Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([CH2:1][CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([O-:15])=[O:14]
Reactant: C=CCCCCCCCCCC
Reactant: O=[N+]([O-])O
Product: CCCCCCCCCC=CC[N+](=O)[O-]
Temperature: 100 °C

Procedure:
1-Dodecene (222 mL, 1.0 mole) and concentrated nitric acid (96 mL, 1.5 moles) were mixed together at room temperature. The solution was heated to 100° C. for 4 hours with rapid stirring then cooled to room temperature. The organic layer separated and washed with a saturated sodium chloride solution (3×75 mL). After drying over magnesium sulfate and filtering, the orange oil was vacuum distilled (0.5 Torr, 36° C.) which removed unreacted 1-dodecene. The remaining orange/red oil is a mixture containing 1-nitro-2-dodecene and 1-nitro-2-dodecanol. This oil was further reacted with methanesulfonyl chloride and triethylamine to dehydrate the alcohol and produce more 1-nitro-2-dodecene. After this dehydration step, the structure of 1-nitro-2-dodecene was confirmed by IR and GC analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>O1CCOCC1.O>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH:13]2[C:17]([OH:19])=[O:18])(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2C(=O)O)cc1
Reaction time: 1 h

Procedure:
To a solution of (+)4-benzyloxycarbonyl-2-piperazinecarboxylic acid (1.90 grams, 7.2 mmol) in dioxane-water (10 ml, ca. 1:1) is added 1N sodium hydroxide solution (15 ml, 15 mmol) followed by 4-methoxybenzenesulfonyl chloride. The solution is stirred for 1 hour, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The combined extracts are dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 2:1 ethyl acetate-hexanes with 1% acetic acid) to provide (+)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](O)=O)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:60][N:61]1[C:69]([CH2:70][CH:71]2CCN[CH2:73][CH2:72]2)=[N:68][C:67]2[C:62]1=[N:63][C:64]([N:83]1[C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][C:86]=3[N:85]=[C:84]1[CH3:92])=[N:65][C:66]=2[N:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1>>[CH3:60][N:61]1[C:69]([CH2:70][CH:71]2[CH2:11][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:73][CH2:72]2)=[N:68][C:67]2[C:62]1=[N:63][C:64]([N:83]1[C:87]3[CH:88]=[CH:89][CH:90]=[CH:91][C:86]=3[N:85]=[C:84]1[CH3:92])=[N:65][C:66]=2[N:77]1[CH2:78][CH2:79][O:80][CH2:81][CH2:82]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of N-(tert-Butoxycarbonyl)-L-alanine (80.0 mg, 0.423 mmol) in N,N-Dimethylformamide (5.0 mL, 0.064 mol) was added HATU (0.154 g, 0.404 mmol), 1-hydroxybenzotriazole (HOBt, 0.00839 g, 0.0621 mmol) and triethylamine (0.10 mL, 0.72 mmol). The resulting yellow solution was stirred at room temperature for 5 minutes before the addition of 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine 520 (0.150 g, 0.310 mmol;). The reaction was stirred at room temperature for 2 hours. The reaction mixture was partitioned between brine and EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH in DCM) to give tert-butyl 4-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidine-1-carboxylate (0.15 g, 78%). LCMS m/z: 618.3 (MH+).
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][C:21]4[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=4[C:23]([NH:25][CH2:26][C:27]#[CH:28])=[O:24])=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[N:7][CH:8]=1)C.[CH2:33](C1C=CN=C(C)C=1)C.ClC1C=C2C(C(C(O)CC3C=CC(CC)=CN=3)=NN2)=CC=1.C1(N)CC1>>[CH:26]1([NH:25][C:23](=[O:24])[C:22]2[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=2[NH:20][C:16]2[CH:15]=[C:14]3[C:19]([C:11](/[CH:10]=[CH:9]/[C:6]4[CH:5]=[C:4]([CH3:33])[CH:3]=[CH:8][N:7]=4)=[N:12][NH:13]3)=[CH:18][CH:17]=2)[CH2:27][CH2:28]1
Reactant: CCc1ccnc(C)c1
Reactant: C#CCNC(=O)c1ccccc1Nc1ccc2c(C=Cc3ccc(CC)cn3)n[nH]c2c1
Agent: CCc1ccc(CC(O)c2n[nH]c3cc(Cl)ccc23)nc1
Agent: NC1CC1
Product: Cc1ccnc(/C=C/c2n[nH]c3cc(Nc4ccccc4C(=O)NC4CC4)ccc23)c1

