Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]([NH2:14])[CH3:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([CH3:18])=O>ClCCCl>[CH:16]([NH:14][CH:12]([C:9]1[NH:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:13])([CH3:18])[CH3:15]
Reactant: CC(N)c1nc(-c2ccccc2)c[nH]1
Reactant: CC(C)=O
Solvent: ClCCCl
Product: CC(C)NC(C)c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.20 g, 1.07 mmol) and acetone (0.062 g, 1.07 mmol) were mixed in 1,2-dichloroethane (4 mL), followed by the addition of NaBH(OAC)3 (0.34 g, 1.61 mmol). The resulting mixture was stirred at rt for 3 h. The reaction was quenched with saturated NaHCO3 solution. The mixture was extracted with EtOAc and the combined extracts were dried over Na2SO4. Filtration followed by evaporation to dryness under reduced pressure yielded crude isopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine, which was used for the next reaction without further purification.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[N+]([O-])([O-])=O.[Na+].[F:15][P-](F)(F)(F)(F)F.[H+]>Cl.O>[F:15][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ccc(N)cn1
Reactant: F[P-](F)(F)(F)(F)F
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [H+]
Solvent: O
Product: COc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
5-amino-2-methoxypyridine (81.5 g, 0.657 mol) was dissolved in a mixture of concentrated hydrochloric acid (120 ml) and water (530 ml). A solution of sodium nitrate (56.5 g, 0.819 mol) in water (100 ml) was added at −5° C. to the solution. The reaction mixture was stirred for 45 minutes at room temperature and sodium nitrate (56.5 g, 0.819 mol) was further added thereto. Hexafluorophosphoric acid (132 ml) was added to the reaction mixture, which was then stirred for 20 minutes at room temperature. The reaction mixture was filtered to obtain a solid, which washed with water and ethyl ether and then dried under reduced pressure. The resulting compound was heated for 15 minutes at 150° C., dissolved in dichloromethane, and then washed with 3N sodium hydroxide solution. The organic layer was dried on anhydrous magnesium sulfate, concentrated under reduced pressure, and then fractionally distilled to give 22.6 g of the titled compound as colorless oil. (Yield: 27%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[C:19](=[O:24])[O:20][C@@H:21]([CH2:22][OH:23])[C@H:14]1[CH2:13][CH2:12]2)C1C=CC=CC=1.O>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[C:19](=[O:24])[O:20][C@@H:21]([CH2:22][OH:23])[C@H:14]1[CH2:13][CH2:12]2
Reactant: O=C1O[C@@H](CO)[C@H]2CCc3cc(OCc4ccccc4)ccc3N12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C1O[C@@H](CO)[C@H]2CCc3cc(O)ccc3N12
Yield: 50.8 %

Procedure:
3.0 g (9.2 mmol) of trans-7-benzyloxy-3-hydroxymethyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one, dissolved in 20 ml of ethanol and 40 ml of tetrahydrofuran, are hydrogenated for 1 h in the presence of 1 g of 10% palladium-on-charcoal containing 50% of water. The mixture is then filtered on silica and the solvent is evaporated off under reduced pressure. 1.1 g of product are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=1)[CH2:9]2.[H][H]>C(O)C.[Pd]>[CH3:30][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:19][CH:18]=1)[CH2:9]2
Reactant: CN(C)CC#Cc1ccc2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCCc1ccc2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Yield: 91 %

