Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[O:10][C:11](C)(C)[CH3:12].CSCC(OCC)=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:11](=[O:10])[CH2:12]2
Reactant: CC(C)(C)OCl
Reactant: Nc1ccc(F)cc1
Agent: CCOC(=O)CSC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane, at -60° to -65° C., was added, dropwise, a solution of 10.8 g (0.1 mol) of t-butyl hypochlorite in 25 ml of dichloromethane. Stirring was continued for 10 minutes at -60° to -65° C., and then was added, dropwise, a solution of 13.4 g (0.1 mol) of ethyl 2-(methylthio)acetate in 25 ml of dichloromethane. Stirring was continued at -60° C. for 1 hour and then was added, dropwise, at -60° to -65° C., a solution of 11.1 g (0.11 mol) of triethylamine in 25 ml of dichloromethane. The cooling bath was removed, and when the reaction mixture had warmed to room temperature, 100 ml of water was added. The phases were separated, and the organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether, to which was added 40 ml of 2N hydrochloric acid. This mixture was stirred at room temperature overnight. The phases were separated and the ether phase was washed
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH2:12](O)[CH3:13]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:12]([C:2]1[CH:11]=[CH:10][C:9]2[C:7](=[O:8])[O:6][CH2:5][C:4]=2[CH:3]=1)=[CH2:13]
Reactant: CCO
Reactant: O=C1OCc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)COC2=O

Procedure:
5-Bromophthalide (50 g, 235 mmol), potassium vinyl trifluoroborate (62.9 g, 469 mmol), and PdCl2(dppf)-CH2Cl2 Adduct (9.58 g, 11.7 mmol) were added to ethanol (500 mL) then TEA (65.4 mL, 469 mmol) was added. The reaction mixture was degassed then heated at reflux for 8 h. The reaction was worked up by diluting with ethyl acetate and washing with brine twice. The organic layer was dried and evaporated to dryness. The crude product was purified by MPLC (silica, 600 g column) with 25% EtOAc/hexane (3 L) then with 30% EtOAc/Hexane (2 L) to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](#[N:31])[CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].N12CCCN=C1CCCCC2.C(#N)C>>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][C:23]#[N:31])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: CCCCCC=CC#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Yield: 89.89 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (prepared substantially as described in Example 65 of U.S. Pat. App. Pub. No. 2007/0135461 or International App. No. PCT/US2006/047369 (published as WO 2007/070514); 12 g, 0.038 mol), oct-2-enenitrile (6.0 g, 0.049 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.6 mL, 0.030 mol) in acetonitrile (120 mL, 2.3 mol) was stirred at room temperature overnight. After being concentrated in vacuo, the resultant residue was purified on silica gel (eluting with 0 to 40% EtOAc in hexanes) to give the desired product (15 g, 89.89%). The enantiomers (first peak retention time 11.02 min, second peak retention time 14.10 min) were separated on a ChiralCel OD-H column (30×250 mm, 5 μM), eluting with mobile phase of 15% ethanol and 85% hexane at 25 mL/min. MS calculated for C23H35N6OSi(M+H)+: m/z=439.264. Found: 439.4. 1H NMR (300 MHz, CDCl3) δ 8.91 (1H, s), 8.38 (1H, s), 8.37 (1H, s), 7.46 (1H, d, J=3.8 Hz), 6.86 (1H, d, J=3.8 Hz), 5.73 (2H, s), 4.59 (1H, m), 3.60 (2H, t, J=8.3 Hz), 3.06 (2H, td, J=16.8 and 7.5 Hz), 2.21 (1H, m), 2.01 (1H, m), 1.40-1.21 (6H, m), Hz), 0.91 (3H, t, J=6.3 Hz), 0.00 (9H, s) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([F:12])[C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CO.[Zn]>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:4]([F:12])=[CH:5][C:6]=1[NH:9][C:34](=[O:35])[O:36][CH2:37][CH3:38]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(NCc2ccc(F)cc2)c1F
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1cc(F)c(NCc2ccc(F)cc2)c(F)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a stirred solution of compound 3 (0.062 g, 0.21 mmol, 1.0 equiv) in methanol (0.560 mL) was added zinc powder (0.068 g, 1.04 mmol, 5.00 equiv) followed by ammonium chloride solution (55.3 mg, 1.04 mmol, 5.00 equiv) drop wise. After being stirred for 4 h at RT, DIPEA (48.0 μL, 0.260 mmol, 1.25 equiv) and ethyl chloroformate (20.0 μL, 0.210 mmol, 1.00 equiv) were added to reaction mixture at 10° C. and the stirring was continued for another 2 h at RT. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2×75 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by neutral alumina column chromatography (EtOAc/Hexane 18:82) to afford to compound 4A (0.017 g, 21%) as an off-white solid. TLC: 50% EtOAc/Hexane (Rf: 0.50); 1H NMR (500 MHz, CDCl3): δ 7.30-7.27 (m, 2H), 7.00 (t, J=8.5 Hz, 2H), 6.88 (d, J=11.5 Hz, 1H), 6.26 (br s, 1H, Exc), 4.40 (d, J=6.0 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.75 (br s, 1H, Exc), 3.50 (s, 2H, Exc), 1.30 (t, J=7.0 Hz, 3H); LC-MS: m/z=340 (M++1) at RT 3.46 (94.3% purity); UPLC purity: 95.2%
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][P:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:18][C:17]2[CH:16]=[CH:15][C:14]([P:11]([CH3:13])([CH3:10])=[O:12])=[CH:20][CH:19]=2)[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CP(C)(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(Nc2ccc(P(C)(C)=O)cc2)n1

