Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:25]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31].C[O-].[Na+]>CO>[OH:32][CH:29]([CH2:30][OH:31])[CH2:28][NH:27][C:1](=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Reactant: NCC(O)CO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)NCC(O)CO

Procedure:
Methyl 10,12-tricosadiynoate (1.69 g, 4.67 mmol) was dissolved in methanol. 3-Amino-1,2-propanediol (0.509 g, 5.6 mmol) and sodium methoxide 2.5% solution in methanol (0.146 g, 3 mol %) was added. The mixture was refluxed for 3 hours and the solvent evaporated. The crude product was recrystallized from chloroform. Yield: 1.00 g (51%). 1H NMR (60 MHz, CDCl3): δ0.7-1.0 (m, 3H, CH3CH2), 1.3 (s, br, 28H, CH2), 2.0-2.4 (m, 6H, CH2), 3.3-3.8 (m, 5H, 2×CH2 +CH (propanediol)), 6.0-6.3 (m, 1H, NH).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[O:18]1[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22].[Si:25]([O:42][CH2:43][CH2:44][OH:45])([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Si:25]([O:42][CH2:43][CH2:44][O:45][CH2:20][C@H:19]([OH:18])[C:21]([O:23][CH3:24])=[O:22])([C:38]([CH3:40])([CH3:41])[CH3:39])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H]1CO1
Reactant: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Product: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 43.1 %

Procedure:
Magnesium trifluoromethanesulfonate (3.95 g, 12.24 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (5 g, 48.98 mmol) and 2-(tert-butyldiphenylsilyloxy)ethanol (14.72 g, 48.98 mmol) at 10° C. The resulting suspension was stirred at 10° C. for 10 minutes and then warmed to 45° C. and stirred for 3 days. The crude product was purified by flash silica chromatography, eluting with 0 to 30% ethyl acetate in isohexane to afford the product (8.50 g, 43.1%). 1H NMR (400 MHz, CDCl3) δ 1.05 (9H, s), 3.10 (1H, d), 3.62 (2H, t), 3.74-3.87 (7H, m), 4.26-4.34 (1H, m), 7.35-7.46 (6H, m), 7.63-7.71 (4H, m); m/z (ESI+) (M+Na)+=425.37; HPLC tR=3.15 min.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[N:4]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36].[H-].[Na+]>ClCCl>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N:17]3[CH2:32][CH2:33][CH2:34][C:35]3=[O:36])=[CH:18][CH:19]=2)[N:4]=1
Reactant: Nc1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: O=C(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1c1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A solution of 4-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}aniline (166 mg, 0.56 mmol) in dichloromethane (4 ml) was treated with diisopropylethylamine (1.12 mmol, 146 mg) followed by 4-chlorobutyryl chloride (80 mg, 0.56 mmol). After stirring at room temperature for 15 minutes a solid suspension of sodium hydride (60% in mineral oil) (22 mg, 0.55 mmol) was added and stirring continued for 30 minutes. The dichloromethane was removed by blowing with air and dimethylformamide added (3 ml) and stirring continued for 30 minutes. The reaction mix was partitioned between dichloromethane and water (2×5 ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give a yellow oil (190 mg) which was purified by mass directed auto prep to give the title compound as a yellow oil (39 mg, 19%).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:13][CH:12]([C:25](O)=[O:26])[CH2:11]2)=[CH:6][CH:5]=1.O[N:30]=[C:31]([O:33][CH2:34][CH3:35])[NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:25]3[O:26][N:32]=[C:31]([O:33][CH2:34][CH3:35])[N:30]=3)[CH2:13][N:14]([C:16]([N:18]3[CH2:23][CH2:22][S:21](=[O:24])[CH2:20][CH2:19]3)=[O:17])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: CCOC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)F)cc2)CN(C(=O)N2CCS(=O)CC2)C1
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: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(OC(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
185 mg (0.37 mmol) of the compound from Example 42A and 50 mg (0.48 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were initially charged in 1.0 ml of DMF and reacted with 210 mg (0.55 mmol) of HATU and 0.19 ml (143 mg, 1.1 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 15 minutes and then the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in 2.0 ml of acetic acid and heated to reflux for 1 h. The reaction mixture was purified by means of preparative HPLC. Yield: 62 mg (33% of theory)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[C:19]#[N:20])([CH3:13])([CH3:12])[CH3:11].O>C(O)C>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[C:19](=[N:8][OH:9])[NH2:20])([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1ccc(C(C)(C)C)cc1C#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)(C)C)cc1C(N)=NO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
Sodium carbonate (57 g.) was added with stirring to a mixture of hydroxylamine hydrochloride (75 g.), 5-tert-butyl-2-methoxybenzonitrile (50 g.) and water (400 ml.) Ethanol (400 ml.) was added, and the mixture was stirred at room temperature for 45 minutes and then heated under reflux for 18 hours. The ethanol was evaporated in vacuo, and the cooled aqueous suspension was extracted three times with diethyl ether. The combined extracts were dried over magnesium sulphate, filtered, and evaporated. The residual glass was triturated with warm diethyl ether, and the solid obtained was filtered off, washed with diethyl ether, and recrystallised from benzene to give 5-tert-butyl-2-methoxybenzamidoxime (48 g.), m.p. 132°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].[Mn]([O-])(=O)(=O)=[O:19].[K+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([OH:19])=[O:15])=[CH:10]2)=[CH:7][CH:8]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(-n2ccc(C=O)c2)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(-n2ccc(C(=O)O)c2)cc1

