Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].C(OCC)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:28][C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=1)[CH3:12]
Reactant: Br[Mg]Cc1ccc2ccccc2c1
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(OCC)C(=O)Cc1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (900 μL, 5.06 mmol) in THF (15 mL) was added slowly a diethyl ether solution of (2-naphtalenylmethyl)magnesium bromide (21) (0.25 M, 25.0 mL, 6.25 mmol) at −78° C. After stirring at for 2.5 h at −78° C., the mixture was gradually warmed to room temperature and stirred for 15 h. To this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate═19/1) to give 1,1-diethoxy-3-(2-naphthalenyl)propan-2-one (22) as a colorless oily substance (675 mg, 2.48 mmol, 49.0%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]>CO.[Pd]>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)#[N:3]
Reactant: N#Cc1ccc(-c2cccc3cncn23)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 54 mg of 5-p-cyanophenylimidazo[1,5-a]pyridine hydrochloride in 5.0 ml methanol is hydrogenated at room temperature and atmospheric pressure for 30 minutes with 0.1 g of 10% palladium on charcoal. The catalyst is filtered and 0.21 ml of 1N sodium hydroxide is added. The filtrate is evaporated, taken up in 10 ml of methylene chloride and filtered through Celite®. Evaporation yields an oil which is chromatographed on silica gel with ethyl acetate to yield 5-p-cyanophenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, m.p. 117°-118°.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:13]2[CH:14]=[C:15]([CH2:18][N:19]3[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[N:21]=[C:20]3[CH2:30][CH3:31])[CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([O:40]C(C)(C)C)=[O:39]>ClCCl>[Br:8][C:9]1[C:13]2[CH:14]=[C:15]([CH2:18][N:19]3[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[N:21]=[C:20]3[CH2:30][CH3:31])[CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)c1c(C)nc(CC)n1Cc1ccc2oc(-c3ccccc3C(=O)OC(C)(C)C)c(Br)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc(CC)n1Cc1ccc2oc(-c3ccccc3C(=O)O)c(Br)c2c1
Temperature: 0 °C
Yield: 24.9 %

Procedure:
Trifluoroacetic acid (7 ml) was added dropwise to a stirred solution of the product of Example 144 (0.892 g) in dichloromethane (30 ml)cooled to 0° C. After 21/2 h the solvent was removed in vacuo to yield an orange oil. The oil was diluted with dichloromethane, washed with hydrochloric acid, dried and the solvent removed in vacuo. The residue was purified by flash column chromatography eluting with dichloromethane/methanol (30:1) to give the title compound as a white solid (200 mg).
Reaction SMILES: O[C@@H:2]([CH3:22])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:14]([O:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]1[C:4](=[O:6])[O:5][C@H:2]1[CH3:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCOCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCOCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-3-hydroxy-2-(2-phenethyloxyethoxy-carbonylamino)-butanoic acid (0.46 g, 1.18 mmol) in dry CH2Cl2 (35 mL), Et3N (0.49 mL, 3.55 mmol) and subsequently TBTU (0.30 g, 1.42 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy:EtOAc (from 100:0 to 0:100) to afford the pure title compound (0.18 g, 60%) as white solid. MS (ESI) m/z: 294 [M−H]+; (ESI) m/z: 292 [M−H]−. 1H NMR (DMSO-d6): δ 1.35 (d, J=6.4 Hz, 3H), 2.81 (t, J=7.1 Hz, 2H), 3.59 (t, 1H), 3.62 (t, J=6.3 Hz, 1H), 4.05-4.21 (m, 2H), 4.85 (dq, J=6.3 Hz, 1H), 5.43 (dd, J=6.1, 9.4 Hz, 1H), 7.15-7.33 (m, 5H), 8.33 (d, J=9.4 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl[C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26][CH2:27][CH3:28])[N:7]=1.C(#N)C.C1COCC1>O>[CH2:27]([S:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:8]1[N:7]=[C:6]([NH:4][CH2:1][CH2:2][CH3:3])[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[N:9]=1)[CH3:28]
Reactant: CCCN
Reactant: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CCCNc1nc(-c2ccccc2SCC)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.5 ml of n-propylamine was added to a mixture of 450 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline, 3 ml of acetonitrile and 3 ml of THF, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 495 mg of 2-(2-ethylsulfanylphenyl)-4-propylamino-7-trifluoromethylquinazoline (Compound of Present Invention 8).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].[CH3:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([N:17]2[CH:18]=[CH:19][C:15]([CH3:14])=[N:16]2)=[C:3]([CH:8]=1)[CH:1]=[O:2]
Reactant: Cc1cc[nH]n1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2ccc(C)n2)c(C=O)c1
Reaction time: 120 h
Yield: 4.3 %

