Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[C:9]([O:13][C:14]([NH:16][C@@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][C@H:18]1[OH:33])=[O:15])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C=O)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][C@H:18]1[O:33][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyldimethylchlorosilane (6.51 g, 43.2 mmol) was added to a solution of (+/−)(3R,4R)-benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylate (prepared according to a published literature procedure: Fink, Brian, et al., WO 2005/066176, 10.1 g, 28.8 mmol) and imidazole (3.92 g, 57.6 mmol) in DMF (60 mL). The mixture was stirred at room temperature overnight. Ice water was added and the reaction mixture was extracted with ether twice, the combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (330 g column, eluting with 5-20% ethyl acetate/dichloromethane) to give (+/−)-(3R,4R)-benzyl 4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (13.3 g,) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14](OC)=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[NH2:21][NH2:22]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:21][NH2:22])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCN(C)CC2)c1
Solvent: CO
Product: CN1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Temperature: 65 °C
Yield: 60.6 %

Procedure:
Methyl 3-((4-methylpiperazin-1-yl)sulfonyl)benzoate (200 mg, 0.670 mmol) was added to the hydrazine (43.0 mg, 1.341 mmol) in methanol and refluxed for 8 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography (3% methanol/DCM) to yield the 3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide (125 mg, 0.406 mmol, 60.6% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.08 (s, 1H), 8.12 (m, 2H), 7.84 (d, 1H, J=7.6 Hz), 7.72 (t, 1H, J=7.6 Hz), 4.57 (m, 1H), 2.88 (m, 4H), 2.32 (m, 4H), 2.10 (s, 3H). Mass [M+H]+: 298.9
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]Cl)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:20]([F:31])[C:19]=1[F:32]>>[Cl:1][C:2]1[C:6]([CH2:7][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([F:31])[C:19]=2[F:32])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: CCc1ccc(-c2snc(Cl)c2CCl)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: CCc1ccc(-c2snc(Cl)c2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 127 following Steps 6 and 7 by coupling 3-chloro-4-(chloromethyl)-5-(4-ethylphenyl)isothiazole and ethyl 3-(4-hydroxy-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.36 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.87 (t, J=8.4 Hz, 1H), 6.76 (t, J=8.7 Hz, 1H), 4.96 (s, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.61 (q, J=7.5, 15.2 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H18ClF2NO3S, 438.1 (M+H). found 438.1.
Reaction SMILES: C([O:3][C:4](=[O:20])/[CH:5]=[C:6](\[CH3:19])/[CH2:7][C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:10])[CH3:9])C.[OH-].[Li+].COC(C)(C)C>O1CCOCC1.O.S([O-])(O)(=O)=O.[Na+]>[C:15]([O:14][C:12]([NH:11][C:8]([CH3:10])([CH3:9])[CH2:7]/[C:6](/[CH3:19])=[CH:5]/[C:4]([OH:20])=[O:3])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)/C=C(\C)CC(C)(C)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: C/C(=C\C(=O)O)CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.1 %

