Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=O)#[N:2].[CH:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(O)C.[CH3:25][NH:26][NH2:27]>C(OCC)(=O)C>[CH3:25][N:26]1[C:1]([NH2:2])=[CH:3][C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]2)=[N:27]1.[CH:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CNN
Reactant: N#CCC(=O)C1CCCCN1
Agent: O=COCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(C2CCCCN2)cc1N
Yield: 66.2 %

Procedure:
Under nitrogen atmosphere, to a 250 mL three-neck reaction flask were added the compound of Example 11A (16.0 g, 55.9 mmol), ethanol (80 mL) and methylhydrazine (12 mL, 224 mmol). The mixture was refluxed for 5 hr. The reaction was stopped. Ethanol was removed by rotary-evaporation to obtain a crude product. The crude product was subject to column chromatography (eluant: petroleum ether:ethyl acetate=1:1) to give 11.7 g of the title compound. Yield: 66.6%. MS (ESI): m/z 315 (M+H)+
Reaction SMILES: N[CH:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].C([N:30](C(C)C)CC)(C)C.[Br:36][CH2:37][C:38](Br)=[O:39].C(OCC)(=O)C>O1CCCC1>[Br:36][CH2:37][C:38]([NH:30][CH:3]([NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH2:2][CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:39]
Reactant: COc1ccccc1CCC(=O)NCC(N)Cc1c[nH]c2ccccc12
Reactant: O=C(Br)CBr
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1CCC(=O)NC(CCc1c[nH]c2ccccc12)NC(=O)CBr
Reaction time: 2 h

Procedure:
To a stirring solution of 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.51 g, 21.369 mmoles) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at 0° C. was added diisopropylethylamine (4.1 ml, 23.537 mmoles) and bromoacetyl bromide (2.05 ml, 23.530 mmoles). After 2 hours, ethyl acetate was added and the reaction mixture washed with water twice, 1.0 N hydrochloric acid (2×), saturated sodium bicarbonate solution (2×), and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a tan foam on a rotary evaporator. In this manner the 2-[((2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane was obtained in quantitative yield. No further purification was necessary.
Reaction SMILES: Cl.[Si]([O:19][CH2:20][C:21]1[N:22]=[C:23]([N:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[N:24]([CH2:30][C:31]#[C:32][CH3:33])[C:25]=1[C:26]([S:28][CH3:29])=N)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[O:47]1CCCC1>>[CH2:30]([N:24]1[C:25]([C:26]([S:28][CH3:29])=[O:47])=[C:21]([CH2:20][OH:19])[N:22]=[C:23]1[N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[CH2:36][CH2:35]1)[C:31]#[C:32][CH3:33]
Reactant: C1CCOC1
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C(=N)SC
Agent: Cl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C(=O)SC
Temperature: 25 °C
Reaction time: 22 h

Procedure:
30 ml of 5N hydrochloric acid was added to a 100 ml tetrahydrofuran solution of 5.05 g of t-butyl 4-[4-(t-butyl diphenylsilanyloxymethyl)-1-(2-butynyl)-5-methylsulfanylcarbonimidoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 22 hours. The solvent was concentrated under reduced pressure. The residue was dissolved in 100 ml of dichloromethane, and 2.05 g of di-t-butyl dicarbonate was added thereto. The solution was made alkaline with 5N sodium hydroxide, and stirred for 2 hours. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.24 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH:15]([CH2:20][CH2:21]O)[C:14]=3[CH:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:3][CH2:21][CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][C:19]2[N:11]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:12]=[CH:13][C:14]1=2
Reactant: OCCC1CCCc2c1cnn2-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: ClCCC1CCCc2c1cnn2-c1ccccc1
Temperature: 90 °C
Yield: 76 %

