Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[F:7][C:8]([F:12])=[C:9](F)F.Cl.[NH:14]=[C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:18]=[C:17]([CH3:30])[S:16]1.C(=O)([O-])[OH:32].[Na+]>CN(C)C=O>[F:7][CH:8]([F:12])[C:9]([N:14]=[C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[CH:18]=[C:17]([CH3:30])[S:16]1)=[O:32]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: FC(F)=C(F)F
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A solution of piperidine (0.57 g, 6.7 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow into the flask (ca. 0.7 liter/hr), with vigorous stirring at 50° C. for 10 hours. After cooling to an ambient temperature, 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline hydrochloride (1.29 g, 5.0 mmol) was added tothe reaction mixture and allowed to react overnight at room temperature and then at 50° C. for 8 hours. After cooling to an ambient temperature, the reaction solution was poured intoa saturated aqueous sodium hydrogencarbonate solution, and extracted twice with toluene (100 ml×2). The toluene layer was washed twice with 5% hydrochloric acid (50 ml×2) and water (50 ml) and then brine (50 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (0.83 g, 2.5 mmol, yield 49%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[C:4]([CH3:23])[C:3]=1[CH3:24].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]3)=[C:4]([CH3:23])[C:3]=2[CH3:24])=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c(Cl)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Yield: 59.9 %

Procedure:
Heat a mixture of tert-butyl 1-(6-chloro-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate (1.5 g, 4.23 mmol), 4-fluorophenylboronic acid (887 mg, 6.34 mmol), Cs2CO3 (5.51 g, 16.9 mmol) and (SP-4-1)-bis[bis(1,1-dimethylethyl)(4-methoxyphenyl)phosphine-κP]dichloro-palladium (J. Org. Chem. 2007, 72, 5104-5112) (29 mg, 0.042 mmol) in a mixture of 1,4-dioxane (30 mL) and H2O (10 mL) under N2 at 90° C. overnight. Partition the reaction mixture between H2O and CH2Cl2. Separate the layers, and extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2) to provide the title compound as a white foam (1.05 g, 60%). ES/MS m/z 415.2 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:29])=[CH2:28]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:28][C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH2:29]
Reactant: C=C(C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Bromosuccinimide (52.0 g, 292 mmol) and benzoylperoxide (2.0 g, 8.0 mmol) were added to a solution of isopropenylbenzene (82.0 g, 694 mmol) in carbon tetrachloride (200 mL). The reaction mixture was heated to reflux. After 18 h, additional N-bromosuccinimide (30.0 g, 168 mmol) was added. After 18 h, the mixture was allowed to cool to ambient temperature and the solid in the mixture was filtered off. The filtrate was concentrated and purified by vacuum distillation (95-120° C., 10 torr). The isolated mixture was purified by silica gel chromatography (100% hexanes) to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCCC1>[N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: NS(N)(=O)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)N1CCOCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 7.8 %

Procedure:
Tetrahydrofuran (3 mL) and morpholine (0.68 mL, 7.8 mmol) were added to sulfamide (500 mg, 5.2 mmol) and the mixture was stirred at 100° C. for 4 hours. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=1/0 to 4/1) was performed to give morpholine-4-sulfonamide (Compound FY) (67 mg, yield: 8%).
Reaction SMILES: C(S[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[N:8]=1)C.[CH3:16][NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1>C1COCC1>[CH3:16][N:17]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[N:8]=1
Reactant: CCSc1nc2cc([N+](=O)[O-])ccc2o1
Reactant: CNC1CCN(C)CC1
Solvent: C1CCOC1
Product: CN1CCC(N(C)c2nc3cc([N+](=O)[O-])ccc3o2)CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
Dissolve 2-ethylsulfanyl-5-nitro-benzooxazole (1.17 g, 5.23 mmol) in anhydrous THF (10 mL) in a reaction tube and blow nitrogen into the vessel for 10 s. Add methyl-(1-methyl-piperidin-4-yl)-amine (1.37 mL, 9.42 mmol) to the solution. Quickly seal the vessel and immerse into a pre-heated oil bath (100° C.) and stir for 24 h. Concentrate the reaction mixture in vacuo, wash with 1.0M NaOH (aq) (2×50 mL), dry over Na2SO4, filter, and concentrate in vacuo. Subject the residue by silica gel flash column chromatography, eluting with 2N NH3 in MeOH/CH2Cl2, to yield the desired product (0.608 g, 40%). MS (ES+) 291.0 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.Cl.[NH2:15]O.O>C(O)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[C:5]#[N:15]
Reactant: NO
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: O=CO
Product: N#Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution containing 0.92 g of 3,4-dihydroxy-5-nitrobenz-aldehyde and 0.49 g of hydroxylamine hydrochloride in 5.0 ml of formic acid was refluxed for 1 h. 50 ml of water was added and the product was filtered and washed with water. Yield 0.3 g (33%), m.p. 175°-178° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9]>>[OH2:9].[C:1]1([CH3:7])[C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)O
Product: O
Temperature: 45 °C

