Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1.C([O-])(=[S:28])C.[K+].O>CC(N(C)C)=O>[SH:28][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CC([O-])=S
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCI)cc1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCS)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6.6 g (0.015 mol) of 1-[4-(3-Iodopropylamino)phenyl]-2-dimethylamino-2-benzyl-propan-1-one are dissolved in 50 ml of dimethylacetamide. To the solution are added 2.42 g of potassium thioacetate and heated up to 50° C. After the reaction mixture is stirred at 50° C. for 2 h, it is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is dissolved in 70 ml of ethanol and the solution is bubbled by nitrogen for 30 min. to remove oxygen. To the solution are added 7 ml of 2 N sodium hydroxide solution and stirred at 0° C. for 30 min. After the reaction mixture is neutralized by adding 2 N hydrochloric acid solution, the resulting solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After ethyl acetate is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:2) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 1.14 (s, 3H), 1.43 (t, 1H), 1.97 (m, 2H), 2.33 (s, 6H), 2.68 (q, 2H), 2.96 (d, 1H), 3.34-3.39 (m, 2H), 3.42 (d, 1H), 4.18 (br, 1H), 6.57 (d, 2H), 6.89-6.92 (m, 2H), 7.10-7.12 (m, 3H), 8.46 (d, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1>Cl.O>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)CCCc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(CCCc1ccccc1)c1cccc(O)c1
Temperature: 190 °C

Procedure:
A mixture of 2-(3-methoxyphenyl)-5-phenylpentane (18.4 g.) and pyridine hydrochloride (94 g.) under nitrogen is heated to 190° C. for 2 hours with vigorous stirring. The reaction mixture is cooled, dissolved in 6 N hydrochloric acid (200 ml.) and diluted with water to 600 ml. The aqueous solution is extracted with ethyl acetate (4×100 ml.), the ethyl acetate extracts dried over sodium sulfate and concentrated under vacuum to yield the crude product. The product is purified by silica gel chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[CH:9][CH:8]=[C:7]([Br:27])[CH:6]=2.[C:28](OC)(OC)(OC)[CH2:29][CH2:30][CH3:31]>>[Br:27][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]4)[C:28]([CH2:29][CH2:30][CH3:31])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(N)cnc3cc(Br)ccc23)CC1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77.9 %

Procedure:
The method described in Part A of Examples 142–144 was used to treat tert-butyl 4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]piperidine-1-carboxylate (15.0 g, 34.5 mmol) with trimethyl orthobutyrate (5.62 g, 37.9 mmol). After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from ethyl acetate to provide 13.1 g of tert-butyl 4-[(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white solid, mp 215–216° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([C:14]1[CH:26]=[CH:25][C:17]2[N:18]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:20][C:16]=2[CH:15]=1)([O-:13])=[O:12]>S(=O)(=O)(O)O>[NH2:11][C:14]1[CH:26]=[CH:25][C:17]2[N:18]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:20][C:16]=2[CH:15]=1.[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([SH:1])[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: NS(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2s1
Reactant: Sc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: Nc1ccc2nc(S(N)(=O)=O)sc2c1
Product: O=[N+]([O-])c1ccc2nc(S)sc2c1
Yield: 90 %

