Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SC)=[NH:8].[CH2:11]([N:13]([CH2:27][CH3:28])[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][S:19][C:18]2[CH:22]=[C:23]([NH2:26])[CH:24]=[CH:25][C:17]1=2)[CH3:12]>CCO>[CH2:27]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][S:19][C:18]2[CH:22]=[C:23]([NH:26][C:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)=[NH:8])[CH:24]=[CH:25][C:17]1=2)[CH3:28]
Reactant: CCN(CC)CCN1CCSc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CCN(CC)CCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl thiophene-2-carbimidothioate hydroiodide (2.266 g, 7.94 mmol) was added to a mixture of 4-(2-(diethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (1.054 g, 3.97 mmol) in EtOH (20 mL). The mixture was stirred for 2 days at room temperature. The reaction was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with CH2Cl2 (50 mL). The aqueous phase was washed with CH2Cl2 (50 mL). The combined organic fractions were washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (CH2Cl2 followed by 3.5% (2M NH3 in MeOH):CH2Cl2). The collected fractions were concentrated, and the sample was subjected again to flash chromatography on silica gel (2.5% MeOH:CH2Cl2). The collected fractions were concentrated to give compound 15 as a brown solid. (1.23 g, 83%). 1H NMR (CDCl3) δ 7.40-7.36 (m, 2H), 7.05 (dd, J=3.9, 4.8 Hz, 1H), 6.73 (m, 3H), 3.65-3.61 (m, 1H), 3.39 (t, J=7.2 Hz, 2H), 3.05-3.02 (m, 2H), 2.67-2.54 (m, 6H), 1.04 (t, J=7.2 Hz, 6H); ESI-MS (m/z, %): 377, 375 (MH+, 35), 278, 276 (100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C
Yield: 19 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (106 mg, 0.312 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (77 mg, 0.377 mmol), 4 N HCl in dioxane (94 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 2 hours. Let reaction cool to room temperature and evaporated off solvent. Purified with normal phase chromatography to yield a white solid (30 mg, 19%), N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide. mp 170-185° C.; LCMS: m/z=507.33 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.58 (d, 1H, J=9.6 Hz), 7.30 (m, 4H), 6.87 (dd, 1H, J=8.6, 2.3 Hz), 5.79 (m, 1H), 3.80 (m, 1H), 3.27 (m, 1H), 2.78 (m, 3H), 2.31 (m, 2H), 2.13 (m, 4H), 1.78 (m, 2H), 1.36 (m, 10H).
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][NH2:21])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(OC)=[O:2].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]2[CH2:11][CH:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:1](=[O:2])[NH:21][CH2:20][C:13]=2[CH:14]=1
Reactant: COC(=O)CC(Cc1ccc(OC)cc1CN)C(=O)OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC1Cc2ccc(OC)cc2CNC1=O
Yield: 76 %

Procedure:
A solution of methyl (±)-3-carbomethoxy-4-[2-(aminomethyl)-4-methoxyphenyl]butanoate (10 g, 24 mmol) and triethylamine (17 mL, 120 mmol) in toluene (100 mL) was heated at reflux for 18 hr. The reaction was then concentrated and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated to afford the title compound (4.8 g, 76%) as tan solid: MS (ES) m/e 264.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])=[CH:6][N:5]=[C:4]([CH:16]=O)[CH:3]=1.[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:18][C:19]([S@:22](/[N:24]=[CH:16]/[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])=[CH:6][N:5]=1)=[O:23])([CH3:21])[CH3:20]
Reactant: Cc1cc(C=O)ncc1OCC(F)(F)C(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(F)(F)C(F)F
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (1.38 g, pale yellow solid) from 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinaldehyde (1.20 g, 4.79 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (872 mg, 7.19 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH2:8][C@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:4][C:5]([OH:7])=[O:6].[CH3:13]C#N>>[NH2:1][CH2:2][C@@H:3]([CH2:8][C@@H:9]([CH3:12])[CH2:10][CH2:11][CH3:13])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC#N
Reactant: CC[C@@H](C)C[C@H](CN)CC(=O)O
Product: CCC[C@H](C)C[C@H](CN)CC(=O)O

