Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH2:15][CH2:16][OH:17])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[C:53]([O:57][C:58](=[O:61])[CH2:59][Zn+])([CH3:56])([CH3:55])[CH3:54]>C(OCC)C.C(OCC)(=O)C.[OH-].[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:53]([O:57][C:58](=[O:61])[CH2:59][C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH2:15][CH2:16][OH:17])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)C(=O)Nc1cc(CCO)c(Br)cn1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1cnc(NC(=O)C(C)(C)C)cc1CCO
Temperature: 45 °C
Reaction time: 12 h

Procedure:
A 250 mL round bottomed flask was charged with N-[5-bromo-4-(2-hydroxyethyl)pyridin-2-yl]-2,2-dimethylpropanamide (1.9 g, 6.31 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.173 g, 0.189 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.180 g, 0.379) and the mixture was flushed with nitrogen for 30 min. tetrahydrofuran was added, followed by a solution of 2-tert-butoxy-2-oxoethylzinc chloride in diethyl ether (0.5 M, 47.9 mL) and the mixture was placed in an oil bath maintained at 45° C. After 12 h, the reaction was recharged with tris(dibenzylideneacetone)dipalladium(0) (0.173 g, 0.189 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.180 g, 0.379) and an additional quandity of 2-tert-butoxy-2-oxoethylzinc chloride in diethyl ether (0.5 M, 12.6 mL) was added. After stirring an additional 2 h in the 45° C. bath, the reaction mixture was diluted with ethyl acetate and 10% ammonium hydroxide solution, filtered to remove solids, and the layers separated. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. Purification by MPLC (eluent 9-90% ethyl acetate/hexanes) afforded tert-butyl{6-[(2,2-dimethylpropanoyl)amino]-4-(2-hydroxyethyl)pyridin-3-yl}acetate. 1H NMR (500 MHz, CDCl3), δ 8.30 (br s, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 3.88 (dd, J=6.5, 6.5 Hz, 2H), 3.55 (s, 2H), 2.88 (dd, J=6.5, 6.5 Hz, 2H), 1.40 (s, 9H), 1.28 (s, 9H); LC/MS (M+1)+=337.0;
Reaction SMILES: I[C:2]1C=CN=C(OC)[C:3]=1C1NC(C2C=CC=CC=2)=CN=1.[I:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[C:23]=1[C:30]1[N:31]([OH:41])[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:33][N:34]=1>>[CH2:2]([C:33]1[N:34]=[C:30]([C:23]2[C:24]([O:28][CH3:29])=[N:25][CH:26]=[CH:27][C:22]=2[I:21])[N:31]([OH:41])[C:32]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:3]
Reactant: COc1nccc(I)c1-c1ncc(-c2ccccc2)[nH]1
Reactant: COc1nccc(I)c1-c1ncc(-c2ccccc2)n1O
Product: CCc1nc(-c2c(I)ccnc2OC)n(O)c1-c1ccccc1

Procedure:
4-Iodo-2-methoxy-3-(5-phenyl-1H-imidazol-2-yl)-pyridine and 2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol: Isonitrosoacetophenone (0.030 g, 0.114 mmol) was reacted as described for the synthesis of 4-ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol and gave 4-iodo-2-methoxy-3-(5-phenyl-1H-imidazol-2-yl)-pyridine (0.008 g, 19%) and 2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol (0.007 g, 16%). 4-Iodo-2-methoxy-3-(5-phenyl-1H-imidazol-2-yl)-pyridine: LCMS (+ESI, M+H+) m/z 378; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.83 (3H, s), 7.17-7.97 (8H, m), 12.29 and 12.60 (1H, 2 br s). 2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol: : LCMS (+ESI, M+H+) m/z 378; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.82 and 3.92 (3H, 2 d), 7.19-8.05 (8H, m), 11.68 and 12.70 (1H, 2s).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][C:14]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[CH2:15][N:16]=2)=[CH:8][C:7]=1[Br:29])(=O)C.C[O-].[Na+]>CO.COC(C)(C)C>[Br:29][C:7]1[CH:8]=[C:9]([C:12]2[CH2:13][C:14]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:18])([F:19])[F:20])[CH2:15][N:16]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Product: OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzyl acetate (1.1 g) in methanol (20 ml) was added sodium methoxide (0.1 g), and the solution was stirred for 1 hour at room temperature. The reaction mixture was returned to room temperature and then diluted with t-butyl methyl ether, washed with water and a saturated aqueous brine and subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain {2-bromo-4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]phenyl}methanol (0.95 g).
Reaction SMILES: C(O)(=O)C.Cl.[Cl:6][C:7]1[CH:16]=[C:11]([C:12]([NH:14][OH:15])=[O:13])[C:10]([OH:17])=[CH:9][CH:8]=1.C(O[CH:21](OCC)[CH2:22][CH2:23][CH2:24][Cl:25])C>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:17][CH:21]([CH2:22][CH2:23][CH2:24][Cl:25])[N:14]([OH:15])[C:12](=[O:13])[C:11]=2[CH:16]=1
Reactant: O=C(NO)c1cc(Cl)ccc1O
Reactant: CCOC(CCCCl)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(Cl)ccc2OC(CCCCl)N1O
Reaction time: 8 h

