Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)[CH:37]=2)O1.C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([O:12][CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:33]5[CH:34]=[N:35][N:36]([CH:38]6[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]6)[CH:37]=5)[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OCc3nnc4ccc(-c5cnn(C6CCNCC6)c5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 50 mL sealable flask was charged with PdCl2(dppf)-CH2Cl2 adduct (0.011 g, 0.013 mmol), 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.44 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.18 g, 0.48 mmol), sat NaHCO3 (0.75 ml, >0.97 mmol) and 4 mL dioxane. The vessel was sealed and the mixture heated at 80 C for 22 h. The mixture was allowed to cool to rt and diluted with EtOAc, the organic layer washed with water, sat. NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was dissolved in 5 mL CH2Cl2 and TFA (1.20 ml, 16 mmol) was added. The mixture was stirred at rt for 10 min and evaporated. The residue was taken up into CH2Cl2 and stirred with minimal 2N NaOH for 1 h (ph basic). The mixture was evaporated and purified by prep hplc. The title compound was obtained as an off-white solid. M/Z=457.3 [M+H], calc 456.5076 for C24H24N8O2.
Reaction SMILES: [Br:1][CH2:2][CH:3]([CH2:29]Br)[C:4]([N:6]1[CH:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][CH2:8][N:7]1C(OCC1C=CC=CC=1)=O)=[O:5]>C(O)(=O)C.CO.[Pd]>[Br:1][CH2:2][CH:3]1[CH2:29][N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[N:6]2[C:4]1=[O:5]
Reactant: CC(C)(C)OC(=O)C1CCCN(C(=O)OCc2ccccc2)N1C(=O)C(CBr)CBr
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCCN2CC(CBr)C(=O)N12
Yield: 15.5 %

Procedure:
13.3 g of 1-benzyl 3-tert.butyl 2-(3-bromo-2-bromomethyl-propanoyl)-hexahydropyridazine-1,3-dicarboxylate in 122 ml of acetic acid and 122 ml of methanol was hydrogenated undera pressure of 1 atmosphere for 16 hours in the presence of 1.4 g of 10% palladium/charcoal, the hydrogenation being carried out under a soda-lime trap. The catalyst was removed by filtration, the filtrate was treated with 3.2 g of sodium acetate trihydrate and then evaporated. The residue was extracted with 300 ml of ethyl acetate and the solution was chromatographed on 400 g of silica gel using diethyl ether/hexane for the elution. There were obtained 1.25 g of tert.butyl 2-bromomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) having a melting point of 109°-111° C. (from hexane), 2.45 g of tert.butyl 2-bromomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate (diastereomer B) having a melting point of 88°-89° C. (from hexane) and 1.20 g of a mixture of the aforementioned diastereomers.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][NH2:10])[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:11][C:12]1[C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[S:15][C:16]=1[C:17](Cl)=[O:18]>>[Cl:11][C:12]1[C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[S:15][C:16]=1[C:17]([NH:10][CH2:9][CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:18]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: NCCn1ccnc1
Agent: Cl
Product: O=C(NCCn1ccnc1)c1sc2ccccc2c1Cl

Procedure:
A 1.47 g. portion of 1H-imidazole-1-ethanamine dihydrochloride was reacted with 3-chloro-benzo[b]thiophene-2-carbonyl chloride as described in Example 1, giving 0.75 g. of the desired product, m.p. 132°-134° C.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.N1C=CC=CC=1.[Br:16]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:16][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1CCCC(CO)C1
Solvent: CC#N
Solvent: c1ccncc1
Product: CN1CCCC(CBr)C1
Temperature: 0 °C
Reaction time: 94 h
Yield: 105.1 %

