Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][C@@H:29]([CH:33]([CH3:35])[CH3:34])[C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C@@H:29]([OH:28])[CH:33]([CH3:35])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC(C)[C@H](O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (9 mg, 25.6%), MS (ISP) m/z=432.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and (S)-2-hydroxy-3-methylbutanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[CH:10]2)=[CH:5][CH:4]=1.O.C(OCC)(=O)C.[CH3:28][N:29](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:28]#[N:29])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2ccc(C#N)cc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 7-methoxy-2-trifluoromethanesulfonyloxynaphthalene (2.23 g) in dimethylformamide (8.9 ml) were added zinc cyanide (598 mg) and tetrakis(triphenylphosphine) palladium (337 mg) at room temperature, and the mixture was stirred at 80° C. for 1 hour. After completion of the reaction, water and ethyl acetate were added and insoluble material was removed. The organic layer was separated and concentrated, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) and dried under reduced pressure to give the title compound (965 mg).
Reaction SMILES: C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:23][C@H:22]1[C:24](O)=[O:25])=[O:20])[CH3:17].[BH4-].[Na+]>O1CCCC1.O>[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:23][C@H:22]1[CH2:24][OH:25])=[O:20])[CH3:17]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]1CO
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
Add isobutylchloroformate (0.41 mL, 3.16 mmol) and N-methylmorpholine (0.35 mL, 3.16 mmol) to a solution of (+/−)-trans-cyclopropane-1,2-dicarboxylic acid monoethyl ester (0.50 g, 3.161 mmol) in tetrahydrofuran (21 mL) at −50° C. Stir for 5 minutes and then filter into a slurry of sodium borohydride (0.084 g, 2.21 mmol) in tetrahydrofuran (9 mL) and cool to −50° C. Warm to room temperature over night and then add 9 mL of water. Remove tetrahydrofuran under reduced pressure and extract aqueous layer with diethyl ether (3×20 mL). Wash combined organic layers with saturated aqueous sodium chloride and dry over magnesium sulfate. Concentrate under reduced pressure and subject residue to silica gel chromatography eluting with 25-65% ethyl acetate in hexanes to provide the desired compound (0.224 g, 49.1%).
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2[CH:3]=C1)[CH2:7]3.C([OH:14])C=C>>[CH:8]12[CH2:7][CH:6]([CH:10]=[CH:9]1)[CH2:5][CH:4]2[CH2:3][OH:14]
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reactant: C=CCO
Product: OCC1CC2C=CC1C2
Temperature: 210 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
After DCPD (dicyclopentadiene, Aldrich, 397 g, 3 mol) and allyl alcohol (Aldrich, 331 g, and 5.7 mol) were put into a 2 L high pressure reactor, temperature was increased to 210° C. After a reaction was conducted for 1 hour while agitating at 300 rpm, reactants were cooled and moved to a distillator. Distillation was repeatedly conducted under reduced pressure of 1 torr using a vacuum pump twice to obtain a product at 56° C. (yield: 52%)
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:29])[CH2:16][CH2:17][CH2:18][C:19]([OH:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH2:6]1)(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:29])[CH2:16][CH2:17][CH2:18][C:19]([OH:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:23])([F:21])[F:22])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(O)(C(F)(F)F)C(F)(F)F)[C@@]4(C)CC[C@@H]32)C1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(O)(C(F)(F)F)C(F)(F)F)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.9 %

Procedure:
To a refluxing solution of the acetate 4 (19 mg) in CCl4 (2 ml), N-bromosuccinimide (9 mg) was added and the mixture was refluxed for 20 min under argon. After cooling, the resulting precipitate was filtered off, and the filtrate was evaporated under vacuo. The residue was dissolved in xylene (1.5 ml) and dropped into a refluxing solution of s-collidine (0.5 ml) in xylene (1.5 ml). After refluxing for 10 min, the mixture was extracted with ethyl acetate. The crude product was dissolved in acetone (5 ml) and treated with p-toluenesulfonic acid (10 mg) by stirring for 14 hr at room temperature. After addition of water, the mixture was extracted with ethyl acetate. The reaction product was purified with preparative TLC (benzene-ethyl acetate, 50:1; two times) to give the 5,7-diene 5 (4.9 mg); UV, λMax (EtOH)262(sh), 271, 282, 293 nm.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]2[C:21]([O:26][C:27]3[CH:35]=[CH:34][C:30]4=[N:31][O:32][N:33]=[C:29]4[CH:28]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[C:12]([F:36])[CH:11]=1)[CH3:8])(C)(C)C>C(O)=O>[N:31]1[O:32][N:33]=[C:29]2[CH:28]=[C:27]([O:26][C:21]3[C:20]([C:18]([NH:17][CH2:16][C:13]4[CH:14]=[CH:15][C:10]([O:9][CH:7]([CH3:8])[C:6]([OH:37])=[O:5])=[CH:11][C:12]=4[F:36])=[O:19])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:35]=[CH:34][C:30]=12
Reactant: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)OC(C)(C)C
Solvent: O=CO
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)O
Yield: 80.4 %

