Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][OH:28])[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C=O)c2)c1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(CO)c2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 6 (38 mg, 0.098 mmol) in methanol (3 mL) was added NaBH4 (11 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 h. Aqueous NaOH was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and saturated NaCl solution. The organic was then dried over Na2SO4, filtered and concentrated to give a residue that could be purified by silica gel chromatography (eluent: 1/4 hexanes/EtOAc). The desired 3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 7 was obtained as a white solid (22 mg, 58%). MS m/z 391.2 [M+H]+; 1H NMR (300 MHz, CDCl3) 0.56 (m, 2H), 0.82 (m, 2H), 2.22 (s, 3H), 2.82 (m, 1H), 4.75 (s, 2H), 5.91 (brs, 2H), 6.75 (brs, 1H), 7.49 (m, 3H), 7.76 (m, 4H), 7.99 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 3-(6-chloro-2-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (4.1 g, 10.7 mmol) in methanol (20 ml) was added 2N aqueous sodium hydroxide solution (10.7 ml, 21.4 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give 3-(6-chloro-2-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (3.3 g, 86%, (2RS,3RS) form: (2RS,3SR) form=1:1).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[N:22]=[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][OH:21])[N:14]2[N:13]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[N:22]=[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH:20]=[O:21])[N:14]2[N:13]=1
Reactant: Cc1nc2cccc(CO)n2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1nc2cccc(C=O)n2n1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of dimethyl sulfoxide (7.83 mL, 110 mmol) in dichloromethane (100 mL) was added oxalyl chloride (4.83 mL, 55.2 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (2-methyl[1,2,4]triazolo[1,5-a]pyridin-5-yl)methanol (3.00 g, 18.4 mmol) in dichloromethane (84.0 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (22.3 mL, 165 mmol) at −78° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (2.80 g, yield 95%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19](O)[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[S:25][CH:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:13][CH:14]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Reactant: Sc1nc2ccccc2o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Sc1nc2ccccc2o1
Yield: 115.1 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (415 mg), which is obtained in a similar manner to that described in Reference example 39(a), 2-mercaptobenzoxazole (277 mg), tributylphosphine (0.46 ml) instead of triphenylphosphine and 1,1′-(azodicarbonyl)dipiperidine (460 mg) instead of diethylazodicarboxylate and the reaction mixture was treated to afford the desired compound (665 mg) as a colorless oil which contained some impurities.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]2=[O:27])[S:5]([CH3:8])(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)C>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][N:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]3=[O:27])[S:5]([CH3:8])(=[O:7])=[O:6])[CH2:37][CH2:36]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCBr)S(C)(=O)=O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)OC(C)(C)C)C3=O)S(C)(=O)=O)CC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To a solution of tert-butyl 2-(5-(N-(2-bromoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (300 mg, 0.650 mmol) in acetonitrile (15 ml), K2CO3 (135 mg, 0.975 mmol) and 1-methylpiperazine (0.080 ml, 0.715 mmol) were added, and the resulting mixture was heated under MW irradiation at 130° C. for 1 hour. Additional K2CO3 (44.8 mg, 0.325 mmol) and 1-methylpiperazine (0.036 ml, 0.325 mmol) were added, and the reaction was submitted to a second microwave cycle at 130° C. for 1 hour. The mixture was diluted with acetonitrile, the insoluble inorganic salts were filtered off, and the filtrate was evaporated under vacuum. Purification by flash chromatography (DCM/MeOH 95/5) afforded tert-butyl 2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (149 mg, 0.310 mmol, 47.7% yield, MS/ESI+ 480.9 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:20](OC(=O)C)(=[O:22])C>C(O)=O>[CH:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCCON=C(C(=O)OCC)c1csc(N)n1
Solvent: O=CO
Product: CCOCCON=C(C(=O)OCC)c1csc(NC=O)n1
Yield: 68.1 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(2-etoxyethoxyimino)acetate (syn isomer, 11.5 g.), acetic anhydride (8.2 g.) and formic acid (3.7 g.) were treated in a similar manner to that of Example A-(4) to give ethyl 2-(2-formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetate (syn isomer, 8.6 g.).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (39.0 g, 110 mmol) in ethanol (100 mL) was added a solution of sodium hydroxide (5.73 g, 143 mmol) in water (100 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure, the residue taken up in water (200 mL), the solution washed with dichloromethane (3×75 mL) and then acidified to about pH 6. The aqueous mixture was extracted with dichloromethane (3×75 mL), and then the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoic acid (31.0 g) as a solid that was used directly in the next step without further purification.
