Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3]1.N>[Ni].C(O)C>[CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=2)[CH2:3]1
Reactant: CC1(C)CCCC(Sc2ccc(C#N)cc2)C1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC1(C)CCCC(Sc2ccc(CN)cc2)C1
Yield: 67.3 %

Procedure:
To a slurry of Raney Nickel (0.2 g, 50% in water) in ethanol (35 mL) add a solution of 4-[(3,3-dimethylcyclohexyl)-thio]-benzonitrile (0.35 g, 1.43 mmol) in ethanol (5 mL) followed by aqueous ammonia (0.88 M, 2 mL) and hydrogenate the mixture in a Parr shaker at 60 psi for 3 h. Filter the mixture through Celite® washing the filter cake with ethanol. Remove the solvent in vacuo to obtain the title compound as a pale yellow oil (0.24 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28](O)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN1CCOCC1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([NH:43][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CN(C)CCN
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reaction time: 2 h
Yield: 60.3 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (73.3 mg, 0.23 mmol) was added to a stirred solution of 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (85 mg, 0.19 mmol), 4-methylmorpholine (0.052 mL, 0.48 mmol) and N1,N1-dimethylethane-1,2-diamine (0.025 mL, 0.23 mmol) dissolved in NMP (1.2 mL) at room temperature. The resulting solution was stirred for 2 hrs. The reaction mixture was purified by preparative HPLC using a Waters SunFire reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated, triturated with diethyl ether and dried to afford 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (59.2 mg, 60.2%) as a white solid. Mass Spectrum: M+H+ 517. NMR Spectrum: (DMSOd6) 1.57 (d, 3H), 2.15 (s, 6H), 2.37 (t, 2H), 3.26-3.34 (m partially hidden by H2O, 2H), 3.50-3.62 (m, 4H), 3.70-3.79 (m, 4H), 5.03-5.12 (m, 1H), 5.61 (s, 1H), 6.34 (dd, 1H), 6.49 (d, 1H), 6.64 (ddd, 1H), 6.82 (d, 1H), 8.10 (d, 1H), 8.32 (d, 1H), 8.61 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)ncc2Cl)CC1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (0.475 g, 2.6 mmol) in dry DMF (8.5 mL) was added tert-butyl piperazine-1-carboxylate (0.51 g, 2.7 mmol) followed by DIEA (0.51 mL, 3.1 mmol) at 0° C., and the mixture was stirred for 1 h. LCMS showed the reaction was completed. The reaction was diluted with water (100 mL), and the white solid was filtered. The residue was washed with water and dried to give the title compound (445 mg, 51%) as a white solid. MS (ES+) C13H18Cl2N4O2 requires: 332. found: 333 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:21]=1.[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)[N:8]=[C:7]4[C:6]=3[CH:21]=2)[CH2:28][CH2:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)N1CCC(S)CC1
Reactant: Brc1ccc2c(c1)-c1nc(-c3ccccn3)cn1CCO2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 140 °C

Procedure:
A mixture of 9-bromo-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 3 (200 mg, 0.58 mmol), 1-tert-butylpiperidine-4-thiol (202 mg, 1.69 mmol), Pd2(dba)3 (160 mg, 10 mol %), XantPhos (68 mg, 20 mol %) and DIPEA (410 μL, 2.34 mmol) in dioxane (5 mL) was purged with argon and heated at 140° C. for 1 h using microwave irradiation. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM then C18, gradient 2-25% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 154 as a white solid (36 mg, 15%). LCMS: RT 2.40 min [M+H]+ 435.1. 1H NMR (CDC3, 400 MHz): δ 8.15-8.14 (1H, m), 7.76 (1H, td, J=8.52, 2.20 Hz), 7.67 (1H, s), 7.33 (1H, dd, J=8.45, 3.89 Hz), 7.15-7.15 (1H, m), 6.96 (1H, d, J=8.43 Hz), 4.46-4.45 (4H, m), 3.03-2.98 (4H, m), 2.20 (2H, t, J=11.00 Hz), 2.06-1.94 (3H, m), 1.66-1.62 (2H, m), 1.06 (9H, s)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[F:18][CH:19]([F:35])[O:20][C:21]1[CH:34]=[CH:33][C:24](/[CH:25]=[N:26]/[S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[F:35][CH:19]([F:18])[O:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:25]([NH:26][S@:27]([C:29]([CH3:31])([CH3:30])[CH3:32])=[O:28])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[CH:33][CH:34]=1
Reactant: COC(C)=O
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(OC(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(OC(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 42.7 %