Procedure:
Reference Example 1. 6 mol Of toluene were added dropwise over a period of 1 hour to a mixture of 3.75 mol sulfuric acid and 2.25 mol fuming sulfuric acid at a mixture temperature of 45 to 60° C. The reaction mixture was heated for another 30 minutes at 45° C., which gave toluenesulfonic acid monohydrate. A mixture of 1 mol trichlorosilane and 6.6 molitoluene was added dropwise to this over a period of 5 hours at 30° C., and the reaction mixture was heated for another 30 minutes at 45° C. After the solution was allowed to cool and separate, the toluenesulfonic acid layer (at the bottom) was removed, after which the top layer was washed with a suitable amount of sulfuric acid/water (50/50 weight ratio), then with a suitable amount of sulfuric acid/water (25/75 weight ratio), and then with pure water in order to remove the acid contained in the top layer. Azeotropic dehydration was then performed for 1 hour in order to remove the water completely. The toluene solution obtained in this manner was put under reduced pressure with a vacuum pump at 60° C. to remove the toluene, which gave a hydrogen silsesquioxane resin whose main skeleton consisted of siloxane units described by formula HSiO3/2. This hydrogen silsesquioxane resin had a number average molecular weight of 1650, and the ratio of the weight average molecular weight/number average molecular weight was 19.4.
Reaction SMILES: C[C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:11]1COCC1>>[CH3:11][CH:8]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[OH:10]
Reactant: C1CCOC1
Reactant: CC1(C(=O)O)CCCCC1
Product: CC(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A three liter three necked round bottom flask was equipped with a thermometer, magnetic stirrer, argon inlet and outlet adapters and a one liter addition funnel containing 922 ml of 1.0 molar BH3 ·THF. 1-Methyl cyclohexanecarboxylic acid (119.2 g; 0.84 mole) was added to the reaction vessel and dissolved in 100 ml of THF. The reaction mixture was cooled with an ice bath to 5° C. the BH3 ·THF was added dropwise over 25 min maintaining the temperature between 5°-15° C. After the addition was complete, the ice bath was removed. After about 5 min, the reaction exothermed and foamed violently. A much slower addition rate and constant cooling should help to avoid this exotherm. The reaction was allowed to stir for 2 hr at room temperature under nitrogen, then 150 ml of methanol was added cautiously. When the foaming ceased, the reaction was concentrated in vacuo using low heat and the residue was treated with 100 ml of 5% acetic acid. After stirring for 30 min, the reaction was transferred to a one liter separatory funnel, diluted with water (slurry dissolved) and extracted three times with ether. The combined ether extracts were washed twice with saturated sodium bicarbonate, twice with brine, dried over anhydrous magnesium sulfate, filtered through celite and concentrated in vacuo (low heat) to give 79.09 g of a clear water-white oil. The oil was distilled on a Kugelrohr apparatus at 75°-130° C. (25 mm of Hg). Most distilled at 90° C. to give 72.11 g of 1-methyl-1-cyclohexylmethanol.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.CCO.[BH4-].[Na+].CCOC(C)=O>C1COCC1>[OH:10][CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
Isophthalaldehyde (150 g, 1.1 mole) was dissolved in THF (1 L) and EtOH (1 L) at 0° C. NaBH4 (11.0 g, 291 mmol) was added portionwise and the mixture stirred 1 hr at 0° C. Addition of 25% aq. NH4OAc and extraction with EtOAc (2×) followed by purification by flash chromatography (20%→40% EtOAc in hexanes) yielded 60 g of 3-(hydroxymethyl)-benzaldehyde.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:21][O:22][CH2:23][CH3:24])[N:15]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6][C:5]=2[N:4]=1.CCN([CH:38]([CH3:40])[CH3:39])C(C)C.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>ClCCl>[CH2:45]([O:44][C:42]([N:2]([C:27]([O:29][CH2:30][C:39]1[CH:38]=[CH:40][CH:6]=[CH:5][CH:10]=1)=[O:28])[C:3]1[C:12]2[N:13]=[C:14]([CH2:21][O:22][CH2:23][CH3:24])[N:15]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:6][C:5]=2[N:4]=1)=[O:43])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOCc1nc2c(N)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N(C(=O)OCc3ccccc3)C(=O)OCc3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 202.2 %

