Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=[O:8])[CH2:3][CH2:2]1.[Li+].[OH-].CO.O>C1COCC1>[C:14]([O:13][C:11]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A mixture of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4.84 g 20 mmol), and LiOH (2.52 g, 60 mmol) in THF (90 mL)/MeOH (90 mL)/H2O (30 mL) was stirred at r.t overnight. Then the solvents were removed, and the pH of the residue was adjusted to 2 by using 2N HCl. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, and concentrated to give 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (4.6 g, yield 100.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH3:27])[C:13]=2[C:14]2[S:26][C:17]3[N:18]=[CH:19][N:20]=[C:21](S(C)(=O)=O)[C:16]=3[CH:15]=2)=[CH:5][CH:4]=1.CC1([N:35]2C(C3SC4N=CN=C(S(C)(=O)=O)C=4C=3)=CN=C2)C=CC=CC1.C(Cl)Cl.N>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH3:27])[C:13]=2[C:14]2[S:26][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:35])[C:16]=3[CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ncn(C)c2-c2cc3c(S(C)(=O)=O)ncnc3s2)cc1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ncn(C)c2-c2cc3c(N)ncnc3s2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(4-methoxyphenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 106) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 17) followed by flash chromatography on silica eluting with DCM:MeOH (0-10%) then 1% NH3. Tan solid (0.91 g, 36%);
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3].[OH-].[Na+]>CO.O>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([OH:13])=[O:12])=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cncc(C(=O)OCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCn1cncc(C(=O)O)c1=O
Reaction time: 16 h

Procedure:
To the compound of Example 21 (5.00 g, 0.024 mole), suspended in methanol (25 mL) and cooled in an ice bath, 1.0N NaOH (29 mL, 0.029 mole) is added dropwise rapidly with stirring. After 16 hours, the solvent is reduced under vacuum, residue diluted with water (50 mL), and washed with ethyl acetate (2×15 mL). The aqueous layer is acidified with 2.0N HCl to pH 1, extracted with ethyl acetate (3×50 mL). The combined organic extracts are washed with water, then brine (twice). The solvent is removed in vacuo to afford the title compound.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.S(Cl)(Cl)=O.[C:16]([Cl:26])(=O)C1C=CC=C(OC)C=1.C=O>[Cl-].[Zn+2].[Cl-]>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([O:11][CH2:16][Cl:26])=[O:10]
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=S(Cl)Cl
Product: COc1cccc(C(=O)OCCl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
A similar procedure (Lu, M. C. et al. J. Med. Chem. 1987, 30, 273-278 and Iyer, R. P. et al. Synth. Commun. 1995, 25, 2739-2749) to that described for the preparation of 50 was followed using m-anisic acid (4.1 g, 26.9 mmol) and thionyl chloride (4 mL), under reflux for 1 h. A mixture of crude m-anisoyl chloride, paraformaldehyde (808 mg, 26.9 mmol) and zinc chloride (28 mg, 0.21 mmol) was then stirred at 80° C. for 16 h. Purification by flash chromatography (hexane/ethyl acetate 19:1) afforded chloromethyl m-methoxybenzoate (47) as a pale green oil (1.4 g, 6.86 mmol, 26%). 1H NMR 3.86 (3H, s, OMe), 5.95 (2H, s, CH2), 7.14-7.17 (1H, m, Ar), 7.36-7.40 (1H, m, Ar), 7.58-7.59 (1H, m, Ar), 7.66-7.69 (1H, m, Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=2[C:13]=1[C:24]([O:26][CH3:27])=[O:25])(=[O:10])=[O:9].[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH:15]([O:22][CH3:23])[C:14]=2[C:13]=1[C:24]([O:26][CH3:27])=[O:25])(=[O:10])=[O:9]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(OC)=CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(OC)CCC2

Procedure:
A mixture of Example 458B (352 mg, 0.9 mmol) and 10% Pd/C (99.8 mg) in ethyl acetate (18 mL) was hydrogenated under 50 psi of hydrogen for 2.5 days. After filtration and concentration, the desired product was isolated in quantitative yield. MS (DCI/NH3) m/e 411 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.7-7.61 (m, 2H), 7.43 (m, 1H), 7.31 (t, 1H), 7.12 (d, 1H), 7.01 (d, 1H), 4.42 (t, 1H), 3.63 (s, 3H), 3.15 (s, 3H), 2.70-2.61 (m, 2H), 1.86 (m, 1H), 1.77-1.55 (m, 3H).
Reaction SMILES: [CH:1]12[CH2:12][CH:9]([CH:10]=[CH:11]1)[CH2:8][C:7]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=1.[OH2:13].[OH2:14].C[N+]([O-])(C)C>ClCCl.[Os](=O)(=O)(=O)=O>[CH:1]12[CH2:12][CH:9]([CH:10]([OH:14])[CH:11]1[OH:13])[CH2:8][C:7]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: C1=CC2CC1Cc1cccnc12
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: ClCCl
Product: OC1C2Cc3cccnc3C(C2)C1O
Reaction time: 18 h
Yield: 99.3 %

