Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH2:13][CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1.C(N(CC)CC)C.CS(C)=O>O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:13][CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(NC2CN(C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 116.6 %

Procedure:
Into a 100 mL 3-Neck round-bottomed flask equipped with reflux condenser were charged 4-fluoro-2-methoxy-1-nitrobenzene (4.086 g) and tert-butyl 3-aminoazetidine-1-carboxylate (4.4 g), triethylamine (9.6 mL), and dimethyl sulfoxide (20 mL). The reaction mixture was heated at 95° C. for 8 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 mL×2), dried over sodium sulfate, and concentrated completely under reduced pressure at 40° C. to give the title compound (9 g) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([Sn:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>>[O:25]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:16][CH2:17][CH2:18][CH3:19])[O:1][C:2]1[CH:15]=[CH:14][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:16][CH2:17][CH2:18][CH3:19])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CCCC[Sn](=O)CCCC
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Product: CCCC[Sn](CCCC)(Oc1ccc(C(=O)c2ccccc2)cc1)O[Sn](CCCC)(CCCC)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
In a bulb-to-bulb distillation apparatus (“Kugelrohr”) 3 g (15.1 mmol) of 4-hydroxy-benzophenone and 1.9 g (7.6 mmol) of dibutyltin oxide are slowly heated to 150° C. in high vacuum (0.009 mbar). The mixture begins to melt and at 200° C. the distillation starts and is finished after about 10 minutes. After cooling the colorless distillate is identified as 4-hydroxy-benzophenone by 1H-NMR spectrum. The residue (about 3.3 g) is crystallized several times from hot toluene. 2.0 g of the title product are obtained as white crystals melting at 150-159° C. The structure is further confirmed by 1H-NMR and 13C-NMR spectra.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:2]1[C:3](=[O:15])[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1[nH]nc2n1C=Cc1ccccc1C2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccccc2)nc2n1C=Cc1ccccc1C2

Procedure:
To a solution of 20 parts of 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one in 300 volume parts of dimethylformamide is added 5.5 parts of a sodium hydride (55%) dispersion in mineral oil under stirring. To the mixture is added 13 volume parts of benzyl bromide dropwise. After stirring for 1 hour, the crystals are collected by filtration to give 2-benzyl-2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from ethanol gives colorless plates melting at 133° - 134° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17].COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:8][C:3]1[C:2]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:10]([F:9])[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: Nc1ncccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cccnc2N)cc1F
Temperature: 110 °C
Yield: 79 %

Procedure:
To 3-bromopyridin-2-amine (5 g, 28.9 mmol) in 500 mL round bottom flask was added (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (7.44 g, 37.6 mmol), PdCl2(dppf)-DCM (2.115 g, 2.89 mmol), DME (108 mL) and 2M Na2CO3 solution (36.1 mL). The reaction mixture was heated in an oil bath at 110° C. for 4 h. The reaction mixture was diluted with EtOAc and washed with water three times, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography eluting with 0-100% of EtOAc (containing 10% of MeOH)/heptane yielding 5.6 g of methyl 4-(2-aminopyridin-3-yl)-2-fluorobenzoate in 79% yield. LCMS (m/z): 247.1 (MH+), 0.50 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O:16][N:17]=O)CCC>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:17][OH:16])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: CCCCON=O
Reactant: O=C1CCc2ccc(Br)cc21
Product: O=C1C(=NO)Cc2ccc(Br)cc21

Procedure:
Similar procedure as described in example 9B was used, starting from 6-Bromo-indan-1-one and n-butylnitrite to give 6-Bromo-indan-1,2-dione 2-oxime. LC-MS: m/e 240 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(=O)NCc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added heptanoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give heptanoic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amide as a light yellow solid (280 mg, 47% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.10 min (97.8%); mp, 208-210° C.; 1HNMR (DMSO-d6)0.86 (t, J=6 Hz, 3H, CH3), 1.25-2.21 (m, 11H, CH2CH2CH2CH2CH2, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.68-4.84 (m, 2H, CH2NH), 5.23 (dd, J=6, 12 Hz, 1H, CH), 7.29-7.75 (m, 3H, Ar), 8.18 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.87, 20.77, 21.98, 23.27, 25.22, 28.31, 30.59, 31.96, 35.37, 38.68, 38.96, 39.23, 39.51, 39.79, 40.07, 40.35, 41.39, 56.47, 117.63, 124.30, 125.39, 133.78, 141.23, 148.44, 154.75, 160.95, 169.51, 172.29, 172.59. LCMS MH=413; Anal Calcd For C22H28N4O4: C, 64.06; H, 6.84; N, 13.58. Found: C, 64.05; H, 6.80; N, 13.58.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([OH:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:21]1([C:24]2[C:29]([CH2:30][CH2:31]O)=[CH:28][N:27]=[C:26]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)[N:25]=2)[CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:31][CH2:30][C:29]2[C:24]([CH:21]3[CH2:23][CH2:22]3)=[N:25][C:26]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=3)=[N:27][CH:28]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)c2ccccc2c1
Reactant: OCCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Product: CCOC(=O)C(C)(C)Oc1cc(OCCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c2ccccc2c1

