Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:46]1([C:52]2[CH:59]=[CH:58][CH:57]=[CH:56][C:53]=2[C:54]#[N:55])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C(Cl)Cl.C(N(CC)CC)C>[C:17]([O:16][C:14](=[O:15])[NH:13][CH:11]1[CH2:10][CH:9]([C:21]([N:49]2[CH2:48][CH2:47][N:46]([C:52]3[CH:59]=[CH:58][CH:57]=[CH:56][C:53]=3[C:54]#[N:55])[CH2:51][CH2:50]2)=[O:22])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
The mixture of 1-benzyl-4-tert-butoxycarbonylamino-pyrrolidine-2-carboxylic acid, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, N-hydroxybenzotriazole, 2-piperazin-1-yl-benzonitrile and triethylamine in DCM is stirred overnight. The crude product is purified to afford {1-benzyl-5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidine-3-yl}carbamic acid tert-butyl ester (41).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[N:6]=[CH:5][C:4]([C:3]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:25])=[CH:9][CH:8]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Reactant: C1COCCN1
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 85 %

Procedure:
As described for example 89, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (144 mg, 0.4 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, using morpholine instead of 2,2,2-trifluoroethylamine, to the title compound (142 mg, 85%) which was obtained as a white solid. MS: m/e=414.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=3[C:24]([O:26]C)=O)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=4[C:24]=3[OH:26])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccc(Cl)cc3n2)c(C(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2oc(-c3ccc4ccc(Cl)cc4n3)c(O)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a being cooled suspension of 7-chloro-2-[2,4-bis-(methoxycarbonyl)phenoxymethyl]quinoline (0.3 g) in N,N-dimethylformamide (6 ml), sodium hydride ((60% in mineral oil) 31 mg). After being stirred at same temperature for 30 minutes and successively at ambient temperature for 3 hours, the resulting mixture was poured into a mixture of ethyl acetate and buffer (pH 4.1). The appeared precipitates were collected by filtration and washed with n-hexane to give 7-chloro-2-(5-methoxycarbonyl-3-hydroxybenzofuran-2-yl)quinoline (0.15
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH:7]=[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH:8]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC(CCCCCCc1ccc2c(n1)NCCC2)c1ccccc1

Procedure:
To a stirred suspension of 10% palladium on carbon (15 mg) in ethanol (2 mL) was added a solution of 3-phenyl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoic acid tert-butyl ester 29-7a (62 mg) in ethanol (3 mL) and the mixture was subjected to an atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through Celite and concentrated at reduced pressure to give 29-8a as an oil.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[N:19]=[C:18]([N:20]2[C:28]3[C:23](=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:17]=[CH:16][N:15]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:12][S:13]([C:14]1[N:19]=[C:18]([N:20]2[C:28]3[C:23](=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:17]=[CH:16][N:15]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-n2ccc3c([N+](=O)[O-])cccc32)n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)c1nccc(-n2ccc3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A suspension of 3-chloroperoxybenzoic acid (77%, 3.11 g) in CHCl3 (40 mL) was slowly added at 0° C. under N2 to a mixture of 1-(2-methylsulfanylpyrimidin-4-yl)-4-nitro-1H-indole (3.93 g, 14.0 mmol) in CHCl3 (50 mL). The resulting mixture was allowed to warm up to RT, and stirred overnight. The reaction mixture was then diluted with DCM (200 mL) and washed with aqueous NaHCO3 (saturated). The resulting yellow precipitate was collected by filtration and dried under reduced pressure to give 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-nitro-1H-indole (2.36 g). The mother liquors were dried over Na2SO4, filtered and evaporated under reduced pressure to give a second aliquot (690 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]1=[O:17].[Br:18]NC(=O)CCC(N)=O>CN(C=O)C>[Br:18][C:7]1[NH:8][C:9]2[C:10](=[O:11])[N:2]([CH3:1])[C:3](=[O:17])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]=2[N:6]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCCCCn1c(=O)n(C)c(=O)c2[nH]cnc21
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)n(C)c(=O)c2[nH]c(Br)nc21
Reaction time: 18 h
Yield: 12.7 %

