Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCl.[NH2:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([C:12]([Cl:15])([CH3:14])[CH3:13])[N:5]=1.[Cl:16]C(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)Cl>[NH2:3][C:4]1[N:9]=[C:8]([Cl:16])[N:7]=[C:6]([C:12]([Cl:15])([CH3:14])[CH3:13])[N:5]=1
Reactant: CSc1nc(N)nc(C(C)(C)Cl)n1
Reactant: ClC(Cl)(Cl)Cl
Agent: ClCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(Cl)c1nc(N)nc(Cl)n1
Reaction time: 0.08 h
Yield: 10 %

Procedure:
Chlorine gas was passed at 35 to 40° C. into a solution of 5 g of 2-amino-4-methylthio-6-(1-chloroisopropyl)-1,3,5-triazine in 0.1 l of trichloromethane (or tetrachloromethane) (15 min). 10 g of potassium carbonate were added to the reaction mixture at room temperature, and the mixture was stirred for 5 minutes and filtered and the solvent removed in vacuo. This gave a product mixture in which approximately 0.5 g (10%) of 2-amino-4-chloro-6-(1-chloroisopropyl)-1,3,5-triazine are present (detection by HPLC comparison with 100% product).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14](=[O:24])[C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:12][CH:13]=3)=[O:20])=[CH:17][CH:16]=2)=[CH:13][CH:12]=1)=[O:7])[CH2:10][CH3:11]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCCOC(=O)c1ccc(O)cc1
Product: CCCOC(=O)c1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(C(=O)OCCC)cc3)cc2)cc1

Procedure:
Propyl p-hydroxybenzoate and terephthalic dichloride are allowed to react in a similar procedure to Example 5. The reaction product is recrystallized from hexane-chloroform (1:1) to yield di(p-propoxycarbonylphenyl)terephthalate, m.p. 136°-139° C., as white crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH:45][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)=[CH:42][CH:41]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(F)cc1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1
Yield: 94 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[(3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 4-fluorobenzylamine and potassium carbonate essentially as described above in example 4. Combine the appropriate fractions and concentrate to give the title compound (0.36 g, 94% Yield) as an oil. Purity by LC/MS (APCI)=100% area, [M+H]+=383 m/e.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9]1([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccc1Br
Reactant: c1ccc(Nc2ccccc2)cc1
Product: Cc1ccccc1N(c1ccccc1)c1ccccc1
Yield: 99.5 %

Procedure:
According to the general procedure A, 2-bromotoluene (188 mg, 1.10 mmol) reacted with diphenylamine (169 mg, 1.00 mmol) to give the title compound (258 mg, 99%) as a white solid at room temperature for 4 h. Reaction of 2-chlorotoluene (70 mg, 0.55 mmol) with diphenylamine (85 mg, 0.50 mmol) proceeded at 80° C. for 21 h to give the title compound (134 mg, 99%). 1H-NMR (400 MHz, CDCl3): δ 7.14-7.27 (m, 8H), 7.01-6.92 (m, 6H), 2.06 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 147.46, 145.37, 136.49, 131.67, 129.61, 128.99, 127.33, 125.95, 121.50, 121.33, 18.56. GC/MS(EI): m/z 259 (M+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[Na+].C(=O)(O)[O-].[Na+].[OH-].[NH4+:53]>>[NH2:53][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCC(N)=O
Reaction time: 2 h

