Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1C(OCC)=O.[OH-].[K+].Cl>CO>[C:7]1([N:6]2[C:2]([OH:1])=[CH:3][CH:4]=[N:5]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cnn(-c2cccc3ccccc23)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccnn1-c1cccc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of ethyl 5-hydroxy-1-(naphthalen-1-yl)-1H-pyrazole-4-carboxylate (480 mg, 1.8 mmol), aqueous potassium hydroxide solution (35%, 2.2 mL, 13.5 mmol) and methanol (5 mL) was heated to reflux for 24 hours. The reaction mixture was then cooled to 0° C., acidified to pH 2 with conc. HCl and refluxed for additional 12 hours to complete decarboxylation. The reaction was then cooled to room temperature and concentrated. The residue was taken up in water and extracted with ethyl acetate, the organic layer washed with water, dried over sodium sulfate and concentrated. Purification by preparative TLC (95% dichloromethane/5% methanol) afforded 1-(naphthalen-1-yl)-1H-pyrazol-5-ol.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[N:9]=[C:8]2[NH:10][CH2:11][CH2:12][CH2:13][C:7]2=[CH:6][CH:5]=1>FC(F)(F)C(O)=O>[NH:10]1[C:8]2=[N:9][C:4]([CH:3]=[O:2])=[CH:5][CH:6]=[C:7]2[CH2:13][CH2:12][CH2:11]1
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc2c(n1)NCCC2
Reaction time: 16 h

Procedure:
Dimethoxy-1,2,3,4-tetrahydropyridino[2,3-b]pyridin-7-ylmethane was dissolved in trifluoroacetic acid (14 mL) and stirred under nitrogen for 16 hrs. The mixture was quenched with saturated sodium bicarbonate, extracted with methylene chloride, dried over sodium sulfate, filtered, in vacuo and purified by flash chromatography (5% MeOH/CH2Cl2 ). EI-MS m/z 163 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[N:34]=[C:35]=[O:36]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:34]([C:27]3[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=3[O:25][CH3:24])[C:35]2=[O:36])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: COc1ccc(N=C=O)c(OC)c1
Product: COc1ccc(-n2c(=O)c3cnc4c(OC)cccc4c3n(C3CCCC3)c2=O)c(OC)c1
Yield: 55.9 %

Procedure:
1-Cyclopentyl-3-(2,4-dimethoxy-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (25 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and 2,4-dimethoxyphenyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 448 [M+1]+.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=4)[NH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:24](Br)[CH3:25]>CN(C)C=O>[O:6]1[C:7]2([CH2:12][CH2:11][CH:10]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=4)[N:15]([CH2:24][CH3:25])[CH:14]=3)[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: N#Cc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a suspension of sodium hydride (60%, 1.63 g, 0.068 mol) in anhydrous N,N-dimethylformamide (150 ml) was added 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1H-indole (9.0 g, 0.032 mol) at room temperature. The mixture was stirred for 30 minutes at room temperature then ethylbromide (14.6 g, 0.13 mol) was added at room temperature. The reaction was allowed to stir for overnight, then quenched with water (50 ml). The mixture was extracted with methylene chloride (3×150 ml) and water (3×150 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum. Chromatography (hexanes) afforded 5.5 g (69%) of product as a white solid: mp 124-126° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH:7]=1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1ccccc1
Reactant: COc1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cl)cc1C=Cc1ccccc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
Palladium acetate (21 mg, 7 mol %) was added to a solution of 2-bromo-4-chloroanisole (300 mg, 1.4 mmol), styrene (211 mg, 2 mmol), triethylamine (13 μL, 0.1 mmol) and triphenylphosphine (50 mg, 1.9 mmol) in acetonitrile (6 mL), and the mixture was refluxed for 8 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the solvent was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate (15 mL). After the solution was washed successively with 2N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (118 mg, 35.6%) as a white powder.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:14].O>CCOCC>[CH3:1][C:6]1([OH:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:5]1[CH3:4]
Reactant: CC1Cc2ccccc2C1=O
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CC1=Cc2ccccc2C1(C)O