Procedure:
1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (0.06 g, 0.25 mmol) was dissolved in DMF (2 ml) and N-bromosuccinamide (0.045 g, 0.25 mmol) added. The mixture was stirred for 18 h, concentrated and the crude purified by eluting through an aminopropyl SPE (5 g) with first methanol then 5% acetic acid/methanol to elute product. The product was further purified by mass directed auto prep to yield the title compound as a white solid (0.01 g, 12%). NMR δH (400 MHz, d6-DMSO) 0.86 (t, 3H, J=7 Hz), 1.21-1.35 (m, 4H), 1.59-1.68 (m, 2H), 3.22 (s, 3H), 3.91 (t, 2H, J=7.5 Hz), 14.39 (br. s, 1H); m/z 315, 317 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([Cl:31])[CH:33]=3)=[CH:16][CH:15]=[C:14]([C:19]([F:21])([F:22])[F:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2N)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
To a mixture of 0.150 g (0.453 mmol) of (3′-amino-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (3 mL) is added 0.19 mL (1.4 mmol) of triethylamine followed by 0.069 mL (0.54 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight at room temperature then an additional 0.21 mL (1.6 mmol) of 3-chlorobenzoyl chloride is added and the mixture is stirred for an additional two days. The mixture is concentrated under reduced pressure and purified by flash silica gel chromatography to provide 0.23 g (quant.) of [3′-(3-chloro-benzoylamino)-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester.
Reaction SMILES: I.[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]1=[NH:13])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[N:13]\[C:27](=[O:28])[C:26]1[CH:30]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=1[O:31][CH3:32])[CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCCCn1c(C)c(C)sc1=N
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 1A (312 mg, 1 mmol) and triethylamine (0.42 mL, 3 mmol) in CH2Cl2 (15 mL) at 0° C. was added 5-chloro-2-methoxybenzoyl chloride (Waterstone, 205 mg, 1 mmol), the mixture was allowed to warm to room temperature and was stirred for 14 hours. The solution was washed sequentially with water, brine, dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.93 (t, J=7 Hz, 3H), 1.35 (sextet, J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 2.21 (s, 3H), 2.26 (s, 3H), 3.78 (s, 3H), 4.26 (t, J=7 Hz, 2H), 7.10 (d, J=9 Hz, 1H), 7.44 (d-d, J=9 Hz, 3 Hz, 1H), 7.70 (d, J=3 Hz, 1H); MS (ESI+) m/z 353 (M+H)+.
Reaction SMILES: [CH2:1]([Si]1(Cl)N(C)[C@@H](C)[C@H](C2C=CC=CC=2)O1)[CH:2]=[CH2:3].[CH:18](=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CCOC(C)=O>C1(C)C=CC=CC=1>[C:21]1([CH2:20][CH2:19][C@@H:18]([OH:27])[CH2:3][CH:2]=[CH2:1])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CCCc1ccccc1
Reactant: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CC[C@H](O)CCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Enantioselective allylation of dihydrocinnamaldehyde to give (3R)-1-phenyl-hex-5-en-3-ol: To a cooled (−10° C.) solution of (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (380 mg, 1.5 mmol) in toluene (5 mL) was added dihydrocinnamaldehyde (1.0 mmol). The reaction mixture was maintained at −10° C. for 2 h. To this cooled solution was added 1N HCl (4 mL) and EtOAc (4 mL) and the mixture was vigorously stirred for 15 min. The layers were separated and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organics were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give (3R)-1-phenyl-hex-5-en-3-ol in 84% yield and 88% enantiomeric excess (ee).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.B(Cl)(Cl)Cl.O>ClCCl>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]2[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(Cc2cccnc2OC)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cc2ccc[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
To a solution of mesityl bromide (0.77 g) in tetrahydrofuran(2.6 mL) was added tert-butyllithium (1.48 mol/L solution in pentane, 5.3 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 1 hour. To the reaction mixture was added a solution of 2-methoxypyridine (0.33 g) in tetrahydofuran (3 mL). The temperature was raised to 0° C., and the mixture was stirred for 1 hour. The temperature was raised to room temperature, and the reaction mixture was stirred for additionally 1 hour. To the reaction mixture was added a solution of 4-methoxybenzaldehyde (0.57 g) in tetrahydrofuran (4.2 mL), and the mixture was stirred for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1-2/1) to give 4-methoxyphenyl 2-methoxypyridin-3-yl methanol (0.43 g). To a solution of the obtained 4-methoxyphenyl 2-methoxypyridin-3-yl methanol (0.41 g) in acetic acid (2.1 mL) was added 10% palladium carbon powder (0.21 g), and the mixture was stirred for 10 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1-4/1) to give 2-methoxy-3-(4-methoxybenzyl)-pyridine (0.29 g). To a solution of the obtained 2-methoxy-3-(4-methoxybenzyl)pyridine (0.023 g) in dichloromethane (0.5 mL) was added boron trichloride (1 mol/L solution in dichloromethane, 0.06 mL) at 0° C. The temperature was raised to room temperature, and the mixture was stirred for 1 hour. After boron trichloride (1 mol/L solution in dichloromethane, 0.06 mL) was added to the reaction mixture, the mixture was stirred for additionally 15 hours. To the reaction mixture was added water, and the mixture was extracted with a mixture of dichloromethane and ethanol (10/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=8/1) to give 3-(4-methoxy-benzyl)-1H-pyridin-2-one (0.0017 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13](=[O:14])[N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH:7]3[C:6]=2[N:15]=1.[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl.CCN(C(C)C)C(C)C>[Br:16][C:17]1[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:18]=1[S:27]([N:11]1[CH2:10][CH2:9][N:8]2[C:13](=[O:14])[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[N:15][C:6]=3[CH:7]2[CH2:12]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: Cc1ccc2c(n1)C1CNCCN1C2=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(n1)C1CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN1C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To the solution of 2-methyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (may be prepared as described in Intermediate 8; 100 mg) in dichloromethane (3.5 ml), DIPEA (0.129 ml) was added under argon atmosphere at room temperature then 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (159 mg) was added at 0° C., and then the ice water bath was removed and the reaction mixture allowed to stir at room temperature for 3 h. The reaction mixture was partitioned between DCM (40 ml) and (20 ml) sodium bicarbonate. The organic phase was washed with sodium bicarbonate (20 ml), HCl (2×20 ml) and water (2×20 ml) and then it was dried using phase separator before the DCM was removed under vacuum to give the title compound (170 mg), which was used in next step without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:18][C:19](=[O:28])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.[NH:29]([CH3:31])[CH3:30].CCN(CC)CC>C1COCC1>[CH3:30][N:29]([CH2:2][C:3]1[N:4]=[C:5]([NH:18][C:19](=[O:28])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH3:31]
Reactant: O=C(Nc1nc(CCl)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Into a solution of Compound 70 (50 mg, 0.12 mmol) in 5 mL of THF was added NH(Me)2 (40% solution in water, 0.1 mL) and NEt3 (0.1 ml) at room temperature. The solution was stirred at room temperature for 1 hour. The solution was washed with 5 mL of water and dried (Na2SO4), filtered and concentrated. The residue was purified on silica (eluted with 5-100% ethyl acetate in hexane) to give Compound 71 (44 mg, 84%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:32])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:37][C:38]([NH:40][C:41]1[S:45][C:44]([C:46]2[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=2[F:53])=[N:43][C:42]=1[C:54](O)=[O:55])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:54]([C:42]3[N:43]=[C:44]([C:46]4[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=4[F:53])[S:45][C:41]=3[NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])=[O:55])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:22])([F:21])[F:23])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
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: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 45 °C
Reaction time: 14 h