Procedure:
To a suspension of ethyl 3-(4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate hydrochloride (300 mg, 665 μmol) DMAP (15 mg, 123 μmol) and DIEA (1.86 ml, 10.6 mmol) in dichloromethane (6 mL), benzyl chloroformate (380 μl, 2.66 mmol) was added. The reaction mixture stirred at room temperature for 20 h, more benzyl chloroformate (908 60 μl, 5.32 mmol) was added and stirring continued for another 6 h. Afterwards the mixture was poured into dichloromethane (50 mL), extracted with HCl (1M, 20 mL) and water (20 mL). The aqueous layer was extracted with dichloromethane (50 mL), organic phases were combined, dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound (0.459 g, quant.) as colorless oil; LC-MS (UV peak area, ESI) 86%, 683.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].Cl([O-])=[O:39].[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:24])[F:25])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:39])=[O:11])=[CH:8][C:7]=1[C:14]([F:17])([F:15])[F:16]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C(=O)O)cc3C(F)(F)F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 214, step 2, 4-{3-chloro-4-[2-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-3-trifluoromethyl-benzaldehyde was treated with sodium chlorite in the presence of sodiumdihydrogenphosphate-dihydrate in tert.-butanol, 2-methyl-2-butene and water to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=562.0 [M−H+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14][OH:15])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:6]([O:10][C:11]([NH:12][CH2:13][CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[O:16])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.60 mL, 7.76 mmol) was added to a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (1.04 g, 6.46 mmol) and triethylamine (1.35 mL, 9.70 mmol) in dichloromethane (35 mL) cooled to 0° C. The solution was stirred for one hour, after which time it was diluted with ethyl acetate, washed with saturated NaHCO3 (2×), brine, dried over Na2SO4 and concentrated to a thick colorless liquid (1.37 g, 89%).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.Cl[P:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O1CCCC1.[Zn].C1(C)C=CC=CC=1>[C:18]1([PH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84 %

Procedure:
20×10-3 cm3 of 1,2-dibromoethane was added dropwise in a nitrogen gas atmosphere to a suspension of 461 mg (7.05 mg-atoms) of zinc (powder) in 10 cm3 of tetrahydrofuran, the mixture was heated to reflux for about 2 minutes and cooled to room temperature, 30×10-3 cm3 of chlorotrimethylsilane was added and the mixture was stirred for about 2 minutes to prepare an activated zinc. Subsequently, 1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise and the mixture was stirred at room temperature. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 hydrochloric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was determined by gas chromatography, giving diphenylphosphine in 84% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C([O-])([O-])=O.[Na+].[Na+]>CO.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:12]([C:11]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2cc(Br)ccc2s1

Procedure:
A solution of 5-bromo-2-fluorobenzaldehyde (6 g, 29.6 mmol), methyl thioglycolate (2.64 mL, 29.6 mmol), and Na2CO3 (3.14 g, 29.6 mmol) in methanol was heated to reflux for 1 hour, poured into brine, and extracted with ethyl acetate (3×). The combined extracts were washed with brine and filtered through silica gel to provide the desired product. MS (ESI(−)) m/e 270 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].Br[CH2:25][C:26]#[C:27][CH2:28][CH2:29][CH3:30].C(OCC)C>O>[NH3:5].[CH2:25]([N:5]1[CH2:6][CH:7]2[CH:3]([C:2]2([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH3:1])[CH2:4]1)/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH3:30]
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: CCCC#CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCC/C=C/CN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 57 mg, 0.19 mmol) dissolved in N,N-dimethylformnamide (2 ml) was added sodium hydrogen carbonate (630 mg, 7.52 mmol) and 1-bromo-2-hexyne (H. A. J. Charles, and R. J. Batten, J. Chem. Soc., Perkin Trans 1, 1987, 1999, 33 mg, 0.2 mmol) and the reaction mixture was heated at 50° C. for 20 h. After cooling diethyl ether (5 ml) and water (7 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×5 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (5 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (33 mg, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:21])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.3 %

