Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:37][CH3:38])=[C:19]([CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH2:26][CH2:25]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:37][CH3:38])=[C:19]([CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:28][CH2:29]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCN1CCC(Cc2cccc(-c3nsc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CC2CCN(CCC(=O)O)CC2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 90 °C
Yield: 13.9 %

Procedure:
To a solution of ethyl 3-(4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)propanoate (D141) (0.63 g, 1.133 mmol) in Isopropanol (5 mL) and Water (5.00 mL) was added NaOH (2.266 mL, 1.133 mmol). The reaction solution was heated to 90° C. for 1 hour. The solvent was evaporated in vacuo and the residue was acidified to pH=2-3, extracted with ethyl acetate, washed with water, dried and purified by Mass Directed AutoPrep to afford 3-(4-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-1-piperidinyl)propanoic acid (E106) (83 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 1.00 (3H, t), 1.28 (6H, d), 1.44 (2H, m), 1.72 (3H, m), 2.63 (4H, m), 2.83 (4H, m), 3.17 (4H, m), 4.79 (1H, m), 7.24 (2H, m), 7.32 (1H, d), 7.59 (1H, dd), 7.94 (1H, dd), 8.07 (1H, d). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C28H34ClN3O3S requires 527.2. found 528.1 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.[CH2:22]=[N:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CO>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]([C:8]1[CH2:22][N:23]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(Cl)c(Cl)c2)O1
Reactant: C=NCCN1CCOCC1
Solvent: CO
Product: O=C(NCc1ccc(Cl)c(Cl)c1)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Temperature: 25 °C
Yield: 22 %

Procedure:
A mixture of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide (66 mg, 0.2 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.5 mL, 0.3 mmol) was heated at 70° C. for 1.5 h. The reaction mixture was then cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as eluent. The fractions containing the product were combined and concentrated to give a white powder (23.3 mg, 22% yield). 1H NMR (500 MHz, DMSO) δ: 9.50 (1H, br s), 8.08 (1H, t, J=6.2 Hz), 7.59 (1H, d, J=8.2 Hz), 7.53 (1H, d, J=1.8 Hz), 7.28 (1H, dd, J=8.2, 1.8 Hz), 4.42 (2H, d, J=6.1 Hz), 4.04 (2H, s), 4.02–3.95 (2H, m), 3.81–3.77 (2H, m), 3.73–3.37 (6H, m), 3.15–3.06 (2H, m). HRMS calcd for C18H22Cl2N3O4 (M+H): 414.09875. found: 414.0987.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>O1CCOCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([CH3:12])[CH:14]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(N)cc1C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: C1COCCO1
Product: Cc1ccc(NS(=O)(=O)c2cccnc2Cl)cc1C
Yield: 62.6 %

Procedure:
The title compound (966 mg, 3.26 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.11 g, 5.21 mmol) and 3,4-dimethylaniline (698 mg, 5.73 mmol) in 1,4-dioxane (30 mL) using the methods of (IntC1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][C:12](=[O:14])[NH:11][CH:10]2[CH2:15]O)=[CH:5][CH:4]=1.ClC(F)C(N(CC)CC)(F)[F:20]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][C:12](=[O:14])[NH:11][CH:10]2[CH2:15][F:20])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C2OC(=O)NC2CO)cc1
Reactant: CCN(CC)C(F)(F)C(F)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1ccc(C2OC(=O)NC2CF)cc1
Yield: 62 %