Procedure:
3-[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propanamide (2.4 g, 8.1 mmol) was treated with mCPBA (3.24 g, 14.1 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.99 g, 15.7 mmol) according to a modification of the method described in Part D of Example 8. The reaction was not washed with 10% aqueous sodium hydroxide prior to the addition of ammonium hydroxide. After the amination reaction was stirred for two hours, 10% aqueous sodium hydroxide (25 mL) and saturated aqueous sodium bicarbonate (25 mL) were sequentially added with stirring. A precipitate formed and was isolated by filtration. The solid was triturated twice with 25% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried in a vacuum oven for three days to provide 0.685 g of 3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propanamide as tan needles, mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)[C:9]=2[CH3:26])=[CH:4][CH:3]=1.[CH2:27](O)[C:28]1[O:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]([CH2:27][C:28]4[O:32][CH:31]=[CH:30][CH:29]=4)[N:24]=[N:23][N:22]=3)[C:9]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: OCc1ccco1
Reactant: Cc1c(-c2nnn[nH]2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(-c2nnnn2Cc2ccco2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
A mixture of 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-tetrazole (113 mg, 0.28 mmol) obtained in Step 1 of Example 52, furfuryl alcohol (0.05 ml, 0.56 mmol) and triphenylphosphine (146 mg, 0.56 mmol) was dissolved in tetrahydronfuran (3 ml) and cooled down to 0° C. Then, diisopropyl azodicarboxylate (0.11 ml, 0.56 mmol) was slowly added thereto at 0° C. After stirring for 2 hours at room temperature, the resulting solution was quenched with saturated ammonium chloride solution (1 ml). The mixture was extracted with ethyl acetate, and then the solvent of the organic layer was removed under a reduced pressure. The residue contained two regioisomers were separated by silica gel column chromatography (hexane/ethyl acetate=1/5), and repurified by reverse phase preparative HPLC, to obtain two compound, one of which was the title compound (22 mg, 16%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:6]=1[NH:15]C(=O)CCC.[CH3:23][C:24]([O-:27])([CH3:26])[CH3:25].[K+].O>CN(C=O)C>[C:24]([O:27][C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[C:3]([C:2]([CH3:1])([CH3:21])[CH3:22])[NH:15]2)=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])([CH3:26])([CH3:25])[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: CCCC(=O)Nc1cc(F)c([N+](=O)[O-])cc1C#CC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Oc1cc2[nH]c(C(C)(C)C)cc2cc1[N+](=O)[O-]
Yield: 21.1 %

Procedure:
A solution of N-(2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide (500 mg, 1.63 mmol) and t-BuOK (0.37 g, 3.26 mmol) in DMF (10 mL) was heated at 70° C. for 2 h. The mixture was poured into water and then extracted with EtOAc (50 mL×3). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give 6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole (100 mg, 21%). 1H-NMR (300 MHz, DMSO-d6) δ 11.35 (brs, 1H), 7.99 (s, 1H), 7.08 (s, 1H), 6.25 (s, 1H), 1.34 (s, 9H), 1.30 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:18][N:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[C:16]=2[O:15][C:14]1=[O:17]
Reactant: O=c1[nH]c2cccc(OC3CCCCO3)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)oc2c(OC3CCCCO3)cccc21
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a suspension of 7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (300 mg) and potassium carbonate (529 mg) in dimethylformamide (3 ml) was added methyl iodide at ambient temperature, and the mixture was stirred for 3 hours under nitrogen atmosphere. Water was added to the reaction mixture, and the resulting precipitates were collected by filtration to give 3-methyl-7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (299 mg).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][C:19]1([CH3:37])[O:36][CH:22]2[CH:23]3[CH2:28][O:27][C:26](=[O:29])[CH:25]=[C:24]3[CH2:30][CH:31]([O:32][CH2:33][O:34][CH3:35])[CH:21]2[O:20]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C.C(OCC)(=O)C>[CH3:18][C:19]1([CH3:37])[O:36][CH:22]2[CH:23]3[CH2:28][O:27][CH:26]([OH:29])[CH:25]=[C:24]3[CH2:30][CH:31]([O:32][CH2:33][O:34][CH3:35])[CH:21]2[O:20]1
Reactant: COCOC1CC2=CC(=O)OCC2C2OC(C)(C)OC12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCOC1CC2=CC(O)OCC2C2OC(C)(C)OC12
Reaction time: 2 h
Yield: 179.7 %

