Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([C:5]1[C@H]2C[C@@H]3O[C@@]3(CO)[C@@H:7]2[C@H:8](OC(=O)NC)[O:9][CH:10]=1)=O.N1C=CC=CC=1.[C:28]([O:31][C:32](=[O:34])[CH3:33])(=O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:28][O:31][C:32]([C:33]1[CH:7]=[CH:8][O:9][CH2:10][CH:5]=1)=[O:34]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@@]3(CO)[C@H]12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=CCOC=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
500 mg of the (1S,4aS,6S,7R,7aR)-6,7-epoxy-7-(hydroxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydrocyclopenta [c] pyrane-4-carboxylic acid methylester were dissolved in dichloromethane followed by addition of 0.4 ml of pyridine and 50 mg of DMAP. Next, 0.32 ml of acetic anhydride were dropped in followed by stirring for 4 hours at room temperature. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with 2N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless foamy substance from the hexane-ether eluate in the form of (1S,4aS,6S.7R,7aR)-7-(acetoxymethyl)-6,7-epoxy-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydro [c] pyrane-4-carboxylic acid methylester (465 mg, yield: 82%). The physicochemical properties of this compound are described in Table 10, Compound No. 46.
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18](=[O:36])[CH2:19][CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29]COCCOC)=[CH:25][CH:24]=3)=[O:22])[CH:16]=[CH:17][C:9]1=2>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([C:18](=[O:36])[CH2:19][CH2:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)=[O:22])[CH:16]=[CH:17][C:9]1=2
Reactant: COCCOCOc1ccc(C(=O)CCC(=O)c2ccc3c(c2)OCCO3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCC(=O)c1ccc2c(c1)OCCO2)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat TFA (0.5 mL) was added to a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-((2-methoxyethoxy)methoxy)phenyl)butane-1,4-dione 11 (0.35 mmol) in CH2Cl2 (5 mL) stirred at room temperature. The solution was further stirred overnight at room temperature. The volatiles were evaporated under vacuum. The residue was purified by flash chromatography over silica gel eluting with 1% methanol in CH2Cl2 to get 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-hydroxyphenyl)butane-1,4-dione 4 as an off white solid (21% yield). 1H NMR (CDCl3, 400 MHz): δ ppm 3.37 (m, 4H), 4.29 (m, 2H), 4.33 (m, 2H), 5.76 (s, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.93 (m, 1H), 7.60 (m, 2H), 7.94 (d, J=8.8 Hz, 2H); ESIMS found C18H16O5 m/z 313 (M+H).
Reaction SMILES: C([Li])CCC.CCCCCC.Cl[CH2:13][CH2:14][I:15].[CH3:16][O:17][C:18]1C=C[C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=1>C1COCC1>[I:15][C:14]1[C:18]([O:17][CH3:16])=[CH:23][N:22]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:13]=1
Reactant: ClCCI
Reactant: COc1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cnc(C(F)(F)F)cc1I
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 16 %

Procedure:
In an oven-dried flask, 5-methoxy-2-(trifluoromethyl)pyridine was dissolved in THF (20 mL). This mixture was cooled at −78° C., and then 2.5 M n-butyllithium in hexane (2.60 mL, 6.5 mmol) was added. After stirring at this same temperature for 40 minutes, 1-chloro-2-iodoethane (0.60 mL, 6.6 mmol) was added. The reaction was kept at −78° C. for an additional 30 minutes, and then quenched with saturated aqueous ammonium chloride. The mixture was warmed to room temperature, partitioned between ethyl acetate and water, and the organic layer dried with magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 40% ethyl acetate in heptanes) to yield 0.3128 g (16%) of 4-iodo-5-methoxy-2-(trifluoromethyl)pyridine. 1H NMR (400 MHz, DMSO-d6) δ: 8.38 (s, 1H), 8.29 (s, 1H), 4.05 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[Cl:18])([CH3:10])([CH3:9])[CH3:8].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC(C)=O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:13][C:12]=1[Cl:18])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(O)cc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(Cl)c1
Temperature: 60 °C
Yield: 126.8 %

