Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][C:27]([F:30])([F:29])[F:28])=[C:6]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][CH2:14][C:13]4[C:19]([C:23]([NH2:25])=[O:24])=[N:20][N:21]([CH3:22])[C:12]=4[C:11]=3[N:10]=2)[CH:7]=1.CN(C)C=O.CCN(C(C)C)C(C)C.[C:45]([N:52]1[CH2:59][CH2:58][CH2:57][C@H:53]1[C:54](O)=[O:55])([O:47]C(C)(C)C)=[O:46]>O>[NH:52]1[CH2:59][CH2:58][CH2:57][CH:53]1[C:54]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][C:27]([F:29])([F:28])[F:30])=[C:6]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[CH2:15][CH2:14][C:13]4[C:19]([C:23]([NH2:25])=[O:24])=[N:20][N:21]([CH3:22])[C:12]=4[C:11]=3[N:10]=2)[CH:7]=1)=[O:55].[F:30][C:27]([F:28])([F:29])[C:45]([O-:47])=[O:46]
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc(N)ccc3OC(F)(F)F)ncc1CC2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc(NC(=O)C4CCCN4)ccc3OC(F)(F)F)ncc1CC2
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 499.9 %

Procedure:
To a suspension of 8-(5-amino-2-trifluoromethoxy-phenylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (146 mg, 0.4 mmol) in anhydrous dimethylformamide (5 mL) TBTU (190 g, 0.6 mmol) HOBT (81 mg, 0.6 mmol), and DIPEA (0.104 ml, 0.6 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Then BOC-L-proline (129 mg, 0.6 mmol) was added and the reaction was stirred for an additional 3 h. The reaction mixture was diluted with water and the precipitate was collected, diluted with DCM (10 mL) and treated with TFA (1 mL). Evaporation of the solvent gave the title compound as trifluoroacetate salt (113 mg, 44% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[C:8](Br)=[N:7][CH:6]=1)[CH3:2].[CH2:14]([Mg]Br)[CH3:15].O.C(OCC)(=O)C>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:9]1[C:8]([CH2:14][CH3:15])=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:13]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1cnc(Br)c(Br)c1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(CC)c(Br)c1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
Method-1: To a 0° C. cooled solution of ethyl-5,6-dibromonicotinate (1.0 g, 3.24 mmol, 1.0 eq., prepared by following the procedure described in WO2011024004) in THF (10 mL) was added [1,3-bis(diphenylphosphino)propane]dichloronickel (II) (351 mg, 0.65 mmol, 0.2 eq) and the solution was stirred for 5 min. Ethyl magnesium bromide (1M in THF, 3.88 mL, 3.88 mmol, 1.2 eq) was then added drop-wise to the above mixture at 0° C. The resulting mixture was continued to stir at the same temperature for 3 h. Water (10 mL) was then added to the above mixture, followed by ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was evaporated and the crude residue was purified by flash column chromatography (silica gel, diethyl ether-hexane system as eluent) to afford 500 mg (60%) of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.06 (d, J=1.5 Hz, 1H), 8.40 (d, J=1.5 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 3.05 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H); GC-MS (m/z) 257, 259 [M+, Br79, 81].
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([C:16](=[O:18])[CH3:17])[CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 91.5 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline (Rami et al, WO 03/068749) (500 mg, 2.42 mmol), DMAP (5 mg) in pyridine (2 mL) was added acetic anhydride (0.46 mL, 4.9 mmol). The mixture was stirred at room temperature for 10 h, and then heated at 60° C. for 5 h. After cooling, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaHCO3, 1N HCl, brine, dried, and evaporated. The residue was purified by chromatography to give a light yellow solid (550 mg, 92%).
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=O)[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].O.NN>C(O)C>[C:1]([C:4]1[C:9]2[CH2:10][CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C1Cc2c(cccc2C(=O)O)Sc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2c1CCc1ccccc1S2
Reaction time: 2 h
Yield: 42.2 %

Procedure:
The mixture of 1.0 g of 9carboxy-10,11-dihydro-11-oxodibenzo[b,f]thiepin, 1.0 g of hydrazine hydrate and 30 ml of ethanol was heated under reflux on water bath for 4 hours. The reaction mixture was concentrated to about 15 ml to separate crystals on cooling, which were collected by filtration. They were added to the mixture of 1.0 g of sodium hydroxide and 20 ml of diethylene glycal and the resulting mixture was heated with stirring at 190°-200° C. for 2 hours. After cooling, 300 ml of water was added to the mixture, which was extracted with diethyl ether. The aqueous layer was acidified with conc. hydrochloric acid and extracted with chloroform, and the solvent was evaporated therefrom. The thus obtained residue was chromatographed over silica gel and eluted with benzene-ethyl acetate (1:1), and there was obtained 0.4 g of 9-carboxy-10,11-dihydrodibenzo[b,f]thiepin as yellow prismatic crystals having a melting point of 186°-187° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH3:17][O:18][C:19](=[O:45])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:41](=[CH:42][CH:43]=1)[O:40][C:27]1([CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)[CH2:26][C:25]2=[O:44]>CC(C)=O>[CH3:17][O:18][C:19](=[O:45])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:41](=[CH:42][CH:43]=1)[O:40][C:27]1([CH2:28][CH2:29][N:30]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:31][CH2:32]1)[CH2:26][C:25]2=[O:44]
Reactant: Fc1ccc(CCBr)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(F)cc3)CC1)O2
Temperature: 50 °C
Reaction time: 54 h
Yield: 94.2 %

