Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[C:20]=3[CH3:28])(O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[C:20]=3[CH3:28])=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c([C@]2(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C2=CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C

Procedure:
Mesyl-Cl (17.2 mL, 221 mmol) was added dropwise to a stirred, <5° C. internal temperature mixture of (3R,9aS)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (66.6 g, 170 mmol) and triethylamine (71.1 mL, 510 mmol) in CH2Cl2 (1000 mL) (exotherm occurs, so must keep addition slow), and the reaction was allowed to warm to room temperature for 30 minutes, by which time reaction was complete. The solution was washed with 500 mL 10% w/w NaHCO3 aqueous solution. The organics were dried over MgSO4, filtered and concentrated. The resulting material was taken up in a minimal amount of EtOAc (125 mL) with some heating (solution kept <50° C.) until all solids dissolved. The solution was allowed to cool with stirring, then dropwise overnight 350 mL hexanes was added. By the next morning the solution had clarified and there was considerable powder. The solids were collected by filtration and washed with 20% EtOAc/Hexanes, providing product. The mother liquors were concentrated until precipitate appeared, which was filtered to give additional (S)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.C(O[Si](C)(C)CO[CH:16]1[CH2:18][CH2:17]1)C.[BH4-].[Na+]>CC(O)=O.CO.C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:16]2[CH2:18][CH2:17]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: CCO[Si](C)(C)COC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Clc1cc(Br)ccc1NC1CC1
Temperature: 68 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chloroaniline [C.A.S. 38762-41-3], (1 g, 4.843 mmol) in AcOH (19 ml) and MeOH (10 mL) stirred at room temperature and under nitrogen atmosphere was added dropwise (1-ethoxycyclopropyloxy-trimethylsilane [C.A.S. 27374-25-0] (1.199 ml, 5.57 mmol). The reaction mixture was then refluxed at 67-69° C. for 3 h. The mixture was then concentrated in vacuo to yield intermediate D30′. In another flask, NaBH4 (0.366 g, 9.687 mmol) was suspended in THF (10 mL) and cooled to 5° C. Then, BF3.Et2O complex (1.228 ml, 9.687 mmol) was added dropwise. The resulting reaction mixture was stirred under a N2 atmosphere at 5° C. for 1 h. Then, to this mixture was added a solution of D30′ in THF (5 mL) dropwise at 5-10° C. over 20 min. After stirring at r.t. for 5 h., at reflux temperature for 2 h., and then removing THF by distillation, the mixture was cooled to r.t. and poured into water. The resulting mixture was extracted with Et2O. The organic layer was washed with water and dried (Na2SO4) followed by the removal of the volatiles under vacuo. The crude product thus obtained was purified by column chromatography (silica gel; Heptane/EtOAc 99:1 as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D30 (0.390 g, 32.6%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:6](=[O:14])[C:7]([C:12]#[N:13])=[CH:8]OCC)[CH2:3][CH2:2]1.[C:25]([N:28]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]1=[O:35])(=[NH:27])[NH2:26]>COCCOC>[C:12]([C:7]([C:6](=[O:14])[N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)=[CH:8][NH:27][C:25](=[NH:26])[N:28]1[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]1=[O:35])#[N:13]
Reactant: CC1(C)CN(C(=N)N)C(=O)N1
Reactant: CCOC=C(C#N)C(=O)N(CC1CC1)c1cccc(C(F)(F)F)c1
Solvent: COCCOC
Product: CC1(C)CN(C(=N)NC=C(C#N)C(=O)N(CC2CC2)c2cccc(C(F)(F)F)c2)C(=O)N1
Reaction time: 48 h
Yield: 47 %

