Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:30]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:31][C:32]([O-])=[O:33].Cl>O1CCCC1.O.C(OCC)(=O)C>[O:33]=[C:32]([C:14]1[CH:15]=[CH:16][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:31][C:30]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 180.9 %

Procedure:
To a solution of 3-phenoxybenzoic acid (13.5 g, 63.0 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (11.2 g, 69.3 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (10 g, 34.8 mmol) and the mixture was stirred at room temperature for 2 hrs. To the reaction solution were added ethyl acetate (50 ml) and water (50 ml), and conc. hydrochloric acid was added until the pH of the aqueous layer became acidic. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-oxo-3-(4-phenoxyphenyl)propionate (17.9 g, 100%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][C:27](Cl)=[S:28]>CC(C)=O>[CH3:9][N:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[C:27](=[S:28])[O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1
Reactant: S=C(Cl)Oc1ccc2ccccc2c1
Reactant: CNc1cccc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(N(C)C(=S)Oc2ccc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a mixture of 1.22 g of 6-methyl-2-methylaminopyridine and 1.38 g of anhydrous potassium carbonate in 20 ml of acetone was added dropwise 2.23 g of 2-naphthylchlorothioformate in 20 ml of acetone under agitation at room temperature. The reaction mixture was stirred overnight at room temperature and inorganic salts were removed by filtration. After acetone was removed by distillation under a reduced pressure, the residue was purified by the column chromatography (silica gel, developed with ethyl acetate/benzene=1/9 (V/V), to obtain 2.62 g of O-2-naphthyl N-methyl-N-(6-methyl-2-pyridyl)thiocarbamate as a solid in a yield of 85%. A portion of the product was recrystallized from ethanol to give colorless crystals having a melting point of 149.5° C.-150.5° C. Elemental analysis of the crystals is given below.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C(=O)N([Br:20])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClC1C=CC=CC=1>[Br:20][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([CH3:12])[C:2]=1[OH:1]
Reactant: Cc1nc2ccccc2cc1O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1nc2ccccc2c(Br)c1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
3-Hydroxy-2-methyl-quinoline (76 mg) was dissolved in chlorobenzene (7 ml) to prepare a solution. N-Bromosuccimide (180 mg) and 2,2′-azobisisobutyronitrile (23 mg) were added to the solution, and the mixture was stirred at 80° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give 4-bromo-3-hydroxy-2-methyl-quinoline (35 mg, yield 31%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=[O:14])[N:5]=1)([O-])=O>[Pd].C(O)(C)C>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=[O:14])[N:5]=1
Reactant: NC(=O)CCCCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CC(C)O
Product: NC(=O)CCCCn1ccc(N)n1

