Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:3]2[CH:2]=[CH:8][C:6]([NH2:7])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (2 g, 11.59 mmol) in dioxane (100 ml) and water (10 ml) was added (4-chlorophenyl)boronic acid (3.6 g, 23.02 mmol), K3PO4 (5.01 g, 23.18 mmol) and Pd(PPh3)4 (0.7 g, 0.58 mmol) with stirring for 4 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 5% ethyl acetate in petroleum ether to afford 4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (2.0 g, 69%). Next, to a solution of 5-(4-chlorophenyl)-2-nitroaniline (300 mg, 1.21 mmol) in ethanol (10 ml) was added hydrogen chloride (0.5 ml, 3.63 mmol) and Zn powder (800 mg, 12.3 mmol) in portions at room temperature and stirred for 2 h at 85° C. The resulting mixture was concentrated under vacuum to give a residue and dissolved in water (100 ml), adjusted to pH 8 with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml) and dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% to 20% ethyl acetate in petroleum ether to produce 4-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (200 mg, 76%). Finally, a solution of 4-(4-chlorophenyl)benzene-1,2-diamine (150 mg, 0.69 mmol) in heptafluorobutanoic acid (2 ml) was stirred for 8 h at 120° C. Then the reaction was quenched with water (50 ml), adjusted to pH 7 with sodium bicarbonate and extracted with ethyl acetate(3×100 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% to 10% ethyl acetate in petroleum ether to produce 6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (49.5 mg, 18%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:9][CH:10]=3)[C:5]([CH2:31][CH:32]=[CH2:33])([CH2:28][CH:29]=[CH2:30])[C:4]=2[CH:3]=1.C([Li])CCC.[N:39]1[C:46](F)=[N:45][C:43](F)=[N:42][C:40]=1F>C1COCC1.C1(C)C=CC=CC=1.O>[C:22]1([N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[CH:7]=[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][C:2]([C:40]5[N:42]=[CH:43][N:45]=[CH:46][N:39]=5)=[CH:3][C:4]=4[C:5]3([CH2:31][CH:32]=[CH2:33])[CH2:28][CH:29]=[CH2:30])=[CH:10][CH:9]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CCC1(CC=C)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: Fc1nc(F)nc(F)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCC1(CC=C)c2cc(-c3ncncn3)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 60 %

Procedure:
To a solution of 2-bromo-7-(diphenylamino)-9,9-diprop-2 -enylfluorene (22.16 g, 0.045 mol), in THF (200 mL), cooled in a dry ice-acetone bath, a solution of n-butyl lithium in hexanes (1.6M, 30 mL, 0.048 mol), was added by syringe over 5 minutes. After 25 minutes, over a 30 minute period, a solution of cyanuric fluoride (2.025 g, 0.015 mol), in THF (100 mL) was added to result in a greenish fluorescent solution, which turned orange at the end of additon. The mixture was allowed to warm up slowly to room temperature, diluted with toluene and water, and the organic phase was dried and concentrated. The residue was chromatographed over alumina (eluted with 1:3 toluene-heptane), rechromatographed over silica gel (eluted with 1:3 toluene-heptane), and then crystallized from 1:3 toluene-heptane. The desired product was obtained as a bright yellow solids, 11.84 g, 60% yield, m.p. 235-237° C. Recrystallization from 2:1 heptane-toluene raised its m.p. to 236-238° C. Mass Spec: m/z 1314 (M+). Anal. Calcd. for C96H78N6: C, 87.64%; H, 5.90%: N, 6.3%. Found: C, 87.59%; H, 6.06%; N, 6.15%.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][CH:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19][CH2:18]2)[CH3:16])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>[OH-].[Na+]>[CH:1]1([CH2:7][N:8]2[C:13]([CH2:14][CH:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:19][CH2:18]3)[CH3:16])=[N:12][NH:11][C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(C(C)CC(=O)NNC(=O)NCC2CCCCC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1N1CCN(C(C)Cc2n[nH]c(=O)n2CC2CCCCC2)CC1
Yield: 48.8 %