Procedure:
Under an argon atmosphere, 18 microliters of diisobutyl aluminum hydride (0.5N toluene solution) was added at -78° C. to a 0.5 ml toluene solution of 2.1 mg 1,5,6,7,8,8a-hexahydro-7,8-(dimethylmethylenedioxy)-6-methoxymethoxy-3H-2-benzopyran-3-one, and stirring was conducted for 2 hours. After the temperature was elevated to 0° C., the reaction mixture was diluted with diethyl ether, and a saturated sodium sulfate aqueous solution was added until a white precipitate was formed. To the obtained reaction mixture was added ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford 3.8 mg of 1,5,6,7,8,8a-hexahydro-7,8-(dimethylmethylenedioxy)-6-methoxymethoxy-3H-2-benzopyran-3-ol having the following properties (yield 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[SH:10])([O-])=O.[C:11](OC(=O)C)(=O)[CH3:12]>C(O)(=O)C.[Zn]>[CH3:11][C:12]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cnccc1S
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc2cnccc2s1
Yield: 44.5 %

Procedure:
A mixture of 1.3 g of 3-nitropyridine-4-thiol in 4 ml of acetic acid and 15 ml of acetic anhydride containing 1.5 g of zinc dust was heated at reflux for four hours. The reaction mixture was cooled and concentrated to an oil. The oil was dissolved in 5N sodium hydroxide and the alkaline solution was extracted with diethyl ether. The extracts were combined, dried and concentrated to dryness to afford 557 mg of 2-methylthiazolo[4,5-c]pyridine. M+Theory 150; Found 150.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:13][CH2:12][CH:8]([C:9](O)=[O:10])[CH2:7][CH2:6]1)=O.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>ClCCl.CO>[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][N:17]1[C:9]([CH:8]1[CH2:12][CH2:13][NH:5][CH2:6][CH2:7]1)=[O:10]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)C1CCN(C(=O)C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: O=C(C1CCNCC1)N1CCc2ccccc2C1
Yield: 76.1 %

Procedure:
N-Trifluoroacetyl isonipecotic acid (2.56 g, 11.4 mmol), tetrahydroisoquinoline (1.82 g, 13.7 mmol), EDCI (2.63 g, 13.7 mmol), HOBT (1.85 g, 13.7 mmol) and triethylamine (1.38 g, 13.7 mmol) were stirred in dry dichloromethane (30 mL) at 25° C. for 6 h. The reaction was quenched with water and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried over MgSO4 and purified by column chromatography (40/60 EtOAc/hexanes). The solid obtained was stirred with excess K2CO3 in MeOH at 25° C. overnight (16 h). After evaporation of MeOH, the residue was partitioned between dichloromethane and basic water. Evaporation of the organic phase gave pure product as a colorless solid (2.12 g, 76% for two steps). 1H NMR (CDCl3) (mixture of two rotamers) δ 7.23-7.16 (m, 4H), 4.73 (s, 1H), 4.67 (s, 1H), 3.83 (t, J=5.9 Hz, 1H), 3.74 (t, J=5.8 Hz, 1H), 3.21-3.16 (m, 2H), 2.92 (t, J=5.7 Hz, 1H), 2.85 (t, J=5.7 Hz, 1H), 2.76-2.67 (m, 3H), 2.29 (s, 1H), 1.80-1.73 (m, 4H); 13C NMR (CD3OD-CDCl3) δ 6 175.5, 175.3, 135.8, 135.1, 134.0, 133.8, 129.6, 129.3, 127.9, 127.6, 127.4, 127.3, 127.0, 48.2, 45.8, 45.4, 44.2, 41.4, 40.2, 39.6, 39.5, 30.5, 29.5, 29.4, 29.1; LRMS: m/z (relative intensity), 244 (M+, 37%), 188 (100%), 132 (74%); HRMS: calcd. for C15H19N2O 244.1576, found 244.1574. MP: 75-76° C.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl-].[NH4+].[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:23]1[O:19][CH2:20][C:21]#[C:22][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: C1CCOC1
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Product: C(#CC1c2ccccc2C=Cc2ccccc21)COC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This preparation illustrates methods according to step 1 of the process for preparing the compounds of formula A. In this preparation a solution containing 8 g. of 5-chloro-5H-dibenzo[a,d]cycloheptene in 200 ml. of anhydrous tetrahydrofuran is added dropwise, under nitrogen, to a stirred solution containing 0.042 moles of 3-(2-tetrahydropyranyloxy)-prop-1-ynyl-1-magnesium chloride in 210 ml. of anhydrous tetrahydrofuran, at room temperature. The resulting mixture is heated for 2 hours at reflux and then allowed to stand, with stirring, for 16 hours at room temperature. The reaction mixture is then treated, first with 25 ml. of saturated aqueous ammonium chloride solution, then with 75 ml. of water, and then concentrated under reduced pressure to remove most of the organic solvent resulting in a two-phase liquid-liquid system, which is then shaken and extracted with three 60 ml. portions of ethyl ether. The ethereal extracts are combined and washed consecutively with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine. The washed extracts are dried over sodium sulfate-potassium carbonate and then evaporated under reduced pressure affording a residue of 5-[3-(2-tetrahydropyranyloxy)-prop-1-ynyl]-5H-dibenzo[a,d] cycloheptene, which is divided into two portions, one of which is further purified by column chromatography on silica gel. The other portion is used directly as starting material for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26]C)=[O:24])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:28]3[CH2:34][CH:33]4[O:35][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[N:9]=2)=[CH:4][CH:3]=1.C12OC(CC1)CN(C1N=C(Cl)N=C3N(C4CCN(C(OC)=O)CC4)N=CC=13)C2.[Cl-]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:22]4)[N:15]=[CH:16][C:11]3=[C:10]([N:28]3[CH2:29][CH:30]4[O:35][CH:33]([CH2:32][CH2:31]4)[CH2:34]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(N)cc4)nc32)CC1
Agent: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(Cl)nc32)CC1
Agent: [Cl-]
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(N)cc4)nc32)CC1

