Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.O1CCOCC1>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CO.C(Cl)Cl>[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Reactant: CN1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(Nc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Add 1-bromo-3-nitro-5-(trifluoromethyl)benzene (3 g, 11.11 mmol), Cs2CO3 (9.5 g, 27.78 mmol), 1-methylpiperidin-4-amine (1.9 g, 16.67 mmol) to 1,4-dioxane (25 mL), then under N2, add Pd(OAc)2 (50 mg, 0.22 mmol) and BINAP (207 mg, 0.33 mmol). Stir the reaction at 120° C. under N2 overnight. TLC (DCM:MeOH=10:1) shows the reaction is complete. Cool to room temperature and filter off the solid. Concentrate the filtrate to get the crude product. Purification by chromatography (silica gel, DCM:MeOH-10:1) affords the title compound (3.44 g, 99%). MS: (M+1): 304.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:25]([F:28])([F:27])[F:26])=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[C:3]([C:25]([F:28])([F:26])[F:27])[C:2]([Br:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(C(F)(F)F)cc2N)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
A stirred suspension of 1,1-dimethylethyl 4-{[5-bromo-2-nitro-4-(trifluoromethyl)phenyl]amino}-1-piperidinecarboxylate (D66, 1.10 g, 2.3 mmol) in ethanol (50 ml) at room temperature under argon was treated with Raney Nickel (30 mg) followed by dropwise addition over 10 minutes of hydrazine hydrate (0.50 ml, 16 mmol). The mixture was stirred well at room temperature for 20 minutes, then heated at 45° C. for 1 hr, before cooling to 20° C. and filtering through Kieselguhr. The filtrate was concentrated under vacuum to afford the title compound as a white solid (0.98 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[F:39])[NH:23][C:22]4[NH:40][N:41]=[C:42]([C:43]5[S:44][CH:45]=[CH:46][CH:47]=5)[C:21]3=4)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[Mn+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:31]4[C:36]([F:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=4[F:39])[N:23]=[C:22]4[NH:40][N:41]=[C:42]([C:43]5[S:44][CH:45]=[CH:46][CH:47]=5)[C:21]=34)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1=C(c2c(F)ccc(F)c2F)Nc2[nH]nc(-c3cccs3)c2C1c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2c(F)ccc(F)c2F)nc2[nH]nc(-c3cccs3)c2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
254 mg (2.93 mmol) of manganese oxide is added to 300 mg (0.45 mmol) of ethyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-3-(thiophen-2-yl)-6-(2,3,6-trifluorophenyl)-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in solution in 10 ml of dichloromethane. The reaction mixture is placed in an ultrasonic bath for 5 minutes and then stirred at room temperature for 20 hours. It is then filtered on silica (eluent: 65:35 cyclohexane/ethyl acetate) to yield 254 mg (85%) of ethyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-3-(thiophen-2-yl)-6-(2,3,6-trifluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][S:24][C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([S:2]([CH3:1])=[O:3])=[CH:9][CH:8]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1
Reactant: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: Clc1cccc(CBr)c1
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(Cl)c5)o4)cc23)cc1
Yield: 84 %

Procedure:
In the same manner as in Example 7 and using 5-[3-[4-(methylsulfinyl)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 3-chlorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 84%) was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([OH:26])[C:12]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][C:13]=3[N:14]=2)=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(O)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[OH:26][C:11]1[C:12]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][C:13]=2[N:14]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)=[CH:3][CH:4]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(Br)cc3)nc(O)c2C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(Nc3nc(O)c4c(n3)CCN(C(=O)OC(C)(C)C)C4)cc2)cn1
Temperature: 110 °C

Procedure:
tert-Butyl 2-(4-bromophenylamino)-4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.4 g, 3.32 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole (0.691 g, 3.32 mmol), dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium (II), Pd-118 (0.108 g, 0.17 mmol) and potassium carbonate (1.837 g, 13.29 mmol) in DMF (5 mL), water (2.5 mL) and ethanol (0.833 mL) were charged in a thick wall glass, which was sealed and heated at 110° C. for 20 minutes. The raction mixture was allowed to cool down, the crude was filtered through celite and the filtercake washed with ethanol. The solvent was evaporated under reduced pressure. The crude was used in the next step without further purification. MS (ESI) (M+1) m/z 423
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[C:9]1([PH:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[OH:7][C:4]1[CH:5]=[CH:6][C:1]([OH:8])=[CH:2][C:3]=1[P:15](=[O:22])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1cc(O)ccc1O