Procedure:
To a mixture of 3-amino-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (86.6 mg, 0.189 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (89.5 mg, 0.251 mmol), and HATU (221.8 mg, 0.5833 mmol) was added DMF (2.0 mL) followed by DIPEA (164.3 mg, 1.271 mmol). The reaction mixture was stirred at 45° C. for 14 h, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark semi-oil (110.3 mg, 73%). LCMS calc. for C36H42F5N6O7S (M+H)+: m/z=797.3. found 797.3.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[N:11]=1.Cl>O.CO>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:11]=1
Reactant: COC(=O)CCCCc1noc(-c2ccccc2O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCc1noc(-c2ccccc2O)n1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
Add boron tribromide (4.9 mL, 51.7 mmol) dropwise to a stirred solution of methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.0 g, 10.3 mmol) in methylene chloride (70 mL) at 0° C. under nitrogen. Allow to warm to room temperature and stir for 5 hours. Cool the mixture to 0° C., add methanol (20 mL) dropwise and allow to warm to room temperature. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:9), to provide methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate, which is used without further purification. Add a solution of sodium hydroxide (800 mg, 20 mmol) in water (15 mL) to a solution of methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (2.6 g, 9.4 mmol) in methanol (30 mL) at room temperature and stir the mixture for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (2×150 mL). Wash the combined organic extracts with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by vacuum filtration to afford the title compound (2.4 g, 89% over two steps). APCI MS m/z 261 [C13H14N2O4—H]−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.Cl.[CH3:11][NH:12][O:13][CH3:14].CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:9]
Reactant: CNOC
Reactant: O=C(O)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCOCC1
Temperature: 29 °C
Reaction time: 24 h
Yield: 59.2 %

