Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8]CC)(=O)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:8][CH2:1][CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CC=CCC(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC=CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
A solution of ethyl hexa-3,5-dienoate (4.0 g, 28.6 mmol) in dry tetrahydrofuran (200 mL) was treated with a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 28.6 mL, 28.6 mmol). The mixture was stirred at room temperature for 2 hours, and then quenched with water. The mixture was acidified with 1.0 N aqueous hydrochloric acid and extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated to a yellow oil. 1H NMR (300 MHz, CDCl3) δ6.4-6.1 (m, 2H), 5.67 (m, 1H), 5.13 (d, J=17 Hz, 1H), 5.00 (d, J=11 Hz, 1H), 3.66 (t, J=6.6 Hz, 2H), 2.34 (q, J=6.6 Hz, 2H), 2.13 (broad s, 1H). The oil was dissolved in dichloromethane, cooled to 0° C. and treated with pyridine (10 mL) and p-toluenesulfonyl chloride (5.72 g, 30 mmol). The mixture was stirred for one hour, then warmed to room temperature and stirred for 3 hours. The mixture was then concentrated, and the residue was dissolved in ethyl acetate, washed sequentially with water, 1.0 N aqueous hydrochloric acid, 1.0 N aqueous sodium hydroxide, and saturated aqueous sodium chloride, then was dried over magnesium sulfate and concentrated to provide a yellow oil. This yellow oil was purified by flash column chromatography, eluting with 10% ethyl acetate/hexane, to give a colorless oil (3.84 g, 53%). 1H NMR (300 MHz, CDCl3) δ7.78 (d, J=8 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 6.22 (td, J=17, 10 Hz, 1H), 6.04 (dd, J=11, 10 Hz, 1H), 5.10 (d, J=17 Hz, 1H), 5.02 (d, J=10 Hz, 1H), 4.05 (t, J=7 Hz, 2H), 2.44 (s+m, 5H).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:30][C:31]([CH3:33])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl>[F:29][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:24][CH2:25][N:26]([CH:31]([CH3:33])[CH3:30])[CH2:27][CH:28]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)=O
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCNCC3)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)N1CC=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a stirred solution of 6-chloro-2-(1,2,3,6-tetrahydro-pyridin-4-yl)-quinoline-5-carboxylic acid (4,4-difluorocyclohexylmethyl)-amide (150.00 mg, 0.33 mmol, 1.00 eq) in 1,2-dichloroethane (5.00 mL, 33.33 V) was added acetone (0.05 mL, 0.66 mmol, 2.00 eq) and glacial acetic acid (0.04 mL, 0.66 mmol, 2.00 eq), then the reaction mixture was stirred at RT for 1 h and then cooled to 0° C. Sodium cyanoborohydride (43.54 mg, 0.66 mmol, 2.00 eq) was added and stirred at RT for 16 h. The solvent was removed and the crude product was purified by flash column chromatography using to afford 6-chloro-2-(1-isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexyl methyl)-amide (100.00 mg, 0.21 mmol, 62.5%, pale yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.83 (t, J=6.03 Hz, 1H), 8.00-7.96 (m, 3H), 7.76 (d, J=9.02 Hz, 1H), 6.91 (s, 1H), 3.27 (t, J=6.12 Hz, 4H), 2.70-2.65 (m, 4H), 2.04-2.02 (m, 2H), 1.86-1.74 (m, 5H), 1.33-1.17 (m, 2H), 1.05 (br s, 6H). m/z: 462.3 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.C([Li])(C)(C)C.[CH:19]([B:21](O)O)=[CH2:20].Cl>C1COCC1.CCCCC.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:21]([CH:19]=[CH2:20])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: C=CB(O)O
Reactant: COCOCc1cc(F)ccc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=CB1OCc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Compound 5b (2.0 g, 8.0 mmol) in THF (30 mL) was cooled to −78° C. and tert-butyllithium (9.9 mL, 16.8 mmol) as 1.7 M solution in pentane was added slowly. After stirring at −78° C. for 30 min, dibutyl ester of vinyl boronic acid was added dropwise. The mixture was stirred at −78° C. for 1 h, then was warmed up to room temperature and stirred overnight. Concentrated HCl (4 mL) was added and was stirred at room temperature for 4 h. Water (10 mL) was added and THF was removed under reduced pressure. The residue was extracted with ethyl ether, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (9:1 hexane/ethyl acetate) to give 11 (383 mg, 30%) as a yellowish oil; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 5.27 (s, 2H), 6.25 (t, J=8.5 Hz, 1H), 6.50 (d, J=9.4 Hz, 2H), 7.06-7.15 (m, 2H), 7.89 (dd, J=5.6, 7.9 Hz, 1H); ESI-MS m/z (M+H)+; HPLC purity: 98.7%; Anal. (C9H8BFO 0.1H2O)C, H.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])[CH:8]=1.[CH:19](OC)(OC)[O:20]C.[CH:26]([O-])([O-])[O-]>CO.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>[CH3:26][O:17][C:15]([C:5]1[CH:4]=[C:3]([N:2]([CH3:1])[CH3:18])[CH:8]=[C:7]([S:9]([F:10])([F:11])([F:12])([F:13])[F:14])[CH:6]=1)([O:20][CH3:19])[CH3:16]
