Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18]([CH2:19][CH:20]([OH:30])[CH2:21][CH2:22]2)=[CH:17][C:16]3([CH3:32])O)[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[Si:1]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH:17]=[C:16]3[CH3:32])[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CCC(O)CC1=CC3(C)O
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CC1=CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)O[Si](C)(C)C(C)(C)C)CC[C@H]3[C@H]12
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
A solution of 20-tert-butyldimethylsilyloxy-7-methyl-pregn-5-ene-3,7-diol (298 gm, 0.59 mol) in toluene (3 L) and cyclohexanone (1.03 L) was azeotroped to remove 750 mL of solvent. A solution of aluminum isopropoxide (121 gm) in toluene (620 mL) was added and the solution azeotroped to remove another 650 mL of solvent. A reflux condenser was added and the solution refluxed overnight. The solution was cooled to 40° C. and Supercell® (125 gm) and water (125 mL) were added. After stirring for 10 min, the mixture was filtered and the solids washed with toluene (550 mL). The solvent was removed by rotoevaporation to yield a orange liquid which was purified by column chromatography on silica gel eluted with hexane, followed by 5-10% ethyl acetate in hexanes. The title compound was isolated as a mixture of 20α- and 20β-isomers (199.4 gm, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH2:4][OH:5]
Reactant: Nc1cccc(F)c1C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1cccc(F)c1CO
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A solution under argon of 2-amino-6-fluorobenzoic acid (5 g; 32 mmol) in anhydrous tetrahydrofuran (100 ml) is treated with lithium aluminium hydride (1M in tetrahydrofuran; 64 ml; 64 mmol) at ambient temperature. The reaction medium is agitated for 3 hours, then hydrolyzed at 0° C. with a saturated aqueous solution of ammonium chloride (100 ml). The resulting mixture is extracted with ethyl acetate (2×70 ml). The combined extracts are washed with water and with a saturated aqueous solution of sodium chloride, then dried over magnesium sulphate and concentrated to produce 3.8 g of the desired product, a white solid (m.p.: 93° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate and NaOH in ethanol was stirred at 50° C. for 3 h after which it was cooled to RT and neutralized with conc. HCl. The solvent was removed under reduced pressure to obtain crude 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:32]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CC(O)=O>CCOC(C)=O.[Fe]>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:32])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:21])([F:23])[F:22])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (92.3 mg, 0.189 mmol) and iron powder (295.6 mg, 5.293 mmol) was added AcOH (2.0 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc, filtered through a pad of diatomaceous earth (eluted with EtOAc). The filtrate was washed with a saturated aqueous solution of Na2CO3, dried over Na2SO4, and concentrated to give the crude sub-title compound as dark semi-solid (86.6 mg). The crude product was used directly in the next step without further purification. LCMS calc. for C21H30F3N4O4 (M+H)+: m/z=459.2. found 459.2.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([N+:37]([O-])=O)[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][N:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:37][C:35]1[CH:34]=[CH:33][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]([CH3:32])[C:16]([CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][N:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:36]=1
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 274.9 %

Procedure:
To a solution of 45 (1.1 g, 0.717 mmol) in MeOH (30 mL) and water (10 mL) was added ammonium chloride (211 mg, 3.95 mmol) and zinc (1.61 g, 17.76 mmol) and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was cooled to RT then concentrated to dryness. The residue was partitioned between DCM and water and the organic phase was collected, dried over Na2SO4, filtered and concentrated to afford the title compound 46 (1.04 g, 100% yield), which was used crude in the next step with no additional purification. MS (m/z): 528.1 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Si]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[NH2:30])(C(C)(C)C)(C)C>CN1C(=O)CCC1>[C:1]([O:15][CH2:16][CH2:17][CH2:18][N:19]1[C:20]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:30]=[C:1]1[CH2:2][CH2:3][CH2:4][CH3:5])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1c(N)cnc2ccccc12