Procedure:
Into a flame dried 2 L three neck round bottomed flask equipped with a mechanical stirrer, nitrogen gas inlet, pressure equalizing addition funnel, and drying tube were charged p-benzoquinone (30.16 g, 0.2790 mol) and toluene (750 mL). Diphenylphosphine oxide (56.42 g, 0.2790 mol) in toluene (250 mL) was added dropwise over 0.5 hour to the stirred solution at room temperature under nitrogen. The solution color changed from a dark brown to yellow with the formation of a gum. Upon further stirring, a grey solid formed. The solid was isolated, washed with toluene and then diethyl ether, and dried at 110° C. in flowing air to afford 74.0 g (85% crude yield) of an off-white solid. Recrystallization from ethanol afforded 2,5-dihydroxyphenyldiphenylphosphine oxide as a white solid (62.86 g, 73% recovery), m.p. 216-218° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH3:32])[C:22]([C:24]5[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=5Cl)=[O:23])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:33])[N:7]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:6]2=[O:42])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+]>[Pd].ClCCl.CO>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N:21]([CH3:32])[C:22]([C:24]5[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[CH:28]=5)=[O:23])=[CH:19][CH:20]=4)[NH:10][C:9]=3[C:8](=[O:33])[N:7]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:6]2=[O:42])[CH2:2][CH2:3]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1nn(C)cc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reaction time: 192 h
Yield: 9 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (81.5 mg, 0.14 mmol) (prepared as described in example 104), 10% palladium on carbon (313 mg), and sodium acetate (28.3 mg, 0.35 mmol) in dichloromethane (25 mL) and methanol (25 mL) was hydrogenated at 50 psi on a Parr apparatus for 8 days. At this time, the reaction was filtered through a pad of celite and washed with a 90/10 dichloromethane/methanol solution (100 mL). The filtrated was concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 1,3-dimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.0 mg, 9.1%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ13.122 (broad s, 1H), 6.79 (m, 9H), 6.33 (s, 1H), 4.76 (s, 2H), 3.70 (s, 2H), 3.47 (d, J=6.96 Hz, 2H), 3.11 (s, 3H), 2.87 (s, 3H), 1.75 (s, 3H), 0.85 (broad s, 1H), 0.026 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][CH:9]=[N:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:6]2[CH2:5][C:4]([CH3:18])=[N:3]1.[BH4-].[Na+].B(O)(O)O>C1COCC1>[CH3:1][N:2]1[C:7]2=[N:8][CH:9]=[N:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:6]2[CH2:5][CH:4]([CH3:18])[NH:3]1
Reactant: CC1=NN(C)c2ncnc(-c3ccccc3)c2C1
Agent: OB(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1Cc2c(-c3ccccc3)ncnc2N(C)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a stirred solution of 1,3-dimethyl-5-phenyl-1,4-dihydropyridazino[3,4-d]pyrimidine (260 mg) in dry THF (15 mL), sodium borohydride (414 mg) was slowly added, followed by boric acid (670 mg) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours and solvents were removed under reduced pressure. The resulting oil was diluted with dichloromethane (50 mL), washed with 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a residue which was purified by column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to afford 1,3-dimethyl-5-phenyl-1,2,3,4-tetrahydropyridazino[3,4-d]pyrimidine (95 mg) as colorless oily liquid. 1H NMR (DMSO-d6): δ 1.00-1.02 (d, 3H), 2.62-2.71 (t, 2H), 3.22 (s, 3H), 3.31-3.34 (m, 1H), 5.28-5.31 (d, 1H), 7.43-7.51 (m, 5H), 8.36 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10](=[O:11])[C:9](Br)=[C:8]([CH3:13])[N:7]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH3:15])[CH:6]=1)=[O:4].[F:24][CH:25]([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][NH:2][C:3]([C:5]1[C:10](=[O:11])[C:9]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:25]([F:35])[F:24])[CH:31]=2)=[C:8]([CH3:13])[N:7]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH3:15])[CH:6]=1)=[O:4]
Reactant: OB(O)c1cccc(C(F)F)c1
Reactant: CNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(Br)c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(-c2cccc(C(F)F)c2)c1=O
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid methylamide (preparation 9, 100 mg, 0.267 mmol), 3-difluoromethyl-phenylboronic acid (67 mg, 0.390 mmol), palladium (0) tetrakis(triphenylphosphine) (25 mg, 0.022 mmol) in acetonitrile (2 mL) is added 2 M aqueous K2CO3 solution (0.30 mL, 0.60 mmol). After stirring for 18 h at 75° C., the reaction mixture is purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1% NH4OH, 60° C.). Yield: 80 mg (71% of theory); ESI mass spectrum: [M+H]+=422; Retention time HPLC: 0.99 min (Z018_S04).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26](OC4C=CC([N+]([O-])=O)=CC=4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.Cl.[F:39][C:40]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26]([N:42]4[CH2:43][CH2:44][C:40]([F:45])([F:39])[CH2:41]4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Reactant: FC1(F)CCNC1
Agent: Cl
Product: O=C(N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1)N1CCC(F)(F)C1

