Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([Cl:15])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3].Cl.[CH2:17]([O:20][NH2:21])[CH2:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:15][C:5]1[C:4]([C:2]([NH:21][O:20][CH2:17][CH2:18][CH3:19])=[O:3])=[C:13]([Cl:14])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Reactant: CCCON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCONC(=O)c1c(Cl)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 30° C., 10.7 g (0.04 mol) of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate in 100 ml of methylene chloride were slowly added dropwise to a solution of 4.50 g (0.04 mol) of O-propylhydroxylamine hydrochloride and 4.05 g (0.04 mol) of triethylamine in 200 ml of methylene chloride. After stirring for 2 hours at room temperature, the reaction mixture was washed with dilute phosphoric acid, dried and concentrated. The resulting residue was chromatographed over silica gel (eluent:toluene/ethyl acetate=9/1). 11.50 g.of methyl 2,4-dichloro-3-propoxyaminocarbonylbenzoate were obtained.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])[CH:15]=2)[O:10][C:9]([C:23]2[N:28]=[CH:27][N:26]3[CH:29]=[CH:30][CH:31]=[C:25]3[CH:24]=2)=[CH:8]1)(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[OH:22][CH:19]([CH2:20][OH:21])[CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:23]1[N:28]=[CH:27][N:26]3[CH:29]=[CH:30][CH:31]=[C:25]3[CH:24]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCC(O)CO)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: OCC(O)COc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1
Temperature: 60 °C
Yield: 43.8 %

Procedure:
A solution of 6-(2,3-Dihydroxy-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 86A) (100 mg, 0.236 mmol) in toluene (8 ml) was treated at 0° C. with trifluoro acetic acid (2 ml) and heated at 60° C. for 5.5 hours. The solution was concentrated under vacuum, the residue dissolved in ethyl acetate and washed successively with a saturated solution of sodium hydrogenocarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography (gradient cyclohexane/ethyl acetate: 0-100% then ethyl acetate/methanol:90/10) to yield the title compound (38 mg, 44%) as a brown-yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1COCC1.C(OCC)(=O)C>[O:16]1[CH2:17][CH2:18][N:13]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([OH:12])=[O:11])[CH2:14][CH2:15]1
Reactant: O=C(O)Cc1ccccc1CCl
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8 mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and the solution was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate and extracted with H2O (2×). The aqueous phase was lyophilized and the residue was purified by silica gel chromatography (Biotage/0-10% methanol-CH2Cl2) to give the title compound 2-(2-(Morpholinomethyl)phenyl)acetic acid as a colorless solid (2.22 g, 87%). 1HNMR (400 MHz, CD3OD) δ 7.37-7.44 (m, 3H), 7.29-7.33 (m, 1H), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H). LCMS: Anal. Calcd. for C13H17NO3: 235. found: 236 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11]>O1CCOCC1.C(Cl)Cl>[CH:10]([NH:13][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1)([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: OCc1ccnc(Br)c1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)Nc1cc(CO)ccn1
Temperature: 110 °C