Procedure:
Next, 1-(4-methoxyphenyl)pyrrole-3-carbaldehyde was added to an aqueous solution (100 ml) of sodium hydroxide (4.38 g) and an aqueous pyridine solution (water 100 ml and pyridine 180 ml) of potassium permanganate (8.65 g) at 20-30° C., and stirred at room temperature for six hours. After completion of the reaction, the reaction solution was filtered through Celite, the filtrate was acidified by the addition of hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo and the precipitated solid was purified with ethyl acetate/n-hexane to give the titled compound (8.52 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9](=[O:19])[NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:17][CH2:18]3)[C:9](=[O:19])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=c1[nH]c2ncc(Br)cc2n1CCN1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(CCn2c(=O)[nH]c3ncc(Br)cc32)CC1
Reaction time: 0.17 h

Procedure:
The compound obtained in Step 2 of Example 59 (100 mg) was dissolved in chloroform (10 ml). Triethylamine (0.128 ml) and methanesulfonyl chloride (0.036 ml) were added dropwise under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and then stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (developed with methanol-chloroform) to give the title compound (82 mg) as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[C:20]2[NH:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=3)[C:17]([CH3:34])([CH3:33])[CH2:16][C:15]=2[C:14]([C:35](O)=[O:36])=[CH:13][CH:12]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[C:20]2[NH:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:22]=3)[C:17]([CH3:33])([CH3:34])[CH2:16][C:15]=2[C:14]([C:35]([NH:9][S:6]([CH:3]2[CH2:5][CH2:4]2)(=[O:8])=[O:7])=[O:36])=[CH:13][CH:12]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2c(C(=O)O)ccc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(C(=O)NS(=O)(=O)C3CC3)ccc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of 60% sodium hydride (50 mg, 1.2 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (151 mg, 1.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (50 mg, 0.13 mmol) and 1,1′-carbonyldiimidazole (41 mg, 0.25 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid-[8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-amide (13 mg, 20%) as a white solid: LC/MS m/e calcd for C25H30ClN3O4S (M+H)+: 505.05, observed: 504.1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][OH:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].[C:20](OC(=O)C)(=[O:22])[CH3:21].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:20]([O:17][CH2:16][C:12]1[CH:13]=[CH:14][C:15]2[C@H:6]([NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N[C@@H]1CCCc2cc(CO)ccc21)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1ccc2c(c1)CCC[C@H]2NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (546 mg, 2 mmol) in 10 mL of dry DCM was added acetic anhydride (0.30 mL, 3 mmol) and triethylamine (0.8 mL, 6 mmol), followed by DMAP (10 mg). After stirring for 2 h at RT, the solution was evaporated to dryness and directly submitted to flash chomatography (SiO2, DCM) to give (R)-(5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl acetate as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[CH2:5].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:4]([C:3]1[CH:6]=[C:7]([I:10])[CH:8]=[CH:9][C:2]=1[O:1][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][O:12][CH3:11])=[CH:23][CH:22]=1)=[CH2:5]
Reactant: COCOc1ccc(C(=O)O)cc1
Reactant: C=Cc1cc(I)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1cc(I)ccc1OC(=O)c1ccc(OCOC)cc1
Temperature: 23 °C
Reaction time: 21 h
Yield: 79 %

