Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:15].CCOC(C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N+:7]([O-:15])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C)nc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-methoxy-2-methylpyridine (15 g, 0.121 mol) in DCM (200 mL) was added 3-chloro peroxybenzoic acid (23.14 g, 0.134 mol, Aldrich). The reaction was stirred at rt for 3 h. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of reaction, the reaction mixture was concentrated under reduced pressure providing the product as a yellow oil. The oil was dissolved in EtOAc (50 mL) and passed through a silica gel plug (60-120 mesh) and the plug eluted with 10% MeOH in CHCl3 to give the title compound as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (d, J=2.4 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 6.98 (dd, J=2.7 and 8.7 Hz, 1H), 3.78 (s, 3H), 2.26 (s, 3H). MS (ESI, positive ion) m/z: 140.0 (M+H).
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N+:16]([O-:22])=[C:17](N)[N:18]=[N+:19]([O-:20])[C:14]=2[CH:13]=1)[CH:9]=[CH2:10]>CN(C=O)C>[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N+:16]([O-:22])=[CH:17][N:18]=[N+:19]([O-:20])[C:14]=2[CH:13]=1)[CH:9]=[CH2:10]
Reactant: C=CCOc1ccc2c(c1)[n+]([O-])nc(N)[n+]2[O-]
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)[n+]([O-])nc[n+]2[O-]
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a stirred solution of t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) in DMF (15 ml) at 60°-65° C. was added 7-allyloxy-3-amino-1,2,4-benzotriazine- 1,4-dioxide 23 (205 mg, 0.875 mmol) in small portions over 5 min. After 30 min additional t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) was added, and shortly thereafter the deep red solution effervesced and lightened appreciably in color over a period of a few minutes. After an additional 30 min the resultant orange solution was reduced under vacuum to a brown solid which was sequentially flash chromatographed (10% EtOAc/CH2Cl2) and crystallized (CH2Cl2 /petroleum ether) to give 72 mg (38% yield) of the product 24 as light orange crystals, mp 147°-148° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20](Br)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:31]5[S:32][CH:33]=[CH:34][N:35]=5)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(-c5nccs5)cc43)CC2)cc1
Yield: 3 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.56 g) and 2-tributylstannylthiazole (2.778 g) synthesized in accordance with the method described in Synthesis, 757 (1986). were treated as in Production Example 13-2 to give the title compound (0.017 g) as pale yellow crystals (yield: 3.0%).
Reaction SMILES: FC1C=C([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])C=CC=1S(C)(=O)=O.[F:19][C:20]1[CH:21]=[C:22](CC(=O)C)[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27].FC1C=CC(CC(=O)C)=CC=1S(C)(=O)=O>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Agent: CC(=O)Cc1ccc(F)c(S(C)(=O)=O)c1
Product: Cc1nc(N)sc1-c1ccc(F)c(S(C)(=O)=O)c1

Procedure:
The titled compound is prepared via an analogous method to 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Intermediate AA) by replacing 1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one (AA3) in step AA4 with 1-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one (AG3).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][C:10]=1[Cl:28])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:10]1[CH:11]=[C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C2CCNCC2)cc1Cl

Procedure:
A mixture the product of Example 60C (100 mg) and trifluoroacetic acid (1 mL) in dichloromethane (4 mL) was stirred at ambient temperature for 3 hours. The mixture was concentrated and the crude title compound was used in the next step without further purification. MS: 211 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH:10]([F:15])[F:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: FC(F)Oc1cccnc1Br
Temperature: 55 °C
Yield: 42.7 %

Procedure:
A mixture of 2-bromopyridin-3-ol (3.55 g, 20.4 mmol), sodium chlorodifluoroacetate (6.22 g, 40.8 mmol), and NaOH (0.90 g, 22.4 mmol) in DMF (20 ml) was heated at 55° C. for 111 h. The reaction was allowed to cool to rt and concentrated, and resulting residue was partitioned between EtOAc/sat. Na2CO3 (80 ml/40 ml). The organic phase was collected and washed with brine (40 ml), dried (Na2SO4), concentrated and the resulting residue was purified by flash chromatography (SiO2, 100:0-0:100 hexanes-EtOAc) to provide 1.95 g (43%) of 2-bromo-3-(difluoromethoxy)pyridine: LCMS (m/z, MH+): 225.9, tR=0.74 min; 1H NMR (CDCl3, 400 MHz) δ 8.23-8.33 (m, 1H), 7.52-7.60 (m, 1H), 7.27-7.35 (m, 1H), 6.60 (t, J=72.4 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@@H:10]([C:15](O)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13].O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C1C=CC=CC=1>[S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)([OH:28])(=[O:27])=[O:26].[CH2:1]([O:8][C:15](=[O:16])[C@@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C[C@@H](N)C(=O)OCc1ccccc1
Yield: 95.1 %