Procedure:
A procedure similar to the preparation of example 10 (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid was followed giving example 11. 380 mg; 29.0%. 1H NMR (CD3OD) δ 2.90 (dd, J=3.9, 8.8 Hz, 1H), 2.80 (dd, J=7.6, 5.1 Hz, 1H), 2.40 (dd, J=3.2, 12.51 Hz, 1H), 2.20 (dd, J=8.8, 6.8 Hz, 1H), 2.05 (m, 1H), 1.55 (m, 1H), 1.30 (m, 3H), 1.10 (m, 2H), 0.85 (m, 6H); MS, m/z (relative intensity): 187 [M+1H, 100%], 211 [M+1H+CH3CN, 30%].
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].C(O)C.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O>[NH2:12][C:3]1[C:4]([NH2:5])=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc(N)c1N
Temperature: 0 °C

Procedure:
To a solution 3-methyl-2,4-dinitroaniline (30 g) in boiling ethanol (750 mL) is added dropwise over 90 minutes a solution of sodium sulfide nonahydrate (109.6 g) in water (750 mL). At the end of the addition, the mixture is refluxed for 30 minutes then poured into ice (2000 g) and allowed to stand until all the ice has melted. The mixture is then extracted with methylene chloride and the organic layer is dried over magnesium sulfate and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with methylene chloride to afford 2,3-diamino-6-nitrotoluene as an orange solid.
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].[C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[CH:7]([CH3:9])[CH3:8]>O.C(O)(=O)C>[N:1](=[C:11]([C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[OH:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)C(C)C
Reaction time: 0.5 h
Yield: 116.1 %

Procedure:
A solution of sodium nitrate (43.8 g.) in water (92 ml.) was added dropwise, with stirring, to a solution of ethyl isobutyrylacetate (100.3 g.) in acetic acid (80 ml.) at 0°. After stirring at 0° for 30 minutes then at room temperature for 3 hours, (100 ml.) was added and the mixture extracted with ether. The extracts were washed with water, saturated sodium bicarbonate solution and water. After drying (CaSO4), the solution was evaporated to give ethyl 2-oximino-4-methyl-3-oxopentanoate (112 g.) as a crude oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].N1C=CC=CC=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
m-Nitroaniline, 10.0 g (0.072 mole), is dissolved in 150 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at room temperature while nonanoyl chloride, 12.9 g (0.073 mole), is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is then passed through a florisil column and crystallized at -20° C. There is obtained N-(3-nitrophenyl) nonanamide (M.P. 63.0°-63.5° C.). Analysis shows 9.88% nitrogen as against a calculated value of 10.06% for C15H21N2O3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[O:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:18][CH:17]([OH:16])[CH2:19][CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])[CH2:8][CH2:7]1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CO1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
A mixture of 4-(3,4-dichlorophenoxy)piperidine (WO 0058305, WO 0177101) (4.40 g) and 2-(2-oxiran-2-ylethyl)-1H-isoindole-1,3(2H)-dione (J. Med. Chem. 1979, 22(6), 631-9. 5.00 g) in ethanol (50 ml) was stirred at 60° C. for 12 h. The mixture was cooled down and left overnight. The formed crystals were collected by filtration, washed with cold ethanol and dried under vacuum to afford the sub-title compound as a white solid (3.0 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][C:4]([C:10]([NH:12][NH2:13])=[O:11])=[N:3]1.F[C:15](F)(F)C(O)=O.C(OC(OCC)OCC)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][C:4]([C:10]2[O:11][CH:15]=[N:13][N:12]=2)=[N:3]1
Reactant: Cn1nc(C(=O)NN)cc1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(OCC)OCC
Product: Cn1nc(-c2nnco2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methyl-5-nitro-1H-pyrazole-3-carbohydrazide (3.81 g, 20.6 mmol) in DCM (30 mL) was added 2,2,2-trifluoroacetic acid (4 mL, 51.9 mmol). The mixture was stirred for about 2 h then concentrated under reduced pressure. To the residue was added triethoxymethane (31.4 mL, 206 mmol) and the mixture was refluxed for about 24 h. The reaction was cooled to ambient temperature and continued to stir for about 16 h. The reaction mixture was concentrated under reduced pressure and the material was partitioned between DCM (25 mL) and saturated NaHCO3 (10 mL). The organic layer was separated and the aqueous layer was back extracted with DCM (25 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure and triturated with ether (2×30 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][NH:21][CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH2:19][CH2:20][N:21]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:22]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCNC4)n2)cc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCN(CC(=O)OC(C)(C)C)C4)n2)cc1Cl