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (1.31 mmol) in 1 mL of DMF is added 4-(dimethylphosphoryl) aniline (0.221 g, 1.31 mmol) and potassium carbonate (0.217 g, 1.57 mmol). The mixture is heated at 110° C. until formation of the desired compound. The reaction mixture is basified with saturated sodium bicarbonate solution. The suspension is filtered and washed with ethyl acetate.
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:38])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:37])[C:19](=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:12][CH2:11]1.[CH3:45][N:46]([CH2:54][CH2:55][CH:56]=O)[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>>[C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:38])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([C:19](=[O:36])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH2:32][N:31]([CH2:56][CH2:55][CH2:54][N:46]([C:47]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:53])[CH3:45])[CH2:30][CH2:29]3)[CH3:37])[CH2:14][CH2:15]1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc2c(c1)CCNC2
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc2c(c1)CCN(CCCN(C)C(=O)OC(C)(C)C)C2
Yield: 79.4 %

Procedure:
The compound (47 mg, 78.6 μmol) obtained in Example 63b and tert-butyl methyl(3-oxopropyl)carbamate (Bioorg. Med. Chem., 12, 19, 2004, 5147-5160) (18 mg, 94.3 μmol) were used to give the title compound (48 mg; yield, 79%) as a colorless oily substance according to the method described in Example 41a.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-])([OH:8])=[O:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[O:18])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[O:18])=[CH:15][C:16]=1[N+:6]([O-:8])=[O:7]
Reactant: O=C(c1ccc(Br)cc1)c1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(c1cccc([N+](=O)[O-])c1)c1ccc(Br)c([N+](=O)[O-])c1

Procedure:
A 2 L, 3 necked round bottomed flask equipped with a mechanical stirrer, thermocouple and ice-bath was charged with concentrated H2SO4(aq) (635 mL) and concentrated HNO3(aq) (62 mL). The flask and its contents were cooled to 0° C. (4-Bromo-phenyl)-(3-nitro-phenyl)-methanone (127 g, 0.42 mol) was added over a period of 1 h and the temperature was kept under 10° C. Thirty minutes later, the reaction was complete by thin layer chromatographic analysis (Hexanes/EtOAc 6:4). The reaction was poured into ice-H2O (2 L). The solids were filtered, washed with H2O (4 L), saturated NaHCO3(aq) (1 L) and an additional portion of H2O (1 L). The product was dried at 45° C., for 48 h yielding (4-Bromo-3-nitro-phenyl)-(3-nitro-phenyl)-methanone in 95% (138.4 g, 0.39 mol).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>CCCCCCC>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: C=C(Cl)C#N
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Solvent: CCCCCCC
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g) and 2-chloroacrylonitrile (26.6 g) is stirred at about 80° C. for 24 hours. n-Heptane (125 ml) is allowed to run in, and unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide as well as n-hepiarie are distilled off (distillate 50 ml) by raising the external temperature to about 130° C. The mixture is cooled to about 20° C. and the suspension is stirred at about 20° C. for 1 hour. The product is isolated by filtration and washed with n-heptane (100 ml). The product is dried in vacuo at about 60° C. Yield: 31.55 g=71.6% (beige powder).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8][C@@H:9]([O:10]S(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[O-][CH2:29][CH3:30].[Na+]>C(O)C.C(=O)([O-])O.[Na+]>[CH2:29]([O:10][C@H:9]1[CH2:8][N:7]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12)[CH3:30]
Reactant: CC[O-]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCO[C@H]1CN(C(=O)OC(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 80 °C
Yield: 7 %