Procedure:
The title compound is prepared by first converting 2-mercaptobenzothiazole to 6-nitro-2-benzothiazolesulfonamide and then reducing to the 6-amino analog. 2-Mercaptobenzothiazole was converted to 2,2'-bis-benzothiazole disulfide in 90% yield: m.p. 175-177° C. Nitration in concentrated sulfuric acid gave 6-nitro-2-mercaptobenzothiazole in 59%. m.p. 255-258° C. The sulfenamide was formed by reaction with aqueous sodium hydroxide and sodium hypochlorite and oxidized in the next step without further purification. The oxidation was accomplished by dissolving the sulfenamide in dimethoxyethane, cooling the solution to -5° C., adding the m-chloroperoxybenzoic acid in dimethoxyethane and working up the reaction in the standard manner to obtain a 70% yield: m.p. 179-180°; MS, m/e 259 (M, calcd. 259). Anal. (C7H5N3O4S2) CHN.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[C:6]([F:12])[CH:5]=1)=O.[CH2:13]([CH2:15][NH2:16])[OH:14]>C1(C)C=CC=CC=1>[F:12][C:6]1[CH:5]=[C:4]([CH:2]([NH:16][CH2:15][CH2:13][OH:14])[CH3:1])[CH:9]=[C:8]([F:10])[C:7]=1[F:11]
Reactant: NCCO
Reactant: CC(=O)c1cc(F)c(F)c(F)c1
Solvent: Cc1ccccc1
Product: CC(NCCO)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
A mixture of 3,4,5-trifluoroacetophenone (2.0 g), ethanolamine (2.0 g), and toluene (20 mL) was heated under reflux in a Dean-Stark apparatus for 2.5 hours. The reaction solution was concentrated under reduced pressure, and then the residue was diluted with ethanol (30 mL) and sodium borohydride (1.0 g) was added under ice-cooling. The mixture was stirred at room temperature for three hours and then diluted with a 2 N sodium hydroxide solution and chloroform. Thereafter, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (chloroform:methanol=50:1 to 5:1) to obtain 860 mg of the title compound.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].O1CC[CH2:8][CH2:7]1.[CH:11]1[CH2:17][CH:16]=CC=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:3]([C:2]1[CH:13]=[CH:12][CH2:11][CH2:17][CH2:16][C:1]=1[Li:5])[CH2:4][CH2:7][CH3:8]
Reactant: [Li]CCCC
Reactant: C1=CC=CCC=C1
Reactant: C1CCOC1
Solvent: Cc1ccccc1
Product: [Li]C1=C(CCCC)C=CCCC1
Temperature: -78 °C

Procedure:
n-Butyllithium (50 ml of 1.53M heptane solution) was introduced into a previously dried and nitrogen purged 100 ml Pyrex-glass pressure tube equipped with a perforated crown cap over a self-sealing rubber gasket. After adjusting the temperature of this solution to -78° C., 20 ml of tetrahydrofuran and 8 ml of 1,3,5-cycloheptatriene (0.077 moles) were added. The solution turned red in color almost immediately after addition of the 1,3,5-cycloheptatriene. This reaction mixture was maintained at -78° C. for 15 minutes. The temperature was adjusted to 0° C. and the solution maintained at this temperature for one hour. During this period the solution became very dark in color. Dilution of 38 ml of this n-butylcycloheptadienyllithium solution with 279 ml of toluene gave a red-violet solution having a molarity of 0.1255 as determined by disulfide titration. This titration method is described in C. A. Uraneck, J. E. Burleigh, and J. W. Cleary, Analytical Chemistry 40, 327 (1968).
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[C:12]([C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=5)[CH:23]=[C:22]([CH3:36])[N:21]=4)[CH:17]=[CH:16][N:15]=3)[CH:11]=[CH:10][N:9]=2)C(C)=CC=1.Cl.NO>>[CH3:36][C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH2:3])[CH:13]=3)[N:19]=2)[CH:25]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccnc(-n4c(C)ccc4C)c3)n2)n1
Agent: Cl
Agent: NO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccnc(N)c3)n2)n1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A mixture of the above described 2-[2-(2,5-dimethyl-pyrrol-1-yl)-pyridin-4-yl]-4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (280 mg, 0.577 mmol), hydroxylamine hydrochloride (200 mg, 2.89 mmol) 1.5 M NaOH-sol. (0.96 mL, 1.44 mmol) in 1-propanole (3 mL) was stirred at 120° C. for 3 h in a sealed tube. Cooled to rt, poured the reaction mixture directly on a silica gel column and chromatographed with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.050 g, 27%) as an off-white solid. MS (ISP) 408.4 [(M+H)+]; mp 217° C.
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[CH2:46][CH2:45][C@H:44]([OH:47])[CH2:43]3)[CH2:38][CH2:37]2)[CH:30]=[CH:31][C:32]=1[N+:33]([O-])=O>>[NH2:33][C:32]1[CH:31]=[CH:30][C:29]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]3[CH2:46][CH2:45][C@H:44]([OH:47])[CH2:43]3)[CH2:38][CH2:37]2)=[CH:28][C:27]=1[O:26][CH3:25]
Reactant: COc1cc(N2CCC(N3CC[C@H](O)C3)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1cc(N2CCC(N3CC[C@H](O)C3)CC2)ccc1N

