Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[S:13][C:14]=1[CH3:15])(OCC)=O)C.[H-].[Na+].[CH3:31][O:32][CH2:33][O:34][C:35]1[C:39]([CH:40]=O)=[CH:38][N:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:36]=1.O>O1CCCC1>[CH3:31][O:32][CH2:33][O:34][C:35]1[C:39](/[CH:40]=[CH:9]/[C:10]2[N:11]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:13][C:14]=2[CH3:15])=[CH:38][N:37]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:36]=1
Reactant: CCOP(=O)(Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of tert-butyl 4-{4-[(diethoxyphosphoryl)methyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate (2.0 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.20 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.1 g) was added to the reaction mixture, and the mixture was heated under reflux for 4 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (5:95-25:75, v/v) to give tert-butyl 4-(4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazol-2-yl)piperazine-1-carboxylate as a yellow oil (1.3 g, yield 57%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:22]([NH2:25])[CH:23]=[CH2:24].C(=O)([O-])O.[Na+]>>[CH2:22]([NH:25][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:23]=[CH2:24]
Reactant: CCCCCCCCCNc1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCCCCCCCC)c2scc(C)c2n1
Yield: 57.2 %

Procedure:
In a sealed tube were heated 391 mg (1.2 mmol) of 2-chloro-4-nonylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 238 mg (yield: 57.2%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.[H+].[B-:27]([F:31])([F:30])([F:29])[F:28]>C(Cl)Cl>[F:28][B-:27]([F:31])([F:30])[F:29].[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S+:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Clc1ccc(CSc2ccc(Cl)cc2)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: Clc1ccc(C[S+](Cc2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Yield: 77.4 %

Procedure:
5.2 g (19.4 mmol) of 4-chlorophenyl 4-chlorobenzyl sulfide, 4.14 g (29.0 mmol) of 4-chlorobenzyl alcohol and 14.15 g (87 mmol) of hydrogen tetrafluoroborate (54% in diethyl ether) in 20 ml of methylene chloride are reacted as in Example 6a) to give 7.23 g (77.4% of theory) of 4-chlorophenylbis(4-chlorobenzyl)sulfonium tetrafluoroborate in the form of white-beige crystals of melting point 147°-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.CN(C)[CH:27]=[O:28].[K+].[Br-]>C(OC)(C)(C)C>[CH3:24][O:23][C:21]1[CH:22]=[C:2]2[C:3]([CH2:4][N:5]([CH:6]3[CH2:11][CH2:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:8][CH2:7]3)[C:27](=[O:28])[NH:1]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CNC2CCN(Cc3ccccc3)CC2)c(N)c1
Reactant: CN(C)C=O
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: COc1ccc2c(c1)NC(=O)N(C1CCN(Cc3ccccc3)CC1)C2
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2.5 g (7.682 mmol) of 2-amino-4-methoxy-N-(1-phenylmethyl-4-piperidinyl)-benzylamine, 1.62 g (10 mmol) of N,N′-carbonyldiimidazole, and 25 mL of dimethylformamide was heated to 90° C. with stirring for 2.5 hours. After cooling, the mixture was stirred into 100 mL of ice water, the suspension formed was overlaid with 10 mL of tert-butylmethylether, the precipitate formed was suction filtered, washed with water, and then with tert-butylmethylether. After drying in vacuo, 1.9 g (70% of theoretical) of colorless crystals were obtained. IR (KBr): 1664 (C═O) cm−1; MS: M+=351.
Reaction SMILES: [CH:1]([N:3]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9])=[CH2:2].C(Cl)(Cl)(Cl)[Cl:11]>>[Cl:11][CH:1]([N:3]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]1=[O:9])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: C=CN1C(=O)CCC1=O
Product: CC(Cl)N1C(=O)CCC1=O
Reaction time: 24 h

