Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[N:14][CH:13]=1)C.O(CC)[Li].CC([O-])=O.[Na+]>C1COCC1.C(O)(=O)C>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C:11]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[O:10])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C1CNCCNC1
Agent: CC(=O)[O-]
Agent: [Li]OCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)N1CCCNCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of homopiperazine (12.5 g, 125 mmol) and ethyl-6-chloronicotinate (9.28 g, 50 mmol) in THF (150 mL) was cooled to 0° C. and LiOEt (1 M in THF, 50 mL, 50 mmol) was then added over 20 minutes. The resulting mixture was stirred at 0° C. for 2 h, then warmed to 20° C. and held at this temperature for 17 h. The resulting mixture was then treated with 162 mL of an aqueous solution containing 1.53 g of NaOAc and 8.2 mL of acetic acid. The resulting layers were separated and the organic was diluted with hexane (50 mL) and extracted again with the same aqueous solution as utilized above. The aqueous pH was then increased to 10 through addition of 50% NaOH(aq) (15 mL). After extraction with dichloromethane (3×250 mL) the combined organics were dried over sodium sulfate, filtered, and concentrated to yield the title compound as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)=[O:2].[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:68](O)[CH2:69][OH:70]>C(OCC)(OCC)OCC.C(OCC)(=O)C.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[O:2]1[CH2:68][CH2:69][O:70][CH:1]1[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: COC(=O)Cc1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(4-formylphenyl)acetate (1.72 g, 9.66 mmol) was dissolved in ethylene glycol (2.3 mL) and triethyl orthoformate (1.8 mL). Tetrabutylammonium tribromide (0.048 g) added and the reaction stirred at RT for 1 hour. Further tetrabutylammonium tribromide (0.434 g) added and the reaction stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0-15% ethyl acetate in iso-hexane to afford impure methyl 2-(4-(1,3-dioxolan-2-yl)phenyl)acetate (0.84 g). This material was dissolved in THF (15 mL) and cooled to −78° C. A solution of lithium aluminium hydride (1.0 M in THF, 6.00 mL, 6.00 mmol) was added drop-wise. The reaction mixture was allowed to warm to RT over 18 hours. The mixture was sequentially treated with water (0.228 mL), 2M aqueous sodium hydroxide (0.228 mL) and water (3×0.228 mL). The mixture was diluted with ethyl acetate and magnesium sulfate added. The mixture was stirred at RT for 1 hour and then filtered through celite. The filter cake was washed with further ethyl acetate and the filtrates combined. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0-40% ethyl acetate in iso-hexane to afford the title compound (0.315 g, 17%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH2:16]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]([CH3:19])[CH3:18].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:16]([N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:6](=[O:8])[C:5]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CNCC(C)C
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)CN(CC(C)C)C(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 64.8 %

Procedure:
To a slurry of 106.5 g of 2,6-dinitrobenzoic acid in 1000 ml of toluene was added with stirring 133.2 g of diisobutylamine. Next 44.9 g of phosphorus oxychloride was added dropwise at such a rate to maintain the temperature below 40° C. The mixture was heated to 50° C. for 12 hrs and poured into 500 ml of aqueous 5% NaHCO3 solution with stirring. The organic layer was separated, washed with 500 ml water, and the toluene removed under reduced pressure. The remaining solid was recrystallized from hot ethanol to give 105.2 g of N,N-diisobutyl-2,6-dinitrobenzamide, a yellow solid, mp 97°-99° C.
