Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:5][O:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1CCc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
40 g of finely powdered aluminium chloride are added in portions to a stirred solution of 20.6 g of 6-methoxy-indane-1-carboxylic acid methyl ester and 15.5 g of benzoyl chloride in 200 ml of absolute methylene chloride at 20° C., in an anhydrous atmosphere, stirring is continued overnight at room temperature and the reaction solution is then poured onto 500 g of ice and extracted with 3 times 100 ml of methylene chloride. The organic phases are washed successively with 500 ml of saturated sodium bicarbonate solution, 500 ml of 2 N hydrochloric acid and 500 ml of water, dried over anhydrous sodium sulphate and evaporated in vacuo. The evaporation residue, when crystallised from ether-petroleum ether after treatment with active charcoal, gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid methyl ester of melting point 89°-91° C.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:6]=1[Br:5]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)cc1Br
Temperature: 0 °C
Yield: 99 %

Procedure:
To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5° C. (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2-bromo-4-chloro-benzoic acid methyl ester (26 g, 99%), which was directly used in the following step.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:30](=[O:31])[N:7]2[C:8]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:9]([CH2:12][OH:13])[CH2:10][S:11][C@H:6]12)(=[O:3])[CH3:2].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:43])C=1>C(O)(C)C>[C:1]([NH:4][CH:5]1[C:30](=[O:31])[N:7]2[C:8]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])=[C:9]([CH2:12][OH:13])[CH2:10][S:11](=[O:43])[C@H:6]12)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS(=O)[C@H]12

Procedure:
To a stirred, cooled (0°-5° C.) solution of 876 mg. of benzhydryl 7-acetamido-3-hydroxymethyl-3-cephem-4-carboxylate in a mixture of 40 ml. of methylene chloride and 20 ml. of isopropanol there was added dropwise 407 mg. (equivalent, about 85% pure) of m-chloroperbenzoic acid in 20 ml. of isopropanol, During the addition a precipitate was formed which was collected and washed with ethyl acetate yielding 800 mg. of the titled compound, m.p. 178°-179° C. The NMR, IR, and UV spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11]>[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Zn]
Product: Clc1cc(Cl)c(Cl)nc1Cl

Procedure:
at 95.07 percent pentachloropyridine conversion with 98.13 percent of the pentachloropyridine added accounted for in the final products. Of the metallic zinc used in the reaction, 95.61 percent reacts with chloropyridines with 91.72 percent resulting in the formation of 2,3,5,6tetrachloropyridine. Of the metallic zinc added, 100 percent oxidizes during the reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]([CH3:26])([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH3:17])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:26]
Reactant: CC(C)(N)c1ncco1
Reactant: Cc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Product: Cc1ccc(C(=O)NC(C)(C)c2ncco2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methyl-pyridine-2-carboxylic acid and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): 356.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][C:22](=[O:26])[CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].C([C:31]([O:33][CH3:34])=[O:32])#N.C(O)(=O)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[CH2:24][CH2:23][C:22]([OH:26])=[C:21]3[C:31]([O:33][CH3:34])=[O:32])[C:10](=[O:15])[C:11]([F:13])([F:12])[F:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)C#N
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC(=O)C3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)CCc2c1cccc2N(C(=O)C(F)(F)F)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of N-(4-cyanophenyl)-2,2,2-trifluoro-N-(5,6,7,8-tetrahydro-6-oxo-1-naphthyl)acetamide (1.17 g, 3.27 mmol) in THF (15 ml) was added dropwise over a 15 minute period to a stirred suspension of 80% NaH (0.30 g, 10 mmol) (Aldrich) in methyl cyanoformate (1.5 ml, 19 mmol) (Aldrich) and THF (15 ml) under nitrogen. The reaction mixture was stirred 30 minutes at room temperature then quenched with acetic acid (0.7 ml, 12 mmol). The solution was concentrated in vacuo onto silica gel (3 g) and the absorbed material purified by chromatography on silica gel (30 g) eluting with ether:hexane (1:4 to 1:3) to give methyl 5-(N-(4-cyanophenyl)-2,2,2-trifluoroacetamido)-3,4-dihydro-2-hydroxy-1-naphthalene carboxylate (0.64 g). 1H NMR (CDCl3, 200 MHz) δ: 2.5-2.9 (m, 4H, CH2CH2), 3.93 (s, 3H, CH3), 7.10 (d, J=8 Hz, 1H, Ar), 7.32 (t, J=8 Hz, 1H, Ar), 7.39 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 2H, Ar), 7.82 (d, J=8 Hz, 1H, Ar), 13.35 (s, 1H, OH). Anal. Calculated for C21H15F3N2O4: C, 60.58; H, 3.63; N, 6.73. Found: C, 60.66; H, 3.66; N, 6.68.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:8]([C@@H:18]([NH2:20])[CH3:19])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:31]1[C:36]([Cl:37])=[CH:35][N:34]=[C:33]([NH2:38])[N:32]=1>C(O)CCC>[Cl:37][C:36]1[C:31]([NH:20][C@H:18]([C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:19])=[N:32][C:33]([NH2:38])=[N:34][CH:35]=1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1ccccn1
Reactant: Nc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(N)ncc1Cl)c1cc2cccc(Cl)c2nc1-c1ccccn1