Procedure:
To a stirred solution of diisopropylamine (16.70 mL, 119.1 mmol) in THF (80 mL) at 0° C. was added dropwise 2.5M n-butyllithium (48.82 mL, 122.0 mmol) and stirring was continued for 15 min. The solution was cooled to −78° C. and methyl acetate (9.219 mL, 116.2 mmol) was added dropwise and stirring continued for 30 min. A solution of Ti(O-iPr)3Cl (58.30 mL, 244.1 mmol) in THF (20 mL) was introduced dropwise at −78° C. and stirring was continued for 45 min. A solution of 378 (16 g, 58.12 mmol) in THF (20 mL) was then added dropwise and stirring was continued for 3 h. The reaction was quenched at −78° C. by dropwise addition of satd. aq. NH4Cl and warmed to RT. The mixture was thrice extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20 to 60% EtOAc) to afford 8.67 g (43%) of (R)-methyl 3-(4-(difluoromethoxy)phenyl)-3-((S)-1,1-dimethylethylsulfinamido)propanoate (380) as a low melting white solid along with 9.67 g impure material.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:16](#[N:20])[CH2:17][C:18]#[N:19].NC(C(O)=O)C.C(O)(=O)C>O.C1C=CC=CC=1>[C:18]([CH:17]([C:16]#[N:20])[CH2:14][CH2:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=1)#[N:19]
Reactant: COC(=O)c1ccc(CCCC=O)cc1
Reactant: N#CCC#N
Agent: CC(N)C(=O)O
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(CCCCC(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3.36 g (1.0 eq) of 4-(4-carbomethoxyphenyl)butanal, 1.29 g (1.2 eq) of malononitrile, 0.05 g of D,L-alanine, 1 mL of glacial acetic acid, and 60 mL of benzene is refluxed with azeotropic removal of water. After 3 hours, about 85% of the theoretical amount of water should be formed and removed. The mixture then is cooled to room temperature and poured into water. The aqueous layer is extracted twice with benzene and the combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography with 1:1 ethyl acetate:hexanes and concentration of the eluant yield methyl 4-(5,5-dicyanopentyl)benzoate as an oil. IR (film) max ν max 2240, 1718, 1615, 1280, and 1110 cm-1 ; 1H NMR (CDCl3) delta 7.99 (d, J=8.1 Hz, 2H, Ar), 7.24-7.29 (m, 3H, Ar, vinyl), 3.90 (s, 3H, --CH3), 2.79 (t, J=7.4 Hz, 2H, benzyl), 2.60-2.64 (m, 2H, --CH2C=C), 1.94-1.97 (m, 2H, --CH2 --).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH:45]1([C:48](Cl)=[O:49])[CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([C:48]([N:31]2[CH2:32][CH2:33][C:27]3[C:28](=[N:29][C:24]([N:21]4[CH2:20][CH2:19][CH:18]([O:17][C:16]5[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=5[F:8])[CH2:23][CH2:22]4)=[C:25]([NH:34][CH:35]([CH3:37])[CH3:36])[N:26]=3)[CH2:30]2)=[O:49])[CH2:47][CH2:46]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(C(=O)C1CC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (0.5 mL) was added cyclopropanecarboxylic acid chloride (0.017 mL, 0.188 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (8.1 mg, 15%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 0.69-0.79 (m, 4H), 1.18 (d, J=6.6 Hz, 6H), 1.91 (dd, J=19.5, 5.6 Hz, 2H), 2.13 (dd, J=14.3, 6.2 Hz, 2H), 2.52-2.53 (m, 1H), 2.57-2.64 (m, 0.9H), 2.75 (t, J=6.2 Hz, 1.1H), 2.88-2.99 (m, 2H), 3.22-3.31 (m, 2H), 3.72-3.77 (m, 0.9H), 3.95 (t, J=5.8 Hz, 1H), 4.10-4.16 (m, 1H), 4.42 (br s, 1.1H), 4.67 (br s, 0.9H), 4.80-4.87 (m, 1H), 5.61-5.67 (m, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.65-7.70 (m, 1H), 7.86 (dd, J=11.2, 1.9 Hz, 1H); ESI-MS m/z [M+H]+ 479.5.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:12][CH:13]=[C:14](Br)[N:15]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C=O)C.CCOC(C)=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:12][CH:13]=[C:14]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc2ccccc2s1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1-c1cc2ccccc2s1
Temperature: 100 °C
Yield: 91 %

