Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:19][CH:18]3[CH:14]([CH2:15][NH:16][CH2:17]3)[CH2:13]1)[N:6]=[CH:5]2.[F:20][C:21]1[C:22]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[F:20][C:21]1[C:22]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:23]([C:24]([N:16]2[CH2:17][CH:18]3[CH:14]([CH2:13][N:12]([C:7]4[N:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[N:8]=4)[CH2:19]3)[CH2:15]2)=[O:25])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: Fc1ccc2nc(N3CC4CNCC4C3)ncc2c1
Product: O=C(c1cccc(F)c1-n1nccn1)N1CC2CN(c3ncc4cc(F)ccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 43 and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C23H19F2N7O, 447.16; m/z found 448.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.99 (s, 1H), 7.77 (d, J=15.8, 2H), 7.61 (dd, J=11.0, 5.5, 1H), 7.53-7.43 (m, 2H), 7.37-7.29 (m, 2H), 7.24 (s, 1H), 3.93 (d, J=9.9, 1H), 3.79 (dd, J=12.3, 7.4, 2H), 3.71-3.62 (m, 1H), 3.62 (s, 3H), 3.20 (dd, J=11.0, 5.3, 1H), 3.12-2.98 (m, 2H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH2:30]=O>>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH3:30])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: C=O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1, with racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride from Example 2, Step 1 and formaldehyde instead of acetone. The crude purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2; Found: 401.2.
Reaction SMILES: O.NN.[N+:4]([C:7]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10])([O-])=O.[H][H]>CO.[Ni]>[NH2:4][C:7]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10]
Reactant: [H][H]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1OC
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1OC
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Hydrazine hydrate (1.33 mL, 41.5 mmol) was added dropwise to a solution of 116 (2.83 g, 8.3 mmol) in methanol (142 mL) gently refluxing over Raney nickel (500 mg, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the product (2.18 g, 6.5 mmol) as a brown oil: 1H NMR (270 MHz, CDCl3) δ 1.6-2.0 (m, 3H), 2.1-2.2 (m, 1H), 3.4-3.7 (m, 4H), 3.8 (s, 3H), 3.8-3.9 (2×s, 6H), 4.4 (br s, 1H), 4.7-4.3 (br s, 1H), 6.6 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 144.7, 144.5, 141.6, 134.6, 107.1, 66.9, 61.0, 60.9, 60.5, 56.8, 50.9, 28.6, 24.9, 21.1, 14.2.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)(OCC)=[O:2].C(CCCCC1C(=O)CCC=1)(OCC)=O.[CH:31]1[C:32](/[CH:47]=[N:48]/[OH:49])=[CH:33][CH:34]=[N+:35]([CH2:37][N+:38]2[CH:43]=[CH:42][C:41](/[CH:44]=[N:45]/[OH:46])=[CH:40][CH:39]=2)[CH:36]=1.[Br-:50].[Br-].[H-].C([Al+]CC(C)C)C(C)C.[K+].[Br-]>>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:11](=[O:15])[CH:12]=[CH:13][CH2:14]1.[CH:33]1[C:32](/[CH:47]=[N:48]/[OH:49])=[CH:31][CH:36]=[N+:35]([CH2:37][N+:38]2[CH:39]=[CH:40][C:41](/[CH:44]=[N:45]/[OH:46])=[CH:42][CH:43]=2)[CH:34]=1.[Br-:50].[Br-:50]
Reactant: CCOC(=O)CCCCC1=CCCC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Product: O=C1C=CCC1CCCCCO

Procedure:
Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone as methoxime (Example 24) with diisobutyl aluminum hydride in the manner described in Example 17 gives crystals, m.p. 33°-35° C. IR (KBr) 3420, 1630, 1050, 886 cm-1. λmaxMeOH 243 (12,020).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[N:3][CH:2]=1.Cl[CH2:10][CH2:11][N:12]([CH2:23][CH2:24]Cl)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+]>COCCOCCOC.C(OCC)C.CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:24][CH2:23][N:12]([C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])[CH2:11][CH2:10]2)=[N:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N(CCCl)CCCl
Reactant: NCc1ccncn1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCN(Cc2ccncn2)CC1
Temperature: 150 °C

