Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[O:6][CH2:7][C:8]([OH:10])=O.Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CCN(CC)CC.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[O:6][CH2:7][C:8]([N:18]([O:19][CH3:20])[CH3:17])=[O:10]
Reactant: COc1ccc(OCC(=O)O)cc1OC
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(OCC(=O)N(C)OC)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.5 %

Procedure:
To a mixture of CHCl3 (100 mL) with 2-(3,4-dimethoxyphenoxy)acetic acid (4.244 g), N,O-dimethylhydroxyamine hydrochloride (2.341 g), WSC.HCl (4.984 g) and HOBt.H2O (3.513 g), Et3N (3.62 mL) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated, H2O (400 mL) was added, and the organic layer extracted with AcOEt (500 mL) was washed successively with saturated aqueous sodium dicarbonate (400 mL), water (400 mL) and brine (400 mL), dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt) to give the titled compound (4.01 g, pale brown oil.)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])O1.Br[C:22]1[N:30]2[C:25]([CH:26]=[N:27][C:28]([S:31][CH3:32])=[N:29]2)=[CH:24][C:23]=1[CH3:33]>>[CH3:33][C:23]1[CH:24]=[C:25]2[N:30]([C:22]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[N:29]=[C:28]([S:31][CH3:32])[N:27]=[CH:26]2
Reactant: CSc1ncc2cc(C)c(Br)n2n1
Reactant: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Product: CSc1ncc2cc(C)c(-c3ccccc3NS(C)(=O)=O)n2n1

Procedure:
N-[2-(6-Methyl-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide was prepared in an analogous fashion to Example 47a after: replacing 2-methoxybenzeneboronic acid with N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide, and replacing 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine with 7-Bromo-6-methyl-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine, to give after purification via normal phase chromatography (EtOAc/hexane as eluant) N-[2-(6-Methyl-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide as a yellow solid (0.12 g, 44%). LC/MS (E/I+) 349.04 (M+H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH3:22])([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12](=[O:14])[N:13]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.O>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH3:22])([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:18][CH2:17]2)[C:12](=[O:14])[N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CC2CCNCC2)SC(N[C@H]2CC3CCC2C3)=NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(CC2CCN(S(C)(=O)=O)CC2)SC(N[C@H]2CC3CCC2C3)=NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
To a solution of 2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-5-(piperidin-4-ylmethyl)thiazol-4(5H)-one (64 mg, 0.20 mmol) in CH2Cl2 (1.5 mL) was added methanesulfonyl chloride (Aldrich, 34 mg, 0.30 mmol) and triethylamine (60 mg, 0.60 mmol), and the reaction mixture was stirred at room temperature for ca. 18 h. Water (30 mL) was then added, and the crude product was extracted with CH2Cl2 (3×60 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, 0-3% MeOH in CH2Cl2) afforded the title compound as a white solid (34 mg). MS (ESI, pos. ion) m/z: 400 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[Cl:42]C(O[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=O.Cl.C(OCC)(=O)C>C(OCC)(=O)C.O>[ClH:42].[CH3:1][C:2]1([CH2:13][N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:22])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(CN2CCCN(C(=O)OCc3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of tert-butyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-homopiperazine-1-carboxylate prepared in Example 645 (250 mg, 0.655 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride (10 ml). To the solution, triethylamine (0.27 ml, 1.96 mmol) and benzyl chloroformate (0.19 ml, 1.31 mmol) were added followed by stirring at room temperature for 3 hours. To the reaction mixture, water was added, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=1/1) to afford a light yellow oil. The resulting oil was dissolved in ethyl acetate. To the solution, a saturated hydrochloric acid/ethyl acetate solution was added, and the precipitates were filtered off to afford benzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)homopiperazine-1-carboxylate hydrochloride (246 mg, yield 83%) as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:12][C:13]1[CH:21]=[C:20](F)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:39])=[C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=1.Cl>O>[Cl:12][C:13]1[CH:21]=[C:20]([N:36]2[CH2:35][CH2:34][N:33]([C:31]3[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=3[CH3:39])[CH2:38][CH2:37]2)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: Cc1ccc(F)cc1N1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)cc1N1CCN(c2cc(Cl)c(C(=O)O)cc2[N+](=O)[O-])CC1
Yield: 76.7 %