Solvent: CN1CCCC1=O
Product: CCCCC(=O)OCCCn1c(CCCC)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Valeryl chloride was added to a solution of the product from step (ii) (4.85 g) in NMP at rt. The mixture was stirred at rt for 15 min, heated at 100° C. for 6 h, cooled, and partitioned between EtOAc/saturated NaHCO3 solution. The organics were separated washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with EtOAc, yield 2.15 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][O:16][CH3:17].CC(OC(C)=O)=O.[N+:25]([O-])([OH:27])=[O:26]>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:11]([N+:25]([O-:27])=[O:26])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: COCCOc1cc(C(=O)OC)ccc1OC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COCCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Temperature: 50 °C
Yield: 56 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of methyl 4-methoxy-3-(2-methoxyethoxy)benzoate (5.6 g, 23.3 mmol) and Ac2O (12 mL) in AcOH (60 mL) was dropped fuming nitric acid (90%, 4 mL). The reaction was heated at 50° C. for 3 hours, and the residue was purified by silica gel chromatography with 0-15% EtOAc/hexane as eluants to afford methyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a solid (3.67 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.34 (s, 1H), 4.26 (m, 2H), 3.91 (s, 3H), 3.82 (s, 3H), 3.68 (m, 2H), 3.33 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH:27]([CH3:29])[CH3:28])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])[CH3:4].[CH3:31]I>C1COCC1>[CH2:3]([O:5][C:6]([C:8]1([N:17]([C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[O:26][CH:27]([CH3:29])[CH3:28])[CH3:31])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccccc2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(N(C)C(=O)c2cccc(C)c2OC(C)C)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.7 %

Procedure:
To a solution of NaH (sodium hydride, 60% dispersion, 86.0 mg, 2.15 mmol)) in anhydrous THF (20 mL) is added dropwise the solution of 2-(2-isopropoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (6) (410 mg, 1.07 mmol) in THF (5 mL) at 0° C. After stirring for 20 min, methyl iodide (452 μL, 7.26 mmol) is added dropwise and the resulting suspension is warmed up to RT and continued stirring overnight. After being quenched by saturated aqueous solution of ammonium chloride (5 mL), the reaction mixture is diluted in EtOAc (50 mL). The organic layer is separated, washed with water (1×5 mL) and brine (2×5 mL), dried over anhydrous Na2SO4 and concentrated in in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 0%-30% EtOAc in heptane) to give the pure product (118) as a colorless oil (240 mg, 57%).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH:18]([C:20]1[N:21]=[C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:43])[CH2:32][N:33]3[C:37]([CH3:38])=[CH:36][C:35]([C:39]([F:42])([F:41])[F:40])=[N:34]3)[CH2:27][CH2:26]2)[S:23][CH:24]=1)=[CH2:19].C(N(CC)CC)C>CN(C)C=O.O>[C:2]1([C:1]2[CH2:19][CH:18]([C:20]3[N:21]=[C:22]([CH:25]4[CH2:30][CH2:29][N:28]([C:31](=[O:43])[CH2:32][N:33]5[C:37]([CH3:38])=[CH:36][C:35]([C:39]([F:41])([F:40])[F:42])=[N:34]5)[CH2:27][CH2:26]4)[S:23][CH:24]=3)[O:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: ON=Cc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3CC(c4ccccc4)=NO3)cs2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of benzaldehyde oxime (49 mg, 0.4 mmol) in N,N-dimethylformamide (3 mL) was added N-chlorosuccinimide (54 mg, 0.4 mmol), followed by addition of 4-(4-ethenyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 4, Step C) (103 mg, 0.27 mmol) and triethylamine (41 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for 5 h, then diluted with water, extracted with dichloromethane (2×). The organic layers were combined and dried (MgSO4), and filtered. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel using 55-70% ethyl acetate in hexanes as eluant to give 90 mg of the title product, a compound of the present invention as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13]S(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O-])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+].C(OCC)(=O)C.O>CS(C)=O>[C:18]([O:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of (R)-1-t-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (20 g) in dimethyl sulfoxide (200 ml) was added sodium benzoate (22 g) under nitrogen. After stirring at 100° C. for 1 hour, the solution was taken up into a mixture of ethyl acetate and water. The organic layer was separated, and washed with water and brine successively. The dried solvent was evaporated to give (S)-3-benzoyloxy-1-t-butoxycarbonylpyrrolidine (22 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[C:19](=O)([O-])[O-:20].[Cs+].[Cs+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:19][O:20][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)c(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