Procedure:
4-Benzyloxybenzoic acid (15.0 g, 65.72 mmol) in dichloromethane (150 mL) and dimethylformamide (0.75 mL) was cooled to 0° C. After 30 minutes, the mixture was treated with neat oxalyl chloride (11.5 mL, 131.44 mmol) dropwise over 25 minutes. The resulting mixture was stirred at room temperature for 120 minutes followed by evaporation of solvent under reduced pressure to provide the title compound as a light yellow solid (18.2 g, 112% yield). 1HNMR (300 MHz, CDCl3) δ 7.03 (d, 2H, J=8.9 Hz), 7.23-7.43 (m, 5H), 8.07 (d, 2H, J=8.9 Hz).
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:18][CH2:19][CH2:20][OH:21])[CH3:17])[CH2:12][CH2:11]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[ClH:1].[ClH:1].[OH:21][CH2:20][CH2:19][CH2:18][N:16]([CH3:17])[CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: CN(CCCO)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(CCCO)C1CCNCC1
Reaction time: 2 h
Yield: 183.4 %

Procedure:
42.8 g of 1-benzyl-4-[(3-hydroxypropyl)-methylamino]-piperidine-dihydrochloride are dissolved in 450 ml of methanol, combined with 5 g of 5% palladium-charcoal and hydrogenated at about 50° C. with hydrogen at 4-5 bar. The catalyst is filtered off, the methanol is distilled off and the residue is stirred in acetone. Ether is added, the mixture is left to stand for about two hours and then the crystals are suction filtered. 28.7 g of 4-[-(3-hydroxypropyl)-methylamino]-piperidine-dihydrochloride are obtained in the form of a solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[N+:20]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:8]=[CH:7][C:6]=1[CH2:9][C:10]([OH:12])=[O:11])([O-:22])=[O:21]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-trifluoromethylphenyl acetic acid (2.5 g, 12.25 mmol) in 8 mL of glacial acetic acid at 0° C. under an anhydrous atmosphere was added 5 mL of fuming H2SO4 (11% SO3) (caution!) followed by cautious addition of 90% HNO3 (3.5 mL, 73.14 mmol) within 10 min. The reaction mixture was then stirred at room temperature for 2 h and poured into ice-water. The resulting solid was filtered and washed with cold deionized water to give the desired product after drying as off-white solid, 2.5 g (82%); 1H NMR (200 MHz, CDCl3) δ 4.02 (s, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 8.28 (s, 1H). T used directly into the following reactions.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH3:12][NH:13][CH3:14].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][CH:7]([N:13]([CH3:14])[CH3:12])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: CNC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 5.0 gm (32 mMol) 1,4-cyclohexanedione mono-ethylene ketal and 10.80 gm (240 mMol) dimethylamine were added 2.0 mL acetic acid and the mixture was stirred at 0° C. for 1.5 hours. To this solution were then added 3.62 gm (58 mMol) sodium cyanoborohydride and the reaction stirred for an additional hour at ambient. The pH of the reaction mixture was adjusted to ~7 with 16 mL acetic acid and stirred 18 hours at ambient. The volatiles were removed under reduced pressure and the residue dissolved in cold 5% tartaric acid solution and then the aqueous phase was made basic with 5N sodium hydroxide. This aqueous phase was extracted well with dichloromethane. These organic extracts were combined and concentrated under reduced pressure to give 5.04 gm (85% of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([NH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: Nc1cccc2c1CCCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 24.39 g of 1-amino-5,6,7,8-tetrahydronaphthalene and 18.6 ml of acetic anhydride in 230 ml of DCM is left stirring for 1 hour at RT. It is concentrated under vacuum, the residue is taken up with ether and the precipitate formed is drained. 26.8 g of the expected product are obtained, m.p.=158° C.