Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31]C1C=CC=CC=1C=O>>[F:31][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[O:9]1
Reactant: O=Cc1ccccc1F
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2ccccc2F)Oc2ccc(O)cc21

Procedure:
2-(2-Fluorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of 2′,5′-dihydroxyacetophenone and 1.4 ml of 2-fluorobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (400 MHz, d6-DMSO) δ: 9.45 (s, 1H), 7.67 (m, 1H), 7.47 (m, 1H), 7.32-7.25 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.04 (dd, 1H, J 8.9, 3.0 Hz), 6.95 (d, 1H, J 8.9 Hz), 5.77 (dd, 1H, J 13.5, 2.8 Hz), 3.26 (dd, 1H, J −16.9, 13.5 Hz), 2.76 (dd, 1H, J −16.9, 2.8 Hz).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=1[S:49](Cl)(=[O:51])=[O:50].[Cl-].[NH4+]>O1CCCC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:49]([C:43]3[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:42]=3[F:41])(=[O:51])=[O:50])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2c(F)cccc2F)c1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) at room temperature, and the mixture was stirred for 15 min. After stirring, 15-crown-5 (143 mg) and 2,6-difluorobenzenesulfonyl chloride (159 mg) were added dropwise and the mixture was further stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2) to give the title compound as a colorless oil (yield 213 mg, 87%).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]2[C:35]([C:36](O)=[O:37])=[C:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[O:33][C:29]2=[N:30][C:31]=1[Cl:32].Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.Cl>[Br:25][C:26]1[CH:27]=[C:28]2[C:35]([C:36]([NH:2][CH3:1])=[O:37])=[C:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[O:33][C:29]2=[N:30][C:31]=1[Cl:32]
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(Br)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
HATU (1.69 g, 4.45 mmol) was added to a stirring solution of 5-bromo-6-chloro-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid (1.1 g, 3.0 mmol), methylamine hydrochloride (1.00 g, 14.8 mmol), and DIEA (2.59 mL, 14.8 mmol) in a sealable tube in DMF (20 mL) at rt. The reaction tube was sealed and allowed to stir at rt for 2 hours. LCMS and TLC indicate complete conversion. The solution was then diluted with EtOAc (50 mL) and 1 M HCl (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated to give a tan solid. This solid was adsorbed onto SiO2 and eluted on silica gel with a 0-5% MeOH in DCM gradient over 40 CV (very slow gradient) to give 5-bromo-6-chloro-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (1.1 g, 2.7 mmol, 92% yield) as a white fluffy solid. LCMS: m/e 385 (M+H)+ LCMS retention time: 3.04 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=4 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, CDCl3) δ ppm 8.50 (s, 1H), 7.89 (dd, J=9.0 Hz, 2H), 7.23 (dd, J=8.7 Hz, 2H), 5.85 (br s, 1H), 3.00 (d, J=4.8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3[N:13]([NH2:18])[C:14]([NH2:17])=[N:15][N:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.O=[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:22]=O>C(O)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3[N:13]4[N:18]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:17][C:14]4=[N:15][N:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(c3nnc(N)n3N)CC2)cc1
Reactant: O=CC(=O)c1ccccc1
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C2(c3nnc4nc(-c5ccccc5)cnn34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[1-(4-methoxyphenyl)cyclopropyl]-4H-1,2,4-triazole-3,4-diamine (70.2 mg, 0.286 mmol) and oxo(phenyl)acetaldehyde hydrate (0.0435 g, 0.286 mmol) in acetic acid (1.2 mL) was stirred at RT overnight. The mixture was diluted with methanol (3.0 mL) and subject to preparative RP-HPLC to afford the two regioisomers.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@H:4]([NH:24]C(=O)OC(C)(C)C)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:14]3([CH2:17][O:16][CH2:15]3)[O:13][C:11]=2[CH:12]=1.[ClH:33].C(OCC)C>ClCCl>[NH2:24][C@@H:4]([CH2:3][CH:2]([CH3:32])[CH3:1])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:14]([CH2:17][OH:16])([CH2:15][Cl:33])[O:13][C:11]=2[CH:12]=1
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)OC1(COC1)c1cnccc1-2)NC(=O)OC(C)(C)C