Procedure:
To a stirred solution of 0.20 g (1.8 mmol) of 1-(pyrimidin-4-yl)methanamine and 0.61 g (2.2 mmol) benzyl bis(2-chloroethyl)carbamate in 4 mL anhydrous diethylene glycol dimethyl ether was added 3.20 mL (18.3 mmol) of N,N-diisopropylethylamine and 0.05 g (0.40 mmol) of sodium iodide. The resulting solution was heated to 150° C. for 6 h. After cooling to ambient temperature, 12 mL of methanol was added to the mixture followed by 250 mL of diethyl ether. The resulting white precipitate was isolated by vacuum filtration while washing with diethyl ether. Diluted the solid with 100 mL of saturated sodium bicarbonate and extracted the aqueous solution with ethyl acetate (3×100 mL). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white solid which was used without further purification. LC/MS: m/z (ES) 313.1 (MH)+.
Reaction SMILES: [N+:1]([CH:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][C:7]([O:9]C)=[O:8])([O-:3])=[O:2].[Li+].[OH-].Cl>COCCOC>[N+:1]([CH:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(CCC(=O)OC)[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCCC(CCC(=O)O)[N+](=O)[O-]
Reaction time: 24 h
Yield: 85.7 %

Procedure:
Methyl 4-nitroheneicosanoate (5a) (147 mg, 0.38 mmol) was dissolved in 1,2-dimethoxyethane (DME) (2 mL) and sat. aq LiOH solution (2 mL) was added. The mixture was left for 24 h, then it was acidified with dilute HCl (10%, 10 mL) and the mixture was extracted with EtOAc (2×10 mL). The extracts were concentrated under a stream of dry N2 and the residue was subjected to flash column chromatography on silica (Et2O/hexane, 100/20, then Et2O/hexane/HOAc, 60/40/1) to afford 4-nitroheneicosanoic acid (6a) (121 mg, 85%) as a white solid; mp 55-56° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=[CH:15]2)[CH2:12][CH2:13]1
Reactant: c1ccc(CN2CCC(n3cnc4cccnc43)CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1cnc2c(c1)ncn2C1CCNCC1
Yield: 95.6 %

Procedure:
The title compound was prepared from 130 mg of 3-(1-benzyl-piperidin-4-yl)-3-H-imidazo[4,5-b]pyridine (from Step C), 130 mg of 10% palladium on carbon and 130 mg of ammonium formate in 6 mL of MeOH, using a procedure analogous to that described in Example 95, Step C to provide 86 mg of the title compound as a solid
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][NH:17][C:18]([NH2:20])=[O:19]>>[NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=[N:16][NH:17][C:18]([NH2:20])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NNC(N)=O
Reactant: Nc1ccccc1C(=O)c1ccccc1
Product: NC(=O)NN=C(c1ccccc1)c1ccccc1N

