Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.OP([O-])(O)=O.[K+].[OH-].[Na+].[CH3:10][O:11][C:12]([C@@H:14]1[C@H:19]([C:20]([O:22]C)=[O:21])[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:13]>CC(C)=O.C(OCC)(=O)C.CCCCCC>[CH3:10][O:11][C:12]([C@@H:14]1[C@H:19]([C:20]([OH:22])=[O:21])[CH2:18][CH:17]=[CH:16][CH2:15]1)=[O:13]
Reactant: COC(=O)[C@H]1CC=CC[C@H]1C(=O)OC
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)[C@H]1CC=CC[C@H]1C(=O)O
Reaction time: 24 h
Yield: 90.9 %

Procedure:
(1R, 6S)-6-Methoxycarbonyl-3-cyclohexene-1-carboxylic acid (2-3) was prepared following the procedure of Ohno and co-workers4, that had been successfully applied by Appella et al.3 of the Gellman group. Precaution was taken to make sure all glassware was clean. All glassware was washed in acid bath and rinsed twice with Millipore water. To Millipore water (2.6 L) was added KH2PO4 (61.79 g, 454 mmol) and the pH of the resulting solution adjusted to 8 by adding a prepared solution of 2.5 M NaOH and using a pH meter calibrated at pH 4 and pH 10. The diester 2-2 (45 g, 227 mmol) was dissolved in reagent grade acetone (131 mL) and this solution added to the aqueous KH2PO4 solution. Pig liver esterase (10.5 mL, 48189 units) was added, and the resulting solution was stirred for 24 hours. The reaction was monitored by TLC (1:1 hexane:ethyl acetate, Rf (2-2)=0.67, Rf(2-3)=0.24). After ascertaining that reaction was complete, the enzyme was filtered off through celite in a fritted glass funnel. The resulting solution was then acidified with 1M HCl to a pH about 2 and then extracted three times with ethyl acetate (1200 mL total). The organic extracts were dried over MgSO4, concentrated, and dried under vacuum overnight to afford 38 g (91%) of 2-3 as a thick yellow oil: 1H NMR (300 MHz, CDCl3): δ 11.24 (br s, 1H, OH), 5.68 (m, 2H, HC═CH), 3.70 (s, 3H, OCH3), 3.07 (m, 2H, CHCOOCH3 and CHCOOH), 2.62-2.54 (m, 2H, CH2CHCOOCH3 or CH2CHCOOH), 2.41-2.32 (m, 2H, CH2CHCOOCH3 or CH2CHCOOH); 13C NMR (75 MHz, CDCl3): δ 179.6 (C), 173.5 (C), 125.0 (CH), 124.8 (CH), 51.7 (CH3), 39.4 (CH), 39.2 (CH), 25.5 (CH2), 25.3 (CH2); MS-ESI m/z 207.1 [M+Na]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[C:13]([CH3:14])=[C:12]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:17])[O:11][N:10]=1.Cl[C:25]1[S:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:26]=1.C(N(CC)CC)C.CN(C)C=O>O>[CH3:8][C:9]1[C:13]([CH3:14])=[C:12]([NH:15][C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:25]3[S:29][N:28]=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)[N:26]=3)[CH2:22][CH2:23]2)=[O:17])[O:11][N:10]=1
Reactant: Fc1cccc(-c2nsc(Cl)n2)c1
Reactant: Cc1noc(NC(=O)N2CCNCC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(F)c4)ns3)CC2)c1C
Yield: 44.8 %