Procedure:
The title compound was prepared analogously to 2-{3-[2-(5-Ethyl-pyridin-2-yl)-vinyl]-1H-indazol-6-ylamino}-N-prop-2-ynyl-benzamide described above, substituting 2,4-dimethyl-pyridine for 4-ethyl-2-methyl-pyridine in the step where 1-(6-Chloro-1H-indazol-3-yl)-2-(5-ethyl-pyridin-2-yl)-ethanol was prepared, and substituting cyclopropyl amine in place of propargyl amine in the final step of the sequence. 1H NMR (DMSO-d6): δ 9.85 (1H, s), 8.56 (2H, m), 8.20 (3H, m), 7.53 (5H, m), 7.35 (1H, s), 7.2 (1H, d, J=6.5 Hz), 7.0 (1H, s), 2.83 (1H, m), 0.70 (2H, m), 0.56 (2H, m). ESIMS (M+H+): 410.3.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][NH:7][CH:8]=1.C([O:17][C:18](=[O:23])[C:19](Br)([CH3:21])[CH3:20])C>O1CCCC1>[CH3:20][C:19]([CH3:21])([N:7]1[CH:8]=[C:4]([CH3:3])[C:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6]1)[C:18]([OH:23])=[O:17]
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cn(C(C)(C)C(=O)O)nc1-c1ccccc1

Procedure:
Sodium hydride (25.0 g. of 57% dispersion in oil, 0.6 mole) was added to a stirred solution of 4-methyl-3-phenylpyrazole (79.0 g., 0.5 mole) in tetrahydrofuran. Ethyl-2-bromoisobutyrate (136.0 g., 0.7 mole) was added and the solution was refluxed for 4 hours. The solvent was removed by evaporation and the residual ester mixture was hydrolyzed by refluxing with methanolic sodium hydroxide solution (40 g. sodium hydroxide in 600 ml. of 30% methanol-water). After cooling, the alkaline reaction solution was extracted with ether and the aqueous phase was acidified with concentrated hydrochloric acid. The solution was extracted with chloroform, and the chloroform layer was evaporated to give a crude acid mixture in which α,α,4-trimethyl-3-phenylpyrazole-1-acetic acid was the major isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])=[O:9])=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)(=[O:23])=[O:22])[CH:3]=1.[N:35]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:42][CH2:41][CH2:40][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:15])=[O:9])=[C:4]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:25]=2)(=[O:22])=[O:23])[CH:3]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cccc(CS(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCN1CCCC1)c1cccc(CS(=O)c2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 18.7 %

Procedure:
Following General Procedure R, the title compound (17 mg, 19%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid (76 mg, 0.14 mmol), 2-(pyrrolidin-1-yl)ethanamine (26 μl, 0.21 mmol), EDC (53 mg, 0.28 mmol) and DMAP (cat.) in DMF (2 ml).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11]C=[CH:9][C:8]=2OC)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].NC1N(C2CC[S:27]CC2)N=CC=1C#N>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][S:27][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16]
Reactant: COc1ccccc1-n1ncc(C(N)=O)c1N
Reactant: N#Cc1cnn(C2CCSCC2)c1N
Product: NC(=O)c1cnn(C2CCSCC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide but substituting 5-amino-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole-4-carbonitrile provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.67 (s, 1H), 4.09-3.97 (m, 1H), 2.89-2.82 (m, 2H), 2.72-2.68 (m, 2H), 2.15-2.10 (m, 4H). MS: (M+H m/z 227.1).
Reaction SMILES: [CH2:1]([S:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Mg].II.[C:22](=[O:24])=[O:23].Cl>O1CCCC1.O>[CH2:1]([S:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]([OH:24])=[O:23])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C=O
Reactant: CCCCCCCCCCSc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCSc1ccc(C(=O)O)cc1
Temperature: -70 °C