Procedure:
To a solution of 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1,2,4-oxadiazole (0.0726 g, 0.196 mmol) in DMF (1.963 ml) was added K2CO3 (0.054 g, 0.393 mmol) followed by tert-butyl bromoacetate (0.030 ml, 0.206 mmol). After about 48 h the reaction mixture was filtered, concentrated in vacuo and purified by chromatography to provide tert-butyl 2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate as a colorless oil that solidified on standing. LCMS (Table 1, Method c) Rt=3.41 min, m/z 486 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[NH:14][C@H:13]1[CH2:17][I:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[O:21].B(F)(F)F.CCOCC>O1CCCC1>[O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[N:14]([CH:20]([OH:21])[C:19]([O:23][CH3:24])=[O:22])[C@H:13]1[CH2:17][I:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1CI
Reactant: COC(=O)C=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(O)N1C(=O)[C@H](NC(=O)COc2ccccc2)[C@@H]1CI
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of 0.360 g (1.0 mmol) of cis-3-phenoxyacetamido-4-oxo-2-azetidinylmethyl iodide, 0.440 g (5.0 mmol) of methyl glyoxylate, and 246 μl (2.0 mmol) of boron trifluoride etherate in 10 ml of anhydrous tetrahydrofuran is stirred at ambient temperature under an argon atmosphere for 5 hours. At this time 123 μl (1.0 mmol) of boron trifluoride etherate is added and the mixture is stirred for an additional 2 hours. The tetrahydrofuran is removed in vacuo and the residue is taken up in ethyl acetate and extracted with aqueous NaHCO3 and brine. The ethyl acetate solution is dried, filtered and evaporated to give 0.350 g of crude product which is purified by preparative thin-layer chromatography (silica gel GF); 0.174 g of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH:11]([CH3:12])[CH2:10]1>>[OH:9][CH:11]([CH3:12])[CH2:10][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC1CO1
Reactant: Nc1ccc(Cl)cc1
Product: CC(O)CNc1ccc(Cl)cc1
Yield: 61 %

Procedure:
4-Chloroaniline is reacted with 1,2-epoxypropane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-4-chloro-aniline with a yield of 61.0%; b.p.: 158°-164° C./0.3 mm Hg.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:23]=[C:24]([CH3:31])[C:25]([C:29]#[N:30])=[C:26]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:19])[N:27]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccccn2)c1C#N
Temperature: 120 °C
Yield: 29 %

Procedure:
(S)-1-(1-Methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (151 mg, 0.522 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (80 mg, 0.475 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.248 mL, 1.42 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 20-35% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was taken up in DMF and further purified by preparative HPLC (acid mode) eluting with 1-25% ACN in water. The fractions containing the desired compound were combined, neutralized with NaHCO3, and extracted with EtOAc (200 mL). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the title compound (53 mg, 29%). 1H NMR (500 MHz, CD3OD) δ ppm 1.34-1.41 (m, 3 H), 2.31 (d, J=1.46 Hz, 3 H), 3.88 (d, J=1.46 Hz, 3H), 5.68-5.79 (m, 1 H), 6.67 (d, J=2.44 Hz, 1 H), 7.47 (dd, J=7.32, 4.88 Hz, 1 H), 7.58-7.61 (m, 1 H), 7.67 (d, J=7.81 Hz, 1 H), 7.86 (s, 1 H), 7.99 (t, J=7.81 Hz, 1 H), 8.68-8.73 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H20N8, 385; found 385.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=O)[N:6]=1)([CH3:4])[CH3:3].NCCC(O)=O.COC1C=CC(/C=[C:45]2/[C:46]([NH:48][C:49]([S:51]/2)=[NH:50])=[O:47])=CC=1OC1CCCC1>>[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=[C:45]2[S:51][C:49](=[NH:50])[NH:48][C:46]2=[O:47])[N:6]=1)([CH3:3])[CH3:4]
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Agent: NCCC(=O)O
Product: CC(C)(C)c1nc(C=C2SC(=N)NC2=O)nc(C(C)(C)C)c1O
Yield: 11.2 %

