Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.N#N.C(N(CC)CC)C.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.[Cu]I>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:32]#[C:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccccc1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(C#Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.4 %

Procedure:
A solution of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (50 mg, 0.159 mmol) in N,N-dimethylformamide (6 mL) and evacuated and charged with N2 three times, then treated with triethylamine (0.044 mL, 0.318 mmol), phenylacetylene (0.175 mL, 1.59 mmol), and copper (I) iodide (3.0 mg, 0.0159 mmol). The mixture re-evacuated and charged with N2 twice more, then charged with tetrakis(triphenylphoshine)palladium (0) (20.2 mg, 0.0175 mmol) and evacuated and charged with N2 a final two times. The reaction mixture was stirred at rt for 16 h, then concentrated in vacuo, dissolved in MeOH/CH3CN (1:1)(4 mL) and was filtered through a 0.45 fritted μM autovial prior to purification via mass directed preparative HPLC that afforded 13 mg of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 1.87-1.99 (m, 1H), 2.01-2.15 (m, 1H), 2.32-2.47 (m, 4H), 3.87-3.99 (m, 1H), 6.66 (brs, 2H), 7.08 (brs, 1H), 7.40-7.51 (m, 4H), 7.59-7.67 (m, 2H); MS (ES+): m/z 289.13 [MH+].
Reaction SMILES: [F:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13].[I:19]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]1[C:3]([I:19])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13]
Reactant: ClI
Reactant: CN1C(=O)C(C)(C)c2ccc([Si](C)(C)C)c(F)c21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)C(C)(C)c2ccc(I)c(F)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-fluoro-1,3,3-trimethyl-6-(trimethylsilyl)indolin-2-one (9.9 g, 37.3 mmol) in dichloromethane (500 ml) at 0° C. was added iodine monochloride (37.3 ml, 37.3 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as off-white crystals (9.82 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][OH:17])[N:3]=1
Reactant: NCCCCCO
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: OCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[5-(hydroxy)pentylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 5-hydroxypentylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Na].[CH3:2][C:3]1[N:7]2[C:8](=[S:12])[NH:9][N:10]=[CH:11][C:6]2=[CH:5][N:4]=1.[CH3:13]I>CO>[CH3:2][C:3]1[N:7]2[C:8]([S:12][CH3:13])=[N:9][N:10]=[CH:11][C:6]2=[CH:5][N:4]=1
Reactant: Cc1ncc2cn[nH]c(=S)n12
Reactant: CI
Agent: [Na]
Solvent: CO
Product: CSc1nncc2cnc(C)n12
Temperature: 25 °C

Procedure:
To a solution of 0.23 gm. of sodium in 10 ml. of methanol is added 1.66 gm. of 6-methyl-imidazo[1,5-d]-as-triazine-4(3H)-thione with warming to produce a solution. The mixture is cooled to room temperature and 0.75 ml. of methyl iodide is added. Cooling overnight gives a solid which is recrystallized from a mixture of 20 ml. of acetone and 6 ml. of ethanol and treated with charcoal. This solid is recrystallized from 20 ml. of ethanol, giving the desired product, m.p. 182.5°-184° C.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:8]1([N:14]2[C:22](=[O:23])[C:21]3[C@@H:20]4[C:24]([CH3:26])([CH3:25])[C@@:17]([CH3:27])([CH2:18][CH2:19]4)[C:16]=3[NH:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[CH:3]1([CH2:2][N:15]2[C:16]3[C@:17]4([CH3:27])[C:24]([CH3:26])([CH3:25])[C@@H:20]([CH2:19][CH2:18]4)[C:21]=3[C:22](=[O:23])[N:14]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Reactant: ICC1CCCC1
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2)n1CC1CCCC1
Temperature: 100 °C
Yield: 3.8 %

