Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:19])=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=2)[CH:7]=1.[H-].[Na+].Cl[S:23]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:14]([O:13][C:12]([N:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]2[C:8]=1[CH3:19])[S:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1)(=[O:25])=[O:24])=[O:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2ccc(F)cn12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccc(F)cn3c2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of compound 6-C (0.70 g, 2.64 mmol) in DMF (20 mL) was cooled in an ice bath and treated with a 60% dispersion of NaH in mineral oil (0.126 g, 3.17 mmol) and stirred at ambient temp for 30 min. The solution was cooled on an ice bath and treated with methyl 4-(chlorosulfonyl)benzoate (1.24 g, added in portions). The resultant solution was stirred at ambient temperature for 18 hours. The solution was poured into ice water, and the resultant suspension was made basic with careful addition of a saturated aqueous solution of NaHCO3. The solid was collected by filtration, washed with water and air dried. The solid was pre-absorbed onto silica gel and purified by flash chromatography, using a gradient of EtOAc (10-60%) in heptanes as the eluant to afford compound 6-D as a colorless solid (1.1 g, 90%). MS: m/z 464.1 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:15][C:13]1[N:14]=[C:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(CCN2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: ClCc1cccc(CCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[6-(2-Morpholin-4-ylethyl)pyridin-2-yl]methanol (122 mg) and diisopropylethylamine (104 mg) were dissolved in 2.5 mL of dichloromethane, and 47 μL of methanesulfonyl chloride was added dropwise to the solution at ice temperature, and then the mixture was stirred at room temperature overnight. After removing the solvent from the reaction mixture under reduced pressure, the residue was purified by chromatography on silica gel (chloroform-methanol-aqueous ammonia=300:10:1) to give 80 mg of 4-[2-(6-chloromethylpyridin-2-yl)ethyl]morpholine as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[S:7][CH:6]=[C:5]([C:8](OC)=[O:9])[CH:4]=1.CO.[BH4-].[Na+]>C1COCC1>[F:1][CH:2]([F:12])[C:3]1[S:7][CH:6]=[C:5]([CH2:8][OH:9])[CH:4]=1
Reactant: COC(=O)c1csc(C(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1csc(C(F)F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of methyl 5-(difluoromethyl)thiophene-3-carboxylate (267 mg) in THF (5 ml)-MeOH (1 ml) was added NaBH4 (263 mg) at room temperature, and the reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was quenched with water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (192 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=4)[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CC(N2CCC(CC3CCNCC3)CC2)C1
Reactant: N#Cc1ccc(Br)cn1
Product: N#Cc1ccc(N2CCC(CC3CCN(C4CCC4)CC3)CC2)cn1

Procedure:
Example 22 was prepared using an analogous process to that described in Example 21 from 1-cyclobutyl-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 6) and 5-bromo-2-pyridinecarbonitrile. The compound displayed 1H-NMR and mass spectral data that were consistent with structure. MS electrospray (+ion) 339 (MH+).
Reaction SMILES: [C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].Br[CH2:27][C:28]#[N:29].[H-].[Na+]>CN(C)C=O>[C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:27][C:28]#[N:29])[C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: N#CCBr
Reactant: O=C(O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21

Procedure:
3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one is alkylated with bromoacetonitrile in dimethylformamide solution in the presence of sodium hydride to yield after work-up, 3-(1-carboxy-3-phenylpropylamino)-1-cyanomethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, used directly in the next step.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17](F)[C:18]=3[O:20][CH3:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:29])=[CH:6][C:7]([F:28])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([NH:2][CH3:1])[C:18]=3[O:20][CH3:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1OC
Temperature: 50 °C
Reaction time: 25 h