Procedure:
A mixture of 5-(3-nitropyrazol-1-yl)valeramide (3.6 g.) and 3% w/w palladium on carbon (0.54 g.) was stirred in isopropanol (20 ml.) under an atmosphere of hydrogen. The temperature was kept below 40° by external ice cooling. After 4 hours no more hydrogen was absorbed. The mixture was filtered and the filtrate was evaporated in vacuo to give 5-(3-aminopyrazol-1-yl)valeramide as an oil which crystallised. This product (2.5 g.) was stirred in acetonitrile (25 ml.) and 2,2,2-trifluoroethylisothiocyanate (2.17 g.) was added. After 18 hours the mixture was filtered and the residue was washed with acetonitrile then ether to give 5-(3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazol-1-yl)valeramide, m.p. 172°-174°.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>CC(O)=O>[Br:20][CH:1]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:2]
Reactant: CCc1nc2ccccc2n(C)c1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(Br)c1nc2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of a 3-ethyl-1-methyl-1H-quinoxalin-2-one (1 g) and anhydrous sodium acetate (0.523 g) in glacial AcOH (10 mL) was added dropwise over 10 min. a solution of bromine (0.273 mL) in glacial AcOH (6 mL). The resulting pale yellow suspension was stirred at rt under nitrogen for 2 h, cooled to 0° C., filtered and washed with cold-water to give the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:3][OH:4].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1>C1COCC1.C([O-])(O)=O.[Na+]>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([C@H:2]2[CH2:3][O:4][C:22](=[O:23])[NH:1]2)=[CH:6][CH:7]=1
Reactant: N[C@H](CO)c1ccc(-c2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N[C@@H](c2ccc(-c3ccccc3)cc2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of (S)-2-amino-2-(biphenyl-4-yl)ethanol (171 mg, 0.802 mmol) in THF (12 mL) under argon atmosphere was added CDI (132 mg, 0.814 mmol). The solution was stirred at room temperature for 2 hours. The mixture was diluted with saturated aqueous NaHCO3 solution (40 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with 0.5M aqueous HCl solution (30 mL), brine (40 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was dissolved in DCM and concentrated under reduced pressure to provide crude (S)-4-(biphenyl-4-yl)oxazolidin-2-one (156 mg) as a beige solid, which was used without further purification. LCMS m/z 240.1 (M+H)+, Rt 0.80 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(-c3cnn(C)c3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:12][CH2:13][CH:14]=[CH2:15])[C:6]([O:8]CC=C)=[O:7])[CH:2]=[CH2:3].[OH-].[Na+:17]>C1(C)C=CC=CC=1.O>[CH2:13]([O:12][CH:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:6]([O-:8])=[O:7])[CH:14]=[CH2:15].[Na+:17]
Reactant: C=CCOC(=O)C(OCC=C)OCC=C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOC(OCC=C)C(=O)[O-]
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
21.2 g (0.1 mole) of allyl diallyloxyacetate is dissolved in 42 g of toluene then 3.92 g (98 mmoles) of sodium hydroxide dissolved in 50 g of water is introduced into this solution. This bipbase reaction medium is agitated vigorously for 30 minutes at 30° C., then decanted and the aqueous phase is collected and subjected to a vacuum distillation to eliminate the freed allyl alcohol by azeotropic distillation. The aqueous phase is then poured into acetone to precipitate the expected sodium diallyloxyacetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]
Reactant: NCCNC(=O)c1ccccc1O
Reactant: COC(C=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(CNCCNC(=O)c1ccccc1O)OC
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of N-(2-aminoethyl)-2-hydroxybenzamide (332 mg, 1.85 mmol), dimethoxyacetaldehyde (0.475 mL, 1.85 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyboro hydrid (588 mg, 2.80 mmol). The resulting mixture was stirred overnight, then diluted with EtOAc (50 mL), washed with 10 mL of water and then brine, dried over MgSO4, and conc in vacuo to yield 441 mg (97%) of the product as a colorless oil. MS (ESI) 269 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]=3[CH:21]=[N:20]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:23]2[CH2:24][CH2:25][CH2:26][C:27]3[N:19]([C:16]4[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=4)[N:20]=[CH:21][C:22]2=3)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: O=C(Cc1ccc(Cl)cc1)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The compound was from prepared from 4-chlorophenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method A. The product mixture was crystallized from 4:1 CH3CN:H2O to give the title compound as an off-white crystalline solid (37.6 mg). 1H NMR (400 MHz, MeOD-d4, mixture of rotamers) δ 8.18 (s, 0.9H), 7.84 (s, 0.1H), 7.56 (m, 2H), 7.25-7.37 (m, 6H), 4.02 (s, 0.2H), 3.92 (s, 1.8H), 2.81 (t, J=6.2 Hz, 2H), 2.49 (m, 2H), 1.90 (m, 2H); MS: (ES) m/z calculated for C20H18ClFN3O [M+H]+ 370.1, found 370.1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=O)=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8](/[CH:9]=[CH:10]/[CH:11]=[CH:2]/[C:1]([O:4][CH3:5])=[O:3])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COc1cc(C=CC=O)ccc1OC(C)=O
Solvent: c1ccccc1
Product: COC(=O)/C=C/C=C/c1ccc(OC(C)=O)c(OC)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 880 mg (4.0 mmol) of 4-acetoxy-3-methoxycinnamaldehyde in 100 mL of benzene, 2000 mg (6.0 mmol) of methyl (triphenylphosphoranilydene)acetate was added. The mixture was stirred at 80° C. for 4 h and passed through silica gel (eluent ethyl acetate-hexane, 1:1) to remove the excess of the Wittig reagent.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[OH:33]OS([O-])=O.[K+].Cl>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([OH:33])=[O:31])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a suspension of aldehyde 47 (200 mg, 0.446 mmol, scheme 15) in DMF (10 mL) was added Oxone® (330 mg, 0.535 mmol) at RT and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was cooled to 0° C., treated with 1N aqueous HCl (20 mL) and stirred at RT for an additional hour. The resultant precipitate was collected by filtration, washed with water (30 mL) and dried. The crude product was triturated with MeOH to afford title compound 225 (165 mg, 80% yield) as a beige solid. NMR (400 MHz, CD3OD) δ (ppm): 9.66 (bs, 1H), 8.98 (dd, J=1.9, 0.9 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.22 (dd, J=8.1, 1.9 Hz, 1H), 8.17 (dd, J=8.1, 0.9 Hz, 1H), 7.77 (dd, J=13.7, 2.5 Hz, 1H), 7.45 (bs, 1H), 7.37 (t, J=9.1 Hz, 1H), 7.26 (dd, J=8.9, 1.5 Hz, 1H), 6.62 (d, J=5.3, 0.8 Hz, 1H), 2.60-2.52 (m, 1H), 0.69-0.56 (m, 2H), 0.50-0.37 (m, 2H). [Carboxylic OH is not seen]. MS: 465.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][C:7]([N+:16]([O-:18])=[O:17])=[CH:8][C:9]=2[CH3:15])[N:4]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:15][C:9]1[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc2cc([N+](=O)[O-])cc(C)c2nc1OC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC

Procedure:
A suspension of 0.249 g (1.0 mmol) of 2,3-dimethoxy-5-methyl-7-nitro-quinoxaline, 0.178 g (1 mmol) of N-bromosuccinimide and 0.016 g (0.1 mmol) of azo-isobutyronitrile in 3 ml of CCl4 is heated at reflux for 20 hours. The reaction mixture is washed with water and brine and concentrated using a rotary evaporator. Crystallization from ethyl acetate yields the title compound. TLC: hexane/ethyl acetate 6/1: Rf=0.63, 1H-NMR (CDCl3): δ 8.64 (d, J=3, 1H), 8.41 (d, J=3, 1H), 5.02(s, 2H), 4.27(s, 3H), 4.20 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].Cl[CH2:13][CH:14]=[C:15]([CH3:35])[CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28].CCCCCC.O>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:35][C:15]1([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28])[CH2:14][CH2:13][C:8]2[C:6](=[C:5]([CH3:9])[C:4]([CH3:10])=[C:3]([OH:11])[C:2]=2[CH3:1])[O:7]1
Reactant: CC(=CCCl)CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Temperature: 30 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Trimethylhydroquinone (8.4 g), 1,7,11,15-tetrachloro-3,7,11,15-tetramethyl-hexadec-2-ene (22 g) and acetic acid (30 cc) are introduced into a 250 cc reactor. A solution of zinc chloride (1.5 g) in anhydrous acetic acid (15 cc) is then added over the course of 10 minutes. The temperature rises from 25° to 30° C. The reaction mixture is stirred for 2 hours at 30° C. and is then poured into a mixture of hexane (100 cc) and water (100 cc). The organic phase is removed by decanting, and washed with a mixture (100 cc) of methanol and water (50:50 by volume). A white precipitate forms in the hexane phase; it is filtered off and washed with a mixture (50 cc) of methanol and water (50:50 by volume). After drying under reduced pressure, 2,5,7,8-tetramethyl-2-(4',8',12'-trichloro-4',8',12'-tri-methyl-tridecyl)-chroman-6-ol (14.3 g) is obtained in the form of white crystals melting at 102°-104° C. The yield is 62%.
Reaction SMILES: Br[C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([NH:10][CH3:11])[N:4]([CH2:12][CH2:13][OH:14])[N:3]=1.S(=O)(=O)(O)O>C(O)(C)C>[NH2:7][C:6]1[CH:2]=[N:3][N:4]([CH2:12][CH2:13][OH:14])[C:5]=1[NH:10][CH3:11]
Reactant: CNc1c([N+](=O)[O-])c(Br)nn1CCO
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CNc1c(N)cnn1CCO
Yield: 64 %