Procedure:
A 200 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel was thoroughly purged with nitrogen and dried. To the flask, methylmagnesium bromide (3.0 mol/l ether solution) (16.9 ml, 50.7 mmol) and dehydrated ether (50 ml) were introduced. To the flask, a solution of 2-methyl-1-indanon (3.70 g, 25.3 mmol) in dehydrate ether (20 ml) was dropwise added at room temperature with stirring. Then, the reaction mixture was stirred for 2 hours and poured into cold water. The resultant mixture was introduced into a separatory funnel to separate an organic phase. The aqueous phase was extracted by ether (100 ml×3) and a combined organic phase was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 1,2-dimethyl-1-hydroxy-indene. The compound thus obtained was dissolved in toluene (30 ml) and, thereto, 0.1 g of p-toluenesulphonic acid was added. The reaction mixture was refluxed for 3 hours to remove water. The organic phase thus obtained was introduced into a separatory funnel and washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After removing a solvent, it was purified by column chromatography (developer; hexane) to obtain 2.70 g (GC 94%) of a pale yellow solution (yield: 74%).
Reaction SMILES: [F-].[Cs+].COCCOC.[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1I>CCOC(C)=O.CCCCCC>[NH2:20][C:21]1[C:22]([C:14]2[CH:15]=[CH:16][C:11]([S:10][CH3:9])=[CH:12][CH:13]=2)=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: CSc1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(N)c(-c2ccc(SC)cc2)c1

Procedure:
Prepared according to the general procedure Coupling-1 (CsF, DME, 20° C.) using [4-(methylthio)phenyl]boronic acid and methyl 4-amino-3-iodo-benzoate as starting material. Flash chromatography (Hexane:EtOAc, 70:30) afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]2O)[CH:5]=[CH:6][C:7]=1[OH:8].CCN(S(F)(F)[F:29])CC>C(Cl)Cl>[F:29][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)c(F)c2)[C@H](O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)c(F)c2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129 %

Procedure:
To (3S,4S)-tert-butyl 4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate (2.99 g, 9.60 mmol) in DCM (75 mL) at 0° C. was added DAST (6.34 mL, 48.0 mmol) dropwise. The reaction was then allowed to warm to room temperature and stir for 2 h. The reaction was slowly quenched with ice water. The reaction was then extracted with dichloromethane, washed with additional water, dried with magnesium sulfate, filtered and concentrated in vacuo to afford (3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (3.88 g, quantitative yield) as a yellow viscous oil: LC-MS [M−H]+ 312.2; 1H NMR (500 MHz, DMSO-d6) δ 7.22-7.10 (m, 1H), 7.00-6.76 (m, 3H), 5.76 (s, 2H), 4.60 (td, J=10.1, 5.2 Hz, 1H), 4.50 (td, J=10.1, 5.2 Hz, 1H), 4.27 (br. s., 1H), 4.07-3.78 (m, 2H), 3.66-3.50 (m, 1H), 3.00-2.65 (m, 4H), 1.81-1.69 (m, 1H), 1.63-1.50 (m, 1H), 1.46-1.30 (m, 14H), 1.20-1.01 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][N:29]3C(=O)C4=C(Cl)C(Cl)=C(Cl)C(Cl)=C4C3=O)[CH:23]=[CH:24][CH:25]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C(O)C.C(N)CN>C(#N)C.C(Cl)Cl.CO.CCN(CC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(CCCN3C(=O)c4c(Cl)c(Cl)c(Cl)c(Cl)c4C3=O)c2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(CCCN)c2)c1
Temperature: 60 °C
Yield: 172.5 %