Procedure:
A mixture of 3-azatricyclo[7.2.1.02,7]dodeca-2,4,6,10-tetraene (Preparation 25, 0.96 g, 6.11 mmol), trimethylamine N-oxide dihydrate (0.75 g, 6.73 mmol) and osmium tetroxide (2.5 wt % solution in 2-methyl-2-propanol, 2 □l) in dichloromethane (15 ml) were stirred for 18 h. A further portion of osmium tetroxide (2.5 wt % solution in 2-methyl-2-propanol, ca. 1 □l) was added and the reaction mixture was stirred for a further 18 h. The reaction mixture was subjected to chromatography eluting with hexane and then ethyl acetate to give the title compound as a solid (1.16 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[F:7][C:8]([F:28])([F:27])[C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:13]=[CH:14][CH:15]=2)[N:10]=1.C(N(CC)CC)C>C(OCC)(=O)C>[F:27][C:8]([F:7])([F:28])[C:9]1[C:18]([C:19]([NH:1][C:2]2[NH:6][N:5]=[N:4][N:3]=2)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1nnn[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Yield: 52.9 %

Procedure:
5.03 g of anhydrous 5-amino-tetrazole were suspended with stirring at 8° C. in 230 ml of ethyl acetate and a solution of 21.9 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride in 230 ml of ethyl acetate and a solution of 18 g of triethylamine in 180 ml of ethyl acetate were simultaneously added to the reaction mixture over 15 minutes. The mixture returned to room temperature and was refluxed for one hour and cooled. The mixture was vacuum filtered and the recovered product was dissolved in one liter of water. The filtrate wash waters were added to the solution and the pH was adjusted to 1 by addition of 20% hydrochloric acid. The mixture was vacuum filtered and the recovered product was dissolved in 50 ml of 2 N sodium hydroxide. 150 ml of water were added to the solution and the mixture was heated to reflux and cooled. The mixture was acidified with 100 ml of 20% hydrochloric acid and was vacuum filtered. The product was dried and crystallized from 250 ml of acetic acid to obtain 12.279 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(1H-tetrazol-5-yl)-3-quinolinecarboxamide melting at >260° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([CH2:14]CC#N)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([CH2:14][CH2:20][C:19]([OH:22])=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCCC1(c2ccccc2)CCCCC1=O
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)CCC1(c2ccccc2)CCCCC1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 3-(2-oxo-1-phenylcyclohexyl)propanenitrile (5.05 g, 22.22 mmol) in acetic acid (11.1 mL), conc. HCl (33.2 mL), and water (11.1 mL) was refluxed for 16 h under N2, cooled to room temperature, and poured into water (66 mL). The product separated out as an layer of oil. The suspension was cooled to 0° C. in an ice bath for 30 min. with occasional swirling and the crystallized product was collected by filtration and rinsed several times with water, and dried in vacuo to obtain 3-(2-oxo-1-phenylcyclohexyl)propanoic acid (Int. 2-B, 4.77 g, 85% yield) as a white crystalline solid. HPLC: tR=2.47 min, YMC Combiscreen ODS-A 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.1% TFA; Final solvent: 90% aq. MeOH-0.1% TFA. LC/MS: m/e 247.2 (M+H)+, 229.2 (M+H-H2O)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[C:2]1[C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1>[CH3:2][O:1][C:10]1[CH:5]=[CH:6][C:7]([C:12]([C:2]2[O:1][C:10]3[C:5]([C:4](=[O:11])[CH:3]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:13])=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1cc(=O)c2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: COc1ccc(C(=O)c2cc(=O)c3ccccc3o2)cc1
Temperature: 0 °C