Reaction SMILES: CO[C:3]1[NH:4][CH2:5][CH2:6][CH:7]=1.[C:8]1([C:14]2[CH:22]=[CH:21][C:17]([CH2:18][C:19]#[N:20])=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N12CCCCC1C=NCCC2>C(OCC)C>[C:14]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:15]=[CH:16][C:17]([C:18]([C:19]#[N:20])=[C:3]2[CH2:7][CH2:6][CH2:5][NH:4]2)=[CH:21][CH:22]=1
Reactant: N#CCc1ccc(-c2ccccc2)cc1
Reactant: COC1=CCCN1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOCC
Product: N#CC(=C1CCCN1)c1ccc(-c2ccccc2)cc1

Procedure:
Stir 32.7 g of 2-methoxypyrroline, 63.8 g of 4-phenylbenzylcyanide and 5 g of 1,5-diazabicyclo[5,4,0]undec-5-ene for 26 hours at 110°. After cooling, take up the mixture with 500 ml of diethyl ether. Filter the formed precipitate and recrystallize it from 400 ml of ethanol with activated charcoal to obtain 12.2 g (14% of theory) of the title compound (m.p. 168° to 170°).
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][CH3:35])[CH2:22][C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccncc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccncc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-((4-pyridylmethyl)amino)-pentyl)piperidin-4-yl)methyl)benzamide (0.8 g) as starting compound, acetaldehyde (0.12 ml) and sodium cyanoborohydride (0.14 g) were reacted and treated in the same manner as in Example 136 to give 0.35 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-pyridylmethyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:31][N:14]3[C:15](=[O:30])[CH2:16][CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=4)[CH2:19][C@@H:13]3[CH2:12]2)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CO>CO>[OH:10][C@@H:11]1[CH2:31][N:14]2[C:15](=[O:30])[CH2:16][CH2:17][N:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][N:21]=3)[CH2:19][C@@H:13]2[CH2:12]1
Reactant: O=C(O[C@H]1C[C@H]2CN(c3ccc(C(F)(F)F)cn3)CCC(=O)N2C1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@H](O)CN12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To (8S,9aS)-5-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-1H-pyrrolo[1,2-a][1,4]diazepin-8-yl 4-nitrobenzoate (135 mg, 0.291 mmol, Part C) in methanol (2.5 mL) was added potassium carbonate (24 mg, 0.174 mmol). The mixture was stirred at room temperature for 1.5 hours and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=10:1) to give 78 mg (85% yield) of the titled compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 1H), 2.28 (m, 1 H), 2.45 (m, 1H), 2.63 (m, 1 H), 3.35 (m, 3 H), 3.44 (m, 1 H), 3.92 (m, 1H), 4.17 (m, 1H), 4.42 (m, 2H), 5.09 (br s, 1H), 7.00 (d, J=8 Hz, 1 H), 7.80 (d, J=8 Hz, 1 H), 8.43 (s, 1 H); MS (ESI) m/z 316.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.CN(C)[CH:22]=[O:23].O>C(OCC)C>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:22]=[O:23])[CH3:2]
Reactant: CCOC(OCC)c1ccccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCOC(OCC)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.4 g of 2-bromobenzaldehyde diethyl acetal in 200 ml of dry diethyl ether at -65° C. was added 27.5 ml of a 1.6 M solution of butyllithium in hexanes. The solution was stirred at this temperature for 30 min. then slowly warmed to -40° C. when 3.4 ml of dimethylformamide was added dropwise. The reaction was warmed to room temperature then 100 ml of water was added and the organic layer was separated. The aqueous layer was extracted with two 100 ml portions of ether and the combined organic extracts were dried over sodium sulfate and evaporated to give 8.5 g of 2-formylbenzaldehyde diethylacetal as an oil; ; 1H-NMR (200 MHz, CDCl3) d 5.06 (CHOEt).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[CH3:18])[CH2:4][CH2:3]1.N1(C2CCN(C3C=CC(N)=C(OC)C=3)CC2)CCCCC1>>[CH3:18][C:10]1[C:9]([CH2:8][N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:15]
Reactant: Cc1c(CN2CCN(C)CC2)cccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Product: Cc1c(N)cccc1CN1CCN(C)CC1

Procedure:
