Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][N:7]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>O1CCCC1>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:35])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc(-c2cccc(NC(=O)c3ccc(OC)cc3)c2)cnc1N
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 3-amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide (20 mg, 0.07 mmol) and triethylamine (160 mg, 0.16 mmol) in tetrahydrofuran (1 mL) was added p-anisoyl chloride (20 mg, 0.12 mmol) slowly at room temperature. The mixture was allowed to stir overnight. The reaction was quenched with water (10 mL) at 0° C. and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (30 mL), saturated aqueous sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated at reduced pressure to afford 3-amino-N-methyl-6-[3-({[4-(methyloxy)phenyl]carbonyl}amino)phenyl]pyrazine-2-carboxamide (13 mg, 48% yield) as yellow solid. 1H NMR (400 MHz, d6-DMSO): 10.10 (s, 1H), 8.85 (s, 2H), 8.30 (s, 1H), 8.02 (d, 2H), 7.90 (m, 2H), 7.40 (m, 1H), 7.02 (d, 2H), 3.80 (s, 3H), 2.82 (br s, 3H); MS (EI) for C20H19N5O3: 378 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+].[C:14](O)(=[O:16])C>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:10])[O:16][CH3:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 706.3 %

Procedure:
1,4-dicyanobenzene (6.41 g, 50 mmol) was suspended in methanol (100 ml), and sodium methoxide (0.27 g, 5.0 mmol) was added. The mixture was stirred at room temperature for 22 hours. After the reaction was completed, acetic acid (0.31 g, 5.1 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Dichloromethane (50 ml) and diethyl ether (50 ml) were added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 4-cyanobenzenecarboximidate (5.77 g) as colorless powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([CH3:17])[CH:9]=2)[CH2:4][CH2:3]1.[CH3:18]OC(OC)N(C)C.N1CCCC1.C([O-])=O.[NH4+]>CN(C)C=O.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:12][CH:13]=2)[NH:14][CH:18]=[CH:17]3)[CH2:4][CH2:3]1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CN1CCN(c2ccc3[nH]ccc3c2)CC1
Temperature: 50 °C

Procedure:
A solution of 1-methyl-4-(3-methyl-4-nitro-phenyl)-piperazine (10a), (2.63 g, 11.2 mmol), N,N-dimethylformamide dimethyl acetal (4.7 mL, 35.84 mmol) and pyrrolidine (1.5 mL, 17.9 mmol) in anhydrous N,N-dimethylformamide (20 mL) was heated at 120° C. for 18 hours. The reaction mixture was concentrated in vacuo, taken up in ethanol (50 mL) containing 2 mL of water and to this was added ammonium formate (3.67 g, 58.2 mmol). Palladium, 10 wt. % on activated carbon (0.84 g) was added and the suspension was stirred and heated at 50° C. for 30 minutes. The reaction mixture was then filtered through a celite pad and the pad rinsed with hot methanol (20 mL). The combined filtrate and washings were concentrated in vacuo and the residue was taken up in ethyl acetate (100 mL), washed with aqueous saturated sodium bicarbonate solution (2×100 mL), brine, dried (MgSO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting first with hexane and then 15% ethyl acetate/hexane to afford the desired title compound as an off-white solid, 1.44 g, 60%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:18][CH:19]([CH2:23][CH2:24][Br:25])[C:20](Cl)=[O:21]>C(OCC)C>[Br:18][CH:19]([CH2:23][CH2:24][Br:25])[C:20]([NH:10][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:9])=[O:21]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](NC(=O)C(Br)CCBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (S)-1-(4-fluorophenyl)ethanamine (3.2 g, 23 mmol) in diethyl ether (50 mL) and triethylamine (9.6 mL, 69 mmol) at 0° C. was added 2,4-dibromobutanoyl chloride (7.3 g, 27.6 mmole) and the mixture was allowed to warm to rt and stirred for 12 h. A solid formed which was removed by filtration, washed with ethyl acetate, and then discarded. The combined filtrates were evaporated under reduced pressure and the residue was subjected to silica gel chromatography eluting with 20-30% ethyl acetate/petroleum ether yielding 4.5 g of 2,4-dibromo-N—((S)-1-(4-fluorophenyl)ethyl)butanamide as a brown solid. LCMS (method O) RT=0.99 min, m/z 366, 368, 370 (M+H+, M+H++2, M+H++4); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.44 (m, 3H) 2.27-2.46 (m, 2H) 3.46-3.58 (m, 2H) 4.55-4.66 (m, 1H) 4.81-5.00 (m, 1H) 7.03-7.24 (m, 2H) 7.30-7.45 (m, 2H) 8.89 (d, J=8.03 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:15][Br:16])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reaction time: 5 h
Yield: 61.2 %

