Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:5](=[O:17])[CH2:4]1)[CH3:2].[C:18](=[O:22])([O:20][CH3:21])[NH2:19].CC(C)([O-])C.[Li+].O1CCCC1.O>O1CCCC1.C1(C)C=CC=CC=1>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([NH:6][C@H:3]([CH2:1][CH3:2])[CH2:4][C:5]([NH:19][C:18](=[O:22])[O:20][CH3:21])=[O:17])=[CH:8][CH:9]=1
Reactant: COC(N)=O
Reactant: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](CC(=O)NC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Reaction time: 2 h
Yield: 79 %

Procedure:
866 mg (3.57 mmol) of (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone produced in Example 6 and 402 mg (5.4 mmol) of methyl carbamate were dissolved in tetrahydrofuran (15 mL) and further mixed with a lithium tert-butoxide/tetrahydrofuran solution (1 mol/L, 5.4 mL, 5.4 mmol) at room temperature. After stirring at the same temperature for 2 hours, water (5.0 mL) was further added to the reaction solution and extraction with toluene (10 mL) was repeated twice. The residue obtained by concentration of the separated organic layer after washing with water was purified on silica gel column chromatography to obtain methyl (R)-{3-[4-(trifluoromethyl)phenylamino]-pentanoyl}carbamate as a white solid (897 mg, isolated yield: 79%). 1H-NMR (CDCl3, 400 MHz/ppm): 5 0.98 (3H, t), 1.5-1.8 (2H, m), 2.9-3.2 (2H, m), 3.77 (3H, s), 3.8-3.9 (1H, m), 4.2-4.3 (1H, br), 6.60 (2H, d), 7.37 (2H, d), 7.9-8.1 (1H, br)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]1)[CH3:35])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([N:34]([CH3:35])[C@@H:36]4[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]4)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CN([C@@H]1CCCN(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1Br
Product: CN([C@@H]1CCCNC1)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (R)-tert-butyl 3-(2-bromo-N-methylphenylsulfonamido)piperidine-1-carboxylate. MS (ESI): mass calcd. for C27H32FN5O4S, 541.21; m/z found, 542.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][CH:13]([C:20](=[O:32])[N:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][C:16]([O:18]C)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][CH:13]([C:20](=[O:32])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCN(CCCCC)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To a solution of methyl 5-(3,4-dichlorophenylsulfonyl)-4-(N,N-dipentylcarbamoyl)pentanoate (40.3 g) in ethanol (500 ml) was added a 2N sodium hydroxide solution (40 ml). After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo, acidified with a dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with water, dried over MgSO4, and evaporated at reduced pressure. The residue was recrystallized from diethyl ether-hexane to give 38.2 g of 5-(3,4-dichlorophenylsulfonyl)-4-(N,N-dipentylcarbamoyl)pentanoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:17]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:17]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:27])=[O:28])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [Pd]
Product: CCOC(=O)CCc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 91.6 %

Procedure:
Palladium (15.7 mg, 10% on activated carbon) was added to a suspension of 3-{1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl}-acrylic acid ethyl ester [100 mg, Reference Example 37] in industrial methylated spirit (25 mL). The resultant suspension was then stirred under an atmosphere of hydrogen for 16 hours. The reaction mixture was then filtered through a pad of celite and the filtrate evaporated in vacuo. The resultant solid was triturated with water, filtered and dried to give the title compound (92 mg) as a white solid, m.p. 280-282° C. MS: 502 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([CH3:11])[CH:9]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C(OCC)C>[Cl:1][C:2]1[C:3]([C:8]2([CH3:11])[CH2:15][CH2:14][C:16](=[O:17])[CH:18]=[CH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C=O)c1ncccc1Cl
Reactant: C=CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC1(c2ncccc2Cl)C=CC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a 0° C. solution of the product of Example 38D (0.71 g, 4.19 mmol) in diethyl ether (10 mL) was added a solution of potassium hydroxide (3M in methanol, 0.56 mL, 1.68 mmol), followed by methyl vinyl ketone (0.47 g, 0.55 mL, 6.70 mmol). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with diethyl ether, and washed with water and brine. The organic layer was concentrated, and the residue was chromatographed on silica gel eluting with 25% ethyl acetate-hexane to give the title compound (0.20 g, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.53 (dd, J=1.5, 4.6, 1H), 7.92 (dd, J=1.5, 8.0, 1H), 7.45-7.26 (m, 2H), 5.92 (d, J=10.2, 1H), 2.82-2.67 (m, 1H), 2.64-2.52 (m, 1H), 2.31 (ddd, J=4.8, 7.2, 17.3, 1H), 2.12-2.00 (m, 1H). MS (DCI) m/z 222 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](O[C:10](=[O:11])[C:2]=12)=[O:8].[NH2:12][NH2:13]>C(O)(=O)C>[N:1]1[C:2]2[C:10](=[O:11])[NH:12][NH:13][C:7](=[O:8])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: NN
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2ncccc12
Temperature: 125 °C
Reaction time: 0.05 h