Procedure:
Thionyl cloride (4 mL) is slowly added at room temperature over a solution of 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)ethanol (516 mg, 2.13 mmol) in 25 mL of toluene. The reaction mixture is heated at 90° C. during 2 hours. The solvent is eliminated at reduced pressure. The crude is diluted in ethyl acetate and washed twice with a NaHCO3 solution. The solvent is next evaporated at reduced pressure, to obtain 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazole (423 mg, 1.62 mmol, 76%, oil).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.[NH2:18][C:19]1[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=1>C(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[NH:1][C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)=[CH:7][CH:8]=1
Reactant: Nc1cccnc1Cl
Reactant: COc1ccc(C(=O)c2ccccc2N)cc1
Solvent: ClCCl
Product: COc1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 180 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 20.0 g (0.088 mole) of 2-amino-4'-methoxybenzophenone and 13.0 g (0.097 mole) of 3-amino-2-chloropyridine (96%) was heated at 180° C. under a nitrogen atmosphere for 2.0 hr. The reaction mixture was cooled to approximately 70° C. and 100 ml of methylene chloride was added slowly. After the mixture had cooled to room temperature, another 50 ml of methylene chloride was added and the mixture was stirred overnight. The suspended solid was collected by filtration, air dried, dissolved in methanol and basified with 3 N sodium hydroxide. The suspension was diluted with 500 ml water and extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. Analysis by mass spectra (EI and CI) indicated the residue was a mixture of [2-[(3-amino-2-pyridyl)amino]phenyl](4-methoxphenyl)methanone and the title compound. The residue-mixture was dissolved in 250 ml toluene with a catalytic amount of para toluene sulfonic acid and the solution was refluxed overnight under a nitrogen atmosphere while separating water in a Dean-Stark trap. The reaction mixture was filtered while hot. The product precipitated as the filtrate cooled to room temperature and was collected by filtration. After recrystallization from benzene the product weighed 1.8 g, m.p. 198.5°-200°-5° C. (d).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]1=[O:25])=[O:4].[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:22][C:20]([CH3:21])([CH3:23])[C:19]([O:18][CH2:17][N:9]1[C:10](=[O:16])[C:11]2[N:12]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH:28]=[O:29])[CH:13]=[N:14][C:15]=2[N:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:27])([CH3:26])[CH3:1])[C:8]1=[O:25])=[O:24]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1c(=O)c2c(ncn2-c2ccccc2C=O)n(COC(=O)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 37 h
Yield: 31.7 %

Procedure:
2,2-Dimethylpropionic acid [3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (10.2 g), 2-formylphenylboronic acid (8.04 g), and copper(II) acetate (7.30 g) were suspended in N,N-dimethylformamide (50 ml), pyridine (4.34 ml) was added thereto, and the mixture was stirred at room temperature for 37 hours. The reaction mixture was diluted with ethyl acetate; and washed with water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 4.12 g of the title compound from the elution fraction of hexane-ethyl acetate (1:2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[F:21].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:18]2[CH:17]=[CH:16][C:15]([O:19][CH3:20])=[C:14]([F:21])[C:13]=2[F:12])=[O:8])[CH:10]=1
Reactant: COc1cccc(F)c1F
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)ccc2Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 111.5 %

Procedure:
To a solution of 5-bromo-2-chlorobenzoyl chloride 21d (3.4 g, 13.4 mmol) and 1,2-difluoro-3-methoxybenzene 21b (2.4 g, 16.7 mmol) in dichloromethane (40 mL) was added anhydrous aluminium chloride (1.82 g, 13 mmol) at 0° C. The mixture was stirred at 0° C. for 16 hours. Then the reaction mixture was quenched with hydrochloric acid (4 mL, 2 M) and warmed up to room temperature. The mixture was extracted with dichloromethane (40 mL×4). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21e as yellow liquid (5.4 g, 96.4%). This material was not further purified.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]([O:12]C)=O)[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)[CH:2]=[CH2:3].[NH2:18][C@@H:19]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)[C:20]([N:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH3:23])=[O:21].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>CN(C=O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]([NH:18][C@@H:19]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)[C:20]([N:22]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH3:23])=[O:21])=[O:12])[N:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(F)(F)F)nn1CC(=O)OC
Reactant: CN(C(=O)[C@@H](N)Cc1cccc(Br)c1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCc1cc(C(F)(F)F)nn1CC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)N(C)c1ccc(Cl)cc1
Yield: 24.3 %

