Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:14])[CH2:9][C:10](OC)=[O:11])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:17]>>[Cl:1][C:2]1[C:7]2[CH:8]([CH3:14])[CH2:9][C:10](=[O:11])[NH:17][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)CC(C)c1c(Cl)ncnc1Cl
Reactant: [NH4+]
Agent: [OH-]
Product: CC1CC(=O)Nc2ncnc(Cl)c21
Temperature: 60 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Add methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate (24.00 g, 96.35 mmol) to 30% aqueous ammonium hydroxide (100.00 mL, 7.5 eq) in a sealed tube. Seal and stir the mixture at 60° C. overnight. Cool the mixture in an ice bath. Filter the solid and wash with cold water to give 4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (11.35 g, 60%). MS (ES) m/z=198 [M]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1.Br[CH2:26][CH2:27][CH2:28][CH3:29].C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CC(C)=O>[CH2:26]([O:16][C:13]1[CH:14]=[C:15]2[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]2=[N:11][CH:12]=1)[CH2:27][CH2:28][CH3:29]
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Reactant: CCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCCCOc1cnc2c(c1)c(-c1cnn(C)c1)cn2COCC[Si](C)(C)C
Yield: 69.9 %

Procedure:
According to the general procedure using: 27 (60 mg, 0.174 mmol), 1-bromobutane (143 mg, 1.05 mmol), K2CO3 (241 mg, 1.74 mmol) and n-Bu4NI (6.4 mg, 17 μmol) in acetone (4.0 mL) were heated at reflux for 22.5 h. Purification by PTLC using AcOEt:hexane=6:4 (v/v) as eluent gave 28j as a clear oil (48.7 mg, 70%).
Reaction SMILES: [Cl:1][C:2]([Cl:19])([Cl:18])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=[O:14])[CH2:9][CH2:8]1)=[O:6]>[OH-].[K+].C(O)C.O>[Cl:19][C:2]([Cl:1])([Cl:18])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)=[O:6]
Reactant: CCOC(=O)C1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Yield: 43 %

Procedure:
Ethyl 1-(2,2,2-trichloroethoxycarbonyl)piperidine-4-carboxylate (158 g, 0.48 mol) was dissolved in a 2 N potassium hydroxide-ethanol solution (500 mL) and water (500 mL), followed by heating under reflux for about 1 hour. After cooling, to the reaction mixture was added water (300 mL), followed by extraction with ethyl acetate (300 mL×3). The aqueous layer was added a 10% aqueous citric acid solution, followed by extraction with ethyl acetate (500 mL×3), and the acidic fraction extracted was washed with saturated brine (300 mL). The resultant was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated. The residue was washed with hexane to obtain 62.9 g of 1-(2,2,2-trichloroethoxycarbonyl)piperidine-4-carboxylic acid as a colorless crystal (yield 43%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]#[N:13]>CCOC(C)=O.CCO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH2:11][C:12]#[N:13])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c(CC#N)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(N)cccc1CC#N
Yield: 77 %