Procedure:
A mixture of (1S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine (0.090 g, 0.32 mmol) in n-butanol (3 mL) was treated with DIEA (0.11 mL, 0.64 mmol, 2.0 eq), followed with 4,5-dichloropyrimidin-2-amine (0.062 g, 0.38 mmol, 1.2 eq) at 100° C. for 8 h. The reaction mixture was concentrated and purified by column chromatography on a Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to provide 5-chloro-N4-((S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)pyrimidine-2,4-diamine [PI3Kδ IC50=105 nM] as a white solid. 1H-NMR (DMSO-d6) δ ppm 8.65-8.76 (m, 1H), 8.53 (s, 1H), 8.11-8.20 (m, 1H), 8.07 (d, J=1.96 Hz, 1H), 7.91-8.00 (m, 2H), 7.86 (s, 1H), 7.62 (t, J=8.02 Hz, 1H), 7.51-7.58 (m, 1H), 6.03-6.25 (m, 1H), 1.38-1.63 (d, J=7.04, 3H), Mass Spectrum (ESI) m/e=412 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Product: c1cnc(NCCCOc2cccc(CN3CCCCC3)c2)nc1

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.0 g) and 2-chloropyrimidine (0.92 g) were fused at 160° C. for one hour. The reaction mixture was worked-up in a manner similar to that of Example 3 to give the title compound as an oil. This was treated with oxalic acid to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]pyrimidine dioxalate (0.8 g), m.p. 181°-183° C. (recrystallised from methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCc1ccc(F)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(F)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3,4-difluoro-phenyl)-ethanol (1.00 g, 6.33 mmol) in tetrahydrofuran (63.0 mL) at 0° C. was added triethylamine (1.95 mL, 13.9 mmol) followed by methanesulfonyl chloride (0.538 mL, 6.96 mmol). The solution was allowed to warm to room temperature overnight, quenched with water (20 mL), and diluted with ethyl acetate (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with saturated NaHCO3 (1×20 mL), brine (1×20 mL), dried over MgSO4, filtered, and concentrated to give the title compound. 1H NMR (CDCl3) δ 2.92 (s, 3H), 3.01 (t, J=6.59 Hz, 2H), 4.37–4.40 (m, 2H), 6.94–6.97 (m, 1H), 7.03–7.06 (m, 1H), 7.07–7.15 (m, 1H) ppm. 19F NMR (CDCl3) 8–140.48–, 137.71 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]2)=[C:6]([CH:9]=1)[CH:7]=O.[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([NH2:34])[C:26]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:27][CH:28]=2)=[CH:19][N:18]=1.OOS([O-])=O.[K+]>O>[C:30]([N:29]1[C:26]2[CH:27]=[CH:28][C:23]([C:20]3[CH:19]=[N:18][C:17]([NH2:16])=[N:22][CH:21]=3)=[CH:24][C:25]=2[N:34]=[C:7]1[C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: Cc1ccn(-c2ccc(Cl)cc2C=O)n1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: Cc1ccn(-c2ccc(Cl)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 60 °C
Yield: 13 %