Procedure:
K2CO3 (414 mg, 3 mmol) and 1-(2-bromo-ethyl)-4-fluoro-benzene (0.21 ml, 1.5 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (254 mg, 0.752 mmol, Intermediate 1, hydrochloride salt) in acetone (10 ml). The mixture was stirred at 50° C. for 54 h, then the solvent was evaporated and the residue was partitioned between water and DCM. The organic phase was dried, then evaporated and the crude residue was purified by column chromatography (eluent:DCM/MeOH 99:1 to 98:2) to give (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (300 mg) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[NH:19])=[CH:4][CH:3]=1.[Br:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CC(=O)CC>[BrH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH2:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)[C:11]2=[NH:19])=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(CBr)cc1
Reactant: N=c1[nH]c2ccccc2n1CCCOc1ccc(F)cc1
Solvent: CCC(C)=O
Product: Br
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a solution of 1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (0.96 g, 3.36 mmol) in 2-butanone (50 ml) was added 4-bromomethyl benzaldehyde (1.0 g, 5.03 mmol). The reaction was heated to reflux where it was maintained for 48 h. After this time, the suspension was cooled to rt and filtered. The collected solid was washed with additional 2-butanone and then dried to provide 4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzaldehyde hydrobromide salt (0.80 g, 49%) as a yellow solid which was used without further purification. HPLC-MS 404 [M+1]+.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH:5]=1)=[O:3].[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][S:2]([C:4]1[S:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[S:33])=[CH:16][C:15]=2[F:21])[CH:5]=1)=[O:3]
Reactant: CS(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CS(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a suspension of 234 (280 mg, 0.868 mmol) in THF (8 mL) was added 2-phenyl acetyl isothiocyanate (185 mg, 1.04 mmol). The reaction mixture was stirred for 3 hours, concentrated; the solid residue washed with Et2O and dried, to afford title compound 235 (229 mg, 53% yield) as a white-rose solid. 1HNMR: (DMSO-d6) δ (ppm): 12.41 (s, 1H), 11.75 (s, 1H), 8.54(d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.96(d, J=13.5 Hz, 1H), 7.48(d, J=5.0 Hz, 2H), 7.30-7.26(m, 2H), 7.26-7.18 (m, 3H), 6.69(d, J=5.5 Hz, 1H), 3.25 (s, 2H), 2.98 (s, 3H). MS (m/z): 500.1 (M+1).
Reaction SMILES: CO.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:14]([N+:25]([O-])=O)[CH:13]=1>[Fe].C(O)(=O)C>[NH2:25][C:14]1[CH:13]=[C:12]([C:4]2[O:3][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH:5]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1N
Temperature: 25 °C

Procedure:
0.69 g of iron powder was added to a suspension of 7.0 mL of methanol and 7.0 mL of acetic acid containing 1.4 g of tert-butyl 4-(benzofuran-2-yl)-2-nitrobenzoate and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the obtained residue and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain 0.88 g of tert-butyl 2-amino-4-(benzofuran-2-yl)benzoate as white solid.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:22]=[CH:21][C:17](C(O)=O)=[CH:16][CH:15]=2)[CH2:9]1.[C:23]([BH3-])#N.[Na+].C=O.C(O)(=O)C>CO>[CH3:23][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2([CH:15]=[CH:16][CH:17]=[CH:21][CH2:22]2)[C:3]([OH:5])=[O:4])[CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: [BH3-]C#N
Reactant: O=C(O)c1ccc(C2CCCNC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCCC(C2(C(=O)O)C=CC=CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-piperidin-3-ylbenzoic acid trifluoroacetate (0.32 g, 1.1 mmol), sodium cyanoborohydride (0.066 g, 1.1 mmol), 36% aqueous formaldehyde (0.15 mL, 1.8 mmol) and acetic acid (0.5 mL) in methanol (4 mL) was stirred overnight at ambient temperature. The mixture was filtered through silica gel, concentrated and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2I)=[CH:4][CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1c(I)c(/C=C/c2ccc(Cl)cc2)nc2sccn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=c1c(-c2ccccc2)c(/C=C/c2ccc(Cl)cc2)nc2sccn12
Temperature: 25 °C
Yield: 5932.6 %