Procedure:
(E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ethylester (1.95 g; 6.83 mmol) was dissolved in 1,4-dioxane (25 mL) and water (15 mL). Lithium hydroxide (0.18 g; 7.52 mmol) was added and the reaction mixture was stirred for 12 hours at room temperature. Water (150 mL) and tert-butyl methyl ether (150 mL) was added. The aqueous phase was diluted with an aqueous solution of sodium hydrogensulfate (10%) until pH 2,5 and extracted with tert-butyl methylether (3×100 mL). The combined organic phases were dried (magnesium sulfate) and evaporated in vacuo. The residue was recrystallized from heptane (20 mL) to afford 0.6 g of (2E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:25][C:23]([F:24])([F:26])[C:19]1[CH:18]=[C:17]([C@H:9]2[CH2:8][C@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(F)(F)F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3cccc(C(F)(F)F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.128 g, 0.35 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 2.72 mL, 15.55 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (31 mg, 28%). 1H NMR (600 MHz, dmso) δ 1.77-1.86 (m, 2H), 1.86-1.93 (m, 1H), 2.01-2.08 (m, 1H), 2.71 (dt, 1H), 2.81-2.87 (m, 1H), 3.11-3.16 (m, 1H), 3.76-3.83 (m, 1H), 5.99 (s, 1H), 7.50-7.55 (m, 1H), 7.55-7.59 (m, 1H), 7.64-7.68 (m, 1H), 7.72 (s, 1H). HRMS Calculated for [C15H15F3N2O2+H]+: 313.1164. Found: 313.1153
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:7]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:17]([O:30]C)[CH:16]=3)=[CH:13][N:12]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:8]=2[N:9]=[CH:10][N:11]=1>ClCCl>[NH2:5][C:6]1[C:7]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:17]([OH:30])[CH:16]=3)=[CH:13][N:12]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)c3ccccc3)c(O)c1)cn2C1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of boron tribromide in dichloromethane (0.9 ml of a 1M solution) was added dropwise with stirring to a solution of the product from Example 32, N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzamide (130 mg) in dichloromethane (6 ml) at -10° C. under nitrogen, after the addition the reaction mixture was allowed to warm to 0° C. and stirred at 0° C. for 1.5 hours. The reaction mixture was quenched by the dropwise addition of saturated aqueous sodium bicarbonate solution (5 ml) at 0° C. There was an exotherm and the temperature of the mixture rose to 10° C. The mixture was allowed to warm to ambient temperature, then extracted with dichloromethane to give N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-hydroxyphenyl]benzamide, m.p. 173-175° C. (with decomposition). The structure was confirmed by 1H nmr and mass spectra.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][OH:9])[N:7]=1.Br[C:12]1[CH:17]=[CH:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][CH3:27])[N:23]([CH3:28])[C:22]=3[CH:29]=2)[C:14](=[O:30])[CH:13]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][O:9][C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH2:26][CH3:27])[N:23]([CH3:28])[C:22]=4[CH:29]=3)[C:14](=[O:30])[CH:13]=2)[N:7]=1
Reactant: OCc1csc(C(F)F)n1
Reactant: CCc1nc2ccc(-n3ccc(Br)cc3=O)cc2n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1nc2ccc(-n3ccc(OCc4csc(C(F)F)n4)cc3=O)cc2n1C
Temperature: 100 °C
Yield: 30.5 %

Procedure:
To a suspension of (2-(difluoromethyl)thiazol-4-yl)methanol (39 mg) and 4-bromo-1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)-one (52.3 mg) in toluene (1 ml) was added potassium tert-butoxide (35.3 mg) at 100° C. The mixture was stirred at 100° C. under dry atmosphere (CaCl2 tube) for 30 min. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by recrystallization from EtOH-water to give the title compound (20.0 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=O)[NH:10][C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([N:4]1[C:12]2[C:11]([Cl:22])=[N:10][C:9](=[O:14])[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: O=P(Cl)(Cl)Cl
Product: C=CCn1cnc2c1c(Cl)nc(=O)n2CCCCC
Yield: 71.2 %

Procedure:
A mixture of 7-allyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (0.80 g, 3.0 mmol) and phosphoryl chloride (10.0 mL, 100 mmol) was refluxed for 2 h. The excess phosphoryl chloride was removed by vacuum distillation. The residue was diluted with ice-water, neutralized with solid K2CO3, and then extracted with DCM three times. The combined organic layers were dried, filtered and concentrated to provide the crude product (0.60 g), which was used for next step without further purification. LCMS calculated for C13H18ClN4O (M+H): 281.1; found: 281.1.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH3:12]>>[NH2:12][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1ccc(Cl)cc1Cl
Reactant: N
Product: NC(=O)c1ccc(Cl)cc1N