Procedure:
In a 50 mL round-bottom flask with magnetic stirrer, N-[3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]propyl]-3,4,5,6-tetrachlorophthalimide (347 mg, 522 μmol) was dissolved in acetonitrile (2 mL), tetrahydrofuran (1 mL), and ethanol (1 mL). Ethylenediamine (157 μL, 2.35 mmol, 4.5 equiv.) was added. The flask was equipped with a reflux condenser, three-way stopcock, and Ar balloon, and the atmosphere was exchanged. The mixture was heated in an oil bath at 60° C. for 160 min. The resulting yellowish solution and fine, colorless precipitate were cooled to room temperature. TLC (SiO2, CH2Cl2/MeOH/Et3N 90:10:5, UV detection) demonstrated disappearance of the starting material which was replaced with two major new spots (Rf approx. 0.5 and 0.4) besides nonpolar byproducts. The mixture was evaporated and the residue chromatographed on SiO2 (23×2.5 cm, CH2Cl2/MeOH/Et3N 93:7:5, then 9:1:1). Fractions containing the two major products were combined, evaporated, and dried (50° C./oil pump vacuum) to yield 358 mg of crude 3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]propanamine as a yellowish, turbid glass, which was used in the subsequent step without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15](N)[CH:16]([CH3:18])[CH3:17].N(CCO)(CCO)CCO>C1(C)C=CC=CC=1>[CH2:15]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:16]([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)CN
Solvent: Cc1ccccc1
Solvent: OCCN(CCO)CCO
Product: CC(C)Cc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
4-chloro-3-nitro-quinoline is reacted with isobutyl amine in the presence of triethanolamine (TEA) at between −10 and +15° C. in toluene, while excluding moisture. After washing and phase separation, the organic solution is ready for the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][NH2:13]>O>[CH3:12][NH:13][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CN
Solvent: O
Product: CNc1ncc([N+](=O)[O-])c(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-5-nitropyrimidin-4-amine (1.0 g, 5.8 mmol) and methylamine (2.0 M solution in THF, 14 mL, 28 mmol) was allowed to stir in a sealed vessel for 1 h. The mixture was then heated to 60 deg. C. for 30 min. The reaction was cooled to ambient temperature, and an additional amount of methylamine (2.0 M solution in THF, 8 mL, 16 mmol) was added and the reaction was sealed and heated to 60 deg. C. for 30 min. The reaction was cooled, diluted with water, and the precipitate was collected by filtration. The solid was rinsed with small portions of water followed by diethyl ether. The material was dried in under reduced pressure to give N2-methyl-5-nitropyrimidine-2,4-diamine 48 as a light yellow solid. MS (ES'): 170 (M+H)+; Calc. for C5H7N5O2=169.14.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29][CH:30](C(OCC)=O)[C:31]([O:33]CC)=[O:32])=[CH:26][CH:27]=5)[C:22]([C:41]#[N:42])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:27]=5)[C:22]([C:41]#[N:42])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc2c(c1)c(C#N)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(CCC(=O)O)ccc54)ccc3o2)n1
Yield: 130.8 %

Procedure:
A mixture of ethyl 3-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-3-cyanoindol-5-yl}-2-ethoxycarbonylpropionate (0.72 g) and 1N sodium hydroxide solution (5 ml) in methanol (10 ml) was stirred under reflux for 3 hours. After cooling, the mixture was made acidic with diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in xylene (10 ml) containing acetic acid (7.5 ml) and the mixture was stirred under reflux for 7 hours. After removal of solvent by evaporation, the residue was partitioned between diluted hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatogaphy on silica gel and eluted with a mixture of chloroform and methanol. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give 3-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-3-cyanoindol-5-yl}propionic acid (0.78 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[CH3:26])[C:20](O)=[O:21])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([C:20](=[O:21])[NH:39][C:36]5[CH:37]=[N:38][C:33]([N:30]6[CH2:29][CH2:28][O:27][CH2:32][CH2:31]6)=[CH:34][CH:35]=5)[CH:23]=[CH:24][C:25]=4[CH3:26])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Product: Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)nc2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 3 of Example 21 and 6-morpholinopyridine-3-amine to obtain the title compound (see Table 1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(Cl)(Cl)=O.[N+](C1C=CC=CC=1C(Cl)=O)([O-])=O.[CH2:29](O)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(OCC)(=O)C.N1C=CC=CC=1.C(#N)C.CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCO
Agent: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCOC(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A mixture of 83.5 g of o-nitrobenzoic acid, 1 ml of dimethylformamide and 100 ml of thionyl chloride was heated under reflux for 3 hours. The resulting reaction mixture was concentrated under reduced pressure with an aspirator to yield yellow, oily o-nitrobenzoyl chloride. The thus obtained o-nitrobenzoyl chloride was added dropwise to 300 ml of acetonitrile, in which 88.4 g of n-dodecanol and 41 ml of pyridine were dissolved, at room temperature with stirring over a period of 30 minutes. After one hour's stirring, the resulting solution was mixed with 600 ml of ethyl acetate, and washed three times with 500 ml of water being used for each wash, to extract the product with the ethyl acetate. The ethyl acetate solution was dried over sodium sulfate, and then concentrated to give 143 g of light yellow oily dodecyl o-nitrobenzoate.
Reaction SMILES: B.[O:2]1CCCC1.[OH:7][CH:8]([C:12]1[C@H:17]([C:18]([O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[N:16]2[C:34](=[O:46])[C@@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@H:15]2[S:14][CH:13]=1)[CH2:9][CH:10]=[CH2:11].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[OH:7][CH:8]([C:12]1[C@H:17]([C:18]([O:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[N:16]2[C:34](=[O:46])[C@@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@H:15]2[S:14][CH:13]=1)[CH2:9][CH2:10][CH2:11][OH:2]
Reactant: C1CCOC1
Reactant: C=CCC(O)C1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)C(C(O)CCCO)=CS[C@H]12