Procedure:
To a solution of methyl 2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (110 mg, 0.48 mmol) and (S)-2-amino-3-(3-bromophenyl)-N-(4-chlorophenyl)-N-methylpropanamide (194 mg, 0.48 mmol) in DMF (2 mL) was added HATU (228 mg, 0.6 mmol) and DIEA (193 mg, 1.5 mmol). Upon completion of the reaction, the product was purified by reverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford (S)-2-(2-(5-allyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-3-(3-bromophenyl)-N-(4-chlorophenyl)-N-methylpropanamide (68 mg, 24%) as a solid. MS (m/z): 582.9 [M+H]+; HPLC retention time 4.52 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][O:3]1)(=[O:19])=[O:18]
Reactant: OCC1CCOCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A stirred solution of 16.2 grams (0.137 mole) of 1,3-dioxan-4-ylmethanol and 16.7 grams (0.165 mole) of triethylamine in 250 mL of methylene chloride was cooled to about -20° C., and a solution of 17.3 grams (0.151 mole) of methanesulfonyl chloride in about 25 mL of methylene chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature as it stirred for one hour. The reaction mixture was then washed with water and dried with magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to a residue. The residue was purified using column chromatography on silica gel, yielding 18.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=O.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]#[N:9]
Reactant: Cn1ncc(I)c1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(I)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A round-bottom flash was charged with Preparation 20, 4-iodo-1-methyl-1H-pyrazole-5-carboxamide (222 g, 886 mmol) and DCM (2.22 L) and the reaction mixture was cooled to 0° C. 2,6-Lutidine (310 mL, 2.66 mol) and trifluoroacetic anhydride (253 mL, 1.77 mol) were added. After reaction was complete, saturated aqueous sodium bicarbonate (800 mL) was added and the layers separated. The aqueous layer was washed with DCM (800 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (800 mL), 1N HCl (800 mL), and brine (800 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was suspended in heptanes (˜2 L) and granulated at 0-5° C. for 30 min. The solid was collected via filtration and dried in a vacuum oven to afford 4-iodo-1-methyl-1H-pyrazole-5-carbonitrile as a colorless solid (196 g, 95% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=[O:4].[F:6][C:7]1[C:8]([CH2:40]O)=[C:9]([F:39])[C:10]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)C(C)(C)C)=[C:18]([F:29])[CH:17]=3)=[CH:13][C:12](=[O:30])[C:11]=2[C:31]=1[NH:32]C(=O)C(C)(C)C>S(=O)(=O)(O)O>[NH2:32][C:31]1[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:29])[CH:17]=3)[O:15][C:10]=2[C:9]([F:39])=[C:8]([CH2:40][O:4][C:3](=[O:5])[CH2:2][Cl:1])[C:7]=1[F:6]
Reactant: O=C(O)CCl
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Agent: O=S(=O)(O)O
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCl)c(F)c3o2)cc1F
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 96.9 %

Procedure:
100 g (1.06 mol) of chloroacetic acid and 30 mL of sulfuric acid were added to 10.8 g (20.0 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in EXAMPLE 118 (4), and the mixture was stirred at 100° C. for 20 minutes. The reaction solution was poured into 1 L of ice-water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with diisopropyl ether, to give 8.00 g of Compound 159 (yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1.COC(OC)[N:23]([CH3:25])C.O.[NH2:29]N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:25][NH:23][N:29]=1
Reactant: CSc1nccc(CC(=O)c2ccc(Cl)cc2Cl)n1
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: O
Product: CSc1nccc(-c2c[nH]nc2-c2ccc(Cl)cc2Cl)n1
Reaction time: 0.1 h

Procedure:
The title compound is prepared from 1-(2,4-dichloro-phenyl)-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone as described in Example 1, Step 1.3, using N,N-dimethylformamid-dimethylacetal and hydrazine monohydrate. Title compound: m.p.: 218-219° C.; single peak at 6.07 min (System 1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>C1COCC1>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
To a solution of 75 g of methyl 4-hydroxybenzoate in 700 ml THF at 22° C. were added 19.7 g of a 60% dispersion of sodium hydride in mineral oil. After the mixture was stirred for 90 minutes, 84.3 g of benzyl bromide was added dropwise. The reaction was heated at reflux for 18 hours, cooled to room temperature and 50 ml methanol was added. The mixture was evaporated and the resulting residue extracted with three portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and evaporated to a solid. Recrystallization from cold methanol gave 28.7 g of the title compound: 300 MHz 1H NMR (CDCl3) δ3.96 (s, 3H), 5.19 (s, 2H), 7.05 (d, J=9 Hz, 2H), 7.42 (s, 5H), 8.05 (d, J=9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3,3-bis(4-chlorophenyl)propionate (Step B, 0.78 g, 3.9 mmol), lithium hydroxide monohydrate (0.33 g, 7.8 mmol) in 1:1:1 MeOH/THF/water (15 mL) was stirred at room temperature overnight. The resulting mixture was partitioned between 2 M aqueous hydrochloric acid (50 mL) and ether (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.29-7.23 (m, 4H), 4.49 (t, 1H), 3.02 (d, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]([CH3:15])=[CH:9][C:7]=1[OH:8].[C:16]1([CH:22]2[O:27][C:25](=[O:26])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCCl>[CH3:15][C:10]1[C:11](=[O:14])[C:12]([CH3:13])=[C:6]([CH3:5])[C:7](=[O:8])[C:9]=1[CH:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: O=C1CCC(c2ccccc2)O1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC1=C(C)C(=O)C(C(CCC(=O)O)c2ccccc2)=C(C)C1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
Aluminum chloride (1.4 g, 0.01 mole) was added to a 1,2-dichloroethane solution (20 ml) of 2,3,5-trimethylhydroquinone (1.5 g, 0.01 mole) and the mixture was heated at 80° C. A 1,2-dichloroethane solution (10 ml) of 4-phenylbutyrolactone (1.6 g, 0.01 mole) was added dropwise to the mixed solution over the 2-hours period, and the reaction was carried out under the same conditions for further 18 hours. After cooling, 2N-hydrochloric acid (40 ml) was added to the reaction solution, followed by stirring for 10 minutes, and the reaction product was extracted with isopropyl ether. The organic layer was washed with water, dried and evaporated and the residue was dissolved in tetrahydrofuran (30 ml). A 10% aqueous solution (5 ml) of ferric chloride was added to the solution, followed by stirring at room temperature for 10 minutes, and the reaction product was extracted twice with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed on a silica gel column, followed by elution with isopropyl ether to give 4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-4-phenylbutyric acid (1.2 g, 38%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 36 to 38 were prepared.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:25])[C:22]([C:23]#[N:24])=[CH:7][C:6]2[CH:5]=[C:4]([O:10][CH3:11])[C:3]([OH:12])=[C:2]([Br:1])[CH:9]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: N#CCC(=O)Nc1cccc(Cl)c1
Product: COc1cc(C=C(C#N)C(=O)Nc2cccc(Cl)c2)cc(Br)c1O
Yield: 64.9 %

