Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]CC2C=CC=CC=2)[C:10]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31]O>CC(O)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:31])[CH:13]=[CH:12][C:11](=[O:15])[C:10]=1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: c1ccc(COc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1C=CC(=O)C(OCc2ccccc2)=C1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3-tribenzyloxybenzene 8 (2.0 g, 5.0 mmol) in HOAc (30 mL), K3Fe(CN)6 (0.82 g, 2.5 mmol) and 30% H2O2 (1.3 g, 11.5 mmol) were added and the resulting solution stirred at room temperature for 18 h. The solution was diluted with 50 mL CH2Cl2 and the organic layer subsequently washed with H2O, saturated aqueous NaHCO3 and brine. Drying and concentration resulted in a red oil. Purification by radial chromatography (2 mm thickness, EtOAc/hexane, 1:19, v/v) afforded 9 as a red oil. 1H NMR (CDCl3): δ7.36-7.32 (m, 10 H), 6.58 (s, 2 H), 5.20 (s, 4 H). 13C NMR (CDCl3): δ184.1, 145.2, 136.1, 134.6 128.5, 128.4, 128.1, 75.1. Anal. Calcd for C20H18O4: C, 74.99; H, 5.03. Found: C, 75.04; H, 5.06. HRMS (FAB) calcd for C20H16O4 (M+H+): 320.1049. Found: 320.1059.
Reaction SMILES: Br.[N:2]1[CH:7]=CC=C[CH:3]=1.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=O.C[NH:18]C>C(Cl)Cl>[CH2:15]([O:14][C:8](=[O:13])[CH:9]=[C:10]([NH2:18])[CH2:12][N:2]([CH3:7])[CH3:3])[CH3:16]
Reactant: c1ccncc1
Reactant: CCOC(=O)CC(C)=O
Reactant: CNC
Agent: Br
Solvent: ClCCl
Product: CCOC(=O)C=C(N)CN(C)C
Reaction time: 2 h

Procedure:
Pyridine-hydrobromide-perbromide (48 g) was added to a solution of ethyl acetoacetate (19.4 g) in anhydrous methylene chloride (500 ml) at room temperature in 20 minutes. The mixture was stirred for 2 hours and then added dropwise to a solution of dimethylamine (48.8 g) in anhydrous methylene chloride (100 ml) at -15°-0° in 1 hr. The resulting mixture was cooled to -20° and ammonia was bubbled through the mixture under stirring for 1 hr and for 2 hr at room temperature. The reaction went to completion, by leaving the mixture overnight at about 5° C. After evaporation of the solvent the residue was treated with ether the solid was filtered off and the solution evaporated, to yield a brown oil, which was purified by column chromatography on silica gel to give the title compound (10.8 g) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH:28]2[CH2:32][CH2:31][CH:30]=[CH:29]2)[CH:25]=[C:24]([CH3:33])[C:23]=1[OH:34].C1(C)C=CC=CC=1>CC(CC(C)=O)C.C1COCC1>[OH:9][C:3]1[C:4]([CH3:8])=[CH:5][C:6]([CH:31]2[CH2:30][CH2:29][CH:28]([C:26]3[CH:25]=[C:24]([CH3:33])[C:23]([OH:34])=[C:22]([CH3:21])[CH:27]=3)[CH2:32]2)=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1O
Reactant: Cc1cc(C2C=CCC2)cc(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C2CCC(c3cc(C)c(O)c(C)c3)C2)cc(C)c1O

Procedure:
Into a 2-liter flask having a stirrer, a condenser and a thermometer, 286 g of 2,6-dimethylphenol and 40 g of p-toluenesulfonic acid (hereinafter “PTS”) were introduced, and a solution of mixture of 106 g of 2,6-dimethyl-4-(2-cyclopenten-1-yl)phenol and 106 g of toluene was added dropwise over a period of 1 hour while stirring the mixture kept at 100° C., followed by further stirring for 4 hours at 80° C. To the reaction solution thus obtained, THF and MIBK were added, and the resultant solution was washed with water until it turned neutral, followed by removal of the solvent and 2,6-dimethylphenol using an evaporator.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:4]=2[C:3]=1[CH2:18][CH2:19][CH3:20].[H-].[Na+].CN(NC(Cl)=[S:28])C.[CH3:30][N:31]([CH3:34])[CH:32]=O>C(Cl)Cl>[CH3:34][N:31]([C:32](=[S:28])[O:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:4]=2[C:3]=1[CH2:18][CH2:19][CH3:20])[CH3:30]