Procedure:
A Suzuki coupling procedure similar to that used for the synthesis of ethyl 4-(6-(4-aminophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, using methyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate as the chloride component (68%, MS=464.2 (M+H))
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2>CS(C)=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][N:16]([CH2:21][C@H:20]([OH:19])[CH2:22][O:23][C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[CH:26]=[CH:27][NH:28]5)[CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2c(C3=CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.12 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.78 g, 4.12 mmol). The product was isolated as an orange granular solid. Yield 0.61 g (34%). mp 225°-230° C. FDMS m/e=432 (M+ of free base). α[D]589 =+1.98 (c=1.01, dimethylsulfoxide).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[F:35][C:36]([F:42])([F:41])[S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:24][CH:22]([S:19]([NH:18][CH2:17][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][S:37]([C:36]([F:42])([F:41])[F:35])(=[O:39])=[O:38])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH3:25])(=[O:21])=[O:20])[CH3:23]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCNS(=O)(=O)C(F)(F)F)cc2)cc1
Yield: 38.5 %

Procedure:
The title compound (130 mg, 38%, slow crystallizing-foam) was prepared from (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylene chloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), and trifluoromethanesulfonyl chloride (0.07 mL, 0.664 mmol) in a manner analogous to the procedure described in Example 40.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:53](=[O:54])[N:6]2[C:7]([C:40]([O:42]CC3C=CC([N+]([O-])=O)=CC=3)=[O:41])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([C:27]([O:29]CC6C=CC([N+]([O-])=O)=CC=6)=[O:28])[CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:55]([CH2:58][CH2:59][CH2:60]O)=[N+]=[N-]>>[NH2:55][CH2:58][CH2:59][CH2:60][N+:23]1[CH:24]=[C:25]([C:27]([OH:29])=[O:28])[CH:26]=[C:21]([C:19]([C:16]2[N:17]=[CH:18][N:13]3[CH:12]=[C:11]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:53](=[O:54])[N:6]5[C:7]=4[C:40]([O-:42])=[O:41])[S:15][C:14]=23)=[O:20])[CH:22]=1
Reactant: [N-]=[N+]=NCCCO
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(C(=O)OCc6ccc([N+](=O)[O-])cc6)c5)c4s3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5cc(C(=O)O)c[n+](CCCN)c5)c4s3)[C@H](C)[C@H]12
Yield: 16.5 %