Procedure:
Pyridine (200 mg) and a 40% aqueous solution (200 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was stirred at 50° C. for 25 hours. The solvent was distilled off, and ethanol was added to the residue. The resultant mixture was stirred, and solids were collected by filtration and washed with ethanol and diethyl ether to obtain the title compound (33 mg) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+]>CCO>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate (Compound D10, 60 mg, 0.171 mmol) in 2 ml of TBF and 7 ml of EtOH at 0° C. was added NaBH4 (6.5 mg, 0.171 mmol) and the mixture stirred for 3 h. The reaction was quenched by slow addition of cold water. Solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and solvent removed under reduced pressure. The crude product was purified by flash chromatography (silica, ethyl acetate/hexane, 1:3) to afford the title compound as a red oil.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8]2)=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[OH:23][C:6]1[C:5]([C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10](=[O:16])[N:11]2[CH3:15]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2C)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of 5-hydroxy-1-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.11 mmol), β-alanine (805 mg, 9.0 mmol) and NaOMe solution (13.5 mL, 6.8 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 1. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH 2 with 6 M HCl, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to give 30 mg of the title compound as a light yellow solid. MS: (−) m/z 366.28 (M-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH:6]=[C:5]2[S:17]([CH2:20][CH2:21][O:22]C1CCCCO1)(=[O:19])=[O:18]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH:6]=[C:5]2[S:17]([CH2:20][CH2:21][OH:22])(=[O:18])=[O:19]
Reactant: O=S(=O)(CCOC1CCCCO1)c1cn(CC2=NCCN2)c2ccc(Cl)cc12
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(CCO)c1cn(CC2=NCCN2)c2ccc(Cl)cc12
Temperature: 47.5 °C
Reaction time: 3 h

Procedure:
The 5-chloro-1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3-[2-(tetrahydro-pyran-2-yloxy)-ethanesulfonyl]-1H-indole (0.028 g) prepared in the previous Step was dissolved in 4 ml acetic acid:water (2:1) and stirred at 45-50° C. for 3 h. The solvents were removed under reduced pressure and the crude product was purified by column chromatography (silica gel) eluting with 3-5% methanol in methylene chloride with 0.1% ammonium hydroxide added. The 2-[5-Chloro-1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonyl]-ethanol thus obtained weighed 0.005 g after drying.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](P(=O)(OCC)OCC)[P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[CH:22]/[P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
To a mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.00 g), tetraethyl methylenediphosphonate (1.15 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.17 g) at 0° C. The mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (3:1, v/v) to give diethyl (E)-2-(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)ethenylphosphonate as colorless crystals (1.08 g, yield 73%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 89-90° C.
Reaction SMILES: F[C:2]1[C:3]([C:12]#[C:13][Si](C)(C)C)=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[NH2:18][C@@H:19]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])[CH3:20].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:24]([C:23]1[CH:22]=[C:21]([C@H:19]([N:18]2[C:2]3[C:3](=[C:4]([C:10]#[N:11])[C:5]([C:6]#[N:7])=[CH:8][CH:9]=3)[CH:12]=[CH:13]2)[CH3:20])[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: C[C@@H](N)c1cccc(C#N)c1
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@H](c1cccc(C#N)c1)n1ccc2c(C#N)c(C#N)ccc21
Temperature: 60 °C
Yield: 45.1 %