Procedure:
A 10 mL aliquot of 5-chloro-2-(3-methyl-pyrazol-1-yl)-benzaldehyde from the above reaction is filtered (in DMF, 50% pure by LC-MS, calculated mass based on purity is 235 mg, 1.10 mmol). The crude aldehyde is treated with 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (200 mg, 0.78 mmol). Oxone (478 mg, 0.78 mmol) is added as a water solution (2 mL). The resulting mixture is warmed to 60° C. for 2 hours and cooled to room temperature. The reaction mixture is poured into water and extracted with EtOAc (3×). The combined organics are dried (MgSO4), filtered, and concentrated. Purification via flash chromatography (12 g silica gel, 0-6% MeOH/CH2Cl2) followed by mass triggered HPLC(CH3CN/H2O) affords the title compound (45 mg, 13%). LCMS (ESMS): m/z 458.20 (M++1)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[CH2:23][CH2:24][CH3:25].[H-].[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[C:17]([CH2:23][CH2:24][CH3:25])[CH:18]=1)[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: CCCc1cc(O)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCC(=O)OCC)ccc1OCCc1nc(-c2ccccc2)oc1C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A solution of 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-3-propylphenol (0.37 g, 1.10 mmol) in dry DMF (4 mL) was cooled in an ice bath and treated with NaH (0.13 g, 3.3 mmol, 60% oil dispersion). After 10 min, ethyl bromoacetate (0.37 mL, 3.3 mmol) was added. The ice bath was removed, and the mixture was placed in an oil bath (T=85° C.). After 18 h, the reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between EtOAc (70 mL) and water (40 mL). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by radial chromatography using 5% ethyl acetate in dichloromethane to give a white solid (0.34 g, 73%). 1H NMR (400 MHz, CDCl3), δ 7.97 (dd, J=7.8, 2.4 Hz, 2H), 7.41-7.39 (m, 3H), 6.77-6.73 (m, 2H), 6.61-6.63 (m, 1H, 4.54 (s, 1H), 4.28-4.24 (m, 2H), 2.96 (t, J=6.4 Hz, 2H), 2.50 (t, J=7.1 Hz, 2H), 2.37 (s, 3H), 1.51 (q, J=7.6 Hz, 2H), 1.31-1.29 (m, 5H), 0.84 (t, J=7.0 Hz, 3H); MS (FIA) m/e 424 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[CH3:12][NH2:13].C1COCC1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:13][CH3:12])=[O:6]
Reactant: CN
Reactant: Cc1ccc(C(=O)Cl)cc1I
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(I)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a cooled (0° C.) solution of 3-iodo-4-methylbenzoyl chloride (2.80 g; 10.0 mmol) in DCM (10 mL) was slowly added a 2 M solution of methylamine in THF (11 mL, 2.2 eq.). Upon completion of the addition, the ice bath was removed and the mixture was stirred overnight. All volatiles were removed in vacuo and the residue was treated with aq. NaHCO3 (25 mL) and subsequently extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO4 and evaporated. The target compound 3-iodo-N,4-dimethylbenzamide (2.62 g, 95% yield) was used without further purification.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:24][CH2:23]2)[CH2:11]1)[S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Product: CN([C@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1)S(C)(=O)=O

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 26, Step H in Step A and methylsulfonyl chloride in Step B, the title compound can be prepared.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])(=[O:8])=[O:7])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=1[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])(=[O:8])=[O:7]
Reactant: CN(C)C(=O)c1c(S(=O)(=O)NC(C)(C)C)ccn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1c(S(N)(=O)=O)ccn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of 5.63 g of 3-[[(1,1-dimethylethyl)amino]sulfonyl]-N,N,1-trimethyl-1H-pyrrole-2-carboxamide in 75 ml, of methylene chloride was added 75 mL of TFA. The reaction mixture was allowed to stir at room temperature overnight ca. 16 hours. The reaction mixture was concentrated in vacuo. Three portions of diethyl ether were added to the residue and removed by evaporation to remove residual TFA, affording 4.21 g of the title compound as a gray solid, m.p. 185°-190.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16](=O)[CH3:17])[CH2:11][C:10]=3[C:19](=[O:21])[O:20][C:5]=2[CH:4]=1.[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][CH:16]([CH3:17])[CH2:15][N:12]1[CH2:13][CH2:14][C:9]2[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:20][C:19](=[O:21])[C:10]=2[CH2:11]1)[CH3:23]
Reactant: CCN
Reactant: COc1ccc2c3c(c(=O)oc2c1)CN(CC(C)=O)CC3
Product: CCNC(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1
Yield: 43.2 %

Procedure:
Prepared by the method described for Example 51 from 1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (14.9 g, 0.052 moles) and ethylamine (5 ml, 0.07 moles). Recrystallization from ethyl acetate gave the product (7.1 g), mp 97°-100° C.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]2[NH:18][C:17](=[NH:19])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>CCO.[Pd]>[ClH:1].[ClH:1].[NH:19]=[C:17]1[NH:18][CH:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([NH2:2])=[CH:10][CH:9]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: N=C1CCCCC(Cc2ccc([N+](=O)[O-])cc2)N1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(Cc2ccc(N)cc2)N1
Yield: 176.1 %

Procedure:
The product from Example 273 (0.55 g, 1.8 mmol) in 30 mL of EtOH was reduced with 5% Palladium on carbon under 5 psi of hydrogen. Solvent removal in vacuo followed by lyophilization in water gave 0.46 g (97%) of the title material.
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)=[O:10])C1C=CC=CC=1>O1CCCC1.[Pd]>[C:9]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)([OH:10])=[O:8]
Reactant: CCOC(=O)CN1CCC(CCC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(CCC(=O)O)CC1