Procedure:
(S)-1-[1-(4-Amino-3-methoxy-phenyl)-piperidin-4-yl]-pyrrolidin-3-ol was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with (S)-1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-pyrrolidin-3-ol (150 mg, 99%). LC/MS (E/I+) 292.15 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH3:25])[CH:5]=[CH:6][CH:7]=1.[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCCC1.O>[Br:27][CH2:25][C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:26])[C:14]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cccc1Cn1c(C)nc(=O)c2sc(N3CCOCC3)nc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(CBr)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a 40 mL I-CHEM reaction vial equipped with a stirbar, was added Example 60, 4-[(3-chloro-2-methylphenyl)methyl]-5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (1 g, 2.56 mmol), N-bromosuccinimide (0.569 g, 3.20 mmol), and 2,2′-azobis(2-methylpropionitrile) (0.084 g, 0.512 mmol). The solids were taken up in tetrahydrofuran (THF) (25.6 ml) and stirred overnight at room temperature. After overnight stirring, the reaction was diluted with water (˜10 mL) transferred to a separatory funnel and extracted with dichloromethane DCM (˜50 mL). The organic layer was dried over sodium sulfate and concentrated to a residue. The residue was re-dissolved in a minimum amount of DCM (˜2 mL) and injected onto a 25 g SNAP silica cartridge for purification (eluting with a gradient: 5%-75% THF (1% methanol (MeOH)) into DCM, over 30 column volumes). Fractions containing the desired material were pooled and concentrated to afford 5-(bromomethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (752 mg, 1.601 mmol, 62.6% yield). LC/MS Theoretical m/z MH+=470.78 Found: 470.8; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.46-3.56 (m, 4H) 3.66 (t, J=4.93 Hz, 5H) 4.46 (s, 2H) 5.58 (s, 2H) 6.53 (d, J=8.08 Hz, 1H) 7.14 (t, J=7.96 Hz, 1H) 7.37 (d, J=7.83 Hz, 1H).
Reaction SMILES: C(OC([N:7]([CH2:15][CH:16]([C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[OH:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>O1CCCC1.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>[CH2:8]([NH:7][CH2:15][CH:16]([C:18]1([CH3:23])[O:19][CH2:20][CH2:21][O:22]1)[OH:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CCOC(=O)N(Cc1ccccc1)CC(O)C1(C)OCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1(C(O)CNCc2ccccc2)OCCO1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2 g) was added to a mixture of 2-[2-(N-allyloxycarbonyl-N-benzylamino)-1-hydroxyethyl]-2-methyl-1,3-dioxolane (10.5 g), triphenylphosphine (0.86 g), and morpholine (3 ml) in tetrahydrofuran (100 ml) at ambient temperature in a stream of nitrogen. The mixture was stirred at the same condition for 2 hours and concentrated under reduced pressure to give a residue. The residue was subjected to a column chromatography on silica gel (150 g) and eluted with a mixture of methanol and chloroform (2:98, and then 5:95, V/V) to give 2-(2-benzylamino-1-hydroxyethyl)-2-methyl-1,3-dioxolane (5.60 g) as a syrup.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][C:8]#[N:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][C:17]1([CH3:20])[CH2:19][O:18]1.O>COCCOC>[CH3:16][C:17]1([CH3:20])[O:18][C:8](=[NH:9])[N:7]([CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH2:19]1
Reactant: CC1(C)CO1
Reactant: N#CNC[C@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)CN(C[C@H]2CCCO2)C(=N)O1

Procedure:
A mixture of Example 32A (0.6 g, 4.9 mmol), cesium carbonate (1.6 g, 4.9 mmol) and 2,2-dimethyloxirane (0.35 g, 4.9 mmol, Alfa-aesar) in 1,2-dimethoxyethane (20 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to afford the title compound. LCMS (APCI+) m/z 198 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][N:15]3C(=O)C4=CC=CC=C4C3=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CCN(Cc2ccc(F)cc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCC1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of N-[2-[1-(4-fluorobenzyl)piperidin-4-yl]ethyl]phthalimide (12.7 g) and hydrazine hydrate (2.02 ml) in ethanol (150 ml) was refluxed for 2 hours. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was chromatographed on alumina eluting with chloroform and the fractions containing the object product were collected and evaporated to give 2-[1-(4-fluorobenzyl)piperidin-4-yl]ethylamine (4.5 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cccc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(Cl)c1OC1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 4-(2,6-dichlorophenoxy)piperidine-1-carboxylate (5.54 g) was mixed with 50 ml of mixture of TFA and CH2Cl2 (1:1). The mixture was stirred at room temperature for 4 hours. The solvents were removed under vacuum residue was Freeze-dried using CH3CN/water system. The desired 4-(2,6-dichlorophenoxy)piperidine was obtained as TFA salt (white solid) in 100% yield.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Br[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:25])[CH2:20][CH2:21][O:22]2)=[CH:17][C:16]=1[Cl:26]>C(Cl)Cl>[C:1]([NH:5][CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:25])[CH2:20][CH2:21][O:22]2)=[CH:17][C:16]=1[Cl:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C1CCOc2cc(CBr)c(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NCc1cc2c(cc1Cl)C(=O)CCO2
Reaction time: 16 h