Procedure:
190 g of 2,4-dichlorobenzamide was dissolved in 1.5 liters of aqueous ammonia, and to the resulting solution was added 100 g of cuprous chloride. The mixture was reacted at 80° C. for 15 hours in an autoclave, and then neutralized. The crystals deposited were collected by filtration. Yield: 122 g (71.5%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c1C
Yield: 33.6 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (40 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (50 mg) give 29 mg (33%) of the title compound as a light orange solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:11][CH2:12][CH2:13][CH3:14])=[N:8][O:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+].CO.Cl>C1COCC1.O>[CH2:11]([C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nocc1C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nocc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a suspension of (E and/or Z)-3-butyl-isoxazole-4-carboxylic acid ethyl ester (10.0 g, 51 mmol) in THF (100 mL) was added a solution of lithium hydroxide monohydrate (4.25 g, 101 mmol) in water (100 mL) and then methanol (100 mL) added and the resulting mixture stirred at room temperature for 1 h. The mixture was acidified to pH 1 with HCl (2 N) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (8.33 g, 97%) which was obtained as an off white solid. MS: m/e=168.1 [M−H]+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[N:10]([CH3:13])[NH:9][C:8]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl>O>[C:1]1([N:7]2[C:11](=[O:12])[N:10]([CH3:13])[N:9]([S:19][C:18]([Cl:22])([Cl:21])[Cl:17])[C:8]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: Cn1[nH]c(=O)n(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)n(-c2ccccc2)c(=O)n1SC(Cl)(Cl)Cl

Procedure:
To a solution of 38.2g (0.2 mole) 4-phenyl-1-methyl urazole in 200 ml water was added a solution of 8g (0.2 mole) sodium hydroxide in 20 ml water. A mixture of 37.2g (0.2 mole) trichloromethylsulfenyl chloride and 3g of an emulsifier solution (as in example 1) in 25 ml water was then added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The reactants were mixed so that the reaction mixture was kept at a pH greater than 7. The precipitate that formed was filtered and the filter cake washed with water. After drying and recrystallizing from benzene-cyclohexane (1:1, by volume) there was obtained 65g (91%) 4-phenyl-1-methyl-2-(trichloromethylthio) urazole having a melting point of 154° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[S:7][C:6]([CH2:5][CH2:4][C:3]([OH:18])=[O:2])=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1ccc(-c2ccccc2F)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCc1ccc(-c2ccccc2F)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
500 mg (1.9 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-propionic acid methyl ester was dissolved in 5 ml of dioxane and 5 ml of a 2 N sodium hydroxide solution. The reaction mixture was stirred at room temperature for 16 h, diluted with water and acidified to pH=2 by the addition of concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 398 mg.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]1.CC(O)C.CCN(C(C)C)C(C)C>O>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 0.5 g, 1.264 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (283 mg, 1.517 mmol), iPrOH (4 mL) and DIPEA (0.442 mL, 0.327 g, 2.53 mmol) were subjected to MW irradiation at 140° C. for 30 min. The vial was cooled to RT and the RM was added to water (100 mL) and the resulting precipitate was collected by filtration. The obtained solid was washed with water (50 mL) and dried to afford the title compound as an off-white powder. LC-MS (Condition 6) tR=1.47 min, m/z=488.9/490.9 [M+H—H2C═C(CH3)2], m/z=545/547.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:17]([CH3:18])=[CH:16][S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][O:14][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:9]2[C:17]([CH3:18])=[CH:16][S:15][C:10]=2[N:11]=1
Reactant: Cc1csc2[nH]c(=O)nc(-c3ccccc3F)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(-c2ccccc2F)c2c(C)csc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 13.57 g of 4-(o-fluorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 271 ml of dimethylformamide is added 2.8 g of 63% sodium hydride. The mixture is stirred at room temperature for 1 hour. Then, 22.15 g of methyl iodide in 66 ml of dimethylformamide is added dropwise thereto. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-(o-fluorophenyl)-5-methyl-thieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 177° - 179°C. From the second fraction, 1-methyl-4-(o-fluorophenyl)-5-methyl-1,2-dihydrotheino[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 275° - 277°C. From the the third fraction, 3-methyl-4-(o-fluorophenyl)-5-methyl-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 176° - 178°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:22])=[N:13][C:14]([S:17][CH2:18][C:19](=[O:21])[NH2:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:22])=[N:13][C:14]([S:17]([CH2:18][C:19](=[O:21])[NH2:20])=[O:31])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc(SCC(N)=O)ncc1C(=O)Nc1ccc(F)cc1
Solvent: ClCCl
Product: Cc1nc(S(=O)CC(N)=O)ncc1C(=O)Nc1ccc(F)cc1
Yield: 65.7 %