Procedure:
N-vinylsuccinimide, 50.0 g. (0.40 mole) is dissolved in 1000 ml. carbon tetrachloride, 5.20 g. (0.020 mole) of stannic chloride is added and the mixture is stirred while saturating with hydrogen chloride for 6 hours at 20°-30° C. After 24 hours, the mixture is resaturated with hydrogen chloride for 1.5 hours. At the end of 48 hours, the solution is decanted and the gummy residue is washed with ten 100 ml. portions of carbon tetrachloride. The combined extracts are slurried with 10 g. of diatomaceous earth, filtered and the filtrate concentrated under reduced pressure to approximately 400 ml. The N-(1-chloroethyl)-succinimide is filtered and dried at 20°-30° C. under reduced pressure to yield 38.4 g. (59%) of white solid melting at 83.5°-84.5° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:6][C:7]([N:9]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]1[C:15](OC)=[O:16])=[O:8])[CH:4]=[CH2:5].CC(C)=O>C(O)C>[CH2:3]([O:6][C:7]([N:9]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]1[CH2:15][OH:16])=[O:8])[CH:4]=[CH2:5]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Temperature: 40 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a suspension of sodium borohydride (5 g) in ethanol (50 ml) was added (2S,4R)-1-allyloxycarbonyl-2-methoxycarbonyl-4-hydroxypyrrolidine (10 g) in ethanol (10 ml) at 5° C. and the resulting mixture was stirred at 40° C. for 4 hours. After cooling to 0° C., the reaction mixture was added dropwise to cooled acetone (20 ml) at 10° C. The mixture was evaporated in vacuo and the residue was extracted with ethyl acetate (200 ml×2). The organic layer was washed with brine, dried over magnesium sulfate, evaporated and chromatographed on silica gel (120 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 V/V) to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-hydroxymethylpyrrolidine (4.45 g).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:20][CH2:19][N:18]([CH:15]([CH3:16])[CH3:17])[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: CC(C)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: N#CCNC(=O)C1(N)CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.6 mmol), 4-(4-isopropyl-piperazin-1-yl)-benzoic acid hydrochloride (0.6 mmol), HOBT (0.6 mmol), WSCD (0.6 mmol) and triethylamine (0.6 mmol) are dissolved in DMF (2 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in ethyl acetate/diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 218-220° C., Rf=0.28 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: Cl[C:2]1[CH:25]=[N:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]=1.[CH2:26](B(O)O)[CH3:27].C([O-])([O-])=O.[K+].[K+]>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>[CH2:26]([C:2]1[CH:25]=[N:24][C:5]2=[N:6][C:7]([C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]=1)[CH3:27]
Reactant: Cc1ccc(-c2nc3cc(Cl)cnc3nc2-c2ccc(C)cc2)cc1
Reactant: CCB(O)O
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: [K+]
Product: CCc1cnc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture comprising 7-chloro-2,3-di-p-tolylpyrido[2,3-b]pyrazine (step 1) (2.5 g, 7.24 mmol), ethyl boronic acid (0.748 g, 10.14 mmol) and K2CO3 (2.9 g, 21.73 mmol) was degassed with argon and treated with Pd(PPh3)4(0.418 g, 0.362 mmol). The resulting mixture was flushed with argon and heated at 100° C. for 12 h and heating continued overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. Purification of the crude product by chromatography on silica eluting with 10% EtOAc in hexane afforded the titled compound;
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:36]=[CH:35][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:34])[C:15]([CH2:25][CH2:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:37](Cl)([CH3:40])(=[O:39])=[O:38].N1C=CC=CC=1>CC(C)=O>[CH:28]1([CH2:27][CH2:26][CH2:25][C:15]2([CH3:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([OH:23])=[C:13]([C:8]3[NH:7][C:6]4[CH:35]=[CH:36][C:3]([NH:2][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:4][C:5]=4[S:10](=[O:12])(=[O:11])[N:9]=3)[C:14]2=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 88 %

Procedure:
A solution of Example 38B (0.357 g, 0.674 mmol), mesyl chloride (0.209 mL, 2.69 mmol), and pyridine (0.436 mL, 5.39 mmol) in acetone (15 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.339 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[N:33])=[CH:4][N:3]=1.C(=O)([O-])[O-:35].[K+].[K+].OO>CS(C)=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH2:33])=[O:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C#N)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(-c2csc3c(C(N)=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 3.9 %

