Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=CC(S(Cl)(=O)=O)=C[CH:21]=1.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][C:20]([CH3:30])([CH3:25])[CH3:21])=[O:12])=[N:9][CH:10]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
5-(Methoxycarbonyl)pyridine-2-carboxylic acid (7.72 g, 42.65 mmol) was suspended in tert-butanol (70 mL) and pyridine (25 mL) and cooled in an ice-water bath. 4-Toluenesulfonyl chloride (19.4 g, 102 mmol) was added in one portion and the mixture was stirred 30 minutes in the ice-water bath. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was then slowly poured into a stirring mixture of saturated aqueous sodium bicarbonate (300 mL) and ethyl ether (150 mL). The resulting two-phase mixture was then extracted with ethyl ether (3×150 mL). The extracts were combined, washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (5.8 g, 51% yield) was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1.[C:25](Cl)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[F:24][C:22]1[CH:21]=[CH:20][C:16]2[CH2:17][CH2:18][CH2:19][C:12]3[S:11][C:10]([NH:9][CH:6]4[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25](=[O:27])[CH3:26])[CH2:4][CH2:5]4)=[N:14][C:13]=3[C:15]=2[CH:23]=1
Reactant: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCC1CCC(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.5 %

Procedure:
To a stirred, septum capped solution of trans-N2-[4-(aminomethyl)cyclohexyl]-9-fluoro-5,6-dihydro-4H-benzo-[6,7]cyclohepta-[d][1,3]thiazol-2-amine (0.165 g, 0.394 mmol) in 3.0 ml anhydrous pyridine was added 0.034 ml (0.038 g, 0.48 mmol) acetyl chloride dropwise. Stirring at room temperature was continued for 90 minutes and the solution was then poured into 50 ml water and extracted with EtOAc (2×50 ml). The combined extracts were evaporated to yield 0.126 g of the crude product as a viscous golden oil. The oil was chromatographed on preparative TLC eluting with EtOAc to yield 28% (0.042 g) of the desired product as a white solid: 1H-NMR (CDCl3) δ 1.13 (4H, m), 1.43 (1H, m), 1.80 (2H, m), 1.98 (3H, s), 2.05 (2H, m), 2.21 (2H, m), 2.80 (4H, m), 3.10 (2H, t, J=6.5 Hz), 3.24 (1H, m), 5.00 (1H, d, J=7.8 Hz), 5.75 (1H, m), 6.81 (1H, dt, J=2.8, 8.2 Hz), 7.04 (1H, m), 7.69 (1H, dd, J=2.7, 10.8 Hz); m.p. 88-91° C.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[Br:9]Br.Br>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Br:9][C:2]([CH3:3])([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:1]
Reactant: BrBr
Reactant: CC(C)C(=O)C(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)C(C)(C)Br
Yield: 85.7 %

Procedure:
2,4-dimethyl-3-pentanone (330 g, 2.89M) in chloroform (800 ml) was cooled in an ice water bath to 10° C. and bromine (462 g, 2.89M) was added slowly over 3 hours. After the addition, a slow stream of nitrogen was introduced to the mixture and HBr gas was slowly evolved from the flask. The nitrogen was left bubbling over a weekend to remove all of the HBr produced and then sodium carbonate (5 g) was added. The reaction mixture was then filtered through Celite and the chloroform removed using a rotary evaporator. Distillation of the crude product using a 1′ (2.54 cm) vigreux gave essentially pure 2-bromo-2,4-dimethyl-3-pentanone (478 g, 2.47M) b.pt. 50-52° C./10 mb (1000 Nm−2).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[C:8](=O)([O:11]C)[O:9][CH3:10].C[O-].[Na+]>CS(C)=O>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH2:4][C:8]([O:9][CH3:10])=[O:11]
Reactant: COC(=O)OC
Reactant: CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CC(=O)C(C)(C)C
Temperature: 45 °C
Yield: 69 %

Procedure:
3,3-Dimethyl-2-butanone (10 g; 0.10 mol) was dissolved in DMSO (50 mL) and dimethyl carbonate (27 g; 0.30 mol; 3.0 equiv) was added. Sodium methoxide (10.8 g; 0.20 mol; 2.0 equiv) was added, resulting in a temperature rise to 30° C. The reaction mixture was heated to 40-50° C. for 4 h and then cooled to room temperature overnight. The reaction was quenched into a mixture of water (25 mL) and concentrated HCl (25 mL). Toluene (25 mL) was added and an additional 25 mL of water was added to dissolve salts. The layers were allowed to settle and the lower aqueous layer was removed and discarded. The organic layer was washed with water (25 mL), dried (Na2SO4), and filtered to afford 60 g of a toluene solution of 11. Analysis of this solution indicated 18.2 wt % of 11 to indicate a 69% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([F:17])[C:12]([C:18]#[N:19])=[C:11]([F:20])[C:10]=1F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C>[NH:1]([C:11]1([F:20])[CH:10]=[C:9]([F:8])[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CC1=C(F)C(C#N)C(F)(Nc2ccccc2)C=C1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 0.85 g of aniline in 20 ml of acetonitrile was dropwise added, while stirring, to a solution of 2.0 g of tetrafluoroisophthalonitrile and 2.0 g of triethylamine in 30 ml of acetonitrile. After dropwise adding, the mixture was stirred at room temperature for 1 hour and an aqueous sodium bicarbonate solution was then added. The mixture was extracted with chloroform and the chloroform extract was washed 5 times with an aqueous sodium chloride solution. After drying with magnesium sulfate, the chloroform was distilled off. The resultant crude crystal was purified by silica gel chromatography (solvent:hexane). Thus, 2.3 g (87% yield) of the desired compound No. 6 was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CC1(C)C2C(=CC([N+]([O-])=O)=CC=2)NC1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[C:8]2[C:7](=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=2)[NH:11][C:12](=[O:17])[CH2:13]1
Reactant: CC(=O)Nc1cccc(NC(=O)C=C(C)C)c1
Agent: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)CC2(C)C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The mixture of 3,3-dimethyl-6-nitroindoline 3-Methyl-but-2-enoic acid (3-acetylamino-phenyl)-amide (1.05 g, 4.52 mmol) and AlCl3 (5.0 g, 37.5 mmol, Aldrich, 99.99%) in 50 ml of anhydrous chlorobenzene was stirred at 120° C. (oil bath temperature) under N2 overnight, cooled to RT, poured into 10 ml of ice cold HCl, stirred for 30 min, and extracted with EtOAc. The organic portions were combined, washed with brine, dried with Na2SO4, filtered, condensed, and purified by flash column chromatography (1% of MeOH in CH2Cl2). The titled compound was obtained as an off-white solid. MS (ES+): 233.2 (M+H)+. Calc'd for C13H16N2O2—232.28.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([CH:18]=O)=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:21][N:22]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34][CH2:18][C:14]2[CH2:15][CH2:16][O:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:20][C:12]=3[CH:13]=2)=[CH:35][CH:36]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C=O)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(CNc2ccc(CN(C)C4CCOCC4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 26 %

Procedure:
Into a solution of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbaldehyde (191 mg)) and 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (159 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (168 mg). The resulting mixture was stirred at room temperature for 4.5 hours, additional sodium triacetoxyborohydride (76 mg) was added thereto and the resulting mixture was stirred further for 4 days. The reaction mixture was mixed with an aqueous solution of sodium bicarbonate under ice cooling and was extracted with dichloromethane, and the extract was washed with an aqueous solution of sodium chloride. The extract was dried (anhydrous magnesium sulfate) and was then concentrated under reduced pressure. The residue was subjected to purification using silica gel column chromatography (ethyl acetate/methanol=10/1), 4 N hydrochloric acid was added to the resulting product and the precipitate was collected by filtration and was washed with ethyl acetate to obtain N-[4-[(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)]phenyl]-N-[7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-yl]methylamine (compound 34) (88 mg) as a light yellow powder.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[CH3:9][N:10]([CH3:14])[C:11](=[O:13])[CH3:12].[CH2:15]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:9][N:10]([CH3:14])[C:11](=[O:13])[CH2:12][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)N(C)C
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)CC(O)(Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred ice-cold (0° C.) solution of 10 g (0.1 mole) diisopropylamine in 100 ml of anhydrous THF under nitrogen gas is added, dropwise, 40 ml (2.5 M) n-butyllithium over a period of about 15 min to form lithium diisopropylamine solution, which is a pale yellow. To the amine solution is added 8.8 g (0.1 mole) N,N-dimethylacetamide in 10 ml THF, dropwise, via syringe, over a period of 10 min. The resulting lithium enolate of N,N-dimethylacetamide solution is deep yellow, and is stirred for 45 min at 0° C. A solution of 18.5 g (0.095 mole) benzylphenylketone in 20 ml of THF is added rapidly over a period of about 2 min to the enolate solution. An orange N,N-dimethyl-3,4-diphenyl-3-hyroxybutyramide solution is formed, and is stirred at 0° C. for about 15 min. Then 40 ml (2.5 M) n-butyllithium is added dropwise via syringe to form a deep red dianion solution. The dianion solution is stirred at about -20° C. for 30 min. Methyl bromide (19 g, 0.2 mole, 2 equivalents) in 20 ml THF is added slowly to methylate the dianion. The resulting N,N-dimethyl-2-methyl-3,4-diphenyl-3-hydroxybutyramide mixture is held at about -20° C. for about 1 h, and a cloudy yellow suspension is formed. The suspension is warmed to room temperature (25° C.), then quenched with 200 ml of a 0° C. solution of 2 N HCl, which is added with rapid stirring. The quenched, pale yellow solution is diluted with 200 ml ether. The organic layer is recovered and washed with brine and dried over anhydrous MgSO4. The mixture is filtered, yielding a pale yellow solution of N,N-dimethyl-2-methyl-3,4-diphenyl-3-hydroxybutyramide, which is reduced in the following step.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=3)[CH:22]=2)=[CH:10][CH:9]=1.[CH3:35][N:36]([CH3:46])[C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41]>N1C=CC=CC=1>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:40](=[O:41])[C:39]4[CH:43]=[CH:44][CH:45]=[C:37]([N:36]([CH3:35])[CH3:46])[CH:38]=4)=[CH:32][CH:33]=3)[CH:22]=2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(Nc2cc(-c3cccc4c3oc3ccccc34)ncn2)cc1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=O)Nc2ccc(Nc3cc(-c4cccc5c4oc4ccccc45)ncn3)cc2)c1

Procedure:
To a solution of N-(6-dibenzofuran-4-yl-pyrimidin-4-yl)-benzene-1,4-diamine trifluoroacetic acid (compound A1) (500 mg, 1.1 mmol) in pyridine (10 mL) is added at 10° C. 3-dimethylaminobenzoyl chloride (288 mg, 1.21 mmol) portion wise. After 14 h at ambient temperature the mixture is evaporated and the crude product is purified by crystallization.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13](=[O:16])[C:12]3=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12](=[O:17])[C:13]1=[O:16]
Reactant: BrCCCCBr
Reactant: O=C1Nc2c(cccc2-c2ccccc2)C1=O
Product: O=C1C(=O)N(CCCCBr)c2c1cccc2-c1ccccc1

Procedure:
The title compound was prepared according to the process step described in the text is from Page 7, line 34 to Page 8, line 5 of WO 94/29272 using 7-phenyl-1H-indole-2,3-dione and 1,4-dibromobutane.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:7]1)C.[OH-].[K+].Cl>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:8]2[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:11])[N:6]([CH2:5][C:4]([OH:28])=[O:3])[N:7]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccc(OC)cc2)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)O)c2=O)cc1

Procedure:
3.58 g (8.91 mmol) of ethyl[3-(4-chlorophenyl)-4-(4-methoxyphenylmethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetate from Example 78A are placed in 40 ml methanol and stirred overnight at room temperature with 4 ml of 20% aqueous potassium hydroxide. It is adjusted to pH 6 with 1 N hydrochloric acid and purified by preparative HPLC [Method 12]. 2.71 g (81% of theory) of the target compound are thus obtained.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1C=O.OO.S([O-])(O)=[O:21].[K+]>CO>[CH3:6][O:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[OH:21]
Reactant: O=S([O-])O
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=S(=O)(O)O
Agent: OO
Agent: [K+]
Solvent: CO
Product: COc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Conc. sulfuric acid (0.4 ml) was added to a mixed solution comprising 3.3 g of 2,4-dimethoxybenzaldehyde and 30 ml of methanol, and under ice-cooling, 2.93 ml of 30% hydrogen peroxide aqueous solution was added to the mixture. After stirring at room temperature for 4 hours, a 5% aqueous potassium hydrogen sulfite solution was added to the mixture and the solvent was removed under reduced pressure. The residue was extracted with diethyl ether, the extract was washed and dried and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 2.1 g of 2,4-dimethoxyphenol (yield: 69%, state: colorless oily product).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:23][N:21]2[C:22]3[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=3[CH:19]=[CH:20]2)[C:13](=[O:39])[CH2:12]1)=[O:10])C1C=CC=CC=1.N[C@@H:41]1C[CH2:44][N:43]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:42]1>>[CH2:46]([N:43]1[CH2:42][CH2:41][CH:1]([NH:8][C:9]([CH:11]2[CH2:23][N:21]3[C:22]4[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=4[CH:19]=[CH:20]3)[C:13](=[O:39])[CH2:12]2)=[O:10])[CH2:44]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1ccccc1)C3
Product: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NC1CCN(Cc2ccccc2)C1)C3
Yield: 30 %

Procedure:
The compound of Example 3b was synthesized in a manner similar to the synthesis of the compound of Example 3a, but using (R)-3-amino-1-benzylpyrrolidine as the amine in the last step. Cleavage of 100 mg of functionalized resin (0.52 mmol/g) and purification by RP-HPLC provided 10.5 mg (30%) of the title compound as a white powder. MS (M+H)+=602.5.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[C:11](=[O:35])[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=1)[C:2]1C=CC=[CH:4][CH:3]=1>ClCCl.CO>[CH2:16]([C:13]1[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:11](=[O:35])[C:10]([CH2:9][NH:8][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:15][CH:14]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1ccc(CNCc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCNCc1ccc(CCCC)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O

Procedure:
3-benzylaminomethyl-6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine, oil, Rf 0.15 (dichloromethane/methanol 95:5)
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[Cl:7][C:8]1[CH:9]=[C:10](I)[C:11]([NH2:14])=[N:12][CH:13]=1.C1N2CCN(CC2)C1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:7][C:8]1[CH:9]=[C:10]2[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[NH:14][C:11]2=[N:12][CH:13]=1
Reactant: Nc1ncc(Cl)cc1I
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Temperature: 110 °C

