Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[N:9]([S:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:21])=[O:20])[CH2:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>C(O)C.[Pd]>[CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[C:12]([F:18])[CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[S:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCS(=O)(=O)N1Cc2c(F)cccc2C=C1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)CCS(=O)(=O)N1Cc2c(F)cccc2CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.5 %

Procedure:
Under a hydrogen atmosphere, 9 mg of methyl 3-[(3-benzyl-8-fluoroisoquinolin-2(1H)-yl)sulfonyl]propanoate and 9 mg of 10% Pd/C were dissolved in 1 mL of ethanol, followed by stirring at room temperature for 2 hours. After completion of the reaction, to the reaction liquid was added diethyl ether, followed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain 10 mg (yield 100%) of a title compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18]/[C:19](/[CH3:28])=[C:20](/[CH2:26][CH3:27])\[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:28])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:26][CH3:27])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCOC(=O)/C(CC)=C(/C)N
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 3-amino-2-ethylcrotonate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methyl-1-butenyl]ureido}-benzoate, m.p. 112°-115° C.,
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:16]2[CH2:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[CH2:17]2)=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2.CN([C:27]1[CH:32]=CC=CN=1)C.[C:33]1(C)C=CC=C[CH:34]=1>>[Cl:1][C:2]1[C:3]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:18](=[O:23])[CH2:17][CH2:33][CH3:34])=[CH:32][CH2:27]2)=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2
Reactant: CCC1(C)Cc2c(C)c(C)c(C3CC(=O)CC(=O)C3)c(Cl)c2C1
Reactant: CN(C)c1ccccn1
Reactant: Cc1ccccc1
Product: CCCC(=O)C1=CCC(c2c(C)c(C)c3c(c2Cl)CC(C)(CC)C3)CC1=O
Yield: 53 %

Procedure:
To a solution 7.12 g of the 5-(7-chloro-2-ethyl-2,4,5-trimethylindan-6-yl)-cyclohexane-1,3-dione in 70 ml of absolute toluene was added 15 ml of buryric anhydride. After refluxing for 4 hours, toluene and excess butyric anhydride were evaporated under reduced pressure to afford a residue. To the solution of the residue in 100 ml of toluene was added 0.56 g of dimethylaminopyridine and refluxed for 20 hours. The reaction mixture was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 4.64 g of the title compound as yellow solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:8]=2)[N:3]=1.C(OC([N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([NH2:43])[CH:41]=2)[C:36](=[O:44])[NH:35]1)=O)(C)(C)C.C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.C(Cl)Cl>[CH:18]1([C:16]2[CH:17]=[C:13]([NH:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:8]=4)[N:3]=[C:2]([NH:43][C:40]4[CH:41]=[C:42]5[C:37]([C:36](=[O:44])[NH:35][NH:34]5)=[CH:38][CH:39]=4)[N:11]=3)[NH:14][N:15]=2)[CH2:20][CH2:19]1
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(N3CCCCC3)ccc2n1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(N5CCCCC5)ccc4n3)ccc12
Temperature: 90 °C

Procedure:
To (2-Chloro-6-piperidin-1-yl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (80 mg, 0.217 mmol) in NMP (1 mL) was added 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (65 mg, 0.26 mmol) and heated to 90° C. for 12 hr in a sealed tube. Solution was poured into sat. NaHCO3, resulting in a brown solid. The dried solid was taken up in 5 ml of methylene chloride and treated with 5 mL of TFA for 6 hr. The reaction was evaporated and the title compound was isolated by preparative HPLC to give a yellow solid (47,5 mg). HNMR (500 MHz, dmso); δ11.45 (1H, bs), 10.45 (1H, bs), 8.0 (1H, s), 7.70 (1h, m), 7.6 (1H, m), 7.5 (1H, m), 7.4 (1H, s), 7.1 (1H, m), 6.25 (1H, bs), 3.3 (4H, bs), 2.80–2.55 (7H, m), 0.80 (2H, m), 0.40 (2H, m); HPLC tr=3.51 min (10% to 90% MeCN over 8 min, total time 12 min, 3×150 mm C18 column) FIA m/e 482.5 (M+H), 480.2 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12])#[N:2].[H][H]>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12])#[N:2]
Reactant: N#Cc1ccccc1/C=C\C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccccc1CCC(=O)O
Yield: 90.7 %