Procedure:
To a solution of 2-formyl-4-methoxyphenylboronic acid (2.5 g, 13.89 mmol) in CH2Cl2 (30 mL) and DMF (15 mL) are added 3-methyl-1H-pyrazole (0.80 g, 9.72 mmol), Cu(OAc)2 (3.78 g, 20.84 mmol), pyridine (2.27 mL, 27.78 mmol) and molecular sieves (2.5 g) at room temperature. The mixture is stirred at the same temperature for 5 days with loose cap. The mixture is filtered through a short pad of diatomaceous earth and the solids are washed with CH2Cl2. The combined filtrates are concentrated and the remaining residue is diluted with water and ethyl acetate. The layers are separated and the aqueous phase extracted with EtOAc (3×). The combined organics are dried (MgSO4), filtered, and concentrated. The remaining residue is purified via flash chromatography (silica gel, 0-15% EtOAc/heptane) to afford 5-methoxy-2-(3-methyl-pyrazol-1-yl)-benzaldehyde (90 mg, 3%).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:24][S:25]([O:1][CH:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 5 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester (7.55 g, 33.2 mmol), triethylamine (5.1 mL, 37 mmol), and 4-dimethylaminopyridine (36 mg, 0.3 mmol) was dissolved in 100 mL of dichloromethane and cooled to 5° C. in an ice bath. Methanesulfonyl chloride (2.6 mL, 33.2 mmol) was added to the solution dropwise and the reaction warmed to room temperature and stirred at room temperature for 18 hours. The reaction was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed to afford 3-methanesulfonyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester as a clear yellow oil (10.2 g); 1H NMR (300 MHz, DMSO-d6): 5.09-5.01 (m, 1 H), 4.28 (s, 1 H), 4.22 (s, 1 H), 3.01 (s, 3 H), 2.20-1.97 (m, 6 H), 1.71-1.66 (m, 2 H), 1.46 (s, 9 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:10])([CH3:9])[CH2:6][C:7]#[CH:8].CN(C)C=O.N1C=CN=C1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([O:10][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][C:7]#[CH:8]
Reactant: C#CCC(C)(O)CCCCl
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(C)(CCCCl)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 7-chloro-4-hydroxy-4-methyl-1-heptyne in 80 ml. of dimethylformamide at 0° C., is added 43.8 g. (0.644 moles) of imidazole and 35.02 g. (0.322 moles) of chlorotrimethylsilane. The mixture is stirred at room temperature for 45 minutes, poured into water and extracted with hexane. The hexane solution is washed with dilute sodium bicarbonate solution, dried over magnesium sulfate and the solvent removed leaving an orange liquid. This liquid is distilled giving the desired product in the fraction boiling at 83°-88° C., 1.5 mm. as a colorless liquid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH2:25][CH:24]1[C:33](O)=[O:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:33]([CH:24]2[O:23][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25]2)=[O:34])[CH2:7][CH2:6]1
Reactant: O=C(O)C1COc2ccccc2O1
Reactant: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: O=C(NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1)C1COc2ccccc2O1
Yield: 48.3 %

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 23, 100 mg, 0.326 mmol) was reacted as described for Example 99 with 2,3-dihydro-1,4-benzodioxine-2-carboxylic acid (71 mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol) to give title compound (73.9 mg).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:22]1([CH3:39])[CH:27]=[CH:26][C:25](S(OCC2CCCCC2)(=O)=O)=[CH:24][CH:23]=1>>[CH:22]1([CH2:39][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCCCC2)c1
Yield: 55.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (212 mg, yield: 55.4%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.Cl.C(OCC)(=[O:12])C>C(O)C>[NH2:2][C@@H:1]1[CH2:7][C@H:4]([C:3]([OH:8])=[O:12])[CH:5]=[CH:6]1
Reactant: CCOC(C)=O
Reactant: O=C1NC2C=CC1C2
Agent: Cl
Solvent: CCO
Product: N[C@H]1C=C[C@@H](C(=O)O)C1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To 4.58 g (42 mmol) of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one, 190 ml of 1N hydrochloric acid was added, and the mixture was refluxed for 2 hours with heating. The solvent was evaporated, and the resulting white crystals were washed with 30 ml of acetone, followed by drying to give 6.59 g of crude crystals of the subject (+)ACP acid. This crude crystals were dissolved in ethanol (20 ml) with heating, and thereafter ethyl acetate (85 ml) was added to the resulting solution, followed by cooling to room temperature. The crystals thus deposited were filtrated to give 4.26 g (25.7 mmol; yield: 61.2%) of the subject (+)ACP acid (melting point: 169-172° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH2:18]1[O:26][C:25]2[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=2[O:19]1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:22]=[CH:21][C:20]4[O:19][CH2:18][O:26][C:25]=4[CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3ccc4c(c3)OCO4)cc2)on1
Yield: 67 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesul-fonamide was prepared in the same manner as described in Example 14b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 3,4-methylenedioxyphenylboronic acid resulting in a 67% yield of final product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>C(#N)C>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]3[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]3[N:3]=[C:2]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1nn2c(-c3cccc(Cl)c3)cc(Cl)nc2c1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nn2c(-c3cccc(Cl)c3)cc(N3CCC[C@H]3CO)nc2c1I
Yield: 130.9 %