Procedure:
A mixture of (iodomethyl)cyclopentane (prepared according to W. L. Corbett US 20040067939; 352 mg, 1.68 mmol) and (4R,7S)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 90 mg, 0.34 mmol) was heated in an oil-bath at 100° C. for 6 days. The reaction mixture was allowed to cool and it was then diluted with dichloromethane (200 mL) and washed with water (5×30 mL), aqueous sodium thiosulfate solution (2×30 mL) and brine (30 mL). The organic extract was dried (magnesium sulfate), filtered, evaporated, and the residue purified on an Isco 40 g column, eluting with 30-100% ethyl acetate/hexanes and then held under high vacuum to give (4R,7S)-1-(cyclopentyl)methyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (4.5 mg, 4%) as a semi-solid. ES(+)-MS (M+H) 351.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]2[C:11]([NH:16][C:17]3[CH:18]=[C:19]([NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[N:12][N:13]([CH3:15])[CH:14]=2)[CH:5]=1)=O.[N:37]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.CS(C)=O>CC(O)C>[CH3:23][C:22]1[CH:21]=[CH:20][C:19]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:18][C:17]=1[NH:16][C:11]1[C:10]([C:6]2[CH:5]=[C:4]([NH:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:9]=[CH:8][N:7]=2)=[CH:14][N:13]([CH3:15])[N:12]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nn(C)cc1-c1cc(S(C)=O)ncn1
Reactant: NCCN1CCOCC1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nn(C)cc1-c1cc(NCCN2CCOCC2)ncn1
Temperature: 80 °C

Procedure:
The mixture of N-{3-[4-(6-Methanesulfinyl-pyrimidin-4-yl)-1-methyl-1H-pyrazol-3-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (30 mg, 0.058 mmol) and 2-Morpholin-4-yl-ethylamine (100 uL) in 2-propanol is heated to 80° C. for 3 hours. The reaction mixture is cooled to room temperature and condensed. The crude product is then treated with 1 mL DMSO and purified by LC/MS to afford N-(4-Methyl-3-{1-methyl-4-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-1H-pyrazol-3-ylamino}-phenyl)-3-trifluoromethyl-benzamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][N:26]=[N+:27]=[N-:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Yield: 107.4 %

Procedure:
To a solution of (2-hydroxyethyl)carbamic acid t-butyl ester (1.5 g, 6.2 mmol) in tetrahydrofuran (75 ml) were added diphenylphosphoryl azide (3.0 ml, 13.9 mmol), triphenylphosphine (3.7 g, 14.1 mmol), and a 40% solution of diethylazodicarboxylate in toluene (5.1 g, 13.9 mmol) in an ice bath under an atmosphere of nitrogen, and then the mixture was stirred for 4 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:1) as the eluant to afford (2-azidoethyl)carbamic acid t-butyl ester (1.24 g, yield 72%) as a colorless and transparent syrup.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:25])(=[S:24])[CH3:23]>C(#N)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:25]=[C:22]([CH3:23])[S:24][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(N)=S
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC#N
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (0.437 g, 1.18 mmol) (Example 26, Step 2) in acetonitrile (10 mL) in a 25 mL round bottom flask was added thioacetamide (0.088 g, 1.18 mmol) and the solution heated to reflux (2 hours) until all solid dissolved. The reaction was cooled to room temperature. The acetonitrile was removed in vacuo and the resulting product precipitated from methanol by the addition of water yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-methylthiazole (0.226 g, 55%, ca. 85% purity by 1H NMR): mp 229°-233° C. 1HNMR (CDCl3) 300 mHz δ7.98 (d, J=8.11 Hz, 2H ), 7.66-7.61 (m, 2H), 7.52 (d, J=8.48 Hz, 2H), 7.13 (t, J=8.48 Hz, 2H), 3.31 (s, 1H), 3.10 (s, 3H). MS (EI-thermospray): m/z 348 (M+). HRMS Δ=-2.3 mmu.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH:43]=O)[CH:34]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:43][C:35]2[CH:34]=[N:33][C:42]3[C:37]([CH:36]=2)=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CN(Cc1cnc2ccccc2c1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
Sodium triacetoxyborohydride (1.29 g, 6.09 mmol) is added to a stirred solution of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester (1.09 g, 4.29 mmol), quinoline-3-carboxaldehyde (0.68 g, 4.3 mmol), acetic acid (0.25 ml, 4.37 mmol), and 1,2-dichloroethane (15 ml). The reaction is stirred for 18 h at room temperature under nitrogen. The reaction is poured into 2N NaOH (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 15% acetone/hexanes to yield (1.02 g, 60%) of 4-{isobutyl-[(quinolin-3-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=398.2 (M+1); 1H NMR (CDCl3): δ=8.93 (1H, d), 8.09 (1H, d), 8.02 (1H, s), 7.79 (1H, d), 7.70-7.66 (1H, m), 7.55-7.51 (1H, m), 4.16 (2H, br s), 3.79 (2H, s), 2.63-2.57 (3H, m), 2.27 (2H, d), 1.77-1.65 (3H, m), 1.52-1.48 (2H, m), 1.44 (9H, s), 0.85 (6H, d).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.C1(C)C=CC=CC=1.[CH3:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1>C(O)(=O)C>[CH3:7][C:6]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH3:16])=[CH:20][CH:21]=2)[C:2]([CH3:4])=[CH:1][CH:5]=1
Reactant: CCOc1ccc(N)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOc1ccc(-n2c(C)ccc2C)cc1
Temperature: 25 °C