Procedure:
A solution of 8.2 g of (unpurified, about 90% pure) 2-cyano-3-ethoxyacrylic acid N-isopropyl-N-(3-trifluoromethylphenyl)amide (compound IV: R4 =CH(CH3)2 ; R5, R6 =H; R7 =C2H5) in 20 ml of abs. DME was added dropwise to a suspension of 3.91 g (25 mmol) of 1-amidino-4,4-dimethyl-2-oxoimidazolidine in 16 ml of abs. DME at 20°, and the mixture was stirred at 22°-24° for 4.5 hours. The mixture was then evaporated in vacuo at a maximum bath temperature of 25°. The oily residue was taken up in 250 ml of ether and extracted six times with 25 ml of water each time. The etherial solution was then dried over MgSO4, filtered and evaporated in vacuo (<26°). The residue (12.7 g) was partially crystalline. The latter was taken up in 40 ml of ether, 2 ml of pentane were added, the mixture was left to stand at 4°-6° for 2 days and subsequently the crystals were filtered off with suction. Drying (over P4O10 at 20°-24°, 6-8 mbar, 48 hours) resulted in 5.12 g (=47% yield) of TLC-pure compound II (R1, R2 =CH3 ; R3, R5, R6 =H; R4 =CH(CH3)2), melting point 121°-122° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:13]([O:16][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cc(O)ccc1-c1cc(OC)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Yield: 99.6 %

Procedure:
A solution of ethyl 2′-fluoro-4-hydroxy-5′-methoxy-[1,1′-biphenyl]-2-carboxylate (15.84 g), 4-methoxybenzyl chloride (17.09 g) and potassium carbonate (18.85 g) in DMF (110 mL) was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (22.3 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:40][C:41]12[CH2:48][CH:45]([NH:46][CH2:47]1)[CH2:44][C:43]([CH3:50])([CH3:49])[CH2:42]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:46]1[CH2:47][C:41]3([CH3:40])[CH2:48][CH:45]1[CH2:44][C:43]([CH3:50])([CH3:49])[CH2:42]3)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc2[nH]1
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a solution of 1H-Indole-2,5-dicarboxylic acid 2-ethyl ester (890 mg, 3.8 mmol) in dry DMF (10 mL) at room temperature under an inert atmosphere of nitrogen was added HOBt (570 mg, 4.2 mmol) and EDAC (951 mg, 4.9 mmol), and the resulting solution was stirred for 30 min. 1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane hydrochloride (796 mg, 4.2 mmol) was added to the solution followed by DIPEA (1.98 mL, 11.4 mmol), and the reaction mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (20 mL) followed by extraction with DCM (3×50 mL). The combined organic phases were dried (MgSO4), filtered, and evaporated in vacuo. The resulting solid was purified by silica gel chromatography using a mixture of ethyl acetate and heptane (1:2) as eluent. Pure fractions were collected, the solvent evaporated in vacuo and dried in vacuo at 50° C. affording 800 mg (57%) of the title compound as a solid. MS-ESI m/z 369; 1H NMR (300 MHz, CDCl3) δ 0.94 (d, 3H), 1.04 (d, 3H), 1.14-1.19 (m, 4H), 1.24-1.29 (m, 2H), 1.39-1.45 (m, 4H), 1.58-1.63 (m, 1H), 1.76-1.79 (m, 1H), 3.25-3.30 (m, 1H), 3.35 (d) and 3.65 (d, 1H), 4.06-4.09 (m) and 4.64-4.67 (m, 1H), 4.42 (q, 2H), 7.27 (s, 1H), 7.39-7.46 (m, 2H), 7.82 (d, 1H), 9.05 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([N:28]5[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]5)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: OC1CCNCC1
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCC(O)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to piperidin-4-ol via General Procedure B. The product was purified via reverse phase HPLC to give 12.9 mg of 251. MS (Q1) 464.8 (M)+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].C(OO)(C)(C)C.[CH2:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>[Mo](=O)(=O)=O>[CH3:20][CH:19]([O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: CCc1ccccc1
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Product: CC(ON1C(C)(C)CC(=O)CC1(C)C)c1ccccc1
Yield: 67 %