Reactant: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OC(CO)(CCl)c1cnccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of ((S)-tert-butyl (4-methyl-1-(spiro[chromeno[3,4-c]pyridine-5,3′-oxetan]-8-yloxy)pentan-2-yl)carbamate (10 mg, 0.023 mmol) (prepared as described in Example 19, Part D) in dichloromethane (1 mL) cooled to 0° C. was added 1M HCl in diethyl ether (234, 0.023 mmol) dropwise and the solution stirred for 30 min. The reaction was then warmed to room temperature and stirred for 2 h. After completion of reaction, the volatiles were removed under reduced and purified by preparative HPLC to afford product (8-(((S)-2-amino-4-methylpentyl)oxy)-5-(chloromethyl)-5H-chromeno[3,4-c]pyridin-5-yl)methanol (2.08 mg, 5.52 μmol, 24% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.82 (m, 1H), 8.69 (m, 1H), 8.35 (m, 1H), 8.09 (m, 1H), 6.94 (m, 1H), 6.82 (s, 1H), 4.36-4.20 (m, 6H), 3.73 (m, 1H), 1.82-1.68 (m, 3H), 1.04 (m, 6H); LCMS (ESI) m/e 377.2 [(M+H)+, calcd for C20H26ClN2O3 377.2]; LC/MS retention time (Method E): tR=1.71 min; HPLC retention time (method A): tR=8.12 min; HPLC retention time (method B): tR=9.87 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].S(Cl)([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][Cl:20])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: Cc1c(CO)oc2ccc(Br)c(OC(C)C)c12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(CCl)oc2ccc(Br)c(OC(C)C)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-yl) methanol (0.3 g, 1 mmole) in 10 mL dichloromethane was added 0.73 mL of thionyl chloride and the reaction was stirred at room temperature for 2 hours. The solvent was concentrated in vacuo, the residue was added toluene to provide 0.33 g of 5-bromo-4-isopropoxy-3-methyl-2-chloromethyl-1-benzofuran.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]>CO.C1COCC1.[Pd]>[NH2:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(=O)OC)ccc1N
Reaction time: 8 h

Procedure:
To a mixed solution of methyl 3-ethoxy-4-nitrobenzoate (6.05 g) in methanol (100 ml) and THF (100 ml) was added 10% Pd/C (50% wet, 0.60 g), and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to give a crude product (5.21 g) of the title compound. The obtained crude product was used for the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.Cl.[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]([NH2:31])[CH3:30].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]([NH:31][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:30]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: CC(N)c1ncco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A round-bottomed flask was charged with 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (300 mg, 0.81 mmol) and 1-oxazol-2-yl-ethylamine dihydrochloride (244 mg, 1.0 mmol). DMF (4 ml) was added followed by N,N-diisopropylethylamine (0.9 ml, 5.15 mmol) and HATU (337 mg, 0.89 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and diluted with petroleum ether. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 268 mg (71%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as an off-white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([OH:9])[CH:8]=1.CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C@@H:27]1[CH2:31][C@@H:30]([O:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH2:29][N:28]1[C:38]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:39]>CN(C)C(=O)C>[CH3:35][N:34]([CH3:36])[C:33]([O:32][C@H:30]1[CH2:29][N:28]([C:38]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:39])[C@H:27]([CH2:26][CH2:25][O:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:31]1)=[O:37]
Reactant: COc1ccc(CCc2ccccc2)c(O)c1
Reactant: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCOC(=O)N1C[C@H](OC(=O)N(C)C)C[C@H]1CCOc1cc(OC)ccc1CCc1ccccc1
Yield: 99.4 %

Procedure:
670 mg of 5-methoxy-2-(2-phenylethyl)phenol (prepared as described in Preparation 1) were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 360 mg of potassium t-butoxide and 1000 mg of (2S,4R)-2-(2-chloroethyl)-4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1500 mg (yield 99%) of the title compound as an oily substance.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[N:3]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[O:2]2.C(#N)C.O.[BH4-].[Na+]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].C(OCC)(=O)C>[OH:2][CH:1]1[CH2:7][CH:4]([NH:3][C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6]1
Reactant: O=C(c1ccccc1)N1OC2C=CC1C2
Agent: [Mo]
Agent: [BH4-]
Agent: [C-]#[O+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(NC1C=CC(O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
