Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].C(N(C(C)C)C(C)C)C.[F:25][C:26]([F:44])([F:43])[C:27]1[CH:28]=[C:29]([C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:34][C:33]([F:35])([F:36])[C:31]1[CH:30]=[C:29]([C:37]([CH3:41])([CH3:42])[C:38]([N:14]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH3:15])=[O:39])[CH:28]=[C:27]([C:26]([F:43])([F:25])[F:44])[CH:32]=1
Reactant: CNc1cnccc1-c1ccccc1Cl
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: 37.5 °C
Yield: 88.4 %

Procedure:
A solution of 12.2 g (55.8 mmol) [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and 15.3 ml (89 mmol) N-ethyldiisopropylamine in 130 ml dichloromethane was cooled in an ice bath and a solution of 19 g (59.6 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 30 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40° C. for 20 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 24.7 g (88%) of the title compound as white crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][CH2:56][CH2:57][N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]c2c1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(CCCN3CCOCC3)c2c1
Temperature: 90 °C
Yield: 80.6 %

Procedure:
A mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.139 mmol), 4-(3-chloropropyl)morpholine (27 mg, 0.166 mmol) and K2CO3 (58 mg, 0.417 mmol) in dry DMF (20 mL) was heated to 90° C. for 3 hours. Product was extracted with ethyl acetate (100 mL), organic phase washed with water (3×10 mL) and brine (2×10 mL), then dried over Na2SO4, filtered and concentrated to afford N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1-(3-morpholinopropyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (95 mg, crude) as a yellow oil. LCMS: (M+H)+=848.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:16](Cl)(Cl)=[O:17]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]([CH:10]([CH3:12])[CH3:11])[C:13](=[O:15])[O:14][C:16]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Solvent: C1COCCO1
Product: CC(C)C1C(=O)OC(=O)N1c1ccc(Cl)cc1
Reaction time: 45 h

Procedure:
To 4.9 g of N-(4-chlorophenyl)valine (0.0215 mole) in 50 ml of 1,4-dioxane is slowly passed a stream of phosgene gas as the solution is stirred. Cooling is applied to keep the solution at RT. When the solution is saturated with phosgene, the phosgene is shut off and the mixture is allowed to stir under nitrogen at RT. After 45 hr, about two-thirds of the dioxane is removed by distilling at aspirator pressure. The residue is diluted with hexane, then allowed to crystallize overnight at RT. The solid is collected by filtration and washed with hexane, with care being taken to minimize exposure to air. The solid is dried in vacuo to yield 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione, m.p. 137°-138°.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][O:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:29][O:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:34][CH2:33]1
Reactant: COCC1CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: COCC1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4-(methoxymethyl)piperidine via General Procedure E to give 21.9 mg of 280 following reverse phase purification. MS (Q1) 491.3 (M)+
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([OH:28])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([OH:26])([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)[C:15]([F:18])([F:17])[F:16]>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[CH:13]([CH3:27])[C:14]([OH:26])([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)[C:15]([F:17])([F:16])[F:18])[O:28][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: NC(=O)CBr
Product: Cc1cnc(C(O)(C(C)c2ccc(OCC(N)=O)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 2-bromoacetamide and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=404.4 (MH+).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[F-].[K+].[N+](C1C=C(S(O[CH2:26][C@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O>C1COCC1>[O:28]1[CH2:29][C@@H:27]1[CH2:26][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCN(C[C@H]1CO1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 1,2,3,4-tetrahydroisoquinoline (5 g, 7.52 mmol) in THF (100 mL) was added KF (8.57 g, 150.4 mmol) at 0° C. (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (10.7 g, 41.4 mmol) was added to the reaction in 1 h. The solution was stirred at room temperature overnight. The solid was removed by filtration and washed with THF. The solution was then concentrated and the residue used for next step without further purification (11.3 g Yield 80%). LCMS (m/z): 190.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2ccccc2N1
Yield: 92.4 %