Procedure:
To benzyl alcohol (8.2 g) dissolved in benzene (30 mL) was added D-leucine (5.0 g) and p-toluenesulfonic acid monohydrate (8.0 g). The reaction was warmed to reflux with removal of water overnight. Once TLC indicated consumption of starting material, the reaction was cooled, and the resulting solid was filtered and washed with EtOAc to give the title compound as a white powder (14.26 g, 99%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)(=[O:16])=[O:15])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.Cl>[NH2:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][CH2:10][O:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCCCOc2nc(Cl)ncc2Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)NCCCOc2nc(Cl)ncc2Br)c1
Reaction time: 2 h

Procedure:
A solution of 70 mg (0.16 mmol) of N-[3-(5-bromo-2-chloro-pyrimidin-4-yloxy)-propyl]-3-nitro-benzenesulfonamide in 5 ml of THF is mixed at 0° C. with 1.0 ml of a 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid. After 2 hours, the reaction solution is mixed again with 0.2 ml of Ti(III)Cl solution and stirred for another hour. The batch is made basic with 1N NaOH solution and then filtered. The filter cake is rewashed 2× in each case with 50 ml of ethyl acetate/MeOH (30 ml/20 ml). The filtrate is concentrated by evaporation in a rotary evaporator and then extracted with ethyl acetate (2×). The combined organic phases are washed with NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1, Flashmaster II). 32 mg (0.08 mmol, corresponding to 49% of theory) of the product is obtained.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:12])([O:3][CH3:4])=[O:2].[CH3:25]CO>>[C:1]([C:5]1[S:6][C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9]=1[NH:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[O:12])([O:3][CH2:4][CH3:25])=[O:2]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Reactant: CCO
Product: CCOC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 36 h
Yield: 59 %

Procedure:
A solution of Ti(OEt)4 (0.10 mL, 0.476 mmol, 11.8 equiv), N-(2-carbomethoxy-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.014 g, 0.040 mmol), and EtOH (10 mL) was heated at the reflux temp. for 36 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in EtOAc and purified by flash chromatography (gradient from 10% EtOAc/hexane to 20% EtOAc/hexane) to afford N-(2-carboethoxy-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.0086 g, 59%): 1H NMR (CDCl3) δ1.30 (d, J=7.4 Hz, 3H), 1.35 (s, 9H), 2.30 (s, 3H), 4.24 (q, J=7.4 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 7.30 (br s, 1H), 7.86 (s, 1H), 9.68 (s, 1H); 13C NMR (CDCl3) δ14.3, 20.8, 31.8 (3C), 35.2, 60.6, 105.1, 117.2, 121.0 (2C), 129.7 (2C), 133.8, 135.2, 145.9, 152.1, 164.2, 164.8.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Na+].[Cl-].[OH2:22]>>[OH:1][CH2:2][CH2:3][NH:4][CH2:8][CH2:7][NH:6][C:5](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCC1=NCCN1CCO
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCCCCCC(=O)NCCNCCO

Procedure:
22 g of 1-(2-hydroxyethyl)-2-undecyl-2-imidazoline and 300 ml of water was stirred at 40°-50° C. for 24 hours. The resulting soapy solution was salted with 50 g of NaCl and then extracted with 500 ml ethyl acetate. The organic layer was dried, filtered and concentrated to give 23 g of solid. This material was dissolved in hexane by heating at 50 C. for 2 hrs., then cooled to room temperature and filtered to afford 18.8 g of pure product, m.p. 92°-94° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>C(#N)C>[CH2:28]([N:30]([CH2:12][CH:8]1[O:7][C:6]2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=[C:2]([F:1])[C:11]=2[O:10][CH2:9]1)[CH2:31][CH3:32])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-ethylethanamine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.2), 87 (6), 86 (bp), 58 (5), 56 (3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: Cc1cccc2oc(-c3cc([N+](=O)[O-])ccc3F)nc12
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2c(C)cccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-4-methylbenzoxazole (218 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: C(C1C=C2C(=CC=1)N(C)C=C2C1CCC(=O)CC1)#N.O1[C:24]2([CH2:29][CH2:28][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]#[N:40])[CH:37]=4)[N:32]([CH:41]([CH3:43])[CH3:42])[CH:31]=3)[CH2:26][CH2:25]2)[O:23]CC1>>[C:39]([C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH:41]([CH3:43])[CH3:42])[CH:31]=[C:30]2[CH:27]1[CH2:28][CH2:29][C:24](=[O:23])[CH2:25][CH2:26]1)#[N:40]
Reactant: CC(C)n1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Agent: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Product: CC(C)n1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Yield: 77.1 %