Procedure:
To 25 mL of acetic acid at 100° C. was added 2,3-pyridinedicarboxylic anhydride (5.00 g, 34 mmol). Once the solution was homogeneous, it was removed from the oil bath and anhydrous hydrazine (2.0 ml, 64 mmol) was added dropwise over 5 minutes. The reaction was returned to reflux. After 3 min, the solution crystallized and became a solid mass. The reaction was heated in a 125° C. bath for 10 minutes then cooled to room temperature. The solid was transferred to a Büchner funnel and washed with 2×10 mL of acetic acid. The solid was dried under high vacuum to afford 6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione 77. 1H-NMR (400 MHz, DMSO): δ 9.10 dd, J=4.7, 2.0 Hz, 1H), 8.50 (dd, J=7.8, 1.6 Hz, 1H), 7.86 (dd, J=8.2, 4.7 Hz, 1H).
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[OH2:16]>>[O:16]=[PH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1
Reactant: O
Reactant: ClP1Oc2ccccc2-c2ccccc21
Product: O=[PH]1Oc2ccccc2-c2ccccc21

Procedure:
Another reference (German Offenlegungsschrift 27 30 371, pp. 18 and 19) describes that 6-chloro-(6H)-dibenz-oxaphosphorin at 130° C. is combined with a large amount of water, the hydrolysis is carded out, the water is distilled off under reduced pressure and the 6-oxo-dibenzoxaphosphorin is then obtained. The operation described is technically very problematical and can hardly be carried out on a large scale, since water vaporizes at 130° C. and cools the reaction mixture. It is therefore necessary to work under increased pressure if the temperature of 130° C. is to be maintained and thus uncontrolled crystallization is to be prevented, since the target compound melts significantly above the boiling point of water.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].[I:15]I.S(=O)(O)[O-].[Na+]>CN(C)C=O>[I:15][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[NH:8][N:7]=1
Reactant: II
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Yield: 84.8 %

Procedure:
A solution of 4-nitro-1H-indazole (50.0 g; 306 mmol) in N,N-dimethylformamide (600 mL) was cooled to 5° C. under a nitrogen atmosphere with stirring. Powdered potassium hydroxide (68.8 g; 1226 mmol) was added. A solution of iodine (156 g; 613 mmol) in DMF (200 mL) was added slowly to the reaction mixture over 2 hours maintaining the temperature between 5 and 10° C. The mixture was stirred at 25° C. for 24 hours. Additional iodine (39.0 g; 153.2 mmol) and potassium hydroxide (17.2 g; 306.5 mmol) was added. The mixture was stirred at 25° C. for a further 12 hours. The reaction mixture was added to an aqueous solution of sodium bisulfite (10% solution; 3300 mL) with stirring. The resulting precipitate was collected by filtration and washed with water. The material was dried in a vacuum oven at 40° C. The material was dissolved in methylene chloride/methanol (10:1; 1.5 L) and filtered through Celite® to remove inorganic impurities. Concentration of the solution under vacuum gave 3-iodo-4-nitro-1H-indazole as a yellow solid (75 g).
Reaction SMILES: Cl[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[F:14][C:15]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:16]=1[NH2:17].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:14][C:15]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: CSc1ccc(N)c(F)c1
Reactant: COC(=O)c1nn(C)c(=O)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1nn(C)c(=O)cc1Nc1ccc(SC)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.4 %