Procedure:
To a suspension of potassium carbonate (994 mg, 7.2 mmol) and 4-tert-butyl-3-chlorophenol (440 mg, 2.4 mmol) in acetone (5 ml) was added t-butyl bromoacetate (370 mg, 1.9 mmol) was added and the mixture was refluxed at 60° C. for 14 hours. Filtrating of potassium carbonate, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 10:1) to furnish the tert-butyl (4-tert-butyl-3-chlorophenoxy)acetate (720 mg, 100%). The mixture of tert-butyl (4-tert-butyl-3-chlorophenoxy)acetate (720 mg, 2.4 mmol), TFA (2.0 ml), DCM (2.0 ml) was stirred for 5 hours at room temperature. After being concentrated in vacuo, the residue was triturated with hexane to furnish the title compound (582 mg, 100%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 1.45 (9H, s), 4.67 (2H, s), 6.76 (1H, dd, J=2.6, 8.6 Hz), 6.96 (1H, d, J=2.6 Hz), 7.35 (1H, d, J=8.6 Hz).
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1>C(O)C.[Pd]>[C:13]1([C:4]2[N:1]=[C:36]([CH2:32][NH:1][C@H:4]3[C:13]4[C:8](=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:10]=[CH:11][CH:12]=4)[CH2:7][CH2:6][CH2:5]3)[O:35][C:34]=2[C:33]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A mixture of (1R)-1-azido-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (0.95 mg) and 10% Pd/C (0.2 g) in a mixture of ethanol (20 ml) and THF (20 ml) was stirred under H2 for 2 hours. The catalyst was filtered off and filtrate was evaporated. The residue was dissolved in DMF (10 ml) and then K2CO3 (600 mg) and (4,5-diphenyloxazol-2-yl)methyl bromide (700 mg) were added thereto. After being stirred for 2 hours at room temperature, the mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-(4,5-diphenyloxazol-2-yl)methylamino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.4 g).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C@H:8]([OH:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C:18]1[CH:17]=[CH:16][C:15]([OH:22])=[CH:14][C:13]=1[CH2:12][CH2:11]3.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27]>ClCCl.CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27].[CH3:1][N:2]([CH3:23])[C@H:3]1[C@H:8]([OH:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C:18]1[CH:17]=[CH:16][C:15]([OH:22])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: ClCCl
Product: CN(C)[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C

Procedure:
17β-Methylamino-oestra-1,3,5(10)-triene-3,16α-diol (1.7 g) was dissolved in dichloromethane (17 ml) and a solution of maleic acid (0.63 g) in methanol (6.3 ml) was added. The resulting solution was evaporated to low volume and acetone was added to give pure 17β-dimethylamino-oestra-1,3,5(10)-triene-3,16α-diol (Z)-2-butenedioate (1:1) (salt) as prisms (1.76 g; 75.5%), m.p. 188°-194° C., [α]D +36.1° (c 0.98 in MeOH).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH:6]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24]([CH3:27])(=[O:26])=[O:25])[NH:13][C:12]=2[CH:11]=1)([CH3:8])[CH3:7]>>[CH:6]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24]([CH3:27])(=[O:25])=[O:26])[N:13]([CH2:2][CH2:3][CH2:4][Cl:5])[C:12]=2[CH:11]=1)([CH3:8])[CH3:7]
Reactant: CC(C)Oc1ccc2c(c1)Nc1cccc(S(C)(=O)=O)c1S2
Reactant: ClCCCBr
Product: CC(C)Oc1ccc2c(c1)N(CCCCl)c1cccc(S(C)(=O)=O)c1S2
Yield: 104.2 %

