Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[I-].[K+].[F:9][CH:10]([F:28])[O:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1([CH2:26]Br)[O:23][CH:22]([CH2:24][CH3:25])[CH2:21][O:20]1.O>CN(C)C=O>[F:28][CH:10]([F:9])[O:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1([CH2:26][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)[O:23][CH:22]([CH2:24][CH3:25])[CH2:21][O:20]1
Reactant: CCC1COC(CBr)(c2ccc(Cl)cc2OC(F)F)O1
Reactant: c1nc[nH]n1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1COC(Cn2cncn2)(c2ccc(Cl)cc2OC(F)F)O1
Temperature: 25 °C

Procedure:
5.9 parts of 1,2,4-triazole sodium salt, a catalytic amount of potassium iodide and 12 parts of the 2-(2'-difluoromethoxy-4'-chlorophenyl)-2-bromomethyl-4-ethyl-1,3-dioxolane prepared in (b) are stirred in 100 ml of dimethylformamide for 16 hours at a bath temperature of 130° C. The reaction mixture is cooled to room temperature, poured into 500 ml of water and extracted with 2×300 ml of diethyl ether. The combined organic phases are washed with 2×200 ml of water, dried over sodium sulfate, filtered, and the solvent is removed by evaporation. The oily residue is chromatographed through a 50 cm column of silica gel with a 1:1 mixture of methylene chloride/diethyl ether as eluant. The eluant is removed by evaporation to give a yellow oil with a refractive index nD27 : 1.5132.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18].[C:23]([O:27][C:28]([NH:30][C:31]1([C@H:34]2[CH2:38][NH:37][CH2:36][C@H:35]2[F:39])[CH2:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN1CCCCC1>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:37]2[CH2:38][C@H:34]([C:31]3([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:32][CH2:33]3)[C@H:35]([F:39])[CH2:36]2)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[C@@H:15]1[CH2:17][C@@H:16]1[F:18]
Reactant: CC(C)(C)OC(=O)NC1([C@H]2CNC[C@H]2F)CC1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CS(C)=O
Solvent: CN1CCCCC1
Product: Cc1c(N2C[C@@H](F)[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture consisting of 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (45 mg, 0.144 mmol), (3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine (52.8 mg, 0.216 mmol), 1-methylpiperidine (18.5 mg, 0.186 mmol) and dimethyl sulfoxide (1.8 ml) was stirred at an outer temperature of 80° C. for 7 hours. When analysis was carried out by a high performance liquid chromatography after completion of the reaction, formed ratio of the compound of interest 5-amino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was 4%. Also, residual ratio of the starting material was 90%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]([NH:14][C:15]([NH:17][CH2:18][CH2:19]Cl)=[O:16])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][CH:8]=1.O1CCN=C1>>[F:11][C:10]([F:13])([F:12])[CH:9]([NH:14][C:15]1[O:16][CH2:19][CH2:18][N:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:21])[F:1])[CH:4]=1
Reactant: O=C(NCCCl)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: C1=NCCO1
Product: FC(F)(F)c1cccc(C(NC2=NCCO2)C(F)(F)F)c1

Procedure:
Using the same procedure as in example III step B and starting from N-[α-(3-trifluoromethyl phenyl) trifluoroethyl] N'-(β-chloroethyl) Urea, dl 2-[α-(trifluoromethyl) 3-trifluoromethyl benzylamino)] oxazoline is produced. It melts at 129°-132°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:28](I)[CH3:29].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:28][CH3:29])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCNc2ccc(Cl)cc2)cc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc(C(=O)OC)cc1)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 11 h