Procedure:
A solution of 5-(3-dimethylamino-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.055 g, 0.14 mmol) in ethanol (25 mL) was treated with 10% palladium on carbon (15 mg). The mixture was shook vigorously under 45 p.s.i. hydrogen for 3 h. The resulting reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure. Silica gel column chromatography of the resulting material using 5:1 CHCl3-MeOH afforded 5-(3-dimethylamino-propyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.051 g, 83%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.85 (m, 2H), 2.27 (s, 6H), 2.36 (t, 2H), 2.74 (t, 2H), 4.25 (s, 2H), 4.76 (s, 2H), 6.92-7.36 (m, 11H), 7.80 (d, 1H). GC-MS: 400 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]([C:13]3[C:14]([C:41]([CH3:49])([CH3:48])[O:42][SiH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[C:15]([C:19]4[CH:20]=[C:21]([NH:26][C:27]5[CH:32]=[CH:31][C:30]([C:33]([N:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)=[O:34])=[CH:29][N:28]=5)[C:22](=[O:25])[NH:23][CH:24]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:8][CH2:7][C:6]=2[CH:50]=1.Cl.[C:52]([O-])([O-])=O.[Na+].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:11])(=[O:12])[N:9]([C:13]3[C:14]([C:41]([CH3:49])([CH3:48])[O:42][SiH2:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[C:15]([C:19]4[CH:20]=[C:21]([NH:26][C:27]5[CH:32]=[CH:31][C:30]([C:33]([N:35]6[CH2:36][CH2:37][O:38][CH2:39][CH2:40]6)=[O:34])=[CH:29][N:28]=5)[C:22](=[O:25])[N:23]([CH3:52])[CH:24]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:8][CH2:7][C:6]=2[CH:50]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(-c2c[nH]c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cn3)c2)cccc1N1CCc2cc(Br)ccc2S1(=O)=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2cccc(N3CCc4cc(Br)ccc4S3(=O)=O)c2C(C)(C)O[SiH2]C(C)(C)C)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of 5-[3-(6-Bromo-1,1-dioxo-3,4-dihydro-1H-1lambda*6*-benzo[e][1,2]thiazin-2-yl)-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (0.05 g, 0.06 mmol), conc. HCl (1 mL) in methanol (10 mL) was stirred rt for 30 min. The mixture was neutralized with solid Na2CO3 and concentrated to afford a dark residue. Purification by silica gel chromatography (methylene chloride/acetone) afforded 0.01 g of 5-[3-(6-bromo-1,1-dioxo-3,4-dihydro-1H-1lambda*6*-benzo[e][1,2]thiazin-2-yl)-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one as a pale solid MS (ESI) 682.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH:30]4[CH2:32][CH2:31]4)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC>C1(C)C=CC=CC=1.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>[CH:30]1([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:13]([C:10]3[NH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH:33]=[CH2:34])=[CH:7][N:6]=4)=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH2:32][CH2:31]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1)C1CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 5-bromo-2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in toluene (2 mL) were added tributyl(vinyl)tin (115 μL) and tetrakistriphenylphosphinepalladium(0) (40 mg), and the mixture was stirred under argon atmosphere at 110° C. overnight. After cooling to room temperature, the reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography. The title compound (120 mg, yield 67%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 463 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:39][CH3:40])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]1[C@@H:9]([NH:16][C:17]([C:19]2[S:20][C:21]([CH2:39][CH3:40])=[C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[C:31]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:30]=[N:29][C:28]=34)[CH:23]=2)=[O:18])[C:10]([F:14])([F:15])[CH2:11][CH2:12][CH2:13]1
Reactant: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OCC(F)(F)F)cnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1sc(C(=O)N[C@@H]2[C@H](N)CCCC2(F)F)cc1-c1cnn2cc(OCC(F)(F)F)cnc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
tert-Butyl{(1R,2R)-2-[({5-ethyl-4-[6-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]thiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamate (34.0 mg, 0.056 mmol) was dissolved in dichloromethane (1.0 mL) and trifluoroacetic acid (0.100 mL, 1.30 mmol) was added. The reaction was stirred at 40° C. for 2 h. The reaction mixture was quenched with 1N KOH in MeOH and concentrated under reduced pressure. The residue was mixed with water and extracted 3× with dichloromethane. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-20% MeOH/DCM) to give the title compound (23.0 mg, 0.046 mmol). LRMS (APCI) calc'd for (C21H22F5N5O2S) [M+H]+, 504.1; found 504.0. 1H NMR (CDCl3, 500 MHz) δ 8.48 (s, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.03 (s, 1H), 4.52 (m, 1H), 4.43 (d, J=7.8, 2H), 3.36 (s, 1H), 2.96 (q, J=7.2, 2H), 2.17 (s, 1H), 1.48-2.02 (m, 5H), 1.33 (t, J=7.3, 3H).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]3[C:22]([CH:23]=[O:24])=[CH:21][N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1>CCOCC>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]3[C:22]([CH:23]([CH2:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[OH:24])=[CH:21][N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)sc1ncc(C=O)n12
Reactant: BrCCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc2c(c1)sc1ncc(C(O)CCc3ccccc3)n12