Procedure:
Crude 2-isopropoxy-6-methylsulphonyl-10-(3-chloropropyl)phenothiazine (128 g.) is prepared by reacting 1-bromo-3-chloropropane (100 g.) with 2-isopropoxy-6-methylsulphonylphenothiazine (m.p. 179°-180°C.; 100 g.).
Reaction SMILES: CN(C(ON1N=NC2[CH:12]=[CH:13][CH:14]=[N:15]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:32]1[N:33]([C:41]2[N:62]=[CH:61][CH:60]=[CH:59][C:42]=2[C:43]([NH:45][CH:46]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:47]([OH:51])[C:48]([OH:50])=O)=[O:44])[CH:34]=[C:35]2[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]2.C1(N)CC1>ClCCl>[CH:14]1([NH:15][C:48](=[O:50])[CH:47]([OH:51])[CH:46]([NH:45][C:43](=[O:44])[C:42]2[CH:59]=[CH:60][CH:61]=[N:62][C:41]=2[N:33]2[CH:34]=[C:35]3[C:40]([CH:39]=[CH:38][CH:37]=[CH:36]3)=[N:32]2)[CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:12][CH2:13]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-n1cc2ccccc2n1
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
HATU (201 mg, 0.528 mmol) and Et3N (0.127 ml, 0.913 mmol) were successively added to a suspension of 3-[2-(2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoic acid (200 mg, 0.480 mmol) and cyclopropylamine (0.034 ml, 0.48 mmol) in dichloromethane (50 ml) at 5° C., and the mixture was stirred for 5 minutes. A pH of 10 was adjusted by adding Et3N (0.1 ml, 0.720 mmol), stirring was continued for 1 hour at 5° C. and then overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and poured into 50 ml of water. The precipitate formed was filtered off with suction and dried in vacuo to give 136 mg of the title compound as a white solid.
Reaction SMILES: C(C1C=C[C:8]([C:11]([CH3:40])([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:29]2C=CC(CC(C)C)=CC=2)([CH3:28])[C:25]([OH:27])=[O:26])[C:12]([OH:14])=[O:13])=CC=1)C(C)C.[OH-].[K+]>C(O)C.O>[O:39]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]([CH3:8])([CH3:40])[C:12]([OH:14])=[O:13]
Reactant: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCC(=O)CCCCC(C)(C)C(=O)O)C(=O)O
Yield: 86 %

Procedure:
According to the procedure given for 210f, 209c (30.0 g, 81.0 mmol) was saponified with KOH (85%, 18.9 g, 286 mmol) in ethanol (143 mL) and water (48 mL) at reflux for 5 h. The solid product obtained after extraction and drying was purified by flash chromatography (silica; hexanes/ethyl acetate=90/10) to afford 210c (22.0 g, 86%) as a white solid. Mp 60-61.5° C. 1H NMR (CDCl3): δ 11.40 (br., 2H), 2.41 (t, 4H, J=7.3), 1.62-1.48 (m, 8H), 1.32-1.18 (m, 4H), 1.18 (s, 12H). 13C NMR (CDCl3=77.0 ppm): δ 211.11, 184.74, 42.49, 42.14, 40.42, 24.92, 24.62, 23.99. HRMS (LSIMS, gly): Calcd for C17H31O5 (MH+): 315.2171, found: 315.2183. HPLC: 94.5% pure. Anal. (C17H30O5) C, H.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19](OCCC(C)C)=[O:20].Cl>CCOCC>[OH:20][N:19]=[C:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]1=[O:18]
Reactant: CC(C)CCON=O
Reactant: O=C1CCc2c(OCc3ccccc3)cccc21
Agent: Cl
Solvent: CCOCC
Product: O=C1C(=NO)Cc2c(OCc3ccccc3)cccc21
Temperature: 25 °C
Yield: 86 %