Procedure:
To a stirred solution of Intermediate 1 (100 mg, 0.231 mmol) in toluene (20 ml) and ethanol (10 ml) was added phenylboronic acid (33 mg, 0.276 mmol) and Pd[(C6H5)3P]4 (26 mg, 0.023 mmol) in) followed by sodium carbonate (Na2CO3) (48 mg, 0.461 mmol) in water (10 ml). The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was allowed to cool to room temperature. The residue obtained after evaporation was partitioned between ethyl acetate (500 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried (Na2SO4) and concentrated to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 5 g of the product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 6.85 (d, J=4.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 3H), 7.77 (m, 4H), 7.88 (d, J=7.8 Hz, 1H), 8.02 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 265.31 (M−H)−.
Reaction SMILES: CN(C=O)C.[C:6]([C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)#[N:7].Cl.[C:26]1([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH2:35][NH2:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)CCl>[C:32]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:39]=[CH:38][CH:37]=[C:34]([CH2:35][NH:36][C:22](=[O:24])/[CH:21]=[CH:20]/[C:10]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:8]([C:6]#[N:7])[CH:9]=2)[CH:33]=1
Reactant: NCc1cccc(-c2ccccc2)c1
Reactant: Cc1cn(-c2ccc(/C=C/C(=O)O)cc2C#N)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cn(-c2ccc(/C=C/C(=O)NCc3cccc(-c4ccccc4)c3)cc2C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a DMF (0.2 mL) solution of (E)-3-[3-cyano-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (15 mg) and 3-phenylbenzylamine monohydrochloride (16 mg), TEA (0.007 mL), HOBT (10 mg) and EDC (14 mg) were added one by one, and the reaction mixture was agitated at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (Carrier: Chromatorex®NH, elution solvent:hexane-ethyl acetate system), and 5 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1.[CH2:16](Br)[CH:17]=[CH2:18]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:18][CH:17]=[CH2:16])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Cl)nn2)c(O)c1
Reactant: C=CCBr
Product: C=CCOc1ccc(-c2ccc(Cl)nn2)c(O)c1

Procedure:
3-Chloro-6-(2,4-dihydroxyphenyl)pyridazine was reacted with allyl bromide under similar conditions to those described in Example 1(i), to give 3-chloro-6-(4-allyloxy-2-hydroxyphenyl)-pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:10](=[N:1]/[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1)\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1ccc(/N=C/c2ccccc2)cc1F
Temperature: 25 °C
Yield: 70 %

Procedure:
To a stirred solution of 4-amino-2-fluorophenol (1.27 g, 10 mmol) in 30 mL of toluene at room temperature under nitrogen in a Dean Stark apparatus was added benzaldehyde (1.01 ml, 10 mmol) followed by p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol). The mixture was heated to reflux for 4 hours. The reaction was cooled to room temperature and a solid crystallized out of the reaction mixture. The mixture was cooled to 0° C. and then filtered and the solids rinsed with toluene. The isolated tan crystals were dried under high vacuum (1.5 gm, 70% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH:15]=O)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1.[CH3:30][S:31][CH2:32][CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClCCCl>[CH3:29][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH2:15][NH:34][CH2:33][CH2:32][S:31][CH3:30])[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)C=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CSCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CSCCNCC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,1-dimethyl-2-oxo-ethyl)-phenyl]-amide (as prepared in the previous step, 60.0 mg, 0.154 mmol) and 2-methylsulfanyl-ethylamine (84 mg, 0.92 mmol) in 2 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (49.0 mg, 0.231 mmol). After stirring at RT for 3 h, the mixture was treated with EtOAc (40 mL) and washed with aqueous saturated NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1-3% MeOH/DCM) to afford the title compound (45.0 mg, 63%) as a white solid. 1H-NMR (1:1 CD3OD/CDCl3; 400 MHz): δ 8.22 (d, 1H, J=8.6 Hz), 7.78 (s, 1H), 7.27 (dd, 1H, J=8.6, 2.0 Hz), 7.14 (d, 1H, J=2.0 Hz), 5.73 (m, 1H), 2.77 (s, 2H), 2.68 (t, 2H, J=6.3 Hz), 2.55 (t, 2H, J=6.3 Hz), 2.27 (m, 2H), 2.06 (m, 2H), 1.92 (s, 3H), 1.57 (t, 2H, J=6.3 Hz), 1.35 (s, 6H), 1.07 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H35N5OS, 466.3 (M+H). found 466.2.
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[NH:5][CH:6]=[C:7]([C:13](=[O:24])[C:14]1[C:19]([CH3:20])=[C:18]([F:21])[C:17]([F:22])=[CH:16][C:15]=1F)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].Cl.ClCCl>O1CCOCC1.C(OCC)C>[F:21][C:18]1[C:19]([CH3:20])=[C:14]2[C:15](=[CH:16][C:17]=1[F:22])[N:5]([C@@H:3]1[CH2:4][C@@H:2]1[F:1])[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]2=[O:24]
Reactant: CCOC(=O)C(=CN[C@@H]1C[C@@H]1F)C(=O)c1c(F)cc(F)c(F)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)c(F)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
In 25 ml of anhydrous dioxane was dissolved 2.40 g of ethyl 3-[(1R,2S)-2-fluorocyclopropylamino]-2-(2,4,5-trifluoro-6-methylbenzoyl)acrylate, and 338 mg of 60% sodium hydride in oil was added thereto under cooling with ice, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into a mixture of 50 ml of 1N hydrochloric acid and 50 ml of dichloromethane, followed by stirring. The organic layer was separated. The aqueous layer was extracted with 100 ml of dichloromethane, and the extract was combined with the organic layer. The combined organic layer was dried over anhydrous sodium sulfate, the dichloromethane was removed by distillation, and the residue was dried in vacuo to yield yellow crude crystals. The crude crystals to yield with diethyl ether, filtered, and dried to yield 1.76 g of the titled compound as a pale yellow powder. The product was recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].Cl.C(=O)([O-])[O-].[K+].[K+].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21](=[O:20])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][NH:10]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccccc1NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2ccccc2OC)c1=O
Yield: 77.5 %