Procedure:
Methyl 4-[3-[N-(4-chlorophenyl)amino]propoxy]benzoate (1.2 g) and sodium bicarbonate (1.58 g) were dissolved and suspended in DMF (10 ml), and ethyl iodide (1.52 ml) was added thereto. The mixture was heated with stirring at 100° C. for 11 hours, and cooled. Water and ethyl acetate were added thereto and the mixture was separated into layers. The organic layer was washed with water 3 times, and concentrated under reduced pressure to give the oily desired product (1.38 g).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:21]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1B(O)O)=[O:22].[F-].[K+].B(O)O>O1CCOCC1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[CH:21]=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: O=Cc1ccsc1B(O)O
Agent: OBO
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3sccc3C=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Methyl 2-bromo-3-cyclohexyl1H-indole-6-carboxylate (prepared as described in published International patent application WO 2004/087714), (3-formyl-2-thienyl)boronic acid (1.2 eq), spray-dried KF (5 eq) and Pd(tBu3P)2 (0.2 eq) were dissolved in dioxane (0.15 M); the reaction mixture was stirred under N2 at RT for 4 h, then more KF, boronic acid and catalyst were added and stirring was continued overnight. All volatiles were evaporated in vacuo and the title compound was isolated by flash chromatography (PE/EtOAc 8:2). Yield 99%; MS (ES+) m/z 368 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][N:13]([C:15]([O-])=O)[CH2:12][C:11]([F:19])([F:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.ClC1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37]>CO.CCOC(C)=O.[Pd]>[F:18][C:11]1([F:19])[CH2:12][N:13]([C:15]2[CH:35]=[CH:34][N:33]=[CH:32][C:31]=2[N+:36]([O-:38])=[O:37])[CH2:14][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)[O-])CC(F)(F)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)-3,3-difluoropiperidine-1-carboxylate (1 eq) in 5 mL of methanol and 5 mL of EtOAc was added 10% Pd/C (0.1 eq). The resulting suspension was stirred at H2 atmosphere overnight. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo. The residue was dissolved in 5 mL of isopropanol and DIPEA (2.0 eq) and 4-chloro-3-nitropyridine (1.5 eq) were added. The reaction mixture was stirred at 70° C. for 3 hours, at which point the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with 120 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (5% methanol in EtOAc:hexanes=1:1) to yield (S)-tert-butyl 5,5-difluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate (19%). LC/MS (m/z): 359.0 (MH+), Rt: 0.65 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][C:10]([C:19]([NH2:21])=[NH:20])=[N:9]2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(#N)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:20][C:19]([C:10]2[CH2:11][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[NH:21])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N=C(N)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N=C(NS(=O)(=O)c1ccc(F)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
Part B: To a stirred solution of 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine.HCl (1.87 gram, 5 mmol) and 4-fluorophenylsulfonyl chloride (0.97 g, 5 mmol) in anhydrous acetonitrile (20 ml) is added triethylamine (2.1 ml, 15 mmol) and the resulting mixture is stirred at room temperature for 16 hours. After concentration in vacuo, the residue is dissolved in a mixture of Ethyl acetate and water. The Ethyl acetate layer is collected, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is recrystallised from methyl-t-butyl ether to give N-[(4-fluorophenyl)sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine (1.22 gram, 54% yield). Melting point: 200-203.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH2:9]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[CH:21]1[C:22]2[C:17](=[C:16]([NH:15][CH2:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccc3cnccc23)C1
Agent: Cl
Solvent: CO
Product: c1cc(NCC2CCCNC2)c2ccncc2c1
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 34 (171 mg) and 10% hydrogen chloride/methanol solution (2.5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (139 mg) as light yellow powdery solid.
Reaction SMILES: CC(C)CC([O:6][C:7](=O)[CH2:8][C@H:9]1[CH2:14][C@@H:13](/[CH:15]=[CH:16]/[C:17]2[C:18]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[N:19][C:20]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])=[N:21][C:22]=2[CH:23]([CH3:25])[CH3:24])[O:12]C(C)(C)[O:10]1)C.CC(C1C(/C=C/[C@@H](O)C[C@@H](O)CC(OC)=O)=C(C2C=CC(F)=CC=2)N=C(N(S(C)(=O)=O)C)N=1)C.[OH-].[Na+].Cl>C(OCC)(=O)C.C(#N)C>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:18]2[C:17](/[CH:16]=[CH:15]/[C@@H:13]3[CH2:14][C@@H:9]([OH:10])[CH2:8][C:7](=[O:6])[O:12]3)=[C:22]([CH:23]([CH3:25])[CH3:24])[N:21]=[C:20]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[N:19]=2)=[CH:37][CH:36]=1
Reactant: CC(C)CC(C)OC(=O)C[C@H]1C[C@@H](/C=C/c2c(-c3ccc(F)cc3)nc(N(C)S(C)(=O)=O)nc2C(C)C)OC(C)(C)O1
Agent: COC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@@H](O)CC(=O)O1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
For reference purposes 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 4-methylpentan-2-yl ester was prepared from rosuvastatin methyl ester (EP 521471). Thus, rosuvastatin methyl ester (30 g, 61 mmol) was added to 200 mL of acetonitrile and 2N aqueous NaOH was added until the pH was stable at 12.5. The reaction mixture was stirred for 2 h at 20° C. Then the pH was lowered to 5.0 with 2N aqueous HCl. To the reaction mixture was added 200 mL of ethyl acetate and the organic phase was separated and washed 2 times with 100 mL of water. The ethyl acetate phase was dried over Na2SO4, filtered and evaporated to a syrup (≈30 g of rosuvastatin acid). Part of this syrup (20 g) was dissolved in toluene and heated to reflux under azeotropic water removal for 4 h. The reaction mixture was cooled to 20° C. and stirred for 18 h. The precipitated solid was filtered, washed with toluene (2×10 mL) and dried to give 16.1 g (35 mmol) of N-(4-(4-fluorophenyl)-5-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.62 (dd, 2H), 7.11 (dd, 2H), 6.72 (dd, 1H), 5.48 (dd, 1H), 5.28-5.20 (m, 1H), 4.38-4.30 (m, 1H), 3.58 (s, 3H), 3.52 (s, 3H), 3.38-3.30 (m, 1H), 2.80-2.60 (m, 2H), 2.10-2.00 (m, 1H), 1.95-1.85 (m, 1H), 1.73-1.68 (m, 1H), 1.28 (d, 3H), 1.26 (d, 3H).
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](C)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[C:29]([C@@H:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1)#N>>[CH3:29][C@@H:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 94 %