Reactant: CN(C)C=O
Reactant: CN(C)NC(=S)Cl
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OCC)oc12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(OC(=S)N(C)C)ccc2c(=O)cc(C(=O)OCC)oc12
Reaction time: 0.5 h

Procedure:
Ethyl 7-hydroxy-4-oxo-8-n-propyl-4H-1-benzopyran-2-carboxylate (1 g) in anhydrous dimethylformamide (4 ml) is cooled to 0° and treated under nitrogen with sodium hydride (50% dispersion in mineral oil, 180 mg) with stirring for 30 minutes. Dimethylaminothiocarbamylchloride (465 mg) is added and the mixture is stirred 15 minutes at 0°, warmed to 80° and maintained as such for 18 hours. The mixture is cooled, diluted with methylene chloride (50 ml) and washed with water (3×100 ml)), dried over sodium sulfate and reduced to dryness in vacuo. The residue is recrystallized from ethyl acetate and hexane to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:20])=[O:19])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.59 g, 8.46 mmol), p-toluenesulfonyl chloride (1.93 g, 10.1 mmol) and triethylamine (TEA) (2.35 mL, 16.9 mmol) in CH2Cl2 (15 mL), dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) was added. As soon as the DMAP was added, the suspension became clear. The solution was then stirred at room temperature for 1 h. It was washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (2.55 g).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].Br[CH2:28][CH2:29][O:30][CH3:31]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([CH2:28][CH2:29][O:30][CH3:31])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
LDA (2M solution in THF/heptane/ethylbenzene, 24.48 ml, 0.049 mol) was added under an argon atmosphere to THF (150 ml) at −5° C., piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (6.3 g, 6 ml) in THF (100 ml) was then added dropwise and the mixture was stirred for 2 hour at 0° C. Then 1-bromo-2-methoxy-ethane (6.8 g) was added at 0° C. and the mixture was stirred overnight at RT. The solvent was evaporated off, the residue partitioned between AcOEt and water. The layers were separated, the organic layer was washed with brine, dried over sodium sulphate and then concentrated to give 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8 g) as a brown oil which was essentially pure and used in the next step without further purification. MS (ESI): 216.3 [(M-Boc)H+].
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH2:27])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=1)([CH3:9])[CH3:8]>>[ClH:1].[CH3:9][C:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:27][C:3](=[O:4])[CH2:2][Cl:1])[S:19][C:20]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:12][CH:11]=1)([CH3:6])[CH3:8]
Reactant: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Reactant: O=C(Cl)CCl
Product: CC(C)(C)c1ccc(-c2nc(NC(=O)CCl)sc2-c2ccncc2)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
Chloroacetyl chloride (0.55 g, 4.85 mmol) was added to a solution of [4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (1.0 g, 3.23 mmol) in N,N-dimethylacetaminde (10 mL) and the mixture was stirred at 60° C. for 14 hours. The solvent was concentrated under reduced pressure and the resultant residue was washed with ether and dried. The crude crystals obtained was recrystallized from ethanol to obtain the title compound (0.94 g, yield 69%).