Procedure:
3-(Hydroxymethyl)-1-methylpiperidine (2 g, 15.5 mmoles) was dissolved in anhydrous acetonitrile (32 mL) and anhydrous pyridine (2.02 mL, 24.8 mmoles) was added and the solution was cooled to 0° C. Dibromotriphenylphosphorane (8.49 g, 20.2 mmoles) was added at 0° C. and the mixture was allowed to warm up to 25° C. and was stirred for 94 h. The mixture was evaporated to dryness and the residue was chromatographed on a silica gel column (30×5 cm) using gradient elution with dichloromethane, 35% diethyl ether in dichloromethane and 5-10% methanol in dichloromethane as the eluant to give 3-(bromomethyl)-1-methylpiperidine (3.13 g, 100%): FABMS: m/z 192.1 (MH+); δH (CDCl3) 1.52 (1H, m, CH2), 1.99 (2H, m, CH2), 2.43 (1H, m, CH2), 2.75 (2H, m, CH2), 2.82 (1H, m, CH), 2.86/2.88 (3H, s, NCH3), 3.42/3.49 (2H, dd, —CH2Br) and 3.56 ppm (2H, m, CH2); δC (CDCl3) CH3: 44.3; CH2: 22.1, 26.6, 35.4, 54.8, 58.2; CH: 34.6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:23]([O:25]C)=[O:24])=[CH:15]2.[OH-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:23]([OH:25])=[O:24])=[CH:15]2
Reactant: CCCCCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 891.9 %

Procedure:
To a solution of methyl 2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)octanoate (0.04 g, 0.09 mmol), as prepared in the preceding step, in methanol (5.0 mL) was added a solution of NaOH (0.1 g, 2.5 mmol) in H2O (0.3 mL), and the reaction was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4-5 with 10% HCl, and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (4% methanol in methylene chloride) to give the title compound as an oil (0.34 g, 90%). 1H-NMR (400 MHz, CDCl3) δ 7.72 (m, 1H), 7.48 (m, 1H), 7.26 (d, 8.9 Hz, 1H), 7.02 (d, J=2.7 Hz, 2H), 6.77 (dd, J=8.9, 2.4 Hz, 1H), 6.50 (m, 2H), 6.28 (d, J=2.9 Hz, 1H), 4.27 (dd, J=14.2, 8.6 Hz, 1H), 3.99 (m, 3H), 3.32 (t, J=6.7 Hz, 2H), 2.85 (br s, 1H), 1.95 (m, 2H), 1.67 (m, 1H), 1.30 (m, 9H), 0.84 (t, J=6.6 Hz, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. for C25H33N3O3 424.2 (M+H); Found: 424.7.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COc1cc(/C(C#N)=C\c2ccc(Cl)c([N+](=O)[O-])c2)cc(OC)c1OC
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc(/C(C#N)=C\c2ccc(Cl)c(N)c2)cc(OC)c1OC
Reaction time: 1 h
Yield: 33.6 %

Procedure:
(E)-3-(3-nitro-4-chlorophenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-ene-nitrile 330 mg was dissolved in 8 ml of acetic acid then zinc was added to the mixture. The mixture was stirred vigorously for one hour then filtered and concentrated. The residue was purified on a silica gel plate (dichloromethane) to give 102 mg of desired product (yield 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=O)=[CH:6]2.Cl.[CH3:16][NH:17][O:18][CH3:19].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:18][N:17]([CH3:16])[C:12]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(C(=O)N(C)OC)cc2c1
Reaction time: 6 h
Yield: 73.9 %

Procedure:
To a solution of 5-methoxyindole-2-carboxylic acid (5 g, 26 mmol) in N,N-dimethylformamide were added N,O-dimethylhydroxyamine hydrochloride (3.04 g, 31.2 mmol) and WSC (5.98 g, 31.2 mmol), 1-hydroxybenzotriazole (4.21 g, 31.2 mmol) and triethylamine (7.24 ml, 52 mmol), and the mixture was stirred for 6 hours. To this reaction solution were added ethyl acetate and 10% (Wt) citric acid, and the organic layer was extracted. The aqueous layer was extracted twice with ethyl acetate, and combined with the organic layer. The mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline. The organic layer was separated, and dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (4.5 g, 70%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)=[O:2].[CH3:11][N:12]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>>[CH:1]([C:3]1[S:7][C:6]([C:8]([N:23]([CH3:24])[CH2:22][CH2:21][CH2:20][N:12]([CH3:11])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Product: CN(CCCN(C)C(=O)c1ccc(C=O)s1)C(=O)OC(C)(C)C
Yield: 79.1 %