Procedure:
2-(2-Methyl-3-nitrophenyl)acetonitrile (Askam, V. et al. J. Chem. Soc. C (1969)1935–1936;) was hydrogenated over 5% palladium-charcoal 50 mg in EtOAc/EtOH 1:1 (14 ml) for three hours. The mixture was filtered through celite, and the filtrate was concentrated to give the title compound 77 mg (77%) as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([C:13]2[S:17][C:16](B(O)O)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[C:22]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][CH3:35])=[CH:27][C:23]=1[C:24]([NH2:26])=[O:25].C(OCC)(=O)C>O1CCOCC1.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>[C:36]1([CH:33]([CH2:34][CH3:35])[C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:22]([C:16]3[S:17][C:13]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[CH:14][CH:15]=3)=[C:23]([CH:27]=2)[C:24]([NH2:26])=[O:25])=[O:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Reactant: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC(C(=O)Nc1ccc(-c2ccc(-c3ccccc3)s2)c(C(N)=O)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.5 ml of saturated aqueous sodium carbonate solution, 37 mg (0.18 mmol) of 5-phenyl-2-thiopheneboronic acid and 14 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 50 mg (0.12 mmol) of the compound of Example 5A in 3 ml of dioxane. The mixture is stirred at 80° C. overnight and, after addition of 50 ml of ethyl acetate, extracted three times with 50 ml of water. The organic phase is dried over magnesium sulfate and freed of solvent under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 10:90→95:5). 18 mg (30% of theory) of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:13])=[CH:8][CH2:7][CH2:6]2.P(Cl)(Cl)(Cl)=O.[C:19]([O-])(=[O:21])C.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:13])=[C:8]([CH:19]=[O:21])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC=C2C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCC(C=O)=C2C
Temperature: 72.5 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
To a solution of Compound B (0.44 g, 2.5 mmole) in dry dimethylfomamide (1.3 ml, 16.8 mmole) at ice cooling and stirring under argon atmosphere, phosphorus oxychloride (0.62 ml, 6.65 mmole) was added drop-by-drop in 2 minutes. The reaction mixture was stirred in an oil bath of 70-75° C. for 3 hours. After cooling in an ice bath, ice (6 g) was added, then sodium acetate (anhydrous, 3.7 g) was added, and the mixture (pH 6) was warmed in an oil bath at 70-75° C. for 15 minutes. After cooling, it was extracted with ether (1×10 ml and 3×5 ml), the combined organic solutions were washed with water (3×3 ml), dried (magnesium sulfate), decolorized (with activated carbon), and evaporated. The residue (0.33 g) was recrystallized from cyclohexane (2 ml) and dried over potassium hydroxide in a vacuum giving the pure product 6-Methoxy-1-methyl-3,4-dihydro-2-naphthaldehyde (Compound C, 0.22 g, 44%) as light brown crystals, mp. 70-72° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C1COCCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-morpholin-4-yl-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and morpholine following General Procedure C.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10](I)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1>C1COCC1.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Cc1ccc(Br)nc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1ccc(C2CN(C(=O)OC(C)(C)C)C2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-Boc-3-iodoazetidine (126-1) (500 mg, 1.77 mmol) in THF (5 mL) was added a solution of Reike Zinc (1.4 mL, 0.1 g/mL in THF, 2.2 mmol); a slight exotherm was noted upon addition of the zinc. After stirring for 1 h at room temperature, a solution of 2-bromo-5-methylpyridine (304 mg, 1.77 mmol) in THF (2 mL) was added, followed by bis(tri-tert-butylphosphine)palladium(0) (90 mg, 0.17 mmol) and the reaction was heated at 75° C. for 2 h. After stirring for 16 h at room temperature, the reaction was filtered through Celite, rinsing with EtOAc. The filtrate was washed with aqueous NaHCO3 (sat.) and brine, and the organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/hexane) to provide 126-2 as a colorless oil. MS: m/z=249.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:14]1([C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=3[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: O=CC1=Cc2cc(Br)ccc2OC1
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: Cc1ccccc1
Product: O=CC1=Cc2cc(-c3ccccc3)ccc2OC1

Procedure:
The starting material is prepared as follows: 6-Bromo-2H-1-benzopyran-3-carboxaldehyde (5.00 g, 20.9 mmol), phenylboronic acid (2.81 g, 23.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (725 mg, 0.63 mmol) are dissolved in 50 ml of toluene and treated with 25 ml of aqueous 2M sodium carbonate under nitrogen. The mixture is heated at reflux for 6 hours. The reaction mixture is cooled and extracted with ether (3×). The combined ethereal extracts are dried (MgSO4) and evaporated. Flash chromatography (silica gel, 5% ethyl acetate/hexane), yields 6-phenyl-2H-1-benzopyran-3-carboxaldehyde, m.p. 108°-110° C., which is converted to the final product as described above.
Reaction SMILES: F[B-](F)(F)F.N1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[C:32]1[C:33]([NH2:52])=[N:34][CH:35]=[C:36]([C:38]2[C:39]([CH2:49][O:50][CH3:51])=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[CH:42]=2)[CH:37]=1.[CH3:53][N:54]([CH3:59])[CH2:55][C:56](O)=[O:57].CN1CCOCC1>CN1C(=O)CCC1>[NH2:52][C:33]1[N:34]=[CH:35][C:36]([C:38]2[C:39]([CH2:49][O:50][CH3:51])=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:56](=[O:57])[CH2:55][N:54]([CH3:59])[CH3:53])[CH2:45][CH2:44]3)[CH:42]=2)=[CH:37][C:32]=1[C:24]1[O:23][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=1
Reactant: COCc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: COCc1nn(C2CCN(C(=O)CN(C)C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
Benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium tetrafluoroborate (115 mg) was added to a stirred suspension of 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-piperidin-4-ylpyrazol-4-yl]pyridin-2-amine] (121 mg), 2-(dimethylamino)acetic acid (32.4 mg) and 4-methylmorpholine (0.066 ml) in NMP (1.5 ml) at 25° C. The mixture was stirred at 25° C. for 5 hours and purified by preparative HPLC using a Waters OBD reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to provide the title compound (101 mg, 69.0%). NMR Spectrum: (DMSOd6) 1.73-1.85 (m, 1H), 1.87-1.98 (m, 1H), 2.04-2.16 (m, 2H), 2.21 (s, 6H), 2.72-2.82 (m, 1H), 3.08 (d, 1H), 3.13-3.22 (m, 2H), 3.41 (s, 3H), 4.15-4.23 (m, 1H), 4.41 (s, 2H), 4.41-4.51 (m, 2H), 7.40-7.48 (m, 2H), 7.66 (bs, 2H), 7.78 (dd, 1H), 7.84 (dd, 1H), 8.23 (s, 1H), 8.43 (d, 1H), 8.50 (d, 1H); Mass spectrum: M+H+ 490.
Reaction SMILES: Cl.[OH:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].[H-].[Na+].[C:10]([N:12]=[C:13](SC)[S:14][CH3:15])#[N:11]>CN(C)C=O>[NH2:11][C:10]1[N:12]=[C:13]([S:14][CH3:15])[N:5]=[C:4]([CH:3]([OH:2])[CH3:7])[N:6]=1
Reactant: CC(O)C(=N)N
Reactant: CSC(=NC#N)SC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(C(C)O)n1
Temperature: 65 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
Under a nitrogen atmosphere 2-hydroxypropanimidamide hydrochloride (4.97 g) was suspended in dry N,N-dimethylformamide (25 mL) and sodium hydride (1.66 g, 60 wt % in mineral oil) was added in one portion. When gas evolution ceased the white suspension was heated to 65° C. After 1 h dimethyl cyanocarbonimidodithioate (6.24 g) was added and the mixture was stirred at 65° C. for 18 hours. The reaction mixture was concentrated and triturated with water (200 mL). The resulting precipitate was filtered off, washed with water and the aqueous layer was extracted with 5% methanol in dichloromethane (3×100 mL). The combined organic extracts were dried (sodium sulfate) and concentrated before being purified by flash chromatography eluting with 10% methanol in dichloromethane to give the title compound (300 mg) as a yellow oil that solidified on standing.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[CH2:16][CH2:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1
Reactant: COC(=O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CC[C@H]1CCC(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 102.8 %