Procedure:
A stirred mixture of tosylate (35b) (20 mg, 0.05 mmol), ethanol (1 mL) and sodium ethoxide solution in ethanol (21% wt, 94 μL, 0.25 mmol) was heated under an atmosphere of argon at 80° C. for 16 hours. The mixture was diluted with aqueous saturated sodium hydrogen carbonate solution (10 mL) then extracted with tert-butyl methyl ether (3×5 mL). The organic phase was dried (MgSO4), filtered and reduced in vacuo to leave an oil. Flash chromatography over silica, eluting with diethyl ether:pentane mixtures 65:35 to 83:17 gave ethoxyalcohol (59) as a pale yellow solid (1 mg, 7%). TLC (Rf=0.50, Et2O); analytical HPLC main peak, Rt=15.35 min., HPLC-MS 218.1 [M+2H−tBu]+, 296.1 [M+Na]+, 569.3 [2M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:7]=1.Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH:7]=1
Reactant: Clc1cccc(OCCBr)c1
Reactant: COC(=O)CCc1cccc(CNS(=O)(=O)c2ccccc2)c1
Product: COC(=O)CCc1cccc(CN(CCOc2cccc(Cl)c2)S(=O)(=O)c2ccccc2)c1

Procedure:
Following the procedure described in Step A of Example 2, 3-[3-(benzenesulfonylamino-methyl)-phenyl]-propionic acid methyl ester was alkylated with 1-(2-bromo-ethoxy)-3-chloro-benzene to provide the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, 2H), 7.60-7.49 (m, 3H), 7.22 (d, 1H), 7.13-7.06 (m, 4H), 6.88 (m, 1H), 6.60 (d, 1H), 6.52 (m, 1H), 4.42 (s, 2H), 3.88 (s, 2H), 3.65 (s, 3H), 3.47 (t, 2H), 2.87 (t, 2H), 2.54 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][C:24]([OH:26])=O)[N:22]=1)=[CH:5]2.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[N:22]=1)=[CH:5]2
Reactant: C1COCCN1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1)N1CCOCC1
Yield: 68 %

Procedure:
The compound (44 mg, 0.11 mmol) prepared in Example 31 and morpholine instead of methylamine were reacted according to the same procedure as Example 82 to give the title compound (35 mg, Yield 68%).
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5]1.F[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[N:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH:15]=[CH:14]2.O>CC(N(C)C)=O>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:16]2[CH:15]=[CH:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:9][C@H:6]4[CH2:7][CH2:8][C@H:4]([NH2:3])[CH2:5]4)[CH:12]=3)[C:17]2=[O:21])=[CH:28][CH:27]=1
Reactant: N[C@H]1CC[C@H](O)C1
Reactant: COc1ccc(Cn2ccc3cc(F)ccc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@H](N)C4)ccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
106 mg (4.20 mmol) of sodium hydride (95%) were suspended in 3 mL of dimethyl acetamide and 193 mg (1.40 mmol) of (1S,3S)-3-amino-cyclopentanol (34), dissolved in 1 mL of dimethyl acetamide, were added dropwise. After 1 h, 402 mg (1.42 mmol) of 2-(4-methoxy-benzyl)-6-fluoro-2H-isoquinolin-1-one (9), dissolved in another 3 mL of dimethyl acetamide, were added. The reaction mixture was stirred at 80° C. until the reaction was complete. The mixture was poured into water, extracted three times with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers were evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide. The obtained crude product was purified by silica gel chromatography to yield 250 mg of the title compound (39). Rt=1.20 min (Method E). Detected mass: 365.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.[CH3:20][O:21][CH:22]([C:25]#[N:26])[C:23]#[N:24].O>CN(C=O)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:25]([NH2:26])[C:22]([O:21][CH3:20])=[C:23]([NH2:24])[N:15]=2)=[N:6]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Reactant: COC(C#N)C#N
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Temperature: 100 °C

Procedure:
100 mg of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide 1-2-4 (0.39 mmol, 1.0 eq.) and 37 mg methoxymalononitrile (0.39 mmol, 1.0 eq.; for preparation see: US2003/144538 A1, 2003) were dissolved in 1 mL DMF. The mixture was heated for 30 min in a microwave oven at 100° C. After addition of 10 mL water, the precipitated, crude product was filtered off and was purified by flash chromatography yielding 66 mg (0.19 mmol, 48%) of analytically pure target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH2:11][CH2:12][CH3:13].[H][H]>C(O)C.[Pd]=O>[CH3:15][N:2]([CH3:1])[C:3](=[O:14])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH2:11][CH2:12][CH3:13]
Reactant: CCCc1[nH]cnc1/C=C/C(=O)N(C)C
Reactant: [H][H]
Agent: O=[Pd]
Solvent: CCO
Product: CCCc1[nH]cnc1CCC(=O)N(C)C
Yield: 99 %