Procedure:
5-Formylthiophene-2-carboxylic acid (300 mg, 1.92 mmol) and tert-butyl methyl[3-(methylamino)propyl]carbamate (466 mg, 2.31 mmol) were used to give the title compound (517 mg; yield, 83%) as a colorless oily substance according to the method described in Example 41a.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[C:19]3\[C:20](=[O:25])[NH:21][C:22](=[O:24])[S:23]\3)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]>C(Cl)Cl.CO.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(/C=C3/SC(=O)NC3=O)cc2)nc1
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCc1ccc(CCOc2ccc(C[C@H]3SC(=O)NC3=O)cc2)nc1
Reaction time: 18 h

Procedure:
A stock solution of the Rh(COD)2BF4 (10.6 mg, 26.1 μmol) in DCM (9.5 mL) was made in a glove box. Ligand SL-WO03-2 ((S)-1-[(S)-2-(2i -diphenylphosphinophenyl)ferrocenyl]ethyl-dicyclohexyl phosphine) (8.4 mg, 12.5 μmol), was weighed into a vial and 500 μL of the Rh(COD)2BF4 stock solution was added. A solution of 5-[1-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-meth-(E)-ylidene]-thiazolidine-2,4-dione (4.5 mL of a stock solution containing 78.2 mg in 35 mL MeOH) was added to the reaction vial containing the catalyst solution. The vial was purged with N2 (5×) and H2 (5×) and finally charged with 25 bar of H2. After 18 h the H2 was released and the reaction vial was purged with N2 (3×). A sample of the reaction vial was taken and diluted with an equal volume of EtOH containing 1% formic acid. e.e. (Method 4) 75%, Rt 36.11 min, conversion 50%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][C:20]=3Br)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Zn](C)[CH3:43].C1(C)C=CC=CC=1>C1COCC1.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>[Cl:39][C:32]1[C:33]([F:38])=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[C@H:29]([O:28][C:27]1[C:22]2[O:21][C:20]([CH3:43])=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[C:23]=2[CH:24]=[N:25][C:26]=1[NH2:40])[CH3:30]
Reactant: C[Zn]C
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1oc2c(O[C@H](C)c3c(Cl)ccc(F)c3Cl)c(N)ncc2c1-c1cnn(C2CCNCC2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(4-{6-amino-2-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.0299 mmol), 2.0 M Me2Zn in PhMe (0.04 mL, 0.08 mmol), and Pd(PPh3)4 (2.9 mg, 0.0025 mmol) in THF (1 mL) was degassed and refilled with argon (3×), then heated at 100° C. for 30 min using a CEM microwave reactor. The solution was passed through a PL-Thiol SPE cartridge to remove metals. The material was then dissolved in dioxane and EtOH, charged with 4M HCl in Dioxane (0.2 mL) and stirred at rt for 4 h. The solution was concentrated in vacuo, redissolved in DMF (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 2.28-2.39 (m, 4H), 2.43 (s, 3H), 3.16-3.26 (m, 2H), 3.55-3.62 (m, 2H), 4.61 (dt, J=10.0, 5.0 Hz, 1H), 6.50 (q, J=6.7 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.40 (dd, J=9.1, 4.8 Hz, 1H), 7.79 (s, 1H), 7.89 (s, 1H), 7.99 (s, 1H). MS (ES+): m/z 504.06/506.07 (100/71) [MH+]. HPLC: tR=2.73 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][C:6]([CH3:12])=[C:5]2[CH2:13][C:14]([O:16]C)=[O:15].[CH3:18][S:19]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)(=[O:21])=[O:20].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])/[C:7](=[CH:26]\[C:25]1[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:29][CH:28]=1)/[C:6]([CH3:12])=[C:5]2[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: COC(=O)CC1=C(C)Cc2cc(F)c(F)cc21
Solvent: c1ccncc1
Solvent: O
Product: CC1=C(CC(=O)O)c2cc(F)c(F)cc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
Methyl 5,6-difluoro-2-methylindene-3-acetate (1.19 g, 5.0 mmol) from Example 2, Part E and of p-methylsulfonylbenzaldehyde (0.76 g, 5.0 mmol) in dry pyridine (10 ml) are treated under nitrogen with Triton B (5.0 g, 5.1 mmol). The deeply colored solution is kept overnight. Water (2 ml) is added, the solution is stirred for 15 minutes and is poured into excess water. The mixture is extracted with ether (2×50 ml). The aqueous phase is added to 10% HCl-ice. The solution of the precipitate is extracted into methylene chloride and is dried (MgSO4). The solvent is evaporated to leave an orange solid which is recrystallized from benzene to give (Z)-5,6-difluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-indene-3-acetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Br)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:22][CH2:21][CH2:20][C:19]([OH:24])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)CCCOc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a 250 mL flask, equipped with a reflux condenser, magnetic stirrer, and under inert atmosphere, was added 2-benzyloxy-phenol (8.0 g, 40 mmol), 4-bromobutanoic acid ethyl ester (5.7 mL, 40 mmol), potassium carbonate (7.2 g, 52 mmol), and ethanol (100 mL). The reaction mixture was heated to reflux with stirring for 8 hours. The reaction was cooled to room temperature and the insoluble byproduct was removed by suction filtration. 2N aqueous sodium hydroxide (30 mL) was added to the filtrate. This solution was heated to 50° C. for 2 hours. The solution was cooled to room temperature, the ethanol removed under reduced pressure, and the resulting solution was adjusted to pH 9. The aqueous solution was washed with ethyl acetate (2×30 mL) and residual ethyl acetate was removed under reduced pressure. The solution was cooled to 0° C. with an external ice bath and then acidified to pH 2 with 6N aqueous hydrochloric acid. The precipitated product was collected by suction filtration and dried under vacuum. The product (7.2 g, 63%) was isolated as a white powder. 1H-NMR (400 MHz, DMSO-d6): δ 12.0, s, 1H(COOH); δ 7.4, multiplet, 5H (Benzylic aryl H's); δ 7.0, multiplet, 2H (Aryl H's); δ 6.9, multiplet, 2H (Aryl H's); δ 5.0, s, 2H (Benzylic CH2); δ 4.0, t, 2H (CH2 α to phenoxy); δ 2.4, t, 2H(CH2 α to COOH); δ 1.9, multiplet, 2H (remaining CH2 group).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[OH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[C:8]#[N:9].[OH-].[Na+].C(=O)=O>O.COCCOC>[F:3][CH:2]([F:4])[O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(O)cccc1F
Reactant: FC(F)Cl
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(F)cccc1OC(F)F
Reaction time: 1 h

