Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:36])=[C:27]([CH:35]=1)[C:28]([O:30]C(C)(C)C)=[O:29].C([O-])(C)(C)C.[K+]>CS(C)=O>[CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:24]2[C:23]([Cl:22])=[CH:35][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:36])[CH:25]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OCC2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
A mixture of (1-benzhydrylpiperidin-4-yl)methanol (370 mg, 1.3 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (328 mg, 1.3 mmol) and potassium tert-butanolate (295 mg, 2.6 mmol) in DMSO (4 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (10 mL×4). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was washed with ethyl acetate (5 mL) and filtered to afford 4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoic acid (480 mg, 82%) as a white solid. LCMS (ESI) m/z: 454.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][C:42]([F:45])([F:44])[F:43])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][C:42]([F:45])([F:44])[F:43])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: FC(F)(F)Oc1ccccc1Sc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccccc3OC(F)(F)F)cc2)c1C
Yield: 32.3 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(2-(trifluoromethoxy)phenylsulfanyl)benzene (0.214 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-fluoro-3-methyl-4-[4-(2-trifluoromethoxyphenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.089 g, 32%) as a solid. MS calcd. for C27H19F4O3S [(M−H)−] 499, obsd. 499.1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:21]=[CH:20][CH:19]=[CH:18]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:9]1[C:28](O)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH2:37])C>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH:18]=[CH:19][CH:20]=[CH:21]3)=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:9]1[C:28]([NH:37][C@H:36]([C:35]([OH:34])=[O:42])[CH2:38][CH:39]([CH3:40])[CH3:41])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from 1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid and L-leucine ethyl ester hydrochloride followed the procedure of Example 2 Step 4 as a white solid: 1H NMR (DMSO-d6) δ 0.76 (d, J=6.5 Hz, 3 H), 0.77 (d, J=6.5 Hz, 3 H), 1.20-1.40 (m, 1 H), 1.40-1.50 (m, 1 H), 1.50-1.60 (m, 1H), 4.28-4.40 (m, 1 H), 5.55 (d, J=16.1 Hz, 1 H), 5.61 (d, J=16.2 Hz, 1 H), 6.21 (t, J=2.0 Hz, 2 H), 7.20-7.50 (m, 12 H), 7.55-7.65 (m, 3 H), 8.89 (d, J=7.8 Hz, 1 H), 12.64 (br s, 1 H); MS (ESI) m/z 506 (MH+); MS (ESI) m/z 504 ([M-H]−); HRMS calcd for C32H32N3O3: 506.2444; found (ESI+): 506.2429; Anal. calcd for C32H31N3O3.0.25 H2O: C, 75.35; H, 6.22; N, 8.23. Found: C, 75.42; H, 5.86; N, 7.98.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>ClCCl.CO>[P:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: O=P(O)(O)CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
To a solution of 11.54 g of 1-(diethylphosphono)-4-(nonafluorobutyl)butane in 50 mL of dichloromethane was added 10.7 g of bromotrimethylsilane. After 18 hr at room temperature, the solution was concentrated to a nearly colorless liquid, and the intermediate silylphosphonate ester was dissolved in 250 mL of methanol. The resultant solution was stirred at room temperature for 1 hr, and then concentrated to give a white solid. Dissolution in methanol and concentration were repeated two more times, and recrystallization of the crude product from acetonitrile gave 8.39 g of 1-phosphono-4-(nonafluorobutyl)butane (CF3(CF2)3(CH2)4PO3H2) as colorless needles, m.p. 123-124° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:8]([CH3:16])[C@@H:9]([O:14][CH3:15])/[CH:10]=[CH:11]/[CH:12]=[CH2:13])[C@@H:4]([CH3:7])[CH:5]=[O:6].CC(=CC)C.Cl([O-])=[O:23].[Na+].P([O-])(O)(O)=O.[Na+].Cl>C(O)(C)(C)C.O.[Cl-].[Na+].O>[CH3:1][O:2][C@H:3]([C@@H:8]([CH3:16])[C@@H:9]([O:14][CH3:15])/[CH:10]=[CH:11]/[CH:12]=[CH2:13])[C@@H:4]([CH3:7])[C:5]([OH:23])=[O:6]
Reactant: [O-][Cl+][O-]
Reactant: C=C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)C=O
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CC(C)(C)O
Solvent: O
Product: C=C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)C(=O)O
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
