Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[CH2:9]([O:16][C:17](C[N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([O-])=[O:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O.C(OCC)C.C1COCC1>[C:1]([CH2:2][C:22]([C@H:21]1[CH2:25][CH2:26][CH2:27][NH:20]1)=[O:23])#[N:3].[CH:17]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: CC#N
Reactant: O=C(CN1CCC[C@@H]1C(=O)[O-])OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCC(=O)[C@H]1CCCN1
Product: O=COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
Under nitrogen atmosphere, to a 1000 mL of reaction flask were added dried acetonitrile (15.54 mL, 298.6 mmol) and anhydrous THF (350 mL). The mixture was cooled to −78° C. To the mixture was slowly added n-butyl lithium (171 mL, 1.6 mol/L, 273.7 mmol). The resultant mixture reacted with stirring for 30 min at −78° C. A solution of the compound of Example 4A (65.51 g, 248.8 mmol) in THT (100 mL) was added. The reaction was further kept for 1 hr at −78° C. Then, the reaction was warmed to −20° C. for 30 min, and finally warmed to room temperature for 30 min. The reaction was stopped. Ethyl ether (100 mL) was added to the reaction system to dilute. Water (100 mL) was added for quenching the reaction. pH was adjusted with diluted hydrochloric acid to 3. The organic phase was washed with saturated saline, dried and concentrated. The concentrated organic phase was separated by column chromatography to give 59.5 g of the title compound as pale yellow liquid. Yield: 87.8%. MS (ESI): m/z 273 (M+H)+
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH2:16][CH3:17])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.B(O)(O)[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]([C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[N:5]=1)[CH3:17]
Reactant: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1CC
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(CC)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Yield: 38.4 %

Procedure:
methyl 2-(4-chloro-6-ethyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.190 g; 0.559 mmol), p-tolylboronic acid (114 mg; 0.839 mmol), tetrakis(triphenylphosphine) palladium(0) (64.6 mg; 0.056 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.344 mL; 2.236 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 30 min. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 85 mg (35%) of the title compound as a yellow oil.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([O:37][CH2:38][CH2:39][OH:40])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[CH2:12][N:13]([CH3:22])[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)CC)C.[C:48]([Cl:51])(=[O:50])[CH3:49].Cl>C(Cl)Cl>[OH2:21].[ClH:3].[C:48]([O:40][CH2:39][CH2:38][O:37][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:12][N:13]([CH3:22])[C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:30][CH2:29]1)(=[O:50])[CH3:49].[C:48]([O:40][CH2:39][CH2:38][O:37][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:12][N:13]([CH3:22])[C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:30][CH2:29]1)(=[O:50])[CH3:49].[ClH:51]
Reactant: CC(=O)Cl
Reactant: CN(CC(CCN1CCC(OCCO)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCCOC1(c2ccccc2)CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of 0.6 g of the compound obtained in EXAMPLE 1 and 0.3 ml of triethylamine in 20 ml of DCM is cooled to 0-5° C., 0.08 ml of acetyl chloride is added and the mixture is left stirring while the temperature is allowed to rise to RT. The reaction mixture is concentrated under vacuum and the residue is chromatographed on silica, eluting with DCM and then with a DCM/MeOH (97:3; v/v) mixture. The product obtained is dissolved in DCM, the mixture is acidified to pH 1 by adding ethereal hydrogen chloride and the precipitate formed is drained. 0.23 g of the expected product is obtained, m.p.=95° C. ##STR45##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford desired N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)benzamide (0.02 g, 20%).
Reaction SMILES: [C:1]1([CH3:44])[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:43])[CH2:21][CH2:22][S:23]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:1]1([CH3:44])[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:43])[CH2:21][CH2:22][SH:23])=[CH:5][CH:6]=1
Reactant: Cc1ccc(OCCCCCCCCCCCNC(=O)CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(OCCCCCCCCCCCNC(=O)CCS)cc1

Procedure:
The compound 25 (0.181 g) was dissolved in 1 ml of methylene chloride, and 0.5 ml of trifluoroacetic acid was added to that while being stirred, to obtain a brown-colored solution. After a white-colored precipitate was generated by adding 0.16 ml of triethylsilane, the supernatant solution was distilled away under reduced pressure. The solid obtained was dissolved by the new addition of 20 ml of methylene chloride, and was washed twice with 30 ml of aqueous saturated sodium hydrogen carbonate solution and twice with 30 ml of saturated brine. After the collected organic phase was dehydrated with magnesium sulfate, the desiccant agent was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. The reaction mixture was purified by chromatography, and 0.1 g of the compound f, which was a white solid, was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.CO/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18].P(Cl)(Cl)(Cl)=O>O.C(O)(=O)C>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: CO/C=C/C(=O)OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)/C=C/c1c(OC)cc(OC)cc1OC
Reaction time: 3 h
Yield: 90.5 %