Procedure:
A mixture of (2-bromo-pyridin-4-yl)-methanol (500 mg, 2.66 mmol), isopropylamine (0.45 mL, 5.32 mmol), NatOBu (790 mg, 7.98 mmol) and Pd(tBu3P)2 (136 mg, 0.26 mmol) in 1,4-dioxane (5 mL) is heated in a microwave reactor at 110° C. for 45 min. The reaction is diluted with DCM (50 mL) and washed with saturated aqueous NH4Cl. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound that is used without further purification. MS (ESI) m/z 167.1 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[C:16]([C:27]([CH3:29])=[CH2:28])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])C1C=CC=CC=1.CO>[Pd].C(O)C>[OH:8][C:9]1[CH:18]=[C:17]([OH:19])[C:16]([CH:27]([CH3:29])[CH3:28])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C=C(C)c1cc(C(=O)OC)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: COC(=O)c1cc(C(C)C)c(O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
10% Palladium on carbon (350 mg) was added to a suspension of methyl 2,4-bis-benzyloxy-5-isopropenylbenzoate [prepared as per WO 2006/109085 A1] (3.88 g, 10.0 mmol) in ethanol (30 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. Methanol (20 ml) was added to aid dissolution and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered, the catalyst was rinsed with methanol (3×20 ml) and the combined filtrates were evaporated in vacuo to afford methyl 2,4-dihydroxy-5-isopropylbenzoate (2.10 g, 100%) as a colourless solid. 1H NMR (DMSO-d6) 10.54 (1H, s), 10.44 (1H, br s), 7.52 (1H, s), 6.37 (1H, s), 3.85 (3H, s), 3.08 (1H, m), 1.13 (6H, d). MS: [M+H]+ 211.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([CH:23]=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.O.CN([CH:35]=[O:36])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([C:23]([CH:35]=[O:36])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:25])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CN(C1CCc2cc3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C1CCc2c(C=O)c3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of the product from Step 9 of Example 1 (15 mg) in 2 mL of DMF was added 15 μL of POCl3. After stirring for 10 min, 2 mL of water was added and the reaction mixture was stirred for 24 h. The solid was collected by filtration to give the title compound (˜16 mg). 1H NMR (500 MHz, acetone-d6) δ 10.11 (s, 1H), 8.15 (m, 1H), 8.10 (m, 2H), 7.48 (t, 2H), 7.45 (m, 1H), 7.27 (m, 2H), 4.68 (m, 1H), 4.30 (m, 1H), 4.06 (t, 1H), 3.62-3.68 (m, 1H), 3.18-3.27 (m, 1H), 3.10 (s, 3H), 2.10 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:17][C:16](=O)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:35])=O>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([Cl:35])[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1
Reactant: COC(=O)CCCCCOc1ccc2[nH]c(=O)n(-c3ccc(C)cc3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1

Procedure:
2.5 g of 6-[[1-(4-methylphenyl)-2-oxo-2,3-dihydro-1H-benzoimidazol-6-yl]oxy]hexanoic acid methyl ester was mixed with 10 ml of phosphorus oxychloride, and the mixture was refluxed for 2 hours. After cooling, it was stirred into saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the combined organic phases were dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 1.28 g was obtained.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:5]1>O>[Br:1][C:7]1[C:6]([C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])=[N:5][N:4]([CH3:3])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: Cn1nc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1C(=O)O
Solvent: O
Product: Cn1nc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(Br)c1C(=O)O
Reaction time: 1 h

Procedure:
At 40° C., 255 mg (1.60 mmol) of bromine are added dropwise to a solution of 0.50 g (1.45 mmol) of 1-methyl-3-nonafluorobutyl-1H-pyrazole-5-carboxylic acid in 3.5 ml of water and the reaction mixture is afterstirred firstly for one hour at 60° C. and then for three days at room temperature. The aqueous phase is extracted three times with dichloromethane and the organic phase is dried over sodium sulphate. The dichloromethane is distilled off at reduced pressure on a rotary evaporator. This gives 0.54 g of 4-bromo-1-methyl-3-nonafluorobutyl-1H-pyrazole-5-carboxylic acid (80%) as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7])(=O)[OH:2].[CH3:12][NH2:13]>>[CH3:12][NH:13][C:1]([O:4][C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:7])=[O:2]
Reactant: O=C(O)Oc1ccccc1O
Reactant: CN
Product: CNC(=O)Oc1ccccc1O
Yield: 98 %