Procedure:
(±)-2-[4-({[2-(Benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro- phenoxy]-propionic acid tert-butyl ester (0.17 g, 0.33 mmol) was stirred in formic acid (5 mL) at room temperature 2 hours. Formic acid was removed in vacuo and the product stored over night under high vacuum to afford a white solid (0.12 g, 80% yield).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.O=C1[NH:15][CH:14](C(O)=O)[CH2:13]C1.C(CN)O>>[NH:1]1[CH:2]([C:7]2[O:9][CH2:13][CH2:14][N:15]=2)[CH2:3][CH2:4][C:5]1=[O:6]
Reactant: O=C1CCC(C(=O)O)N1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: NCCO
Product: O=C1CCC(C2=NCCO2)N1

Procedure:
In a similar manner, pyroglutamic acid, i.e. 5-oxo-2-pyrrolidinecarboxylic acid, where R=H and m=0 in the above formula (I), can be condensed with ethanolamine and cyclodehydrated to form the corresponding monomer 2-(2-pyrrolidon-5-yl)-2-oxazoline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][CH2:31][C:32]#[N:33])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17](CC[Si](C)(C)C)[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][CH2:31][C:32]#[N:33])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCCC#N)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#CCCCc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of 4-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-butyronitrile (45.7 mg, 0.094 mmol) in THF (4 mL) is added 0.188 mL of a 1M solution of TBAF in THF. The mixture is stirred at 65° C. for 1 h then is allowed to cool to RT. The mixture is poured into 1N HCl and extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by reverse phase Biotage using a gradient of 0-30% EtOH/water as eluent to furnish the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7](C(C2NC3=NC=C(F)C=C3C=2)=CC2CCOCC2)=[CH:6][C:5]=1F>[Pd].CO>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3[nH]2)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1
Temperature: 50 °C
Yield: 268.1 %

Procedure:
A mixture of 2-fluoro-4-[1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl]-benzoic acid methyl ester (250 mg, 0.63 mmol) and 10% palladium on activated carbon (75 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo to afford 2-fluoro-4-[1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethyl]-ethyl]-benzoic acid methyl ester (230 mg, 91%) which was used in the next step without further purification: LC/MS m/e calcd for C22H22F2N2O3 [M+H]+ 401.43, observed 400.9.
Reaction SMILES: [CH:1]1[C:18]2[C:5](=[C:6]3[C:15](=[CH:16][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[S:8](=[O:20])(=[O:19])[NH:7]3)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23]I>C1COCC1>[CH3:23][N:7]1[S:8](=[O:19])(=[O:20])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]2[C:6]1=[C:5]1[C:18](=[CH:17][CH:16]=2)[CH:1]=[CH:2][CH:3]=[N:4]1
Reactant: CI
Reactant: O=S1(=O)Nc2c(ccc3cccnc23)-c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1c2c(ccc3cccnc23)-c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
5H-6-Thia-4,5-diaza-chrysene 6,6-dioxide (Example Compound 2) (50 mg, 0.18 mmol) was added to solution of NaH (60% dispersion in mineral oil; 11 mg, 0.27 mmol) dissolved in dry THF (3 ml), under argon, at 0° C., and the mixture was stirred for 15 min. Methyliodide (29 mg, 0.22 mmol) was added and the reaction was allowed to warm to room temperature and stirring continued for 12 h. After completion of the reaction (monitored by TLC), the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with water and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (3:1) as the eluent to give the title compound (27 mg, 52%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH:28]([C:29]([NH:31][OH:32])=[O:30])CCNCC2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11].IC>CO.ClCCl.O>[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH:28]([C:29]([NH:31][OH:32])=[O:30])[CH2:7][CH2:6][N:3]([CH3:1])[CH2:4][CH2:5]2)(=[O:20])=[O:21])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11]
Reactant: CCN(CC)CC
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCCC2C(=O)NO)cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C)CCC2C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.08 mL) was added to a suspension of the product of Example 292, 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide (0.10 g), in methanol (6 mL) to give a solution which was cooled to 0° C. lodomethane (0.025 mL) was then added. After 30 min the reaction mixture was allowed to warm to 25 ° C. After 20 min additional iodomethane (0.02 mL) was added followed by additional triethylamine (0.015 mL). After 18hours the reaction mixture was diluted with dichloromethane and water. The aqueous phase was washed with dichloromethane (3×). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The material obtained was combined with material from a previous reaction run on the same scale and chromatographed on silica gel to give 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-methyl-1,4-diazepane-5-carboxamide (0.067 g). Electrospray Mass Spec 382.2 (N+H)+
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]1[N:19]2[C@@H:13]([S:14][CH2:15][CH2:16][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:18]2=[O:20])[CH2:12][CH2:11][CH2:10]1.IC>C1COCC1>[CH3:1][O:7][CH2:8][C@H:9]1[N:19]2[C@@H:13]([S:14][CH2:15][CH2:16][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:18]2=[O:20])[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](CO)N2C1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A solution of potassium tert-butoxide (1 M in THF, 1.55 mL, 1.55 mmol) was added dropwise to a 0° C. solution of tert-butyl (4S,7S,10aS)-7-(hydroxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (513 mg, 1.55 mmol) in THF (5 mL). The reaction mixture turned yellow in color. After 15 min of stirring, iodomethane (441 mg, 3.10 mmol) was added. The ice bath was removed and the reaction mixture was stirred at rt overnight. Water was added to the reaction and the mixture was concentrated to remove most of the THF. The aqueous solution was then extracted with EtOAc. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give tert-butyl (4S,7S,10aS)-7-(methoxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (83 mg, 0.24 mmol, 16% yield) as a colorless oil. Anal. Calcd. for C16H28N2O4S m/z 344.4. found: 345.1 (M+H)+.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[C-:18]#[N:19]>C(Cl)Cl.C(=O)(O)[O-].[Na+].O>[C:12]1([CH2:11][N:8]2[CH2:9][CH2:10][C@H:6]([C:18]#[N:19])[CH2:7]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#C[C@H]1CCN(Cc2ccccc2)C1
Temperature: 60 °C
Yield: 109.3 %