Procedure:
A solution of N-(3,4-dimethylisoxazol-5-yl)piperazine-1-carboxamide trifluoroacetate (300 mg, 0.887 mmol), 5-chloro-3-(3-fluorophenyl)-1,2,4-thiadiazole (190 mg, 0.887 mmol), triethylamine (0.618 ml, 4.43 mmol) and N,N-dimethylformamide (3 ml) was stirred at room temperature for 2 hours and the reaction mixture was poured into water. A solid was collected by filtration and recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (160 mg, 44.8%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:44]([CH3:48])([CH3:47])[C:45]#[N:46])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[O:33])=[CH:28][N:27]=4)[C:22](=[O:40])[N:21]([CH3:41])[N:20]=3)[C:14]=1[CH:42]=[O:43])[CH:8]=[CH:7]2.[BH4-].[Na+]>CO.ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:44]([CH3:48])([CH3:47])[C:45]#[N:46])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[O:33])=[CH:28][N:27]=4)[C:22](=[O:40])[N:21]([CH3:41])[N:20]=3)[C:14]=1[CH2:42][OH:43])[CH:8]=[CH:7]2
Reactant: Cn1nc(-c2cccc(-n3ccc4cc(C(C)(C)C#N)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cn1nc(-c2cccc(-n3ccc4cc(C(C)(C)C#N)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reaction time: 0.17 h

Procedure:
A solution of 2-[8-fluoro-2-(2-formyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile (224 mg, 0.35 mmol) in methanol (2.8 ml) and dichloromethane (4.3 ml) was cooled in an ice bath. To this was added a solution of sodium borohydride (65 mg, 1.7 mmol) in water (0.75 ml), via slow drop-wise addition. The mixture was stirred for 10 minutes and additional sodium borohydride (as describe above was added twice more over 20 minutes. The aqueous upper phase was carefully removed from the biphasic reaction solution. Methanol (1 ml) was added and with rapid stirring 3 more additions of aqueous sodium borohydride were made (as described above) over about 25 minutes. Water (60 ml) and dichloromethane (60 ml) were added and the material was transferred to a separatory funnel and the organic phase was collected. This was washed with an equal volume of 50% diluted brine solution and the dichloromethane phase collected. The aqueous phases were back extracted with dichloromethane (2×40 ml). The combined organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by HPLC on silica gel, eluting with 1% to 8% methanol/dichloromethane to provide the desired product which was further purified by crystallization from hot dichloromethane/hexane to provide desired product as a white solid (120 mg). (M+H)+=650 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6H) 3.53-3.81 (m, 8H) 3.83-3.91 (m, 1H) 3.92 (s, 3H) 4.26-4.45 (m, 2H) 6.62 (dd, J=7.55, 1.89 Hz, 1H) 7.00 (d, J=8.31 Hz, 1H) 7.22 (dd, J=12.46, 1.89 Hz, 1H) 7.33 (d, J=7.18 Hz, 1H) 7.42 (dd, J=7.93, 1.51 Hz, 1H) 7.53 (d, J=1.89 Hz, 1H) 7.57 (t, J=7.93 Hz, 1H) 7.65-7.70 (m, 1H) 7.78 (dd, J=8.69, 2.27 Hz, 1H) 8.41-8.47 (m, 2H) 8.70 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:13])[C@@H:5]2[NH:10][CH:11]=O.N1C(C)=CC=CC=1C.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:13])[C@@H:5]2[N+:10]#[C-:11]
Reactant: CC1(C)OCC[C@@H]2[C@@H](NC=O)C(=O)N21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: [C-]#[N+][C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
To a solution of (6R,7R)-2,2-dimethyl-7-formamido-1-aza-3-oxabicyclo[4.2.0]octan-8-one (345 mg) were added 2,6-lutidine (2.05 ml) and phosphorus oxychloride (0.52 ml) at 0° C. After stirring for 3 hours at 0° C., the mixture was poured into a mixture of ethyl acetate (80 ml) and ice-water. The organic layer was separated, washed in turn with 10% phosphoric acid, water, brine, an aqueous mixture of sodium bicarbonate and sodium chloride (1:1), and brine, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with a mixture of petroleum ether and ether (1:1) and dried over phosphorus pentoxide to give (6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (205 mg).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]2=3)=[CH:23][CH:22]=1
Reactant: Brc1ccc(Br)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCC2CCCCC2C1
Product: Brc1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: 200 °C
Yield: 25.1 %