Procedure:
N-(Cyclohexylmethyl)-2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]butanoyl}hydrazinecarboxamide D13 (0.90 g, 2.08 mmol) in 2M NaOH aqueous solution (20 mL) was heated at reflux for 18 hrs. The pH was adjusted to 8 with conc. HCl and the resulting yellow slurry was extracted twice with DCM (50 mL and 20 mL). The combined organic extracts were filtered and DCM evaporated under reduced pressure to a light yellow glassy solid. Purification by flash chromatography (Silica gel 60 Å, 45 μm 10% methanol in dichloromethane) afforded 0.42 g (48.8%) 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-2,4-dihydro-3H-1,2,4-triazol-3-one D14 as a cream solid.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N=C=NCCCN(C)C)C.[C:37]([CH:39]1[CH2:42][N:41]([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:40]1)#[N:38]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:23][CH2:24]4)=[CH:20][C:16]([C:17]([NH:46][S:43]([N:41]4[CH2:42][CH:39]([C:37]#[N:38])[CH2:40]4)(=[O:45])=[O:44])=[O:19])=[C:15]([F:25])[CH:14]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: N#CC1CN(S(N)(=O)=O)C1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: N#CC1CN(S(=O)(=O)NC(=O)c2cc(C3CC3)c(OCC34CC5CC(CC(C5)C3)C4)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a mixture of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.20 g, 0.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.26 g, 1.38 mmol) and 4-dimethylaminopyridine (0.17 g, 1.38 mmol) in anhydrous dichloromethane (10 mL) was added 3-cyanoazetidine-1-sulfonamide (0.22 g, 1.38 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The mixture was quenched with 1 M aqueous hydrochloride acid (30 mL) followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography using 10-60% ethyl acetate (containing 2% acetic acid) in hexanes as an elute to afford the title compound as colorless solid (0.23 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.95 (d, J=13.0 Hz, 1H), 4.35-4.22 (m, 4H), 3.84-3.74 (m, 1H), 3.65 (s, 2H), 2.09-1.99 (m, 4H), 1.75-1.67 (m, 12H), 0.95-0.87 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 488.2 (M+1); MS (ES−) m/z 486.3 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][N+:13]([O-])=[CH:14][CH:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.CC(C)([O-])C.[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: [O-][N+]1=CC2CN=C(c3ccccc3F)c3cc(Cl)ccc3N2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1ccccc1C1=NCc2cncn2-c2ccc(Cl)cc21

Procedure:
A solution of 50 mg of 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1H-imidazo[1,5-a][1,4]benzodiazepine 2-oxide in 3 ml of ethanol contianing 25 mg of potassium t-butoxide was heated to reflux for 10 min. The mixture was evaporated partially and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase was dried and evaporated. Crystallization of the residue from ether yielded product with mp 148°-151° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH2:19][OH:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CCN(CC)CC>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH:19]=[O:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(CO)c(COC)nc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1ncc2c(-c3cncc(C)c3)c(C=O)c(COC)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a mixture of [1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (110 mg), Et3N (0.29 ml) in N,N-dimethylsulfoxide (3 ml) was added sulfur trioxide-pyridine complex (168 mg) at room temperature and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous NaHCO3, water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane(3:1) to give 1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (86 mg) as a white crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH:27][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: C=CS(=O)(=O)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Yield: 72.2 %

Procedure:
A stirred mixture of 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 2; 0.43 g, 1.04 mmol), ethyl vinyl sulphone (0.17 g, 1.4 mmol), tri-o-tolylphosphine (91 mg), palladium(II) acetate (16 mg), triethylamine (0.31 ml) and acetonitrile (4 ml), under nitrogen, was heated under reflux for 18 hours, allowed to cool, then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a dichloromethane to dichloromethane:ethanol (99:1) gradient, to afford the title compound as a foam (0.34 g). Rf 0.80 (SS 2). [α]D25 -50° (c=0.1, CH3OH). Found: C,65.16; H,6.17; N,5.97. C25H28N2O4S; 0.125 CH2Cl2 requires C,65.15; H,6.15; N,6.05%. δ(CDCl3)--mixture of rotamers: 1.42(3H,t), 1.70-1.88(4H,m), 2.78(1H,m), 3.05-3.48(5H,m), 4.20(1H,m), 5.16-5.28(2H, br q), 5.30(0.25H,s,CH2Cl2), 6.64-7.82(1H,m), 6.96 and 7.05(1H, 2×s), 7.30-7.45(7H,m), 7.55-7.80 and 8.00(2H, m and s), 8.32(1H,br s).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Na].[CH:17](=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C(O)C>[C:1]([N:4]1[CH:17]([OH:26])[CH2:18][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: O=CC=Cc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)C(c2ccccc2)CC(O)N1C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of diethyl acetamidomalonate (75.0 g, 345 mmol) in ethanol (375 ml) at 0° C. was added sodium metal (6.9 g, 36 mmol). Cinnamaldehyde (50.0 g, 378 mmol) was added dropwise to the resulting solution. The reaction was warmed to rt and allowed to stir for 2 h. Acetic acid (7 ml) was added, and the solution was concentrated. The residue was dissolved in EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was triturated with hexanes/EtOAc to yield diethyl 1-acetyl-5-hydroxy-3-phenylpyrrolidine-2,2-dicarboxylate as a white solid (96%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[NH:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21]C)=[O:19])=[O:4].C[O-].[Na+].[Cl-].[NH4+]>CO>[CH3:14][O:13][C:11]1[CH:12]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:15][C:16](=[O:23])[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH:6]2[CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: CCOC(=O)CC(=O)Nc1ccc(OC)cc1C=CC(=O)OC
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CC1c2cc(OC)ccc2NC(=O)C1C(=O)OC
Temperature: 0 °C