Procedure:
A solution of 2-carbamoylmethylsulfanyl-4-methylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (77 mg, 0.24 mmol) and m-CPBA (64 mg, 0.37 mmol) in 2 mL of dichloromethane was stirred at ambient temperature for 16 h. The reaction was concentrated in vacuo and chromatographed through SiO2 (5–10% methanol/dichloromethane), to afford 53 mg (66% yield) of the titled product. ApcI-MS m/z 337 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].[H-].[Na+].[C:11](=O)([O:15]CC)[O:12][CH2:13][CH3:14]>>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][C:11]([O:12][CH2:13][CH3:14])=[O:15]
Reactant: CC(=O)c1cccs1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cccs1
Temperature: 71 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(thiophen-2-yl)ethanone (2.944 g, 23.3 mmol) and Diethyl carbonate (70 mL) at 0° C. was added sodium hydride (1.86 g, 46.6 mmol). The resulting off-white slurry solution was gradually warmed to 71° C., and stirred for 1.5 hour. The reaction mixture was poured into ice-HOAc—H2O, and extracted with ethyl acetate. The organic phase was washed (brine), dried (MgSO4) and concentrated to give a brown liquid. The crude product was purified via flash chromatography (silica gel cartridge with eluent of 0-3% ethyl acetate/hexane) to afford ethyl 3-oxo-3-(thiophen-2-yl)propanoate as an amble liquid, 4.193 g (91%). LCMS m/z 388.99, 390.09 (M+23); HPLC: Rt 2.01 min. (4.0 min. gradient, Column: YMC Combiscreen C-18, Method A).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Br:27][CH2:28][CH2:29][S:30][C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[S:36][C:35]=12>>[Br:27][CH2:28][CH2:29][S:30][C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[C:37]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[S:36][C:35]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCBr)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCBr)c4s3)[C@H](C)[C@H]12
Yield: 46.1 %

Procedure:
The procedure of Example 1a) was repeated, except that 1.01 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.62 g of 7-(2-bromoethyl)thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 780 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(2-bromoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:11]3[C:22]([OH:23])=[C:21]4[C:16]([CH2:17][C@@:18]([OH:29])([C:25]([CH2:27]Br)=[O:26])[CH2:19][C@@H:20]4[OH:24])=[C:15]([OH:30])[C:12]=3[C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:10].C(Cl)(Cl)Cl.[OH-:35].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[C:9]([C:11]3[C:22]([OH:23])=[C:21]4[C:16]([CH2:17][C@@:18]([OH:29])([C:25]([CH2:27][OH:35])=[O:26])[CH2:19][C@@H:20]4[OH:24])=[C:15]([OH:30])[C:12]=3[C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:10]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CBr)C[C@@H]3O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O

Procedure:
In order to introduce a hydroxyl group at the 14- position of compound (IX), said position is first provided with a bromine atom in conventional bromination step (Br2, CHCl3, 23°, 16 hrs). The 14-bromodaunomycinone (X), after being freed of CHCl3, is dissolved in aqueous acetone and subjected to hydrolysis with NaOH (1.1 eq, reflux 5 mins) to afford adriamycinone (XI) which is recovered after water workup and extraction with CHCl3 /MeOH. This portion of the process forms the subject of Example 7. ##STR4##
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[S:17])[NH2:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:19][C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)=O>>[CH3:32][C:28]1([CH3:33])[CH2:27][CH2:26][C:25]([CH3:34])([CH3:35])[C:24]2[CH:23]=[C:22]([C:20]3[N:16]=[C:15]([N:11]4[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]4)[S:17][CH:19]=3)[CH:31]=[CH:30][C:29]1=2
Reactant: CC(C)(C)OC(=O)N1CCCN(C(N)=S)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCCNCC4)n3)ccc21

Procedure:
The preparation is carried out as already described starting from 1.12 g (4.55 mmol) of 4-thiocarbamoyl-1,4-diazepane-1-carboxylic acid tert-butyl ester from step a and 1.93 g (6.25 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone.