Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50]O)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:59]>CCOCC>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][Br:59])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)CCO2
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: Clc1c(CBr)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c1CCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 212.3 %

Procedure:
To a solution of compound 48 (578 mg, 0.81 mmol) in Et2O (14 mL) was added pyridine (0.007 mL, cat.) and phosphorus tribromide (0.038 mL, 0.40 mmol) at 0° C. under an atmosphere of nitrogen. After being stirred for 20 hours at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the crude product 49 (654 mg) as yellow oil.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=O.[C:9](O)(=O)/[CH:10]=[CH:11]/[C:12](O)=O>C1C=CC=CC=1>[C:4]1(=[O:6])[O:8][C:1](=[O:7])[CH:2]=[CH:3]1.[CH2:9]=[CH:10][CH2:11][CH3:12]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: O=C(O)/C=C\C(=O)O
Solvent: c1ccccc1
Product: C=CCC
Product: O=C1C=CC(=O)O1

Procedure:
This invention relates to the preparation of esters of maleic acid with monohydric alcohols and to the preparation of monohydric esters of mixtures of maleic acid and fumaric acid. For various reasons maleic in the form of the anhydride is the principal starting material for maleic esters but the principal reason is because the anhydride is the form in which maleic is commercially produced. Maleic anhydride is commercially produced by the oxidation of hydrocarbons such as benzene or butene. Maleic anhydride is obtained by oxidizing the hydrocarbon feed at high temperature and over a suitable catalyst to produce a gaseous effluent of maleic anhydride together with impurities. The gaseous effluent is cooled and scrubbed in water to produce a crude solution of maleic acid. The aqueous solution of maleic acid is then fed to dehydration column in which the maleic acid is dehydrated by contacting with a volatile water insoluble entraining agent such as xylene which does not undergo chemical reaction in the system. The water and entraining agent are removed as overhead vapors and maleic anhydride is removed as bottoms.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][NH2:4].[CH2:6]([O:9][C:10]1[C:18]([O:19][CH3:20])=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[O:21][CH3:22])[C:7]#[CH:8]>>[CH3:1][CH:2]([CH3:5])[CH2:3][NH:4][C:14](=[O:15])[C:13]1[CH:12]=[C:11]([O:21][CH3:22])[C:10]([O:9][CH2:6][C:7]#[CH:8])=[C:18]([O:19][CH3:20])[CH:17]=1
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: CC(C)CN
Product: C#CCOc1c(OC)cc(C(=O)NCC(C)C)cc1OC

Procedure:
According to the same method as that of Production Example 1, 2-methylpropylamine was used in place of 2,2-dimethylpropylamine, 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(2-methylpropyl)-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 21 of the present invention) represented by the formula:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)[C:7]([Cl:19])=[CH:6][C:3]=1[CH:4]=O.[C:20]1(C)C=CC=CC=1>>[Br:1][C:2]1[CH:9]=[C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)[C:7]([Cl:19])=[CH:6][C:3]=1[CH:4]=[CH2:20]
Reactant: CCc1ccc(Cc2cc(Br)c(C=O)cc2Cl)cc1
Reactant: Cc1ccccc1
Product: C=Cc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Reaction time: 1 h

Procedure:
To a suspension of Ph3PCH3I (3.151 g, 7.8 mmol) in 22 mL of dry toluene, was added dropwise with KN(TMS)2 (15.64 mL, 7.8 mmol, 0.5 M in toluene) under argon. After it was stirred for 1 h, a solution of 2-bromo-5-chloro-4-(4-ethylbenzyl)benzaldehyde (1.76 g, 5.2 mmol) in 17 mL of toluene was added. This reaction mixture was stirred at room temperature and monitored by TLC (PE, Rf=0.8). After being stirred for 4 h, the reaction mixture was quenched by addition of 5 mL of saturated NaHCO3. The organic layer was washed 2× with H2O, 2× with brine, dried over anhydrous Na2SO4. Concentration under reduced pressure provided the crude product, which was purified by column chromatography on silica gel (PE), to give the title compound as a colorless oil. Yield: 3.0 g (96%). 1H NMR (CDCl3, 300 MHz) δ 7.54 (s, 1H), 7.33 (s, 1H), 7.14 (d, J=2.1 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 6.92 (dd, J=11.0, 17.6 Hz, 1H), 5.68 (dd, J=17.6, 0.9 Hz, 1H), 5.37 (dd, J=11.0, 0.9 Hz, 1H), 4.02 (s, 2H), 2.63 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:32])[NH:21][CH2:22][CH2:23][N:24]4[C@H:29]([CH3:30])[CH2:28][CH2:27][CH2:26][C@@H:25]4[CH3:31])[CH:17]=[CH:16][C:15]=3[F:33])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][N:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)[Cl:50]>COCCOC.O>[ClH:50].[CH3:30][C@H:29]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH3:31])[N:24]1[CH2:23][CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:33])=[C:14]([NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:38]4[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[CH:19]=1)=[O:32]
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: Cn1cc(B(O)O)cn1
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4cnn(C)c4)ccn23)c1
Product: Cl

Procedure:
7-Bromo-N-(5-(2-(2,6-cis-dimethylpiperidin-1-yl)ethylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 4C) (50 mg, 0.097 mmol), 1-methyl-1H-pyrazol-4-ylboronic acid (24.38 mg, 0.194 mmol) and cesium carbonate (126 mg, 0.387 mmol) was dissolved in DME (215 μl)/water (108 μl) to form a solution. Nitrogen was bubbled though the reaction mixture for 2 minutes. PdCl2(dppf).CH2Cl2 adduct (3.95 mg, 4.84 μmol) was added and the mixture was heated using microwave radiation at 100° C. for 15 mins. The water was removed and the organic portion was dry loaded onto silica. The crude product was purified by chromatography on silica eluting with 0-20% 2M NH3 in MeOH and the product fractions were combined and concentrated in vacuo. The product was dissolved in MeOH and passed through a 1 g 2,4,6-trimercaptotriazine silica. The solvent was removed in vacuo and the residue was triturated with ether. The resulting precipitate was filtered and dried in the oven to afford the title compound;
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I.O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:23])[C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)C(F)(F)F)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
N-(1-benzyl-4-piperidinyl)-2,2,2-trifluoroacetamide (1.0 g, 3.49 mmol) was added to a suspension of 60%-sodium hydride (147 mg, 3.67 mmol) in tetrahydrofuran (20 ml) at room temperature and stirred for 30 minutes. Then, methyl iodide (0.239 ml, 3.84 mmol) was added thereto and stirred for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/1) to obtain N-(1-benzyl-4-piperidinyl)-2,2,2-trifluoro-N-methylacetamide (731 mg, 70%).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[C:13]([C:15]1[C:16](=[O:22])[NH:17][C:18](C)=[CH:19][CH:20]=1)#[N:14].BrCCC>C1COCC1>[CH2:8]([C:18]1[NH:17][C:16](=[O:22])[C:15]([C:13]#[N:14])=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH3:11]
Reactant: Cc1ccc(C#N)c(=O)[nH]1
Reactant: [Li]CCCC
Solvent: CCCBr
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCc1ccc(C#N)c(=O)[nH]1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (20.5 mL, 2 eq) in THF (200 mL) was cooled to −5° C. n-Butyllithium (53.5 mL, 2.9 M in hexanes, 2 eq) was added over 10 minutes. The solution was allowed to rise to 0° C., stirred for 0.5 hours, then cooled again to −30° C. 3-Cyano-6-methyl-2(1H)pyridinone (10 g, 75 mmol) was added portionwise, and the mixture was allowed to warm to room temperature and stirred for 2 hours. The solution was then cooled to −50° C., and 1-bromopropane (6.8 mL, 1 eq) was added. The solution was allowed to warm to room temperature, stirred for 1 hour, and then quenched with a saturated ammonium chloride solution. The THF was evaporated and the aqueous phase extracted with DCM (2×100 mL). The organics were washed with saturated aqueous NaCl, dried over Na2SO4, and evaporated to yield intermediate (24a) as an orange solid (10.8 g, 61 mmol), which was used without further purification. MS m/z: [M+H+] calcd for C10H12N2O, 177.2. found 177.0. 1H-NMR (DMSO) 7.87 (1H, d), 6.05 (1H, d), 2.38 (2H, t), 1.41 (2H, m), 1.15 (2H, m), 0.93 (1H, d), 0.73 (3H, t).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:39]=[CH:38][C:37]([N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)=[CH:43][CH:42]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(-n3cncn3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-1,2,4-triazol-1-yl)aniline (Maybridge, 108 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: C(Cl)Cl.Cl.[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1.C(N(CC)CC)C.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(OCC)C>[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH2:12][O:13][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cncc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a methylene chloride solution (20 mL) of 3-bromo-5-(hydroxymethyl)pyridine hydrochloride (described in example 69a) (1.00 g, 4.48 mmol) under nitrogen was added triethylamine (2.50 mL, 17.9 mmol, 4 eq) and tert-butyldimethylsilyl chloride (0.75 g, 5.0 mmol, 1.1 eq). The resulting solution was heated to reflux for 18 h, cooled to room temperature and diluted with diethyl ether (200 mL). The organic phase was washed with 2.5N NaOH (1×100 mL), water (3×100 mL) and saturated brine (1×100 mL). The ether solution was dried over anhydrous magnesium sulfate, filtered, and reduced to an colorless oil. The procedure resulted in 1.10 g (81%) of the title compound. The product required no additional purification. TLC analysis (Rf 0.19, ethyl acetate) MS (CI, CH4) m/z 302 (M+1,100), 304 (96), 330 (M+29,4), 332 (4)
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>C(O)C>[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CS(=O)c1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Yield: 16.1 %

Procedure:
2-Methylsulphinyl-3-nitro-4-phenylpyrrole (2.0 g, 0.008 mol) was partially dissolved in ethanol (150 ml) and a solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.37 g, 0.008 mol) in a little ethanol was added to it. The mixture was refluxed for seven days, after which the mixture was stripped and chromatographed on a silica gel column, collecting the required product by elution with ethyl acetate. The crude solid was recrystallised from 2-propanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-nitro-4-phenylpyrrole (0.46 g), m.p. 182°-184°.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[C:10]([F:14])[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O1CCOCC1.O.[Cu]Br>[Br:22][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[C:10]([F:14])[CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Br
Reactant: N#Cc1c(F)cccc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(F)cccc1-c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
5′-Amino-3,2′-difluorobiphenyl-2-carbonitrile (2.87 g, 12.5 mmol) was dissolved in hot 1,4-dioxane (4 mL), 48% aqueous hydrobromic acid (40 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (0.86 g, 12.5 mmol) in water (1.5 mL) over 20 min. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (5.38 g, 37.5 mmol) in 48% hydrobromic acid (10 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (500 mL) and extracted with ethyl acetate (2×300 ml). The combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (200 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give a black solid. Purification by chromatography on silica gel eluting with isohexane (containing 0.5% methanol) on a gradient of ethyl acetate (2-6%) gave 5′-bromo-3,2′-difluoro-biphenyl-2-carbonitrile (2.48 g, 68%) as a yellow solid: δH (400 MHz, CDCl3) 7.13 (1H, dd, J 9 and 9), 7.27-7.30 (2H, m), 7.53-7.59 (2H, m), 7.64-7.69 (1H, m).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:11]=[N:10][S:9][N:8]=1)[C:4]([OH:6])=[O:5].[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>>[Cl:12][CH:13]([Cl:17])[C:14]([O:1][N:2]=[C:3]([C:7]1[CH:11]=[N:10][S:9][N:8]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(O)C(=NO)c1cnsn1
Reactant: O=C(Cl)C(Cl)Cl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1cnsn1
Yield: 47 %

Procedure:
2-Hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (4.8 g.) and dichloroacetyl chloride (9.2 g.) were reacted according to a similar manner to that of Example 6(a) (4) to give crystals of 2-dichloroacetoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (3.7 g.).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1>COCCOC.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>[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCCCOc1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A mixture of sodium carbonate (0.978 g), tetrakis(triphenylphosphine)palladium(0) (0.267 g), 4-butoxyphenylboronic acid (1.16 g) and 3-bromopyridin-2-amine (0.799 g,) in DME (23 mL) and water (4.6 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (0.690 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37]([NH2:39])=[NH:38].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:38]=[C:37]([N:33]3[CH2:34][CH2:35][CH2:36][CH:32]3[CH3:31])[N:39]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)c2ccc(F)cc2)C1
Reactant: CC1CCCN1C(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCN1c1nc2c(c(-c3ccc(F)cc3)n1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a mixture of 3-(4-fluoro-benzoyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.62 mmol) and 2-methyl-pyrrolidine-1-carboxamidine trifluoroacetate (0.14 g, 0.58 mmol) in MeCN (3 mL) was added K2CO3 (0.190 g, 1.4 mmol). The mixture was heated at reflux for 15 h, then cooled to rt, diluted with H2O and extracted with CH2Cl2 (2×). The combined organic extracts were dried and concentrated. The residue was purified by FCC to give the title compound (0.193 g, 81%) as a clear oil. MS (ESI): mass calcd. for C23H23FN4O2, 412.5; m/z found, 413.4 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[C:17]1([CH2:16][CH2:15][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH3:13])=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc2ccccc2n1CCc1ccccc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 37.9 %

Procedure:
Methyl 1H-indole-2-carboxylate (526 mg) and (2-bromoethyl)benzene (1.11 g) were dissolved in DMA (15 ml), cesium carbonate (2.93 g) was added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give the object product (318 mg) as an oil.
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]([OH:9])(=O)[CH2:6][CH3:7].C(Cl)(=O)CC.[Cl-].[CH2:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18].CCCCC1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:5](=[O:9])[CH2:6][CH3:7])=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CCC(=O)O
Reactant: CC(C)Cc1ccccc1
Agent: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Solvent: CCCCc1ccccc1
Product: CCC(=O)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
In a 500 ml. 3-necked, round bottomed flask there was placed 25.50 ml. (40.14 g., 0.29 mmole) of phosphorus trichloride and 43.65 ml. (43.34 g., 0.58 mmole) of propionic acid. This mixture was stirred for 2.25 hours under nitrogen atmosphere at room temperature to prepare the propionyl chloride. By NMR propionyl chloride formation was complete in about 1.5 hours. Then 80 ml. of anhydrous methylene chloride was added and the resulting solution was cooled to about -5° C. (an ice-methanol bath). While stirring the cooled mixture, 87.50 g. (0.66 mmole) of alumium chloride (technical grade) was added. After 10 minutes of stirring, 67.11 g. (0.50 mmole) of isobutylbenzene was added dropwise from an addition funnel over 55 minutes while maintaining the temperature of the mixture at about 0° to 5° C. The isobutylbenzene was about 99.6% pure and contained about 0.3% n-butylbenzene. The mixture was stirred for an additional 1.25 hours to insure as complete a reaction as possible and then poured into a solution of 250 ml. of ice water and 150 ml. of concentrated hydrochloric acid with vigorous stirring. The Friedal-Crafts reaction was complete in about 45 minutes under these conditions (by GLC analysis). The resulting mixture was extracted three times with 300 ml. portions of methylene chloride. The combined methylene chloride extracts were washed with 250 ml. of water and three times with 250 ml. of molar concentration aqueous sodium carbonate solution. The aqueous sodium carbonate extracts were back-extracted with 100 ml. of methylene chloride and the combined methylene chloride layers were dried over sodium sulfate. The dried methylene chloride solution was concentrated under vacuum to give crude p-isobutylpropiophenone as a pale yellow oil weighing 97.85 g. By GLC analyses, 3% methylene chloride was present. The chemical yield was about 95 g. or about 100% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)ccc21

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (34 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (44 mgs) was converted to the title compound (40 mgs as a white solid). 1H-NMR (CDCl3): δ 10.29 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.74-7.72 (m, 1H), 7.41-7.35 (m, 2H), 7.22 t, J=7.8 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.97 (s, 1H), 6.54 (s, 1H), 3.31 (s, 3H), 2.33-2.31 (m, 2H), 2.06-2.04 (m, 2H), 1.30 (s, 6H). LC/MS: found (M+H)+=488.22; MP: 136-138° C.