Reaction SMILES: F[C:2]1([F:16])[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH2:3]1.[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:16][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])=[CH:12][CH:13]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(O)c1cccc(O)c1
Reactant: O=C(C1=CCC(F)(F)C=C1)c1ccccc1
Product: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1

Procedure:
As shown by reaction (1), 4,-4-difluorobenzophenone is reacted with 3-hydroxybenzoic acid to obtain 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid. The reaction is carried out in a suitable aprotic solvent, such as dimethylsulfoxide or N,N-dimethylformamide, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. The 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid (A) is then reacted with 3-aminophenol, as shown by reaction (2) to obtain 3-[4-(3-aminophenoxybenzoyl)phenoxy]benzoic acid (B). This reaction is carried out in a suitable aprotic solvent, under an inert atmosphere, at an elevated temperature of about 100° to 140° C. for about 8 to 64 hours. At the end of the reaction period, the reaction mixture is cooled, then poured into water, which is then neutralized to precipitate the monomer (B). If desired, the crude monomer can be purified by recrystallization or by dissolving it in a suitable solvent and precipitating it from solution into a suitable non-solvent.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=2[O:26]C)=[C:4]([CH3:28])[N:3]=1.C[S-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=2[OH:26])=[C:4]([CH3:28])[N:3]=1
Reactant: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To the product from example 30 step (v) (250 mg) in DMF (20 ml), sodium thiomethoxide (180 mg) was added and stirred at 100° C. for 16 h. The solvents were evaporated, and crude product purified by RPHPLC to give the subtitle compound as a colourless gum, 120 mg.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH2:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:24][CH:23]=1>C(O)C>[ClH:1].[C:28]([CH2:27][O:26][C:25]1[CH:31]=[CH:32][C:22]([NH:21][C:2]2[C:11]3[C:6](=[N:7][C:8]([CH3:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:23][CH:24]=1)(=[O:29])[NH2:30]
Reactant: NC(=O)COc1ccc(N)cc1
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Cl
Solvent: CCO
Product: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OCC(N)=O)cc1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate (2.0 g), 4-aminophenoxy acetamide (1.13 g) and absolute ethanol (30 ml) was boiled under reflux for 1 hour and then cooled to ambient temperature. The mixture was filtered to give ethyl 4-[4-(carbamoylmethoxy)anilino]-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate hydrochloride, m.p. 215°-217° C.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.[CH3:29]C1C=C(CS)C=CC=1>>[OH:26][CH2:25][C@H:24]([NH:23][C:21]1[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=[C:13]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:29])[CH:2]=2)[N:22]=1)[CH3:27]
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Reactant: Cc1cccc(CS)c1
Product: Cc1cccc(CSc2nc(N[C@H](C)CO)c3ncc(=O)[nH]c3n2)c1
Yield: 43.2 %

Procedure:
The titled compound (75 mg) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (0.20 g) and 3-methyl-benzenemethanethiol (75 mg).
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:24](=[O:28])[CH2:23][CH2:22][C:21]([CH3:30])([CH3:29])[C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>ClCCl>[C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:24](=[O:28])[CH2:23][CH2:22][C:21]([CH3:30])([CH3:29])[C:20]=3[CH:19]=2)=[O:17])=[CH:13][CH:14]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)Cc1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3=O)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2ccc(C(=O)Oc3ccc(CC(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 29.7 %