Procedure:
6-Chloro-2-(3-chloropropyl)-2,3-dihydro-3-hydroxy-4H-1,3-benzoxazin-4-one was prepared by adding 250 ml. of glacial acetic acid saturated with hydrogen chloride gas to 37 g. of 5-chlorosalicylhydroxamic acid. 4-Chlorobutyraldehyde diethyl acetal (34 g.) and 50 ml. of glacial acetic acid saturated with hydrogen chloride gas were then added simultaneously with stirring at a rate to maintain a temperature of 25° to 40° C. The resulting mixture was stirred and heated at 55° to 60° C. for 2 hours and then allowed to stand at room temperature overnight. Mixture was poured into a mixture of ice and water, and when oil solidified it was removed by filtrating, washed with water, and air-dried. The crude product weighed 31.5 g. and melted at 70°-75° C. A sample recrystallized from ligroin at 80°-81° C.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:23]=[CH:22][C:12]([CH2:13]P(=O)(OCC)OCC)=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[OH:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.CCCCCC.CCOC(C)=O>C1COCC1>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12](/[CH:13]=[CH:37]/[C:36]4[CH:39]=[CH:40][C:33]([OH:32])=[CH:34][CH:35]=4)=[CH:22][CH:23]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(C)cc3s2)cc1)OCC
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc(O)cc4)cc3)sc2c1
Yield: 66.8 %

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0.10 g, 0.266 mmol) in dry THF (10 ml), potassium t-butoxide (0.063 g, 0.559 mmol) and 4-hydroxybenzaldehyde (0.033 g, 0.266 mmol) in dry THF (5 ml) to give the title compound (0.061 g, 67%) as a pale orange solid after work-up and flash chromatography (2:1 Hexane/EtOAc).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.ClCCl.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>O>[CH3:20][S:21]([O:9][CH2:8][CH2:7][C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cccc1CCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1cccc1CCOS(C)(=O)=O
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 49 g of 1-methyl-1H-pyrrole-2-ethanol, 47.6 g of N,N-diethylethanamine and 500 ml of dichloromethane, there were added portionwise 34 ml of methanesulfonyl chloride. Stirring was continued overnight at room temperature. The reaction mixture was diluted with water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 85.5 g (100%)of 1-methyl-1H-pyrrole-2-ethanol methanesulfonate (ester) (interm. 3);
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:20]1([CH2:19][O:18][C:3]2[C:2]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=3)=[CH:17][C:6]([C:7]([NH:9][C@@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[OH:16])=[O:8])=[CH:5][N:4]=2)[CH2:22][CH2:21]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31, using 5-bromo-6-cyclopropylmethoxy-N-(trans-2-hydroxy-cyclohexyl)-nicotinamide and 4-trifluoromethylphenylboronic acid (commercially available) as starting materials. MS (ISP): 435.4 (M+H)+.
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9]([C:13]([CH3:15])=C)[C:10]([OH:12])=[O:11])[C:7](=[O:16])[CH:6]1[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:3])[CH3:2].[O:28]=[O+][O-]>CO>[C:1]([S:4][CH:5]1[N:8]([CH:9]([C:13](=[O:28])[CH3:15])[C:10]([OH:12])=[O:11])[C:7](=[O:16])[CH:6]1[N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])(=[O:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1SC(C)=O
Solvent: CO
Product: CC(=O)SC1C(N2C(=O)c3ccccc3C2=O)C(=O)N1C(C(C)=O)C(=O)O
Yield: 63 %

Procedure:
To a solution of α-[4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-isopropenyl acetic acid (100 mg) in methanol (10 ml) at 0° C. is introduced excess ozone. After the gas at the outlet makes a potassium iodide starch paper coloured, the reaction mixture is bubbled with sulfur dioxide gas. The reaction mixture is concentrated, and the obtained residue is dissolved in aqueous solution of sodium hydrogen carbonate, washed with ether, neutralized with hydrochloric acid, and extracted with methylene chloride. The extract solution is washed with water, dried, and evaporated to give α-[4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-acetyl-acetic acid (64 mg). Yield: 63%. Foam. IR: νmaxCHCl3 1780, 1730, 1680 cm-1.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10](Cl)[N:5]2[N:4]=1.CC(O)C.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.C(N(CC)CC)C>C(N(CC)CC)C>[CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10]([NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:5]2[N:4]=1
Reactant: CN(C)c1nc2nc3c(c(Cl)n2n1)SCCC3
Reactant: NCCN1CCOCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(C)c1nc2nc3c(c(NCCN4CCOCC4)n2n1)SCCC3
Reaction time: 1 h