Procedure:
In a 20 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the potassium carbonate (201.60 mg, 1.46 mmol) was suspended in clean, dry N,N-dimethylformamide (2.00 ml, 25.83 mmol) and the 2-chloro-4-fluoro-5-nitro-benzoic acid 1b (160.10 mg, 0.73 mmol) was added to the reaction mixture and stirred until it appeared all the organic solid was taken up into solution. The 1-(5-fluoro-2-methyl-phenyl)-piperazine 16d (170.00 mg, 0.88 mmol) was added to the reaction and the reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere overnight. The reaction mixture was diluted with 10 ml of water and treated with 10 ml of 2N HCl. The product mixture was stirred until no further gas evolved and was then filtered under vacuum. The orange solid that was collected was washed with water and dried under high vacuum. The product, 2-chloro-4-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-5-nitro-benzoic acid 16e (222.30 mg, 0.56 mmol), was isolated as a yellow solid and was carried on without further purification. LCMS (m/e)=394 (M+H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH:1]1([NH:7][C:22]([C:21]2[CH:25]=[CH:26][N:27]=[CH:28][C:20]=2[NH:19][C:17]([C:15]2[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=[C:11]([CH:8]3[CH2:10][CH2:9]3)[N:16]=2)=[O:18])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(NC1CCCCC1)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 26 %

Procedure:
According to the general method described in step 3 of example 53, reaction of cyclohexylamine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (26%) as amorphous yellow solid.
Reaction SMILES: C(O)(=O)C.C(OC(=O)C)(=O)C.[CH:12]1([C:21]([OH:23])=[O:22])[CH:14]([C:15]([OH:17])=[O:16])[CH:13]1[C:18]([OH:20])=O>>[O:22]=[C:21]1[O:23][C:18](=[O:20])[CH:13]2[CH:12]1[CH:14]2[C:15]([OH:17])=[O:16]
Reactant: O=C(O)C1C(C(=O)O)C1C(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C1C2C(=O)OC(=O)C12
Yield: 82.9 %

Procedure:
Acetic acid (58.8 ml, 933 mmol) and acetic anhydride (20.4 ml, 185 mmol) were added to cyclopropane-1,2,3-tricarboxylic acid (24.4 g, 140 mmol), followed by reacting the mixture while heating under reflux for 2 hours, concentrating the reaction solution into a half volume, filtering off deposited crystals, washing them with heptane and drying under reduced pressure, to obtain 2,4-dioxo-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (18.1 g, 116 mmol, 83%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([NH:32][S:33]([C:36]1[S:37][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:40]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([C:18]4[CH:19]=[N:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)=[CH:39][CH:40]=1)(=[O:34])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cn1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.2) (0.448 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.414 g, 1.2 mmol) according to the general procedure III. Obtained as an off-white solid (0.45 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[C:7](Cl)(=[O:11])[C:8]([Cl:10])=[O:9]>>[C:1]([O:5][O:6][C:7](=[O:11])[C:8]([Cl:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)(C)OOC(=O)C(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl hydroperoxide (9.0 g; 0.1 mole) in petroleum spirit (80 ml) was added dropwise over a period of 1 hour to a stirred solution of oxalyl chloride (25.4 g; 0.2 mole) in petroleum spirit (80 ml) at a temperature of 0° C. On completion of the addition the reaction mixture was stirred for a further 3 hours at a temperature of 0° C. The solvent and excess oxalyl chloride were evaporated under reduced pressure at ice bath temperature to give tert-butylperoxyoxalyl chloride as a colourless oil (16.6 g; 92%) suitable for use in further preparations.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:19][OH:20])[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ON=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (74.9 g, 299.8 mmol) in methanol (900 mL) was added hydroxylamine hydrochloride (104 g, 1.49 mol) followed by sodium hydroxide (600 mL, 10% aqueous, 1.5. mol). The resultant suspension was heated to reflux for 2 hours and then cooled to room temperature. The mixture was concentrated in vacuo and the residue taken up in ether and water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by recrystallization from ethyl acetate-hexanes to provide 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (67.9 g, 86%) as a white solid. 1H NMR (CDCl3): δ 8.69 (s, 1 H), 7.71 (dd, 2 H), 7.53 (t, 1 H), 7.18–7.16 (m, 2 H), 7.03 (t, 2 H), 4.37 (s, 2 H); 19F NMR (CDCl3) δ −111.77; MS m/z 265 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=2)[CH2:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>CC(O)=O.CCOC(C)=O>[CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[C:7]([N+:12]([O-:14])=[O:13])=[C:6]([OH:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)nc(C2CC2)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(O)cc(C2CC2)nc1O
Temperature: 30 °C
Reaction time: 8 h
Yield: 514 %