Reactant: CC(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Reactant: COC(OC)OC
Reactant: [O-]C([O-])[O-]
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: COC(C)(OC)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Reaction time: 3 h
Yield: 96.9 %

Procedure:
1-(3-Dimethylamino-5-pentafluorosulfanylphenyl)ethanone (650 mg) was dissolved in methanol (50 ml) and admixed while stirring with trimethyl orthoformate (715 mg) and DL-10-camphorsulfonic acid (10 mg). After stirring for 3 h, more orthoformate (200 mg) was added, and the mixture was stirred for 2 h and left to stand overnight. Then the solvent was drawn off and the residue was dried under high vacuum. 730 mg of crude product were obtained, which were converted directly in the next stage.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.FC(F)(F)C(O)=O.[C:30]1([C:36]2[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[C:44]([O:48][C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]1[CH2:60][N:59]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C@H:58]([C:68](O)=[O:69])[CH2:57]1)=[O:54])=[O:50])([CH3:47])([CH3:46])[CH3:45]>ClCCl.C(N(CC)CC)C>[C:30]1([C:36]2[CH:37]=[CH:38][C:39]([CH2:40][NH:41][C:68](=[O:69])[C@@H:58]3[CH2:57][C@@H:56]([NH:55][C:53](=[O:54])[CH2:52][NH:51][C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])[CH2:60][N:59]3[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[CH:42][CH:43]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)NCc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
Triethylamine (130 μL), 1-hydroxybenzotriazole (59 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89 mg) were added to a solution of the 4-phenylbenzylamine trifluoroacetate (B, 126 mg) and trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 150 mg) in dichloromethane (10 mL) at 0° C. The mixture was stirred at room temperature for 16 hr and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=99:1 to 98:2, v/v) to give the title compound (178 mg) as a colorless foam:1H NMR (400 MHz, CDCl3) δ 1.45 (s, 18H), 1,67 (s, 2H), 2.01 (brs, 1H), 2.64 (br s, 1H), 3.27 (br s, 1H), 3.68-3.81 (m, 3H), 4.23-4.70 (m, 3H), 5.17 (br s, 1H), 6.43 (br s, 1H), 7.32-7.36 (m, 3H), 7.44 (t, J=7.6 Hz, 2H), and 7.53-7.57 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)([CH2:11]2)[C:9]1=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH3:24]>CCOCC.C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:13][CH:12]1[CH2:11][C:10]1([C:9](=[O:22])[CH3:24])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CC1CNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a flame-dried, 10 mL round-bottomed flask was added a solution of 1-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in 2 mL of ether and 1.0 mL of THF under Ar (g). The solution was cooled in a dry ice/acetone bath with stirring. A solution of MeLi was added drop-wise and the resulting orange colored mixture was stirred at −78° C. for 3 hours. The solution was warmed to ambient temperature and quenched with 15 mL of 1N HCl. The organic layer was extracted with EtOAc (2×20 mL) and the combined layers washed with brine (20 mL). The organic layer was dried over sodium sulfate for 2 hours and filtered, concentrated under reduced pressure, and dried for 1 hour to afford 1.1 g of a brown oil. The oil was purified on a filter pad of silica eluting with 100/1 (v/v) CHCl3/MeOH. The desired fractions were collected, concentrated under reduced pressure, and dried to afford a yellow oil. Yield: 0.659 g 52%; 1H NMR (300 MHz, CDCl3) 7.46 (d, 1H, J=2.1 Hz, ArH), 7.39 (d, 1H, J=5.4 Hz, ArH), 7.20 (dd, 1H, J=5.4, 2.1 Hz, ArH), 4.73 (m, 1H, NH), 3.41 (m, 1H, CH2N), 3.15 (m, 1H, CH2N), 2.04 (s, 3H, CH3), 1.80 (m, 1H, CHCH2N), 1.45-1.58 (m, 9H, tert-Bu), 1.20 (dd, 2H, J=4.5 Hz, ArCCH2).