Procedure:
To a stirred solution of 2-hydroxy-5-iodostyrene, 4-(methoxymethoxy)benzoic acid, and DCC in methylene chloride at 23° C. was added DMAP, and the resulting mixture was stirred at 23° C. for 21 hours. The reaction mixture was then filtered over celite and concentrated in vacuo. Purification by flash chromatography (SiO2, hexanes:ethyl acetate 5:1) yielded (2-vinyl-4-iodophenyl)-4-methoxymethoxybenzoate as a colorless solid (4.6 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc(C)c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc(Br)cc(C)c1N
Temperature: 145 °C
Yield: 21.6 %

Procedure:
To 2-methoxy-6-methyl-phenylamine (10.0 g) dissolved in acetonitrile (200 mL) was added N-bromosuccinimide (14.3 g) and the reaction mixture was heated to 145° C. for 15 minutes in a sealed microwave process vessel. The crude mixture was filtered through Celite, diluted with diethyl ether (200 mL) and washed with sodium hydroxide (2 M, 2×100 mL) and brine (1×100 mL). The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 3.4 g (26%) of the title compound as a black solid. NMR (500 MHz, DMSO-d6): 2.06 (s, 3H), 3.77 (s, 3H), 4.55 (s, 2H), 6.78 (d, 1H), 6.82 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[S:14]>C(#N)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:13]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[S:14])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ccc2nc(NC(=S)n3ccnc3)sc2c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To 6-methoxybenzo[d]thiazol-2-amine (0.53 g, 2.94 mmol) in acetonitrile (20 mL) was added 1,1′-thiocarbonyldiimidazole (0.681 g, 3.82 mmol). The reaction mixture was stirred at 65° C. for 24 hours. The precipitate was filtered and washed with acetonitrile (2×20 mL) to yield the product. The product was taken directly to the next step without any further purification or characterization.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][NH:19][C:20]2[CH:29]=[N:28][C:27]3[C:22](=[CH:23][C:24]([F:31])=[C:25]([F:30])[CH:26]=3)[N:21]=2)=[O:11])[CH:5]=1.[OH-].[Na+]>CO.O>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[F:31])[N:21]=[C:20]([NH:19][CH2:18][C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][N:12]1[C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:32])=[O:2])=[O:11])[CH:29]=[N:28]2
Reactant: COC(=O)c1cccc(C(=O)N2CCCC[C@H]2CNc2cnc3cc(F)c(F)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(C(=O)N2CCCC[C@H]2CNc2cnc3cc(F)c(F)cc3n2)c1
Reaction time: 12 h
Yield: 95.6 %