Procedure:
A solution of 4-(decylthio)bromobenzene (32.9 g) in dry tetrahydrofuran (100 ml) was added over about 30 minutes to a stirred, refluxing suspension of magnesium turnings (2.64 g) and one crystal of iodine in dry tetrahydrofuran (100 ml). The mixture was then stirred at reflux for 2 hours after which it was cooled to -70° C. Carbon dioxide was passed through the stirred solution at -70° C. for about 2 hours. The solution was warmed to room temperature and was then poured into a mixture of ice and water (1.251). Hydrochloric acid was added to bring the pH to 1, the precipitate was collected and washed with water, dried and then crystallized from cyclohexane to yield 4-(decylthio)benzoic acid (20.29 g) in the form of white crystals, m.p. 108°-109° C. [Elemental analysis: C,69.2; H,8.9; S,11.1%; calculated: C,69.34; H,8.9; S,10.88%].
Reaction SMILES: [CH:1]([N:4]([CH3:15])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][O:13][CH3:14])[CH2:6]1)([CH3:3])[CH3:2].[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]([N:4]([CH3:15])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:18])[CH3:19])[C@H:7]([CH2:12][O:13][CH3:14])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the crude dihydrobromide salt of (1R,3R,4S)-N1-isopropyl-3-(methoxymethyl)-N1-methylcyclohexane-1,4-diamine prepared according to the procedure of Example 4b, Step 2 (270 mg) in dichloromethane (5 mL) was treated with tert-butoxycarbonylaminoacetic acid (126 mg), diisopropylethylamine (0.80 ml) and HATU (516 mg). The mixture was stirred for 3 h at rt. Ethyl acetate and saturated aqueous NaHCO3 were added and the layers were separated. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to provide tert-butyl 2-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexylamino)-2-oxoethylcarbamate (185 mg) as a yellow gum, used without further purification. MS found: (M+H)+=372.4.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[F:43])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]3[CH2:28][CH2:27]3)[N:21]=2)[CH:16]1[CH3:44])C1C=CC=CC=1.[H][H]>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:26]1([NH:25][C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH:16]([CH3:44])[C:17]3=[N:18][C:19]=2[N:29]2[CH2:30][CH2:31][CH:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH2:33][CH2:34]2)[CH2:28][CH2:27]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1c2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CC3)nc2CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCc2nc(NC3CC3)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc21
Reaction time: 8 h

Procedure:
Combined 6-benzyl-N-cyclopropyl-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (110 mg, 0.178 mmol) and Pd(OH)2 (20 wt %, 12.5 mg, 0.018 mmol) in THF (888 μL) was purged with hydrogen and allowed to stir under hydrogen (balloon) overnight. The reaction mixture was filtered through Celite™, washed with EtOAc, and concentrated under reduced pressure to give the title compound as a TFA salt (78 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:18])[CH:16]=[CH2:17])[CH:12]=[CH:13][CH:14]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br.[Li+].[Cl-].[Li]OC(C)=O.O.O>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:17][CH2:16][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:10]=1)=[O:18]
Reactant: Brc1ccccc1Br
Reactant: C=CC(O)c1cccc(COC2CCCCO2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1Br)c1cccc(COC2CCCCO2)c1
Temperature: 90 °C

Procedure:
A mixture of the allylic alcohol of Example 1, Step 11, (30.14 g, 121 mmol), 1,2-dibromobenzene (16 mL), Pd(OAc)2 (830 mg), LiCl (5.38 g), LiOAc.2H2O (31.6 g), and Bu4NCl (67.96 g) in 240 mL of DMF was degassed and heated to 85° C. under N2 for 30 min and at 90° C. for 45 min. It was then added to ice and 25% aq. NH4OAc (2 L). The title ketone was extracted in EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with EtOAc:hexane 10:90; yield: 29.53 g (60%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]=[O:22])[O:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].C1(B(O)O)C=CC=CC=1.[C:32](=O)([O-])[O-:33].[Na+].[Na+]>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.C(O)C>[CH:21]([C:20]1[CH:19]=[CH:18][C:4]([O:5][C:6]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:7]=2[C:8]#[N:9])=[C:3]([O:33][CH3:32])[CH:2]=1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(C=O)c(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: OB(O)c1ccccc1
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1cc(C=O)ccc1Oc1cc(C(F)(F)F)ccc1C#N
Reaction time: 16 h
Yield: 14 %