Molybdenum hexacarbonyl (12.1 g, 45.8 mmol) was added to a solution of the bicycle 7 (6.10 g, 30.3 mmol) in a 7:1 mixture of acetonitrile and water (280 cm3). The suspension was stirred for 30 minutes at room temperature, then sodium borohydride (0.60 g, 15.9 mmol) was added and the suspension was heated under reflux for 4 hours. Upon completion of reaction, the mixture was allowed to cool to room temperature, filtered though a celite plug, and evaporated to dryness to give a brown solid. Flash chromatography (SiO2, 80% ethyl acetate in petrol) gave the alcohol 8 (3.60 g, 17.7 mmol, 58%) as a light yellow solid; m/z (EI) Found [M]+ 203.0945 ([M]+ C12H13NO2 requires 203.0946).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Br:13]Br.Br>C(Cl)(Cl)Cl>[Br:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:11])[C:2]2([CH3:12])[CH3:1]
Reactant: BrBr
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: Br
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)Nc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
3,3-Dimethyl-1,3-dihydro-2H-indol-2-one (1.12 g, 0.00695 mol) was dissolved in chloroform and stirred at room temperature under nitrogen. Bromine (1.12 g) was added and the mixture was heated under reflux until HBr evolution ceased and the bromine colour was discharged from the solution. The solution was washed with sodium metabisulphite solution and sodium hydrogen carbonate solution, dried (MgSO4), filtered and concentrated to dry under reduced pressure to give 5-bromo-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a yellow solid. 1H NMR (CDCl3) 1.39 (6H s), 6.8 (1H d), 7.3 (2H m), 7.9 (1H broad).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][S:6]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[C:12](OC)=[O:13])(=[O:8])=[O:7].CS(C1C=C(C=CC=1Cl)C(O)=O)(=O)=O.CC1N=CC(O[Si](C)(C)C)=CC=1.CI.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:3][C:2]([NH2:4])=[N:1][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[C:9]([S:6]([CH3:5])(=[O:7])=[O:8])[CH:10]=1
Reactant: N=C(N)N
Reactant: COC(=O)c1ccc(Oc2ccc(C)nc2)c(S(C)(=O)=O)c1
Agent: CS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: Cc1ccc(O[Si](C)(C)C)cn1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(Oc2ccc(C(=O)N=C(N)N)cc2S(C)(=O)=O)cn1

Procedure:
In analogy with Example 2, reacting guanidine with methyl 3-methylsulfonyl-4-(6-methyl-3-pyridyloxy)benzoate [obtainable by reacting 3-methylsulfonyl-4-chlorobenzoic acid with 6-methyl-3-trimethylsilyloxypyridine and subsequently esterifying the product with methyl iodide/K2CO3 in DMF] gives N-diaminomethylene-3-methylsulfonyl-4-(6-methyl-3-pyridyloxy)benzamide, m.p. 197-199°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](OCC)=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(SC)nc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ncc(CO)c(OCc2ccccc2)n1
Reaction time: 0.75 h

Procedure:
To a solution of ethyl 4-(benzyloxy)-2-(methylthio)pyrimidine-5-carboxylate (S25, 3.02 g) in tetrahydrofuran (50 mL), lithium aluminum hydride (1.51 g) was added portionwise under ice cooling, and the mixture was stirred at the same temperature for 45 minutes. To the reaction mixture, saturated aqueous sodium hydrogencarbonate (300 mL) and ethyl acetate (200 mL) were added. The insoluble matter was removed by filtration through Cerite. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 70 to 30% hexane in ethyl acetate) to obtain oily (4-(benzyloxy)-2-(methylthio)pyrimidin-5-yl)methanol (S26, 818 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH2:26][OH:27])[CH2:24][S:25][C@H:20]12)(=[O:17])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>ClCCl>[C:8]([NH:18][C@@H:19]1[C:31](=[O:32])[N:21]2[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH2:26][O:27][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:24][S:25][C@H:20]12)(=[O:17])[CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:10]
Reactant: O=C1CCC(=O)O1
Reactant: O=C(O)C1=C(CO)CS[C@@H]2[C@H](NC(=O)C(O)c3ccccc3)C(=O)N12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(O)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
In dichloromethane (40 ml) was dissolved 7β-mandelamido-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (4.65 g), followed by addition of succinic anhydride (1.50 g). The mixture was stirred at room temperature for 1 hour and a half. After the reaction had been completed, the mixture was treated as in Example 8 to obtain 7β-mandelamido-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid (4.45 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[N+:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]>>[CH3:10][N:5]1[C:4]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:3]=2[C:2]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([N+:32]([O-:34])=[O:33])[CH:40]=2)=[N:8][CH2:7][C:6]1=[O:9]
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2cccc([N+](=O)[O-])c2)c2cc(-c3ccccc3)ccc21
Yield: 26 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3-nitrophenyl boronic acid. The title compound (60 mg) was obtained as a beige solid, (yield=26%).