A well stirred mixture of 3.00 g (11.2 mmol) N-(4-fluoro-2-nitro-6-trifluoromethyl-phenyl)-acetamide and 6.00 g (18.4 mmol) caesium carbonate in 90 mL methanol was heated for 10 min at 100° C. in the microwave. After cooling the solvent was eliminated i.vac. and the residue remaining was combined with 100 mL water. The aqueous phase was acidified with 10% citric acid and the product was extracted with 100 mL ethyl acetate. The organic phase was dried and evaporated down i.vac. The residue obtained was purified by flash chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [CH:1]12[CH2:7][NH:6][CH:5]1[CH2:4][N:3]([C:8]1C=N[C:15]3[C:10](=[CH:11]C=[CH:13][CH:14]=3)[N:9]=1)[CH2:2]2.ClC1N=C(C)C=C(C)[N:20]=1>>[CH3:13][C:14]1[CH:15]=[C:10]([CH3:11])[N:9]=[C:8]([N:3]2[CH2:4][CH:5]3[CH:1]([CH2:7][NH:6]3)[CH2:2]2)[N:20]=1
Reactant: c1ccc2nc(N3CC4CNC4C3)cnc2c1
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(N2CC3CNC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 8, using 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C11H16N4, 204.27; m/z found 205.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH:1]1([CH2:4][N:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]3[CH2:16][O:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[C:33](=[O:34])[CH2:32][N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:37][CH:36]=3)[CH2:27][CH2:28]2)[CH2:3][CH2:2]1
Reactant: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CCN(CC(=O)N(Cc3nc4c(c(=O)[nH]3)COCC4)CC3CC3)CC2)cc1
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a well stirred suspension of 2-[(Cyclopropylmethyl-amino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (15.66 g, 57.6 mmol) in dichloromethane (600 mL) was added 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (16.45 g, 59.3 mmol), followed by triethylamine (24 mL, 173 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (21.41 g, 140 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (13.26 g, 69.2 mmol). The resulting yellow suspension was stirred for 12 h, filtered and then washed with water three times (250 mL, 150 mL, then 50 mL). The organic layer was washed twice with brine (50 mL), dried with Na2SO4, filtered and concentrated in vacuo (33.34 g). The residue was dissolved in 750 mL dichloromethane, and washed with a pH 9 KHCO3/K2CO3 solution (2×100 mL). The organic layer was washed twice with brine (50 mL), dried with Na2SO4, filtered and concentrated in vacuo (23.4 g). The crude material was dissolved in approximately 25 mL MeOH resulting in an orange solution and placed in a freezer overnight to form a slurry. The mixture was filtered, washed with MeOH and dried in vacuo to yield 21.959 g of the title compound as a white solid. HRMS calculated for C27H34N4O5 495.2607. found (ESI, [M+H]+), 495.2607, retention time=3.717 min. CHN analysis: calculated (results). C, 65.57 (65.17), H, 6.93 (6.64), N, 11.33 (11.39).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>O.CCO.ClCCl>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[N:11][OH:12])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC1(C)CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC1(C)CCC(=NO)CC1
Temperature: 25 °C

Procedure:
A solution of 4,4-dimethylcyclohexanone (30 g, 0.238 mol), hydroxylamine hydrochloride (32.8 g, 0.476 mol) and sodium acetate (39.0 g, 0.476 mol) in H2O/EtOH (720 mL, 5/1) was heated under reflux. The reaction was monitored by TLC and cooled to room temperature upon completion. It was diluted with dichloromethane (500 mL). The organic layer was separated, washed with brine (100 mL) and dried over Na2SO4. Solvent was removed under reduced pressure, and 4,4-Dimethylcyclohexanone oxime was obtained as colorless solid, which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:21].[ClH:22].[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccccc1NC1CCNCC1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.0025 mole) in dry 1,2-dichloroethane (5 mL) (under an atmosphere of nitrogen for 10 minutes) was added, 2-chloroaniline (0.352 g, 0.0027 mole), acetic acid (0.125 g, 0.00209 mole) and sodium triacetoxyborohydride (0.442 g, 0.00209 mole). The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched in cold aqueous 1N NaOH solution and the product was extracted with dichloromethane. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was stirred with hexane. The hexane was then decanted and the residue was dried to afford 0.615 g (79%) of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a solid. 1H NMR (DMSO-d6): δ 7.6 (dd, 1H), 7.1 (t, 1H), 6.8 (d, 1H), 6.54 (t, 1H), 4.8 (d, 1H), 3.9 (d, 3H), 3.5 (m, 1H), 2.9 (bs, 2H), 1.8 (d, 2H), 1.4 (s, 9H), 1.3 (d, 1H). To a stirred, cooled (0° C.) solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.150 g, 0.00048 mole) in dioxane (0.5 mL) was added dioxane.HCl (1.5 mL). The stirring was continued at the same temperature for 10 minutes, then the mixture was gradually brought to ambient temperature with continued stirring for a further 15 minutes. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with dry ether and dried to afford 0.118 g (99%) of (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)[CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Oc1ccc(F)cc1
Product: Oc1ccc(F)cc1Cc1ccc(F)cc1

Procedure:
Alkylation of 4-fluorophenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4′-fluorobenzyl)phenol. This material was converted to compound 77, mp 228-230° C., and compound 78, mp 134.5-139° C., by the procedure similar to that in Example 18 method B.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:15][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)c2ccccc12
Yield: 111.8 %

Procedure:
A mixture of 4-methylnaphthoic acid (10 g, 54 mmol), N-bromosuccinimide (10 g, 56 mmol) and AIBN (100 mg) in CCl4 (250 mL) was refluxed for 3 hr. The reaction mixture was concentrated and dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over MgSO4. Evaporation of the solvent gave the desired product (16 g, 80%).
Reaction SMILES: C[N+]1([O-])CCOCC1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:31])[CH:17]([C:19]2[CH:30]=[CH:29][C:22]3[N:23]([CH3:28])[C:24](=[O:27])[N:25]([CH3:26])[C:21]=3[CH:20]=2)[OH:18])=[C:12]([Cl:32])[CH:11]=1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:31])[C:17]([C:19]2[CH:30]=[CH:29][C:22]3[N:23]([CH3:28])[C:24](=[O:27])[N:25]([CH3:26])[C:21]=3[CH:20]=2)=[O:18])=[C:12]([Cl:32])[CH:11]=1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)c1ccc2c(c1)n(C)c(=O)n2C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C(=O)c1ccc2c(c1)n(C)c(=O)n2C)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
4-Methyl-morpholine-4-oxide (280 mg) and tetrapropylammonium perruthenate (36 mg) were added to a solution of 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (424 mg) in DCM (5 ml) with 3 A molecular sieves. The mixture was stirred for 3 h at room temperature, filtered over SiO2 (10 g) and concentrated to give the title compound (410 mg) as a white foam. MS (m/e)=409.1 [M+H+].
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C[Li].CCOCC.[O:20]1[C:25]2[C:26]([C:33](OCC)=[O:34])=[C:27]3[N:32]([C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH:31]=[CH:30][CH:29]=[CH:28]3>C1COCC1>[O:20]1[C:25]2[C:26]([C:33]([O:12][CH2:11][CH:8]3[CH2:9][CH2:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]3)=[O:34])=[C:27]3[N:32]([C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH:31]=[CH:30][CH:29]=[CH:28]3
Reactant: CCCCN1CCC(CO)CC1
Reactant: CCOC(=O)c1c2c(n3ccccc13)CCCO2
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCN1CCC(COC(=O)c2c3c(n4ccccc24)CCCO3)CC1
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
A stirred solution of (1-butyl-4-piperidinyl)methanol (125 mg, 0.72 mmole) in dry THF (5 ml) at 5° C. under argon was treated with 1.5M methyllithium in ether (0.35 ml, 0.50 mmole). After 10 minutes, a solution of ethyl 3,4-dihydro-2H-pyrano[2,3-b]indolizine-10-carboxylate (55 mg, 0.22 mmole) in dry THF (5 ml) was added and the mixture heated under reflux for 3 h. The mixture was then allowed to cool and concentrated in vacuo. The residue was treated with 10% Na2CO3 solution (10 ml) and extracted with ethyl acetate (2×40 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with 3% methanol/chloroform to afford the title compound as a pale pink oil (65 mg, 78%).