Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11].[Na+].[Cl-].C1C=CC=CC=1.CCCCCC>O1CCCC1>[I:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:11]
Reactant: O=C(Cl)c1ccccc1I
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccccc1I)N1CCOCC1

Procedure:
A solution of 15 ml of morpholine in 30 ml of tetrahydrofuran was reacted with a solution of 8.0 g o-iodobenzoyl chloride in 20 ml tetrahydrofuran for 10 minutes. The product was obtained in the manner described in Example 3, using saturated NaCl instead of H2O. There was obtained by recrystallization from benzene/hexane 6.8 g of N-o-iodobenzoylmorpholine as hard, translucent crystals, m.p. 86°-87°, Rf 0.73.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([N:13]([CH3:22])[N:14]([CH3:21])[C:15](=[O:20])[CH2:16]2)=[N:11][C:10]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:22][N:13]1[C:12]2=[N:11][C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]([OH:8])[C:18](=[O:19])[N:17]2[CH2:16][C:15](=[O:20])[N:14]1[CH3:21]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N(C)N2C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N(C)N2C
Yield: 97.6 %

Procedure:
A solution intermediate 21, ethyl 7-benzyloxy-1,2-dimethyl-3,6-dioxo-2,3,4,6-tetrahydro-1H-pyrimido[2,1-c][1,2,4]triazine-8-carboxylate, (0.306 g, 0.82 mmol) in a mixture of ethyl acetate (60 ml) and ethanol (60 ml),at 25° C., over 10% palladium on activated carbon (50 mg) and was treated with 1 atm of hydrogen for 1 h to give 0.226 g (97% yield) of the title amide as a white solid after recrystallization from ethyl acetate. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.47 (3H, t, J=7.1 Hz, CH3), 3.28 (3H, s, NCH3), 3.36 (3H, s, NCH3), 4.51 (2H, q, J=7.1 Hz, OCH2), 4.68 (2H, s, CH2), 10.60 (1H, s, OH). MS (ESI+) m/z 283 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:28]([NH2:35])[C@@H:27]1[OH:36]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:35][C@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][C@H:27]2[OH:36])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 4, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: N1C=CC(CC(=O)C)=CC=1.FC1C=C(C=CC=1OC)C=O.[O:22]=[C:23]([CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=1>>[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[C:23](=[O:22])[CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:27][CH2:26]2)=[CH:48][CH:47]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Cc2ccncc2)CC1
Agent: CC(=O)Cc1ccncc1
Agent: COc1ccc(C=O)cc1F
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)C(=Cc2ccc(F)cc2)c2ccncc2)CC1

Procedure:
1,1-Dimethylethyl 4-[4-(4-fluorophenyl)-2-oxo-3-(4-pyridinyl)-3-butenyl]-1-piperidinecarboxylate was prepared by the same method as described for step 1 of Example A-1 by replacing 4-pyridylacetone and 3-fluoro-p-anisaldehyde with the ketone of step 2 of the present Example and 4-fluorobenzaldehyde, respectively.
Reaction SMILES: [C:1]([NH:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][Br:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Br-:15].[C:1]([NH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][P+:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(CCCCBr)NC(=O)c1ccccc1
Solvent: CC#N
Product: O=C(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)c1ccccc1
Product: [Br-]
Yield: 43.6 %

Procedure:
A solution of 2.84 g. (10 mmoles) of the N-benzoyl-5-bromovaleramide prepared above and 3.93 g. (15 mmoles) of triphenylphosphine in 50 ml. of acetonitrile was heated at reflux, under nitrogen, for 72 hours. The acetonitrile was removed by rotary evaporation and the resultant solid was triturated with benzene (3×) then was recrystallized from methylene chloride:ethyl acetate to afford the desired [4-benzoylaminocarbonylbutyl]-triphenylphosphonium bromide weighing 2.38 g. (43.7% yield) melting at 193°-194°.
Reaction SMILES: O[CH:2]1[CH:7]([C:8](=[S:11])[NH:9][CH3:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]1([CH2:22][O:23][CH3:24])[CH2:19][O:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:24][O:23][CH2:22][C:3]1([CH2:19][O:20][CH3:21])[CH:2]=[C:7]([C:8](=[S:11])[NH:9][CH3:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1
Reactant: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(COC)(COC)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=S)C1=CC(COC)(COC)Oc2ccc([N+](=O)[O-])cc21
Yield: 21.1 %

Procedure:
A mixture of 550 mg of 3,4-dihydro-3-hydroxy-2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 0.16 g of p-toluenesulfonic acid monohydrate and 8 ml of toluene was refluxed with heating for 1.5 hours. Toluene was added to the mixture. After it was washed with water and dried, the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 110 mg of oily 2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23]CCCC>>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:15][CH2:14][C:13](=[N:17][C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:23]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCCCC
Reactant: c1ccncc1
Reactant: CC(C)[C@H]1CC[C@@H](N2CCC(=O)CC2)CC1
Product: CC(C)[C@H]1CC[C@@H](N2CCC(=Nc3ccccc3)CC2)CC1

Procedure:
cis-1-(4-Isopropyl-cyclohexyl)-piperidine-4-on (5.0 g, 23.4 mmol), pyridine (3.3 g, 35.3 mmol) and molecular sieves (20 g, 4 Å) were stirred in 100 ml pentane at room temperature for 6 days. The molecular sieves were filtered off and the solvent was evaporated. The crude product was used without any further purification for the following steps.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)[C:15]([N+:27]([O-:29])=[O:28])=[CH:14][CH:13]=1>C1COCC1>[CH2:1]([O:8][C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=2)[C:15]([N+:27]([O-:29])=[O:28])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Nc2nc(OCc3ccccc3)ccc2[N+](=O)[O-])cc1
Temperature: 65 °C
Yield: 70.1 %

Procedure:
To a solution of benzyl alcohol (1.32 g, 12.2 mmol) in THF (15 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil, 488 mg, 12.2 mmol). The mixture was stirred at room temperature for 0.5 h at which time 6-chloro-N-(4-ethylphenyl)-3-nitropyridin-2-amine (1.21 g, 4.03 mmol) was added. The mixture was heated in a sealed tube overnight at 65° C. The reaction vessel was cooled to room temperature and the mixture was quenched with saturated NaHCO3. The mixture was extracted with EtOAc and the organics were dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (2% EtOAc in hexanes gradient to 15% EtOAc in hexanes) gave the title compound (987 mg) as a yellow solid. NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.6 Hz, 3H), 2.66 (q, J=7.6 Hz, 2H), 5.34 (s, 2H), 6.25 (d, J=9.1 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.41-7.28 (m, 5H), 7.45 (d, J=8.4 Hz, 2H), 8.40 (d, J=9.1 Hz, 1H), 10.51 (broad s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2[nH]cnc12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(-n2cnc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 15.6 %

Procedure:
A round bottom flask charged with molecular sieves, 4A (189 mg, 1.918 mmol) was flame-dried, then allowed to cool to room temperature. To this vial were added 4-bromo-1H-benzo[d]imidazole (0.378 g, 1.918 mmol), copper (II) acetate (0.523 g, 2.88 mmol), and 4-fluorophenylboronic acid (0.805 g, 5.76 mmol) followed by CH2Cl2 (Volume: 9.59 ml) and triethylamine (0.695 ml, 4.99 mmol). The heterogeneous green reaction was stirred at room temperature. After 19 h, the reaction mixture was filtered through a disposable filter funnel and the filter cake rinsed with CH2Cl2. The filtrate was concentrated to afford a green residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 0-100% EtOAc in hexanes over 25 min, tr=13 min) gave 4-bromo-1-(4-fluorophenyl)-1H-benzo[d]imidazole (158 mg, 0.299 mmol, 15.56% yield) as a white solid. LC-MS showed by-product was present. The material was re-dissolved in a minimal amount of CH2Cl2 (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (12 g column, 30 mL/min, 0-25% EtOAc in hexanes over 13 min, tr=10 min) gave Preparation 47A (158 mg, 0.299 mmol, 15.56% yield) as a white solid. LC-MS showed the product was 55% pure. The mixture was further purified by MPLC (40 g column, 36 mL/min, 30-60% EtOAc in hexanes) to afford Preparation 47A as a white solid (51 mg, 9.1%). MS (ESI): m/z=291.0 [M+H]+. HPLC Peak tr=1.70 minutes was product. HPLC conditions: Column:Luna C18 4.6×30 mm 3u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:43][C:44]1[S:48][N:47]=[C:46]([CH3:49])[CH:45]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:43][C:44]2[S:48][N:47]=[C:46]([CH3:49])[CH:45]=2)=[O:40])=[CH:18][CH:17]=1
Reactant: Cc1cc(N)sn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4cc(C)ns4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (40 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (20 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 5-amino-3-methylisothiazole hydrochloride (22 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated, and the residue was then purified by chromatography (chloroform:acetone=2:1) to give the title compound (17.5 mg, yield 29.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH2:9][C:10]([CH3:12])=O)[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4]C=1.Cl[OH:16].CCCCCC.[CH2:23]([Cl:25])Cl>>[Cl:25][CH:23]1[C:2](=[CH2:1])[CH:7]([CH2:8][C:9](=[O:16])[CH2:10][CH3:12])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4]1
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Reactant: ClCCl
Reactant: OCl
Solvent: CCCCCC
Product: C=C1C(Cl)CCC(C)(C)C1CC(=O)CC
Yield: 59 %