Reaction SMILES: [OH-].[K+].C(OC([C:8]1[C:9]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:10][N:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH2:19][OH:20])[C:12]=12)=O)C>CO>[OH:20][CH2:19][C:13]1[C:12]2[N:11]([N:10]=[C:9]([C:21]([F:27])([F:26])[C:22]([F:23])([F:24])[F:25])[CH:8]=2)[C:16]([O:17][CH3:18])=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1c(C(F)(F)C(F)(F)F)nn2c(OC)ccc(CO)c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CO)c2cc(C(F)(F)C(F)(F)F)nn12
Temperature: 150 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A 4 mol/L aqueous potassium hydroxide solution (7.0 mL) was added to a solution of the compound of Example 352 (3.33 g) in methanol (50 mL). The mixture was refluxed for 2 hours. Subsequently, the mixture was concentrated and made acidic. The resultant crystals were collected by filtration. To this product, 1,2-dichlorobenzene (50 mL) was added and the mixture was stirred at 150° C. overnight. Evaporation of the solvent and subsequent purification by silica gel column chromatography (hexane:ethylacetate=3:1→1:1) afforded the title compound as a colorless powder (1.28 g).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54]([NH:73][C:74]1[S:75][CH:76]=[C:77](/[C:79](=[N:83]/[O:84][CH2:85][C:86]([O:88][CH:89]([C:96]2[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=2)[C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)=[O:87])/[C:80](O)=[O:81])[N:78]=1)([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClC.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:80](=[O:81])/[C:79](/[C:77]4[N:78]=[C:74]([NH:73][C:54]([C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=5)([C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=5)[C:67]5[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=5)[S:75][CH:76]=4)=[N:83]\[O:84][CH2:85][C:86]([O:88][CH:89]([C:96]4[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=4)[C:90]4[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=4)=[O:87])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: CCl
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethyl-thio)-3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg: 1.06 mMol.) and (Z)-2-(2-tritylaminothiazol-4-yl)-2-(diphenylmethoxycarbonylmethoxyimino)acetic acid (728 mg: 1.11 mMol.) in chloromethane (8 ml) cooling at -30° C. are added N-methylmorpholine (0.27 ml: 2.46 mMol.), phenyl dichlorophosphate (0.19 ml: 1.27 mMol.), and the mixture is stirred at -30° C. for 30 minutes. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=10:1) to give 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(diphenylmethoxycarbonylmethoxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.07 g) as yellow foam. Yield: 73%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N(C(C)C)C(C)C)C.[C:26]1([S:32][N:33]([CH2:39][CH2:40]OS(C)(=O)=O)[C:34](=[O:38])[O:35][CH2:36][CH3:37])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(C=CC(O)=CC=1)O>CS(C)=O.N1C=CC=CC=1>[C:26]1([S:32][N:33]([CH2:39][CH2:40][O:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([F:1])[CH:15]=[C:14]([F:16])[CH:13]=3)=[CH:11][CH:10]=2)[C:34](=[O:38])[O:35][CH2:36][CH3:37])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: CCOC(=O)N(CCOS(C)(=O)=O)Sc1ccccc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 4.3 g of 4-(3,5-difluorophenoxy)phenol and 1.58 g of pyridine or 2.58 g of ethyl diisopropylamine in 35 ml of dry dimethyl sulfoxide is metered at a constant rate at +25° C. in the course of 5 hours to a solution of 6.4 g of ethyl N-phenylthio-2-methylsulfonyloxyethylcarbamate and 0.2 g of hydroquinone in 20 ml of anhydrous dimethyl sulfoxide, with stirring. The mixture is stirred for 5 more hours at room temperature. After this, the reaction mixture is poured into ice-water and extracted three times with an ether/hexane mixture (1:4), and the combined organic phases are washed with water and dried over sodium sulfate. After the solvents have been distilled off in vacuo, the crude product is purified by chromatography, by which process ethyl N-phenylthio-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate is isolated, nD20 1.5700.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[C:12]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([NH:29][CH2:30][C:31]4[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=4)=[N:26][C:27]=3[F:28])=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:28][C:27]1[N:26]=[C:25]([NH:29][CH2:30][C:31]2[CH:32]=[N:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)[CH:24]=[CH:23][C:22]=1[CH2:21][C:12]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=2)[NH:10][CH:11]=1