Procedure:
5-Chloro-7-(3-chlorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (237 mg), DIPEA (0.2 mL) and (S)-2-pyrrolidinemethanol (120 mg) are stirred at 90° C. for 2 hours in an acetonitrile (15 mL) solvent. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (360 mg). 1H NMR (CDCl3, 300 MHz): δ 7.84 (s, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.45 (m, 3H), 6.10 (s, 1H), 4.47 (bs, 1H), 3.83-3.53 (m, 4H), 2.36 (s, 3H) 2.18-1.98 (m, 3H), 1.78 (m, 1H).
Reaction SMILES: [C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C:11](=[O:13])[C@H:10]([N:14]2[C:18]3[N:19]=[C:20]([NH2:24])[NH:21][C:22](=[O:23])[C:17]=3[S:16][C:15]2=[O:25])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1>[C:1]([O:4][CH:5]([C@@H:8]1[CH2:12][C@H:11]([OH:13])[C@H:10]([N:14]2[C:18]3[N:19]=[C:20]([NH2:24])[NH:21][C:22](=[O:23])[C:17]=3[S:16][C:15]2=[O:25])[O:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: CCC(OC(C)=O)[C@@H]1CC(=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(OC(C)=O)[C@@H]1C[C@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a stirred solution of 1-[(2S,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-oxo-tetrahydrofuran-2-yl]propyl acetate (compound 22b, 2.8 g, 7.6 mmol) in THF (50 mL) was added lithium tri-tert-butoxyaluminum hydride (1M in THF, 15 mL, 15 mmol). After being stirred at room temperature for 2 hours, the resulting solution was quenched by saturated NH4Cl solution and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:10 methanol in DCM) to afford 1.76 g crude product of 1-[(2S,4S,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl acetate (compound 22c). MS obsd. (ESI−) [(M−H)+]: 369. (Refer to Tetrahedron 1984, 40, 125-135).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:21].[Na+].C(#N)C>O.C(OCC)(=O)C.[Ru](Cl)(Cl)Cl>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:21])=[O:19])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCc1cn(Cc2ccccc2)nn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C(O)CCCCCc1cn(Cc2ccccc2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(1-Benzyl-1H-1,2,3-triazol-4-yl)hexan-1-ol (100 mg, 0.386 mmol), sodium periodate (330 mg, 1.542 mmol), and ruthenium trichloride (1.6 mg, 7.7 μmol) were taken up in water (640 μl), ethyl acetate (320 μl) and acetonitrile (320 μl) to give a brown suspension. The reaction was stirred overnight at room temperature under nitrogen. The mixture was diluted with ethyl acetate and water and the black precipitate formed was removed by filtration. The organics were dried with MgSO4, filtered and concentrated under reduced pressure to give the crude title product.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].Cl.[Cl:7][C:8]1[CH:17]=[C:12]([C:13]([NH:15][OH:16])=[O:14])[C:11](O)=[CH:10][CH:9]=1.[OH-].[Na+]>O.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:5][CH:1]3[CH2:2][CH:3]([CH3:4])[O:16][N:15]3[C:13](=[O:14])[C:12]=2[CH:17]=1
Reactant: C/C=C/C=O
Reactant: O=C(NO)c1cc(Cl)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CC2Oc3ccc(Cl)cc3C(=O)N2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
400 ml. of tetrahydrofuran is combined with 100 gm. crotonaldehyde and placed in an ice bath. 125 gm. of hydrogen chloride are passed in at a temperature of about 20°-30° C. 182 gm. of 5-chlorosalicylhydroxamic acid is added in one portion and the reaction temperature is allowed to rise to about 31° C. The mixture is stirred at room temperature for about two hours and then 273 gm. of 50% w/w sodium hydroxide diluted with water to 600 ml. is dripped in. The reaction temperature is maintained from about 30° C. to about 40° C. during the alkali addition. When the addition is completed the mixture is heated to about 50° C. in vacuo for approximately one-half hour in order to remove as much tetrahydrofuran as possible. A solid precipitates which is diluted with 600 ml. of water, cooled, filtered and washed with excess water and pulled dry. The crude cake is returned to the reactor and dissolved in 900 ml. of boiling isopropanol, the solution is filtered hot and the reactor rinsed with 100 ml. hot isopropanol. The filtrate is cooled overnight to crystallize. The crystals are filtered, washed with isopropanol and dried at about 100° C. 134 gm. of 7-chloro-2-methyl-3,3a-dihydro-2H,9H-isoxazolo (3,2-b) (1,3) benzoxazin-9-one (m.p. 147° C.-151° C.) for a yield of 57.6% is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH3:24])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1CCCN1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Product: CC1CCCN1c1nc2c(Cl)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and 2-methylpyrrolidine. Brown foam. MS (ESI): 401.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: NC1CCCCC1
Product: Brc1ccnc(NC2CCCCC2)c1
Yield: 12.8 %