Procedure:
This compound was prepared in the manner described above for intermediate 6a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole with 3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-isopropyl-indole (5.86 g, 16 mmol) to afford 3.46 g (63%) of the title compound as a white solid: mp 106-107° C.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][C:7]([N:9]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][O:11][C:10]1=[O:21])=[O:8])C.BrC[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH2:12]([O:11][C:10](=[O:21])[CH:6]([C:7]([N:9]1[CH:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][O:11][C:10]1=[O:21])=[O:8])[CH2:5][CH2:4][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)CCC(=O)N1C(=O)OCC1Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of the compound of example 67 (5.0 g, 16.38 mmol) in anhydrous THF (160 mL) was cooled to −78° C. A solution of NaHDMS in THF (1M, 16.4 mL, 16.4 mmol) was injected over 10 minutes. The reaction mixture was stirred for an additional 20 minutes, after which time, a solution of tert-butyl bromoacetate in anhydrous THF (10 mL) was slowly injected. After stirring for 1 h at −78° C. and 3 h at −48° C., the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted several times with ethyl acetate. The recombined organic layer was successively extracted with brine, a saturated sodium hydrogen carbonate solution, brine and water. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude product was flashed with 20% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 400 MH: 1.24(t, J=7.2, 3H); 1.44(s, 9H); 2.54(m, 2H); 2.77(m, 3H); 3.31(m, 1H); 4.14(m, 4H); 4.43(m, 1H); 4.69(m, 1H); 7.26(m 5H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][CH:21]=[O:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=[O:31].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][C:11]2[O:12][C:13]3[C:19]([CH2:20][C:21]([OH:31])=[O:22])=[CH:18][C:17]([Cl:23])=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cc2nc3cc(Cl)cc(CC=O)c3o2)cc1OC1CCCC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(Cc2nc3cc(Cl)cc(CC(=O)O)c3o2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-cyclopentyloxy-4-methoxybenzyl)-5-chlorobenzoxazole-7-ethanal (2.0 g, 0.005 mol) in 50 ml of acetone was treated with 20 ml of 1 N Jones reagent and stirred for 1 hour at room temperature. Excess Jones reagent was destroyed by the addition of 50 ml of 2-propanol and the low boiling solvents were stripped under reduced pressure. Water (50 ml) and saturated sodium chloride (50 ml) were added and the aqueous residue was extracted with 2×75 ml of ethyl acetate. After drying, the ethyl acetate was evaporated to give 2.1 g of a brown foam. Solution of this material in CH2Cl2 and flash chromatography on silica gel afforded 0.72 g of the title acid as a yellow foam after elution with 500 ml of 0.5% CH3OH in CH2Cl2. The foam was dissolved in 3 ml of CH3OH and allowed to crystallize for 1 hour at freezer temperatures. After filtration, a total of 0.27 g of yellow title compound, mp 131-133° C., was isolated.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1(C)C=CC=CC=1.CCO.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>[N:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=3)[NH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccncc1
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=Cc1ccc2[nH]nc(-c3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 64.2 %

Procedure:
To a suspension of 3-iodo-1H-indazole-5-carboxaldehyde (200 mg, 0.74 mmol) and 4-pyridineboronic acid (110 mg, 0.89 mmol) in toluene/EtOH (1:1, 8 mL) in a sealed tube was added Na2CO3 (2 N, 1 mL) followed by Pd(PPh3)4 (85 mg, 0.074 mmol). The reaction mixture was put under vacuum, and re-charged with N2 three times, then kept at ca. 100-110° C. for ca. 4-5 hr. The reaction mixture was cooled to rt, diluted with water, and extracted with EtOAc. The organic phase was washed with brine, and dried. Concentration followed by purification by flash chromatography afforded 3-(4-pyridinyl)-1H-indazole-5-carboxaldehyde (106 mg, 64%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].C1C(=O)N([Cl:20])C(=O)C1>CC(O)=O>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:20])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1sccc1C(N)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1sc(Cl)cc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-acetylamino-thiophene-3-carboxylic acid amide (2.38 g, 12.9 mmol) is dissolved in AcOH (25 mL). NCS (1.9 g, 14.3 mmol) is added and the resulting suspension is stirred at room temperature. After overnight stirring, another 150 mg (1.13 mmol) of NCS is added to the mixture and stirring is continued at 35° C. for 3 h. The mixture is evaporated, and the resulting residue is suspended in water, sonicated, and filtered to give the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][N:9]=2)=[CH:6][CH:7]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Oc1ccc(-c2ccc(-c3cccs3)cn2)cc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(-c2ccc(-c3cccs3)cn2)cc1
Temperature: 80 °C