Procedure:
The reaction of α-dihydro-ionone and hypochlorous acid was carried out as described in Example 1 except that hexane was substituted for methylene chloride. A 59% yield of 4-(5-chloro-6-methylene-2,2-dimethylcyclohexyl-2-butanone was obtained. The spectral data was identical to that reported in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:19][C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:38])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[Br:38][C:7]1[N:8]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)[C:9]2[C:5]([C:6]=1[S:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCn1cc(-n2c(Br)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a stirred solution of compound 3 (100 mg, 0.22 mmol) in CCl4 (10 mL) was added NBS (44.85 mg, 0.25 mmol) at RT under inert atmosphere and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 10-15% EtOAc/Hexanes to afford compound 4 (55 mg, 47%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H), 7.78-7.77 (m, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.25-7.24 (m, 2H), 7.20 (s, 1H), 7.14 (d, J=8.5 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 4.20 (t, J=7.5 Hz, 2H), 2.03-1.98 (m, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.01 (t, J=7.5 Hz, 3H); LC-MS (ESI): 93.3%; m/z 520.8 (M++2); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 5.02 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:11][OH:12])(C)[CH2:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:21]([O:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(CO)Cc2cc(F)ccc2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC1Cc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To an ice cold solution of (5-fluoro-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (854) (0.530 g, 3.15 mmol) in DCM (3.2 mL) was added triethylamine (0.878 mL, 6.3 mmol), DMAP (0.077 g, 0.63 mmol) and acetic anhydride (0.222 mL, 2.4 mmol). The solution was stirred at 0° C. for 2 h. The layers were separated and washed with water (2×5 mL), 1N HCl (5 mL), brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired (5-fluoro-2,3-dihydrobenzofuran-2-yl)methyl acetate (866) (0.530 g, 80.0%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:46])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:46])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: Cc1ccc(COC(=O)Cl)cc1
Product: Cc1ccc(COC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
4-Methylbenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.2 mmol) and 4-methylbenzyl carbonochloridate (63.5 mg, 0.22 mmol) according to General Procedure H to give 20 mg (22.3%) of white solid. Anal. Calcd. for C27H34N4O2 m/z 446.3, found: 447.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.45 (d, J=8.7 Hz, 2H), 7.19 (d, J=7.6 Hz, 2H), 7.11 (d, J=7.6 Hz, 2H), 6.96 (d, J=3 Hz, 2H), 4.98 (m, 2H), 3.68 (dm, 1H), 3.28 (m, 1H), 2.97 (m, 1H), 2.70 (m, 1H), 2.50 (m, 1H), 2.31 (s, 3H), 2.04 (m, 1H), 1.92 (m, 2H), 1.78 (m, 3H), 1.62 (m, 1H), 1.30 (m, 6H).
Reaction SMILES: C1([SH:7])C=CC=CC=1.F[C:9]1[CH:10]=[C:11]([C:16]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:17])[CH:12]=[C:13]([F:15])[CH:14]=1.[CH2:23]([Mg]Br)[CH3:24].C([Mg]Br)=C>C1COCC1>[F:15][C:13]1[CH:12]=[C:11]([C:16]([OH:17])([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:23][CH3:24])[CH:10]=[C:9]([SH:7])[CH:14]=1
Reactant: CC[Mg]Br
Reactant: O=C(c1cc(F)cc(F)c1)c1nccs1
Reactant: Sc1ccccc1
Agent: C=C[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)(c1cc(F)cc(S)c1)c1nccs1