Procedure:
To a suspension of 5.40 g (0.02 mole) of 2-(dimethylamino)-5-chloro-7,8-dihydro-9H-thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine in 20 ml of 2-propanol 2,125 g (0.021 mole) of triethylamine and 2.73 g (0.021 mole) of 2-aminoethylmorpholine are successively added, and the reaction mixture is boiled for one hour. Upon cooling triethylamine hydrochloride gets separated, which is filtered and washed with 2-propanol. The filtrate is evaporated to dryness in vacuo and the residue is dissolved in chloroform. The solution thus obtained is extracted twice with water, dried over anhydrous Na2SO4 and evaporated in vacuo. The oily product is suspended in ethyl acetate, the crystalline product thus obtained is filtered off and washed with ethyl acetate.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[C:15]([CH:21]=1)[C:16]([O:18]CC)=[O:17])=[O:9].Cl>CCO>[Cl:3][C:4]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[C:15]([CH:21]=1)[C:16]([OH:18])=[O:17])=[O:9]
Reactant: CCOC(=O)c1cc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN(CC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.00 mL 1 M aqueous NaOH solution was added to a solution of 1.00 g (1.934 mmol) ethyl 5-[2-(2-chloro-4-trifluoromethyl-phenoxy)-acetylamino]-2-(2-diethylamino-ethoxy)-benzoate in 30 mL EtOH and the mixture was stirred for 3 h at RT. 4.00 mL 1 M aqueous HCl was added and again the mixture was stirred for 1 h. The reaction mixture was evaporated down i. vac., combined with water and the precipitate was filtered off.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][CH3:30])[CH:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][C:24]=1[O:29][CH3:30]
Reactant: COc1cc(Br)ccc1Cl
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: COc1cc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)ccc1Cl
Yield: 24.1 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.00 mmol) synthesized in Reference example 61 and 4-bromo-1-chloro-2-methoxybenzene (332 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 100 mg (yield 24%). Melting point was 168 to 171° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17]>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:17]#[C:16][C:15]([CH3:19])([CH3:18])[CH3:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1OC
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC(C)(C)C)cc1OC
Temperature: 100 °C
Yield: 91.1 %

Procedure:
A mixture of methyl 4-bromo-2-methoxybenzoate (1.2 g, 0.0049 mol), copper(I) iodide (0.093 g, 0.00049 mol), 3,3-dimethyl-1-butyne (0.70 mL, 0.0059 mol) and bis(triphenylphosphine)palladium(II) chloride (0.34 g, 0.00049 mol) in Et3N (10 mL) was heated at 100° C. in a 50 mL sealed reaction vessel for 16 hours. After cooling, the mixture was filtered through Celite® and the filter cake was washed repeatedly with ethyl acetate. The filtrate was concentrated under vacuum and the residue was purified by column chromatography on silica gel to give a viscous oil (1.10 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([OH:29])=O)[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6][CH:7]=1.[CH3:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CO>[CH3:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([C:27]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([CH3:30])=[CH:32][CH:33]=3)=[O:29])[CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6][CH:7]=1
Reactant: COc1cc(Nc2ncc(C)c(N3CCCC(C(=O)O)C3)n2)cc(OC)c1OC
Reactant: Cc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Nc2ncc(C)c(N3CCC[C@H](C(=O)NCc4ccc(C)cc4)C3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8.2 (380 mg, 0.866 mmol), TEA (0.362 mL, 2.60 mmol) and 4-methylbenzylamine (0.331 mL, 2.60 mmol) in DCM (21.7 mL) was added HATU (494 mg, 1.299 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was then concentrated and the residue was adsorbed onto a plug of silica gel and purified by chromatography through a 50 g silica gel column, eluting with 0.5 to 10% MeOH in DCM to give 8 as a stereomeric mixture. This mixture was brought up in a mixture of MeOH and DCM and purified by supercritical fluid chromatography using an ODH (21×250 mm, 5 um) column. The stereoisomer was then resolved with a mixture of 35% MeOH with 0.2% diethylamine going to 40% MeOH with 0.2% diethylamine at 4 minutes with a flow rate of 65 mL per minute to provide 8. 1H NMR (300 MHz, CDCl3) δ ppm 1.61 (br. s., 1H) 1.66-1.81 (m, 1H) 1.81-2.00 (m, 2H) 2.07 (s, 3H) 2.30 (s, 3H) 2.37-2.72 (m, 1H) 2.76-3.12 (m, 1H) 3.16-3.55 (m, 1H) 3.55-3.88 (m, 10H) 3.99 (d, J=11.98 Hz, 1H) 4.13-4.50 (m, 2H) 6.51 (br. s., 1H) 6.84 (s, 2H) 6.95-7.26 (m, 4H) 7.34 (br. s., 1H) 7.85 (s, 1H); M+H 506.27637.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[CH:22]=NC2N(O)N=[N:25][C:19]=2[CH:18]=1.C1(N)CCC1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:25][CH:19]1[CH2:18][CH2:17][CH2:22]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: NC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CCC1