Procedure:
A mixture of 4-bromo-2-chloropyridine (0.5 g, 2.6 mmol) and cyclohexylamine (0.26 g, 2.6 mmol) was heated in a CEM Microwave at 150 degrees for 15 minutes at 300 W. The resulting crude material was purified by flash chromatography (0% to 30% ethyl acetate/hexane) to give 85 mg of the title compound. MS m/z 256.8 (ESI: M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)=O.Cl.[NH2:24][NH:25]C(N)=O.N1C=CC=CC=1>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[C:3](=[O:2])[NH:24][NH:25][C:5]=2[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Reactant: NNC(N)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CSc1nccc(-c2[nH][nH]c(=O)c2-c2ccc(F)cc2)n1

Procedure:
A solution of 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-propionic acid methyl ester, 3, (1 g, 3.7 mmol), semicarbazide HCl (0.653 g, 5.8 mmol) and pyridine (10 mL) is heated at 90° C. for 12 hours. The solution is then concentrated in vacuo to afford a semi-solid residue which is taken up in methanol and the resulting solid removed by filtration. The filtrate is concentrated in vacuo to afford the desired compound as a white solid, which is used without further purification.
Reaction SMILES: [F:1]C1C=C(NCC#C)C=CC=1C(N[C@H](C(OCC)=O)CCC(OCC)=O)=O.[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:39][N:40]([CH2:63][C:64]#[CH:65])[C:41]3[CH:62]=[CH:61][C:44]([C:45]([NH:47][C@H:48]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:46])=[CH:43][CH:42]=3)[CH:37]=2)[N:32]=[CH:31][N:30]1[CH2:66][O:67][C:68](=[O:73])[C:69]([CH3:72])([CH3:71])[CH3:70].BrCC1C=C2C(=CC=1)N=CN(COC(=O)C(C)(C)C)C2=O>>[F:1][C:61]1[CH:62]=[C:41]([N:40]([CH2:63][C:64]#[CH:65])[CH2:39][C:36]2[CH:37]=[C:38]3[C:33](=[CH:34][CH:35]=2)[N:32]=[CH:31][N:30]([CH2:66][O:67][C:68](=[O:73])[C:69]([CH3:71])([CH3:70])[CH3:72])[C:29]3=[O:28])[CH:42]=[CH:43][C:44]=1[C:45]([NH:47][C@H:48]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:46]
Reactant: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Reactant: C#CCNc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)c(F)c1
Agent: CC(C)(C)C(=O)OCn1cnc2ccc(CBr)cc2c1=O
Product: C#CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)c(F)c1

Procedure:
The compound was prepared from compound (9) in a similar manner to that for the preparation of compound (5) from compound (4) in Example 1 using the reagent quantities and conditions set out in Table A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]Br>C1C=CC=CC=1>[Br:14][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: c1ccccc1
Product: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
In a 500 mL round-bottomed flask was added 1-(4-chloro-3-nitrophenyl)ethanone (11.98 g, 60 mmol) in benzene (75 ml) to give a white suspension. Bromine (9.59 g, 60.0 mmol) was added dropwise over 5 minutes to give a deep red solution. Stirred for 1 hour to give a yellow solution that was concentrated in vacuo to a yellow solid. Recrystallized from 9:1 hexane/ethyl acetate to give 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone as yellow needles.