Procedure:
A solution of 8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 4-(tert-butoxycarbonylmethyl)phenyl Ester (Compound 19, 0.11 g, 0.229 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.85 mL and stirred at ambient temperature for 2.5 h. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with ethyl acetate (×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a solid which was subjected to flash column chromatography over silica gel (230-400 mesh) using ethyl acetate as the eluent to afford the title compound (0.024 g, 25%).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:20]1[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1.CCCCC>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[C:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: O=C(c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCCCC
Product: FC(F)(F)c1ccc(C(=C2CCCNC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
To a solution of phenyl(4-(trifluoromethyl)phenyl)methanone (1.5 g, 6.0 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (1.3 g, 6.5 mmol) in THF (20 mL) was added Zn (1.8 g, 28.5 mmol) and the resulting mixture was stirred at rt for 10 min and was then cooled to 0° C. To this was added TiCl4 (1.4 mL, 13.5 mmol) dropwise. The reaction mixture was stirred first at rt for 15 min and then at 50° C. for 4 h. The solvent was removed under vacuum. Then it was cooled to 0-5° C. and added 2N HCl solution and extracted with ethyl acetate. The combined organic layer was washed with K2CO3 solution, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude product. It was cooled to 0-5° C., pentane was added and stirred for 30 min and dried under vacuum to afford 3-(phenyl(4-(trifluoromethyl)phenyl)methylene)piperidine (1.1 g, 57% yield) as a grey solid. MS (ESI, pos. ion) m/z: 318 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([OH:29])(=O)C.[O-]C#[N:32].[Na+]>O1CCCC1.O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]([CH3:25])[C:26]([NH2:32])=[O:29])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reactant: CC(=O)O
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(N)=O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reaction time: 16 h
Yield: 81.8 %

Procedure:
A 25-mL round bottom flask was charged with N1-(2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-N4-methylbenzene-1,4-diamine (0.100 g, 0.28 mmol) in tetrahydrofuran (1 mL). To this stirred solution at rt was added acetic acid (0.33 mL, 5.72 mmol) and sodium cyanate (0.186 g, 2.86 mmol). After 16 h, the reaction mixture was diluted with water (20 mL) and saturated sodium bicarbonate was added until pH˜8, at which time, a solid formed. The resultant solid was isolated by filtration, and was purified by chromatography on silica using dichloromethane/methanol (10:0 to 19:1) as eluent to afford 1-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)-1-methylurea (0.090 g, 80%) as a white solid. MW=392.88. 1H NMR (DMSO-d6, 500 MHz) δ 8.18 (s, 1H), 7.95 (t, J=2.0 Hz, 1H), 7.80 (dt, J=7.5, 1.5 Hz, 1H), 7.46-7.39 (m, 2H), 7.31 (s, 1H), 7.25 (s, 4H), 5.73 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 3.13 (s, 3H), 2.85 (t, J=7.5 Hz, 2H), 2.09 (quin, J=7.5 Hz, 2H). MS: ESI+, m/z 393 [M+H]+. Treatment with 1.25M HCl in methanol (0.15 mL, 0.19 mmol) afforded the title compound (0.048 g, 90%) as a light yellow solid. MW=429.34. M.p. 154-157° C. decomp. 1H NMR (DMSO-d6, 500 MHz) δ 13.93 (br s, 1H), 9.19 (br s, 1H), 7.92-7.89 (m, 1H), 7.76-7.71 (m, 1H), 7.60-7.52 (m, 2H), 7.33 (s, 4H), 7.18 (s, 1H), 5.87 (s, 2H), 3.16 (s, 3H), 3.07 (t, J=7.0 Hz, 2H), 2.90 (t, J=7.5 Hz, 2H), 2.19 (quin, J=7.5 Hz, 2H); ESI MS m/z 393 [M+H]+.