Procedure:
A number of methods for preparing 1,3,4-benzotriazepine-2-ones have been described in the literature. In general, the compounds are prepared by either of two methods from a 2-aminobenzophenone. In the first method, the 2-aminobenzophenone is treated with semicarbazide to give an aminobenzophenone semicarbazone. This product is cyclized to give the benzotriazepine-2-one. See Bull. Chem. Soc. Jap., 43, 135-138 (1970); Japanese publications 70 11,148 (CA 73:25544a) and 70 11,147 (CA 73:25545b). Alternately, a 2-amino-benzophenone hydrazone is treated with phosgene to give the desired benzotriazepine-2-one. See U.S. Pat. No. 3,176,008; J. Pharm. Sci. 63(b), 834-41 (1974) and J. Med. Chem. 7(3), 386 (1964).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1CCCCC1.C(O)(=O)C.C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:9](=[CH:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C(=C/c1ccccc1)C(=O)c1ccccc1O
Yield: 83.9 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (618 mg, 2.6 mmol), benzaldehyde (265 μL, 2.6 mmol), 12.0 mL benzene, piperidine (13 μL, 0.13 mmol) and glacial acetic acid (7.5 μL, 0.13 mmol), refluxed for 2 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 708 mg (83%) of 5 as clear crystals. mp=109-110° C.; IR (film) 2978.4; 1737.4; 1692.4; 1643.3; 1145.8 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.92 (bs, 1H), 7.86 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.4 Hz), 1H, 7.37-7.28 (m, 5H), 7.04 (d, J=8.4 Hz. 1H), 6.83 (t, J=7.3 Hz, 1H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 201.6, 163.8, 162.8, 142.3, 137.2, 133.0, 131.9, 131.6, 130.7, 130.3, 129.1, 120.2, 119.6, 118.5, 82.8, 28.1; LRMS (electrospray): Mass calculated for C20H20O4, [M]+, 324.13. Found [M+23]+, 347.3. An NOE difference experiment was conducted for this compound and a positive NOE was seen for the alkene proton when the tert-butyl signal was irradiated and a positive NOE was seen for the tert-butyl signal upon irradiation of the alkene proton.
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.[CH2:17]([NH2:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>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:29][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCCCCCCCCCCCN
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(dodecylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-dodecylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH:1]1([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:11]2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:39]>CO>[ClH:39].[CH:1]1([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][NH:24][CH3:25])=[CH:11]2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(Cc1cn(S(=O)(=O)C2CCCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1cn(S(=O)(=O)C2CCCCC2)c(-c2cccnc2F)c1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
tert-Butyl {[1-(cyclohexylsulfonyl)-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (420 mg) was dissolved in methanol (10 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at 70° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 256 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[N:13]=[C:14]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[NH:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[NH:25]1[CH2:28][CH:27]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:26]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:13][C:14]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4]([N:25]1[CH2:28][CH:27]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:26]1)=[O:5]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1cc(C)c(-c2nc(C3CCOCC3)[nH]c2C)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-c2[nH]c(C3CCOCC3)nc2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
The mixture of 2,4-dimethyl-5-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)benzoic acid (compound 164.2, 157 mg, 0.5 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 126 mg, 0.65 mmol), EDCI (143 mg, 0.75 mmol), HOBt (93 mg, 0.55 mmol) and DIEA (345 μL, 2.00 mmol) in DMF (4 mL) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with EtOAc (30 mL). The organic phase was washed with saturated NaHCO3 (10 mL), brine (3×20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC with 5% methanol in dichloromethane and lyophilized to give 95 mg (42%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[C:29]([NH:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:31])[CH3:30]>>[CH3:11][N:8]1[C:7]([CH2:12][N:13]2[CH2:14][CH2:15][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17][CH2:18]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:29](=[O:31])[CH3:30])=[CH:34][CH:35]=1)=[N:3][C:4]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CC(=O)Nc1ccc(-c2nc(N3CCOCC3)c3nc(CN4CCN(S(C)(=O)=O)CC4)n(C)c3n2)cc1

Procedure:
4-(2-Chloro-9-methyl-8-((4-(methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4-acetamidophenylboronic acid via General Procedure A and purified via reverse phase HPLC to give 25.9 mg 134 as a white solid. MS (Q1) 529.3 (M)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([NH2:10])=[S:9])[CH:2]=1.Br[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:18]([Cl:26])[CH:17]=1)[C:13](=O)[CH3:14]>C(O)C>[Cl:26][C:18]1[CH:17]=[C:16]([C:12]2[S:9][C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:10][C:13]=2[CH3:14])[CH:21]=[CH:20][C:19]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CC(=O)C(Br)c1ccc(S(N)(=O)=O)c(Cl)c1
Reactant: NC(=S)Nc1cccnc1
Solvent: CCO
Product: Cc1nc(Nc2cccnc2)sc1-c1ccc(S(N)(=O)=O)c(Cl)c1
Temperature: 60 °C
Yield: 16.9 %