Reaction SMILES: [C:1]1([C:7]2[C:8](O)=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:22])=O>CC#N>[Cl:22][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccccn2)ncc1-c1ccccc1
Solvent: CC#N
Product: Clc1nc(-c2ccccn2)ncc1-c1ccccc1

Procedure:
5-Phenyl-2-pyridin-2-ylpyrimidin-4-ol (4-1; 206 mg, 0.826 mmol) was stirred in 4 ml of anhydrous MeCN. Phosphorous oxychloride (0.077 ml, 0.83 mmol) was added and the resulting mixture was heated to reflux. After 1 h the reaction was cooled and concentrated in vacuo and quenched with half-saturated aqueous NaHCO3. The mixture was extracted 3× with DCM. The combined organic phases was dried over Na2SO4, filtered and concentrated to provide 4-chloro-5-phenyl-2-pyridin-2-ylpyrimidine (4-2). 1H NMR (CDCl3): δ 8.88 (s, 1H), 8.84 (s, 1H), 8.57 (d, J=8.0 Hz, 1H), 7.90 (dt, J=1.5, 7.6 Hz, 1H), 7.53 (m, 5H), 7.46 (dd, J=4.9, 7.1 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C1(C)C=CC(S([N:29]=[N+]=[N-])(=O)=O)=CC=1.[BH4-].[Na+]>O1CCCC1.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][C:13]=1[NH2:29])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1N
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A solution of 38.1 g (0.15 mol) of 5-chlorothiophene-2-sulfonic acid tert-butylamide in 300 ml of dry tetrahydrofuran was cooled to -70° C, and n-BuLi (190 ml, 1.6M in hexane) was added, maintaining the temperature <-65° C. After addition, the mixture was allowed to warm to -20° C. and stirred at this temperature for 30 min. A solution of p-toluenesulfonyl azide (34 g, 0.17 mol) in 100 ml of dry tetrahydrofuran was added, maintaining the temperature at -20° C., and the cooling bath was removed. After the mixture had reached room temperature, water (100 ml) was added. The organic phase was isolated and the aqueous phase was extracted with toluene (2×50 ml). To the combined organic phases was added hexadecyltributylphosphonium bromide (7.62 g, 15 mmol) followed by the dropwise addition of a solution of sodium borohydride (6.58 g, 0.174 mol) in 20 ml of water with stirring and cooling to room temperature. The mixture was stirred over night at room temperature, and water (100 ml) was added. The organic phase was isolated, washed with water (2×100 ml), dried, and evaporated to dryness. The oily residue was dissolved in ethyl acetate (150 ml) and washed with 1N sodium hydroxide (6×100 ml). The organic phase was dried with sodium sulfate, and evaporated to afford a quantitative yield (40.6 g) of crude title compound as an oil, which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:71][C@@H:72]([CH2:75][CH3:76])[CH2:73][OH:74]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:71][C@@H:72]([CH2:75][CH3:76])[CH2:73][OH:74])=[O:19])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Reactant: CC[C@H](N)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](CO)NC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 42 mg, 0.089 mmol) in DMF (4 ml) was added BOP (48 mg, 0.11 mmol) and DIPEA (23 mg, 0.10 mmol), followed by (S)-2-aminobutan-1-ol (16 mg, 0.10 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as a light yellow solid.