The title compound of step B was prepared from 1-methyl-4-[(2-methyl-3-nitrophenyl)methyl]-piperazine in an analogous manner as that described for the synthesis of 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Example 22, step C). 1H NMR (400 MHz, DMSO-d6) δ 6.52 (d, J=6.8 Hz, 1H), 6.53 (d, J=6.8 Hz, 1H), 6.40 (d, J=7.5 Hz, 1H), 4.69 (s, 2H), 3.28 (s, 2H), 2.14-2.40 (m, 8H), 2.11 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][NH:11][C:12](=[O:22])[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]OS(OC)(=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([CH3:25])[C:12](=[O:22])[C:13]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1nc[nH]c(=O)c1OCc1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)OC(C)(C)C)c(OCc2ccccc2)c1=O

Procedure:
Using a procedure described in U.S. Patent Publication No. 2005/0090668, a solution of 5-benzyloxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid tert-butyl ester was first treated with NaH (1.3 equiv.) in DMF followed by the addition of dimethylsulfate (1.3 equiv.) to give mainly the desired product after 2 h at room temperature. The reaction mixture was quenched with cold HCl (1N, 30 vol.) and extracted with EtOAc (3×30 vol.). The combined organic extracts were washed with dilute HCl and brine, dried and concentrated to an oil. Chromatography of the crude product (eluted with 40-60% EtOAc/hexane) gave 88% yield of the N-methylated compound (Synthon A).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:12]2[C:13]([O:21]C)=[CH:14][CH:15]=[C:16]([CH2:18][CH:19]=[CH2:20])[CH:17]=2)[C:7]([O:10]C)=[CH:8][CH:9]=1)[CH:2]=[CH2:3].[Cl-].[Al+3].[Cl-].[Cl-].NC(N)=S.Cl>ClCCCl>[CH2:3]=[CH:2][CH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:12]2[CH:17]=[C:16]([CH2:18][CH:19]=[CH2:20])[CH:15]=[CH:14][C:13]=2[OH:21])[CH:5]=1
Reactant: C=CCc1ccc(OC)c(-c2cc(CC=C)ccc2OC)c1
Agent: Cl
Agent: NC(N)=S
Agent: [Al+3]
Solvent: ClCCCl
Product: C=CCc1ccc(O)c(-c2cc(CC=C)ccc2O)c1

Procedure:
The 4,4′-diallyl-2,2′-bianisole is added to a mixture of aluminum chloride, thiourea and 1,2-dichloroethane slowly over 3 hours at 50° C. Temperature and stirring is maintained for an additional 3-4 hours. Reaction mix is cooled and added to HCl and phases are separated. The organic layer is added to charcoal, filtered and the solvent distilled, to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Solvent: C1CCOC1
Product: Fc1cc(Br)c2[nH]ccc2c1
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
2-bromo-4-fluoro-1-nitrobenzene (3.5 g, 15.9 mmol) was dissolved in anhydrous THF (160 ml) under N2. The reaction was cooled to −45° C. and vinyl magnesium bromide (3 eq, 1M) was added, the mixture was stirred for 30 min at this temperature. The reaction was quenched with NH4Cl (sat.) and 1N HCl. The aqueous layer was then extracted 3× with ether. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and then concentrated under reduced pressure. The product was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 11.45 (bs, 1H), 7.50 (t, 1H), 7.40 (dd, 1H), 7.25 (dd, 1H), 6.50 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([NH2:14])=O)=[O:7].C(N(CC)CC)C>ClCCl.O1CCOCC1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]#[N:14])=[O:7]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCc2ccccc2Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])c(NC(=O)CCc2ccccc2Cl)c1
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