Procedure:
To a solution of 2-methylindole (61.2 g) in acetic acid (525 g) at 15° C. was added sodium cyanoborohydride (81 g) in portions. The reaction was then drowned in ice and water (1500 g) and the aqueous solution neutralized with sodium hydroxide (350 g). The mixture was extracted with 3 portions of ether (300 ml). The ether fractions were water washed, dried, and evaporated to give 57.4 g of an oil which was identical with an authentic sample by IR and TLC.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:21][CH:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)C(O)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 3-(4-benzyloxyphenyl)-2-hydroxypropanoate (c.f. International Patent Appl., Publication No. WO 9101337) (5.72 g) in methanol (120 mL was added to an ice cooled suspension of 10% Palladium charcoal (1.90 g) in methanol (30 mL) under a nitrogen atmosphere. Solid ammonium formate (6.4 g) was added and the mixture heated at reflux for 15 minutes, then allowed to cool to room temperature. The catalyst was removed by filtering the reaction mixture through diatomaceous earth and the solvent evaporated. The residue was suspended in dilute hydrochloric acid (2M, 100 mL) and extracted with ethyl acetate (2×400 mL). The combined ethyl acetate solutions were washed with water (400 mL), brine (400 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with 1.5% methanol in dichloromethane as eluent to afford the title compound, mp 42°-43° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)nc1
Reactant: CC(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)C(=O)Nc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-amino-5-cyanopyridine (0.500 g, 4.2 mmol) in dry dichloromethane (20 mL) was added triethylamine (0.830 g, 6.3 mmol) and the mixture was stirred at 0° C. To the reaction mixture, 2-chloropropionyl chloride (0.800 g, 6.3 mmol) was added dropwise, and the reaction mixture was stirred at 0° C. for an hour and then at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (100 mL) and was washed with water (150 mL). The reaction mixture was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 15-20% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]4[N:44]([N:48]=[C:49]([C:51](O)=[O:52])[CH:50]=4)[CH:45]=[CH:46][CH:47]=3)=[O:41])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[NH:54]1[CH2:58][CH2:57][C@@H:56]([NH:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])[CH2:55]1.CN(C=O)C>CCOC(C)=O>[C:62]([O:61][C:60](=[O:66])[NH:59][C@@H:56]1[CH2:57][CH2:58][N:54]([C:51]([C:49]2[CH:50]=[C:43]3[C:42]([C:40](=[O:41])[NH:39][CH2:38][C:28]45[CH2:37][CH:32]6[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]6)[CH2:29]4)[CH2:35]5)=[CH:47][CH:46]=[CH:45][N:44]3[N:48]=2)=[O:52])[CH2:55]1)([CH3:65])([CH3:63])[CH3:64]
Reactant: O=C(O)c1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)c2cc3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccn3n2)C1
Reaction time: 20 h

Procedure:
BOP (680 mg, 1.5 mmol) is added to a mixture of 4-[(adamantan-1-ylmethyl)carbamoyl]-pyrazolo[1,5-a]pyridine-2-carboxylic acid (417 mg, 1.18 mmol), tert-butyl (R)-pyrrolidin-3-ylcarbamate (242 mg, 1.30 mmol), iPr2Net (620 μL, 3.6 mmol) and DMF (12 mL) under N2. The reaction vessel is sealed and the solution is left to stir for 20 h. EtOAc (50 mL) is added. The solution is washed with H2O (2×50 mL) and brine (50 mL). The organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (2% MeOH in CH2Cl2) affords (R)-(1-{4-[(adamantan-1-ylmethyl)carbamoyl]pyrazolo[1,5-a]-pyridine-2-carbonyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester as a tan solid. MeOH (6.8 mL) and 4 M HCl in dioxane (1.7 mL) are added. After 20 h, the volatiles are removed under reduced pressure to afford a light tan solid. 15% Aqueous K2CO3 (50 mL) is added. The solution is extracted with EtOAc (5×50 mL). The combined organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (1% NH4OH in 9:1 CH2Cl2:MeOH) affords the title compound as a tan foam. 1H NMR (300 MHz, CDCl3) δ: 8.48 (ddd, 1H), 7.62 (dd, 1H), 7.22 (dd, 1H), 6.87 (t, 1H), 6.50 (bt, 1H), 3.42-4.20 (m, 5H), 3.20 (d, 2H), 2.14 (septet, 1H), 1.96-2.04 (m, 3H), 1.55-1.88 (m, 12H). LC-MS m/z (M+H+): 422.3; RT=1.2 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:31]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: COc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 32.7 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 90 mg of 4-methoxyisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 77 mg of the target compound.
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([O-:11])([O-])=[O:9].[Na+].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:11])=[O:9]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccccc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccccc1
Yield: 99.9 %

Procedure:
A. Spitzer and R. Stewart, J. Org. Chem., 1974, 39, 3936 disclose nitrating aromatics in the presence of a trifluoroacetic acid medium. In one example benzene and sodium nitrate were reacted together in a 1:1 molar ratio at room temperature to form nitrobenzene in a 99.9% yield. In another example sodium nitrite was reacted with benzene in the same 1:1 molar concentration and at the same temperature as the nitrate example, however, nitrobenzene yield was only about 3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:18]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1CN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)c1ccccc1
Temperature: 16 °C
Yield: 87.1 %