Procedure:
N2-[4-(4-amino-7-cyanothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (A-825289.0, 50 mg, 0.11 mmol), potassium carbonate (61 mg, 0.44 mmol), and hydrogen peroxide (0.150 mL, 30% aqueous) were heated in dimethylsulfoxide (1 mL) for 25 minutes at 150° C. in a microwave. The mixture was evaporated, diluted in dimethylformamide, filtered, and the filtrate was purified by RP-HPLC to yield the title compound (2 mg, 4% yield): 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.57 (s, 1H), 8.00 (d, 1H), 7.71 (d, 1H), 7.58–7.62 (m, H), 7.06–7.35 (m, 5H), 4.04 (s, 3H); RP-HPLC (Conditions i) Rt 11.7 min. MS: 470.0 MH−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH:23][C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[S:27][CH:28]=3)=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([NH:23][C:21]([NH:20][C:16]3[N:15]=[C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)[CH:19]=[CH:18][CH:17]=3)=[O:22])[N:25]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C2=CCNCC2)n1)Nc1csc(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester was suspended in CH2Cl2 (10 mL) and treated with TFA (5 mL). Stirred at RT for 30 min. Quenched with saturated NaHCO3 and filtered yellow solid. Washed solid with H2O and MeOH to give 1-(2-pyridin-4-yl-thiazol-4-yl)-3-(1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea as a yellow solid. MS m/z: 379.1 (M+H). Calc'd for C19H18N6OS-378.45.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:27][N:28]([CH3:43])[CH2:29][CH2:30][CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:31][CH2:30][CH2:29][N:28]([CH3:43])[CH3:27])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 200 °C
Yield: 403.1 %

Procedure:
A 5 mL microwave vial was charged with Compound 157 (290 mg, 0.79 mmol), 3-(dimethylamino)propyl-4-methylbenzenesulfonate (224 mg, 0.87 mmol), potassium carbonate (218 mg, 1.58 mmol) and 2 mL of anhydrous DMF, under nitrogen atmosphere. The reaction mixture was heated at 200° C. for 30 min. in microwave with high absorption. The reaction was quenched with addition of water, and the solid precipitate out was collected by filtration and purified through preparative HPLC to provide title compound (1438 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3H) 1.99 (qd, J=6.61, 6.44 Hz, 2H) 2.20 (s, 6H) 2.26 (s, 3H) 2.53-2.56 (m, 2H) 3.41 (q, J=7.33 Hz, 2H) 4.25 (t, J=6.19 Hz, 2H) 7.05-7.09 (m, 1H) 7.11-7.14 (m, 1H) 7.54 (d, J=1.52 Hz, 1H) 7.85 (t, J=7.83 Hz, 1H) 7.98 (t, J=6.95 Hz, 2H) 8.06-8.08 (m, 1H) 8.27 (d, J=1.77 Hz, 1H) 12.13 (s, 1H); [M+H] calc'd for C25H30N3O3S, 452.2; found, 452.4.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrN1C(=O)CCC1=O.[C:19]([CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)(=[S:21])[NH2:20].[OH-].[NH4+]>O1CCOCC1.O>[NH:25]1[CH2:26][CH2:27][CH:22]([C:19]2[S:21][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:20]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: CCOC=CC(=O)OCC
Agent: O=C1CCC(=O)N1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(C2CCNCC2)s1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Ethyl 3-ethoxyacrylate (1.50 g, 10.38 mml) was dissolved in dioxane/water and chilled to −10° C. N-Bromosuccinimide (2.03 g, 11.42 mmol) was added and the mixture was stirred 1 hour at room temperature. tert-Butyl 4-carbamothioylpiperidine-1-carboxylate (2.54 g, 10.38 mmol) was added and the mixture was heated at 100° C. for 1 hour. The reaction mixture was poured into 25 mL saturated ammonium hydroxide and extracted with dichloromethane. The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.O.Cl>O>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(NCCCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCc2ccccc2)cc1

