Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH2:16][C:17]([NH:20][C:21](=[O:29])[C@@H:22]([NH:27][CH3:28])[CH2:23][CH:24]([CH3:26])[CH3:25])([CH3:19])[CH3:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35](N(C(C)C)CC)(C)C.BrC[CH:46]=[C:47]([CH3:49])[CH3:48]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:30][CH:31]=[C:32]([CH3:33])[CH3:34])[CH2:16][C:17]([NH:20][C:21](=[O:29])[C@@H:22]([N:27]([CH3:35])[CH2:28][CH:46]=[C:47]([CH3:49])[CH3:48])[CH2:23][CH:24]([CH3:26])[CH3:25])([CH3:19])[CH3:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCBr
Reactant: CN[C@@H](CC(C)C)C(=O)NC(C)(C)CN(CC=C(C)C)c1ccc(OCc2ccccc2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)=CCN(CC(C)(C)NC(=O)[C@H](CC(C)C)N(C)CC=C(C)C)c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C

Procedure:
(S)-4-Methyl-2-methylamino-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide (XIIa, 0.14 g, 0.31 mmol) was dissolved in THF (10 mL), treated with diisopropylethylamine (0.31 g, 2.4 mmol), and 4-bromo-2-methyl-2-butene (0.6 mmol), and heated to 50° C. for 15 hours. The reaction was concentrated and chromatographed on silica gel eluting with 2:1 hexane/EtOAc to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][O:12][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NCCC(O)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (3,4-dihydroxybutyl)carbamic acid tert-butyl ester (2.60 g, 12.7 mmol), triethylamine (2.03 mL, 14.50 mmol) and 4-(dimethylamino)pyridine (0.05 g, 0.4 mmol) in anhydrous dichloromethane (40 mL) at room temperature was added tert-butyldimethylchlorosilane (2.0 g, 13.17 mmol) in one portion. The resulting mixture was stirred at room temperature for 18 hours, washed with water, brine and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave an oil which was purified by column chromatography on silica using ethyl acetate-petroleum ether mixture as eluent to afford a colourless oil.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH2:14][CH3:15])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH2:14][CH3:15])[C:12]=3[N:30]3[CH2:31][CH2:32][C@H:28]([N:27]([CH3:33])[CH3:26])[CH2:29]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCc1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 13 h
Yield: 58.4 %

Procedure:
2-Cyclopropyl-6-ethyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-181) (108 mg, 0.44 mmol) was dissolved in dimethyl sulfoxide (3 ml), then at room temperature, triethylamine (93 μl, 0.66 mmol) and (3S)-3-(dimethylamino)pyrrolidine (73 μl, 0.57 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 13 hours, then cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=93:7) to obtain the entitled compound (87 mg, 58%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](O)=[O:13])=[CH:9][CH:8]=[C:7]2[O:15]C.C[CH2:18][N:19]([CH:23](C)C)C(C)C.[O:26](S(C(F)(F)F)(=O)=O)[S:27]([C:30]([F:33])([F:32])[F:31])(=O)=[O:28]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[S:27]([O:15][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:10]([C:12](=[O:13])[N:19]([CH3:23])[CH3:18])=[CH:9][CH:8]=1)(=[O:28])=[O:26]
Reactant: COc1ccc(C(=O)O)c2c(Cl)cccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c2cccc(Cl)c12
Reaction time: 0.08 h
Yield: 46.7 %

Procedure:
To a mixture of 8-chloro-4-methoxy-1-naphthoic acid (step-6 intermediate) (0.14 g, 0.561 mmol) in DCM (5 mL) was added, DIPEA (0.20 mL, 1.12 mmol) at 0° C. After 5 min stirring, Tf2O (0.11 mL, 0.67 mmol) was added to it. The resulting mixture was stirred for 2 h before quenching with ice water. The aqueous layer was extracted with DCM, and the combined organic layer was washed with, water, brine, dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to furnish the desired trifliate intermediate as a pale yellow oil (100 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>S(Cl)(Cl)=O>[Br:1][C:2]1[O:6][C:5]([C:7]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)[CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(Br)o2)cc1N1CCN(C)CC1
Reaction time: 18 h
Yield: 86.4 %

Procedure:
5-Bromofuroic acid (0.432;2.26 mmol) was heated at reflux in thionyl chloride (10 ml) for 30 minutes, cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in CH2 Cl2 (10 ml) and treated with dry triethylamine (0.32 ml;2.26 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.5 g;2.26 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 2%MeOH/CHCl3 to yield the title compound as a pale yellow foam (0.77 g;86%), which was converted to the oxalate salt, mp=125°-127° C.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([CH3:10])[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1ccc(-c2cccnc2C=O)cc1
Temperature: 90 °C
Yield: 77 %