Reaction SMILES: [C:1]1([C:13](Cl)=[O:14])[CH:6]=[C:5]([C:7](Cl)=[O:8])[CH:4]=[C:3]([C:10](Cl)=[O:11])[CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:13]([C:1]2[CH:6]=[C:5]([C:7]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[O:8])[CH:4]=[C:3]([C:10](=[O:11])[C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:2]=2)=[O:14])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(F)cc1)c1cc(C(=O)c2ccc(F)cc2)cc(C(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5 g of 1,3,5-benzenetricarbonyltrichloride (18.8 mol), 6.7 g of aluminum chloride (50.0 mmol) and 50 mL of distilled dichloromethane (DCM) were put in a 250 mL round flask, which was stirred for 30 minutes at 25° C. for reaction in the presence of nitrogen. 20 mL of dichloromethane and 4.5 g of fluorobenzene (48.8 mmol) were added in 100 mL of Dropping funnel, and the fluorobenzene solution was dropped in the round flask drop by drop. The reaction mixture was stirred for 4 hours in the presence of nitrogen, to which 20 mL of distilled water was added. The reaction mixture was stirred further for more than 12 hours. The organic layer of the reaction mixture was extracted by using dichloromethane, and the organic solvent was eliminated, resulting in a crude product. The crude product was re-crystallized using ethanol to give white brancher [3,5-bis(4-fluorobenzoyl)phenyl](4-fluorophenyl) methanone (yield: 70%). The structure of the [3,5-bis(4-fluorobenzoyl)phenyl](4-fluorophenyl)methanone was confirmed by 1H-NMR, 13C-NMR spectrometry and elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1.[ClH:15]>C(O)C.[Pd]>[ClH:15].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1
Reactant: N#Cc1ccc(F)cc1-n1nccn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(F)cc1-n1nccn1
Reaction time: 4 h

Procedure:
Intermediate 77, 4-fluoro-2–1,2,3-triazol-2-yl-benzonitrile, (0.34 g, 1.8 mmol) was dissolved in ethanol (50 mL). 1N HCl (10 mL) was added along with a catalytic amount of 10%-Pd—C. The mixture was shaken under H2 at 55 psi for 4 h after which it was filtered through Celite and concentrated to give the title compound as the corresponding HCl salt. Yellow solid (0.402 g, 98% yield). 1H-NMR (500 MHz, CD3OD) δ ppm: 8.13 (2H, s), 7.87 (1H, dd, J=4.9, 2.6 Hz), 7.73 (1H, dd, J=4.9, 2.6 Hz), 7.34 (1H, td, J=8.2, 2.7 Hz), 4.35 (2H, s). LCMS [M+H]+ calcd for C9H10N4F: 193.08; found: 193.16.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:13].[CH3:14][S:15](Cl)(=[O:17])=[O:16].N1C=CC=[CH:21][CH:20]=1>>[F:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([O:11][CH2:20][CH3:21])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C(=O)[O-])c1ccc(N)c(F)c1
Product: CCOC(=O)C(C)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A solution of 2-(4-amino-3-fluorophenyl)propionate (1-13, 4 mM) and pyridine (10 ml) was dissoluted with methansulfonylchloride (6 mM) and was stirred at 0° C. for 10 minutes. The combined organic layers were washed with H2O and residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (1:2) as eluant to afford ethyl 2-[3-fluoro-4-(metylsulfonylamino)phenyl]propionate compound (1-26, SU-658).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)[CH:2]=[CH2:3].C1(C)C=CC(S(NN)(=O)=O)=CC=1.CC([O-])=O.[Na+]>C(COC)OC.O>[CH3:12][O:11][C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCc1ccc(O)c(OC)c1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a solution of 123 mg (0.75 mmole) of 4-allyl-2-methoxyphenol (eugenol) and 1.4 gm (7.5 mmole)of p-toluenesulfonhydrazide in 15 ml of dimethoxyethane under reflux was added a solution of 1.7 gm of NaOAc in 15 ml water over a 4 hour period. The mixture was cooled to room temperature, poured into 20 ml of water, and extracted three times with 30 ml of CH2Cl2. The combined organic layers were washed with 50 ml of water, dried over MgSO4, and concentrated under vacuo. The resulting solid was flash chromatographed over silica gel using 10% ethyl acetate in hexane to afford 60 mg of 2-methoxy-4-propylphenol in 48% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:18]([O:20][C@H:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=1)[CH3:19].