Reactant: COc1cnc2c(c1)c(Cc1ccc(NCc3ccc(C(F)(F)F)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc2[nH]cc(Cc3ccc(NCc4ccc(C(F)(F)F)nc4)nc3F)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To [5-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (577, 0.08 g, 0.13 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.110 g, 0.35 mmol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give an off-white solid (P-0187, 8.1 mg, 10%). MS (ESI) [M+H+]+=431.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1OCCOCCOCCOCCOCCOC1.[K].Br[CH2:44][C:45]1[C:46]([C:53]2[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][C:54]=2[Cl:60])=[N:47][O:48][C:49]=1[CH:50]1[CH2:52][CH2:51]1>O1CCCC1.C(O)(C)(C)C>[CH:50]1([C:49]2[O:48][N:47]=[C:46]([C:53]3[C:58]([Cl:59])=[CH:57][CH:56]=[CH:55][C:54]=3[Cl:60])[C:45]=2[CH2:44][O:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=4)=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)[CH2:52][CH2:51]1
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: COc1ccc(COc2ccc(C3CCC(O)CC3)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc([C@H]3CC[C@H](OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
4-[4-(4-Methoxy-benzyloxy)-phenyl]-cyclohexanol (2.24 mmol, 700.00 mg) and 18-crown-6 (2.69 mmol, 710.70 mg) in tetrahydrofuran (10 mL) is treated with tert-butyl alcohol, potassium derivative (2.69 mmol, 2.69 mL; 1M in THF). The mixture is stirred for 30 minutes and 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (3.36 mmol, 1.17 g) is added. The mixture is stirred at room temperature for 5 minutes and heated to 40° C. for 1.5 h. Silica gel is added and the reaction mixture is concentrated under reduced pressure. The crude mixture is purified by silica gel flash chromatography eluting with a gradient of 10-60% EtOAc in hexanes. A second chromatography is performed on silica gel eluting with 0.5% EtOAc in DCM to yield the title compound (960 mg, 74%). MS m/z 577.9 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH:24]=[N:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].[Cl-].[NH4+]>O1CCOCC1.O>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH:24]=[N:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)O
Temperature: 80 °C
Yield: 46.3 %

Procedure:
A mixture of methyl 7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]quinoline-6-carboxylate (Intermediate 71, 0.100 g) and lithium hydroxide monohydrate (0.250 g) in dioxane (4 mL) and water (1.25 mL) was heated at 80° C. overnight. The mixture was cooled and saturated aqueous ammonium chloride was added. This was concentrated in vacuo and the residue was triturated with DCM and methanol, filtered and the filtrate was concentrated in vacuo. The residue was purified by HPLC (C6 Ph) eluting with a mixture of methanol and water containing 0.1% formic acid, with a gradient of 10-40% to give a yellow gum. The product was triturated with ether to give 7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-furo[2,3-c]quinoline-6-carboxylic acid (0.045 g) as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1>>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: CCCCOC(=O)c1ncc[nH]1
Reactant: BrCc1ccc2ccccc2c1
Product: CCCCOC(=O)c1nccn1Cc1ccc2ccccc2c1
Yield: 69.9 %

Procedure:
5.0 g (29.7 mmol) of butyl imidazole-2-carboxylate and 6.6 g (29.7 mmol) of 2-bromomethylnaphthalene were reacted analogously to procedure 8a. 6.4 g (71%) of the product were obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:11]=2N=N1.[C:28]([O:32][C:33]([N:35]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C:36]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]([C:51]3[CH:56]=[CH:55][C:54]([C@@H:57]([CH3:79])[CH2:58][O:59][C:60](=[O:78])[NH:61][C:62]4[CH:67]=[C:66]([CH2:68][NH:69][CH3:70])[C:65]([O:71][C@@H:72]5[CH2:76][CH2:75][O:74][CH2:73]5)=[C:64]([F:77])[CH:63]=4)=[C:53](C)[CH:52]=3)[C:48]([OH:50])=O)=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:28]([O:32][C:33]([N:35]([C:36]1[C:45]2[C:44](=[CH:43][C:42]([NH:46][CH:47]3[C:48](=[O:50])[N:69]([CH3:70])[CH2:68][C:66]4[CH:67]=[C:62]([CH:63]=[C:64]([F:77])[C:65]=4[O:71][C@@H:72]4[CH2:76][CH2:75][O:74][CH2:73]4)[NH:61][C:60](=[O:78])[O:59][CH2:58][C@H:57]([CH3:79])[C:54]4[C:53]([CH3:11])=[CH:52][C:51]3=[CH:56][CH:55]=4)=[CH:41][CH:40]=2)[CH:39]=[CH:38][N:37]=1)[C:81](=[O:82])[O:83][C:84]([CH3:85])([CH3:87])[CH3:86])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1O[C@@H]1CCOC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@@H]3CCOC3)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To BOP (167 mg, 0.377 mmol) and DMAP (115 mg, 0.944 mmol) in CH2Cl2 (40 mL) was added a solution of 38F (157 mg, 0.189 mmol) in DMF (10 mL) via a syringe pump over 6 h. The resulting mixture was stirred at rt for 16 h. The mixture was concentrated and purified by prep HPLC to give 38G (85 mg, 0.104 mmol, 55.3% yield) as a yellow solid. MS (ESI) m/z: 814.