Procedure:
Combine chromone-2-carboxylic acid chloride (10 mmol), and aluminum chloride (30 mmol) in anisole (70 mL). Heat at reflux for 24 hours. Pour the reaction mixture into ice-water (150 mL). Extract twice with dichloromethane. Dry the separated organic layers over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:21]([CH:23]2[CH2:27][CH2:26][C@H:25]([N:28]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24]2)[OH:22])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:21]([CH:23]2[CH2:27][CH2:26][C@H:25]([N:28]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:24]2)=[O:22])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:19])[CH3:20])([CH:15]([CH3:16])[CH3:17])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CC[C@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CC[C@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
A round-bottomed flask was charged with (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanol (3.51 g, 5.83 mmol) in DCM (104 mL) to give a yellow solution. The solution was cooled to about 0° C. Dess-Martin periodinane (7.41 g, 17.48 mmol) was added and the mixture was stirred at about 0° C. for about 2 h then at ambient temperature for about 3 h. The reaction mixture was then re-cooled to about 0° C. and saturated aqueous sodium sulfite (50 mL) was added slowly. The organic solvent was removed under reduced pressure. EtOAc (100 mL) was added and the layers were partitioned. The organic layer was washed with saturated aqueous NaHCO3 (2×20 mL) and brine (3×50 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give a brown oil. The crude material was purified by silica gel chromatography eluting with 5% EtOAc in heptane. A second purification by neutral alumina chromatography eluting with a step-wise gradient of 0-100% EtOAc in heptane yielded (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanone (1.7 g, 50%) as a yellow oil: LC/MS (Table 2, Method n) Rt=3.90 min; MS m/z: 601 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][C:17]=2[N:18]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[ClH:26].C(OCC)(=O)C>>[ClH:26].[CH3:1][CH:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]=2[N:18]=1)[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(Oc1ccc2c(n1)OCCNC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of the compound obtained in step 1 (0.15 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.11 g, 93%) as a white powder.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](C2C=CC=CC=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1I
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)cc1
Product: O=Cc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzaldehyde was prepared according to the method of Example 135, Step 2 using 2-iodobenzaldehyde in place of (S)-1-(2-iodophenyl)ethanol and Intermediate 2 in place of Intermediate 1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].CO.[CH:14]1[CH2:18][CH:17]=[CH:16][CH:15]=1.C1COCC1>CC(CC(C)=O)C>[CH2:16]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11])[CH:15]=[CH:14][CH2:18][CH3:17]
Reactant: Oc1ccc2ccccc2c1
Reactant: C1=CCC=C1
Solvent: C1CCOC1
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: CCC=CCc1c(O)ccc2ccccc12
Temperature: 25 °C

Procedure:
Into a 2-liter flask having a stirrer, a condenser and a thermometer, 144 g of 2-naphthol, 200 g of methanol and 40 g of PTS were introduced, and a solution of mixture of 66 g of cyclopentadiene and 60 g of methanol was added dropwise over a period of 3 hours while stirring the mixture at room temperature, followed by further stirring for 4 hours at room temperature. To the reaction solution thus obtained, THF and MIBK were added, and the resultant solution was washed with 200 ml of an aqueous 10% sodium hydroxide solution five times, and thereafter further washed with water until it turned neutral, followed by removal of the solvent using an evaporator. The results of analysis by GPC thereof are shown in FIG. 11. Its yield determined by GPC was 90% (area ratio). An NMR spectrum of the 1-(2-penten-1-yl)-2-naphthol obtained is shown in FIG. 12.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:21]/[N+:18]([O-:20])=[O:19])[CH:14]=[C:15]([F:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc(F)cc(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
Heat 3-benzyloxy-5-fluoro-benzaldehyde (3.75 g, 16.29 mmol), nitromethane (4.08 g, 66.79 mmol), and ammonium acetate (3.47 g, 44.96 mmol) in acetic acid (54 mL) in 125° C. oil bath under nitrogen for 4 hours. Cool to room temperature and pour into ice/water. Extract with hexanes/ethyl acetate. Dry (magnesium sulfate), filter and concentrate. Purify on 120 g silica gel eluting with 100:0 to 80:20 hexanes:ethyl acetate to give 3.05 g (68.5%) of the desired compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][N:16](C=O)[CH3:17].C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([N:16]([CH3:17])[CH3:15])=[O:14])[CH:6]=[CH:5]2
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc2cc(Br)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Suspended the 6-bromoquinoline-2-carboxylic acid (1.0 g, 3.93 mmol) in CH2Cl2 (20 mL), added DMF (0.91 mL, 11.78 mmol) and cooled in an ice bath. Added oxalyl chloride (0.688 mL, 7.86 mmol) dropwise over a few min. Warmed to rt and stirred for 1 hr then bubbled in dimethylamine gas for several min. The dark amber mixture was stirred at rt overnight. In am, the solution was diluted with water and extracted with CH2Cl2 (3×). Washed extracts with brine (1×), dried over MgSO4, decolorized with charcoal, filtered, evaporated and dried under high vac, rt to afford the title compound (990 mg). LC/MS: m/e 279, 281 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:10]#[N:11].[K+].C>C(O)C.O>[C:1]1([N:7]([C:10]#[N:11])[CH:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CN(C=S)c1ccccc1
Yield: 78.9 %