Procedure:
Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 11.0 ml, 11.0 mmol) was added to diphenylmethyl (4R, 6R, 7R)-3-(1-hydroxybut-3-en-1-yl)-7-phenylacetamidoceph-2-em-4-carboxylate (S-diastereomer, 100 mg, 0.18 mmol) in tetrahydrofuran (2 ml) at 20° C. After 30 minutes water (1 ml) was added and the pH taken to within the range 7 to 8 with dilute aqueous sodium hydroxide. Hydrogen peroxide (30% in water, 0.15 ml, 1.35 mmol) was then added, and the pH maintained at 7 to 8 for 20 minutes, after which water and ethyl acetate were added. The organic layer was washed with brine, dried (MgSO4), and evaporated to give a residue which was purified by chromatography (50 to 100% ethyl acetate in hexane, silica gel) giving the S-diastereomer of the title compound identical to that obtained above (isomer P1), 35 mg (34%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])=[O:4].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.CCOC(C)=O>[O:21]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][CH3:14])=[O:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)COc2ccccc2)c(OC)c1
Yield: 84.6 %

Procedure:
A solution of 2-bromo-2′,4′-dimethoxyacetophenone (5 g, 19.1 mmols) in 25 mL of 2-butanone was added to a suspension of phenol (1.8 g, 19.1 mmols), K2CO3 (2.6 g, 19.1 mmols) and KI (41.5 mg, 0.25 mmols) in 20.0 mL of the same solvent. The solution was then refluxed for 20 hours. The mixture was filtered and the solvent was evaporated off under vacuum. The residue obtained was dissolved in EtOAc and washed with a 10% aqueous solution of NaOH and then with water. The organic extract was dried over Na2SO4, filtered and evaporated under vacuum. Finally, the crude residue was washed with Et2O and dried under low pressure to provide 4.4 g (yield: 84%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:11]=2)=[CH:5][CH:4]=1.[CH3:26]I>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:11]=2)[CH3:26])=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1ccc(Nc2nc(-c3ccccc3)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(-c3ccccc3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (4-methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-amine (51 mg, 0.16 mmol) and methyl iodide (0.07 ml, 1.09 mmol) by a procedure similar to Example 36. 1H NMR (CDCl3): 8.64-8.61 (m, 2H), 7.90 (d, J=8.4 Hz, 1H), 7.59-7.48 (m, 4H), 7.18-7.14 (m, 2H), 7.08-6.98 (m, 2H), 6.94-6.91 (m, 2H), 3.85 (s, 3H), 3.73 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[N:19][OH:20])[N:6]=1)([CH3:4])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1nc(C=NO)nc(C(C)(C)C)c1O

Procedure:
A solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (1.5 g, 6.3 mmol), hydroxylamine hydrochloride (2.2 g, 32.7 mmol), and sodium acetate (2.9 g, 34.9 mmol) in ethanol (20 mL) is heated at reflux for 12 hours. The reaction mixture is poured over water (150 mL) and the precipitate is collected by filtration. Recrystallization from ether/hexane gives the desired 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde oxime as a mixture of isomers (0.62 g, 39%); mp 205°-220° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[S:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:3]1[C:2]([CH3:13])([CH3:1])[S:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:19]
Reactant: CCOC(OCC)N(C)C
Reactant: CC1(C)CC(=O)c2ccccc2S1
Product: CN(C)C=C1C(=O)c2ccccc2SC1(C)C

Procedure:
3,4-dihydro-2-dimethylaminomethylene-3,3-dimethyl-4-thia-1(2H)-naphthalenone was prepared from 3,4-dihydro-3,3-dimethyl-4-thia-1(2H)naphthalenone (426 mg, 1.72 mmol) [Clayton, S E et al, Tetrahedron (1993), 49, 939], and N,N-dimethylformamide diethyl-acetal (1 ml) to give the compound as a yellow solid (113 mg). δH (CDCl3) 8.22 (1H, dd, J 1.6, 7.9 Hz), 7.32-7.14 (3H, m), 6.72 (1H, s), 2.89 (6H, s) and 1.63 (6H, s).