Procedure:
Pd/C (6 mg, 10 wt %) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester (59 mg, 0.14 mmol) in methanol (2 mL). The reaction mixture was evacuated and refilled with hydrogen (3×) then stirred at rt under a balloon of hydrogen for 3.5 h. The reaction mixture was filtered through celite, washing with methanol (5 mL). The filtrate was concentrated in vacuo to afford 59 mg (99%) of (4-{(R)-2-[4-(3-Chlorophenyl)-3-oxo-butyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[C:17]([Cl:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[N:20]1([CH2:25][C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12]2[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[C:26]([CH2:25][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)[CH:27]=3)[N:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: NC(=O)c1cc(Br)ccc1Nc1nc(Cl)ncc1Cl
Product: NC(=O)c1cc(Br)ccc1Nc1nc(Nc2cccc(CN3CCCC3)c2)ncc1Cl

Procedure:
5-Bromo-2-[(5-chloro-2-{[3-(1-pyrrolidinylmethyl)phenyl]amino}-4-pyrimidinyl)amino]benzamide was prepared by contacting 5-bromo-2-[(2,5-dichloro-4-pyrimidinyl)amino]benzamide (Intermediate 37) with 3-pyrrolidinylmethylaniline following a procedure substantially as described for the preparation of Example 1. Mass (M+H)+501, 503, 505
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[N+:22]([O-])([OH:24])=[O:23].S(=O)(=O)(O)O>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cnc(-c2ccccc2OCC)[nH]c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnc(-c2cc([N+](=O)[O-])ccc2OCC)[nH]c1=O
Temperature: 0 °C
Yield: 55 %

Procedure:
Ethyl 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)pyrimidine -5-carboxylate (1.0 g., 3,46 mmoles) was added over a twenty minute period to a cooled (ice-water), stirred mixture of 70% nitric acid (1.7 ml., d= 1.42) and 96% sulfuric acid (0.29 ml., d= 1.84). The mixture was stirred at room temperature for 19 hours. The solution was poured into ice-water (300 ml.). The mixture was triturated and then filtered. The collected solid was recrystallized from acetonitrile to give the title compound (0.64 g., 55%), m.p. 222-224°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][N:9]1[C:15](=[O:16])[CH2:14][CH:13]2[C:17](=[O:18])[CH:10]1[CH:11]=[CH:12]2.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][N:9]1[C:15](=[O:16])[CH2:14][CH:13]2[C:17](=[O:18])[CH:10]1[CH:11]=[CH:12]2)=[N+:20]=[N-:21]
Reactant: O=C1C2C=CC1N(OCCCCCCBr)C(=O)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCCCCON1C(=O)CC2C=CC1C2=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a stirring solution of 3b (100 mg, 0.302 mmol) in DMF (10 mL) was added sodium azide (98 mg, 1.51 mmol). The solution was allowed to stir at 65° C. overnight. After cooling to room temperature, the solution was diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was dried over Na2SO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure to afford 3c as a clear oil (73 mg, 83%). The oil was taken on without further purification immediately, as 3c was found to be unstable. 1H-NMR (CDCl3, 300 MHz): δ 6.70 (dd, J=5.8, 1.0 Hz, 1H), 6.49 (dd, J=6.0, 1.7 Hz, 1H), 5.47 (d, J=1.1 Hz, 1H), 4.50 (d, J=1.6 Hz, 1H), 3.92 (ABX2, JAX=JBX=6.7 Hz, JAB=9.2 Hz, 2H), 3.27 (t, J=7.0 Hz, 2H), 1.71-1.56 (m, 4H), 1.48 (s, 3H), 1.48-1.39 (m, 4H), 1.04 (s, 3H). 13C-NMR (CDCl3, 75 MHz): δ 175.4, 135.3, 134.6, 90.6, 87.1, 75.3, 51.2, 48.8, 28.5, 27.9, 26.7, 26.3, 25.3, 19.6. HRESI-MS calcd for C14H22N4O3 [M+H]+ 295.1765. found 295.1758.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:2].CC1C=CC(S([CH2:27][N+:28]#[C-:29])(=O)=O)=CC=1.[H-].[Na+].C(Cl)Cl>CS(C)=O.CCOCC.CCOCC.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[CH:29][NH:28][CH:27]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 73.4 %