Procedure:
In fact, the reaction of pyrocatechol carbonate with methylamine in the presence of not less than 1 mol equivalent of the abovementioned secondary amines gives pyrocatechol monomethylcarbamate in a yield of 98-99%. The subsequent reaction of the reaction mixture with 1,2-dichloroethyl methyl ether in turn takes place with a yield of above 90%. Compared with the reaction with tertiary amines, the conversion takes place substantially more rapidly (on the bas-is of experience, from eight to ten times faster) and with better selectivity, and consequently a purer and more stable end product is obtained.
Reaction SMILES: C(O)(=O)C(O)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[NH2:19])=[CH:10][CH:9]=1.C1CCN2C(=NCCC2)CC1.[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32]>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[NH:19][S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])=[CH:12][CH:13]=1
Reactant: NC1CCCC1c1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(4-bromo-phenyl)-cyclopentylamine oxalate salt (500 mg, 1.51 mmol), methylene chloride (5.0 mL) and the solution was cooled to 0° C. DBU (1.8 mL, 12.1 mmol) and isopropylsulfonyl chloride (1.02 mL, 9.06 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 233 mg (45%) of the purified title compound. The nmr was consistent with the assigned structure.
Reaction SMILES: [Br-:1].[Li+].C1(C)C=CC(S([CH:12]([C@:14]2([O:28][CH2:27][C@@H:21]([O:22][C:23](=[O:26])[NH:24][CH3:25])[C@@H:18]([O:19][CH3:20])[C@@:16]2([C:29]([CH3:31])=[CH2:30])[OH:17])[OH:15])O)(=O)=O)=CC=1>CC(C)=O>[Br:1][CH2:12][C@:14]1([O:28][CH2:27][C@@H:21]([O:22][C:23](=[O:26])[NH:24][CH3:25])[C@@H:18]([O:19][CH3:20])[C@@:16]1([C:29]([CH3:31])=[CH2:30])[OH:17])[OH:15]
Reactant: [Br-]
Reactant: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC(=O)NC)CO[C@]1(O)C(O)S(=O)(=O)c1ccc(C)cc1
Agent: [Li+]
Solvent: CC(C)=O
Product: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC(=O)NC)CO[C@]1(O)CBr
Temperature: 75 °C
Yield: 94.2 %

Procedure:
0.29 g (3.34 mmol) of lithium bromide is added at room temperature, in a single portion, to a solution of 0.31 g (0.69 mmol) of the compound obtained in Example 10 in 15 ml of acetone. The reaction mixture is placed under stirring and then heated at 75° C. for 1.5 hours. A further 0.26 g (2.99 mmol) of lithium bromide is then added and the whole is again heated at 75° C. for one hour. The acetone is evaporated off under reduced pressure and the residue is taken up in 20 ml of ethyl acetate. Customary treatment of the organic phase yields 0.23 g (0.65 mmol) of the desired product in the form of a white-coloured foam.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH:35]2[CH2:37][CH2:36]2)[C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[N:20][CH:19]=2)[CH2:12][CH2:11]1)#N>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:35]1([N:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]3[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=3)[CH2:11][CH2:12]2)[C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=3)=[N:20][CH:19]=2)[CH2:37][CH2:36]1
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)C3CC3)CC2)n1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
0.5 M solution of zinc chloride in tetrahydrofuran (4.52 mL) is added dropwise at room temperature to a mixture of N-hydroxy-isobutyramidine (58 mg) and N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-6-(4-methanesulfonyl-phenyl)-nicotinamide (160 mg) in ethyl acetate (8 mL). The reaction mixture is stirred at 50° C. for two days and cooled to room temperature. The precipitate is filtered off and heated to 100° C. for 1 h in a mixture of ethanol (6 mL) and glacial acetic acid (3 mL). The solvents are evaporated in vacuo and dichloromethane and 10% aqueous K2CO3 solution are added to the residue. The organic phase is separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is triturated with diethyl ether to give the title compound. LC (method 8): tR=1.51 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)ccc1F

Procedure:
To a solution of methyl 2-fluoro-5-methylbenzoate (17.16 g, 102.1 mmol) in CCl4(250 mL) is added NBS (18.2 g, 102.1 mmol) and AIBN (0.83 g, 5.1 mmol), and the resulting solution is refluxed for 3 hours. After cooling, the mixture is filtered through celite, evaporated, and chromatographed (silica, 5 to 15% EtOAc/hexane) to yield methyl 5-bromomethyl-2-fluorobenzoate, as a white solid.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([NH:4][C:5]3=[O:12])[CH2:2]1)[CH2:9]2.C1(C)C=CC=CC=1.[OH-].[Na+].Br.Br.Br[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>O>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][N:4]2[C:5](=[O:12])[CH:6]3[CH2:11][CH:1]4[CH2:9][CH:8]([CH2:10][CH:3]2[CH2:2]4)[CH2:7]3)[CH2:29][CH2:30]1
Reactant: O=C1NC2CC3CC(C2)CC1C3
Reactant: CN1CCN(CCCBr)CC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN(CCCN2C(=O)C3CC4CC(C3)CC2C4)CC1
Reaction time: 0.08 h