Procedure:
A solution of 13.5 g (0.1 mol) phenyl isothiocyanate and 6.5 g (0.1 mol) potassium cyanide in 100 ml ethanol and 40 ml water was stirred at about 25° C for 1 hour. The solution was then diluted with water, slurried with charcoal and filtered. The filtrate was acidified with concentrated hydrochloric acid. An oil was separated on acidification. The oil solidified on standing and the resulting solid was filtered. The solid was then recrystallized from benzene/hexane to give 12.8 g N-phenyl cyanothioformamide, as a orange solid melting at 73°-81° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:52]=1[C@H:58]([NH2:63])[C:59]([F:62])([F:61])[F:60]>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:63][C@@H:58]([C:52]2[CH:53]=[CH:54][C:55]([F:57])=[CH:56][C:51]=2[F:50])[C:59]([F:60])([F:62])[F:61])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: N[C@@H](c1ccc(F)cc1F)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(N[C@@H](c1ccc(F)cc1F)C(F)(F)F)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and (S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethylamine hydrochloride (EXAMPLE 29, Step C) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H14BrF5N4O3S, 600.0; m/z found, 599/601 [M−H]−. HPLC (reverse phase): RT=10.06 min. 1H NMR (400 MHz, CDCl3): 11.02 (s, 1H), 8.84-8.83 (m, 2H), 8.56 (dd, J=7.4, 1.4 Hz, 1H), 8.31 (dd, J=7.4, 1.4 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.43-7.37 (m, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.13 (dd, J=8.5, 1.8 Hz, 1H), 7.03-6.93 (m, 2H), 6.82-6.80 (m, 1H), 6.06-5.99 (m, 1H).
Reaction SMILES: C([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11](Cl)[CH:10]=1)C1C=CC=CC=1.[CH3:20][NH:21][CH3:22]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[CH2:9]([C:10]1[C:11]([N:21]([CH3:22])[CH3:20])=[N:12][C:13]2[C:18]([C:9]=1[NH2:8])=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:18]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cc(NCc2ccccc2)c2ccccc2n1
Reactant: CNC
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CN(C)c1nc2ccccc2c(N)c1Cc1ccccc1
Yield: 68 %

Procedure:
Benzyl-(2-chloroquinolin-4-yl)-amine (100 mg, 0.372 mmole), copper(II)sulphate pentahydrate (92.9 mg, 0.372 mmole) and dimethylamine (1M in MeOH, 3 mL) were stirred at 150° C. in a microwave oven for 5 hrs. The reaction mixture was dissolved with water and extracted with ethyl acetate. The residue obtained from the organic phases was purified using silica gel chromatography, eluting with dichloromethane:methanol 90:10. Precipitation in isopropyl ether gave a yellowish solid (70.0 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([CH3:15])=[O:14].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:15][C:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:6][C:2]=1[CH3:1])=[O:14]
Reactant: CC(=O)c1nc(-c2ccccc2)[nH]c1C
Reactant: COC(OC)N(C)C
Product: Cc1[nH]c(-c2ccccc2)nc1C(=O)C=CN(C)C
Temperature: -10 °C

Procedure:
A mixture of 10.0 g (0.05 moles) of methyl 5-methyl-2-phenyl-4-imidazolyl ketone [A. C. Verones, et al., J. Het. Chem., 17, 1723 (1980)] and 45.0 ml of N,N-dimethylformamide dimethyl acetal was refluxed for 16 hours in an oil bath. The reaction mixture was cooled at -10° C., then filtered. The product was washed with 50 ml of cold ethanol, air dried and gave 4.6 g of 3-(dimethylamino)-1-(5-methyl-2-phenyl-1H-imidazol-4-yl)-2-propen-1-one as a yellow solid, mp 218°-222° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18]1
Reactant: IC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(C4CCCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and iodocyclohexane.