Procedure:
Following the procedure described for Thiophenol 2, Step 3 and thiophenol 5, Steps 2 and 3 but substituting the ketone from Thiophenol 5, Step 1 for (3,5-difluorophenyl)(thiazol-2-yl)methanone and ethylmagnesium bromide in THF (Aldrich) for vinylmagnesium bromide as starting material the title compound was obtained. Mass spec. 270 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>CN(C)C=O.[Cu]>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)[CH:26]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: Brc1cccnc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl 4-hydroxybenzoate (25.0 g, 110 mmol) in N,N-dimethylformamide (60 ml) was added potassium tert-butoxide (12.3 g, 110 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure, and 3-bromopyridine (25.0 g, 110 mmol), a copper powder (1.76 g, 27.2 mmol) and N,N-dimethylformamide (80 ml) were added. The mixture was stirred at 120° C. for 8 hrs. The reaction solution was filtered with celite and the filtrate was evaporated under reduced pressure. To the residue was added water (500 ml) and the mixture was extracted with ethyl acetate (500 ml). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-2:1) to give the objective substance (18.0 g, 54%, crude).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[N:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[CH2:35][CH2:36][NH2:37]>>[CH3:1][N:2]1[C:10]([CH2:11][NH:37][CH2:36][CH2:35][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][N:29]=2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: NCCc1cnccn1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCCc3cnccn3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2-(pyrazin-2-yl)ethanamine were reacted to give 342. [M+H]+ 485.6.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([N:24]([CH:34]2[CH2:36][CH2:35]2)CC2C=CC(OC)=CC=2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][CH2:50][O:51][Si](C(C)(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:49][CH2:50][OH:51])[CH2:10][C:9]2=[O:14])=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:34]2[CH2:35][CH2:36]2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN(CCO)CC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((2-chloro-5-cyano-3-(2-oxopiperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10 mg, 0.018 mmol) in DMF (0.5 mL) was added cesium carbonate (25 mg, 0.077 mmol) followed by (2-bromoethoxy)(tert-butyl)dimethylsilane (8 mg, 0.033 mmol). The reaction mixture was stirred at room temperature overnight. LC-MS indicated desired product. It was then filtered through a pad of Celite, rinsed with EtOAc. The crude was dissolved in DCE (1 mL), anisole (7.68 μl, 0.070 mmol) (one drop) was added followed by TFA (0.5 mL, 6.49 mmol). The resulting reaction mixture was heated at 60° C. for 1 h. LC-MS indicated completion, and then it was cooled and concentrated. The crude was dissolved in methanol and neutralized with 7N ammonia in methanol. After stirring for 10 min it was concentrated, purification via preparative HPLC gave the title compound as a yellow solid (3.4 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10])#[N:2].[CH2:13]([S:20][C:21]1[N:26]=[C:25]([NH:27]S(C)(=O)=O)[CH:24]=[C:23]([NH:32][C@H:33]([CH3:36])[CH2:34]O)[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-].[CH2:38]([N+](CCCC)(CCCC)CCCC)CCC.Cl>N1C=CC=CC=1>[CH2:13]([S:20][C:21]1[N:26]=[C:25]([NH:27][S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])(=[O:11])=[O:10])[CH:24]=[C:23]([NH:32][C@H:33]([CH3:36])[CH2:34][CH3:38])[N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: C[C@H](CO)Nc1cc(NS(C)(=O)=O)nc(SCc2ccccc2)n1
Agent: Cl
Agent: [F-]
Solvent: c1ccncc1
Product: CC[C@@H](C)Nc1cc(NS(=O)(=O)c2ccccc2C#N)nc(SCc2ccccc2)n1
Reaction time: 4 h

Procedure:
2-Cyanobenzenesulfonyl chloride (0.30 g) was added to the solution of the subtitle product of Example 3 step (0.1 g) in pyridine (1 ml) and N,N-dimethylaminopyridine (30 mg). The reaction mixture was stirred for 4 h. To the reaction mixture was added tetrabutylammonium fluoride (4 ml, 1M in THF) and stirred for 16 h. To this reaction was added aqueous hydrochloric acid (1M, 30 ml). The solvent was evaporated and the residue diluted in EtOAc (100 ml). This was washed with H2O (3×20 ml) and brine (10 ml). The organic layer was dried (MgSO4) and concentrated to yield a solid. The residue was purified by column chromatography (EtOAc/iso-hexane 7:3) followed by column chromatography (EtOAc) to yield the title compound. Yield: 30 mg.