Procedure:
(3R)-1-(phenylmethyl)-3-pyrrolidinyl methanesulfonate (12.9 g, 50.6 mmol) and tertrabytulamonium cyanide (25 g, 93.3 mmol) was mixed in DCM (20 mL) and refluxed at 60° C. for 6 h. The resulting solution was cooled down to room temperature and diluted with saturated sodium bicarbonate solution in water. The aqueous phase was extracted several times with toluene. The organic fractions was combined, washed with brine and concentrated to provide the title compound as an oil (10.3 g, quantit.) which was used without further purification: LC/MS (ES) m/e 187 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13]C1C=CC2CCN(C3CCC3)CCC=2C=1)[C:6]([NH:8][CH3:9])=[O:7])#[N:2].B(Br)(Br)Br.O.Cl>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([NH:8][CH3:9])=[O:7])#[N:2]
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(C#N)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(O)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
3-Cyano-N-methyl-4-(methyloxy)benzamide (E279, Step 2) (346 mg, 1.82 mmol), was dissolved in dry dichloromethane (10 ml), cooled to 0° C. and treated with boron tribromide (1M solution in dichloromethane) (9.11 ml, 9.11 mmol). The mixture was stirred for 30 minutes, allowed to warm to room temperature and stirred for 18 hours. The mixture was cooled in an ice bath, treated with water added dropwise and then allowed to warm to room temperature. The mixture was poured onto 2M hydrochloric acid (10 ml) and extracted with ethyl acetate. The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate dichloromethane (1:1) to afford the title compound (86 mg); MS (ES+) m/e 177 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:10]([OH:22])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](Cl)=[O:41]>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:10]([O:22][C:40](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)C)cc2O)cc1
Reactant: O=C(Cl)c1ccccn1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)C)cc2OC(=O)c2ccccn2)cc1

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with picolinoyl chloride, there is obtained 3-(picolinoyloxy)4-(p-toluyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(picolinoyloxy)-4-(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9]([O:11]CC)=O)=O.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH2:8][C:9](=[O:11])[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: NNc1ccccc1
Solvent: CCO
Product: COc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1OC
Yield: 21.5 %