Procedure:
100 mg (0.19 mmol) of the compound from Example 176A and 83 mg (0.58 mmol) of 3,3-difluoropyrrolidine hydrochloride were reacted according to the General Method 6. Yield: 44 mg (45% of theory)
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:13])/[CH:8]=[CH:9]\[C:10]([O-:12])=[O:11]>>[Cl-:2].[C:7]([O:14][CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:13])/[CH:8]=[CH:9]\[C:10]([O-:12])=[O:11]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: CCCCC(CC)COC(=O)/C=C\C(=O)[O-]
Product: [Cl-]
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (4.1 g, 20 mmol) was slowly added dropwise with mono (2-ethylhexyl) maleate (4.5 g, 20 mmol) produced by Aldrich, while the temperature was maintained at 30° C. or lower. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was heated at 60° C., and pressure was reduced by using an aspirator. The produced oxyphosphorous chloride was evaporated to obtain 2-ethylhexyl maleate chloride (4.5 g, yield: 92%) as a brown oily compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=C)[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2.C(Cl)Cl.[O:35]=[O+][O-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[O:35])[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2
Reactant: C=Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=O)c3ccc(OC(F)(F)F)cc3)nc12
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CC(C#N)(Cn1nc2cc(Cl)cc(C=O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of N-[2-(6-Chloro-4-vinyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (0.29 g) in 35 mL of a 3 to 1 mixture of DCM and methanol was treated with ozone gas for 15 minutes. After stirring one hour at −78° C., the mixture was purged 10 minutes with oxygen and then quenched with dimethyl sulfide followed by a 10% solution of sodium thiosulfate, then diluted with DCM (100 mL). The mixture was separated, and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (0.23 g, 79%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=452. 1H NMR: (400 MHz, CHLOROFORM-d): 1.58 (s, 3H), 5.24 (d, J=13.8 Hz, 1H), 5.47 (d, J=13.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.94 (br. s, 1H), 8.00 (d, J=1.8 Hz, 1H), 8.05 (m, 2H), 8.22 (d, J=1.9 Hz, 1H) and 10.34 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.CN.C=O.[CH3:21][N:22]1[CH2:27]COC[CH2:23]1>O.C(O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:23][N:22]([CH3:27])[CH2:21][N:12]([CH2:13][CH3:14])[C:10]3=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: CN1CCOCC1
Agent: C=O
Agent: CN
Solvent: O
Solvent: CCO
Product: CCN1CN(C)CN(c2nc3ccc(Br)cc3s2)C1=O
Yield: 88 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, methylamine, formaldehyde, and N-methyl morpholine in a mixed solvent of ethanol and water was reacted to give the desired compound 1.56 g (88%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(CC(OCC)=O)(=[O:27])C1C=CC=CC=1.COC1C=CC=C(N)C=1>>[C:1]1([C:7]2[CH:16]=[C:15]([OH:27])[C:14]3[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Agent: COc1cccc(N)c1
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1