Procedure:
A mixture of 10 g. of ethyl p-[(3-phenylpropyl)amino]benzoate (prepared as described in Example 26), 10 g. of KOH and 200 ml. of ethanol-water (9:1) is refluxed for 4 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, cooled and filtered to give off-white crystals. Recrystallization from ethanol gives off-white crystals, m.p. 162°-163° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH3:1][C:2]1([CH3:11])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1(C)Cc2ccccc2N1
Product: CCOC(=O)C(=CN1c2ccccc2CC1(C)C)C(=O)OCC
Temperature: 105 °C

Procedure:
A mixture of 2,2-dimethylindoline (1.47 g) and diethyl ethoxymethylenemalonate (2.0 ml) is heated to 105° C. for 17 hours to afford the title compound as a pale yellow oil. Physical characteristics: 1H NMR (CDCl3) δ7.76, 7.18, 7.12, 6.97, 6.74, 4.24, 3.16, 1.50, 1.34.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:8]=1[CH:15]=[O:16])(=O)=O.[CH2:19](C([SnH3])=C(CCCC)CCCC)[CH2:20]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]([C:8]1[CH:9]=[CH:10][C:11]([C:13]#[N:14])=[CH:12][C:7]=1[CH:19]=[CH2:20])=[O:16]
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: N#Cc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=Cc1cc(C#N)ccc1C=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
125 mg (0.18 mmol) of bis(triphenylphosphine)palladium(II) chloride are added to a solution of 1 g (3.58 mmol) of 5-cyano-2-formylphenyl trifluoromethanesulfonate and 1.15 ml (3.94 mmol) of tri-n-butylvinylstannane in 6 ml of anhydrous and degassed DMF under an argon atmosphere. The reaction mixture is then stirred at 80° C. for 90 min Subsequently, 100 ml of 10% strength potassium fluoride solution are added, and the mixture is stirred at RT for 1 h. The suspension is extracted three times with 20 ml of ethyl acetate each time, and the combined organic phases are washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic solution is dried over magnesium sulfate and concentrated. The residue (0.6 g) is employed without further purification in the next stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH2:10](Cl)Cl>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1
Reactant: ClCCl
Reactant: COc1cncc(Br)c1
Product: CCOc1cncc(Br)c1
Reaction time: 8 h

Procedure:
As shown in step 2-iii of Scheme 2,3-chloroperoxybenzoic acid (9.426 g, 42.06 mmol) was added to 3-bromo-5-methoxypyridine (4.25 g, 21 mmol) in 200 mL of DCM at RT. The reaction was stirred overnight and the mixture was washed with 200 mL of 2 N NaOH and 2×200 mL brine. The organic phase was dried over MgSO4, filtered and the volatiles removed under reduced pressure to provide 3-bromo-5-ethoxypyridine, 1-oxide (Compound 2002, 4.4 g): 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.9 (s, 1H), 7.0 (s, 1H), 4.12 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[CH:19][CH:20]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:30][C:31]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>ClCCl>[CH:18]1[N:11]2[C:12]3[C:17]([N:8]([C:6]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][CH:38]=[C:39]([Cl:40])[C:31]=5[Cl:30])=[CH:22][CH:21]=4)=[O:7])[CH2:9][C:10]2=[CH:20][CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1)c1cccc(Cl)c1Cl
Reaction time: 8 h
Yield: 13.3 %

Procedure:
As described for Example 157, 0.47 g of 4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline, 346 μl of triethylamine and 5 ml of dichloromethane are chilled (ice bath) and 0.415 g of 2,3-dichlorobenzoyl chloride in 2 ml of dichloromethane added. After stirring overnight, an additional 346 μl of triethylamine is added and an additional 0.415 g of 2,3-dichlorobenzoyl chloride added. The mixture is stirred for 2 hours, diluted with 50 ml of dichloromethane and the solution washed with 20 ml each of H2O, 2 N citric acid, 1 M NaHCO3 and brine. The organic layer is dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as solvent to give 0.100 g of white solid, m.p. 230-240° C.