Procedure:
10 g of 4-[2-(benzyloxycarbonyl)ethyl]-1-[(ethoxycarbonyl)methyl]-piperidine are hydrogenated in 150 ml of tetrahydrofuran for 4 hours at ambient temperature under a hydrogen pressure of 50 psi in the presence of 1.3 g of palladium on activated charcoal. The reaction mixture is evaporated down and crystallised from diethylether and a little acetone.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[NH:17][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1.[C:25]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:24])[C:11]([CH3:13])([OH:12])[CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH3:25])[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2ccc(C#N)cc2C(Oc2ccc(=O)[nH]n2)C1(C)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1nc(OC2c3cc(C#N)ccc3OC(C)(C)C2(C)O)ccc1=O

Procedure:
A mixture of 327 mg of 2,2,3-trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethyl sulfate is refluxed for 2 hours. The mixture is filtered, concentrated and chromatographed on silica gel. There is obtained with ethyl acetate/methanol (9:1) 2,2,3-trimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-chroman-3-ol, m.p. 197°-199°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:3]=1.[N:16]1([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>C(O)CCC>[O:29]=[C:25]1[NH:26][CH2:27][CH2:28][N:24]1[CH2:23][CH2:22][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=3)[CH:3]=2)[CH2:18][CH2:17]1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Reactant: O=C1NCCN1CCN1CCNCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(Nc2cc(N3CCN(CCN4CCNC4=O)CC3)ncn2)s1

Procedure:
35-1 (0.25 g, 1.06 mmol), 44-4 (0.21 g, 1.06 mmol) and DIEA (0.69 g, 5.32 mmol) were heated at 150° C. for 3 hours in n-butanol. Upon cooling the precipitate was filtered off, washed with n-butanol and ethyl ether and then dried to afford 44-5. Hi-Res MS: calc: 400.1663 found: 400.1633. 1H-NMR (CD3OD): 8.38(s, 1H); 7.99(s, 1H); 6.14(s, 1H); 3.65(m, 4H); 3.55(m, 2H); 3.39(m, 2H); 3.35(t, 2H); 2.59(complex, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: O=Cc1ccccc1F
Product: Fc1ccccc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 2-fluorobenzaldehyde and cyclopropylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCc1ccc(F)cc1
Reaction time: 12 h

Procedure:
In a 500 ml round-bottomed flask, 0.095 mol of the compound obtained in Step B is dissolved in 250 ml of methanol. 1 g of 10% activated palladium-on-carbon is added and magnetic stirring is carried out under a hydrogen atmosphere for 12 hours. The palladiated carbon is then filtered off, and the methanol is evaporated off under reduced pressure. The oil obtained is purified by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:5]2[C:6]([C:12](O)=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C[CH2:19][N:20]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN.Cl>CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:5]2[C:6]([C:12]([NH:20][CH3:19])=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: Nc1cc2oc(C3CC3)c(C(=O)O)c2cc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C2CC2)oc2cc(N)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 714.3 %

Procedure:
To a solution of 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylic acid (6.5 g, 22 mmol) in dry DMF (500 mL) were added EDCI (2.98 g, 2.4 mmol) and HOBT (6.33 g, 3.6 mmol). The reaction mixture was stirred at room temperature for 2 h, and then Et3N (20 mL) and MeNH2.HCl (7.3 g, 110 mmol) were added to the reaction mixture. After stirring for another 2 hours, the reaction mixture was concentrated in vacuum and Na2CO3 (a.q., 300 mL) was added to the mixture. The resulting solid was filtered to give the crude product, which was purified by column chromatography (DCM:MeOH=30:1) to give the product of 6-amino-5-bromo-2-cyclopropyl-N-methylbenzofuran-3-carboxamide (5.3 g, yield: 78%). 1H-NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 6.77 (s, 1H), 5.88 (s, 1H), 4.11 (s, 2H), 3.04 (d, J=4.8 Hz, 3H), 2.69˜2.73 (m, 1H), 1.10˜1.16 (m, 2H), 1.07˜1.09 (m, 2H). MS (M+H)+: 309/311.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[N:8](C(C)(C)C)[CH:7]=[C:6]([C:21]([O:23]CC)=[O:22])[C:5]2=[O:26].Cl.C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[NH:8][CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:26]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)c(Br)cc2c1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1c[nH]c2nc(N3CCCC3)c(Br)cc2c1=O

Procedure:
A solution of Example 79A (128 mg) in 1:1 6M HCl/ethanol (15 mL) was refluxed for 24 hours then cooled, diluted with water, and filtered. NMR (300 MHz, DMSO) δ 15.22 (s, 1H), 13.11 (br s, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 3.84-3.80 (m, 4H), 1.95-1.91 (m, 4H).