Procedure:
Tert-butyl N-[3-(benzothiophen-2-yl)-5-bromo-pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (100 mg, 0.1975 mmol) was dissolved in DMF (781.2 μL) and treated with piperazine (170.1 mg, 1.975 mmol) and the reaction mixture heated at 100° C. for 30 minutes. The reaction was allowed to cool to ambient temperature and diluted with EtOAc/water and the layers separated. The organic layer was washed with water (3×), dried (MgSO4) and concentrated in vacuo. The material was used crude in the next step (92 mg, 91% Yield). 1H NMR (DMSO) d 1.23 (18H, s), 2.98 (4H, m), 3.59 (2H, m), 3.63 (2H, m), 7.29 (2H, m), 7.74 (3H, m), 7.89 (1H, s) ppm; MS (ES+) 511.98
Reaction SMILES: C(O)CCCCC.[H-].[Na+].[C:10]1([O:16][C:17](=[O:51])[O:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][N:38]([C:41]5[C:49]6[CH:48]=[CH:47][S:46][C:45]=6[CH:44]=[CH:43][CH:42]=5)[CH2:37][CH2:36]4)[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:50])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>O1CCCC1>[CH2:10]([O:16][C:17](=[O:51])[O:18][CH2:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([C:41]4[C:49]5[CH:48]=[CH:47][S:46][C:45]=5[CH:44]=[CH:43][CH:42]=4)[CH2:37][CH2:36]3)[CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:50])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCO
Product: CCCCCCOC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Yield: 12.3 %

Procedure:
To a solution of n-hexylalcohol (50.5 mg) in tetrahydrofuran (5 ml) was added with stirring under ice-cooling 60% sodium hydride (18 mg) by small portions, and the mixture was stirred at the same temperature for 0.5 hr, a solution of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (240 mg) in tetrahydrofuran (1 ml) was added dropwise, and the mixture was stirred under ice-cooling for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester hexyl ester (30 mg).
Reaction SMILES: S(O)(O)(=O)=O.[OH:6][NH2:7].[CH3:8][O:9][CH2:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15].[OH-].[Na+]>O>[CH3:8][O:9][CH2:10][C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[O:6][N:7]=1)([CH3:18])[CH3:17]
Reactant: NO
Reactant: COCC(C)(C)C(=O)CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(C)(C)c1cc(N)on1
Temperature: 100 °C

Procedure:
Hydroxyamine sulfate (1.56 g, 9.504 mmol) is added to a stirred solution of 5-methoxy-4,4-dimethyl-3-oxo-pentanenitrile (2.95 g, 19.008 mmol) and sodium hydroxide (1.635 g, 40.865 mmol) in water (40 mL). The reaction mixture is heated in 100° C. oil bath for 6 hours. After this time, the reaction mixture is diluted with water and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 171 [M+H+].
Reaction SMILES: [NH2:1][CH:2]([CH3:25])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[N:9][CH:10]=1.NN.COC(C)(C)C>CCO>[NH2:1][CH:2]([CH3:25])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[N:9][CH:10]=1
Reactant: CC(N)CCc1ccc(CCCN2C(=O)c3ccccc3C2=O)nc1
Agent: NN
Solvent: CCO
Solvent: COC(C)(C)C
Product: CC(N)CCc1ccc(CCCN)nc1
Reaction time: 1 h