Procedure:
To a solution of 2.00 g (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 20 ml DMF were added 1.18 g HOAT, 615 mg cyclobutylamine and 1.66 g EDC. After stirring for 12 h saturated NaHCO3 solution (3 ml) was added and the mixture passed through a Chem Elute® cartridge eluting with DCM. The crude product obtained after evaporation of the solvent was purified by filtering over a short plug of silica eluting with ethyl acetate. Yield: 1.22 g
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3].ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2(C#Cc3ccc([N+](=O)[O-])cc3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: [Ti+3]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc(C2(C#Cc3ccc(N)cc3)CCC(=O)CC2)cc1OC1CCCC1
Reaction time: 1.5 h

Procedure:
To 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(4-nitrophenylethynyl)cyclohexane (0.19 g, 0.40 mmol) in methanol (1 mL), acetic acid (1.2 mL), and water (1.2 mL) under an argon atmosphere was added titanium trichloride (0.3 g, 2 mmol). After stiring for 1.5 h at room temperature, water (1.2 mL) and ammonium hydroxide (2.5 mL) were added. After stirring an additional 1 h, methanol (17.5 mL), 5% sodium carbonate (17.5 mL) and dichloromethane (35 mL) were added, and stirring was continued for 3 days. The suspension was filtered through Celite®, was washed well with dichloromethane, and was evaporated. Water was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-aminophenylethynyl)cyclohexan-1-one as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.28 (d, J=8.4 Hz, 2H), 7.24 (d, J=2.1 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.64 (d, J=8.1 Hz, 2H), 4.80 (m, 1H), 3.85 (s, 3H), 3.05 (dt, J=14.3, 4.1 Hz, 2H), 2.45 (br d, J=14.6 Hz, 2H), 2.29 (m, 4H), 1.8-2.0 (m, 6H), 1.61 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17](OC(=O)C)(=O)[CH3:18].[OH-].[Na+]>C(O)(=O)C>[NH2:10][C:5]1[N:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:3]=[C:2]2[C:6]=1[C:7](=[O:8])[NH:9][C:17]([CH3:18])=[N:1]2
Reactant: NC(=O)c1c(N)nn(-c2ccccc2)c1N
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nc2nn(-c3ccccc3)c(N)c2c(=O)[nH]1

Procedure:
3,5-Diamino-1-phenylpyrazole-4-carboxamide (10.8 g) prepared as in Example 58 was heated with acetic acid (15 ml) and acetic anhydride (5.1 g) for 16 hours. The solution was poured into 2 M sodium hydroxide solution (200 ml) and a trace of solid was filtered off. The filtrate was adjusted to pH=7 with concentrated hydrochloric acid to precipitate 3-amino-2-phenyl-6-methyl-2,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (6.1 g) which was recrystallised from 2-methoxyethanol (3.6 g yield), m.p. 279°-281° C.
Reaction SMILES: Br.[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:24])=[C:12]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][NH:19][CH2:18]5)[CH:13]=3)[C:8](=[O:25])[C:7]([C:26]([OH:28])=[O:27])=[CH:6]2)[CH2:4][CH2:3]1.C=O.O.[C:32](=O)([O-])O.[Na+]>C(O)=O>[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:24])=[C:12]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19]([CH3:32])[CH2:18]5)[CH:13]=3)[C:8](=[O:25])[C:7]([C:26]([OH:28])=[O:27])=[CH:6]2)[CH2:3][CH2:4]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(-c3ccc4c(c3)CNC4)c(F)cc2c1=O
Reactant: O=C([O-])O
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CN1Cc2ccc(-c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)cc2C1

Procedure:
In 0.50 ml of formic acid was suspended 50 mg of 1-cyclopropyl-6-fluoro-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrobromide, and 27 mg of formalin was added to the suspension, after which the mixture was heated under reflux for two hours. The solvent was then removed by distillation under reduced pressure. To the residue obtained was added 5 ml of water and the pH was adjusted to 7 with a saturated aqueous sodium hydrogencarbonate solution, after which the resulting mixture was extracted with five 5 ml portions of chloroform. The resulting chloroform layer was dried over anhydrous magnesium sulfate and then the solvent was removed by distillation under reduced pressure. Ethanol was added to the residue obtained and the crystals formed were collected by filtration, to obtain 29 mg of pale yellow, crystalline 1-cyclopropyl-6-fluoro-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.