Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][CH3:26])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[C:43]([SiH:47]([CH3:49])[CH3:48])([CH3:46])([CH3:45])[CH3:44].O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][CH3:26])[CH:13]([C:15]1([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:17][CH2:16]1)[O:14][Si:47]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:49])[CH3:48])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(O)C1(C(=O)OC(C)(C)C)CC1
Reactant: C[SiH](C)C(C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CC[C@H](NC(=O)OCc1ccccc1)C(O[Si](C)(C)C(C)(C)C)C1(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}-1-hydroxybutyl)cyclopropanecarboxylate (914.8 mg) and 2,6-lutidine (0.632 mL) in tetrahydrofuran (20 mL) was added under ice-cooling tert-butyldimethylsilane trifluoromethanesulfonate (0.934 mL) and, after warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/1) to give the title compound as a colorless oil (yield: 1.18 g, 98%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)C.[CH3:30][NH:31][CH3:32]>CO>[CH3:30][N:31]([CH3:32])[C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:3]
Reactant: CNC
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Solvent: CO
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)N(C)C)s3)c2cc1OC

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid dimethylamide was prepared from 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (48.8 mg, 0.12 mmol) and dimethyl amine in methanol (2 molar) as described above in the general amide formation procedure. Product was isolated by preparative HPLC:15 mg, 30%. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1 H); 7.84 (s, 1 H); 7.73-7.79 (m, 2H); 7.44-7.59 (m, 3 H); 7.40 (s, 1 H); 3.91 (s, 3 H, NCH3), 3.86 (s, 3 H); 3.01 (s, 3 H); 2.74 (s, 3 H). MS M/z 409 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6](C2C(C(OC)=O)=CC([N+]([O-])=O)=CC=2)[CH:7]=1.Br[C:24]1[C:33]([CH3:34])=[CH:32][C:31]([N+:35]([O-:37])=[O:36])=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].FC1C=CC(OC)=C(B(O)O)C=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[CH:6][C:7]=1[C:24]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][C:31]([N+:35]([O-:37])=[O:36])=[CH:32][C:33]=1[CH3:34]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(F)cc1B(O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1cc(OC)ccc1F
Yield: 38 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5′-fluoro-2′-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2-bromo-3-methyl-5-nitrobenzoate (1.73 g, 6.31 mmol), (PPh3)4Pd (0.22 g, 0.19 mmol), and 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) (1.50 g, 8.8 mmol) to afford 0.77 g (38%) of methyl 2′-fluoro-5′-methoxy-6-methyl-4-nitro-2-biphenylcarboxylate. Data for 2′-fluoro-5′-methoxy-6-methyl-4-nitro-2-biphenylcarboxylate: 8.61 (d, J=2.3, 1H), 8.27 (d, J=2.4, 1H), 7.09 (m, 1H), 6.91 (dd, J=9.0, 4.3, 1H), 6.73 (dd, J=8.2, 3.0, 1H), 3.70 (s, 3H), 3.69 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].Br[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)[NH:29]2.Br.BrCC1C=CC=CN=1.BrCC1(C(F)(F)F)CC=CO1>>[N:29]1[CH:25]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:26][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][C:6]=3[O:21][CH2:20]2)[C:11]1=[O:19]
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Agent: Br
Agent: BrCc1ccccn1
Agent: FC(F)(F)C1(CBr)CC=CO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-2-(trifluoromethyl)furan, 1′-(pyridin-2-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained, which was treated with 4.0 M HCl in dioxane to give the title compound (39%): mp 150-152° C.; 1H NMR (300 MHz, CD3OD) δ 8.89-8.78 (m, 1 H), 8.62-8.47 (m, 1H), 8.07-7.00 (m, 2H), 7.42-6.70 (m, 7H), 5.52-5.31 (m, 2H), 5.05 (d, 1H), 4.89 (d, 1H); 13C NMR(75 MHz, CD3OD) δ 179.4, 163.5, 153.1, 152.7, 148.2, 143.8, 142.8, 133.1, 130.6, 129.3, 127.4, 126.8, 125.7, 125.6, 125.4, 114.9, 110.4, 104.9, 82.0, 58.9, 43.0; MS (ES+) m/z 413 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.C(OCC)(=O)C>[N+:8]([C:7]1[C:2]([NH:21][CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:22])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCNc1ncccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 108.2 %

Procedure:
To 2-chloro-3-nitropyridine (92 mg), tert-butyl(3-aminopropyl)carbamate (102 mg) and potassium carbonate (161 mg), acetonitrile (1.2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 0% hexane in ethyl acetate) to obtain tert-butyl (3-((3-nitropyridin-2-yl)amino)propyl)carbamate (C42, 186 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5](Cl)=[O:6].[CH3:21][NH2:22]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([NH:22][CH3:21])=[O:6]
Reactant: CN
Reactant: COc1ccc(Oc2c(I)cc(C(=O)Cl)cc2I)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(I)c(Oc2ccc(OC)cc2)c(I)c1

Procedure:
3,5-diiodo-4-(4'-methoxyphenoxy)-N-methyl benzamide (Compound 8) was prepared by way of 3,5-diiodo-4-(4'-methoxyphenoxy)benzoyl chloride (see, Example 1.5). The acid chloride was reacted with excess methylamine in tetrahydrofuran at ambient temperature (1 hour), filtered to remove methylamine-hydrochloride precipitate, the solvent evaporated and the product crystallized from 95% ethanol.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])(=O)C.[K+]>C(O)CCC.O>[F:11][C:12]1[C:17]([C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: Fc1ncccc1-c1ncnc2cc[nH]c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.500 g, 3.26 mmol), 2-fluoropyridin-3-ylboronic acid (0.688 g, 4.88 mmol) and potassium acetate (0.959 g, 9.77 mmol) in 1-butanol (25 mL) and water (5 mL) was purged with Ar (vacuum/purge three times) to remove oxygen, then PdCl2Cl2(PtBu2Ph)2 (0.0243 g, 0.0391 mmol) was added. The reaction mixture was stirred in a 100° C. oil bath for 60 min. The brown solution was concentrated in vacuo to a solid residue. The residue was treated with 3:1 CHCl3:IPA (100 mL) and water (70 mL). The mixture was sonicated and the layers separated. The aqueous phase was extracted with 3:1 CHCl3:IPA (50 mL). The combined organic extracts were washed with water (3×70 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 0.74 g crude product as a yellow solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with a gradient of 80% to 100% EtOAc in CH2Cl2, to provide 4-(2-fluoropyridin-3-yl)-5H-pyrrolo[3,2-d]pyrimidine (0.51 g, 73% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 215 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.O>C(Cl)Cl>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:22])=[CH:19][CH:18]=1
Reactant: NCCCCCCO
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCO)c1ccc(F)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
1.0 g (8.53 mmole) of 6-aminohexanol is dissolved in a mixed solution of 17 mL of methylene chloride and 3.6 mL (26 mmol) of triethylamine. After 1 mL (8.53 mmol) of p-fluorobenzoyl chloride is slowly added at 0° C., ice-bath is ended to raise temperature to a room temperature for reaction for 12 hrs. After the reaction, cold water is added to stop the reaction and 20 mL of methylene chloride is used to extract an organic layer to be dried with MgSO4, filtrated and concentrated. Then, re-crystallization is processed in a mixed solution of dichloromethane/n-hexane for obtaining a product of 4-fluoro-N-(6-hydroxyhexyl)-benzamide with a weight of 1.83 g and a yield of 90%. The reactant is confirmed through NMR to be 4-fluoro-N-(6-hydroxyhexyl)-benzamide with a result as follows:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.C(=O)([O-])O.[Na+].O.[C:23]([O:27][C@@H:28]([C:33]1[C:34](I)=[C:35]2[C:42]3[CH2:43][CH2:44][CH2:45][CH2:46][C:41]=3[S:40][C:36]2=[N:37][C:38]=1[CH3:39])[C:29]([O:31][CH3:32])=[O:30])([CH3:26])([CH3:25])[CH3:24]>CN(C)C(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:34]2[C:33]([C@H:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])[C:29]([O:31][CH3:32])=[O:30])=[C:38]([CH3:39])[N:37]=[C:36]3[S:40][C:41]4[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=4[C:35]=23)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(N)cc1)CCCC3
Temperature: 100 °C
Yield: 61.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (140 mg, 0.63 mmol), sodium hydrogen carbonate (178 mg, 2.1 mmol) and water (200 μL) were added to a stirred solution of (S)-methyl 2-(tert-butoxy)-2-(4-iodo-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridin-3-yl)acetate (200 mg, 0.42 mmol) in N,N-dimethylacetamide (4 mL) in a reaction tube. The reaction mixture was degassed with argon for 2 minutes, then bis(tri-tert-butylphosphine)palladium(0) (22 mg, 42 μmol) was added and the vessel was sealed and heated at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between dichloromethane (30 mL) and water (30 mL). The layers were separated and the organic layer was dried (MgSO4) and concentrated in vacuo to yield the crude product as a brown gum. The residue was purified by flash column chromatography on silica eluting with ethyl acetate in heptane (25%) to give the title compound (114 mg, 67%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 0.97 (s, 9H), 1.95-1.30 (m, 6H), 2.68 (s, 3H), 2.85-2.77 (m, 2H), 3.65 (s, 3H), 3.80 (brs, 2H), 5.19 (s, 1H), 6.75-6.68 (m, 2H), 6.99 (d, 1H), 7.19 (d, 1H).