Procedure:
3,5-Bis(t-butyl)-1-methylbenzene (200 mg, 0.98 mmol) was dissolved in carbon tetrachloride (4 ml), and then N-bromosuccinimide (192 mg, 1.08 mmol) and AIBN (α,α′-azabisisobutyronitrile) (2 mg) were added thereto. The mixture was heated under reflux and stirred for 5 hours. The filtrate obtained from the filtration of the reaction mixture was evaporated under reduced pressure to give 170 mg (yield: 61%) of a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[Cl:14][C:15]1[C:16]([CH2:25][CH2:26][NH2:27])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:15]1[C:16]([CH2:25][CH2:26][NH:27][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[N:11][C:3]=2[C:2]([F:1])([F:13])[F:12])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1
Reactant: O=C(O)c1cccnc1C(F)(F)F
Reactant: NCCc1ncc(C(F)(F)F)cc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ncc(C(F)(F)F)cc1Cl)c1cccnc1C(F)(F)F

Procedure:
A solution of 204 mg (1 mmol) of 2-trifluormethyl nicotinic acid, 200 mg (0.9 mmol) of 2-(3-chloro-5-trifluormethyl-pyridin-2-yl)-ethylamine and 620 mg (1.3 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and 230 mg (1.8 mmol) N,N-Diisopropylethylamine in 8 ml methylene chloride is stirred for 20 h at room temperature.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[O:12][N:11]=2)[CH:5]=1.[C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH3:25].[Li]>>[C:28]([O:27][C:24](=[O:26])[CH2:25][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[C:13]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[O:12][N:11]=2)[CH:5]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1

Procedure:
The title compound was prepared from (RS)-3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-benzoic acid methyl ester [prepared from (Z)-3-(hydroxyimino-methyl)-benzoic acid methyl ester [CAS-No. 91186-80-0] by treatment with NCS, cat. amount pyridine in CHCl3 followed by addition of (RS)-tetrahydro-2-(2-propynyloxy)-2H-pyran and slow addition of Et3N in CHCl3 at 23°C.] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (3.00 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)c1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example A.42) (0.65 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.2 mmol) according to the general procedure IVb. Obtained as a white solid (0.43 g, 48%). MS (EI) 448.0 [(M)+]; mp 102.5° C.
Reaction SMILES: C(N)(C)(C)C.[Br:6]Br.[OH:8][C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>ClCCl>[Br:6][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH3:19])[C:9]=1[OH:8]
Reactant: COC(=O)c1cccc(O)c1C
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(C)(C)N
Product: COC(=O)c1ccc(Br)c(O)c1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
To a solution of tert-butylamine (1.6 mL, 15 mmol) in dichloromethane (100 mL) at −78° C. was added drop-wise over 30 minutes a solution of bromine (773 μl, 15 mmol in 15 mL of dichloromethane). The solution was stirred at −78° C. for 30 minutes. While maintaining the temperature at −78° C., a solution of methyl 3-hydroxy-2-methylbenzoate (2.5 g, 15 mmol in 15 mL of dichloromethane) was added to the reaction mixture drop-wise over 30 minutes. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The mixture was washed with 20% aqueous citric acid then brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was purified by silica gel column chromatography. Eluting with 10% diethyl ether in hexane, purified fractions were pooled and concentrated to afford 612 mg, 2.5 mmol (17%) of methyl 4-bromo-3-hydroxy-2-methylbenzoate as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.37-7.29 (m, 2H), 5.71 (s, 1H), 3.81 (s, 3H), 2.53 (s, 3H). MS (EI) for C9H9BrO3: 245 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH:6](SC2C=CC(C)=CC=2)[CH2:5][C:4]1=[O:15])[CH3:2].[C:16]([OH:19])(=[O:18])[CH3:17]>CCOCC.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([N:3]1[CH:6]([O:18][C:16](=[O:19])[CH3:17])[CH2:5][C:4]1=[O:15])[CH3:2]
Reactant: CC(=O)O
Reactant: CCN1C(=O)CC1Sc1ccc(C)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: O
Product: CCN1C(=O)CC1OC(C)=O
Temperature: 110 °C
Yield: 77.6 %