Procedure:
A mixture solution of methyl 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (72 mg, 0.35 mmol), 2-fluoro-4-methylthioaniline (69 mg, 0.44 mmol), Pd(OAc)2 (10 mg, 0.044 mmol). BINAP (40 mg. 0.064 mmol), and Cs2CO3 (197 mg, 0.60 mmol) in toluene (1.5 mL) was sealed in a vial under N2 atmosphere. It was stirred for 10 minutes at room temperature and then heated al 80° C. for 16 hours with stirring. The reaction mixture was cooled to room temperature and diluted with EtOAc. The precipitate was filtered off and washed with EtOAc. The filtrate was washed with water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated to give the crude material that was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) followed by additional silica gel flash column chromatography (10 to 15 to 20% EtOAc in CH2Cl2) to afford 48 mg (42%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:23][N:22]([CH3:31])[N:21]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.FC1C=C(O)C=CC=1C1C(C2C=CN=CC=2)=CN(C[C:51]([F:54])([F:53])[F:52])N=1>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:20]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:23][N:22]([CH2:31][C:51]([F:54])([F:53])[F:52])[N:21]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2F)n1
Reactant: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)c(F)c1
Solvent: CC(C)=O
Product: Fc1cc(OCc2ccc3ccccc3n2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[3-Fluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol and acetone as the solvent provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.46 (m, 2H), 7.80 (s, 1H), 7.31 (t, J=8.3 Hz, 1H), 7.24 (m, 5H), 6.72 (dd, J=8.3, 2.5 Hz, 1H), 6.50 (dd, J=11.6, 2.1 Hz, 1H), 4.81 (q, J=8.4 Hz, 2H); MS: (M+H m/z=479.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>CC(C)=O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[N:5]1[C:15](=[O:16])[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]1=[O:17]
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(C)=O
Product: COc1ccc(OC)c(N2C(=O)c3ccccc3C2=O)c1
Temperature: 185 °C
Yield: 95 %

Procedure:
2,5-dimethoxyaniline (9.96 g, 65.00 mmol) and phthalic anhydride (10.11 g, 68.25 mmol) were mixed, and heated at 185° C. for 15 minutes under N2. After the reaction mixture was cooled, acetone (50 mL) was added. The precipitate was ultrasonicated, filtered, washed with ethyl acetate (10 mL×2), and dried to give the title compound (17.5 g, 95%). MS (ESI) m/z 283.91 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 3.75 (s, 3 H) 3.79 (s, 3 H) 6.83 (t, J=1.70 Hz, 1 H) 6.98 (d, J=1.70 Hz, 2 H) 7.74–7.81 (m, 2 H) 7.91–7.98 (m, 2 H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][C@@H:17]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20]2)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[N:1]([CH2:16][C@@H:17]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:18][C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20]1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCCCOC2)NC(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Temperature: 25 °C

Procedure:
The solution of NaN3 (47 mg, 0.72 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-((R)-oxepan-3-yl)propyl 4-methylbenzenesulfonate (103 mmol, 0.24 mmol) in anhydrous DMF was heated to 80° C. for 2 h. After cooling to rt, the reaction was diluted with EtOAc and washed with H2O, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel to give tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-ylcarbamate. MS ESI +ve m/z 321 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].Cl>C(O)C.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([N:11]=[N:12][N:13]=2)[CH:4]=1)(=[O:10])[CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc2nnnn2c1

Procedure:
To a stirred solution of 8.4 gm. (51.6 mmoles) of 2-chloro-5-acetylpyridine and 8.4 gm. (129 mmoles) of sodium azide in 150 ml of ethanol and 150 ml of water was added 75 ml of 10% HCl over a period of 20 minutes. The reaction mixture was then heated to reflux for 18 hours, cooled in an ice bath and the resulting crystals filtered off to give a first crop of 6.0 gm. A second crop of 1.0 gm. was obtained for a total of 7.0 gm. of A, (84.% yield), m.p. 159°-160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1)=O.[OH-].[K+].O.NN.C>C(O)COCCO.C(=O)(O)[O-].[Na+].O>[CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:6]1[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1
Reactant: Cc1ccccc1C(=O)c1ccc(C(=O)O)o1
Agent: NN
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: Cc1ccccc1Cc1ccc(C(=O)O)o1
Temperature: 145 °C
Yield: 43 %