Procedure:
Under nitrogen, 2-(3-bromo-4-formyl-phenoxy)-4-trifluoromethyl-benzonitrile (0.87 g, 2.6 mmol), phenylboronic acid (336 mg, 2.7 mmol), 1,1′-bis(diphenyl)phosphino-ferrocene palladium (9 mg, 0.13 mmol) and sodium carbonate (331 mg, 3.1 mmol) in dimethoxyethane:water:ethanol solution (7:3:2, 10 mL) was stirred at 60° C. for 6 h and then at 40° C. for 16 h. The mixture was then poured over water, extracted into ethyl acetate, and dried over MgSO4. The crude material was chromatographed on an ISCO CombiFlash Chromatography System to yield 2-(4-formyl-2-methoxy-phenoxy)-4-trifluoromethyl-benzonitrile as a clear oil (117 mg, 14%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Product: COC(=O)c1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cc1
Yield: 76 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.66 g) and methyl 4-(bromomethyl)benzoate (0.31 g) as starting materials, methyl 4-[(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-isopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoate (0.61 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:34][CH2:33][C:28]4([O:32][CH2:31][CH2:30][O:29]4)[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:36].C(OCC)(=O)C.[Cl-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:36])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:34][CH2:33][C:28]4([O:32][CH2:31][CH2:30][O:29]4)[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Temperature: 120 °C
Yield: 81 %

Procedure:
A mixture of 5-[4-(benzyloxy)phenyl]-4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.925 g, 4.01 mmol) and concentrated ammonium hydroxide (50 ml) in dioxane (50 mL) was heated at 120° C. in a pressure vessel for 20 hours. The reaction mixture was allowed to cool to room temperature. Ethyl acetate (300 mL) and saturated sodium chloride aqueous solution (300 mL) were added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (700 mL). The organic layers were combined, washed with water, dried over magnesium sulfate, and the solvent removed under reduced pressure. The compound was purified by flash chromatography on silica using 5% methanol in dichloromethane to give 1.457 g (81%) of 5-[4-(benzyloxy)phenyl]-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.13(s, 1H), 7.49-7.31(m, 8H), 7.121-7.100(d, 2H, J=8 Hz), 6.02(br s, 2H), 5.149(s, 2H), 4.681-4.620 (m, 1H), 3.94-3.88(m, 4H), 2.12-2.03(m, 2H), 1.93-1.90(m, 2H), 1.82-1.71(m, 4H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 6.924 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O1CCCC1.O>[CH:27]1([C:30]([O:26][CH:23]([C:5]2[C:6]3[N:7]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]5[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=5[Cl:22])[C:8]4=[N:9][C:10]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:24][CH3:25])=[O:31])[CH2:29][CH2:28]1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCC(OC(=O)C1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.5 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100 mg, 0.243 mmol), cyclopropanecarboxylic acid (0.0272 mL, 0.342 mmol), triethylamine (0.0733 mL, 0.526 mmol) and 4-dimethylaminopyridine (41.0 mg, 0.336 mmol) in tetrahydrofuran (5.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (98.0 mg, 0.511 mmol) at room temperature. The mixture was stirred at room temperature for 15 hr. Cyclopropanecarboxylic acid (0.0147 mL, 0.185 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53.2 mg, 0.278 mmol) were added to the reaction mixture at room temperature. The mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (61.6 mg, 0.13 mmol, 53%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[NH:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:30][CH2:29][CH2:28][NH:27][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=1)=[O:6]
Reactant: NCCNc1ccc2ccccc2n1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(/C=C/C(F)(F)F)NCCNc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (14 mg, 0.1 mmol) was dissolved in DCM (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (9 μl, 0.1 mmol) and the solution was stirred at room temperature for 10 minutes. This solution was added to a solution of N′-(2-quinolyl)ethane-1,2-diamine hydrochloride (22 mg, 0.1 mmol) in DMF (0.5 ml) followed by triethylamine (42 μl, 0.3 mmol) and the resulting mixture was stirred at room temperature for 40 minutes. Then another equivalent of the acid chloride solution (prepared from 14 mg (E)-4,4,4-trifluorobut-2-enoic acid, 1 ml DCM/DMF and 9 μl oxalyl chloride as described above) was added and stirring was continued for additional 40 minutes. The reaction mixture was diluted with ethyl acetate, washed with sat. sodium bicarbonate solution and brine and dried over magnesium sulfate. The volatiles were removed under reduced pressure and the residue obtained was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 5% to 100% acetonitrile) to yield 13 mg (0.042 mmol, 42%).