Procedure:
6-Cyclopropyl-2,4-dihydroxy-pyridine (1 g, 6.6 mmol) was suspended in AcOH:EtOAc (4:1, 10 mL) at room temperature. The mixture was warmed to 30° C. and a small portion of fuming nitric acid (0.05 ml, 1.2 mmol) was added dropwise, keeping the temperature between 30 and 35° C. Upon addition the mixture became a clear solution. The remainder of the fuming nitric acid (0.25 ml, 6.3 mmol) was added dropwise. The clear solution was allowed to cool to room temperature upon which a precipitate started to form. The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with cold water and Et2O and dried in vacuo at room temperature over the weekend to give the title compound (1.21 g) as a yellow powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C3C(F)=C(F)C(F)=C(F)C=3F)=O)=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2].[CH3:33][NH2:34]>C1COCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:34][CH3:33])=[O:20])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2]
Reactant: CC(=S)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Yield: 80 %

Procedure:
A solution of 5-(S)-thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophe-nyl]oxazolidine-2-one (0.100 g, 0.209 mmol) in 2 M methylamine in THF (1.0 mL) was stirred at r.t. for 1 h. Solvent was removed under vacuum and the residue purified by PTLC (10% MeOH in DCM) to give the pure product as a white solid (0.054 g, 80%). M.p. 176-7° C. MS (m/z): [M+H]+=326.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=[CH:11][CH:12]([C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[CH:18][N:17]=1)[CH:13]1[CH2:15][CH2:14]1)[C:6](OCC)=[O:7])[CH3:2]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]2[C:16]([C:21]=1[CH3:22])=[C:12]([CH:13]1[CH2:15][CH2:14]1)[CH:11]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])[C:6]2=[O:7]
Reactant: CCOC(=O)C(=CC(c1nccc(Cl)c1C)C1CC1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 2-[2-(3-methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-ethylidene]-malonic acid diethyl ester (5.76 g, 16.4 mmol) in Dowtherm A (80 mL) was heated in a preheated oil bath at 230° C. for 15 min. The reaction mixture was cooled to room temperature and purified by flash silica column chromatography (hexane:ethyl acetate, 2:1 to 1:2) to afford the title compound as a yellow solid (3.76 g, 75%). ESI-MS m/z: 306 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ ppm: 9.34 (d, J=7.8 Hz, 1H), 8.40 (s, 1H), 7.12 (d, J=7.8 Hz, 1H), 4.41 (q, 2H), 3.00 (s, 3H), 2.28-2.33 (m, 1H), 1.42 (t, 3H), 1.03-1.08 (m, 2H), 0.71-0.76 (m, 2H).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11].NC1C=CC=CC=1C1C=CC=CC=1.C(#N)CC#N.O.[NH2:39][NH2:40]>>[NH2:11][C:10]1[C:9](=[N:8][NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]([NH2:13])=[N:40][N:39]=1
Reactant: N#CC(C#N)=NNc1ccccc1-c1ccccc1
Reactant: NN
Agent: Nc1ccccc1-c1ccccc1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 61 %