Procedure:
2-Phenyl-4-chloro-7-methoxy-quinoline can be prepared according to Scheme XXXXI. Ethyl benzoylacetate and m-anisidine can reacted together under thermal conditions to afford 2-phenyl-4-hydroxy-7-methoxy-quinoline in the presence of an acid, such as hydrochloric acid and the like. 2-Phenyl-4-hydroxy-7-methoxy-quinoline can be converted to 2-phenyl-4-chloro-7-methoxy-quinoline using a chlorinating agent. For example, the chlorinating can be P(O)Cl3, P(O)Cl3 with PCl5, and the like.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([NH2:18])=[N:15][NH:16][CH:17]=1.O=[C:20]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[CH2:21][C:22](OCC)=[O:23]>C(O)(=O)C>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[CH:17]=[N:16][N:15]2[C:22]([OH:23])=[CH:21][C:20]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[N:18][C:14]=12
Reactant: Cc1c(Cc2c[nH]nc2N)cccc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: Cc1c(Cc2cnn3c(O)cc(-c4ccncc4)nc23)cccc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (115 mg, 0.45 mmol) in acetic acid (2.0 mL) was added ethyl 3-oxo-3-(4-pyridinyl)propanoate (87 mg, 0.45 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 140° C. for 60 minutes. The reaction mixture was cooled and stood for 2 hours. Precipitate was observed, filtered. Solid was washed with acetic acid (1 mL), then ethanol (1 mL×2). Solid was dried. The titled compound was obtained. (87 mg, 50%); LC/MS: MS (ES+) m/e 385 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 4.12 (s, 2H) 6.14 (s, 1H) 7.34 (s, 2H) 7.56 (d, J=9.09 Hz, 1H) 7.67 (s, 1H) 7.81 (br. s., 2H) 8.78 (br. s., 2H) 12.37 (br. s., 1H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][C:3]2[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1cccccc1O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2cccccc2=O)cc1
Yield: 63 %

Procedure:
2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted with p-toluenesulfonyl chloride (0.41 g, 2.0 mmol) in 10 mL of pyridine to afford PZBG-4b in 63% Yield (0.04 g, 0.1 mmol). 1H NMR (400 MHz, CDCl3) δ=7.92 (d, J=8.4 Hz, 2H), 7.46 (d, J=9.2 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.26-7.16 (m, 2H), 7.13-7.06 (m, 1H), 6.98 (t, J=10 Hz, 1H), 2.45 (s, 3H). 13C (125 MHz, CDCl3) δ=179.41, 155.15, 145.50, 141.23, 136.32, 134.61, 133.41, 130.81, 130.00, 129.60, 128.59, 21.78. ESI-MS(+): m/z 277.21 [M+H]+, 293.99 [M+NH4]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7]>C(O)(=O)C.O>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7]
Reactant: COc1cc(CO)cc(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(OC)c1OC

Procedure:
To this oxydation mixture, g 19.8 of 3,4,5-trimethoxy benzyl alcohol dissolved in 160 ml of glacial acetic acid are very slowly added under continuous stirring. The mixture is kept reacting during 30' after the end of the addition and is then cooled, diluted with water and extracted with CHCl3 (3 fractions of 200 ml each).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1>>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[CH2:31][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[C:13]([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[O:12])=[CH:14]1
Reactant: BrCc1cccc(Br)c1
Reactant: O=C(c1ccc2c(c1)OCCO2)c1c[nH]c2ccccc2c1=O
Product: O=C(c1ccc2c(c1)OCCO2)c1cn(Cc2cccc(Br)c2)c2ccccc2c1=O
Yield: 23 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-1H-quinolin-4-one (70 mg, 0.228 mmol) and 74 mg (0.296 mmol) of 1-Bromo-3-bromomethyl-benzene, to give 25 mg of desired compound. LCMS (M+H)+: 476.