Procedure:
In analogy to the procedures described in example 4D] and 4E], 2-(4-hydroxy-naphthalen-2-yloxy)-2-methyl-propionic acid ethyl ester (example 17D]) was reacted with 2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethanol (example 16B]) to give 2-(4-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-naphthalen-2-yloxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C:17](=[O:21])[C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH-].[Na+].CC(OC)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([OH:21])[C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(CC(=O)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1cc(C[C@@H](O)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.08 h

Procedure:
Under an argon atmosphere a solution of 9.59 g (30.7 mmol) 3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-2-oxo-propionic acid in 25 mL THF was combined with 4.26 mL (31.0 mmol) triethylamine, stirred for 5 min and cooled to −30° C. (internal temperature). A solution of 19.7 g (61.0 mmol) (1R)-B-chlorodiisopinocampheylborane in 35 mL THF was added dropwise and after the end of the addition the reaction solution was stirred for 30 min without cooling. 15 mL 4 N NaOH was added (temperature rose to 20° C.), the mixture was stirred for 5 min, cooled to 0° C., combined with 50 mL MTBE and stirred for 20 min. The organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was further reacted without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([NH:26][C:27]([NH:29][CH2:30][CH2:31][C:32]3[N:33]=[N:34][N:35]([CH:37]([CH3:39])[CH3:38])[N:36]=3)=[O:28])[N:25]=2)[CH:22]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[CH:37]([N:35]1[N:34]=[N:33][C:32]([CH2:31][CH2:30][NH:29][C:27]([NH:26][C:24]2[N:25]=[C:20]3[CH:19]=[CH:18][C:17]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:22][N:21]3[CH:23]=2)=[O:28])=[N:36]1)([CH3:39])[CH3:38]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)n1nnc(CCNC(=O)Nc2cn3cc(Br)ccc3n2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)n1nnc(CCNC(=O)Nc2cn3cc(-c4cccnc4)ccc3n2)n1

Procedure:
A microwave vial is charged with pyridine-3-boronic acid (0.031 g, 0.25 mmol), 2M aqueous sodium carbonate (1 ml) and DME (3 ml) and then purged with Argon for 30 minutes at room temperature. 1-(6-Bromo-imidazo[1,2-a]pyridin-2-yl)-3-[2-(2-isopropyl-2H-tetrazol-5-yl)-ethyl]-urea (Intermediate E1)(0.05 g, 0.13 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.016 g, 0.02 mmol) are added and the reaction mixture is heated using microwave radiation at 100° C. for 30 minutes. The reaction mixture is filtered through Celite® (filter agent) and washed through with EtOAc. The crude product is absorbed on silica and purified by flash chromatography, eluting with methanol in DCM (3%) to afford the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1
Reactant: CCOC(=O)CNc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CNc1ccc(N)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
Step B A solution of ethyl 2-(4-(tert-butoxycarbonylamino)phenylamino)acetate (772 mg, 2.62 mmol) in dichloromethane (14 mL) was treated with TFA (7 mL)) and the reaction mixture was stirred at 0° C. for 1.5 h. The resulting mixture was concentrated in vacuo and the residue was treated with EtOAc (200 ml) and washed with sat. aqueous Na2CO3, brine, dried over Na2SO4 and concentrated in vacuo to give ethyl 2-(4-aminophenylamino)acetate as a brown oil (483 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[Cl:14][CH:15]([Cl:19])[C:16](O)=O>Cl.O>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:16]([CH:15]([Cl:19])[Cl:14])=[N:1][C:2]=2[CH:8]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc2[nH]c(C(Cl)Cl)nc2cc1Cl
Reaction time: 0.08 h
Yield: 26.9 %