To (E)-(2R,3R,4S,5S)-3,5-Dimethoxy-2,4-dimethyl-nona-6,8-dienal (1.2 g, 5.3 mmol) in tert-butanol (24 ml) and 2-methyl-2-butene (5.6 ml, 53.1 mmol) at room temperature, was added a solution of sodium chlorite (2.4 g, 26.5 mmol) and sodium dihydrogenphosphate (1.5 g, 10.6 mmol) in water (5 ml). The reaction was stirred vigorously for 1.5 hours, after which brine (10 ml) was added and the reaction acidified to pH5 with 2M hydrochloric acid. The reaction was extracted with dichloromethane (3×), the organics dried through a hydrophobic frit and concentrated in vacuo. The oily residue was left on a vacuum pump overnight to afford the product 3c as an orange solid (1.02 g, 79%). 1H NMR (300 MHz, CDCl3) δ 6.39 (dt, J=16.7 Hz, 10.3 Hz, 10.0 Hz, 1H), 6.23 (dd, J=14.9 Hz, 10.5 Hz, 1H), 5.45 (dd, J=14.9 Hz, 8.7 Hz, 1H), 5.26 (d, J=16.3 Hz, 1H), 5.14 (d, J=10.3 Hz, 1H), 3.91 (dd, J=9.4 Hz, 1.8 Hz, 1H), 3.46 (s, 3H), 3.43 (m, 1H), 3.26 (s, 3H), 2.67 (m, 1H), 1.71 (m, 1H), 1.13 (d, J=7.1 Hz, 3H), 0.78 (d, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)cn1
Solvent: CC#N
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of 5-bromo-2-methylpyridine (5.00 g) in acetonitrile (30 mL) was added 70% m-chloroperbenzoic acid (10.8 g), and the mixture was stirred at room temperature for 30 min. The resulting white precipitate was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and recrystallized (ethyl acetate/hexane) to give the title compound (5.36 g) as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](B(O)O)=[CH:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1ccccc1-c1ccccc1)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 34.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.46 g, 10.0 mmol), 2-biphenylboronic acid (Aldrich; 1.94 g, 10.0 mmol), copper(II) acetate (1.81 g, 10.0 mmol) and triethylamine (1.4 mL, 10.0 mmol) in 1,2-dichloroethane (10 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5-40% ethyl acetate/hexanes, to give N′-biphenyl-2-yl-N-methyl-hydrazinecarboxylic acid tert-butyl ester (1.02 g, 34%) as an off-white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:20][C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([CH3:19])=[N:17]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cccc(O[Si](C)(C)C(C)(C)C)c2n1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(Br)ccc(O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 138.1 %

Procedure:
N-bromosuccinimde (14 g) was added in one portion to a stirred solution of 8-t-butyldimethylsilyloxyquinaldine (15 g) in chloroform at -40° C. under an inert atmosphere. The reaction was warmed to room temperature and then heated to reflux for 6 h. Further N-bromosuccinimide (6 g) was added to the reaction at room temperature and stirring continued for 3 days. The reaction mixture was poured into 5% aqueous sodium metabisulphite solution (300 ml) and extracted with chloroform (3×300 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to afford the title compound as an orange oil (16.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:16])[S:10][CH2:11][CH2:12][C:13](=[O:15])[CH3:14])=[N:6][CH:7]=1.[BH4-].[K+]>CO.O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:16])[S:10][CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])=[N:6][CH:7]=1
Reactant: CC(=O)CCSC(=S)Nc1ccc(Cl)cn1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 1 h
Yield: 62.4 %

Procedure:
The procedure of Example 3 is followed, but a suspension of 3-oxobutyl 5-chloropyrid-2-yldithiocarbamate (17.5 g) in methanol (220 cc) and a solution of potassium borohydride (3.44 g) in distilled water (55 cc) are used as the starting materials at a maximum of 30° C. The reaction is allowed to proceed for 1 hour at between 20° and 30° C. The resulting product (14.2 g; m.p.=115° C.) is dissolved in chloroform (500 cc). The solution is chromatographed on silica (0.2-0.5 mm) (140 g) contained in a column of diameter 3.4 cm. Elution is carried out with chloroform (1,500 cc), this eluate being discarded, and then with chloroform (4 liters). The eluate which is collected is evaporated to dryness under reduced pressure (20 mm Hg) at 45° C. The chromatographed product (11.4 g) is recrystallised from acetonitrile (85 cc). 3-Hydroxybutyl 5-chloropyrid-2-yldithiocarbamate (11.0 g), which melts at 122° C., is obtained.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)=[CH:27][CH:26]=1)[CH3:23]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2nc3cc(C(=O)OC)ccc3nc2-c2ccccc2)cc1
Yield: 42.1 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6, with methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.34 mmol, 1.00 equiv) and 4-ethoxyphenylboronic acid (61 mg, 0.37 mmol, 1.10 equiv) As reactants. Purification via silica gel column (ethyl acetate/petroleum ether (1:5)) yielded 55 mg (43%) of methyl 3-(4-ethoxyphenyl)-2-phenylquinoxaline-6-carboxylate as a yellow powder.