Procedure:
A mixture of 351 mg (1 mmol) of (1'R, 3S, 4R)-3-(1'-tert-butyldimethylsililoxy)ethyl-4-p-methylphenylthio-2-azetidinone and 100 mg (0.5 mmol) of copper (II) acetate monohydrate in 2 ml of acetic acid was heated at 110° C. for 5 minutes with stirring. The reaction mixture was diluted with ether and the insoluble materials were filtered off. The filtrate was washed with saturated sodium bicarbonate solution and then water, dried, and concentrated to produce 223 mg (yield: 77.6%) of the title compound as white crystals.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[S:6][C:5]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:21])([F:20])[F:22])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH3:23])=[CH:4][CH:3]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(Br)s1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(-c2cc(F)cc(F)c2)s1

Procedure:
Synthesized as described in Example 310D using 1-[(5-bromo-2-thienyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 314B) and [3,5-difluorophenyl]boronic acid: MS (ES) m/z 431 (M−1).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)N.CN(C=O)C>O>[Cl:24][C:25]1[CH:31]=[C:30]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([NH:13][C:14]4[CH:15]=[CH:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=4)[C:3]=23)[CH:29]=[CH:27][CH:26]=1
Reactant: CN(C)C=Nc1[nH]nc(Nc2ccc(N(C)C)cc2)c1C#N
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 130 °C