Procedure:
To a mixture of o-methoxybenzylamine (20.0 g, 0.146 mol), tetrahydrofuran (124 mL) and triethylamine (15.6 g, 0.154 mol) was added dropwise benzoyl chloride (20.5 g, 0.146 mol) at −9-0° C., and the dropping funnel was washed with THF (10 mL). Under a nitrogen atmosphere, the reaction mixture was gradually warmed to about 16° C. During warming, THF (total 51 ml) was appropriately added to stir the content. The reaction was confirmed by TLC (eluent: hexane/ethyl acetate (1:1)). The reaction mixture was stirred at about 16° C. for 10 hr, and cooled to 5° C. Water (44 ml) was added thereto, and the mixture was extracted three times with ethyl acetate (120 mL, 40 mL, 40 mL). The combined organic layers were washed successively with 10% hydrochloric acid (40 mL), saturated aqueous sodium hydrogen carbonate solution (40 mL), water (40 mL) and saturated brine (44 mL), and dried over magnesium sulfate (20 g), and the solvent was evaporated under reduced pressure at 40° C. or lower. Ethyl acetate was added to the residue (content 74 g), and the solid was dissolved with heating to 60° C. The solution was gradually cooled to 6° C., the precipitated crystals were collected by filtration, washed with cold ethyl acetate (10 mL), and dried under reduced pressure at 40° C. or lower to give N-benzoyl-2-methoxybenzylamine (30.7 g, 87.1%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])/[CH:17]=[CH:4]/[C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[F:1])[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)c(F)c1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(OC)cc1F
Reaction time: 1 h
Yield: 75.2 %

Procedure:
2-Fluoro-4-methoxy-benzaldehyde (1.24 g, 3.56 mmol) and carbethoxy methylene triphenylphosphorane (2.0 g, 5.78 mmol) were dissolved in THF (10 mL), and the mixture was stirred at 65˜75° C. for 1 hour. After the termination of the reaction, the reactant was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/10) to obtain the title compound (0.6 g, 83%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][CH:4]2[CH2:3]1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CO>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]([OH:8])[CH2:3]1
Reactant: CN1CCC2(c3ccccc3)OC2C1
Reactant: NCc1ccccc1
Solvent: OCCO
Product: CN1CCC(NCc2ccccc2)(c2ccccc2)C(O)C1

Procedure:
A mixture comprising 3.7 g. of 1-methyl-4-phenyl-3,4-epoxypiperidine, 2.5 g. of benzylamine and 10 ml. of ethylene glycol was heated at 150° C. on an oil bath overnight. After work-up by the method described in Example 1, 5.45 g. of residue were obtained from which 4.11 g. of the desired free base 1-methyl-4-phenyl-4-(N-benzylamino)-3-hydroxy piperidine were isolated, this compound having a melting point of 162°-4° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[OH:22][C:23]1([CH2:29][NH:30][CH3:31])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:27][CH2:28][C:23]([OH:22])([CH2:29][NH:30][CH3:31])[CH2:24][CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CNCC1(O)CCNCC1
Agent: Cl
Product: CNCC1(O)CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted with 4-hydroxy-4-methylaminomethylpiperidine dihydrochloride analogously to Example 6 to give 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-hydroxy-4-methylaminomethyl-1-piperidinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 162° (with decomposition).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([NH:21]N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.OS(O)(=O)=O>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[NH:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: c1ccc(CN2CCc3[nH]c4ccccc4c3C2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
1-Benzyl-4-piperidone (1 mmol) was added dropwise to a stirred suspension of phenyl hydrazine (1 equiv.) in a solution of 7% H2SO4 (20 mL) in 1,4-dioxane (20 mL). The reaction mixture was heated at reflux for 18 h then cooled to RT. The solvent was evaporated and the residue recrystallized to afford 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (95%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][CH2:37][CH2:38]O)=[CH:31][CH:30]=1>C(Cl)Cl.[Al]>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][CH2:37][CH2:38][Br:1])=[CH:31][CH:30]=1
Reactant: OCCOCc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution of 2-{[(4-bromophenyl)methyl]oxy}ethanol (139 mg, 0.601 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (87 mg, 49%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[CH:21]([N:18]1[CH2:19][CH2:20][N:15]([C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([O:6][C:5]3[CH:24]=[CH:25][C:2]([C:31]4[S:32][CH:33]=[CH:34][N:35]=4)=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:16][CH2:17]1)([CH3:23])[CH3:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(C)N1CCN(C(=O)C2CCC(Oc3ccc(I)cc3)CC2)CC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4nccs4)cc3)CC2)CC1

Procedure:
To a mixture of 1.04 g (4.09 mmol) of cis-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone, 1.50 g (6.82 mmol) of 4-iodephenol, 1.25 g (4.77 mmol) of triphenylphisphine in 5 ml THF, 1.1 g (4.78 mmol) of di-tert-butyl azodicarboxylate was added at 0° C., and stirred for 12 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with cyclohexane and ethyl acetate=from 100:0 to 2:1. The combined product fractions were evaporated to dryness to yield 0.67 g (14% yields, about 67% purity) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone. A mixture 100 mg (0.15 mmol) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone, 88 mg (0.24 mmol) of 2-tributylstannylthiazole, 15 mg (0.02 mmol) of bis(triphenylphosphine) palladium(II) dichloride and 2 ml of THF was refluxed for 8 hr under Ar. The mixture was evaporated. The residue was purified by column chromatography on silica eluting with cyclohexane and ethyl acetate=from 100:0 to 2:1. The combined product fractions were evaporated to dryness to yield 33 mg (36%) of the title compound. MS (m/e): 414.2 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(C(F)(F)F)cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-trifluoromethyl-benzoic acid