Procedure:
3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-benzoic acid methyl ester (0.5 g) was dissolved in methanol (15 ml) and treated with 1M sodium hydroxide (1.7 ml). The reaction mixture was stirred for 12 h, additional 1M sodium hydroxide (1.7 ml) added and stirring continued for a further 24 h The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 2M hydrochloric acid and extracted with ethyl acetate (×3). the combined organic phase was dried (MgSO4), fioltered and solvent removed at reduced pressure to give the title compound (0.463 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:22][O:21][N:20]([CH3:19])[C:15]([CH:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:14]1)=[O:17]
Reactant: CNOC
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (2.30 g, 9.78 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.14 g, 11.73 mmol) in THF (45 mL) was added EDCl (2.06 g, 10.76 mmol), HOBt (1.45 g, 10.76 mmol), N,N-diisopropylethylamine (5.11 mL, 29.33 mmol). The reaction was stirred at rt for 16 h. The mixture was partitioned between ethyl acetate (75 mL) and H2O (75 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude material was filtered through a plug of silica gel, eluting with 3:1 ethyl acetate/hexanes to afford 1.66 g (61%) of the desired product after concentration of the filtrate. ES-MS m/z 279.03 [M+H]+, HPLC RT (min) 3.07.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][C:22]1([CH3:25])[CH2:24][O:23]1>CN(C)C=O>[CH3:21][C:22]([OH:23])([CH3:25])[CH2:24][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)CO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 g, 7.73 mmol) and cesium carbonate (3.78 g, 11.60 mmol) in N,N-dimethylformamide (DMF) (17 mL) was added 2,2-dimethyloxirane (1.717 mL, 19.33 mmol) and the resulting mixture was stirred at 110° C. for 1 h under microwave irradiation then cooled to room temperature and filtered through celite (50 g). The insoluble material was washed with EtOAc (20 mL) and MeOH (20 mL). The combined filtrate and washings were concentrated in vacuo. Purification of the residue by flash chromatography using a 50 G silica cartridge (gradient: 0 to 100% (20% MeOH in DCM) in DCM) gave 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-2-propanol (2.10 g, 7.89 mmol, 102% yield) as a cream solid which was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@@H:49]([C:53](O)=[O:54])[CH:50]([CH3:52])[CH3:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:53](=[O:54])[C@@H:49]([CH:50]([CH3:51])[CH3:52])[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (1.27 g) and N-(9-fluorenylmethoxycarbonyl)-D-valine (1.00 g) were treated in the same manner as in Preparation Example 9 to obtain the title compound. Since impurities were unable to be removed from this compound, the compound was provided to the next step without purifying it.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=O)=[CH:5]2.[F:13][C:14]([F:31])([F:30])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:25][C@@H:24]3[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@@H:23]3[CH2:22]2)=[N:19][CH:20]=1.C(O)(=O)C.C([BH3-])#N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][NH:29][C@@H:26]1[C@@H:24]3[C@@H:23]([CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([C:14]([F:31])([F:30])[F:13])=[CH:20][N:19]=4)[CH2:25]3)[CH2:28][CH2:27]1)=[CH:5]2
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc2[nH]c(CN[C@H]3CC[C@@H]4CN(c5ccc(C(F)(F)F)cn5)C[C@@H]43)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared by combining 5-fluoro-1H-indole-2-carbaldehyde (30.1 mg, 0.184 mmol) and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine (50 mg, 0.184 mmol) from Example 262 Step B in dichloromethane (0.2 mL) to give a colorless solution. 0.2 mL of acetic acid was added. The reaction was stirred at ambient temperature for 30 minutes, then PS-cyanoborohydride (166 mg, 0.369 mmol) was added. After 18 hours, the reaction was filtered and the solvent was removed in vacuo. The crude material was purified using a 12 g silica gel cartridge eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 12.14 (s, 1H), 8.64 (dd, J=1.5, 0.7, 1H), 7.69 (dd, J=8.9, 2.5, 1H), 7.54-7.46 (m, 2H), 7.14-7.07 (m, 1H), 6.61 (d, J=1.2, 1H), 6.36 (d, J=8.9, 1H), 4.12-4.00 (m, 2H), 3.56 (ddd, J=21.0, 9.4, 3.4, 2H), 3.48-3.40 (m, 1H), 3.28 (ddd, J=3.7, 2.1, 0.9, 1H), 3.04 (dd, J=11.0, 5.8, 1H), 2.78-2.68 (m, 1H), 2.57-2.50 (m, 1H), 2.31-2.04 (m, 1H), 2.02-1.91 (m, 2H), 1.55-1.44 (m, 1H), 1.38-1.28 (m, 1H); MS (ESI+) m/z 419 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[H][H]>CO.[Pd]>[O:11]=[C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH2:14]1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:34]=[CH:35][CH:36]=[C:3]([C:2]([F:38])([F:37])[F:1])[CH:4]=1
Reactant: [H][H]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCNCC2)C1
Yield: 96.7 %

Procedure:
In a round-bottom flask, a slurry of benzyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-1-yl}piperidine-1-carboxylate (0.690 g, 1.30 mmol) and Palladium (10%) on Carbon (0.200 g) in methanol (10 mL) was purged with hydrogen gas for 2 min.; the reaction was then subjected to 1 atm of hydrogen gas for 3 h. The flask was purged with Argon, then the mixture was filtered and concentrated to afford N-(2-oxo-2-{[(3R)-1-piperidin-4-ylpyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide (0.501 g, 97%) as an off-white solid. 1H-NMR (CDCl3) δ: 1.32-1.53 (m, 2H), 1.52-2.04 (m, 6H), 2.15-2.40 (m, 2H), 2.40-2.70 (m, 3H), 2.80-3.00 (m, 3H), 4.00-4.20 (m, 2H), 4.42 (bs, 1H), 6.77 (m, 1H), 7.40-7.55 (m, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 8.08 (s, 1H). MS m/z: 399 (M+1).