Procedure:
To a well stirred solution of 2.4 gm. (0.02 mole) of 4-azatricyclo[4.3.1.13,8 ]undecan-5-one in 300 ml. of toluene, 3.2 gm. of powdered sodium hydroxide are added. After 5 minutes of vigorous stirring, 12 gm. of 1-(3-bromopropyl)-4-methylpiperazine dihydrobromide are added and the mixture heated for 20 minutes on a steam bath. The reaction mixture is cooled and stirred with 50 ml. of cold water. The toluene layer is separated, washed with 2 × 50 ml. of water and extracted with 3 × 100 ml. of 5 N HCl. The acid extracts are combined, washed with 100 ml. of ether, cooled and made basic with 2 N NaOH. The free base is extracted with 3 × 250 ml. of chloroform, dried (MgSO4) and evaporated in vacuo to give 4-[3-(4-methyl-1-piperazinyl)propyl]-4-azatricyclo[4.3.1.13,8 ]undecan-5-one.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:30][CH:15]([CH2:16][CH:17]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH2:18]2)[NH:14][CH2:13][CH:12]3[CH3:31])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(O[BH-](O[C:42](=O)[CH3:43])OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:30][CH:15]([CH2:16][CH:17]([N:19]4[C:20](=[O:29])[C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:27]4=[O:28])[CH2:18]2)[N:14]([CH2:2][CH2:1][CH2:3][C:42]2[CH:43]=[CH:9][CH:10]=[CH:5][CH:6]=2)[CH2:13][CH:12]3[CH3:31])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)NCC3C)c1
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)N(CCCc2ccccc2)CC3C)c1

Procedure:
2-[5-(3-Isopropoxy-phenyl)-4-methyl-2-aza-bicyclo[3.3.1]non-7-yl]-isoindole-1,3-dione (2.92 g, 7.0 mmol) and hydrocinamaldehyde (1.12 g, 8.3 mmol) were dissolved in dichloroethane (115 ml) followed by the addition of sodium triacetoxyborohydride (2.1 g, 9.7 mmol) and allowed to react at room temperature overnight. The reaction was quenched with the addition of a saturated sodium bicarbonate solution (200 ml) and the organic layer separated. The aqueous was then extracted with CHCl3. The combined organic fractions were dried (NaSO4), filtered, and concentrated in vaccu. The crude product was then purified by flash chromatography on an aluminum oxide (neutral, Brockman activity II-III) column and eluting with 8:2 hexane:ethyl acetate giving 3.16 g (83.9%) of the desired product. 1H NMR (CDCl3) δ 7.75 (m, 2H), 7.64 (m, 2H), 7.25 (m, 5H), 6.79 (m, 2H), 6.68 (d, J=7.8, 1H), 5.15 (m, 1H), 4.52 (sept., J=6.0 Hz, 1H), 3.27 (br, 1H), 3.08 (dd, J1=6 Hz, J2=3 Hz, 1H), 2.78-2.52 (m, 6H), 2.25-2.16 (m, 5H), 1.96-1.78 (m, 4H), 1.31 (d, J=6, 6H), 0.78 (d J=6.9, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9]CC(C)(C)N=2)=[C:4]([S:15][CH3:16])[C:3]=1[O:17][CH3:18].Cl.[OH2:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])=[O:20])=[C:4]([S:15][CH3:16])[C:3]=1[O:17][CH3:18]
Reactant: O
Reactant: COc1c(Cl)ccc(C2=NC(C)(C)CO2)c1SC
Agent: Cl
Product: COc1c(Cl)ccc(C(=O)O)c1SC

Procedure:
A mixture of 2-[4-chloro-3-methoxy-2-(methylsulphenyl)-phenyl]-4,4-dimethyloxazoline (9.0 g) and hydrochloric acid (5M) was stirred and heated at reflux for 5 hours. After cooling, the mixture was diluted with water and extracted with dichloromethane. It was dried (MgSO4), filtered and the filtrate was evaporated to dryness to give 4-chloro-3-methoxy-2-(methylsulphenyl) benzoic acid as a white solid, m.p. 98°-99° C.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[CH2:10]([SH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](=[O:5])[S:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCS
Reactant: O=C(Cl)CC(F)=C(F)F
Product: CCCCCCCCSC(=O)CC(F)=C(F)F
Temperature: 70 °C
Yield: 91.3 %