Procedure:
Magnesium (0.146 g) in anhydrous ether (15 mL) was treated with (2-bromoethyl)benzene (0.82 mL) and reacted for 2.5 hours. Solid 7-Methoxy-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3) (0.46 g) was added and reacted for 24 hours. The reaction mixture was quenched with 5% ammonium chloride solution and product was extracted into ethyl acetate. Drying and evaporation of solvent gave crude 7-Methoxy-α-(2-phenylethyl) imidazo[2,1-b]benzothiazole-3-methanol (Formula M-4) which was recrystallized from acetonitrile solution to provide pure 7-Methoxy-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol (Formula M-4) (0.60 g), m.p. 166-167°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:45]([O:52][C:53](=[O:74])[C@H:54]([CH2:70][CH2:71][S:72][CH3:73])[NH:55][C:56](=[O:69])[C@H:57]([CH2:59][C:60]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[NH:62][CH:61]=1)[NH2:58])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[CH2:45]([O:52][C:53](=[O:74])[C@H:54]([CH2:70][CH2:71][S:72][CH3:73])[NH:55][C:56](=[O:69])[C@H:57]([CH2:59][C:60]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[NH:62][CH:61]=1)[NH:58][C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)O
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
10.0 Parts N-t-butoxycarbonyl-L-tyrosylglycylglycine and 2.4 parts N-methylmorpholine are dissolved in 125 parts dimethylformamide and cooled to -15° C. Then 3.8 parts isobutyl chloroformate is added dropwise over a 30 minute period while maintaining the temperature at -15° C. Then, a solution of 12.7 parts L-tryptophyl-L-methionine benzyl ester hydrochloride in 50 parts dimethylformamide is slowly added at -15° C. and the mixture is stirred at this temperature for 30 minutes. The cooling apparatus is removed and the mixture is stirred at ambient temperature for an additional 2 hours. The product is isolated by diluting the reaction mixture with 10 volumes water and extracting with ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure. Purification of the residue by low pressure column chromatography affords N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-tryptophyl-L-methionine benzyl ester.
Reaction SMILES: [N+:1]([C:4]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[Br:17]Br>[Zn].CC(O)=O>[Br:17][C:7]1[CH:8]=[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([NH2:1])=[N:5][CH:6]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ncccc1Sc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1Sc1ccccc1
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
A 500 mL flask was charged with 2-nitro-3-(phenylthio)pyridine (16.3 g, 70.2 mmol) and AcOH (250 mL) and cooled in a water bath. Zinc (22.9 g, 351 mmol) was slowly added and stirred for 5 minutes. The reaction was filtered through celite and the cake washed with CH2Cl2. The CH2Cl2 was removed in vacuo and solution reacted with slow addition of bromine (3.6 mL, 70.2 mmol). After 10 minutes, the HOAc was removed in vacuo and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (1.5 L SiO2 and 30% EtOAc in hexanes) to afford the title compound (18.2 g, 92.21% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]CC)=O)=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[NH4+:31].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:31])=[O:27])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cncc(Cl)c3)nc3c2CCC3)cc1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(-c3cncc(Cl)c3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 48.7 %

Procedure:
A 10-mL vial was charged with ethyl 2-(4-((2-(5-chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.060 g, 0.13 mmol) and ammonium chloride (0.022 g, 0.40 mmol) in methanol (3 mL). To this mixture was added NH3 (3.9 mL, 7N in methanol, 27.0 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 72 h. After this time, the mixture was concentrated under reduced pressure and the residue purified by preparative HPLC (water/acetonitrile with 0.05% TFA) followed by chromatography on silica using dichloromethane/(90:10:0.25 dichloromethane/methanol/aqueous NH4OH) (10:0 to 0:10) as eluent to afford 2-(4-((2-(5-chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide (0.024 g, 48%) as a white solid. MW=378.85. 1H NMR (CD3OD, 300 MHz) δ 8.77 (d, J=1.8 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.20 (t, J=2.1 Hz, 1H), 7.36-7.30 (m, 2H), 7.27-7.21 (m, 2H), 7.15 (s, 1H), 3.52 (s, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.19 (quin, J=7.5 Hz, 2H). MS: ESI, m/z 379 [M+H]+. Treatment with 1.25 M HCl in methanol (0.25 mL, 0.31 mmol) afforded the title compound (0.026 g, 99%) as a yellow solid. MW=415.32. M.p. 193-195° C. 1H NMR (DMSO-d6, 500 MHz) δ 14.32 (br s, 1H), 9.85 (br s, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.43 (t, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.40-7.32 (m, 4H), 7.14 (s, 1H), 6.91 (s, 1H), 3.42 (s, 2H), 3.17 (t, J=7.0 Hz, 2H), 2.95 (t, J=7.0 Hz, 2H), 2.25 (quin, J=7.5 Hz, 2H); ESI MS m/z 379 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:29])[C@H:7]([NH:14][C:15]([C:17]1[N:18]=[C:19]([Cl:28])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH2:8][O:9]C(C)(C)C)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:28][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]([OH:27])=[C:17]([C:15]([NH:14][C@H:7]([CH2:8][OH:9])[C:6]([OH:29])=[O:5])=[O:16])[N:18]=1
Reactant: CC(C)(C)OC[C@@H](NC(=O)c1nc(Cl)c2ccccc2c1O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H](CO)C(=O)O)c1nc(Cl)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 144.8 %