Procedure:
To a solution of acetonyl acetone (11.7 mL, 100 mmol) and toluene (750 mL) was added p-phenetidine (12.9 mL, 100 mmol) and glacial acetic acid (1 mL). The mixture was heated at reflux overnight. After cooling to rt, the mixture was concentrated in vacuo and purified by column chromatography on silica gel (15% EtOAc/hexanes) to give 2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.13-7.10 (m, 2H), 6.97-6.94 (m, 2H), 5.88 (br s, 2H), 4.08 (q, 2H), 2.02 (s, 6H), 1.46 (t, 3H); MS (ESI) 216 (M+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([C:37]2[CH:45]=[CH:44][C:43]([C:46]([O:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63](=[O:66])[CH:64]=[CH2:65])=[CH:51][CH:50]=3)=[O:47])=[CH:42][C:38]=2[C:39]([OH:41])=[O:40])=[O:36])=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18].[N+:67]([C:70]1[CH:75]=[CH:74][C:73]([N:76]=[N:77][C:78]2[CH:94]=[CH:93][C:81]([C:82]([O:84][C:85]3[CH:90]=[CH:89][C:88]([CH2:91]O)=[CH:87][CH:86]=3)=[O:83])=[CH:80][CH:79]=2)=[CH:72][CH:71]=1)([O-:69])=[O:68].O>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]([C:37]2[CH:45]=[CH:44][C:43]([C:46]([O:48][C:49]3[CH:50]=[CH:51][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63](=[O:66])[CH:64]=[CH2:65])=[CH:53][CH:54]=3)=[O:47])=[CH:42][C:38]=2[C:39]([O:41][CH2:91][C:88]2[CH:89]=[CH:90][C:85]([O:84][C:82](=[O:83])[C:81]3[CH:80]=[CH:79][C:78]([N:77]=[N:76][C:73]4[CH:74]=[CH:75][C:70]([N+:67]([O-:69])=[O:68])=[CH:71][CH:72]=4)=[CH:94][CH:93]=3)=[CH:86][CH:87]=2)=[O:40])=[O:36])=[CH:32][CH:33]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: O=C(Oc1ccc(CO)cc1)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCc3ccc(OC(=O)c4ccc(N=Nc5ccc([N+](=O)[O-])cc5)cc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
0.2 g of N,N'-dicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 0.6 g of 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoic acid, 0.4 g of (4-[4-(4-nitrophenylazo)benzoyloxy]phenyl)methanol and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction as mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases are combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from acetone of the fractions which are pure according to thin-layer chromatography gives 0.4 g of (4-[4-(4-nitrophenylazo)benzoyloxy]phenyl)methyl 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42](O)=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42]([NH:1][C:2]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CCCOc1cc(C)ccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1
Product: C/C(=C\C(=O)Nc1ccc(C)cc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1