Procedure:
A solution of the phthalimide 9-2 (3.05 g, 9.05 mmol) in EtOH (50 mL) was treated with hydrazine (2.84 mL, 90.5 mmol) and heated to 500C for 1 hour. The mixture was cooled, methyl t-butylether (100 mL) added, stirred for 1 hour and filtered. The filtrate was concentrated in vacuo to give the desired product 9-3 which was used in Step D without further purification.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].C1(OC)C=CC=CC=1>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[N:1]1([C:10]2[N:18]=[C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)CC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)ncn2-c1nc(NCC2CCNCC2)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
35 mg of the product of Example 31 are mixed with 1 ml of CH2Cl2 and 0.5 ml of TFA containing 10% of anisole. The mixture is left to stir for 2 hours at ambient temperature, followed by concentrating to dryness in the presence of toluene and of CH2Cl2. 40 mg of expected product are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8].[CH3:27]OC(C1SC(C)=CC=1NC1C2C=CNC=2N=CN=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH3:27])=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8]
Reactant: COC(=O)c1sc(C)cc1Nc1ncnc2[nH]ccc12
Reactant: O=C(NCc1cccc(Cl)c1)c1sccc1Nc1ncnc2[nH]ccc12
Product: Cc1cc(Nc2ncnc3[nH]ccc23)c(C(=O)NCc2cccc(Cl)c2)s1
Yield: 50 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid 3-chloro-benzylamide using 5-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester instead of 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester and obtained in 50% yield (HPLC: 98%, RT: 3.85 min). 1H NMR (DMSO-d6) 11.98 (br s, 1H), 11.39 (s, 1H), 8.68 (t, J=6.0 Hz, 1H), 8.39 (s, 1H), 8.28 (d, J=1.1 Hz, 1H), 7.40-7.28 (m, 5H), 6.41 (dd, J=3.3, 1.8 Hz, 1H), 4.48 (d, J=5.9 Hz, 2H), 2.55 (s, 3H); MS (m/z) 398 [M+H]+ (35Cl).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:13]([Sn:17]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])Cl)[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:23]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a solution of 2-bromopyridine (5 g, 31.65 mmol, 1.00 equiv) in freshly distilled THF (50 mL) was added n-BuLi (15.3 mL, 3.80 mmol, 1.20 equiv) dropwise at −78° C. under N2. After stirring for 30 min at this temperature, tributyl(chloro)stannane (12.5 g, 38.40 mmol, 1.21 equiv) was added via a syringe at −78° C. and stirred for additional 1 h. Then the reaction mixture was warmed to room temperature and stirred for another 2 h. The reaction was quenched by the addition of 50 mL of NH4Cl (sat), extracted with 3×100 mL of ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/20) to give 2-(tributylstannyl)pyridine (1.0 g) as a pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[C:18](=[O:19])[C@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][S:15](=[O:29])(=[O:28])[C@@H:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:13]2)[CH2:10][CH2:9]1>ClCCl>[NH2:20][C@@H:17]1[CH2:16][S:15](=[O:29])(=[O:28])[C@@H:14]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:13][N:12]([CH2:11][CH:8]2[CH2:10][CH2:9]2)[C:18]1=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CS(=O)(=O)[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CS(=O)(=O)[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to a solution of tert-butyl (2S,6S)-4-(cyclopropylmethyl)-1,1-dioxido-5-oxo-2-phenyl-1,4-thiazepan-6-ylcarbamate (63 mg, 0.167 mmol) in dichloromethane (5 mL). After 1 h, the mixture was concentrated and aqueous saturated sodium bicarbonate was added. The mixture was extracted with dichloromethane (2×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the crude product (50 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9]Cl)=[N:7][CH:8]=1.[OH:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C(N(CC)C(C)C)(C)C>C(#N)C.O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:11][N:12]2[C:16](=[O:17])[C:15]3[C:14](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]2=[O:22])=[N:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccc(Br)cn1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(Br)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a mixture of 5-Bromo-2-chloromethyl-pyridine hydrochloride (63.7 g, 0.262 mol) and N-hydroxylphthalimide (64 g, 0.393 mol) in acetonitrile (400 mL) was placed in water bath and added N,N-diisopropylethylamine (182 mL, 1.05 mol) using dropping funnel for 10 min. It was heated at 65° C. for 4 hrs and evaporated off the solvent and extra base. Then, water (100 mL) was added to the reaction mixture and stirred for overnight. The resulting solid was filtered, washed with water (2×50 mL) and acetonitrile (100 mL). The white solid was dried on vacuum pump to provide the title compound (84.2 g, 84%) as a white solid. MS-ESI m/z 334.95 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[O:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:4]([C:14]([OH:16])=O)[CH:3]=1.Cl.[F:18][C:19]([F:31])([F:30])[CH2:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[O:10][CH:11]=[CH:12][N:13]=2)[N:5]=[C:4]([C:14]([NH:29][CH2:28][C:25]2[CH:26]=[N:27][C:22]([O:21][CH2:20][C:19]([F:31])([F:18])[F:30])=[CH:23][CH:24]=2)=[O:16])[CH:3]=1
Reactant: NCc1ccc(OCC(F)(F)F)nc1
Reactant: Cc1cc(C(=O)O)nc(Nc2ncco2)n1
Agent: Cl
Product: Cc1cc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)nc(Nc2ncco2)n1

Procedure:
The title compound is prepared from 6-methyl-2-(oxazol-2-ylamino)pyrimidine-4-carboxylic acid (25 mg, 0.11 mmol, Step-1) and (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (28 mg, 0.11 mmol) by the similar manner in Example-2.