Procedure:
To a suspension of tetrahydro-2H-pyran-4-carboxylic acid (9.0 g, 69.2 mmol) in CH2Cl2 (300 mL) was added N,O-dimethylhydroxylamine hydrochloride (8.05 g, 83.0 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (20.0 g, 103.8 mmol) and triethylamine (17.5 g, 173.0 mmol) at 29° C. under N2. The reaction was stirred at 29° C. for 24 hrs. Then the mixture was filtered and the filtrate was washed with 1M HCl and saturated aqueous NaHCO3. The organic layer was concentrated in vacuo to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (7.1 g, 59.7%) as a yellow oil. 1H NMR (CDCl3, 400 M Hz) δ 4.02-3.98 (m, 2H), 3.69 (s, 3H), 3.47-3.41 (m, 2H), 3.17 (s, 3H), 2.90 (t, J=11.6 Hz, 3H), 1.90-1.82 (m, 2H), 1.81-1.62 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]1[CH2:17][CH2:16]1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>C(O)C>[CH:21]1([NH:24][C:2]2[C:10](=[O:11])[C:9]3[N:8]([CH3:12])[N:7]=[CH:6][C:5]=3[C:4](=[O:13])[C:3]=2[N:14]([C:18](=[O:20])[CH3:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:23][CH2:22]1
Reactant: CC(=O)N(C1=C(Cl)C(=O)c2c(cnn2C)C1=O)C1CC1
Reactant: NC1CC1
Solvent: CCO
Product: CC(=O)N(C1=C(NC2CC2)C(=O)c2c(cnn2C)C1=O)C1CC1

Procedure:
6-Chloro-5-(N-acetyl-N-cyclopropylamino)-1-methyl-1H-indazole-4,7 -dione (2 grams prepared as in Example III) and cyclopropylamine (2 grams) in ethanol (25 milliliters) were heated together under reflux for 10 minutes. The solvent was then removed under reduced pressure and the residual red oil purified by chromatography on alumina using methylene chloride as eluant to yield the desired product having a melting point of 75°-78° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=O>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1]/[C:11](/[CH3:13])=[CH:10]\[C:9]([O:15][CH3:16])=[O:14]
Reactant: Cc1ccccc1N
Reactant: COC(=O)CC(C)=O
Product: COC(=O)/C=C(/C)Nc1ccccc1C
Reaction time: 8 h

Procedure:
In a manner similar to that previously described, 96.4 grams (0.9 mole) of o-toluidine is added dropwise to a solution of 116 grams (1 mole) of methyl acetoacetate and the reaction mixture allowed to stand overnight to obtain methyl 3-(2-methylphenyl)aminocrotonate.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:21].OS(O)(=O)=O>CC(O)=O.O>[OH:21][CH:20]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:10]=2)[C:15]1=[O:19]
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1nccs1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(OCCn3ccnc3)cc2CCC1C(O)c1nccs1
Yield: 74.6 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with 2-formylthiazole (0.107 g, 0.94 mmol) in a mixture of HOAc (1 mL) and concentrated H2SO4 (0.100 mL) at room temperature overnight. The resulting biphasic reaction mixture was diluted with water and then extracted with EtOAc. The aqueous portion was made to pH 10 with 50% NaOH and extracted with EtOAc (3×50 mL). The pooled organic extracts were washed well with water, dried, filtered, and concentrated to afford 0.215 g (74%) of the title compound as a golden oil: APCI-MS m/e 370.2 (M+ +1).