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:9][CH2:8]1)=O>C(O)(=O)C.O1CCCC1.O.[Zn]>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][CH:10]1[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(Oc2ccc3ccccc3c2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2cc(OC3CCNCC3)ccc2c1

Procedure:
The resulting 1-(2,2,2-trichloroethoxycarbonyl)-4-(2-naphthalenyloxy)piperidine is dissolved in a mixture of 250 ml of acetic acid, 250 ml of tetrahydrofuran and 125 ml of water. 28.5 g (0.436 mole) of zinc dust is added in portions with stirring and the exothermic reaction allowed to proceed for 21/2 hours. The mixture is filtered and the solvents are removed in vacuo. The residue is partitioned between ether and aqueous sodium hydroxide and the organic phase washed with water and extracted with dilute aqueous hydrochloric acid. The acid extracts are washed with ether, made basic with sodium hydroxide and extracted into ether and toluene and the organic solution washed, dried over magnesium sulfate and concentrated in vacuo to yield 4-(2-naphthalenyloxy)piperidine, which is redissolved in ethanol/ether and treated with dry HCl, and the hydrochloride salt recrystallized from butanone/methanol. M.P. 229.5°-231.5° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([CH:17]([OH:26])[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([C:17](=[O:26])[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH3:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(c1ccccn1)C(O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)c1ccccc1)c1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
A solution of DMSO (5.5 mL, 77.5 mmol) in dichloromethane (10 mL) is added drop wise to a solution of oxalyl chloride (3.3 mL, 39.0 mmol) in dichloromethane (100 mL) with the internal temperature under −60° C. The reaction mixture is stirred for 15 minutes and then a solution of 1-phenyl-2-(pyridin-2-yl)propan-1-ol (2) (7.0 g, 32.8 mmol) in dichloromethane (10 mL) is added slowly to keep the internal temperature under −60° C. After 30 minutes, triethylamine (22.3 mL, 0.16 mol) is added slowly at −78° C. After 15 minutes, the reaction is allowed to warm up to 0° C. for 30 minutes and then quenched with water. The mixture is separated and the aqueous phase is extracted with dichloromethane (2×50 mL). The extracts are combined, washed with brine, dried, concentrated and purified by column chromatography (hexane/ethyl acetate 10:1 to 4:1) to give 3 (6.4 g, 91%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.51-1.54 (m, 3H), 4.84-4.92 (m, 1H), 7.03-708 (m, 1H), 7.18-7.20 (m, 2H), 7.30-7.35 (m, 1H), 7.40-7.43 (m, 1H), 7.52-7.57 (m, 1H), 7.95-7.98 (m, 2H), 8.47-8.48 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CCCC=O
Product: CCCCNc1ccc(C(C)(C)C)cc1
Yield: 90.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4-tert-butylaniline (400 mg, 2.68 mmol) and butyraldehyde (240 μL, 2.68 mmol) were converted to the title compound (500 mg, 84%). 1H NMR (CDCl3) δ 7.27-7.19 (m, 2H), 6.60 (d, J=8.8 Hz, 2H), 3.61 (br s, 1H), 3.13 (t, J=7.0 Hz, 2H), 1.68-1.53 (m, 2H), 1.50-1.40 (m, 2H), 1.32 (s, 9H), 0.99 (t, J=7.3 Hz, 3H); MS(ESI+) m/z 206.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[C:46](=[O:58])[N:47]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[N:48]([CH3:51])[C:49]=1[CH3:50].C(N(CC)CC)C>CN1C(=O)CCC1.CS(C)=O>[CH:52]1([N:47]2[C:46](=[O:58])[C:45]([NH:44][C:17]([C:3]3[C:2]([CH3:1])=[C:6]([CH:7]4[CH2:8][CH2:9][C:10]5([O:11][CH2:12][CH2:13][O:14]5)[CH2:15][CH2:16]4)[O:5][N:4]=3)=[O:19])=[C:49]([CH3:50])[N:48]2[CH3:51])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: Cc1c(C(=O)O)noc1C1CCC2(CC1)OCCO2
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-methyl-5-(1,4-dioxaspiro[4.5]decan-8-yl)isoxazole-3-carboxylic acid (239 mg, 0.894 mmol) in dry NMP (3 mL), HATU (374 mg, 0.984 mmol) was added followed by 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (206 mg, 0.984 mmol) and triethylamine (0.274 mL, 1.967 mmol). The mixture was stirred at room temperature for 16 hours. The resulting mixture was partitioned between EtOAc (20 mL) and 1M NaOH (20 mL). The organic phase was washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-2% MeOH in DCM afforded crude material. Isolated material was dissolved in DMSO (2 mL) and triturated with water (30 mL). The resulting suspension was filtered under reduced pressure and the solid was washed with water (20 mL) and allowed to dry under vacuum to afford the title compound;