Procedure:
A mixture of 3,4,4-trifluoro-3-butenoyl chloride (1.7 g, 0.0107 mole) and 1-octanethiol (0.72 g, 0.0049 mole) is heated at 70° C. for 12 h. The crude product is purified by passing through a short column of silica gel to give 1.2 g of the desired product as a pale yellow oil, a 91% yield.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH2:11])[CH:10]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:29](OCCC(C)C)=O>C1C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]2[C:8]([CH:12]=[N:29][NH:11]2)=[CH:7][CH:6]=1
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(Oc2ccccc2F)cc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Fc1ccccc1Oc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a suspension of 5-(2-fluoro-phenoxy)-2-methyl-phenylamine (2.4 g, 11.04 mmol), acetic anhydride (3.36 g, 33.12 mmol) and potassium acetate anhydrous (1.10 g, 11.16 mmol) in benzene (36 mL) at 80° C. was added dropwise over 30 minutes isoamyl nitrite (2.22 mL, 16.56 mmol) and the reaction mixture was stirred at this temperature overnight. After cooling to room temperature, the precipitate formed was filtered and the filtrate was concentrated under vacuum and the residue treated with 5N HCl (4.5mL) then concentrated HCl (2.5 mL); the mixture was heated at 55° C. for 2.5 h then 60° C. for 15 min. The reaction was cooled to room temperature extracted into benzene (15 mL), the aqueous layer was basified with NH4OH the extracted into EtOAc (2×25 mL), the combined organic layers were dried over Na2SO4 filtered, concentrated and the residue was purified by flash chromatography eluting with Hex:EtOAc 7:3 to yield 1.8 g of 6-(2-fluoro-phenoxy)-1H-indazole: MS: 229 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[C:8]([CH3:15])[CH:7]=1.[CH3:16][N:17]=[C:18]=[S:19]>C(#N)C>[CH3:13][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:18]([NH:17][CH3:16])=[S:19])=[CH:7][C:8]=1[CH3:15])[CH3:14]
Reactant: CN=C=S
Reactant: Cc1cc(CSCCN)oc1CN(C)C
Solvent: CC#N
Product: CNC(=S)NCCSCc1cc(C)c(CN(C)C)o1

Procedure:
A solution of 5-[[2-(amino)ethyl]thio]methyl-N,N,3-trimethyl-2-furanmethanamine (0.5 g) and methylisothiocyanate (0.15 ml) in dry acetonitrile was stirred for 24 hours.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH:33]([CH3:35])[CH3:34])[C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH:33]([CH3:34])[CH3:35])[C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCC(=O)N(CCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCCCC(=O)N(CCCCCO)C(C)C
Yield: 101.2 %

Procedure:
A solution of 5 (4.75 g, 9.02 mmol) and p-toluenesulfonic acid in MeOH (50 mL) was stirred at rt for 12 h, then quenched with solid NaHCO3 and filtered. The filtrate was evaporated under vacuum and the residue was dissolved in ethyl acetate (50 mL). The ethyl acetate layer was washed with water (2×50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 50-60% ethyl acetate/hexane as eluent to afford alcohol 6 (2.35 g, 93%) as a colorless, viscous liquid. TLC:EtOAc/hexanes (1:1), Rf˜0.30; 1H NMR (400 MHz, 55/45 mixture of rotamers) δ 4.58-4.66 and 3.96-4.08 (m, 1H, rotamers), 3.56 and 3.70 (t, J=5.4 Hz, 2H, rotamers), 3.02 and 3.16 (t, J=5.2 Hz, 2H, rotamers), 2.38 and 2.26 (t, J=6.3 Hz, 2H, rotamers), 1.50-1.64 (m, 6H), 1.22-1.40 (m, 8H), 1.13 and 1.09 (d, J=7.5 Hz, 6H, rotamers), 0.84 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, 55/45 mixture of rotamers) δ 172.81, 62.66, 62.60, 48.41, 45.55, 43.56, 41.04, 34.08, 34.0, 32.46, 32.43, 31.86, 31.57, 29.40, 25.87, 25.70, 23.77, 23.73, 22.75, 21.57, 20.72, 14.26.