Procedure:
Pyruvic acid (0.43 ml, 6.24 mmol) was added to a solution of 5-chloro-3-iodopyridin-2-ylamine (Preparation 56, 500 mg, 2.08 mmol), palladium acetate (23 mg, 0.10 mmol) and DABCO (700 mg, 6.24 mmol) in anhydrous DMF (20 ml). The reaction mixture was degassed with argon for 20 min, then heated to 110° C. for 16 h. The solvent was removed in vacuo and the residue suspended in water (10 ml) and acetic acid (5 ml) and then filtered. The solid was dissolved in EtOAc (50 ml), extracted into 2N NaOH solution (50 ml) and the organic layer discarded. The aqueous solution was acidified with concentrated HCl and extracted into EtOAc (2×40 ml). The combined organics were dried (MgSO4) and concentrated in vacuo to give the title compound as a beige solid. δH (CD3OD): 7.14 (1H, s), 8.14 (1H, d), 8.35 (1H, d).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C>C(#N)C>[N:16]1[C:17]2[C:12](=[CH:11][C:10](/[CH:9]=[C:5]3/[C:6](=[O:8])[N:7]=[C:3]([NH:26][CH2:25][C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)[S:4]/3)=[CH:19][CH:18]=2)[CH:13]=[N:14][CH:15]=1
Reactant: NCc1cccs1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2cccs2)S/C1=C\c1ccc2ncncc2c1
Temperature: 145 °C

Procedure:
The suspension of 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one (example 1c, 58 mg, 0.2 mmol), thiophene methyl amine (45.3 mg, 0.4 mmol) and diisopropylethylamine (DIEA) (70 uL, 0.4 mmol) in acetonitrile (1 mL) was heated to 145° C. by microwave for 20 min. After cooling to room temperature, the solid was collected by filtration, washed with a small amount of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a light yellow solid: LC-MS m/e 353 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][C:22]3[C:27]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[O:34])=[CH:13][C:14]=1[O:21][C:22]1[C:27]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CC(C)c1cccc(NC(=O)c2ccc([N+](=O)[O-])c(Oc3ncccc3-c3ccncn3)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(NC(=O)c2ccc(N)c(Oc3ncccc3-c3ccncn3)c2)c1

Procedure:
To a solution of N-(3-isopropylphenyl)-4-nitro-3-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzamide (0.090 g, 0.20 mmol) in MeOH (3 mL) and EtOAc (3 mL) was added NH4OAc (0.030 g) and Pd/C (10%) (0.020 g). The reaction was capped with a septum, and positive H2 pressure was applied with a balloon/needle. The reaction was stirred for several hours, at which point LCMS indicated formation of product. The mixture was filtered through sand/celite, concentrated onto silica gel, and chromatographed with 8:8:8:1 t-BuOMe:hexanes:CH2Cl2:MeOH to afford 4-amino-N-(3-isopropylphenyl)-3-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzamide as a yellow solid. MS m/z=426 [M+H]+. Calc'd for C25H23N5O2: 425.49.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH2:13][CH3:14])[N:7]=1)=[O:5].[CH3:16][Mg]Br.C(O)C.Cl>O1CCCC1.CCOCC.CCOC(C)=O.O>[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH2:13][CH3:14])[N:7]=1)(=[O:5])[CH3:16]
Reactant: CCc1cc(C(=O)N(C)OC)nn1CC
Reactant: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc(C(C)=O)nn1CC
Reaction time: 1 h

Procedure:
N-Methoxy-N-methyl-1,5-diethylpyrazole-3-carboxamide (10.1 g) in dry tetrahydrofuran (180 ml) was cooled in an ice-bath and treated with a 3.0M solution of methylmagnesium bromide in ether (20.68 ml) added dropwise over 10 minutes. After stirring for 1 hour the mixture was treated with a mixture of ethanol (5 ml) and 5M aqueous HCl (1 ml). The mixture was then diluted with EtOAc and water. The organic phase was separated and the aqueous phase extracted twice with EtOAc. The combined organic extracts were dried over MgSO4 and evaporated in vacuo to leave an oil which was chromatographed on silica gel, loading in dichloromethane, and eluting with ethyl acetate/hexane mixtures to give, after evaporation of the requisite fractions, the product as an oil (8.08 g), δ (CDCl3) 1.29 (3H, t, J 7 Hz), 1.45 (3H, t, J 7 Hz), 2.55 (3H, s), 2.64 (2H, q, J 7 Hz), 4.14 (2H, q, J 7 Hz,), 6.55 (1H,s) ppm.