Procedure:
To a solution of 250 mg (1.0 mmole) of 5-(4-methylthiophenyl)-4-hydroxymethyl-oxazolidin-2-one in 30 ml of methylene chloride was added 0.21 ml (1.3 moles) of N-(2-chloro-1,1,2-trifluoroethyl)-diethylamine. The reaction mixture was heated in a teflon bomb at 110° C for 1.5 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed twice with water, dried and concentrated. Chromatography on silica gel afforded 150 mg (0.62 mmole), 62% of 5-(4-methylthiophenyl)-4-fluoromethyl-oxazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH2:6][CH2:7][O:8][CH3:9]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH2:6][CH2:7][O:8][CH3:9]
Reactant: COCCN(CCOC)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: COCCN(CCOC)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In acetic acid (200 ml) was dissolved N,N-bis(2-methoxyethyl)-4-nitrobenzylamine (10.5 g), and to the mixture was added reduced iron (11 g) little by little. The mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added ethyl acetate and precipitates were filtered off. The filtrate was washed with sodium hydroxide solution, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give 4-((N,N-bis(2-methoxyethyl)amino)-methyl)aniline (6.2 g) as red oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]=[O:11])=[CH:4][N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:6][N:7]=1
Reactant: Cc1ncc(C=CC=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncc(C=CCO)cn1
Reaction time: 0.08 h

Procedure:
To a suspension of 2-2 (0.5 g, 3.7 mmol) in MeOH (5 mL) and THF (15 mL) at −78° C. was added sodium borohydride (0.042 g, 1.11 mmol) in one portion. After 5 minutes, the cooling bath was removed, and the mixture allowed to warm and stir for 10 minutes. Concentrated HCl (0.3 mL) was added dropwise, and the volume of the mixture reduced to 2 mL by evaporation. Following the addition of sat. NaHCO3 (10 mL), the mixture was extracted with chloroform, the organics dried over MgSO4, and the solvents evaporated to give alcohol 2-3 as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:24])([F:23])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1>CCOCC>[F:7][C:8]([F:23])([F:24])[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: N#CC1(c2ccc(OC(F)(F)F)cc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC1(c2ccc(OC(F)(F)F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To lithium aluminum hydride (379 mg, 10 mmol) in Et2O (10 mL) was added dropwise a solution of 1-(4-(trifluoromethoxy)phenyl)cyclopentanecarbonitrile (905 mg, 4 mmol) in Et2O (5 mL) at 0° C. The reaction mixture was stirred at room temperature under an atmosphere of nitrogen for 16 h and then quenched with saturated sodium sulfate solution (3 mL) and extracted with Et2O. The organic layer was dried with sodium sulfate and evaporated in vacuo to give (1-(4-(trifluoromethoxy)phenyl)cyclopentyl)methanamine as an oil (810 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of [9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (143.5 mg, 0.379 mmol) in dimethylsulfoxide (2.0 mL) was added Dess-Martin reagent (177.0 mg, 0.417 mmol). The reaction mixture was stirred at room temperature for 2 hrs. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium thiosulfate. The generated precipitate was collected by filtration and washed with water to give the title compound as a colorless solid (129.6 mg, 0.344 mmol, 91%).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH2:16].[Na]>>[S:16]1[CH:4]=[C:3]([C:4]2[C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=[CH:2][CH:3]=2)[CH:2]=[CH:15]1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Reactant: S
Agent: [Na]
Product: O=C(c1ccccc1)c1ccccc1-c1ccsc1

Procedure:
4-chlorobenzophenone and sodium hydrogen sulfide are reacted to produce 4-thiolbenzophenone. The thiol functionalities are then reacted with methyl acrylate or any other oligomeric diacrylate or polyacrylate. One product has the following formula:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([OH:30])=O)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([N:34](CC)C(C)C)(C)[CH3:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N)C>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([NH:34][CH2:31][CH3:32])=[O:30])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)O)n4)n3Cc3ccccc3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2ccccc2)n1
Reaction time: 0.03 h