Procedure:
An oven-dried vial was charged with 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (Example 40C) (0.128 g, 0.528 mmol), (R)-3-(1-aminoethyl)benzonitrile (0.085 g, 0.581 mmol), and K2CO3 (0.080 g, 0.581 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 3.5 h the septum was replaced with a PTFE-faced crimp top and the mixture was subjected to microwave heating (140° C.) for 20 min. Upon cooling, the mixture was poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were filtered (Whatman #2), washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-1-(1-(3-cyanophenyl)ethyl)-1H-indole-4,5-dicarbonitrile (0.0705 g, 0.238 mmol, 45.0% yield) as a tan foam: 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=3.4 Hz, 1H), 7.61 (dt, J=7.8, 1.3 Hz, 1H), 7.50-7.41 (m, 3H), 7.40 (t, J=1.8 Hz, 1H), 7.30-7.27 (m, 1H), 6.93 (dd, J=3.4, 0.7 Hz, 1H), 5.76 (q, J=7.1 Hz, 1H), 2.01 (d, J=7.1 Hz, 3H); MS (LCMS ES+) m/z 297 ([M+H]+, 24%), 338 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:23])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:35]([C:32]3[CH:31]=[CH:30][C:29]([Br:28])=[CH:34][N:33]=3)=[O:36])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(N)c2)CO[C@@]1(C)C(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)CO[C@@]1(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(2R*,5R*)-5-(3-amino-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (0.1 g, 0.253 mmol) in DMF (2.5 ml) was added 5-bromo-pyridine-2-carboxylic acid (78 mg, 0.379 mmol), EDC (0.074 g, 0.379 mmol), HOAt (0.053 g, 0.379 mmol) and DIPEA (0.083 g, 0.632 mmol) and the reaction mixture was stirred for 2 h at 25° C. After evaporation of the DMF the residue was taken up in NaH2PO4 solution and extracted with EtOAc. Combined organic layers were washed with 5% NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The crude product was crystallized from diisopropylether to provide the title compound as a white crystalline solid: TLC (hexane/EtOAc 1:1): Rf=0.61; HPLC RtH5=1.565 min; 1H NMR (360 MHz, CDCl3): δ 11.01 (s, 1H), 9.92 (s, 1H), 8.71 (dd, 1H), 8.21 (d, 1H), 8.10 (dd, 1H), 7.87 (s, 1H), 7.73 (d, 1H), 7.46 (t, 1H), 7.18 (d, 1H), 4.10 (m, 2H), 1.75 (s, 3H), 1.67 (s, 3H), 1.58 (s, 9H); ESIMS: 571, 573 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH2:17]([O:16][C:12](=[O:15])[CH:13]=[CH:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
A vial under nitrogen atmosphere was charged with 6-bromo-quinoline (1 g, 4.8 mmol) and dimethylformamide (15 mL), followed by ethyl acrylate (2.1 mL, 19.2 mmol), triethylamine (6.7 mL, 48 mmol), and palladium (II) acetate (32 mg, 0.142 mmol). The reaction mixture was stirred at 100° C. for 5 h, then the hot mixture was filtered over celite and the filtrate was concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous solution of ammonium chloride, saturated aqueous solution of sodium bicarbonate, then brine. The organic layer was then adsorbed on silica gel. Purification on silica gel with 10-80% gradient of ethyl acetate in hexane provided 952 mg of product as a yellow oil. 1H NMR 500 MHz (DMSO) δ 1.28 (t, 3H), 4.20 (q, 2H), 6.82 (d, 1H), 7.58 (d, 1H), 7.84 (d, 1H), 8.01 (d, 1H), 8.16 (dd, 1H), 8.30 (d, 1H), 8.37 (dd, 1H), 8.93 (dd, 1H); MS (m/z) 228 [M+H+]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(O)C>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]=[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(OCc3ccccc3)cc2)CC1
Agent: Cl
Solvent: CCO
Product: C(=C1CCNCC1)c1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
4-(4-Benzyloxybenzylidene)piperidine-1-carboxylic acid tert-butyl ester (3.80 g, 10 mmol), ethanol (40 ml) and 1 N hydrochloric acid (25 ml) were mixed and stirred at 80° C. for 1 hour. Ethanol was distilled off under reduced pressure and neutralized with sodium hydroxide. The organic layer was dried over sodium sulfate and concentrated to afford the title compound as a pale yellow powder (2.32 g, 83%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([C:20]([F:23])([F:21])[F:22])=[O:9])=[CH:17][CH:18]=1
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.6 %