Procedure:
To a stirred, chilled (0° C.) suspension of crude 3-[[2-[(methoxycarbonyl)ethenyl]-4-methoxyphenyl]amino]-3-oxopropanoic acid, ethyl ester from step 3 in 700 ml of methanol was added, dropwise, a solution of 66.5 g of sodium methoxide (25% in methanol) in 250 ml of methanol. The resulting mixture was heated to reflux over 0.75 hour, cooled to 0° C., and poured into a cold saturated ammonium chloride solution. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with 10% hydrochloric acid solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 1,2,3,4-tetrahydro-6-methoxy-3-(methoxycarbonyl)-2-oxo-4-quinoline acetic acid, methyl ester.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[OH-].[Na+].CO.C1COCC1>O>[N:14]1([CH2:13][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=2[C:3]([OH:20])=[O:2])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of compound 5 (0.85 g) and NaOH (0.304 g) in a mixture of water (9 mL), methanol (5 mL), and THF (45 mL) was stirred at reflux for 24 h and concentrated to dryness. The residue was dissolved in water, and the solution was cooled to 0° C. and adjusted to pH 7 with 10% potassium hydrogen sulfate. The mixture was concentrated to dryness, the residue was treated with methanol, and filtered to remove solids. The filtrate was concentrated to yield compound 6 as a yellow solid.
Reaction SMILES: C1(OC([N:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH:13]([CH2:26][CH3:27])[C:12]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:11]2)=O)C=CC=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[CH2:31]([O:30][C:28](=[O:29])[C:12]1[C:13]([CH2:26][CH3:27])=[C:14]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:15]=[N:10][CH:11]=1)[CH3:32]
Reactant: CCOC(=O)C1=CN(C(=O)Oc2ccccc2)C=C(OCCc2cccc(Cl)c2)C1CC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1cncc(OCCc2cccc(Cl)c2)c1CC
Temperature: 25 °C

Procedure:
The title compound of step 2 (80 mg, 0.175 mmol)) was dissolved in dichloromethane. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (80 mg, 0.35 mmol) was added and the mixture was stirred over night at room temperature. The mixture was partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution with addition of some sodium sulfit. The combined organic extracts were dried over sodium chloride und avaporated to dryness in vacuo. The material was titured with diethyl ether, the solid material was separated by suction filtration, the filtrate was evaporated to dryness, again, to yield the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH2:32]([O:34][CH:35]([O:38][CH2:39]C)[CH2:36][NH2:37])C>O1CCOCC1>[CH3:32][O:34][CH:35]([O:38][CH3:39])[CH2:36][NH:37][C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[CH:21][CH:20]=1)=[O:31]
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(NC(=O)NCC(OC)OC)cc3)CC2)cc1