Procedure:
To 11.8 g of 2-amino-4-chloro-5-sulfamyl aniline in 50 ml of 4 N hydrochloric acid was added 20.5 g of dichloroacetic acid and the suspension refluxed for 6 hours. Concentration in vacuo provided a dark viscous oil which was suspended in 150 ml of water and crystallized through vigorous scratching. The dark brown solid was then dissolved in methanol, the solution brought to a boil, and charcoal added. After boiling for five minutes, the suspension was filtered through filter paper, cooled and then filtered through Celite. Concentration in vacuo gave a viscous oil which upon setting at ambient temperature for 48 hours crystallized. Tritration with acetonitrile provided 4.5 g of beige crystals, m.p. 225°-227°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.CN([CH:19]=[O:20])C.CCOC(C)=O>CCOCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[CH:19]=[O:20]
Reactant: Fc1cc(F)c(Br)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=Cc1cc(Br)c(F)cc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,5-dibromo-2,4-difluorobenzene (17.5 g, 64.2 mmol) in ether (100 mL) at −78° C. was added n-BuLi (2.5 M solution, 30.8 mL, 77 mmol) over a period of 5 min, and the reaction mixture was stirred at −78° C. for 30 min. Then DMF (9.94 mL, 148 mmol) was added in one portion, and the mixture was stirred at −78° C. for 30 min. The reaction mixture was worked up with EtOAc/sat. NH4Cl, and the crude product was purified by silica gel chromatography eluting with 0-10% EtOAc/Hexanes to give the title compound as a slightly yellow oil (8.5 g, 60% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 10.26 (s, 1H), 8.14 (t, J=7.5 Hz, 1H), 7.05 (dd, J=9.8, 8.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]O)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:29]=[C:28]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH:27]=[CH:26][C:25]=1[CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:30]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:32])=[O:33])[C:28]3[CH:27]=[CH:26][C:25]([CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:46])=[C:24]([F:23])[CH:29]=3)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: CCOCCSc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOCCSc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of {4′-[(2-ethoxyethyl)thio]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.94 g, 2.98 mmol), tert-butyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.13 g, 3.13 mmol) and tributylphosphine (1.03 mL, 3.87 mmol) in tetrahydrofuran (25 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.01 g, 3.87 mmol) under stirring at room temperature, and the mixture was stirred for 3 days. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=5/1-hexane/ethyl acetate=3/1) to give a mixture (1.96 g) of tert-butyl 3-(4-{({4′-[(2-ethoxyethyl)thio]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate, {4′-[(2-ethoxyethyl)thio]-2′,6′-dimethylbiphenyl-3-yl}methanol and tert-butyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate as a yellow oil. In the same manner as in Example 144, the title compound (1.25 g, yield 55%, 2 steps) was obtained as a colorless amorphous powder from the above-mentioned mixture (1.96 g).
Reaction SMILES: C([NH:4]/[N:5]=[CH:6]/[C:7]1[CH:17]=[N:16][CH:15]=[C:14]([Cl:18])[C:8]=1[C:9](OCC)=[O:10])(=O)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:18][C:14]1[C:8]2[C:9](=[O:10])[NH:4][N:5]=[CH:6][C:7]=2[CH:17]=[N:16][CH:15]=1
Reactant: CCOC(=O)c1c(Cl)cncc1/C=N/NC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1[nH]ncc2cncc(Cl)c12
Yield: 16.9 %

Procedure:
(E)-ethyl 3-((2-acetylhydrazono)methyl)-5-chloroisonicotinate (220 mg, 0.816 mmol) and aq. NaOH solution (3.26 mg, 0.082 mmol, 2 molar) in 5 mL of dioxane were stirred in a microwave at 165° C. for 60 min. Then the reaction mixture was basified by addition of aq. NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried and concentrated. The crude title compound was purified by chromatography (eluent: DCM/methanol) to give 25 mg (16.88%) of the title compound as beige solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[Br:15]Br.C(=O)=O>O>[OH:1][C:2]1[C:7]([Br:15])=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: CCc1cc(O)ncn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: CCc1ncnc(O)c1Br