Reaction SMILES: [CH2:1]([C:4]1[C:18]([OH:19])=[C:17]([O:20][CH3:21])[C:16]([O:22][CH3:23])=[CH:15][C:5]=1[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)[CH:2]=[CH2:3].[OH-].[NH4+]>>[NH2:13][C:10]1[N:9]=[C:8]([NH2:14])[C:7]([CH2:6][C:5]2[C:4]3[CH2:1][CH:2]([CH3:3])[O:19][C:18]=3[C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)=[CH:12][N:11]=1
Reactant: C=CCc1c(Cc2cnc(N)nc2N)cc(OC)c(OC)c1O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OC(C)C2
Temperature: 0 °C
Yield: 80 %

Procedure:
A mixture of 5-(2-allyl-3-hydroxy-4,5-dimethoxybenzyl)-2,4-diaminopyrimidine (1.50 g, 4.74 mmol) and polyphosphoric acid (50 g) was heated to 95° and maintained at this temperature with stirring until a clear pale yellow syrup was achieved (about 1 h). This syrup was poured into ice-water and the resulting solution basified with ammonium hydroxide. The resulting white solid (1.3 g) was chromatographed on silica gel eluted with MeOH:CH2Cl2 /1:9 to give the title compound as white powder (1.2 g). Recrystallization from 95% ethanol gave clusters of white needles, mp 216°-219°. Anal. Calcd for C16H20N4O3 (316.37); C, 60.74; H, 6.37; N, 17.71. Found: C, 60.48; H, 6.41; N, 17.63.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[N:6]=1)[CH2:2][CH3:3].C(=O)(O)[O-:23].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[O:23])[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccnc(Sc2cccc3cccnc23)n1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1ccnc(S(=O)c2cccc3cccnc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 710 mg. (2.38 mmol) of 8-(4-propyloxy-2-pyrimidylthio)quinoline and 999 mg. of sodium bicarbonate (11.9 mmol) in 40 ml. of methylene chloride cooled to 0° C. was added dropwise over a period of 15 minutes 574 mg. (2.64 mmol) of 85% m-chloroperbenzoic acid in 15 ml. of the same solvent. The reaction mixture was stirred for 30 minutes and was then allowed to warm to room temperature and stirred overnight. The reaction was diluted with methylene chloride and the organic layer washed successively with a saturated sodium bicarbonate solution, water and a saturated brine solution. The organic phase was separated, dried over magnesium sulfate and concentrated to give 745 mg. of crude product which was purified by chromatographing on silica gel, 367 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2
Reactant: C1CCNC1
Reactant: O=C1CCc2cc(Cl)ccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
1155 g (6.4 mol) of 6-chloro-3,4-dihydro-2(1H)-naphthalenone were dissolved in 5 l of toluene, 500 g (7.0 mol) of pyrrolidine and subsequently a solution of 26 g (0.14 mol) of p-toluenesulphonic acid in toluene were added dropwise thereto and the mixture was boiled under reflux. When about 120 ml of water had separated, 4 l of toluene were distilled off and the mixture was left to cool slowly. A solid crystallized out. Filtration and washing with acetone gave 1-(6-chloro-3,4-dihydro-2-naphthyl)pyrrolidine of melting point 117°-118°. Concentration of the mother liquor, suspension of the residue in ether, filtration and washing with acetone gave a further portion of the above product of melting point 117°-118°.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH2:13][C:14]([C:35](OCC)=O)([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([O:40][CH3:41])[C:10]([O:42][CH3:43])=[C:9]([O:44][CH3:45])[C:8]=1[O:46][CH3:47].C(O)(=[O:50])C.C(=O)(O)[O-].[Na+]>C1COCC1.CCCCCC>[CH3:41][O:40][C:11]1[C:10]([O:42][CH3:43])=[C:9]([O:44][CH3:45])[C:8]([O:46][CH3:47])=[C:7]2[C:12]=1[CH2:13][C:14]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:35]2=[O:50]
Reactant: CCOC(=O)C(CCCCOc1ccc(C(=O)OC)cc1)(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)C(=O)OCC
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(CCCCOc2ccc(C(=O)OC)cc2)Cc2c(OC)c(OC)c(OC)c(OC)c2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A hexane solution of n-butyl lithium (1.68 M, 3.27 ml, 5.50 mmols) was dropwise added to a THF (30 ml) solution of ethyl 2-(6-bromo-2,3,4,5-tetramethoxybenzyl)-2-ethoxycarbonyl-6-(4-methoxycarbonylphenoxy)hexanoate (3.00 g, 4.58 mmols), under a nitrogen stream at −90° C. or lower, and stirring was continued for 15 minutes. Then, the temperature was raised to −78° C., and stirring was further continued for 15 minutes. To the reaction mixtures was added a THF (5 ml) solution of acetic acid (1.38 g, 22.9 mmols) at −70° C. or lower, which was then allowed to warm to room temperature, and a saturated aqueous sodium bicarbonate solution was added thereto, which was then extracted with diethyl ether. The organic layer waswashed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (1.22 g) as crystals.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N+:7]=1[O-:21]
Reactant: Cc1cccc(C2OCCO2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cccc(C2OCCO2)[n+]1[O-]
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution 2-(1,3-dioxolan-2-yl)-6-methylpyridine (3.7 g, 15.67 mmol, 1 eq.) in 200 ml of DCM was added mCPBA (7.21 g, 31.35 mmol, 2 eq.) portionwise (exotherm 20° C.>26° C.). The reaction was stirred for 1 hr and 100 ml of 2M aqueous K2CO3 solution was added. The mixture was stirred for 15 mins and the organic layer was separated, washed with water (100 ml), dried over MgSO4 and evaporated to give 2-(1,3-dioxolan-2-yl)-6-methylpyridine 1-oxide (2.4 g, 80% yield) as a yellow liquid.