Procedure:
This compound was prepared using 123 mg (0.5 mmol) of 2-[(biphenyl-2-yl)hydrazono]-malononitrile, which was derived from 2-aminobiphenyl (169 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of the hydrazine hydrate then the solution cleared. Very little solid remained after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 85 mg (61%) of the title compound as an orange solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:23])[NH:17][C@@H:18]([C:20](F)=[O:21])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][C@H:18]([C:20](=[O:21])[NH:7][CH2:8][CH2:9][SH:10])[CH3:19])([CH3:12])([CH3:13])[CH3:14]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (139.5 mg, 1.66 mmol) in 8.1 mL water was added 2-aminoethanethiol hydrochloride (101.2 mg, 0.89 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25b (155.1 mg, 0.81 mmol) in 8.1 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 72.6 mg (36% from 24b) of clean 26b as a colorless oil.
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:21][C:22]1[CH:23]=[C:24]([C:31]#[N:32])[CH:25]=[N:26][C:27]=1[CH:28]1[CH2:30][O:29]1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:31]#[N:32])[CH:25]=[N:26][C:27]=1[CH:28]([OH:29])[CH2:30][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[C:10]2[C:11]([CH3:20])=[C:12]3[C:13](=[CH:18][CH:19]=2)[C:14](=[O:17])[O:15][CH2:16]3)[CH2:5][CH2:6]1
Reactant: N#Cc1cnc(C2CO2)c(Cl)c1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ncc(C#N)cc3Cl)CC2)ccc2c1COC2=O

Procedure:
5-Chloro-6-[1-hydroxy-2-[4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]pyridine-3-carbonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 58 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and 5-chloro-6-(oxiran-2-yl)pyridine-3-carbonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[CH:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:49])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24]1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([NH:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[CH:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:49])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24]1)=[O:21])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)[C@@H](COCc5ccccc5)NC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 83 %

Procedure:
By using N-tert-butyloxycarbonyl-O-benzyl-D-serine (600 mg, 2.03 mmol) and 3α-aminocholestane (866 mg, 2.23 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (1.13 g, yield; 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20]C=3)[CH2:11][CH2:10][C:9]=2[N:8]=1.FC1C=C(C=CC=1)OCC1C=CC2C(=O)NCCC=2[N:35]=1.BrC1C=CC(F)=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:35]=3)[CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: O=C1NCCc2nc(COc3cccc(F)c3)ccc21
Reactant: O=C1c2ccc(COc3cccc(F)c3)nc2CCN1c1ccc(F)cc1
Agent: Fc1ccc(Br)nc1
Product: O=C1c2ccc(COc3cccc(F)c3)nc2CCN1c1ccc(F)cn1

Procedure:
Prepared in a manner similar to the preceding example, 2-((3-fluorophenoxy)methyl)-6-(4-fluorophenyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one, using the common intermediate 2-((3-fluorophenoxy)methyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one as described above and 2-bromo-5-fluoropyridine. 1H NMR (400 MHz, CDCl3) δ 8.49 (1H, d, J=8), 8.32 (1H, d, J=3), 8.03 (1H, dd, J=9.2, 4.0), 7.60 (1H, d, 8), 7.54 (1H, dd, J=23, 8), 7.28 (1H, dd, J=16, 7.6), 6.80 (1H, dd, 7.6, 1.6), 6.74 (1H, ddd, J=23, 8.0, 1.6), 5.26 (1H, s), 4.41 (2H, t, J=6.8), 3.38 (2H, t, J=6.8); LC-MS (M+H)=368.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[NH2:15][CH:16]([C:19]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2=[CH:33][CH:34]=[CH:35][N:21]2[N:20]=1)[CH2:17][CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][NH:15][CH:16]([C:19]1[N:24]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23](=[O:32])[C:22]2=[CH:33][CH:34]=[CH:35][N:21]2[N:20]=1)[CH2:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(NCCC(C)(C)NC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
(1,1-Dimethyl-3-oxo-propyl)-carbamic acid tert-butyl ester (19 mg, 0.564 mmol) and 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 120 mg, 0.376 mmol) were stirred in CH3OH (10 mL) for 1 h at 25° C. The mixture was then treated with NaBH(OAc)3 (119 mg, 0.564 mmol) and stirred for 12 h at 25° C. The mixture was concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 30×100 mm column affording the desired material (100 mg, 57%) as a colorless oil: 13C NMR (CDCl3 100 MHz) δ 161.54, 154.93, 154.42, 144.72, 135.84, 129.53, 128.58, 127.27, 121.99, 117.28, 114.95, 111.94, 110.48, 79.81, 58.05, 51.12, 44.61, 43.07, 35.91, 28.17, 27.07, 26.53, 8.55; LC/MS (ESI+) 468 (M++H).