Procedure:
A mixture of 5 g (16.8 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(4-dimethylamino-phenylamino)-pyrazole, 3.3 g (20.1 mmol) of 3-chloro-aniline hydrochloride and 40 ml of DMF is heated for 8 hours, with stirring, at 130° C. The reaction mixture is then cooled to RT, water is added dropwise thereto, and the reaction mixture is then filtered and the filter residue is dissolved in approx. 20 ml of DMF. After precipitation with water, followed by recrystallization from DMF/water, the resulting crystals are suspended in 10 ml of water. 6 ml of 1N hydrochloric acid are added, the mixture is heated briefly to reflux and filtered and 3 ml of 2N sodium hydroxide solution are added to the filtrate. The crystalline precipitate is filtered off, washed with water and dried under a high vacuum at 120° C., yielding the title compound having a water content of 2.32%; m.p. 250-255° C. (decomp.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:23][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 151 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 28.5 g of 1-decanol (0.18 mol, 1.8 eq.) were added to 64 mL of toluene, and the mixture was heated to reflux for 4 hours, and then cooled to room temperature. 160 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (7.3 g). Subsequently, the resultant was extracted with 100 mL of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 42.2 g of 4-decyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@:17]([CH3:29])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13]([O:14][CH3:15])[C@@H:12]1[OH:30].[CH3:31]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@:17]([CH3:29])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13]([O:14][CH3:15])[C@:12]1([CH3:31])[OH:30]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CO[C@H]1O[C@](C)(COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Solvent: ClCCl
Product: CO[C@H]1O[C@](C)(COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Temperature: -30 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
The product (2.0 g, 4.0 mmol) from Step B and Dess-Martin periodinane (2.0 g) in dichloromethane (30 mL) were stirred overnight at room temperature and was then concentrated under reduced pressure. The residue was triturated with ether ether (50 mL) and filtered. The filtrate was washed with a solution of Na2S2O3.5H2O (2.5 g) in saturated aqueous sodium bicarbonate solution (50 mL), dried (MgSO4), filtered and evaporated. The residue was dissolved in anhydrous Et2O (20 mL) and was added dropwise to a solution of MeMgBr in Et2O (3 M, 10 mL) at −78° C. The reaction mixture was allowed to warm to −30° C. and stirred at −30° C. to −15° C. for 5 h, then poured into saturated aqueous ammonium chloride (50 mL). The two layers were separated and the organic layer was dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel (EtOAc/hexane: 1/9) to afford the title compound as a syrup (1.40 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:17]1[O:18][C:19]2[C:20](=[C:22]([C:34]#[N:35])[C:23]([CH3:33])=[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:25]=2[F:26])[N:21]=1>ClCCl>[F:26][C:25]1[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([CH3:33])[C:22]([C:34]#[N:35])=[C:20]2[C:19]=1[O:18][C:17]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[N:21]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCOCC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
With cooling with ice, morpholine (36 μl, 0.413 mmol) and diisopropylethylamine (140 μl, 0.825 mmol) were added to a dichloromethane (3 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenylbenzoxazole-4-carbonitrile (I-130) (99 mg, 0.344 mmol), followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, then the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (115 mg, 99%) as a white solid.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC(O)=O)[C:12](=[O:13])[CH:11]=C1.C([O:29]C(Cl)=O)C(C)C>C(N(CC)CC)C>[OH:29][C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[CH3:11])=[CH:19][CH:18]=1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.508 g. of PGA1, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.309 g. of p-hydroxyacetophenone, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-hexane (2:3), followed by ethyl acetate-hexane (7:3). The residue obtained by concentration of selected fractions, 0.500 g., an oil, is the title compound, having Rf 0.4 (TLC on silica gel in ethyl acetate-hexane (1:1)).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23](O)=[O:24])[CH:20]=[CH:19][S:18]2.[CH3:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:26][C:2]([CH3:1])([CH3:27])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([NH:34][C:31]1[S:32][CH:33]=[C:29]([CH3:28])[N:30]=1)=[O:24])[CH:20]=[CH:19][S:18]2
Reactant: Cc1csc(N)n1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C)cs2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (250 mg, 0.646 mmol) with 4-methyl-1,3-thiazol-2-amine (82 mg, 0.711 mmol) in the presence of EDCI hydrochloride (247 mg, 1.292 mmol) and DMAP (36.33 mg, 0.323 mmol) in a mixture of DCM and DMF (4:1, 10 mL) to give 110 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 9H), 2.28 (s, 3H), 3.57 (s, 2H), 3.80 (s, 3H), 6.62 (s, 1H), 6.98 (d, J=7.8 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.36-7.40 (m, 2H), 7.88 (d, J=16.2 Hz, 1H), 7.98-8.20 (br m, 1H), 8.55 (br m, 1H), 12.89 (br s, 1H); ESI-MS (m/z) 483.33 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:9].[N:35]([Si](C)(C)C)=[N+:36]=[N-:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]3[N:35]=[N:36][NH:37][N:32]=3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:9]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1noc(-c2ccc(-c3ccc(CC#N)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: Cc1noc(-c2ccc(-c3ccc(Cc4nn[nH]n4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl

Procedure:
Prepared as described in Example 45 using [5-(4′-cyanomethyl-biphenyl-4-yl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and azidotrimethylsilane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH3:20][C:21]1[C:22](=[O:27])[O:23][C:24](=O)[CH:25]=1.C(O)(=O)C>O>[CH3:20][C:21]1[C:22](=[O:27])[N:1]([C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[NH:8][N:7]=3)[CH:3]=2)[C:24](=[O:23])[CH:25]=1
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Reactant: CC1=CC(=O)OC1=O
Solvent: CC(=O)O
Solvent: O
Product: CC1=CC(=O)N(c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)C1=O
Reaction time: 65 h

Procedure:
A stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (0.1 g, 0.4 mmol; prepared in a manner similar to that described in Example 1), 3-methylfuran-2,5-dione (0.045 g, 0.4 mmol) and acetic acid (4 ml) was heated under reflux for 8.25 hours and allowed to stand at ambient temperature for 65 hours, then it was diluted with water (10 ml). The resulting solid was collected by filtration, washed with water (10 ml) and dried in vacuo to give 3-methyl-1-[3-(4oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]pyrrole-2,5-dione (0.068 g) as an off-white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.95 (s, 3H) (CH3), 4.3 (s, 2H) (ArCH2—), 6.7 (s, 1H) (—COCH═CMeCO—), 7.15 (d, 1H) (ArH), 7.2 (s, 1H) (ArH), 7.25–7.35 (m, 2H) (2×ArH), 7.7–7.9 (m, 3H) (3×ArH), 8.2 (d, 1H) (ArH), 12.55 (s, 1H) (CONH); m/z (M+H)+. 346, 100% purity.