Procedure:
6.3 g of chlorodifluoromethane were passed into a stirred mixture of 10.0 g of 2-hydroxy-6-fluorobenzonitrile, 50 ml of 1,2-dimethoxyethane and 25 ml of NaOH (33%) at 75° C. (the reflux condenser was cooled with dry ice), and stirring was continued for one hour at 70-75° C. After cooling, the batch was diluted with 300 ml of water and extracted three times using in each case 150 ml of tert-butyl methyl ether. After the solvent had been vaporated, 6.5 9 of the desired product were obtained as an oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=[O:6].[N+:14]([CH:16](S(C1C=CC(C)=CC=1)(=O)=O)C)#[C-:15]>>[F:11][C:10]([F:13])([F:12])[C:9]1[CH:8]=[CH:7][C:4]([C:5]2[O:6][CH:16]=[N:14][CH:15]=2)=[CH:3][CH:2]=1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Product: FC(F)(F)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1B, substituting 4-(trifluoromethyl)benzaldehyde for 3-fluoro-4-(trifluoromethyl)benzaldehyde and substituting p-toluenesulfonylmethyl isocyanide for 1-(1-isocyanoethylsulfonyl)-4-methylbenzene.
Reaction SMILES: [Zn](CC)[CH2:2]C.FC(F)(F)C(O)=O.N#N.C(I)I.[CH3:18][C:19]1([CH3:34])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[CH2:33])[CH:27]=2)[O:20]1>C(Cl)Cl>[CH:32]1([C:28]2[CH:27]=[C:26]([B:21]3[O:20][C:19]([CH3:34])([CH3:18])[C:23]([CH3:24])([CH3:25])[O:22]3)[CH:31]=[CH:30][CH:29]=2)[CH2:2][CH2:33]1
Reactant: CC[Zn]CC
Reactant: C=Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: N#N
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OB(c2cccc(C3CC3)c2)OC1(C)C
Reaction time: 0.33 h
Yield: 10 %