Procedure:
Using General Procedure A; ethyl 3,4-dimethoxybenzoylacetate (3.00 g, 11.9 mmol, 1.1 equ.) in ethanol (60 mL) was treated at 0° C. with phenylhydrazine (1.17 mL, 10.8 mmol, 1.0 equ.) to afford 3-(3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (920 mg, 2.32 mmol, 22%) after purification by crystallization (ethanol) as a yellow powder. 1H-NMR (400 MHz) CDCl3: 8.00-7.97 (d, 1H), 7.48-7.42 (m, 3H), 7.25-7.21 (t, 1H), 7.17-7.14 (dd, 1 H), 6.91-6.89 (d, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.83 (s, 2H), 13C-NMR (100 MHz) CDCl3: 170.1, 154.4, 151.4, 149.4, 138.1, 128.8, 125.2, 123.8, 120.1, 119.1, 110.7, 107.6, 56.0, 56.0, 39.7; LC/MS-MS: 297.0→218.2 m/z; GS1 and GS2 at 30, DP=96, CE=37, CXP=18, tR=3.98 min.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1.Cl[C:20]1[CH:21]=[C:22]([CH3:27])[N+:23]([O-:26])=[CH:24][CH:25]=1.C(O)(C)(C)C>O>[F:7][C:8]([F:17])([F:18])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:14][C:20]2[CH:21]=[C:22]([CH3:27])[N+:23]([O-:26])=[CH:24][CH:25]=2)=[CH:11][CH:10]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(OCc2ccc(C(F)(F)F)cc2)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.2 g (100 mmol) of potassium tert.-butoxide are added under an N2 atmosphere at 25° C. to 25 ml (183 mmol) of 4-trifluoromethylbenzyl alcohol. 7.2 g (50 mmol) of 4-chloro-2-picoline-N-oxide are subsequently added dropwise, then 10 ml of tert.-butanol are added, and the mixture is stirred for 1 hour at 25° C. and for 30 minutes at 75°-80° C. Water is then added and the mixture is extracted three times using dichloromethane, the extracts are dried and concentrated, and the residue is chromatographed on silica gel using dichloromethane/methanol. The product is obtained from the corresponding fractions, m.p. 113°-115° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][C:10]#[N:11]>[Ni].CCO>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH2:11]
Reactant: CC1CCCC(C)N1CC#N
Agent: [Ni]
Solvent: CCO
Product: CC1CCCC(C)N1CCN
Reaction time: 5 h
Yield: 78.3 %

Procedure:
A mixture of nitrile 279 (3.13 g, 20.6 mmol) and Raney Nickel (50% w/w suspension in water, ca. 2 mL) in EtOH (30 mL) and cNH3 (2 mL) was stirred under H2 (60 psi) for 5 h. The suspension was filtered through Celite, washed with EtOH (3×10 mL) and the solvent evaporated to give diamine 280 (2.52 g, 78%) as a colourless oil which was used without further purification: 1H NMR δ 2.71-2.76 (m, 2H, CH2N), 2.63-2.68 (m, 2H, CH2N), 2.41-2.47 (m, 2H, 2×CH), 1.49-1.55 (m, 2H, CH2), 1.43 (br s, 2H, NH2), 1.25-1.42 (m, 4H, 2×CH2), 1.11 (d, J=6.3 Hz, 6H, 2×CH3); MS m/z 157 (MH+, 100%).
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].O=[C:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1>CN(C=O)C.CCOCC>[Br:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.6 %

Procedure:
To [(3-bromophenyl)methyl](triphenyl)phosphonium bromide (1.13 mg, 2.2 mmol) in DMF (4 mL) was added NaH (52.8 mg, 2.2 mmol). This mixture was stirred at RT for 5 min, then 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (400 mg, 2.0 mmol) was added and the pot stirred at RT for 1 h. The resultant mixture was diluted with Et2O (25 mL), washed with H2O (12+2×8 mL), brine (8 mL), dried over NaSO4, and filtered. The mixture was concentrated and purified with CombiFlash chromatograph to afford the title compound (0.2014 g, 28%). LC-MS m/z 352 (M+H)+.
Reaction SMILES: I[C:2]1[CH:13]=[C:12]([CH3:14])[C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:15]([Cu])#[N:16]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:12]1[C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=[C:2]([C:15]#[N:16])[CH:13]=1
Reactant: Cc1cc(I)cc2c(=O)oc(=O)[nH]c12
Reactant: N#C[Cu]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(=O)[nH]c12
Yield: 61.2 %

Procedure:
600 mg (1.98 mmol) 6-iodo-8-methyl-1H-benzo[d][1,3]oxa zine-2,4-dione (prepared according to known procedures, see G. M. Coppola, Synthesis, 1980, 505), 212 mg (2.37 mmol) CuCN, 377 mg (1.98 mmol) Cul and 114 mg tetrakis(triphenylphosphine) palladium in 60 ml THF are heated 5 h at reflux. After cooling down, the mixture is filtered on Hyflo. The organic phase is washed with water and evaporated. The residue is crystallized from a mixture of dichloromethane, ethyl acetate and hexane to afford 245 mg 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile, which is directly used in the next step.