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2[CH3:43])(=O)C1C=CC=CC=1.O(C)[Na].C(O)(=O)C>CO>[CH3:43][C:39]1[N:38]=[CH:37][N:36]=[C:35]2[C:40]=1[N:41]=[CH:42][N:34]2[C@@H:11]1[O:12][C@@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: Cc1ncnc2c1ncn2[C@@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: CO[Na]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ncnc2c1ncn2[C@@H]1O[C@@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1c (453 mg, 0.78 mmol) in MeOH (7 ml) at 5° C. is added dropwise 0.5 N NaOCH3 in MeOH (0.78 ml) over 5 min. After being stirred at room temperature for 2 h, the reaction solution is chilled to 5° C. and neutralized with glacial acetic acid. Pure 1d crystallized in two crops from this neutral solution as a white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]([C:21]2[CH2:25][CH2:24][CH2:23][CH:22]=2)O)=[C:16]([O:26][CH3:27])[C:15]([CH3:28])=[C:14]2[C:10]=1[C:11](=[O:29])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([OH:36])(=[O:35])[C:31](C)(C)C.[CH2:37](C(CC)(CC)C([O-])([O-])[O-])[CH3:38]>C(OCC)(=O)C>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:21]2/[CH:22]([CH2:31][C:30]([O:36][CH2:37][CH3:38])=[O:35])[CH2:23][CH2:24][CH2:25]/2)=[C:16]([O:26][CH3:27])[C:15]([CH3:28])=[C:14]2[C:10]=1[C:11](=[O:29])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)O
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC(O)C1=CCCC1)C(=O)OC2
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC/C1=C\Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 100 °C

Procedure:
A solution of 1-[2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-1-hydroxyeth-1-yl]cyclopent-1-ene (0.22 g) in triethylorthoacetate (10 ml) was treated with pivalic acid (0.010 g) and then heated to 100° C., and maintained at that temperature for 18 hours. After cooling to ambient temperature, the solution was diluted with 1:1 ethyl acetate:hexanes and washed sequentially with water, saturated aqueous sodium bicarbonate, and brine. Drying over magnesium sulfate was followed by evaporation; chromatography of the residue on silica gel (10% ethyl acetate in hexanes) afforded ethyl (E) 2-[2-[2-[4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl]ethylidene]-cyclopent-1-yl]acetate (0.11 g) as an oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](Cl)=[O:12])(=O)C.[CH2:14](N(C(C)C)C(C)C)C.[CH3:23][C:24]([C:27]([OH:29])=[O:28])([CH3:26])[NH2:25]>C1(C)C=CC=CC=1>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:25][C:24]([CH3:26])([CH3:23])[C:27]([O:29][CH3:14])=[O:28])=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CC(C)(N)C(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(chlorocarbonyl)phenyl acetate (20 mmol, 3.96 g) in toluene (50 ml) were N-ethyl-N,N-diisopropylamine (22 mmol, 2.84 g) and 2-methylalanine (22 mmol, 2.27 g) added. After stirring the reaction mixture at room temperature overnight, the mixture was diluted with 250 ml toluene and was washed with 1.8% HCl/aq (250 ml) and sat. NaCl/aq (250 ml). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL) and 3 drops of conc. H2SO4 were added. The mixture was refluxed for 2 hours and concentrated under reduced pressure. The residue was dissolved in 250 mL EtOAc and washed with sat. NaHCO3/aq (250 ml) and sat. NaCl/aq (250 ml). The organic phase was dried over Na2SO4 and concentrated at reduced pressure. The resulting crude material was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][C:14]=2[F:26])[N:5]=1)(=O)[CH3:2].[CH3:27]OC(OC)N(C)C.[C:35]1([NH:41][NH2:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CCOC(C)=O>[F:26][C:14]1[CH:15]=[C:16]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]([F:19])=[CH:18][C:13]=1[N:6]1[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1]2[N:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:42]=[CH:27][CH:2]=2)=[N:5]1
Reactant: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(C)=O)c1=O
Reactant: COC(OC)N(C)C
Reactant: NNc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 36 %

Procedure:
A mixture of 3-acetyl-1-(2,5-difluoro-4-morpholin-4-ylphenyl)-5-methoxypyridazin-4(1H)-one (340 mg, 0.93 mmol) and N,N-dimethylformamide dimethyl acetal (3.4 mL) was stirred at 120° C. for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (3.4 mL) and phenylhydrazine (0.18 mL, 1.9 mmol) was added. This mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with AcOEt, and washed with saturated NaHCO3 aqueous solution and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt/MeOH to give the title compound (156 mg, 36% yield) as a pale orange solid: mp 211-212° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 2.99-3.15 (4H, m), 3.60-3.88 (7H, m), 6.85 (1H, dd, J=12.8, 7.2 Hz), 6.99 (1H, d, J=2.3 Hz), 7.09 (1H, dd, J=12.8, 7.6 Hz), 7.24-7.50 (5H, m), 7.79 (1H, d, J=1.9 Hz), 8.43 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 466 [M+H]+. Anal. Calcd for C24H21F2N5O3.0.5H2O: C, 60.75; H, 4.67; N, 14.76. Found: C, 60.98; H, 4.71; N, 14.63.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([S:10]([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CN1CCNCC1
Product: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1

Procedure:
The title compound was prepared following the procedure of intermediate Example 2 with to 3-Nitro-benzenesulfonyl chloride (4.4 g, 20 mmol) and N-methyl-piperazine (2.2 ml 20 mmol) as an off white solid (3.6 g, 70%). MS (ESI) m/z=256 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[C:13](#[N:17])/[CH:14]=[CH:15]/[CH3:16].[H-].[Na+].C(O)(=O)C>C(O)C>[C:13]([CH2:14][CH:15]([P:8]([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])(=[O:12])[O:9][CH2:10][CH3:11])[CH3:16])#[N:17]
Reactant: CCOC(OCC)P([O-])OCC
Reactant: C/C=C/C#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(OCC)P(=O)(OCC)C(C)CC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material may be prepared as follows: A solution of 23.5 g of ethyl (diethoxymethyl)phosphonite and 6.7 g of crotononitrile in 30 ml of dry ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 2-cyano-1-methylethyl(diethoxymethyl)phosphinate, b.p. 116° C./0.01 mbar, 31P=+42.2 and +42.0 ppm (CDCl3).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:12]=[CH:11][NH:10][N:9]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1F>CS(C)=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N:10]1[CH:11]=[CH:12][C:8]([CH3:7])=[N:9]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N:9]1[C:8]([CH3:7])=[CH:12][CH:11]=[N:10]1
Reactant: Fc1cc(Cl)ccc1Br
Reactant: Cc1cc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccn(-c2cc(Cl)ccc2Br)n1
Product: Cc1ccnn1-c1cc(Cl)ccc1Br
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Potassium t-butoxide (3.9 g, 0.33 mmol) was dissolved in DMSO (25 mL). To this solution was added 3-methylpyrazole (2.7 g, 0.33 mmol) and the reaction was heated at 50° C. for 30 min. 1-Bromo-4-chloro-2-fluorobenzene (4.6 g, 0.22 mmol) was then added and the reaction was stirred at 50° C. for 16 h. The reaction was cooled to RT and extracted with water and EtOAc, washed with brine, and dried over Na2SO4, filtered and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole and 1-(2-bromo-5-chlorophenyl)-5-methyl-1H-pyrazole as a 4:1 mixture that was used in the next step directly.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH2:30][S:29][C:28](=[O:31])[NH:27][N:26]=2)=[CH:21][CH:20]=1.O>C(#N)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH2:30][S:29][C:28](=[O:31])[N:27]([CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:26]=2)=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: O=C1NN=C(c2ccc(Cl)cc2)CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1SCC(c2ccc(Cl)cc2)=NN1Cc1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
4.19 g of 3-nitrobenzyl bromide and 9.95 g of potassium carbonate are added to a solution of 4.00 g of 5-(4-chlorophenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one in 80 ml of acetonitrile, and the mixture is stirred at 80° for a further 2 h. The mixture is poured into water, extracted 2× with diethyl ether, dried, filtered and evaporated to dryness. A little diethyl ether is added to the residue, which is crystallised and dried in a vacuum drying cabinet at 50° C., giving 5.5 g (86%) of 5-(4-chlorophenyl)-3-(3-nitrobenzyl)-3,6-dihydro-1,3,4-thiadiazin-2-one.