Procedure:
A mixture of 9.2 g (38 mmol) of 9H-tribenz[b,d,f]azepine (synthesized in accordance with J. Org. Chem., vol. 56, p. 3906 (1991)), 44.8 g (190 mmol) of 1,4-dibromobenzene, 5.6 g (100 mmol) of potassium hydroxide, 1.6 g (25 mmol) of copper powder, and 50 ml of decalin was heated at an external temperature of 200° C. for 36 hours in a nitrogen stream while stirring. The reaction mixture was cooled nearly to room temperature, chloroform was added thereto, followed by filtration using Celite to remove the insoluble matter. The filtrate was concentrated. To remove decalin, n-hexane was added to the residue, followed by filtration. The filter cake was purified by silica gel column chromatography to give 3.8 g (25%) of 9-(4-bromophenyl)-9H-tribenz[b,d,f]azepine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)=[O:8])C.Cl.[NH2:19]O>CO>[CH3:1][O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[O:8][N:19]=1)=[O:17]
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(Cl)c2)on1
Yield: 71.3 %

Procedure:
A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.0 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol) in MeOH (60 ml) was heated at 80° C. for 4 h. After cooling, the mixture was filtered and washed with cold methanol to afford 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (2.0 g, 71%). 1H NMR: 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H). Step 2: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanone: In a screw cap vial equipped with stir bar was mixed methyl magnesium iodide (3M in Et2O) (0.79 ml, 2.38 mmol), toluene (1 ml), tetrahydrofuran (0.39 ml, 4.77 mmol) and TEA (1 ml, 7.15 mmol). After cooling to 0° C. a solution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (300 mg, 1.19 mmol) in toluene (5 ml) was added, followed by stirring at 0° C. for 5 h. The mixture was then quenched with aq 1N HCl (6.5 ml, 6.5 mmol), diluted with toluene (35 ml), sequentially washed with water, sat. aq. sodium bicarbonate,water and brine. The organic phase was concentrated in-vacuo. The isolated residue was dissolved in MeOH (8 ml) and 20% aq. KOH (1 ml) was added, followed by stirring at 45° C. for 30 min and then concentrated in-vacuo. The residue was dissolved in toluene (60 ml), sequentially washed with water, sat. aq. sodium bicarbonate and water. The organic phase was concentrated in-vacuo. The crude residue was purified on silica gel using 2% EA in hex. to isolate the desired compound (156 mg, 60%). 1H-NMR: 7.77 (m, 1H), 7.66 (m, 1H), 7.42 (m, 2H), 6.90 (s, 1H), 2.69 (s, 3H). Step 3: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol: In a screw cap vial equipped with stir bar was mixed 1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone (100 mg, 0.45 mmol), sodium borohydride (34 mg, 0.90 mmol) and MeOH (3 ml), followed by stirring at r.t for 3 h and the quenched with water and brine, extracted with DCM. The combined organic phase was dried (Na2SO4), filtered and concentrated in-vacuo to isolate the title compound. 1H-NMR: 7.69 (m, 1H), 7.59 (m, 1H), 7.37 (m, 2H), 6.59 (s, 1H), 5.07 (q, 1H), 3.45 (br. s, 1H), 1.58 (d, 3H).
Reaction SMILES: [BH4-].[Na+].[Br-].[C:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][CH2:18][CH2:19][N+:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([OH:6])=[O:5]>O.[OH-].[Na+]>[C:26]1([C:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][CH2:16][C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:4]([OH:6])=[O:5])[CH:8]=4)[NH:12][CH:11]=3)[CH2:21][CH:22]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc2[nH]cc(CCCC[n+]3ccc(-c4ccccc4)cc3)c2c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reaction time: 3 h

Procedure:
1 g of NaBH4 in 20 ml of water is added, with stirring, to a solution of 4.51 g of 1-[4-(5-carboxy-3-indolyl)-butyl]-4-phenylpyridinium bromide [obtainable from 3-(4-bromobutyl)-indole-5-carboxylic acid and 4-phenylpyridine] in 50 ml of 1N NaOH, and stirring is continued for a further 3 hours at 60°. Working up in the customary manner gives 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid, m.p. 284°-285°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[NH:20][CH:21]([CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH3:22])=[N:6][CH:7]=1.[B-][N+](C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[NH:20][CH:21]([CH:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[CH3:22])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [B-][N+](C)(C)C
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(C)C2CCNCC2)c1
Yield: 24.7 %