Reaction SMILES: CON(C)[C:4](=[O:18])[CH:5]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C([Li])(C)(C)C>C1COCC1>[N:12]1([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:18])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CON(C)C(=O)C(c1ccccc1)N1CCOCC1
Reactant: Brc1ccccn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(c1ccccn1)C(c1ccccc1)N1CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-Methoxy-N-methyl-2-morpholin-4-yl-2-phenylacetamide (215 mg, 0.813 mmol) was dissolved in 10 mL of dry THF and cooled to −78° C. In a separate flask, 2-bromopyridine (97 μL, 1.0 mmol) was dissolved in 5 mL of dry THF and cooled to −78° C., to which was added tert-Butyl lithium (1.20 mL, 1.7M solution in pentane, 2.0 mmol) dropwise. After stirring for 30 minutes, the mixture transferred to the amide flask dropwise and stirred for approximately one hour. The mixture was quenched with NaHCO3(sat), warmed to ambient temperature and poured into water. The aqueous layer was extracted 3× with EtOAc and the combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100/0/0 to 9/1/0.1 CH2Cl2/MeOH/NH4OH), providing partially purified titled product. The residue was further purified by preparative reverse phase HPLC. The appropriate fractions were poured into NaHCO3(aq sat) and extracted twice with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo to provide 2-morpholin-4-yl-2-phenyl-1-pyridin-2-ylethanone. ESI+MS: 283.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:9](F)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[K+:12].C(O[C:16]([S-:18])=[S:17])C>CN(C=O)C>[K+:12].[C:6]([C:5]1[C:4]([F:11])=[CH:3][C:2]2[N:1]=[C:16]([S-:18])[S:17][C:9]=2[CH:8]=1)#[N:7]
Reactant: CCOC(=S)[S-]
Reactant: N#Cc1cc(F)c(N)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc2sc([S-])nc2cc1F
Temperature: 25 °C
Yield: 120.2 %

Procedure:
A mixture of 4-amino-2,5-difluorobenzonitrile (1.0 g, 6.5 mmol) and O-ethylxanthic acid potassium salt (1.2 g, 7.8 mmol) in DMF (15 mL) was heated at reflux for 6 h. The mixture was cooled to rt and partitioned between EtOAc (200 mL) and 1 M aq Na2CO3 (100 mL). The organic layer was separated and the aqueous layer was extracted with additional EtOAc (2×200 mL). The combined organic layers were washed with brine (100 mL), dried over Mg2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2% MeOH in DCM to afford 6-cyano-5-fluorobenzo[d]thiazole-2-thiolate potassium salt (1.94 g) as an orange solid. LCMS (ESI) m/z 211 (M+H)+.
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br)([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C-:21]#[N:22].[K+].CC(C)=O>O>[F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][C:21]#[N:22])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [C-]#N
Reactant: FC(F)(c1ccccc1)C(F)(F)c1ccccc1CBr
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#CCc1ccccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
2-(α,α,β ,β-Tetrafluorophenethyl)benzyl bromide, 3.5 g. (0.01 mole), and 2.0 g. (0.0308 mole) of potassium cyanide are dissolved in 35 ml. of acetone - 5 ml. of water and the solution is heated to refluxing for about 18 hours. The organic phase is separated, acetone is distilled under reduced pressure, and the residual oil is dissolved in benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the product as the residual brown oil.