Thirty milliliters of 1,4-dioxane were added dropwise to a solution of 1.70 ml of titanium tetrachloride in 4 ml of dichloromethane in a nitrogen atmosphere while being cooled with ice. Then, a solution of 2.70 g of 3-[N-(2chlorobenzyl)acetylamino]-4-nitrobenzamide in 65 ml of 1,4-dioxane was added dropwise thereto. After the mixture was stirred for 15 minutes, 3.14 g of triethylamine were added thereto, and the mixture was stirred for 2 hours while being cooled with ice. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and with water. The organic layer was washed with water, and was dried over magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure. The residue was purified through column chromatography [200 ml, a mixture of n-hexane and ethyl acetate at a ratio of 4:1] to give 1.21 g of 3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenznitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)[NH2:5].[CH2:11]([O:13][C:14]([C:16]#[C:17][C:18](OCC)=[O:19])=[O:15])[CH3:12]>CO>[CH2:9]([C:7]1[CH:8]=[C:2]([Br:1])[CH:3]=[C:4]2[C:6]=1[C:18](=[O:19])[CH:17]=[C:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[NH:5]2)[CH3:10]
Reactant: CCc1cc(N)cc(Br)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CO
Product: CCOC(=O)c1cc(=O)c2c(CC)cc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dissolve 3-bromo-5-ethylaniline (4.7g, 23.5mmol) in methanol (100mL) and add diethylacetylene dicarboxylate (5.5mL) at room temperature. Reflux for 10 hours and cool to room temperature. Evaporate the solvent in vacuo and add to diphenylether (100mL) at 250° C. Stir for 15 minutes and let cool to room temperature. Add hexane (500mL) and filter the precipitate. Purify by silica gel chromatography to give 5-ethyl-7-bromo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[CH:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: Brc1ncccn1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ncccn2)CC1
Reaction time: 8 h
Yield: 8 %

Procedure:
To a suspension of 2-bromopyrimidine (175 mg, 1.1 mmols), dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmols) and CuI (10 mg, 0.05 mmols) was added a solution of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (209 mg, 1 mmol). The mixture was stirred overnight, filtered through Celite, concentrated. The residue was partitioned between ethyl acetate and water, organic layer was isolated, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate in hexanes (1:1) to give un-reacted 2-bromopyrimidine (130 mg), then the title compound (23 mg). LCMS m/e (288, M+H).
Reaction SMILES: C[Si](Cl)(C)C.[Na+].[I-].C[O:9][C:10]1[C:11](=[O:37])[C:12]([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:15]=1.O>CC#N>[OH:9][C:10]1[C:11](=[O:37])[C:12]([C:26]2[N:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)[CH:15]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
TMSCl (3.17 mL, 25 mmol) was added at room temperature to a solution of NaI (3.75 g, 25 mmol) in CH3CN (150 mL). After stirring for 30 min, 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (2.06 g, 5 mmol) was added to the resulting suspension. The mixture was stirred for 30 min at room temperature and then refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (1/1) and recrystallized from MeOH/H2O to give the title compound (1.68 g, 84% yield) as a colorless powder: mp 246-248° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 7.17 (1H, d, J=1.9 Hz), 7.33-7.46 (5H, m), 7.53-7.64 (3H, m), 7.71 (1H, d, J=7.5 Hz), 7.83 (1H, d, J=1.9 Hz), 8.83 (1H, s). Anal. Calcd for C20H13F3N4O2: C, 60.30; H, 3.29; N, 14.07. Found: C, 60.09; H, 3.33; N, 14.02.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[CH:14][C:13](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[C:12]2[CH3:22])=[CH:7][CH:6]=1)=[O:4].[CH3:24][NH:25][OH:26]>>[CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[CH:14][C:13](/[CH:17]=[CH:18]/[C:19]([N:25]([OH:26])[CH3:24])=[O:20])=[C:12]2[CH3:22])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1cc(/C=C/C(=O)O)c(C)n1-c1ccc(C(=O)N(C)C)cc1
Reactant: CNO
Product: Cc1cc(/C=C/C(=O)N(C)O)c(C)n1-c1ccc(C(=O)N(C)C)cc1

Procedure:
(E)-3-[1-(4-Dimethylcarbamoylphenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-2-propenoic acid is condensed with N-methylhydroxylamine as described in example 1(a) to yield (E)-3-[1-(4-dimethylcarbamoylphenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-N-hydroxy-N-methyl-2-propenamide, m.p. 172°-174°.