Procedure:
To a solution of 3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]propanoic acid (8.0 mg, 0.020 mmol, prepared as in Example 95, Step 1) in DMF (0.40 mL) was added N,N-diisopropylethylamine (14 μL, 0.080 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (14 mg, 0.036 mmol, Aldrich). After stirring for 2 minutes, ethylamine (11 μL, 0.20 mmol, neat, Aldrich) was introduced, and the reaction was stirred for 15 minutes. The reaction was diluted with MeOH, and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (3.3 mg, 39%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[CH3:15][C:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][NH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.COCCOC>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:20]3[CH:19]=[N:18][NH:17][C:16]=3[CH3:15])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2C
Temperature: 25 °C
Yield: 38.1 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.00 mmol), cesium carbonate (489 mg, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. After cooling to room temperature, 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.208 g, 1.00 mmol), Cs2CO3 (0.489 g, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) were added. The mixture was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.041 g, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was refluxed for 6 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (100 mL), and the extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc). The obtained yellow solid was triturated with EtOAc and collected by filtration to afford the title compound (52.7 mg, 38%) as a pale yellow solid:
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])OC2C=CC(Cl)=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[F:43])[NH2:39]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([NH:39][C:11]([NH:10][C:8]2[O:7][N:6]=[C:5]([C:2]([F:1])([CH3:3])[CH3:4])[CH:9]=2)=[O:20])[CH:40]=[CH:41][C:42]=1[F:43]
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Reactant: COc1cc2ncnc(Oc3cc(N)ccc3F)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)F)no4)ccc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
A mixture of 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (prepared as described in Example 257A) (170 mg, 0.571 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline (prepared as described in Example 266A steps 1 and 2) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea (147 mg, 64%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.44 (brs, 1H), 9.08 (brs, 1H), 8.58 (s, 1H), 7.69 (m, 1H), 7.59 (s, 1H), 7.35-7.42 (m, 3H), 6.14 (s, 1H), 4.00 (s, 6H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 486 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]#[N:12].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11](=[N:14][OH:15])[NH2:12]
Reactant: N#Cc1sccc1C1OCCO1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1sccc1C1OCCO1
Temperature: 40 °C

Procedure:
To a solution of the foregoing nitrile (5.0 g, 27.59 mmol) in ethanol (20 ml) was added a solution of hydroxylamine hydrochloride (3.7 equivalents) and sodium carbonate (1.7 equivalents) in water (50 ml). The resulting mixture was heated to 40° C. for 5 h, then cooled to room temperature. The colourless precipitate was isolated by filtration, dried under a stream of air and azeotroped with toluene (2×) to give 3-(1,3-dioxolan-2-yl)thiophene-2-amidoxime as an off-white solid (4.36 g). 1H NMR (DMSO-d6): δ 9.83 (1H, s), 7.48 (1H, d, J 5.18), 7.15 (1H, d, J 5.18), 6.05 (1H, s), 5.77 (2H, bs), 4.05 (2H, m), 3.91 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:18])[C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:19])=[N:6][C:5]=2[N:20]=1.Br[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:18])[C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:19][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[N:6][C:5]=2[N:20]=1
Reactant: CC(Br)c1ccccc1
Reactant: CC(C)C[C@H](CO)N(C)c1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)N(C)c1nc(SC(C)c2ccccc2)nc2nc(N)sc12
Yield: 62 %

Procedure:
The title compound was synthesized as a mixture of two diastereomers by general method A from the reaction of (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)(methyl)amino]-4-methylpentan-1-ol (31.4 mg, 0.1 mmol) with 1-bromoethylbenzene (13.5 μL, 0.1 mmol) to give 26 mg (62% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[CH3:9][CH:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25]([S:26][C:27]2[CH:32]=[C:31]3[O:33][CH2:34][O:35][C:30]3=[CH:29][C:28]=2I)=[N:24][C:18]2[C:19]([NH2:23])=[N:20][CH:21]=[N:22][C:17]1=2)[CH3:11].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:1]1[CH:5]=[CH:4][C:3]([C:28]2[C:27]([S:26][C:25]3[N:16]([CH2:15][CH2:14][CH2:13][NH:12][CH:10]([CH3:11])[CH3:9])[C:17]4[C:18]([N:24]=3)=[C:19]([NH2:23])[N:20]=[CH:21][N:22]=4)=[CH:32][C:31]3[O:33][CH2:34][O:35][C:30]=3[CH:29]=2)=[CH:2]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccoc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 90.3 %