Procedure:
Using a similar procedure to that described in Example 47-D, N-(5-chloropyridin-2-yl)-2-[[1-(1-Boc-piperidin-4-yl)ethyl]amino]-4-methoxycarbonylbenzamide (0.35 g, 0.68 mmol) and borane trimethylamine complex (0.15 g, 2.0 mmol) afforded 70 mg of the title compound. IS-MS, m/e 417 (m+1); Analysis for C21H25ClN4O3.2HCl: Calcd: C, 51.50; H, 5.56; N, 11.44; Found: C, 51.51; H, 5.73; N, 11.26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:31][CH2:32][CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:31][CH2:32][CH2:33][OH:34])=[O:17])=[N:14][CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.2 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(3,5-difluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (105 mg, 0.24 mmol) in methylene chloride (5 ml), 2-aminoethanol (0.016 ml, 0.26 mmol), 1-hydroxybenzotriazole (36 mg, 0.26 mmol), 4-methylmorpholine (0.029 ml, 0.26 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (51 mg, 0.26 mmol) were added at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (36 mg, 0.07 mmol, 31%) as a white solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1CCCCC1.[CH3:15][O:16][C:17]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[Br:24][CH2:25][CH2:26][CH2:27]Br>C1COCC1.[Cl-].[Na+].O>[CH3:15][O:16][C:17]([C:19]1([CH2:27][CH2:26][CH2:25][Br:24])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: BrCCCBr
Reactant: COC(=O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCCCC1
Product: COC(=O)C1(CCCBr)CCCC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 143.3 %