Procedure:
In the same manner as in Reference Example 63 and using (2-methoxyphenyl)hydrazine•hydrochloride (5.3 g, 30 mmol), water (100 mL), potassium carbonate (9.1 g, 66 mmol) and diethyl ethoxymethylenemalonate (7.8 g, 36 mmol) as starting materials, the title compound (6.1 g, 78%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][NH:13][CH:14]([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH3:12])[CH:14]([CH3:16])[CH3:15])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CNC(C)C
Product: CC(C)N(C)C(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and N-methyl-2-propanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[O:16])[CH2:12]1)[CH:5]=O.Cl.[CH3:29][C:30]1([OH:34])[CH2:33][NH:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][N:32]2[CH2:33][C:30]([OH:34])([CH3:29])[CH2:31]2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:12][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[O:16])[CH2:14]1
Reactant: CC1(O)CNC1
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)c(Cl)c1
Agent: Cl
Product: CC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)c(Cl)c2)C1
Yield: 56 %

Procedure:
Using a similar protocol as described in Example 70 employing 78A and 3-methylazetidin-3-ol hydrochloride as starting materials afforded 34 mg (56%) of 78 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.50 (s, 3H), 3.07 (d, 2H), 3.30 (d, 2H), 3.57 (s, 2H), 4.39 (m, 1H), 4.65 (m, 1H), 4.81 (m, 1H), 5.13 (m, 2H), 5.29 (s, 1H), 6.59 (m, 2H), 7.13 (d, 1H), 7.35 (s, 1H), 7.53 (t, 2H), 7.59 (t, 1H), 8.16 (d, 2H), MS (APCI+) m/z 455 [M+H]+, LC purity: 93%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1I.C([Mg]Br)(C)C.[CH3:15][CH2:16][C:17](=[O:20])[CH2:18][CH3:19].CC(=O)OCC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:17]([OH:20])([CH2:18][CH3:19])[CH2:16][CH3:15]
Reactant: CCC(=O)CC
Reactant: Cc1ccc(Br)c(I)c1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)(CC)c1cc(C)ccc1Br
Temperature: -10 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
To a solution of 1-bromo-2-iodo-4-methylbenzene (28 g, 94 mmol) in THF (10 ml) at −10° C. under nitrogen was slowly added i-PrMgBr (47 ml, 94 mmol). The reaction mixture was stirred for 1 h at −10° C. Then the reaction mixture was cooled to −30° C., and pentan-3-one (8.1 g, 94 mmol) was added dropwise. The reaction mixture was stirred for 1 h at −30° C. under nitrogen and then warmed to rt and stirred for additional 2 h. Then the reaction mixture was quenched with 2N HCl solution and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:0 to 5:1) to give the desired compound (6.5 g, yield 26.9%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.52-7.50 (d, 1H), 7.43-7.40 (d, 1H), 6.95-6.92 (d, 1H), 2.48-2.40 (q, 2H), 2.31 (s, 3H), 1.86-1.78 (q, 2H), 0.77-0.71 (m, 6H). MS: m/z=257 and 259 [M+1]+.