Procedure:
A mixture of 40.0 grams (235 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one, 60.5 grams (470 mmol) of 70% aqueous tert-butyl hydroperoxide, 3.0 grams of molybdenum trioxide, and 200 ml of ethylbenzene is heated at reflux for four hours. Water is collected in a Dean-Stark trap. Solids are removed by filtration, and the filtrate is concentrated under reduced pressure. Kugelrohr distillation of the crude product, followed by recrystallization from methanol, affords 42.8 grams (67% yield) of the title compound as a white solid melting at 77-80° C.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[Br:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=O.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>CC1C=CC=CC=1>[Br:15][CH2:16][C:17]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[O:9][CH:6]([CH2:5][O:4][C:3]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:2]=2[CH3:1])[CH2:7][O:8]1
Reactant: Cc1cccc(C)c1OCC(O)CO
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1OCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1

Procedure:
A mixture of 11.8 parts of 3-(2,6-dimethylphenoxy)-1,2-propanediol, 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of methylbenzene is stirred and refluxed for 3 days. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane. The solution is stirred for 30 minutes with silica gel. The latter is filtered off and the filtrate is evaporated, yielding A + B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(2,6-dimethylphenoxymethyl)-1,3-dioxolane as a residue.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:25]=[C:26]([NH2:31])[CH:27]=[C:28]([F:30])[CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([NH:31][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2cc(F)cc(F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3,5-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (s, 3H), 2.34 (s, 3H), 4.73 (d, J=3.1 Hz, 2H), 5.93 (bs, 1H), 6.39-6.49 (m, 2H), 7.13-7.22 (m, 3H), 7.34 (d, J=7.8 Hz, 1H), 7.63 (t, J=5.9 Hz, 1H), 8.59 (d, J=3.8 Hz, 1H); MS (ESI) m/z 342.7 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd](Cl)Cl.CC(=O)OCC.O.CN(C=O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:28]2[CH:27]=[N:26][C:25]([NH2:24])=[CH:30][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)nc2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
Stir for 5 min 4-methylene-piperidine-1-carboxylic acid tert-butyl ester (5.10 g) under nitrogen and add a 0.5 M THF solution of 9-borabicyclo[3.3.1]nonane (77.49 mL). Stir at 75° C. under nitrogen for 1 h. Cool and add 2-amino-5-bromopyridine (3.8 g), potassium carbonate (3.87 g), and 1,1′-biss(diphenylphosphino)ferrocene)palladium(II) chloride (538.10 mg) and a degassed mixture of DMF (47.83 mL) and water (4.78 mL). Stir at 60° C. during 4 h, then at RT over the weekend. Add water and EA. Separate and extract aqueous layer with EA. Combine the organic layers and dry over sodium sulfate and remove the solvent under vacuum. Purify by silica gel column chromatography, eluting with DCM/methanol (1%)/ammonia (0.1%) to DCM/methanol (3%)/ammonia (0.3%). Triturate the residue with EA to afford 1.85 g of the title compound. MS (ES+): m/z=292 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[O:15][CH:14]([CH3:16])[CH2:13][C:12]2=[C:17]([NH2:19])[CH:18]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:5])[NH:19][C:17]1[C:12]2[CH2:13][CH:14]([CH3:16])[O:15][C:11]=2[CH:10]=[C:9]([O:8][CH3:7])[CH:18]=1)[CH3:2]
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cc(OC)cc2c1CC(C)O2
Reaction time: 3 h