Procedure:
406 mg of compound 50 was obtained in a similar manner to those described in the Examples 1 and 2 using 712 mg of ethyl 4-(2-amino-5-methylphenoxy)butyrate and 551 mg of 3-(1-benzhydrylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:20]3[CH:30]=[C:24]4[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]4[C:22](=[O:31])[N:21]=3)=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)cc1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)cc3)c(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Na].CO[C:4](=[O:9])[C:5]([O:7][CH3:8])=[O:6].[CH3:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12]>CCCCCC>[CH3:8][O:7][C:5](=[O:6])[C:4]([CH2:10][C:11](=[O:12])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)C(=O)OC
Agent: [Na]
Solvent: CCCCCC
Product: COC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
54 g (1 mol) of sodium are suspended in 300 g of n-hexane. 118 g (1 mol) of oxalic acid dimethyl ester, warmed to 60° C., are added dropwise at 0°-5° C. in the course of 1 hour. 100 g of pinacolin are then added rapidly at the same temperature. The mixture is stirred at room temperature for 15 minutes and 222 g of a n-hexane/methanol mixture are then distilled off, at boiling point760 : 50° C., over a 50 cm high packed column in the course of 6 hours. 234.5 g of aqueous sulphuric acid (20.9% strength by weight) are stirred into the bottom product. Separation of the phases and subsequent distillation of the organic phase give, at boiling point8 : 105° C., 159 g of pivaloylpyruvic acid methyl ester (85.0% of the theoretical yield) with a purity of 99.4% (by analysis by gas chromatography).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]=1)[CH3:4].[CH3:34]I.O>CN(C=O)C>[CH2:3]([N:5]([CH3:34])[C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:16][CH:17]=2)[C:9]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]=1)[CH3:4]
Reactant: CCNc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C)c1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 82 %

Procedure:
A mixture of sodium hydride (60% dispersion in mineral oil, 0.13 g) in DMF (5 ml) was stirred under ice-cooling for 5 min. and methyl 2-ethylamino-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.95 g) was added to the mixture, followed by stirring for 10 min. To the mixture was added methyl iodide (0.2 ml) and the mixture was stirred for 20 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give crude crystals, which were recrystallized from ethyl acetate hexane to afford colorless needles (0.88 g, 82%), m.p. 66–69° C.
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]1[C:12](=[O:13])[NH:11][CH2:10][CH2:9][N:8]1[C:14](=[O:35])[CH2:15][C@H:16]([NH:27]C(=O)OC(C)(C)C)[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])([CH3:4])([CH3:3])[CH3:2].[ClH:36].C(OCC)C>CO>[ClH:36].[NH2:27][C@H:16]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])[CH2:15][C:14]([N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C@H:7]1[CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:35]
Reactant: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
97 mg of tert-butyl (R)-4-[(R)-2-(tert-butoxymethyl)-3-oxopiperazin-1-yl]-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate prepared in Step 8 was dissolved in 3 mL of methanol, followed by addition of 2 mL of 2N-hydrochloric acid/diethyl ether and stirring at room temperature for 3 hours. The reaction mixture was concentrated and dried under reduced pressure to afford 64 mg of the title compound as a foamy solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(OCC)(=O)C.[OH-].[K+]>O>[F:1][C:2]1[CH:22]=[C:21]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc2c(c1)C(c1ccc(C(F)(F)F)cc1)=NCC2
Temperature: 165 °C
Reaction time: 0.25 h

Procedure:
A suspension of N-(4-fluorophenethyl)-4-(trifluoromethyl)benzamide (5.3 g, 17.1 mmol) and phosphoric pentoxide (1.2 g, 8.6 mmol) in polyphosphoric acid (40 g) was heated at 165° C. for 4 h and The reaction was cooled to RT and ice was added followed by ethyl acetate (100 mL), KOH (3N, 25 mL), and water (75 mL). The mixture was stirred for 15 min and the organic layer was separated. The aqueous layer was neutralized with KOH (3N) till pH˜7.0 was achieved and extracted with ethyl acetate (250 mL). The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to provide 7-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline. MS (ESI pos. ion) m/z: 294 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 2-(Tetrahydro-2H-pyran-2-yl)ethyl methanesulfonate (142 mg) was added and the reaction was continued for 16 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give crude material (540 mg). The material was purified by normal phase chromatography (ISCO) using 0-20% methanol/EtOAc as eluent to give the title compound as a white solid (88 mg).