Procedure:
To a stirred degassed solution of 3-bromo-2-pyridinecarboxaldehyde (198 mg, 1.06 mmol) and 4-methylbenzene boronic acid (152 mg, 1.12 mmol) in DME/THF (3.5 mL, 2.5:1) were added a 2 M Na2CO3 solution (0.9 mL) and Pd(PPh3)4 (63 mg, 0.055 mmol). The reaction mixture was flushed with Ar and maintained under Ar while being heated at 90° C. overnight. The mixture was then cooled and diluted with EtOAc (40 mL) and brine (30 mL). The organic layer was washed with brine (1×30 mL), dried (Na2SO4), filtered and concentrated. Purification of the resultant oil by column chromatography with silica gel (Hexanes/EtOAc, 2:1) afforded 3-p-tolyl-pyridine-2-carbaldehyde (161 mg, 77%) as a yellow oil. 1H NMR (CDCl3) δ 2.43 (s, 3H), 7.25-7.28 (m, 4H), 7.53 (dd, 1H, J=9, 6 Hz), 7.79 (dd, 1H, J=9, 1 Hz), 8.80 (dd, J=3, 1 Hz), 10.09 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.CC(O)C.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>O>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:7]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)c(Nc2ccnc(Cl)n2)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Temperature: 42.5 °C
Yield: 85.5 %

Procedure:
A mixture of intermediate 14 (0.082 mol) and 5.4 N HCl in 2-propanol (0.086 mol) in water (300 ml) was stirred and warmed to 40-45° C. over 30 minutes. 4-Amino-benzonitrile (0.242 mol) was added at 40-45° C. The reaction mixture was stirred and refluxed for 4.5 hours, then cooled to room temperature. The mixture was alkalized by portionwise addition of NaHCO3. This mixture was extracted with ethylacetate. The organic layer was separated, washed with brine, dried, filtered and the solvent was evaporated. This fraction was stirred in ethanol p.a (100 ml), filtered off, washed with ethanol (50 ml), then dried, yielding 23.1 g (86%) 4-[[4-[(2,4,6-trimethylphenyl)-amino]-2-pyrimidinyl]amino]benzonitrile (comp. 17).
Reaction SMILES: C(=O)(O)O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][CH2:17][C:18]([CH2:20][C:21](=O)[CH3:22])=O.C(=O)=O>C(OCC)C>[C:5]1([NH:11][C:12]2[N:14]=[C:21]([CH3:22])[CH:20]=[C:18]([CH2:17][O:16][CH3:15])[N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COCC(=O)CC(C)=O
Reactant: N=C(N)Nc1ccccc1
Agent: O=C(O)O
Agent: O=C=O
Solvent: CCOCC
Product: COCc1cc(C)nc(Nc2ccccc2)n1
Temperature: 100 °C
Yield: 92 %

Procedure:
A mixture of 7.5 g of phenylguanidine hydrogen carbonate and 7.4 g of methoxyacetylacetone is heated at 100° C. for four hours with stirring, the evolution of carbon dioxide which occurs subsiding as the reaction progresses. After the brown emulsion has been cooled to room temperature, 60 ml of diethyl ether are added and the whole is then washed three times with 20 ml of water each time, dried over sodium sulphate and filtered, and the solvent is evaporated. The 10.5 g of oily residue are dissolved in 140 ml of diethyl ether, and then 4.4 g of 65% nitric acid are added thereto with stirring. The suspension of the resulting nitrate salt is stirred for a further 20 minutes and is then filtered and washed with 100 ml of diethyl ether. 6 g of 30% sodium hydroxide solutions are added with stirring to a mixture consisting of 11 g of the nitrate sale, 80 ml of diethyl ether and 60 ml of water, the organic phase is separated off, washed twice with 40 ml of water each time, dried over sodium sulfate and filtered, and the solvent is evaporated. The 8.7 g of light-brown oily residue are crystallised with 100 ml of petroleum ether (b.p. 50°-70° C.), filtered and dried. The 8 g of pale, beige-coloured crystalline powder melt at 59°-60° C.; yield: 92% of the theoretical yield, relative to phenylguanidine hydrogen carbonate.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH:14]=O)=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH:14]2[NH:6][C:1](=[O:5])[CH:2]([CH3:4])[O:3]2)=[CH:10][CH:9]=1
Reactant: O=CCOc1ccc(Cl)cc1
Reactant: CC(O)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1OC(COc2ccc(Cl)cc2)NC1=O
Yield: 2.4 %