Procedure:
The title compound (11.5 mg) was prepared in the same manner as in steps a) and b) of Example 4, except that 97.2 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[5-(4-nitrobenzyloxycarbonyl)pyridin-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate and 27.0 mg of 3-azido-1-propanol were used as the starting compounds.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[CH2:14][O:15]C(=O)C2C=CC=CC=2)=[CH:4][N:3]=1.CN>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH:13]([CH2:14][OH:15])[CH2:24][OH:25])=[CH:4][N:3]=1
Reactant: Nc1ncc2ncn(COC(COC(=O)c3ccccc3)COC(=O)c3ccccc3)c2n1
Agent: CN
Product: Nc1ncc2ncn(COC(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.844 g (1.88 mM) of 2-amino-9-[(2-benzoyloxyl-1-(benzoyloxymethyl)ethoxy)methyl]-9H-purine and 100 ml of a 40% aqueous methylamine solution was stirred at room temperature for 30 minutes. The mixture was flash evaporated to a yellow oil which was then washed with water. The aqueous layer was then extracted twice with methylene chloride. The aqueous layer containing the product was then flash evaporated to a light yellow oil. Recrystallization of the oil in hot acetonirile yielded the title compound as an analytically pure ivory solid, mpt. 148°-151°.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6]([CH3:9])=[CH:7][O:8][C:4]=2[CH:3]=1.[CH2:13]([O:16][CH2:17][CH2:18]Br)[CH2:14]Br.C(N(C(C)C)C(C)C)C>C(O)C>[CH3:9][C:6]1[C:5]2[CH:10]=[C:11]([CH3:12])[C:2]([N:1]3[CH2:18][CH2:17][O:16][CH2:13][CH2:14]3)=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: BrCCOCCBr
Reactant: Cc1cc2c(C)coc2cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc2c(C)coc2cc1N1CCOCC1

Procedure:
A mixture of 22.8 g (0.141 mole) of 6-amino-3,5-dimethylbenzofuran, 65.8 g (0.283 mole) of 2,2'-dibromodiethyl ether, 36.1 g (0.279 mole) of N-ethyldiisopropylamine and 210 ml of ethanol is boiled under reflux for 16 hours. The residue obtained after removal of the ethanol in vacuo is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried, concentrated by evaporation and the crude product is chromatographed over silica gel with petroleum ether/ether. The excess 2,2'-dibromodiethyl ether is removed in a water-jet vacuum over a Vigreux column and the residue is purified by means of solid distillation (110°-115°/4.10-2 torr). 3,5-dimethyl-6-morpholinobenzofuran is obtained having a melting point of 69°-70°.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>O1CCCC1.[OH-].[Na+]>[C:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OC(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of phenyl-[1-(2-phenylethyl)-4-piperidyl]-ketone (0.10 g) in tetrahydrofuran (0.40 g) was added to wet surface-modified adsorbent of Example 10 (1.0 g) in excess aqueous NaOH pH 9.0 (2.0 mL). This mixture was stirred at ambient temperature for 30 minutes. After this, NaBH4 (20 mg) was added and the resulting mixture was stirred at ambient temperature for 16 hours. The liquid phase was then decanted and the adsorbent was washed with tetrahydrofuran in order to quantitatively extract all product from the resin. The tetrahydrofuran washings were combined with liquid phase and analyzed by chiral High Pressure Liquid Chromatography (HPLC) using a Chiracel OD-R column commercially available from Chiral Technologist Incorporation and 1.0M aqueous NaClO4 /acetonitrile (60/40 by volume) as a mobile phase. The product α-phenyl-[1-(2-phenylethyl )]-4-piperidinemethanol of a moderate enantiomeric purity (enantiomeric excess of S (-)=25 percent) was obtained.