Procedure:
A solution of 54 (3.74 g, 16.91 mmol) and TosMIC (3.30 g, 16.92 mmol) in DMSO/Et2O (1:2, 33 mL) was added via cannula to a vigorously stirred suspension of NaH (842 mg, 35.1 mmol) in Et2O (15 mL) under argon. Stirring was continued for 3 h. Brine and CH2Cl2 were added in small portions. The aqueous layer was extracted with CH2Cl2. The organic extract was washed with brine. The solvent was removed at reduced pressure, and the oily residue was chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to yield a brown solid (3.23 g, 84%): 1H NMR δ 1.23-1.29 (m, 3H), 4.20-4.27 (m, 2H), 6.88-6.90 (m, 1H), 7.53-7.55 (m, 1H), 7.64-7.67 (m, 2H), 8.18-8.21 (m, 2H), 8.78 (br, 1H).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:25]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26]2)[NH:12][C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:24])[CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1)C.CC1(C)CC(C(NC2C(C)=CC3C(=CC=CC=3)N=2)C2C=CC(C(O)=O)=CC=2)C1>>[CH3:29][C:27]1([CH3:30])[CH2:26][CH:25]([CH:11]([NH:12][C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:24])[CH:19]=3)[N:14]=2)[C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:31])=[O:3])=[CH:6][CH:7]=2)[CH2:28]1
Reactant: CCOC(=O)c1ccc(C(Nc2nc3ccc(F)cc3cc2C)C2CC(C)(C)C2)cc1
Agent: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1
Product: Cc1cc2cc(F)ccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1

Procedure:
The title compound was prepared by treating (+/−)-4-[(3,3-dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl ester (intermediate 72) in a similar as described in the experimental for intermediate 26.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:44])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([NH2:43])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[NH2:43][C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:44])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[C:40]([CH3:42])[N:39]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(N)n1
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)nc(N)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-[3-(2-amino-6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K45) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (64 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[O:12])[NH:8][C:7]=12.C(N(CC)CC)C>CN(C)C=O.[Pd](Cl)Cl.[Pd]>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:11]([C:9]1[NH:8][C:7]2=[CH:2][N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=1)=[O:12]
Reactant: O=C(NCc1ccccn1)c1cc2ccnc(Cl)c2[nH]1
Agent: Cl[Pd]Cl
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)c1cc2ccncc2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
7-Chloro-N-(2-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Example 4) (0.06 g, 0.21 mmol) in N,N-dimethylformamide (4.2 mL) was warmed to 60° C. under a nitrogen atmosphere. To the stirring solution were added triethylamine (0.06 mL, 0.43 mmol) and palladium dichloride (spatula tip, catalytic amount), and the reaction mixture was placed under a hydrogen atmosphere. The formation of palladium black was observed within 15 min. After stirring at 60° C. for 2 h, the heating bath was removed and the reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere. The crude reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with saturated NH4Cl and saturated NaCl, and dried over Na2SO4. Filtration and concentration provided N-(2-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (0.015 g, 25%) as an off-white solid: mp 230-236 C; 1H NMR (300 MHz, CD3OD) δ4.73 (2H, s), 7.20 (1H, s), 7.31-7.35 (1H, m), 7.46 (1H, d, J=7.9 Hz), 7.67 (1H, d, J=5.6 Hz), 7.79-7.83 (1H, m), 8.12 (1H, d, J=5.6 Hz), 8.50-8.52 (1H, m), 8.79 (1H, s); ESI MS m/z 253 [C14H12N4O+H]+; HPLC (Method A) 95.5% (AUC), tR=16.7 min.