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C(=O)(O)[O-].[Na+].[Pd]>[F:28][CH:26]([F:27])[O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:20][CH:21]=1
Reactant: FC(F)Oc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=C[O-]
Solvent: CO
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCNC3)cc1
Temperature: 25 °C
Yield: 105.9 %

Procedure:
7-Benzyl-N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (1.01 g, 2.65 mmol), ammonium formate (1.67 g, 26.46 mmol) and palladium, 10% wt. on activated carbon (100 mg) in methanol (20 mL) was heated to 60° C. for 1 h. The mixture was cooled to r.t. and filtered over celite. The filtrate was concentrated under reduced pressure to give a white solid which was taken up in saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to dryness to give 0.82 g of a tan solid. The compound was further purified by silica gel chromatography using a gradient of methanol:chloroform (0-20%) to give the desired compound as an white solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:20]=[CH:19][C:18]=3[CH3:33])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:34]([CH2:36][NH2:37])[OH:35]>CS(C)=O>[OH:35][CH2:34][CH2:36][NH:37][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:20]=[CH:19][C:18]=3[CH3:33])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cc(NC(=O)c4cccc(Cl)c4)ccc3C)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1OCc1csc2c(C(=O)NCCO)cncc12
Temperature: 135 °C

Procedure:
A mixture of 3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (315 mg, 0.65 mmol) (from Example 24 supra) in methyl sulfoxide (3 mL) and ethanolamine (9 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. After cooling to room temperature, the precipitate was filtered off, washed thoroughly with MeOH and dried to give 3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 267 mg, 82.8%).
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:10]([C@H:11]([OH:22])[C:12]3[CH:13]=[CH:14][N:15]=[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.[CH2:23]([CH:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1)[CH2:24][CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:23]([CH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:22][C@H:11]([C:12]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[CH:14][CH:13]=2)[C@@H:10]2[CH2:9][C@@H:8]3[CH2:7][CH2:6][N:5]2[CH2:4][C@@H:3]3[CH:2]=[CH2:1])=[O:33])[CH2:28][CH2:27]1)[CH2:24][CH3:25]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Reactant: CCCC1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](OC(=O)C1CCC(CCC)CC1)c1ccnc2ccccc12

Procedure:
Example 10 was performed as Example 1 except for substitution of 2.7 g of cinchonidine, 1.5 g of 4-n-Propyl-cyclohexanecarboxylic acid, 2.1 g of N,N′-Dicyclohexyl carbodimide (DCC), 1.2 g of N,N-(dimethyl amino)-pyridine (DMAP) and 80 ml of dichloromethane into a round-bottom flask. After filtering and condensing, the residue was subjected to recrystallization from methanol, giving (R)-1-(4-quinolyl)-1-[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl 4-propyl-1-cyclohexanecarboxylate, as a white solid with a chemical purity 91.31%. The optical properties of the resulting compound were tested as in Example 1. The compound exhibited a specific rotation [α] of +5.52 and a helical pitch P of 3.1 μm, with helical twisting power of 32.2 μm−1.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37]>>[C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:42]4[CH2:43][CH2:44][N:39]([C:36](=[O:38])[CH3:37])[CH2:40][CH2:41]4)=[CH:19][C:18]=3[C:24]([F:26])([F:27])[F:25])(=[O:15])=[O:16])[CH2:11][CH:10]2[C:28]([N:30]2[CH2:33][C:32]([F:34])([F:35])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc(S(=O)(=O)C3CC(C(=O)NC4(C#N)CC4)C(C(=O)N4CC(F)(F)C4)C3)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 127 using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118) and 1-acetyl-piperazine. White solid. MS (EI): 632.2 (M+H)+.