Procedure:
2.65 g (10 mmoles) of 3-bromo-1-(2'-hydroxyethyl)-5-methylamino-4-nitropyrazole are hydrogenated for 4 hours according to method (1). After adding 1 g (10 mmoles) sulfuric acid and 10 ml isopropanol, the product separates. 1 g (40 percent of theory) of 4-amino-1-(2'-hydroxyethyl)-5-methylaminopyrazole hydrosulfate are obtained in the form of colorless crystals with a melting point of 138° to 140° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:28]3[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
Reactant: CC1(C)OB(c2csc(CC#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cc(-c2cn(-c3ccccc3Cl)c(=O)c3c(N)n[nH]c23)cs1
Temperature: 120 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (200 mg), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetonitrile (220 mg), tetrakis(triphenylphosphine)palladium(0) (68.1 mg), aqueous sodium carbonate solution (2 M, 0.589 mL) and N,N-dimethylformamide (3.0 mL) was stirred overnight at 120° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (83.6 mg).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[C:13]#[N:14])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[OH:8][CH2:9][CH2:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[C:13]#[N:14]
Reactant: CC(C)(C#N)C(=O)CCOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C#N)C(=O)CCO
Reaction time: 7.5 h

Procedure:
3 g of Pearlman's catalyst (Pd(OH)2 on carbon, 20%) is added to 10 g (43.23 mmol) of 5-benzyloxy-2,2-dimethyl-3-keto-pentane-nitrile of the title compound of Example 10a, dissolved in 100 ml of methanol. It is now hydrogenated for 7.5 hours at 10 bar and at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C=O)cc1C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 4-hydroxy-3-methylbenzaldehyde (8 g, 58.8 mmol) in an hydrous acetonitrile (300 mL), under nitrogen at 0° C., was added caesium carbonate (21 g, 64.6 mmol) and ethyl bromoacetate (6.52 mL, 58.8 mmol). The resulting mixture was allowed to come to room temperature and stirred for 16 h. The reaction mixture was diluted with water (400 mL) and extracted with EtOAc (2×500 mL). The combined organic extracts were dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as brown solid (11.5 g).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH2:7][O:8][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 20 h
Yield: 108 %

Procedure:
A mixture of methyl 2,2-dimethyl-3-hydroxypropionate (100 g, 0.76 mol), 4-toluenesulfonyl chloride (151 g, 0.80 mol), 4-dimethylaminopyridine (4.6 g, 0.038 mol), and pyridine (200 mL) was stirred for 20 hrs and then was diluted with 200 mL toluene, stirred for 30 min and filtered. The filtrate was concentrated to 250 mL at aspirator pressure, diluted with 100 mL toluene, filtered, and concentrated. The residue was suspended in 200 mL hexanes, and the solvent was removed at aspirator pressure to yield the title compound (235 g, 100%) contaminated by a trace of toluenesulfonyl chloride.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=O)(C)(C)C.Cl>[OH-].[K+]>[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Nc1cnc(Cl)cc1C(=O)O
Temperature: 90 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
A suspension of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid (2.46 g) in aqueous 2N potassium hydroxide solution (45 mL) was stirred at 90° C. for 5 hours. After cooling to room temperature, the solution was acidified by slow addition of 6N hydrochloric acid. The formed precipitate was filtered off, washed with water, MTB-ether and hexane and dried in vacuum to afford 700 mg of the title compound of the formula
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].I[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1/[C:16](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:17](=[O:23])[NH:18]2.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][NH:26][C:25]=1/[CH:24]=[C:16]1\[C:17](=[O:23])[NH:18][C:19]2[C:15]\1=[C:14]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)[CH:22]=[CH:21][CH:20]=2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3ccc(C(=O)O)cc3)c21
Yield: 30.4 %

Procedure:
Using Method S above, 4-carboxy-phenyl boronic acid (27.2 mg, 0.164 mmol) (Lancaster) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.137 mmol) (Starting Material 3) using (Ph3P)4Pd (4.8 mg) (Aldrich) as catalyst in DME (5 mL) and solid Na2CO3 (51 mg, 0.48 mmol) at reflux for 18 h to give (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-benzoic acid (yield: 15 mg, 31%).