Procedure:
A slurry of (Z)-3-(2-cyanophenyl)acrylic acid (Example 323a, 4.75 g) in ethanol (50 mL) was added to 5% Palladium (0.292 g) in ethanol (50 mL) and hydrogenated under 2.0 bar hydrogen pressure for 2 h. The reaction mixture was filtered and the filtrate evaporated to dryness to afford the sub title compound as a solid (4.36 g).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][Mg]Br>C1COCC1>[OH:16][CH:15]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8])[CH3:17]
Reactant: C[Mg]Br
Reactant: O=Cc1cnccc1C(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(O)c1cnccc1C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzoyl-pyridine-3-carbaldehyde (114 mg, 0.54 mmol) in THF (3 mL) at −78° C. was added 3.0 M methylmagnesium bromide in THF (0.27 mL) and the reaction mixture was stirred for 15 min. The reaction mixture was then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by chromatography of silica gel with 5% methanol in dichloromethane to yield [3-(1-hydroxy-ethyl)-pyridin-4-yl]-phenyl-methanone as white crystals.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[C:46](C)=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:50]C1C=C(Cl)C=CC=1N>>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([N:27]2[C:32]3=[N:33][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[N:35][CH:36]=[C:31]3[CH2:30][N:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:50])=[CH:43][C:42]=3[Cl:48])[C:28]2=[O:49])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: Cc1cccc(Cl)c1N1Cc2cnc(S(C)(=O)=O)nc2N(c2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C1=O
Product: CC(C)(C)[Si](OCCc1cccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(S(C)(=O)=O)nc32)c1)(c1ccccc1)c1ccccc1

Procedure:
The 1-[3-(tert-butyldiphenylsilyloxyethyl)phenyl]-3-(2,4-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one was prepared in a manner analogous to that for 1-[3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenyl]-3-(2-chloro-6-methylphenyl)-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one of Example 53(d) using 2,4-dichloroaniline in place of 2-chloro-6-methylaniline.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH3:34])[C:31](=[O:33])[CH3:32])[N:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[CH3:35]>>[CH3:34][N:30]([CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)=[C:11]([CH3:35])[CH:12]=1)=[N:18][CH:19]=[N:20]2)[C:31](=[O:33])[CH3:32]
Reactant: Cc1cc(CCl)no1
Reactant: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4cc(C)on4)c(C)c3)c12
Yield: 14 %

Procedure:
The procedure described in Example 3 was repeated using 3-(chloromethyl)-5-methylisoxazole and N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide (obtained as described in Example 75, preparation of starting materials) to give the title compound as a white solid in 14% yield; NMR spectrum (DMSO-d6 373K) 1.95 (s, 3H), 2.23 (s, 3H), 2.43 (s, 3H), 3.57 (s, 3H), 3.88 (t, 2H), 4.47 (m, 2H), 5.15 (s, 2H), 6.29 (s, 1H), 7.05 (d, 1H), 7.15 (d, 1H), 7.34 (d, 1H), 7.48 (d, 1H), 7.54 (dd, 1H), 7.69 (t, 1H), 8.42 (s, 1H), 9.64 (s, 1H); Mass spectrum MH+ 462.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[Cl-:20].[Ca+2].[Cl-]>C(#N)C.[Cl-].C[N+](C)(C)C>[Cl:20][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4]
Reactant: [Cl-]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)O
Agent: C[N+](C)(C)C
Agent: [Ca+2]
Solvent: CC#N
Product: CCCCCCCCCCCCCCC(Cl)C(=O)O
Yield: 92.2 %