Procedure:
Meta-Chloroperbenzoic acid (1.2 g, 11.7 mmol) was added to a solution of (4-bromophenyl)(trifluoromethyl)sulfane (1.7 g, 6.61 mmol) in dichloromethane (30 mL). After stirring at rt for 12 h, the reaction mixture was poured into ice-water and extracted with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4), concentrated, and purified by column chromatography on silica gel (EtOAc/petroleum ether=0:100 to 1:50) to give 859 mg of 1-bromo-4-((trifluoromethyl)sulfinyl)benzene as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.79-7.75 (m, 2H), 7.66 (d, 2H). 13C NMR (CDCl3, 100 MHz): δ 134.8, 133.0, 128.7, 127.4, 124.4 (q, J=330 Hz).
Reaction SMILES: CI.[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[CH:5]=1.[C:14](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[C:6]([CH3:13])[CH:5]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1C
Reaction time: 18 h
Yield: 79 %

Procedure:
Methyl iodide (10.0 mL, 160 mmol) was added to a mixture of 4-bromo-2-methylbenzoic acid (25.0 g, 116 mmol) and potassium carbonate (20.0 g, 145 mmol) in anhydrous dimethylformamide (75 mL) at room temperature under a nitrogen atmosphere and stirred for 18 h. The mixture was poured into water and extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with copper sulfate solution (50 mL) and brine (50 mL), dried and evaporated. Purification by column chromatography on silica gel using 9:1 hexane/ethyl acetate as eluant provided 21.0 g (79%) of methyl 4-bromo-2-methylbenzoate as a clear liquid: 1H NMR (CDCl3) δ7.85 (d, 1H), 7.42-7.47 (m, 2H), 3.95 (s, 3H), 2.64 (s, 3H); IR (neat) 1726 cm-1 ; Mass spectrum m/z 197, 199 (M+H-OCH3).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][OH:7])(=[O:4])=[O:3].C(N(CC)CC)C.[S:15](Cl)([CH3:18])(=[O:17])=[O:16]>C(Cl)Cl>[CH3:18][S:15]([O:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 7606.8 %

Procedure:
To a round-bottom flask containing 2-(methylsulfonyl)ethanol (400 mg, 3.22 mmol) at 0° C. was added DCM (10 ml) and triethylamine (4.91 μl, 0.035 mmol), followed by dropwise addition of mesyl chloride (2.96 mg, 0.026 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 2 hr. The reaction mixture was diluted with DCM and washed with sat NaHCO3 and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified via ISCO (0-60% EtOAc/Hexane) to yield 2-(methylsulfonyl)ethyl methanesulfonate (400 mg, 61%). LCMS (m/z): 203.0 (MH+), retention time=0.37 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].C([SiH](CC)CC)C.[C:33](=O)([O-])[O-:34].[Na+].[Na+]>CN(C=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:33]=[O:34])=[C:3]([CH3:25])[CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: O=C([O-])[O-]
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Temperature: 65 °C
Yield: 76.2 %

Procedure:
A mixture of 3-(4-bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (14.20 g, 31.34 mmol), triethyl silane (10.3 mL, 7.53 g, 62.8 mmol), sodium carbonate (5.43 g, 39.3 mmol), palladium bis(diphenylphosphine)-ferrocene dichloride CH2Cl2-complex (1.28 g, 1.57 mmol) and DMF (250 mL) were stirred under an atmosphere of carbon monoxide at 65° C. over night. After cooling to room temperature, the solvent was evaporated and the residue taken up in MTBE (methyl-tert-butyl ether), filtered and the filtrate was concentrated in vacuum. Purification of the residue on silica gel afforded the title compound (9.60 g, 76%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-].[Na+]>>[O:16]1[CH2:15][CH:14]1[CH2:12][O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCC=C2
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: C1=Cc2cccc(OCC3CO3)c2CC1

Procedure:
7,8-Dihydro-α-naphthol prepared from 5-hydroxy-α-tetralone is allowed to react with epichlorohydrin in an aqueous solution of sodium hydroxide to give 1-(2,3-epoxypropoxy)-7,8-dihydronaphthalene [cf. J. Med. Chem. 21, 913 (1978)].