Procedure:
4,6-Bis-(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxaldehyde (0.5 g, 1.5 mmoles) is treated with β-alanine (0.27 g, 3.1 mmoles) and pseudothiohydantoin (0.21 g, 1.8 mmoles) according to the procedure of Example 6 to give 0.056 g (11%) of 5-[[4,6-bis-(1,1-dimethylethyl]-5-hydroxy-pyrimidinyl]methylene]-2-imino-4-thiazolidinone. MP=278°-281° C. dec.
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]12[O:26][CH2:25][CH2:24][CH2:23][O:22]1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[CH2:29]([N+:36](C)(C)C)[C:30]1C=CC=C[CH:31]=1.C(#N)C=C>CCO>[CH2:1]([N:8]([CH3:27])[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:31][CH2:30][C:29]#[N:36])[C:16](=[O:21])[C:15]12[O:26][CH2:25][CH2:24][CH2:23][O:22]1)(=[O:10])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Agent: [OH-]
Solvent: CCO
Solvent: C=CC#N
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2CCC#N
Temperature: 78 °C
Yield: 348.7 %

Procedure:
A mixture of N-benzyl-N-methyl-2′-oxo-1′,2′-dihydrospiro[1,3-dioxane-2,3′-indole]-5′-sulfonamide (1.00 g, 2.57 mmol) and benzyltrimethylammonium hydroxide (40% aqueous sol'n, 0.112 mL, 0.617 mmol, 0.24 mole % ) in absolute EtOH (20 mL) was heated to 78° C. and acrylonitrile (0.424 mL, 6.44 mmol, 2.5 eq) was added drop-wise. The reaction mixture was heated for 40 minutes longer, cooled to room temperature and filtered. The product was washed with ethanol and dried to give the title compound as a white solid (0.95 g, 84% yield). NMR (300 MHz, DMSO-d6): consistent.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C@@H:7]([OH:10])[CH2:8][OH:9])[CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[NH4+].[Cl-]>C(Cl)Cl>[Si:19]([O:9][CH2:8][C@@H:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[OH:10])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: OC[C@H](O)C1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC[C@H](O)C1CCOCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of (1R)-1-tetrahydro-2H-pyran-4-ylethane-1,2-diol (2.40 g, 16.2 mmol) in 60 mL of CH2Cl2 was cooled to 0° C. under N2. 2,6-Lutidine (3.77 mL, 32.4 mmol) and tert-butyldimethylsilyl chloride (2.57 g, 17.0 mmol) were added and the reaction mixture was stirred and allowed to warm to ambient temperature overnight. The reaction mixture was treated with saturated aqueous NH4Cl solution and the layers were separated. The organic portion was washed successively with aqueous 3.5% NaH2PO4 solution (2×), H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 20% ethyl acetate/hexanes) gave 3.29 g of (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethanol as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](=O)=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:5](=[O:24])[C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=1[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH3:6]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc(F)ccc3n12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-fluoro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2'-chloro-5-fluoro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>[Pt]=O.C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])nc2)C1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(N)nc2)C1
Reaction time: 20 h
Yield: 111.7 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with platinum oxide (200 mg), 251a (2.00 g, 6.78 mmol), ethyl acetate (30 mL) and ethanol (30 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 20 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (10.0 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with methanol (2×50 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 100% yield (2.01 g) of 251b as a white solid: mp 83-84° C.; 1H NMR (500 MHz, DMSO-d6) d 7.53 (d, 1H, J=3.0 Hz), 7.04 (dd, 1H, J=9.0, 3.0 Hz), 6.41 (d, 1H, J=9.0 Hz), 5.32 (br s, 2H), 4.21 (t, 2H, J=6.5 Hz), 3.75 (t, 2H, J=6.5 Hz), 3.25 (m, 1H), 1.37 (s, 9H); MS (ESI+) m/z 266.2 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8].[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH3:12])=[N:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=2[CH3:8])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc([N+](=O)[O-])nc(C)c1Br
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(Cl)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 18.8 %

Procedure:
3-Bromo-2,4-dimethyl-6-nitropyridine (2.2 g, 9.5 mmol) and 2-chloro-4-hydroxypyridine (2.5 g, 19 mmol) were combined in DMA (10 mL) and the solution was sonicated and sparged with Ar for 10 min. K2CO3 (4.0 g, 29 mmol) was added and the reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was poured into water (200 mL) and the precipitated solids were isolated by filtration. The solids were washed with ½ sat. K2CO3 (aq) (3×50 mL) and water (3×50 mL) and dried under high vacuum for 5 h. The crude product was purified by silica gel chromatography (EtOAc/hexanes) to afford 3-((2-chloropyridin-4-yl)oxy)-2,4-dimethyl-6-nitropyridine (0.50 g, 19%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.33-8.30 (m, 2H), 7.15 (d, J=2.3 Hz, 1H), 7.01 (dd, J=5.8, 2.3 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H); MS (ESI) m/z: 280.0 (M+H+).