Procedure:
To a stirred mixture of tert-butylamine (7.3 g, 99.78 mmol) and Et3N (10.1 g, 99.78 mmol) in anhydrous CH2Cl2 (50 mL) was added a solution of 7-bromomethyl-6-chloro-chroman-4-one (25 g, 90.71 mmol) in CH2Cl2 (150 mL) dropwise. Stirring was continued for 16 h. The mixture was concentrated, taken up in H2O, acidified with 10% HCl until pH 1, and extracted with Et2O (discarded). The acidic aqueous layer was neutralized with 5 N NaOH, and extracted with CH2Cl2 (3×). The combined extracts were dried over MgSO4, concentrated to give a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:43])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([C:34]2[CH:33]=[C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:43])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)[CH:37]=[CH:36][N:35]=2)[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CCCC4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C4CCCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M273) (360 mg, 0.589 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (198 mg, 68%).
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:19][C:16]([C:20]([O-:22])=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[CH3:23]CO>[Pd]>[NH2:11][C:12]12[CH2:19][C:16]([C:20]([O:22][CH3:23])=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2
Reactant: CCO
Reactant: O=C(NC12CCCC(C(=O)[O-])(CC1)C2)OCc1ccccc1
Agent: [Pd]
Product: COC(=O)C12CCCC(N)(CC1)C2
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 5-(benzyloxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylate (10 g, 31.5 mmol) in EtOH (50 mL) was added Pd/C (900 mg) under H2 atmosphere at room temperature and stirred overnight. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to afford 5.5 g (96%) of the crude title compound, methyl 5-aminobicyclo[3.2.1]octane-1-carboxylate, as a colorless oil. ESI-MS m/z: 184 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[I:8][C:9]1[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1.C1(=O)OC(=O)C=C1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[I:8][C:9]1[CH:15]=[CH:14][C:12]([N:5]2[C:4](=[O:6])[CH:3]=[CH:2][C:1]2=[O:7])=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)N1
Reactant: Nc1ccc(I)cc1
Agent: CC(=O)[O-]
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1C=CC(=O)N1c1ccc(I)cc1

Procedure:
The title compound was prepared by standard maleimide procedures involving the reaction of p-iodoaniline with maleic anhydride and then subsequent cyclization with acetic anhydride and sodium acetate.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:35][CH2:34][CH2:33][CH2:32][OH:31])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 120 mg (0.19 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride (preparation described above) and 57 μl (0.38 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([C:16]1[C:17]([OH:36])=[CH:18][C:19]2[N:20]([N:22]=[C:23]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:24]=2[C:25]([O:27][CH3:28])=[O:26])[CH:21]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C(C)(C)C)(C)C>[Pd].C(OCC)(=O)C>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:23]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:19]3[CH:18]=[C:17]([OH:36])[C:16]([N:11]([CH2:10][CH2:9][OH:8])[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:21][N:20]3[N:22]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)c(O)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCO)S(C)(=O)=O)c(O)cc12
Reaction time: 2 h

Procedure:
To a solution containing Methyl 6-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-5-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (0.17 g, 0.27 mmol) and ethyl acetate (5.4 mL) was added 10% Pd/C (0.04 g, 0.04 mmol Pd) in one portion under a nitrogen atmosphere. The reaction mixture was stirred for 2 h under an atmosphere of hydrogen gas (balloon), filtered and concentrated to afford Methyl 2-(4-fluorophenyl)-5-hydroxy-6-(N-(2-hydroxyethyl)methylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate as a light yellow oil. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.71 (s, 1H), 8.68 (s, 1H), 7.73 (ddd, J=11.98, 5.33, 2.76 Hz, 2H), 7.46 (s, 1H), 7.25-7.31 (m, 2H), 3.70 (s, 7H), 3.11-3.14 (m, 3H), 0.74 (s, 9H), −0.06-−0.04 (m, 6H). LCMS: retention time: 2.750 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 538 (MH+).