Procedure:
To an ice-cooled solution of 1.91 g (0.008 m) of 4-(phenylmethoxy)-1-indanone in 75 ml of anhydrous ether is added dropwise with stirring 1.2 ml (0.088 m) of isoamyl nitrite while hydrogen chloride is simultaneously bubbled in. After stirring at room temperature for twenty minutes, the reaction mixture is partially concentrated and the solid which separates is filtered to yield 1.83 g (86%) of material sufficiently pure to be used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cccc(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a mixture of 4-{[1-(3-bromo-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (6.7 g, 20.1 mmol) and ytterbium(III) triflate hydrate (1.25 g, 2.01 mmol) in dry tetrahydrofuran (15 mL) at 25° C. was added isobutyraldehyde (1.45 g, 20.1 mmol) and water (0.36 mL, 20.1 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (8.12 g, 100%) as a light yellow oil: LC/MS m/e calcd for C20H22BrNO3 M+: 404.3, observed: 404.0, 406.0.
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:1]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][N:3]2[CH3:8])=[O:18])=[CH:12][CH:11]=1
Reactant: CN1CCCCC1=N
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)Nc1ccc(Cl)cc1
Reaction time: 6 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to the free base in benzene in the usual manner. After drying over K2CO3 and filtering, a benzene solution of 0.05 mole of p-chlorophenylisocyanate is added dropwise with stirring. After addition is complete, further stirring is continued for about 6 hours at room temperature. The benzene is evaporated in vacuo and the solid residue is recrystallized from methanol to give the product, 1-(4-chlorophenyl)-3-(1-methyl-2-piperidylidene)urea.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)([CH3:3])=[CH2:2].[CH2:11]([Zn]CC)C.ICI.[NH4+].[Cl-]>CCCCCC>[CH3:2][C:1]1([CH:4]2[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[CH2:11][CH2:3]1
Reactant: C=C(C)C1CCC(=O)CC1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: CCCCCC
Product: CC1(C2CCC(=O)CC2)CC1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
5.0 g (0.036 mol) of 4-isopropenylcyclohexanone (precursor to Example 4) were placed under inert gas in 150 ml of hexane, and 16.5 g (0.134 mol) of diethylzinc (1M in hexane) followed by 58.0 g (0.22 mol) of diiodomethane were added dropwise at -20° C. The mixture was stirred at -60° C. for 2 hours and then at 0° C. for 6 hours. The reaction solution was kept in a refrigerator overnight and was worked up by pouring it into cold NH4Cl solution and carrying out extraction with ether. The organic phase was washed with sodium thiosulfate solution and water, dried and concentrated. 5.3 g (96% of theory) of a colorless oil were obtained which was reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10].[CH2:18]([NH:20][C:21]([NH2:23])=[O:22])[CH3:19].CC(C)([O-])C.[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:23][C:21](=[O:22])[NH:20][CH2:18][CH3:19])[N:5]=[CH:4][C:3]=1[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: CCNC(N)=O
Reactant: O=C(Nc1cccnc1)c1cnc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: CCNC(=O)Nc1cc(Cl)c(C(=O)Nc2cccnc2)cn1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
Compound ii (1.0 g, 3.7 mmol) and N-ethylurea (362 mg, 4.1 mmol) were dissolved in degassed dioxane (50 mL) under an atmosphere of argon. Potassium tert-butoxide (628 mg, 5.6 mmol), Xantphos (129 mg, 0.22 mmol) and palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) were added sequentially. The mixture was heated at 100° C. with stirring under argon for 16 h. Additional palladium(0)bis(dibenzylideneacetone) (65 mg, 0.11 mmol) and N-ethylurea (560 mg, 6.4 mmol) were added and the mixture heated at reflux for 5 h. The mixture was cooled to RT, diluted with acetonitrile (100 mL) and then adsorbed on to silica by concentration in vacuo. The crude product was purified by flash chromatography (40 g GraceResolv silica cartridge, 0-10% MeOH in EtOAc) to afford iii as a light brown solid (244 mg, 20%). [M+H]+ m/z=320.05.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH:21][C:20]2=[O:28])[CH2:15][CH2:14]1.Cl.[CH:30](O)=O>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:30][N:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:17][CH2:18]3)[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1NCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: O=CO
Agent: Cl
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCn2cnc3ccc(Cl)cc32)CC1
Yield: 27 %