Procedure:
To 2-bromohexadecanoic acid (1 g), after having been dissolved in acetonitrile (50 ml), were added calcium chloride (5 g) and tetramethylammonium chloride (1 g), and the mixture was heated under reflux for 6 hours. The reaction mixture was filtered, concentrated and distributed into chloroform and water, and the chloroform layer was dried over anhydrous sodium sulfate and concentrated to give 2-chlorohexadecanoic acid (0.80 g). 2-Chlorohexadecanoic acid (893 mg), para-nitrophenol (428 mg) and N,N'-dicyclohexylcarbodiimide (634 mg) were dissolved in N,N-dimethylformamide (DMF), and the mixture was stirred for 12 hours. Precipitates were removed by filtration, and DMF was removed by distillation to give the active ester of 2-chlorohexadecanoic acid. To the active ester, which was dissolved in DMF (500 mg), were added again 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (465 mg) and triethylamine (1.2 ml), and the mixture was stirred for 12 hours. The reaction mixture was concentrated, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK135 in the yield of 262 mg.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[Cl:24][C:25]1[N:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:31]([C:28]2[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:19][CH2:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
Diisopropylethylamine (1.34 ml, 8.14 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.5 g, 2.70 mmol) in DCM (20 ml) at room temperature. To this mixture was added 6-chloro-pyridine-3-sulfonyl chloride (0.57 g, 2.70 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.64 g, 65% yield) as a white solid. δH (500 MHz, DMSO) 8.76 (d, J=2.20 Hz, 1 H) 8.19 (dd, J=8.44, 2.57 Hz, 1 H) 7.82 (d, J=8.44 Hz, 1 H) 6.89 (d, J=7.70 Hz, 1 H) 3.48 (d, J=11.92 Hz, 2 H) 3.31 (br. s., 1 H) 2.59-2.68 (m, 2 H) 1.76 (d, J=10.27 Hz, 2 H) 1.30-1.46 (m, 11 H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7](=[O:17])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7](=[O:17])[CH:6]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CCC(=O)c2cc([N+](=O)[O-])ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CN(C(C)=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To the material of Step 2 (4.8 g, 0.0205 mol) in THF (25 mL) at −78° C., was added the lithium bis(trimethylsilyl)amide (20.5 mL of a 1M in THF solution). The diethyl oxalate (3 g, d=1.076 g/mL, 2.8 mL, 0.0205 mol) was then added and the reaction mixture was allowed to warm to room temperature and stir overnight. The slurry was then filtered to give an orange solid. 6.1 g (MW=334.28 g/mol, 90% yield). LC/MS m/z=335 (m+1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][N+:11]([O-])=[C:10]([CH3:15])[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:15][O:20][C:17](=[O:19])[CH3:18])[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCOc1cc[n+]([O-])c(C)c1C
Product: CCCCCCOc1ccnc(COC(C)=O)c1C
Yield: 66.3 %

Procedure:
To 32.6 g (0.1 mol, 1.0 eq.) of 4-hexyloxy-2,3-dimethylpyridine-N-oxide, 40.8 g (0.4 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 5 hours at 87 to 93° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 17.6 g of 4-hexyloxy-2-acetoxymethyl-3-methylpyridine as an oily matter (yield 74.3%).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[C:21]2[CH:28]=O.[CH3:32][N:33]1[CH:37]=[C:36]([C:38](=[O:41])[CH2:39][CH3:40])[CH:35]=[C:34]1[CH:42]=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:28][C:21]3[C:20]4[C:25](=[CH:26][CH:27]=[C:18]([C:17]([F:31])([F:30])[F:16])[CH:19]=4)[N:24]=[CH:23][CH:22]=3)[C:42]([C:34]3[N:33]([CH3:32])[CH:37]=[C:36]([C:38](=[O:41])[CH2:39][CH3:40])[CH:35]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CCC(=O)c1cc(C=O)n(C)c1
Reactant: O=Cc1ccnc2ccc(C(F)(F)F)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CCC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2ccnc3ccc(C(F)(F)F)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-trifluoromethylquinoline-4-carbaldehyde, followed by 1-methyl-4-propionyl-1H-pyrrole-2-carbaldehyde. 567(M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:8]=1[C:9]#[N:10].C1CCCCC=1>CCO.[Pd]>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:8]=1[C:9]#[N:10]
Reactant: COCCCNc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COCCCNc1cccc(N)c1C#N
Temperature: 100 °C
Yield: 84.5 %

Procedure:
To a solution of 2-(3-methoxypropylamino)-6-nitrobenzonitrile (Example 258c) (0.58 g, 2.48 mmol) in EtOH (20 mL) was added cyclohexene (1.26 mL, 12.4 mmol). Then 10% Pd/C (1.32 g) was added, and the reaction mixture was refluxed at 100° C. for 20 minutes, cooled to room temperature, filtered trough Celite which was washed with EtOH (3×20 mL), and evaporated to give 2-amino-6-(3-methoxypropylamino)benzonitrile (0.43 g, 84%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 1.71-1.77 (m, 2H), 3.10 (q, J=6.8 Hz, J=6.8 Hz, 2H), 3.22 (s, 3H), 3.37 (t, J=3.2 Hz, 2H), 5.55 (t, J=5.2 Hz, NH), 5.63 (s, NH2), 5.79 (d, J=7.6 Hz, 1H), 5.93 (d, J=8.0 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H). MS 206 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[N:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:24])=O>>[CH3:1][C:2]1[C:3]([Cl:24])=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(Nc2nc(-c3ccccc3)cs2)nc(O)c1C
Product: Cc1nc(Nc2nc(-c3ccccc3)cs2)nc(Cl)c1C
Yield: 50 %