Procedure:
To a solution of Zn(C2H5)2 (1 M, 6 mL) in DCM (1 mL) was added trifluoro-acetic acid (0.46 ml, 6 mmol) in DCM (1 mL) very slowly under N2 in ice bath. The mixture was stirred for 20 minutes. CH2I2 (1.61 g, 6 mmol) in DCM (1 mL) was added to the mixture. After stirring for 20 minutes, 4,4,5,5-tetramethyl-2-(3-vinylphenyl)-1,3,2-dioxaborolane (690 mg, 3 mmol) in DCM (1 mL) was added. The mixture was stirred at room temperature for 2 hour. the mixture was quenched by NH4Cl solution, extracted with DCM 3 times, washed with brine, filtered and concentrated to give the residue, which was purified preparative TLC and HPLC to give 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 10%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][N:13]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[O:28])[N:20]([CH3:27])[C:21]2=[O:26])[C:14](Cl)=[O:15].N1C=CC=CC=1>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH:11][C:14]([N:13]([CH3:12])[C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:28])[N:20]([CH3:27])[C:21]3=[O:26])=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CN1C(=O)c2cccc(N(C)C(=O)Cl)c2C1=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CN1C(=O)c2cccc(N(C)C(=O)NNc3ccc([N+](=O)[O-])cc3)c2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
p-Nitrophenylhydrazine (1.5 g, 10 mmole), N-methyl-N-(2-methyl-1,3-dioxoisoindolin-4-yl) carbamoyl chloride (2.5 g, 10 mmole) and 2 ml pyridine were combined in 25 ml dry acetonitrile, heated to reflux, then stirred at room temperature for 4 hours. The solid formed was collected and washed with ether to give 2.6 g of product, m.p. 194°-196° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([C:19]3[C:20]([C:26]([F:29])([F:28])[F:27])=[N+:21]([O-:25])[CH:22]=[CH:23][CH:24]=3)[O:17][CH:18]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([C:19]3[C:20]([C:26]([F:27])([F:29])[F:28])=[N+:21]([O-:25])[CH:22]=[CH:23][CH:24]=3)[O:17][CH:18]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(-c2coc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2coc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc(O)c1O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
3-(4-(3,4-Dimethoxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine 1-oxide (1.23 g, 3 mmol) was taken up in dichloromethane (25 mL). The yellowish suspension was cooled to −78° C. under argon and boron tribromide (2.55 mL, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It was then carefully poured into ice-water (100 mL) and stirred for 1 hour. The resulting yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. The solid was recrystallized from ethanol to give 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine 1-oxide as a yellow solid, 0.65 g, (57%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[OH-].[Na+].[C:19](=O)([O-])O.[Na+]>CO>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:10][C:6]=1[C:7]([O:9][CH3:19])=[O:8]
Reactant: O=C([O-])O
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1O
Yield: 45 %

Procedure:
5-Amino-2-hydroxybenzoic acid (200 g, 1.31 mole) was suspended in methanol (2 1), concentrated sulphuric acid (120 ml) was slowly added and the reaction mixture was refluxed for 48 hours under nitrogen. Subsequently the reaction mixture was brought to room temperature and neutralized with 33% aqueous sodium hydroxide (120 ml) and 1M aqueous sodium hydrogen carbonate (to neutral reaction). The reaction mixture was extracted with ether (3×400 ml), the ethereal solution was washed with 1M aqueous sodium hydrogen carbonate (2×100 ml) and water (2×100 ml) and dried over anhydrous magnesium sulphate (50 g) and the ether evaporated. The remaining product was recrystallized from hexane, with activated carbon, to give methyl 2-hydroxy-5-aminobenzoate (98.3 g, 45%), m.p. 93°-95° C. Found (Calc. for C8H9NO3) C 57.38 (57.48), H 5.41 (5.39), N 8.38 (8.38).