Procedure:
1.68 g of 1,3,5-trimethoxybenzene, 2.32 g of methyl trans-3-methoxyacrylate, 0.18 g of water and 6 mL of glacial acetic acid were mixed, 164 mg of phosphorus oxychloride was added into the mixture at an inner temperature of 25° C., the added mixture was stirred for 3 hours at the same temperature to cause a reaction. After completion of the reaction, 36 mL of water was added dropwise into the reaction liquid, and the precipitated crystals were filtrated. The crystals were washed with 20 vol % of aqueous methanol, then, dried to obtain 2.28 g of methyl trans-3-(2,4,6-trimethoxyphenyl)acrylate (white solid). Yield: 91%.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:4]([C:16]([OH:18])=O)=[N:3]1.C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:4]([C:16]([Cl:22])=[O:18])=[N:3]1
Reactant: Cn1nc(C(=O)O)c(=O)n(-c2ccccc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)Cl)c(=O)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.93 g (3.76 mmol) of 2-methyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid and 0.72 g (5.64 mmol) of oxalyl chloride were dissolved in dichloromethane (20 ml). To the mixture, a drop of N,N-dimethylformamide was added and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain 2-methyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonyl chloride as a pale yellow oily substance.
Reaction SMILES: C(O[CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)C.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>O>[C:17]([C:19](=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: CCCc1ccc(C(OCC)OCC)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(C=C(C#N)C(=O)OCC)cc1
Yield: 94 %

Procedure:
A mixture of 20.0 g (90 mmole) 4-n-propylbenzaldehyde diethylacetal, 20.4 g (180 mmole) ethyl cyanoacetate, 7.2 g (93.4 mmole) ammonium acetate and 60 ml toluene are heated at reflux for six hours, cooled and poured into water. The resulting mixture was extracted with ethyl ether, dried (MgSO4) and the volatiles evaporated in vacuo to afford 23.0 g crude yellow oil which was purified by chromatography on a silica gel column, eluting with 2:1 methylene chloride/hexane to give 20.58 g (94%) of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][NH:22][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[N:22]([CH3:21])[CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CNC(C)c1ccccc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N(C)C(C)c2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and methyl-(1-phenyl-ethyl)-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C21H25NO5 [M+H]+: 372.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccc(Br)c3)cc2)c2ccc3ccccc3c2N1
Yield: 60 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.050 mmol) obtained in Example 1, (3), and 3-bromobenzoyl chloride (17 mg, 0.077 mmol), the title compound (15 mg, yield 60%) was obtained as off-white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Rh]>[CH:1]1([C@@H:7]2[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: N[C@H]1CC[C@@H](c2ccccc2)C1
Agent: [Rh]
Product: N[C@H]1CC[C@@H](C2CCCCC2)C1
Yield: 70.1 %

Procedure:
A solution of (1S,3R)-3-phenylcyclopentanamine (second eluting diastereomer from Example 15B, 106 mg, 0.657 mmol) and 1,1,1-trifluoroethanol (20 mL) was added to 5% Rh/Al2O3 (42.4 mg) in a 50 mL pressure bottle. The reaction was heated for 16 hours under 30 psi hydrogen pressure and at 50° C. The mixture was filtered through a nylon membrane, washing with EtOH (50 mL). The solution was concentrated to provide the title compound (77 mg, 70%). MS (DCI) m/z 168 (M+H)+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([F:7])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(Cc2ccccc2)CC1
Temperature: -71 °C
Reaction time: 0.83 h
Yield: 51.1 %

