled to 0° C. and then trifluoroacetic anhydride (18.3 mL, 1.1 equiv) was added dropwise to the reaction. The solution was stirred overnight at room temperature and then evaporated. The residue was dissolved in DCM and then washed twice with water. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 1,3-thiazole-2-carbonitrile. This compound was used in the next step without further purification. 1,3-thiazole-2-carbonitrile (13.11 g, 119 mmol, 1 equiv), hydroxylamine hydrochloride (12.4 g, 1.5 equiv) and DIEA (33 mL, 1.6 equiv) were mixed in absolute EtOH (150 mL). The reaction mixture was refluxed 4 h and then the solvent was evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with water and once with brine. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 15.86 g of 1,3-thiazole-2-amidoxime (yield 93% over two steps).