Procedure:
16.9g (0.19 mole) of lactamide was added to a solution containing 32.3g (0.19 mole) of (4-chlorophenoxy)acetaldehyde and 0.2g of p-toluenesulfonic acid in 500 ml of toluene. The mixture was refluxed with stirring for 5 hours while water was removed azeotropically. Toluene was removed under reduced pressure and the residue, which contained at least two major compounds, was purified by silica chromatography to give 1.1g of 2-(4-chlorophenoxymethyl)-5-methyl-4-oxazolidinone, cis isomer, as a white crystalline solid melting at 84°-86°.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:13][NH:14][C:15](=N)[C:16]([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:15]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[O:13][N:14]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=N)NO
Reactant: N#CN1CCC2(CC1)OCCO2
Product: CC(C)(C)c1noc(N2CCC3(CC2)OCCO3)n1

Procedure:
The title compound is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile and N-hydroxy-2,2-dimethyl-propionamidine following a procedure analogous to that described in Intermediate 2. LC (method 8): tR=1.53 min; Mass spectrum (ESI+): m/z=268 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:5]=1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:42]=[CH:41][C:30]([CH:31](Cl)[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH:31]([N:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:5]=[C:4]2[CH2:1][CH2:2][CH3:3])[C:30]2[CH:41]=[CH:42][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(C(Cl)c2ccc(OC)cc2)cc1
Reactant: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 48 h
Yield: 83.7 %