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:29](=[O:30])[CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][C@H:21]([O:20][CH2:18][CH3:19])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:33][CH:32]=2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(CNCc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(Cl)cc2)Cc2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a suspension of N,N-bis(4-chlorobenzyl)amine (0.958 g, 3.60 mmol) in methylene chloride (30 mL) were added {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) and N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (220 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 1.02 g (62%) of an oil, which solidified upon standing to give white solids.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:28][C@@H:29]1[CH2:34][O:33][CH2:32][CH2:31][NH:30]1>CC(O)CC.C(Cl)Cl>[CH3:28][C@@H:29]1[CH2:34][O:33][CH2:32][CH2:31][N:30]1[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1
Reactant: C[C@@H]1COCCN1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Agent: Cl
Solvent: CCC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc[nH]c2n1
Temperature: 180 °C
Reaction time: 100 h

Procedure:
2-Chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (1.02 g, 4 mmol), diisopropylethylamine (1.40 mL, 8 mmol), and (R)-3-methylmorpholin hydrochloride (826 mg, 6 mmol) were stirred in 2-butanol (5 mL) in a closed microwave tube under argon at 50° C., until all ingredients were dissolved. The reaction was then stirred at 180° C. for 100 hours. The reaction mixture was then cooled to room temperature and diluted with 200 mL of CH2Cl2.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)[CH3:26]>ClCCl>[CH2:25]([C@H:27]1[CH2:28][CH2:29][C@H:30]([C:33]2[CH:34]=[CH:35][C:36]([CH:37]=[C:1]([Br:5])[Br:2])=[CH:39][CH:40]=2)[CH2:31][CH2:32]1)[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CC[C@H]1CC[C@H](c2ccc(C=O)cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@H]1CC[C@H](c2ccc(C=C(Br)Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
148 g of carbon tetrabromide was dissolved in ml of dichloromethane, and 93 g of triphenylphospine was added at 0° C. or less. Next, 48.6 g of 4-(trans-4'-ethylcyclohexyl)benzaldehyde was dissolved in 225 ml of dichloromethane, which then was added dropwise to the first dichloromethane solution over a period of one hour. The combined solutions were then agitated at room temperature for one hour. After completion of the reaction, the dichloromethane was distilled off, and 500 ml of hexane was added to the residue. The resulting crystals were filtrated and further washed with hexane three times. The residue was subjected to recrystallization with hexane to obtain 52 g of 4-(trans-4'-ethylcyclohexyl)-β,β-dibromostyrene.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH3:17])([CH2:14][C:15]#N)[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=O)C.[OH-:22].[K+].Cl.[OH2:25]>C(O)CO>[OH:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH2:14][C:15]([OH:25])=[O:22])([CH3:17])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19]
Reactant: [OH-]
Reactant: O
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC#N)O2