Procedure:
A solution of (E)-N,N-dimethyl-3-(5-propyl-1H-imidazol-4-yl)-2-propenamide (500 mg) in ethanol (25 ml) was added to a suspension of pre-reduced 10% palladium oxide on carbon catalyst (150 mg, 50% paste with water) in ethanol (15 ml). The mixture was stirred in a hydrogen atmosphere for 2 h, then filtered (Hyflo) and evaporated to give the title compound (500 mg) as a colorless oil, t.l.c. on Et3N impregnated SiO2 (ethyl acetate:methanol 4:1), Rf 0.33.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:37][C:38]1([F:43])[CH2:42][CH2:41][NH:40][CH2:39]1.C(N(CC)CC)C>ClCCl>[F:37][C:38]1([F:43])[CH2:42][CH2:41][N:40]([C:19](=[O:20])[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:22])([F:1])[F:23])=[N:4]3)=[CH:17][CH:16]=2)[CH2:39]1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: FC1(F)CCNC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
A solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid (65 mg, 0.2 mmol) in dichloromethane (2 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (33 mg, 0.2 mmol). This mixture was allowed to stir at room temperature for 15 minutes. 3,3-difluoropyrrolidine hydrochloride (29 mg, 0.2 mmol) was then added followed by triethylamine (21 mg, 0.21 mmol) and the stirring continued for 1 hour at room temperature. The reaction mixture was reduced to minimum volume under reduced pressure then purified by mass directed auto-prep to give the title compound as a yellow oil (53 mg, 64%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.I[CH2:14][CH2:15][CH3:16].O>CN(C=O)C>[CH2:14]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)[CH2:15][CH3:16]
Reactant: CCCI
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
Sodium hydride (0.99 g, 50% in oil) was added to dry DMF (5 ml) and the resulting suspension was stirred at room temperature. A solution of 5-hydroxyindole (2.5 g) in dry DMF (15 ml) was added dropwise and a dark purple solution formed. After stirring the mixture for 30 min, 1-iodopropane (3.51 g) was added, and the resulting mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with ether (3x). The combined extracts were washed with water, dried (MgSO4) and evaporated to dryness to give a crude residue which was purified by chromatography (SiO2 ; hexane/ether). 5-n-Propyloxyindole was obtained as a yellow oil (2.03 g).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2O1.[CH3:64][O:65][C:66](C1C=CC(B(O)O)=CC=1)=[O:67]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][C:32]([C:66]([O:65][CH3:64])=[O:67])=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Product: COC(=O)c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and (4-methoxycarbonylphenyl)boronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine. LCMS: ret time: 26.35 min.; purity: 90%; MS (m/e): 514 (MH+).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[O:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ncc(C(=O)OCC)o1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnc(CC)o1
Yield: 98.9 %

Procedure:
To a solution of ethyl 2-vinyloxazole-5-carboxylate (470 mg, 2.81 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (100 mg, 0.094 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is collected and concentrated to give ethyl 2-ethyloxazole-5-carboxylate (470 mg). HPLC retention time=1.09 minutes (condition A); MS (m+1)=170.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.6 Hz, 3 H) 1.36 (t, J=7.2 Hz, 3 H) 2.87 (q, J=7.7 Hz, 2 H) 4.35 (q, J=7.2 Hz, 2 H) 7.71 (s, 1 H)
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)[CH:2]=[CH2:3].[F:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:3]=[CH:2][CH2:1][N:4]2[C:12]3[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=3[C:6]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]2=3)=[CH:22][CH:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC=Cc2ccc(F)cc2)C1
Temperature: 25 °C

Procedure:
5-Allyl-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 0.76 mmol, 1 equiv.) and 4-fluorobromobenzene (134 mg, 0.76 mmol, 1 equiv.) were heated to 100° C. with palladium acetate (5 mg, 0.023 mmol), triphenyl phosphine (12 mg, 0.046 mmol) and triethyl amine (0.22 mL, 2 equiv.) in THF (5 mL) for 14 h. The reaction mixture was cooled to RT and diluted with THF (10 mL), filtered over a Celite bed and concentrated. The concentrate was dissolved in EtOAc (20 mL) and washed with water (5 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product that was purified by HPLC. 1H NMR (DMSO-d6) δ (ppm): 10.0 (bs, 1H), 7.61-7.58 (d, 2H), 7.44-7.40 (dd, 2H), 7.20-7.11 (m, 3H), 6.4 (d, 1H), 6.3 (m, 1H), 5.0 (m, 2H), 4.62 (d, 1H), 4.29-4.25 (m, 1H), 3.78 (m, 1H), 3.5 (m, 1H), 3.18 (m, 2H), 2.98 (s, 3H).