Procedure:
A mixture of 4 parts of 1-[1-{3-[N-(2-amino-5-chlorophenyl)amino]propyl}-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 6 parts of a concentrated hydrochloric acid solution and 30 parts of formic acid is stirred and refluxed overnight. The reaction mixture is evaporated and water is added to the residue. The whole is alkalized with a diluted ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from 2-propanol, yielding 1.1 parts (27%) of 1-{1-[3-(6-chloro-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 214.9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[F:29][C:30]([F:59])([F:58])[C:31]1[C:35](B(O)O)=[CH:34][N:33]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:32]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:35]5[C:31]([C:30]([F:58])([F:59])[F:29])=[N:32][N:33]([C:39]([C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=6)([C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)[C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[CH:34]=5)[CH:26]=4)[N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Reactant: O=C(NCc1ccc(F)cc1)C1CCN(c2ccnc3ccc(Br)cc23)CC1
Product: O=C(NCc1ccc(F)cc1)C1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Yield: 90.3 %

Procedure:
92 mg 1-(6-bromoquinolin-4-yl)piperidine-4-carboxylic acid (4-fluorophenyl)methylamide (compound in Production Example 458) and 114 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 139 mg 1-[6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl)quinolin-4-yl]-piperidine-4-carboxylic acid (4-fluorophenyl)methylamide. This product was reacted in the same manner as in Example 67, to give 80 mg of the title compound as pale yellow crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:18])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH:4]([C:19]([OH:21])=[O:20])[CH2:3]1.CO.[CH2:24](O)[CH3:25]>>[OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:18])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH:4]([C:19]([O:21][CH2:24][CH3:25])=[O:20])[CH2:3]1
Reactant: CCO
Reactant: COc1ccc(C(=O)N2CC(O)CC2C(=O)O)cc1OC
Solvent: CO
Product: CCOC(=O)C1CC(O)CN1C(=O)c1ccc(OC)c(OC)c1
Yield: 60 %

Procedure:
By carrying out the procedure as in Example 11, but replacing 4-hydroxy-1-(3,4-methylenedioxybenzoyl)-pyrrolidine-2-carboxylic acid by 4-hydroxy-1-(3,4-dimethoxybenzoyl)pyrrolidine-2-carboxylic acid and methanol by ethanol, the title product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([OH:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14].[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH:19]=[CH2:18]
Reactant: Oc1cccc(Cl)c1-c1ccccc1Cl
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Cl)c1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 2′,6-dichloro-biphenyl-2-ol (10.0 g, 41.8 mmol) in DMF was added sodium hydride (60% in mineral oil, 2.5 g, 62.7 mmol) and allyl bromide (5.4 mL, 62.7 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 30% ethyl acetate in hexanes provided 11.6 g (100%) of 2-allyloxv-2′,6-dichlorobiphenyl as a light yellow oil
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[CH3:20][CH2:21][O:22][C:23]([CH:25]1[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26]1)=[O:24].Cl.C(N(C(C)C)CC)(C)C.Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[CH2:46]([O:45][C:43]([N:27]1[CH2:28][CH2:29][C:30](=[O:31])[CH:25]([C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:26]1)=[O:44])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CCC1=O
Yield: 62 %

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available ethyl 4-piperidone-3-carboxylate hydrochloride (203.2 mg; 0.98 mmol), diisopropylethylamine (360 μl; 2.08 mmol), and benzyl chloroformate (141 μl; 0.99 mmol). The crude product was purified by chromatography on silica eluting with 15% ethyl acetate in hexane, giving ethyl 1-benzyloxycarbonyl-4-oxo-3-piperidinecarboxylate (185.5 mg) as a colorless oil. MS m/z (positive ion) 323 (M+NH4+; 75), 306 (MH+; 100), 262 (50).