Procedure:
5-(2-Methylbenzoyl)-2-furoic acid [prepared as described in (e) above; 96.6 g.] was added to a solution of potassium hydroxide (70 g.) in diethylene glycol (530 ml.) at 100°-110° C. When the solution was complete, hydrazine hydrate (58%; 53 ml.) was added. The mixture was gradually warmed and then maintained under reflux at 145° C. for 7 hours. Evolution of nitrogen was monitored by collecting the gas over water. Evolution of nitrogen did not completely cease. The reaction mixture was cooled, diluted with water (600 ml.) and stirred while acidifying by dropwise addition of concentrated hydrochloric acid to give crude 5-(2- methylbenzyl)-2-furoic acid in the form of a sticky, brown coloured solid, which was collected, washed with water and dried. The solid thus obtained was dissolved in a mixture of saturated aqueous sodium bicarbonate solution (420 ml.) and water (420 ml.), treated with charcoal and filtered. The filtrate was acidified by the dropwise addition, with stirring, of concentrated hydrochloric acid until the powdery precipitate began to become sticky. The addition of a little 2N aqueous sodium carbonate solution removed this stickiness and a white powdery solid was collected, washed with water and dried to give 5-(2-methylbenzyl)-furoic acid (39 g.), m.p. 136°-138° C., raised to 139°-141° C. by recrystallisation from light petroleum (b.p. 100°-120° C.).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10]1)=[O:8])(=O)C.[OH-].[NH4+]>>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:10]1)=[O:8]
Reactant: CC(=O)SCCC(=O)N1N=C(c2ccccc2)CC1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C(O)C1CC(c2ccccc2)=NN1C(=O)CCS
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
DL-4,5-Dihydro-1-[3-(acetylthio)-1-oxopropyl]-3-phenyl-1H-pyrazole-5-carboxylic acid (6.0g) is treated in an argon atmosphere with 40ml of a cold solution of 6.5N ammonium hydroxide. After 30 minutes at room temperature, the solution is washed with ethyl acetate, treated with concentrated hydrochloric acid to pH 2.5 and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated in vacuo to an oil. Trituration of the oil with ether yields 3.6g of the title compound, melting point 118°-120° C.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:24][O:25]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:24]=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: COC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(-c3ccccc3)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3ccc(C=O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 21.06 g of 4-biphenylyl p-toluenesulphonate in 120 ml of dichloromethane was treated at -2° C. while stirring with 23.6 ml of titanium tetrachloride. The mixture was treated dropwise at the same temperature within 30 minutes with 9.63 ml of dichloromethyl methyl ether, stirred at room temperature for a further 1 hour and then poured on to ice. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with saturated sodium hydrogen carbonate solution and then with water, dried over sodium sulphate and concentrated. Recrystallization of the crude product obtained from 50 ml of ethyl acetate gave 11.65 g of 4'-(p-toluenesulphonyloxy)biphenyl-4-carboxaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[F:9][CH:10]([F:13])[CH2:11]I.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.[Cl-].[NH4+]>[F:9][CH:10]([F:13])[CH2:11][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CC(F)F)c1
Temperature: 100 °C
Yield: 100.6 %

Procedure:
4-Nitro-1H-pyrazole (150 mg, 1.33 mmol) and 1,1-difluoro-2-iodo-ethane (509 mg, 2.65 mmol) were dissolved in acetonitrile (5 mL). Cesium carbonate (917 mg, 2.79 mml) was added and the mixture was heated at 100° C. for 40 min. After cooling down to room temperature, the reaction was diluted with sat. ammonium chloride and extracted with methylene chloride (3×). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated to give 1-(2,2-difluoroethyl)-4-nitro-pyrazole (237 mg) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH2:19][CH:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH2:19][CH:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C:16]2=[O:28])[N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CC(NC(=O)OC(C)(C)C)CC2O)n1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(CC2CC(NC(=O)OC(C)(C)C)CC2=O)n1
Yield: 67 %

Procedure:
Tetrapropylammonium perruthenate (0.07 mmol, 5 mol %) was added to a stirred solution of [6-(4-tert-butoxycarbonylamino-2-hydroxy-cyclopentylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester IV-3 (0.14 mmol) and N-methylmorpholine-N-oxide (0.26 mmol) in dichloromethane (9 mL) and acteonitrile (1 mL) at room temperature, and was allowed to react overnight. When complete, the solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, CH2Cl2:EtOAc, 8:2) to afford pure product as a white solid (67%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].B(O)(O)[C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[S:6]1(=[O:16])=[O:15]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Product: Cc1ccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)cc1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (408 mg) was coupled to p-tolylboronic acid to provide 3-(3-chloropropyl)-1-(4-methylphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (99 mg):