Procedure:
3-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 20:1) to give 23.9 mg (90%) of DZ3-27. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.17 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.07 (s, 1H), 6.97 (s, 1H), 6.49 (s, 1H), 6.08 (s, 2H), 4.17 (t, J=6.9 Hz, 2H), 2.93 (septet, J=6.4 Hz, 1H), 2.64 (t, J=7.1 Hz, 2H), 2.02 (m, 2H), 1.17 (d, J=6.4 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 154.1, 151.8, 151.0, 149.7, 149.0, 147.8, 142.6, 140.4, 131.7, 124.2, 118.9, 117.8, 114.8, 111.5, 110.7, 102.1, 49.2, 42.6, 40.6, 28.0, 20.7; HRMS (ESI) m/z [M+H]+ calcd. for C22H25N6O3S, 453.1709; found. 453.1711; HPLC: method A Rt=6.18, method B Rt=6.67.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:9][CH:8]=2)[CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12])=[CH:18][CH:17]=1
Reactant: BrCC=Cc1ccccc1
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C/C=C/c2ccccc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a solution of methyl 4-[2-((4-fluorophenyl)-2-oxoethyl]benzoate (Example 1, Step 2) (1.0 g, 3.67 mmole) in DMF (10 mL) at 0° C. was added NaH (0.105 mg, 3.6 mmol). After stirring for 10 minutes at 0° C., cinnamyl bromide (0.71 g, 3.6 mmole) was added to the mixture. The reaction was stirred for r.t. for 1 h. and was then quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography to yield 1.02 g of the desired product.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:31][CH2:32][CH:33]([OH:35])[CH3:34]>C1(C)C=CC=CC=1>[S:14]([O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:31]([CH2:32][CH:33]([OH:35])[CH3:34])[C:5]=32)=[CH:10][CH:9]=1)([CH3:17])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Oc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1cc(OS(C)(=O)=O)ccc1C2
Reaction time: 0.75 h
Yield: 28 %

Procedure:
A solution of 2.31 g of (RS)-2-(2-oxoethyl)-6-mesyloxy-1-indanone and 110 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.58 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 2:3). 0.74 g (28%) of (RS)-1-(7-mesyloxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol was obtained as a light brown solid which was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:13]=[C:12](O)[C:11]2[C:6](=[N:7][C:8]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:10]=2)[N:5]=1.O=P(Cl)(Cl)[Cl:27].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl>[Cl:27][C:12]1[C:11]2[C:6](=[N:7][C:8]([C:15]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1cc(O)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: COCc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]napthyridin-4-ol (191 mg, 0.569 mmol) is dissolved in a solution of chloroform (15 mL), POCl3 (0.212 mL, 2.28 mmol) and 2,6-lutidine (0.256 mL, 2.28 mmol). The reaction is heated at reflux overnight. The mixture is concentrated under reduced pressure. The resulting residue is dissolved in EtOAc (50 mL) and extracted with water (50 mL), saturated NaHCO3(aq) (50 mL) and brine (50 mL). The organic extract is dried over Na2SO4 and the solvent removed under reduced pressure. The crude product is purified by column chromatography on silica gel eluting with hexanes/EtOAc (1:1) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5]1.NN>C(Cl)Cl>[CH3:1][N:2]([C:14]([NH:13][C:11]1[S:12][C:8]([CH:4]2[CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15])[NH2:3]
Reactant: CNN
Reactant: O=C=Nc1nnc(C2CCC2)s1
Agent: NN
Solvent: ClCCl
Product: CN(N)C(=O)Nc1nnc(C2CCC2)s1
Temperature: 25 °C

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Cyclobutyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)semicarbazide.