Procedure:
The same procedures as in Step 3 of Example 22 were repeated using 5,6-dimethyl-2-(4-phenylthiazol-2-yl)amino-4-hydroxypyrimidine (5.6 g, 18.77 mmol) and phosphorus oxychloride(7 ml) to afford 3.0 g of the titled compound. (Yield: 50%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[C:17]([F:24])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:25])=[CH:16][C:17]=1[F:24])[CH3:23]
Reactant: CCOc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(C(=O)C2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
To a solution of 4-(4-ethoxy-3-fluoro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.95 g, 2.70 mmol) in 10 mL of DCM, was added 2 mL of TFA. The reaction mixture was stirred at ambient temperature for 2.5 hours, and then solvent was removed by reduced pressure to yield the title product (0.65 g, 2.46 mmol). MS (ESI) m/z 252.0 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.43 min.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].Br[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]Br.[OH-].[Na+]>CN(C=O)C>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[C:2]([N:1]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:18][CH:17]=[CH:16][C:15]=1[S:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Sc1ccc([N+](=O)[O-])cc1
Reactant: BrCCNCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)c1c(Sc2ccc([N+](=O)[O-])cc2)cccc1N1CCNCC1
Temperature: 25 °C
Yield: 82 %

Procedure:
Compound 25 (1.0 equiv.) was dissolved in DMF (40 mL) at room temperature. To this mixture bis(2-bromoethyl)amine (1.0 equiv.) was added, following the addition of NaOH (2.0 equiv.). After being stirred for 2 Hours at room temperature, the reaction mixture was poured into ice-cold water (200 mL) to get crude product. The crude solid was filtered and washed several times with water and purified by silica gel column chromatography (1:3 v/v ethyl acetate/petroleum ether) to provide a yellow solid (380.9 mg, 82% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([CH2:20][C:21]1[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Reactant: Cc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cn2ccc3cccc(OCc4ccccc4)c32)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 7-benzyloxy-1H-indole (0.3 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (55% 70 mg) under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture was added 4-methylbenzyl chloride (0.19 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 7-benzyloxy-1-(4-methylbenzyl)-1H-indole (0.43 g). This material was dissolved in tetrahydrofuran (6 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (86 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]([Br:18])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncnc2c1ncn2Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Nc1ncnc2c1nc(Br)n2Cc1ccccc1

Procedure:
To a stirred solution of 9-benzylpurine (6) (15.0 g, 66.5 mmol) in chloroform (750 mL) was added N-bromosuccinimide (59.26 p. 332.9 mmol) and the reaction mixture vas stirred under an atmosphere of nitrogen at reflux temperature for 3 h. The reaction mixture was then transferred to a separatory funnel and washed with saturated aqueous sodium sulfite (2×250 mL) followed by brine solution (2×250 mL). The chloroform fraction was dried over anhydrous sodium sulfate and concentrated to give a reddish oil, which was purified by flash chromatography on silica gel using EtOAc/hexane (4:6) for elution. Yield 9.72 g. (48%). Mp 199-201° C. 1H NMR (CDCl3) δ 5.39 (s, 2H, benzylic CH2), 7.29-7.33 (m, 5H, Ar—H), 8.29 (s, 1H, purine C2—H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1.[CH2:19]([S:21]SCC)[CH3:20].Cl>C1COCC1>[CH2:19]([S:21][C:15]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[C:8]([C:7]([F:6])([F:17])[F:18])[CH:16]=1)[CH3:20]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: CCSSCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCSc1cc(C(F)(F)F)ncc1C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
7.1 ml of n-butyl lithium (1.6 M hexane solution) was added dropwise to a mixture of 1.62 g of 2,2,6,6-tetrahydropiperidine and 15 ml of THF at −78° C., and the mixture was heated to 0° C., then stirred at 0° C. for 10 minutes. 7 ml of a THF solution of 1.0 g of 6-trifluoromethylnicotinic acid was added to the reaction mixture at −78° C., and the mixture was stirred at −78° C. for 1 hour. Next, 1.42 ml of diethyl disulfide was added to the reaction mixture at −78° C., and heated to room temperature, then stirred at room temperature for 30 minutes. 10 ml of 1 N hydrochloric acid was poured to the reaction mixture, and the reaction mixture was separated into the organic layer and the aqueous layer. 1 N hydrochloric acid was added to the aqueous layer, and the precipitated solid was filtered. The resulting solid was washed with 1 N hydrochloric acid and n-hexane to obtain 0.52 g of 4-ethylsulfanyl-6-trifluoromethylnicotinic acid. The separated organic layer was allowed to stand overnight, and the precipitated solid was filtered, then washed with n-hexane to further obtain 0.68 g of 4-ethylsulfanyl-6-trifluoromethylnicotinic acid. 4-Ethylsulfanyl-6-trifluoromethylnicotinic acid