Procedure:
The title compound II-ay was prepared in 94% yield from 3,3:17,17-bis(ethylendioxy)-6α-methylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.77-0.75 (m, 21H), 1.18 (s, 3H), 0.98 (d, 3H), 0.90 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]=[C:8]2[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.CO.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH:8]2[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1
Reactant: COc1cccc2c1CCN=C2c1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc2c1CCNC2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added 5-methoxy-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline (189 mg, 619 μmol, from step 2), MeOH (3 mL), sodium borohydride (21.8 μL, 619 μmol, Aldrich). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with saturated NaCl (5 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes to give 5-methoxy-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline. MS (ESI pos. ion) m/z: 308 (M+1).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl>>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:17][CH2:18][N:19]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:20][CH2:21]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCC1CCCCC1
Reactant: FC1(c2cccc(OCc3ccccc3)c2)CCNCC1
Agent: Cl
Product: FC1(c2cccc(OCc3ccccc3)c2)CCN(CCCC2CCCCC2)CC1

Procedure:
This material was prepared by the alkylation of 4-(3-benzyloxyphenyl)-4-fluoropiperidine Hydrochloride with 1-bromo-3-cyclohexylpropane and subsequent salt formation with methanolic hydrogen chloride as described in Step 3 of Example 1 in 32% overall yield.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)=[O:12])=[O:7])=[C:4]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:3]=1.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[N:41]1([C:2]2[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])=[O:7])=[C:4]([O:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[CH:3]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCCC3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 106 °C
Yield: 44 %

Procedure:
Using methods substantially equivalent to those described in example 4-F except that the reaction was heated to 106° C., 2-[4-(piperidin-1-yl)-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (200 mg, 0.32 mmol, 44%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and piperidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:18]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:17]1>CO>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:17][C:18]2([OH:16])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CC2(CCO1)CO2
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(O)CCOCC2)CC1
Temperature: 60 °C
Yield: 41.6 %

Procedure:
To a stirred solution of tert-butyl(piperidin-4-ylmethyl)carbamate (22.3 g, 104 mmol) in methanol was added 1,6-dioxaspiro[2.5]octane (14.2 g, 124 mmol, Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984, 19, 113) at room temperature. Then, the mixture was heated at 60° C. for 4 h. The volatile components were removed by evaporation and the resulting viscous oil was precipitated with a mixture of hexane and diethylether. The precipitate was collected by filtration and recrystallized from a mixture of n-hexane and 2-propanol to give the title compound 14.2 g (42%) as a colorless powder.
Reaction SMILES: [CH3:1][C@@H:2]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[CH:7][CH:6]=1)[C:3]#[CH:4].[C:21]1([CH3:33])[CH:26]=[CH:25][C:24]([S:27]([N:30]=[N+:31]=[N-:32])(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.[Cu]I>[CH3:33][C:21]1[CH:22]=[CH:23][C:24]([S:27]([N:30]2[CH:4]=[C:3]([C@@H:2]([C:5]3[CH:6]=[CH:7][C:8]([CH2:9][C:10]4[S:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=4)=[CH:19][CH:20]=3)[CH3:1])[N:32]=[N:31]2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: C#C[C@@H](C)c1ccc(Cc2nc(C(F)(F)F)cs2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc([C@H](C)c3ccc(Cc4nc(C(F)(F)F)cs4)cc3)nn2)cc1
Reaction time: 12 h
Yield: 60.6 %