Procedure:
A mixture of 27 mg (0.06 mmol) of (R)-3-tert-Butoxy-2-[(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-propionic acid tert-butyl ester and 2 ml of trifluoroacetic acid was stirred for 2 h at ambient temperature. Then the excess trifluoroacetic acid was evaporated in vacuo, the residue dissolved in 2 ml of absolute ethanol and the solution was concentrated in vacuo to give a tan solid. 27 mg of the title compound was obtained; MS-(+)-ion: M+1=310.9 amu.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[CH2:1]([S:5]([NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
6.3 g of n-butanesulfonyl chloride was added under ice cooling to 5.61 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and 4.1 g of triethyl amine suspended in 50 ml of chloroform, and the mixture was stirred for 1 hour. Diluted hydrochloric acid was added to the reaction mixture, the chloroform layer was collected by separation, washed and dried, and then the solvent was removed. The resulting crystals were recrystallized from tetrahydrofuran-isopropyl ether to obtain 6.40 g of 2-n-butylsulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.OO.C([O-])([O-])=[O:37].[K+].[K+].O>CS(C)=O.CCOC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:37])=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(C(N)=O)cn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Yield: 47.1 %

Procedure:
6-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile (50 mg, 0.11 mmol) and H2O2 (0.04 mL, 30%), K2CO3 (6.27 mg, 0.046 mmol) in DMSO (0.39 mL) was stirred overnight at room temperature. The reaction was added water and EtOAc. The layer was separated. The organic phase was washed with brine and dried, concentrated to give the product (9.95 mg, 19%) LC-MS Method 2 tR=1.083, m/z=460.1; 1H NMR (CD3OD) 1.21 (m, 1H), 1.51 (d, 3H), 1.53-1.64 (m, 1H), 1.85-1.94 (m, 2H), 2.10-2.21 (m, 1H), 2.29 (m, 1H), 2.42 (m, 1H), 3.03 (m, 1H), 3.39 (t, 2H), 5.52 (m, 1H), 6.99 (d, 2H), 7.21-7.34 (m, 5H), 7.22 (d, 2H), 7.31 (d, 1H), 8.22 (d, 1H), 8.98 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH2:23])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1.[C:28]1([C:34]2[O:35][C:36]([C:42]([F:45])([F:44])[F:43])=[C:37]([C:39](O)=[O:40])[N:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH:23][C:39]([C:37]4[N:38]=[C:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:35][C:36]=4[C:42]([F:44])([F:45])[F:43])=[O:40])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1
Reactant: COCCN1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCCN1CCN(Cc2cnc3sc(-c4ccccc4NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)nc3c2)CC1

Procedure:
The title compound was prepared according to amide synthesis general method B, utilizing 2-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 2-phenyl-5-(trifluoromethyl)oxazole-4-carboxylic acid (1.5 eq). The product was filtered from the crude reaction mixture, evaporated with methanol, and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2) and by prep HPLC. MS Calcd for C31H29F3N6O3S: 622.20. Found (M+H)+ m/z=623.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[Br:7][C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1>>[Br:7][C:8]1[CH:9]=[C:10]([C:14]([OH:16])([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:15])[CH:11]=[CH:12][CH:13]=1
Reactant: CCCC[Mg]Cl
Reactant: CC(=O)c1cccc(Br)c1
Product: CCCCC(C)(O)c1cccc(Br)c1

Procedure:
Grignard coupling of butylmagnesium chloride with 1-(3-bromophenyl)ethanone followed by flash chromatography (0-25% ethyl acetate/hexanes gradient), gave 2-(3-bromophenyl)hexan-2-ol as a yellow oil. Yield (0.99 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.59 (t, J=2.0 Hz, 1H), 7.30-7.37 (m, 2H), 7.19 (t, J=8.0 Hz, 1H), 1.70-1.84 (m, 2H), 1.52 (s, 3H), 1.64 (brs, 1H), 1.18-1.30 (m, 3H), 1.02-1.14 (m, 1H), 0.84 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:11]2=[O:22])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:24][OH:25].N1C=CC=CC=1.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:11]2=[O:22])=[CH:6][C:3]=1[CH:4]=[N:24][OH:25]
Reactant: NO
Reactant: Cc1ccncc1N1CCN(c2ccc(F)c(C=O)c2)C1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccncc1N1CCN(c2ccc(F)c(C=NO)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde (I-113a: 230 mg, 0.769 mmol), hydroxylamine hydrochloride (160 mg, 2.307 mmol) and pyridine (5 mL) were taken in a reaction flask and the flask was stirred at room temperature for 18 hours under nitrogen atmosphere. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The organic layer was dried over Na2SO4 and concentrated. The concentrate was washed with diethyl ether and decanted to afford 170 mg of 2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde oxime (70.8% yield).