Procedure:
3-Pyridylthiourea (0.047 g, 0.31 mmol) is added to a stirred solution of 4-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (Example 23d) (0.10 g, 0.31 mmol) in ethanol (5 ml). The solution is heated at 60° C. for 3 hours. The solvent is removed and the residue is purified by chromatography on silica eluting with ethyl acetate-hexane to give the title compound (0.020 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([CH2:19][CH3:20])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]1=[O:21])[CH:2]=C.[BH4-].[Na+].C[OH:25]>>[CH2:19]([C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:7][CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH2:2][OH:25])[C:5]1=[O:21])[CH3:20]
Reactant: C=CCN1CCCCC(CC)(c2cccc(OC)c2)C1=O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CCC1(c2cccc(OC)c2)CCCCN(CCO)C1=O
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of 1-allyl-3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one (as described in Example 49, Step A) (0.9 g, 3.1 mmol) in MeOH (20 mL) at −78° C. was saturated with 03 for 20 min. The solution was warmed to −40° C. for 10 min then NaBH4 (0.36 g, 9.4 mmol) was added and the reaction mixture was stirred at 25° C. for 1 hr. The MeOH was removed in vacuo, and the residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: C[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[Si](I)(C)(C)C.C(#N)C.Cl>C(Cl)Cl>[OH:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COCC1CCC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: OCC1CCC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A mixture of 4'-(4-methoxymethylcyclohexyl)-4-trifluoromethoxybiphenyl (100 mmol), TMSI (144 mmol), 15 ml of acetonitrile, and 10 ml of methylene chloride was stirred at room temperature for 4 hr. Ice and 6 M HCl were added to the reaction mixture, and the mixture was stirred. The organic phase was washed twice with a saturated aqueous solution of sodium thiosulfate. It was then dried over magnesium sulfate anhydride, and the solvent was distilled off under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (eluting solution: toluene--(1:1) mixture of toluene and ethyl acetate) to give 4'-(4-hydroxymethylcyclohexyl)-4-trifluoromethoxybiphenyl (68 mmol, yield 68%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][CH:19]1[CH2:24][CH:23]([CH3:25])[CH2:22][NH:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:18][C@H:19]1[CH2:24][C@H:23]([CH3:25])[CH2:22][N:21]([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4]3=[CH:9][C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:11][C:3]=23)[CH2:20]1
Reactant: CC1CNCC(C)C1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1nc(N2C[C@@H](C)C[C@H](C)C2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenyl-pyrrolo[3,2-d]pyrimidine (Example 1(e)) (83.8 mg, 0.34 mmol) and 3,5-dimethylpiperidine (cis/trans, Aldrich Chemical Company) (250 μL, 1.72 mmol) was added a solution of K2CO3 (0.19 g, 1.36 mmol) in H2O (2.0 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.0 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% MeOH:CHCl3 on silica gel) and then recrystallized from MeOH/CH2Cl2 to give 85 mg (78%) as a beige colored solid. This material was recrystallized from hot MeOH/CH2Cl2 to give 54 mg (50%) of the title compound as a 95:5 mixture of isomers as colorless crystals. Mp: 225.5-227° C. MS m/z: 321 (M+1). 1H NMR (DMSO-d6; 400 MHz) (for major isomer): δ 0.90 (m, 2), 0.91 (d, 6, J=6.5), 1.73 (m, 2), 2.40 (s, 3), 2.42 (br s, 2), 4.42 (br d, 1, J=8.2), 6.74 (s, 1), 7.40 (m, 1), 7.49 (br s, 2), 7.89 (d, 2, J=7.4), 11.06 (s, 1). Anal. Calcd for C20H24N4: C, 75.00; H, 7.50; N, 17.50. Found: C, 74.87; H, 7.56; N, 17.38.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[N-].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH3:13]>O1CCOCC1>[O:11]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][O:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:12][CH3:13])=[CH:20][CH:19]=1)(=[O:22])=[O:23]
Reactant: CCCCCCC(=O)C=[N+]=[N-]
Reactant: CCOc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CCCCCCC(=O)COS(=O)(=O)c1ccc(OCC)cc1
Yield: 59 %

Procedure:
A 1.0 g quantity of 1-diazo-2-octanone is dissolved in 30 ml of dioxane, and 2.0 g of p-ethyoxybenzenesulfonic acid is slowly added to the solution at room temperature. The mixture is stirred until no nitrogen is evolved. The reaction mixture is distilled in a vacuum to remove the solvent, and the residue is extracted with 50 ml of ether, washed with water and dried over anhydrous sodium sulfate. The dried product is distilled in a vacuum to remove the solvent and obtain an oily product, which is purified by column chromatography (silica gel, developer solvent chloroform), affording 1.26 g of 2-oxooctyl-p-ethoxybenzene sulfonate (Compound 46), m.p. 38° to 39° C. Yield 59.0%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1.[H-].[Na+].Cl[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=1>CN(C=O)C>[N:19]1[N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([NH:7][C@H:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[O:1][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=2)=[O:20])[N:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: O=C(N[C@H]1CCC[C@@H]1O)c1ccccc1-n1nccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCC[C@@H]1Oc1cc(C(F)(F)F)ccn1)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of N-[(1S,2S)-2-hydroxycyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 11; 200 mg, 0.73 mmol) in dry DMF (1.2 ml) was added sodium hydride (60% dispersion in mineral oil, 29.4 mg, 0.73 mmol). To this was then added 2-chloro-4-(trifluoromethyl)pyridine (CAS number 81565-18-6; 133 mg, 0.73 mmol) as a solution in dry DMF (1.2 ml). The reaction was stirred at room temperature for 17 hours and was then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The crude oil was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.