Procedure:
To a solution of 1.5 molar LDA in cyclohexane (60 mmol, 40 mL) cooled to −70° C. was added a solution of cyclopentane carboxylic acid methyl ester (42 mmol, 5.6 g) in THF (15 mL) over 30 min. The mixture was stirred for 1 hr at −70° C. Then a solution of 1,3-dibromopropane (60 mmol, 11.9 g) in THF (30 mL) which had been pre-cooled to −70° C. was added all at once and the reaction mixture was stirred at −70° C. for one hr then at room temperature overnight. The reaction mixture was poured into brine (200 mL), the layers were separated, the aqueous layer was extracted with ether (3×30 mL) and the combined organic layers were washed with brine (20 mL), dried (magnesium sulfate) and concentrated to give a yellow oil (15 g). Distillation through a short path apparatus with a 3″ vigreux column gave a yellow oil, 7.96 g (76%), bp 76-80° C. at 0.3 mm.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]=[CH2:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([P:20]([CH3:23])([CH3:22])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.I[C:47]1[C:52]([CH3:53])=[CH:51][CH:50]=[CH:49][C:48]=1[CH3:54].CCN(C(C)C)C(C)C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:54][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]([CH3:53])[C:47]=1/[CH:12]=[CH:11]/[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([P:20]([CH3:22])([CH3:23])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1cccc(C)c1I
Reactant: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To an oven-dried 50 mL round-bottom flask were added 2-chloro-N-(4-(dimethylphosphoryl)phenyl)-9-vinyl-9H-purin-6-amine (0.32 g, 0.93 mmol), Pd(OAc)2 (10 mg, 0.05 mmol), tri-o-tolylphosphine (30 mg, 0.1 mmol), 2-iodo-m-xylene (0.39 g, 1.67 mmol). The mixture was flushed with Ar and then dissolved in ˜10 mL anhydrous DMF. DIEA (0.39 g, 2.79 mmol) was then added via syringe. The reaction was stirred at 110° C. overnight. The reaction was diluted with EtOAc and filtered through celite, washed with ample ˜5% MeOH/EtOAc, the combined organic layer was washed with water twice, dried over Na2SO4. Final product was purified by silica gel column chromatography (4˜8% MeOH/DCM).
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:18][O:17][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:2]2([CH3:10])[CH3:3]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dichloro-2,5-dimethyl-hexane (Intermediate 1, 25.3 g, 0.14 mol) in anisole (60 mL, 0.55 mol) at 0° C. was added AlCl3 (18.4 g, 0.14 mmol) portionwise. After stirring for 2 h at 0° C., the mixture was poured onto ice and extracted with hexane. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The excess anisole was removed by vacuum distillation and the title compound was obtained as a white solid upon cooling (30.5 g, 100%).
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.B.CSC.B>C1COCC1>[S:1]1[C:5]2[S:6](=[O:12])(=[O:11])[CH2:7][CH2:8][C@@H:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCS(=O)(=O)c2sccc21
Agent: B
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Solvent: C1CCOC1
Solvent: CSC
Product: O=S1(=O)CC[C@@H](O)c2ccsc21
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5,6-Dihydro-4H-thieno[2,3-b]-thiopyran-4-one-7,7-dioxide (13) (1.00 g, 4.94 mmol) in dry THF (14 mL) was added (S)-diphenylprolinol-borane complex from Example 12 (132 mg, 0.494 mmol). The solution was cooled to -15° C. and a solution of borane-dimethyl sulfide (10M, 0.4 mL, 4.0 mmol) in dry THF (6.8 mL) was added at a rate to maintain the internal temperature at -15° C. The solution was stirred at -15° C. for 1 hour then at 22° C. for 6 hours. The product was isolated by the method decribed in Example 34 Step E. The enantiomeric ratio of the purified product was 95:5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCNc1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CO
Product: NCCCNc1cccc(Cl)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
3-(3-chlorophenylamino)propanenitrile (2 g, 0.011 mol) was dissolved in anhydrous THF (20 mL) and heated to reflux under nitrogen. A solution of BH3.MeS in THF was added drop wise and stirred at reflux overnight. The resulting solution was cooled to room temperature. Methanol was added drop wise to quench the reaction. After evaporation of the solution, the crude product was purified by column chromatography to afford the pure product N1-(3-chlorophenyl)propane-1,3-diamine (1.89 g, yield 95%)
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12]P(OCC)(OCC)=O)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=O)[CH3:35].O>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2/[CH:12]=[C:34](/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)\[CH3:35])=[O:6])[CH2:2][CH2:3]1
Reactant: CC(=O)c1ccccc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C(\C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a suspension of N-cyclopropyl-5-(diethylphosphonomethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (450 mg, 1.00 mmol) obtained in Example 321b) in THF (5 ml) was added sodium hydride (50% oil dispersion, 75 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. A solution of acetophenone (117 μl) in THF (5 ml) was added to the obtained reaction mixture, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was stirred at 60° C. for 15 hr and cooled to 0° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/4 to ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (150 mg, 36%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:23]1[CH:27]2[CH2:28][CH:29]3[N:33]([CH:26]2[CH2:25][NH:24]1)[CH2:32][CH2:31][CH2:30]3.C1N2CCN(CC2)C1.O>C(#N)C.CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH:17]=[CH2:18])[C:10]([F:16])=[C:11]([N:24]4[CH2:25][CH:26]5[CH:27]([CH2:28][CH:29]6[N:33]5[CH2:32][CH2:31][CH2:30]6)[CH2:23]4)[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CC2CC3CNCC3N2C1
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=Cc1c(F)c(N2CC3CC4CCCN4C3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 52.7 %

Procedure:
0.93 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylic acid, 0.69 g of decahydropyrrolo[3,4-b]pyrrolizine and 0.36 g of DABCO are refluxed for 2 hours in a mixture of 6 ml of acetonitrile and 3 ml of dimethylformamide. At room temperature, the reaction mixture is treated with 20 ml of water, and the solid is filtered off with suction, washed with water and dried. 0.7 g of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(octahydro-pyrrolo[3,4-b]pyrrolizin-2-y1)-4-oxo-5-vinyl-3-quinolinecarboxylic acid is obtained.