Procedure:
A cooled (0-5° C.) mixture of 2-{4-[(1R)-1-methylprop-2-yn-1-yl]benzyl}-4-(trifluoromethyl)-1,3-thiazole (0.115 g, 0.4 mmol), p-toluenesulfonylazide (66 mg, 0.33 mmol), 2,6-toluidine (48 mg, 0.4 mmol) and CuI (5% mmol) in CHCl3 (5 ml) was stirred for 12 h. The reaction was quenched by adding a buffer solution (pH=5.4) and the product extracted with CHCl3 (3×5 ml). After solvent evaporation the crude was purified by flash chromatography to give pure 1-(4-methylbenzensulfonyl)-4-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}phenyl)ethyl]-1H-1,2,3-triazole (0.95 g, 0.20 mmol) as a yellow oil (50%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1)=[O:35]
Reactant: CSc1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of 3-[2-(methylthio)-4-pyrimidinyl]-2-(3-nitrophenyl)pyrazolo[1,5-a]pyridine (0.82 g, 2.26 mmol) in DCM (22 mL) is added a solution of 50% mCPBA (818 mg, 2.37 mmol) in DCM (6 mL) through an addition funnel. The reaction is stirred for 10 min and saturated aqueous NaHCO3 and the layers are separated. The aqueous layer is extracted with DCM, and the combined organic layers are dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography (50% EtOAC/hexanes eluant) to provide the product (567 mg) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 8.93 (d, 1H, J=6.8), 8.68 (d, 1H, J=5.6), 8.57 (d, 1H, J=8.8), 8.44 (s, 1H, 8.37-8.35 (m, 1H, 8.08 (d, 1H, J=7.6), 7.78 (t, 1H, J=8.0), 7.61-7.65 (m, 1H), 7.21-7.26 (m, 2H), 2.84 (s, 3H).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[O:8]=[C:9]1[NH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]1=[O:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.8 g) was added to a DMF (20 ml) solution of ethyl 3,4-dihydro-3-oxo-2-quinoxalinecarboxylate (4.4 g) under ice-cooling. The reaction mixture was stirred for 10 minutes, to which was added benzyl bromide (2.4 g). The reaction mixture was stirred at room temperature for 3 hours, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (3.6 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][CH2:5][C:6]([CH3:9])([NH2:8])[CH3:7])[CH3:2].[C:12](ON1C(=O)CCC1=O)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C1COCC1>[CH2:10]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]([NH:8][C:12](=[O:13])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:9])[CH3:7])[CH3:11]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCN(CC)CCC(C)(C)N
Solvent: C1CCOC1
Product: CCN(CC)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.8 %

Procedure:
Crude N1,N1-diethyl-3-methylbutane-1,3-diamine (7.00 g, 44.2 mmol) was dissolved into THF (100 mL). To this solution was added CbzOSu (11.0 g, 1 equiv, 44.2 mmol) in one portion. The reaction was left to stir at room temperature for 2 d. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (100 mL). The layers were separated and the organic layer washed with saturated sodium bicarbonate (2×100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 1-5% methanol in DCM. The desired fraction was collected and concentrated to give a colorless oil (6.7 g, yield: 37.8%). 1H NMR (CDCl3, 400 MHz): δ 1.00-1.04 (t, J=7.0, 6H),1.37 (s, 6H), 1.57-1.61 (t, J=6.2, 2H), 2.45-2.51 (q, J=7.0, 4H), 2.52-2.56 (t, J=6.0, 2 H), 5.04 (s, 2H), 7.27-7.36 (m, 5H), 7.57 (bs, 1H). LRMS (ESI+) for C17H28N2O2 (292.2); Found: 293 (MH+).