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 1.0 g (3.48 mmoles) of rac.-6-acetyloxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile, 1.0 g (15.2 mmoles) of 85% KOH, 1 ml of water and 8 ml of ethylene glycol was stirred and refluxed for 16 hr. The reaction mixture was cooled to room temperature, then poured into water. The pH of the solution was adjusted to 8 with 1 N aqueous HCl. The resulting mixture was extracted with two portions of ether (the ether extracts were discarded). The aqueous phase was acidified with 3 N aqueous HCl and worked-up with ether in the usual manner giving 756 mg (82%) of rac.-(6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)acetic acid as a tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:20][C:21]1([CH3:35])[C:26](=[O:27])[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]1>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2([OH:27])[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:22][C:21]2([CH3:35])[CH3:20])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2)C(C)(C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
A solution of 1-Bromo-4-fluorobenzene (5.32 mL, 48.4 mmol) in THF (100 mL) was cooled to −78° C., and treated with the dropwise addition of 1.6 M BuLi in hexane (30.2 mL, 48.4 mmol), at a rate which did not allow the temperature of the reaction to exceed −60° C. The mixture was stirred at −78° C. for 30 minutes, then treated with the dropwise addition of a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (5 g, 22.00 mmol) in THF (50 mL) at a rate which did not allow the temperature to exceed −60° C. The mixture was stirred at −78° C. for 1.5H, then allowed to warm to 10° C. and quenched with saturated NH4Cl (50 mL). The layers were separated, and the organic phase was concentrated in-vacuo. The aqueous was extracted with ethyl acetate (100 mL), and the organic phase was combined with the residue from the original organic phase. This solution was washed 3× with water, 1× with brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was digested with hexanes (70 mL), and the resulting white powder was collected by filtration, rinsed with hot hexanes, and dried under vacuum to yield the title compound (3.3 g, 10.20 mmol, 46.4% yield). MS (ESI+)=324.4, (M+H)+, 250.3, (M-tBuOH)+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:25][C:26]1[CH:54]=[CH:53][C:29]([C:30]([C:32]2[N:36]([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:35]3[CH:42]=[CH:43][C:44]([C:46]([N:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=O)=[CH:45][C:34]=3[N:33]=2)=[O:31])=[CH:28][CH:27]=1)[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26]1[CH:54]=[CH:53][C:29]([C:30]([C:32]2[N:36]([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:35]3[CH:42]=[CH:43][C:44]([C:46](=[S:10])[N:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=[CH:45][C:34]=3[N:33]=2)=[O:31])=[CH:28][CH:27]=1)[CH3:24]
Reactant: CCOc1ccc(C(=O)c2nc3cc(C(=O)N(CC)CC)ccc3n2CCC(C)C)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(=O)c2nc3cc(C(=S)N(CC)CC)ccc3n2CCC(C)C)cc1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
Lawesson's reagent (0.0963 g, 0.238 mmol) was added to a stirred solution of 2-(4-ethoxybenzoyl)-N,N-diethyl-1-isopentyl-1H-benzimidazole-5-carboxamide (0.0451 g, 0.104 mmol) in dry toluene (5 mL) under an atmosphere of N2. The reaction was heated to reflux for 0.5 h, and then cooled to room temperature and concentrated. The residue was purified by column chromatography (3:1 Hexanes:EtOAc) to provide the title compound (0.0137 g, 29%) as a glassy yellow solid. 1H-NMR (CD3OD): δ 8.19 (d, J=9.2 Hz, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.64 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.06 (d, J=9.2 Hz, 21), 4.55 (dd, J=8.4 Hz, J=7.2 Hz, 2H), 4.17 (q, J=7.6 Hz, 4H), 3.53 (q, J=7.6 Hz, 2H), 1.80–1.71 (m, 2H), 1.71–1.58 (m, 1H), 1.44 (t, J=7.6 Hz, 3H), 1.41 (t, J=7.6 Hz, 3H), 1.17 (t, J=7.6 Hz, 3H), 0.97 (d, J=6.4 Hz, 6H). 13C-NMR (CD3OD): δ 201.23, 185.95, 165.57, 149.55, 141.87, 141.18, 136.28, 134.64, 130.31, 124.56, 118.20, 115.41, 112.36, 65.15, 47.48, 44.89, 40.18, 27.20, 22.77, 14.95, 14.07, 11.44. MS (ESI) (M+H)+=452. Anal. Calcd for C26H33N3O2S.0.3H2O: C, 68.33; H, 7.41; N, 9.19. Found: C, 68.44; H, 7.52; N, 9.01.