Procedure:
24.8 g (0.20 mol) of 4-hydroxy-6-ethylpyrimidine are dissolved with 16.8 g (0.20 mol) of sodium hydrogen carbonate in 50 ml of water, and 32 g (0.20 mol) of bromine are slowly added dropwise at 8° to 10° C., with cooling. In the course of the addition, carbon dioxide evolves, and the product precipitates in the form of crystals. The product is separated off by extraction with ethyl acetate and crystallises out when the extract is concentrated using a rotary evaporator. There are obtained 22.7 g (55.9% of the theoretical yield) of a first fraction having a melting point of 177°-179° C. Concentration of the mother liquor yields a further 3.5 g (8.6%); m.p. 175°-177° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:22])[N:17]([CH:19]([CH3:21])[CH3:20])[N:18]=2)=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.[H-].[Na+].I[CH3:32].O>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:22])[N:17]([CH:19]([CH3:21])[CH3:20])[N:18]=2)=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][N:11]([CH3:32])[CH:12]=1
Reactant: CI
Reactant: CC(C)n1nc(-c2nc(-c3cn[nH]c3)c(N)nc2-c2ccccc2)ccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)n1nc(-c2nc(-c3cnn(C)c3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 6-[5-amino-3-phenyl-6-(1H-pyrazol-4-yl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (120 mg) was added to a suspension of NaH (60% in oil) (14.2 mg) and the mixture was stirred at 25-30° C. for 30 minutes. The mixture was cooled in an ice bath and iodomethane (0.1 ml) was added. The mixture was stirred at the same time for 30 minutes and at 20-30° C. for one hour. After addition of water (3.6 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-[5-amino-6-(1-methyl-1H-pyrazol-4-yl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (70 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1([C:16]([F:19])([F:18])[F:17])[O:7][CH:6]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]([CH2:12][CH2:13][C:14]#[N:15])[O:4]1.N.[H][H]>[Co].[Cr].[Co].O1CCCC1>[F:21][C:2]([F:1])([F:20])[C:3]1([C:16]([F:17])([F:18])[F:19])[O:4][CH:5]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:8][CH2:9][CH2:10][NH2:11])[O:7]1
Reactant: N#CCCC1OC(C(F)(F)F)(C(F)(F)F)OC1CCC#N
Reactant: [H][H]
Agent: [Co]
Agent: [Cr]
Agent: N
Solvent: C1CCOC1
Product: NCCCC1OC(C(F)(F)F)(C(F)(F)F)OC1CCCN
Yield: 42.8 %

Procedure:
The compound of Example 56 (9.72 g, 0.031 mole) was mixed with tetrahydrofuran (60 ml), Raney-Cobalt (2.8 g) and ammonia (12 g, 0.706 mole) in a 360 ml Hastelloy-C Shaker tube. The tube was pressurized with hydrogen to 500 psi at room temperature. The tube was then heated at 110° C. for 18 hrs while the hydrogen pressure was adjusted to 1500 psi under the reaction process. The product mixture was filtered first, then was distilled to give the desired product 4.3 g as a clear, colorless liquid. Bp 85° C./0.02 mmHg. H-1 NMR (CDCl3): 3.98 (s, br, 2H), 2.76 (t, J=6 Hz, 4H), 1.80-1.50 (m, 8H), 1.30 (s, br, 4H); F-19 NMR (CDCl3): -81.1 (s, 6F).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[C:21]([O:20][C:18]([N:7]1[CH2:8][CH2:9][C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)C1=C(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)=C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.4 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (6.8 g, 20 mmol), 100 ml 1,4-dioxane and 100 ml 2 M NaOH was stirred at RT for 20 h. After extraction of the reaction mixture with two portions of tert-butyl methyl ether, the combined organic layers were extracted with 1 M aqueous sodium hydroxide solution (100 ml). The combined aqueous layers were cooled to 0° C. by addition of ice (150 g) and acidified to pH 1 with ice-cold 4 M aqueous hydrochloric acid solution (70 ml). The aqueous layer was extracted with three 150 ml-portions of ethyl acetate. The combined organic layers were washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo. Crystallization of the crude acid (6.4 g) from a mixture of n-heptane and ethyl acetate (19:1, 120 ml) gave the title compound as white crystals (5.1 g, 78%).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[C:8](#[N:11])[CH:9]=[CH2:10].[OH-].C[N+](C)(C)CC1C=CC=CC=1.C>C(O)C.CO>[O:7]=[C:3]1[CH:4]=[CH:5][CH:6]=[N:1][N:2]1[CH2:10][CH2:9][C:8]#[N:11]
Reactant: O=c1cccn[nH]1
Reactant: C=CC#N
Agent: C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: N#CCCn1ncccc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a stirred solution of 3.84 g (0.04 mole) of 3(2H)-pyridazinone, 2.33 g (0.044 mole) of acrylonitrile in 50 ml of ethanol, 1 ml of Triton-B (trimethyl benzylammonium hydroxide, 40% methanol solution) was added dropwise. The mixture was stirred for 2 hours at 60° C. and then evaporated to dryness in a vacuum on a steam bath, giving a dark orange oil. The oil was dissolved in ethanol, shaken with Norit and filtered. The filtrate was distilled. Recrystallization of the residue from ethanol and isopropyl ether gave 4.7 g (79% yield) of 3-(3-oxo-2-pyridazinyl)-propionitrile in the form of pale yellow crystals, m.p. 75°-76° C.