Procedure:
A mixture of 10 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate monohydrochloride (described in example XVII of U.S. Pat. No. 4,267,179), 3 parts of 2,2-diethoxy-ethanamine and 100 parts of 1,4-dioxane was stirred for 6 hours at reflux temperature. After cooling, the precipitate was filtered off, washed with 1,4-dioxane and purified by column chromatography (silica gel; CHCl3 /CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was crystallized from 1,4-dioxane, yielding 3.9 parts of N-(2,2-dimethoxyethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]urea; mp. 225° C. (interm. 8).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][CH:14]([CH2:20][CH3:21])/[CH:15]=[CH:16]/[C:17](=O)[CH3:18].NCC1C(=O)NC(C)=CC=1CCC.O=O.Cl>CS(C)=O.O>[CH:14]([C:15]1[CH:16]=[C:17]([CH3:18])[NH:12][C:10](=[O:11])[C:9]=1[C:7]#[N:8])([CH2:20][CH3:21])[CH3:13]
Reactant: CCC(C)/C=C/C(C)=O
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(C)[nH]c(=O)c1CN
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)c1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a stirred solution of t-BuOK (8 g, 71.42 mmol) and cyanoacetamide (6.6 g, 78.57 mmol) in DMSO (80 mL) was added (E)-5-methylhept-3-en-2-one, 2 (9 g, 71.42 mmol) under argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 1 h and then added additional t-BuOK (24 g, 214.28 mmol) was added. Then argon was displaced by oxygen and stirred at RT for 48 h. The reaction mixture was cooled to 0° C., diluted with water (36 mL) followed by 4N HCl (up to pH˜4) and the resulting reaction mixture was stirred for 15 min. The separated solid was collected by filtration, washed with water (10 mL), pet ether (100 mL) and dried to afford the title compound as yellow solid (7 g, 53%). 1H NMR (DMSO-d6, 400 MHz): δ 0.816-0.779 (t, 3H, J=7.6 Hz), 1.178-1.161 (d, 3H, J=6.8 Hz), 1637-1.505 (m, 2H), 2.24 (s, 3H), 2.814-2.760 (m, 1H), 6.239 (s, 1H), 12.324 (bs, 1H); LCMS (ES−) m/z=189.20 (M−H)
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=C[C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].Cl.CONC.C(N(C(C)C)CC)(C)C>ClCCl>[F:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([N:9]([O:8][CH3:4])[CH3:10])=[O:27]
Reactant: O=C(O)c1cccnc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cccnc1F
Temperature: 25 °C
Yield: 80 %

Procedure:
TBTU coupling agent (13 g, 40 mmol) was added to a solution of 2-fluoronicotinic acid (5.6 g, 40 mmol), N-methoxy-N-methylamine hydrochloride (4.4 g, 45 mmol) and diisopropylethylamine (16 ml, 0.1 mol) in dichloromethane (100 ml) under nitrogen. The reaction mixture was stirred at room temperature for eighteen hours. It was diluted with more dichloromethane (200 ml), washed with a 2M aqueous hydrochloric acid solution (50 ml), a saturated sodium bicarbonate solution (100 ml), and brine (100 ml). The organic was dried over magnesium sulfate and, after filtration, concentrated in vacuo. The residue was purified by flash chromatography (120 g SiO2, pentane/ethyl acetate) to afford the title compound as a colourless oil (6 g, 80%). 1H NMR (CDCl3): 3.40-3.45 (3H, s), 3.55-3.65 (3H, s), 7.75-7.80 (1H, t), 7.90-7.95 (1H, t), 8.28-8.30 (1H, d).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:29][CH2:30][CH2:31][O:32][CH3:33])[N:4]=1.Br>C(O)(=O)C>[CH3:33][O:32][CH2:31][CH2:30][NH:29][C:5]1[NH:4][C:3](=[O:2])[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=1
Reactant: COCCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Agent: Br
Solvent: CC(=O)O
Product: COCCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 90 °C
Yield: 68.2 %

Procedure:
A solution of 4-methoxy-N-(2-methoxyethyl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.10 g, 0.22 mmol) in acetic acid (5 mL) was treated with HBr (0.10 mL, 0.90 mmol), heated at 90° C. for 4 h, cooled to RT and quenched with ice water. The solution was treated with NaHCO3 and NaCl, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN (3 mL) and the resulting solid was collected via filtration to afford 2-((2-methoxyethyl)amino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (65 mg, 61%). 1H NMR (400 MHz, DMSO-d6): δ 11.02 (br s, 1H), 8.67 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.29-8.23 (m, 2H), 7.96 (d, J=0.7 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.85 (br s, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.53-3.44 (m, 4H), 3.28 (s, 3H), 2.34 (s, 3H); MS (ESI) m/z: 434.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH:9]=[CH:10][C:2]=2[OH:1])=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: O=C(O)c1cc(-c2cccs2)ccc1O
Product: CCOC(=O)c1sc(NC(=O)c2cc(-c3cccs3)ccc2O)nc1-c1ccccc1
Yield: 58.2 %

Procedure:
Using 2-hydroxy-5-(2-thienyl)benzoic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195(3) gave the title compound.