Procedure:
The reaction was performed in the same manner as in Example 1 with 5-bromovanillin (1.38 g, 5.97 mmol) and N-(3-chlorophenyl) cyanoacetamide (1.16 g, 5.97 mmol) to give the objective N-(3-chlorophenyl)-2-cyano-3-(3-bromo-4-hydroxy-5-methoxyphenyl) propenamide (1.58 g, 65% in yield).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][C:17]=3[F:28])[N:9]=2)[NH:4][N:3]=1.Cl.C[CH2:31][N:32](C(C)C)[CH:33](C)C.[CH2:39]([OH:43])[CH2:40][CH2:41][CH3:42]>CCOC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:13]=[C:12]([N:32]3[CH2:33][C:39]([CH:40]4[CH2:42][CH2:41]4)([OH:43])[CH2:31]3)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][C:17]=3[F:28])[N:9]=2)[NH:4][N:3]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3F)n2)[nH]n1
Reactant: CCCCO
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(N3CC(O)(C4CC4)C3)nc(Sc3ccc(NC(=O)C4CC4)cc3F)n2)[nH]n1
Temperature: 130 °C
Yield: 29 %

Procedure:
A mixture of N-(4-(4-(3-methyl-1H-pyrazol-5-ylamino)-6-chloropyrimidin-2-ylthio)-3-fluorophenyl)cyclopropane-carboxamide (160 mg, 0.38 mmol), 3-cycloropylazetidin-3-ol hydrochloride (70 mg, 0.49 mmol) and DIPEA (0.20 ml) in n-butanol (1.5 ml) were heated in microwave at 130 ° C. for 1 h. Reaction mixture was then cooled to room temperature, diluted with EtOAc (20 ml), washed with sat NaHCO3 solution (10 ml), water (2×10 ml), brine (10 ml), dried (MgSO4), filtered and evaporated in vacuo. Crude product was purified by flash chromatography on silica (EtOAc/Petrol 30 to 80%) to give the title compound as a white solid (55 mg, 29%). 1H NMR (DMSO-d6) 0.33-0.36 (2H, m), 0.42-0.48 (2H, m), 0.82-0.86 (4H, m), 1.21-1.24 (2H, m), 1.85-1.89 (1H, m), 2.08 (3H, s), 2.10-2.15 (1H, m), 3.66-3.75 (4H, m), 5.42 (1H, br s), 5.67 (1H, 1H, s), 5.8 (1H, br s), 7.42 (1H, d), 7.52-7.58 (1H, m), 7.75 (1H, d), 9.27 (1H, s), 10.65 (1H, s), 11.9 (1H, br s). ES+ 496.90.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:19]2[NH:20][C:21]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[O:4]=[C:2]1[N:20]2[C:21]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[CH:15][CH:16]=[CH:17]3)[NH:13]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)NCC1(c2ccccn2)COc2cccc(N)c2N1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h
Yield: 176.2 %

Procedure:
Triphosgene (20 mg, 0.07 mmol) was added to a mixture of N-[(5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide (50 mg, 0.2 mmol), tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (60 μL) at room temperature. The reaction was stirred for 1 h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-[(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide (0.040 g. 70%). LCMS calculated for C17H17N4O3 (M+H)+: m/z=325.1. found: 325.1.