Procedure:
55.75 grams of ethylchlorocarbonate in 100 cc of anhydrous benzene are gradually added at 5° C. to a stirred solution of 81 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine and 46 cc of triethylamine in 700 cc of anhydrous benzene. At the end of the addition, the reaction mixture is slightly warmed and stirring is continued, at room temperature, for 3 hours. After this time the reaction mixture is refluxed for two hours, then cooled, washed with water, dried over Na2SO4 and concentrated to dryness yielding 95.81 grams (83.5 percent of theoretical) of the compound of the title B.p./0.4 mmHg 172° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[C:14]([CH2:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)([OH:16])=[O:15].N1CCCCC1>C(O)C>[C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=[C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([CH2:18][CH2:17][C:14]([OH:16])=[O:15])[CH:20]=3)[NH:24][C:23]2=[O:28])[NH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C(O)CCc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(CCC(=O)O)cc21
Yield: 65.7 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 102.6 mg 5-carboxyethyl-2-oxindole and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The crude solid was purified by chromatography a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 121 mg (66%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][C:13]=2Cl)[N:8]=[CH:7]1)[CH3:2]>CO.[Pt]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][CH:13]=2)[N:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cnc2nc(N3CCNCC3)nc(Cl)c21
Agent: [Pt]
Solvent: CO
Product: CCOC(=O)Cn1cnc2nc(N3CCNCC3)ncc21
Reaction time: 4 h

Procedure:
To a solution of 1.47 g of (6-chloro-2-piperazin-1-yl-purin-7-yl)-acetic acid ethyl ester, 5 in 100 mL of methanol, was added 400 mg of 10% Pt/C and 1.1 g MgO under N2, then the reaction was hydrogenated for 4 h. The catalyst and MgO were filtered and washed with methanol. Evaporation of the methanol in vacuo gave 6.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6](O)=[O:7].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]([Cl:16])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1ccc(F)cc1F
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1ccc(F)cc1F

Procedure:
To a solution of (E)-2,4-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,4-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,4-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: Br[C:2]1[C:11]([N:12]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:19][C:20]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]1([N:12]([CH3:13])[C:11]2[C:2]([CH:19]=[CH2:20])=[C:3]([CH:8]=[CH:9][CH:10]=2)[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cccc(N(C)C2CCCC2)c1Br
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: O
Product: C=Cc1c(C(=O)OC)cccc1N(C)C1CCCC1
Temperature: 100 °C

Procedure:
To a stirred solution of methyl 2-bromo-3-(cyclopentyl(methyl)amino)benzoate (1 equiv.) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then, Pd(PPh3)4 (0.1 equiv.) was added and argon purged for 10 min. and the reaction mixture heated at 100° C. for 2 h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the desired methyl 3-(cyclopentyl(methyl)amino)-2-vinylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:14][CH:13]=2)[N:10]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][C:5]1[C:6]2[CH2:27][NH:26][CH2:25][CH2:24][C:7]=2[N:8]=[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])=[CH:16][CH:17]=2)[N:10]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4F)n2)CNCC3)cc1
Yield: 53 %

Procedure:
tert-Butyl 4-(2-fluorobenzyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate was dissolved in DCM (5 mL). TFA, 10 eq, was added and the reaction was heated to reflux for 2 h. The mixture was neutralized with sat NaHCO3 and the phases were separated. The organic phase was dried with MgSO4 and the solvent was removed under reduced pressure to yield 4-(2-fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (186 mg, 53%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH:10]([F:12])[F:11])=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+]>CO>[F:12][CH:10]([F:11])[C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(C(F)F)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(F)F)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
5-Formyl-2-thiophenecarboxylic acid methyl ester (1.7 g) (synthesized in accordance with the method described in J. Heterocyclic Chem., 28, 17 (1991)) in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.6 g) in methylene chloride (20 ml). The mixture was stirred at room temperature for 2 hours, and then diethylaminosulfur trifluoride (DAST) (0.5 g) was further added. The resulting mixture was stirred at room temperature for 1 hour, and water (10 ml) and saturated aqueous sodium bicarbonate (10 ml) were added. The resulting mixture was allowed to stand overnight. The organic layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-2-thiophenecarboxylic acid methyl ester (0.81 g). 5-Difluoromethyl-2-thiophenecarboxylic acid methyl ester (2.58 g) synthesized in this manner was dissolved in methanol (50 ml), and 1N sodium hydroxide (30 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-2-thiophenecarboxylic acid (2.13 g) as crystals.