Procedure:
To a suspension of 10.0 g (45 mmol) of 2-propyl-6-nitro-quinazolin-4(3H)-one in 160 ml of dry CH2Cl2 was added 9.5 ml (67 mmol) of triethylamine followed by 12.9 g (49 mmol) of 4,4'-dimethoxybenzhydryl chloride. The reaction mixture was stirred for 48 hours and then washed with 10% citric acid (2×20 ml), water (1×20 ml), saturated NaHCO3 (2×20 ml) and brine (1×20 ml). The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was recrystalised from EtOAc to give 17.3 g of white solid. 85% yield. 1H-NMR (CDCl3): 0.87 (t, 3H, J=7.3 Hz), 1.58 (bm, 2H), 2.72 (t, 2H, J=7.8 Hz), 3.80 (s, 6H), 6.88 (d, 4H, J=9 Hz), 7.19 (d, 4H, J=9.0 Hz), 7.73 (d, 1H, J=8.9 Hz), 8.48 (dd, 1H, J=2.8, 9.0 Hz), 9.08 (d, 1H, J=2.8 Hz).
Reaction SMILES: Cl[C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([Cl:18])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C1COCC1>[Cl:18][C:11]1[C:3]([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:2]([NH:33][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CN2CCCCC2)c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2c([N+](=O)[O-])ccc(Cl)c2CN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-(2,6-dichloro-3-nitro-benzyl)-piperidine (21) (0.894 g, 3.09 mmol) and triethylamine (0.606 g, 6 mmol) in anhydrous THF (5 mL), p-methoxy benzylamine (0.823 g, 6 mmol) was added at 0° C. under stirring. The reaction mixture was allowed to warm to room temperature and stirred for additional 12 hours and evaporated to dryness. The product was extracted with EtOAc (100 mL) and washed with water (2×50 mL) and dried (MgSO4). The product was purified by column chromatography (SiO2, hexanes:EtOAc, 95:5 to 9:1) as a yellow oil. Yield: 0.81 g, 67%. 1H-NMR (CDCl3) δ 1.23-1.26 (m, 6H), 2.23 (m, 4H), 3.63 (s, 2H), 3.76 (s, 3H), 3.92 (d, 2H, J=4.4 Hz), 6.65 (d, 1H, J=9.04 Hz), 6.82 (d, 2H, J=8.6 Hz), 7.18 (d, 2H, J=8.6 Hz), 7.18 (d, 2H, J=8.6 Hz) 7.57 (d, 1H, J=9 Hz), 8.29 (bs, 1H). NOE's were observed from H4 to H3, H5, H6. No NOE was observed from H4 to H1, which would have been expected if the other regioisomer was formed. MS (CI) m/z 390 (M+1), 392 (M+2).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@@H:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C=C(C(C)(C)C)C=1O)[CH:43]=[O:44])(C)(C)C.[Pb](=O)=O>C1C=CC=CC=1.ClCCCl>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@:15]([NH2:16])([O:44][CH3:43])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=[Pb]=O
Solvent: ClCCCl
Solvent: c1ccccc1
Product: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@](N)(OC)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.32 g (2.4 mmol) of 7β-amino-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester and 0.56 g (2.4 mmol) of 3,5-di-t-butyl-4-hydroxybenzaldehyde in 100 ml of dry benzene is refluxed for 4 hours under a Dean-Stark trap. The solution is evaporated under reduced pressure to leave a residue which is dissolved in 100 ml of 1,2-dichloroethane and cooled to ca. 5° in an ice bath. Three grams of freshly prepared lead dioxide is added in portions over 20 minutes until the starting material is completely consumed. The mixture is filtered through Celite and the filter cake is washed with two 20 ml portions of cold 1,2-dichloroethane. The filtrate is treated with 25 ml of methanol (distilled from magnesium) and the reaction mixture is allowed to stand at room temperature until complete consumption of the oxidized intermediate and formation of a new slower-moving product is shown by thin layer chromatography. The mixture is evaporated and the residue is dissolved in 30 ml of methanol and treated with 2.5 g of Girard reagent T (trimethylaminoacetohydrazide chloride). The reaction mixture is stirred at room temperature for 3 hours, then evaporated to give a residue which is partitioned between ethyl acetate and 20% sodium chloride solution. The organic phase is washed with 10% sodium chloride solution and saturated sodium chloride solution. The organic phase is dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-7α-methoxy-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: C.[CH3:2][CH2:3][CH2:4][CH2:5]CCCC[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N+]1C=CC=CC=1.[Cl-]>>[CH2:2]=[CH:3][CH:4]=[CH2:5].[CH2:17]=[CH:16][C:15]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCCCCCCCCCCC[n+]1ccccc1
Agent: C
Agent: [Cl-]
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
A toner was prepared by extrusion of the above polymer, 92 percent, 6 percent of REGAL 330® carbon black and 2 percent of CPC (cetyl pyridinium chloride charge additive) followed by micronization to 10 microns. The minimum fix temperature of the toner was 230° F. as determined by no cracking of the fused toner images as a result of a 180 degrees paper crease test (paper folded 180 degrees, visually observed the breadth of cracking at crease) and the minimum fix temperature of the toner was 230° F. when no appreciable, for example a peppered, toned image was removed with SCOTCH® Tape Magic 810, and the hot offset temperature was 320° F. where the toned image sticks to silicone roll fuser as indicated herein. When fused, toner images were observed to offset from paper onto a silicone fuser roll, and then was imprinted onto the same paper or subsequent papers. The hot offset temperature, where the toner failed to release from the fuser roll, was 300° F.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[C:18]2[C:23]([F:26])([F:25])[F:24])(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]2[C:3]([S:9](=[O:10])(=[O:11])[NH:12][C:13]3[C:14]2=[CH:15][CH:16]=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[C:18]2[C:23]([F:26])([F:24])[F:25])=[CH:2][CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3c(C(F)(F)F)ccnc23)-c2cc(Cl)ccc21
Yield: 18.3 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-4-chloro-N-(4-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 280) (340 mg, 0.85 mmol), t-butyl nitrite (0.15 ml, 1.27 mmol), AcOH (4 ml), THF (4 ml) gave the title compound (60 mg, 18%) after purification by column chromatography with DCM/MeOH (98:2) as the eluent.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[C:20]([CH3:22])[CH3:21]>CS(C)=O.O1CCCC1>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@@:13]12[CH2:21][C:20]1([CH3:4])[CH3:22]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)=C1C(=O)Nc2ccc(F)cc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(C)C[C@]12C(=O)Nc1ccc(F)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A solution of NaH (60%) (0.6 g, 15 mmol) and trimethylsulfoxonium iodide (3.3 g, 15 mmol) in dimethyl sulfoxide (30 mL) was stirred for 30 minutes at 25° C. Then a solution of 5-fluoro-3-isopropylidene-1,3-dihydro-indol-2-one (2.6 g, 13.6 mmol) in dry tetrahydrofuran (30 mL) was added dropwise over 20 minutes. After being stirred for 1 hour at 25° C. and 1 hour at 50° C., the reaction solution was poured into ice-cold water and extracted with ether (3×100 mL), washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ether to afford the title compound as white solid (2.39 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCCN1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCN2CCCCC2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, hydroxyethylpiperidine and DBU in DME. ES-MS m/e (%:314 (M+H+, 100).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:16][C:17]([C:19]1[N:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)=O)(=O)OC.O.[NH2:26][NH2:27]>>[CH3:24][N:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]1[N:27]=[N:26][C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]=2[CH:16]=1
Reactant: COP(=O)(CC(=O)c1cccn1C)OC
Reactant: NN
Reactant: O=C1CCCCCC1=O
Solvent: O
Product: Cn1cccc1-c1cc2c(nn1)CCCCC2

Procedure:
light brown solid. MS (EI): 227.2 (M+). Prepared from cycloheptane-1,2-dione, [2-(1-Methyl-1H-pyrrol-2-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.