Procedure:
To a cooled (-71° C.) and stirred solution of diethylaminosulfur trifluoride (634 μl, 4.80 mmol) in anhydrous dichloromethane (15 ml) was added dropwise, via cannula, a solution of 1-tert-butyloxycarbonyl-4-benzyl-4-hydroxypiperidine (700 mg, 2.40 mmol) in anhydrous dichloromethane (15 ml) over 20 minutes, under nitrogen. After a further 50 minutes at -75° C., the mixture was warmed to -10° C. and stirred for a further 2 hours. Water (20 ml) and saturated aqueous potassium carbonate (7 ml) were added and products were extracted with diethyl ether (1×70 ml). The organic solution was washed with brine (1×25 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, hexane-diethyl ether, 86:14) gave 190 mg of 1-tert-butyloxycarbonyl-3,4-dehydro-4-benzylpiperidine and 360 mg (51%) of the title compound as pale yellow oils; δH (360 MHz, CDCl3) 1.44 (9H, s), 1.46-1.78 (4H, m), 2.90 (2H, d, J=22 Hz), 2.98-3.08 (2H, m), 3.86-3.94 (2H, m), 7.16-7.34 (5H, m); m/z (ES) 294 (M+ 1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:5]1.B(Br)(Br)[Br:25].CO>C(Cl)Cl>[BrH:25].[NH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:5]1
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1OC)CC(C1CCCCC1)CC2CN
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Br
Product: NCC1CC(C2CCCCC2)Cc2c1ccc(O)c2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
[1 R, 3 S]1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (0.7 g, 2.3 mmol), from Step 1, was suspended in 20 mL of methylene chloride at -78° C. Boron tribromide (9.7 mL of a 1M solution in methylene chloride, 9.7 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After stirring at ambient temperature for 1 h, the reaction mixture was cooled to -78° C. and 10 mL of methanol was added. The reaction mixture was again allowed to warm to ambient temperature and stirred at ambient temperature for 1 h. The solvent was removed in vacuo and methanol was added to the residue. The methanol solution was concentrated and the residue dissolved in a minimal amount of methanol and added dropwise to a large excess of diethyl ether. The precipitate was filtered and recrystallized from ethanol/diethyl ether to give 0.48 g (65% yield) of [1 R, 3 S]1-aminomethyl-3-cyclohexyl-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide, m.p. 203°-204° C.: 1H NMR (d6 -DMSO) δ: 0.9-1.5 (m, 8H), 1.6-1.9 (m, 5H), 2.0-2.1 (m, 2H), 2.7-3.0 (m, 3H), 3.3-3.4 (m, 1H), 6.5-6.7 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7](N)[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].N([O-])=O.[Na+].[BrH:16]>>[Br:16][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1
Reactant: Br
Reactant: CC(C)Cc1cccc(N)c1
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-isobutylphenylamine (3.80 g) in 48% hydrobromic acid (10 ml) was added aqueous sodium nitrite (2.11 g, 2 ml) below 10° C. over 20 minutes. The reaction mixture was added to a solution of cuprous bromide (7.3 g) in 48% hydrobromic acid (5 ml) at 25° C. After stirred at 25° C. for 1 hour, the mixture was extracted with hexane two times. The extracts were combined, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (150 g) eluting with hexane to give 1-bromo-3-isobutylbenzene (2.61 g) as a colorless oil.
Reaction SMILES: [S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21](O)=[O:22])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:57]([NH:61][CH2:62][C:63]1[CH:64]=[C:65]2[C:70](=[CH:71][CH:72]=1)[C@H:69]([NH2:73])[CH2:68][CH2:67][CH2:66]2)([CH3:60])([CH3:59])[CH3:58]>C1COCC1.C(OCC)(=O)C>[C:57]([NH:61][CH2:62][C:63]1[CH:64]=[C:65]2[C:70](=[CH:71][CH:72]=1)[C@H:69]([NH:73][C:21](=[O:22])[CH2:20][CH:12]1[N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[CH2:16][CH2:15][N:14]3[CH:17]=[CH:18][CH:19]=[C:13]13)[CH2:68][CH2:67][CH2:66]2)([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)NCc1ccc2c(c1)CCC[C@H]2N
Reactant: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)N[C@@H]2CCCc3cc(CNC(C)(C)C)ccc32)cc1
Reaction time: 0.25 h
Yield: 19 %

Procedure:
To a solution of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (300 mg, 0.898 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (0.47 ml, 2.694 mmol, 3.0 eq.) and HATU (410 mg, 1.08 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)-6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine (A50) (0.898 mmol, 1.0 eq.) in THF (5 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude product which was purified by column chromatography (silica gel; 1.5% MeOH/DCM) to yield the desired product as an off-white solid. Yield: 19% (94 mg, 0.171 mmol); MS, Rt=3.2 min; m/z=549.1 [MH]+
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C@:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[C@H:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]2)=[O:16])[CH2:10][CH2:9]1.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(CC)CC)C>C(Cl)Cl>[C:45]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])[C:20]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])([C:30]#[N:31])[CH:19]([CH2:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH:18]2)=[O:16])[CH2:12][CH2:13]1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCNCC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)NC2CCN(C(=O)c3ccccc3)CC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid piperidin-4-ylamide trifluoroacetic acid (80 mg, 0.10 mmol) in methylene chloride (10 mL), benzoyl chloride (21 uL, 0.18 mmol) and triethylamine (84 uL, 0.61 mmol) were added and the mixture was stirred at rt for 1 hr. The reaction was quenched with water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave the crude which was chromatographed on an ISCO machine (0-10% EtOAc/CH2Cl2) to give a white solid. 36 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[CH:25](OC)(OC)OC>O>[C:15]1([CH2:14][O:13][C:11]([N:8]2[CH2:7][CH2:6][CH:5]([N:4]3[C:3]4[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=4[N:1]=[CH:25]3)[CH2:10][CH2:9]2)=[O:12])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(OC)OC
Reactant: Nc1ccccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(n2cnc3ccccc32)CC1

Procedure:
A solution of 2-amino-1-N-[1-(phenylmethyloxycarbonyl)-piperidin-4-yl]aniline (Method C) (500 mg, 1.4 mmol), trimethyl orthoformate (1 ml, 9.7 mmol) and para-toluenesuphonic acid monohydrate (30 mg, 0.16 mmol) were stirred at 100° C. After 2 h the mixture was cooled and water (10 ml) was added. The solution was partitioned with EtOAc (3×20 ml) then the organics were combined, washed with water (10 ml), dried (MgSO4) and concentrated to give the title compound as an oil that did not need further purification (410 mg, 1.2 mmol); NMR: 2.0 (m, 4H), 3.0 (m, 2H), 4.2 (d, 2H), 4.6 (m, 1H), 5.1 (s, 2H), 7.2 (m, 2H), 7.4 (m, 5H), 7.65 (d, 2H) and 8.3 (s, 1H); MS: 336.