Procedure:
A mixture of 15.3 g of 2-(2-p-hydroxyphenyl-5-pyridyl)-thiophene, 6.9 g of K2CO3, 25 g of hexyl iodide and 250 ml of DMF is heated at 80° C. for 16 hours, with stirring, and then cooled and worked up in the customary manner. 2-(2-p-Hexoxyphenyl-5-pyridyl)-thiophene is obtained.
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:10])[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>O.CC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([O:9][C:5]2[CH:4]=[C:3]([OH:10])[CH:8]=[CH:7][CH:6]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Oc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Oc1cccc(Oc2ccnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydroxide (1.68 g; powder 98% pure; 40 mmol) is dissolved in water (30 mL), cooled to 0° C. and treated with benzene-1,3-diol (4.4 g; 40 mmol). Within 15 min, 2,4-dichloropyrimidine (5.95 g; 40 mmol) dissolved in acetone (50 mL) is added dropwise, keeping the reaction temperature below 5° C. After 15 min at 0° C., the ice bath is removed and the reaction kept stirring for additional 17.5 h. After filtering off the precipitate, the solvent is removed under reduced pressure. The residual oil is taken up into EtOAc, washed with sodium bicarbonate solution (10%), water and brine and dried over Na2SO4. After filtering, the crude product is isolated as an oil and purified by flash chromatography over silica gel (eluting with CH2Cl2/MeOH; 0-5%) to give the title compound of Stage 5.1 as a beige solid; ES-MS: [M+H]+; m/z=223; Rf (CH2Cl2/MeOH 9:1)=0.57; HPLC: AtRet=3.50 min.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[Na+].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>[OH-].[Na+]>[CH:8](=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)C=Cc1ccccc1
Reaction time: 4 h
Yield: 75 %

Procedure:
Sodium pyruvate (60.5 g, 0.55 mol) was first added to a cold (0° C.) 1N aqueous solution of sodium hydroxide (550 ml). Benzaldehyde (53 g, 0.55 mol) was then added at such a rate that the temperature was maintained below 5° C. The reaction mixture was then aged four hours at 0° C. with good agitation. Following the age period, the mixture was acidified to pH 1.0 with 6N HCl maintaining a temperature of 0°-5° C. After acidification, the benzalpyruvic acid product was extracted with 500 ml ethyl acetate. Yield: 75-77% by HPLC analysis. Anal. Calcd. for C10H7O3K: C, 56.08; H, 3.30; K, 18.21. Found: C, 56.11; H, 3.31; K, 18.20. 1H NMR (acetone-d6) δ: 7.2 (d, 1H), 7.8 (d, 1H), 7.5 (s, 5H). IR (KBr) cm-1 : 3500sb, 3050-2900s, 1740s, 1695s, 1230s, 1020s.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])#[N:4].[NH2:24]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1.[Na]>CN(C=O)C.C(OCC)(=O)C>[NH2:24][N:9]1[C:5]([C:3]#[N:4])=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8]1
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccccc1[N+](=O)[O-]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(N)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.02 g, 75.6 mmol) was added to a solution ethyl 5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate (17.97 g, 63.00 mmol) in DMF (625 mL). The solution was stirred at it for 15 min and then (aminooxy)(diphenyl)phosphine oxide (17.63 g, 75.59 mmol) was added, and the solution was heated (80° C.) for 17 h. Upon cooling to it aqueous saturated sodium bircarbonate solution (500 mL) was added followed by ethyl acetate (400 mL). The layers were separated and the aqueous layer was back extracted with ethyl acetate (2×200 mL). The combined organic layers dried over sodium sulfate and concentrated to dryness. The crude material was triturated with dichloromethane-hexanes (1:1 v/v 400 mL). The solid was collected, washed with hexanes (100 mL), and dried under vacuum. The material was suspended in ethyl acetate (500 mL) and, heated to reflux for 15 min, and then filtered. The filtrate was concentrated in vacuo to afford the desired product (14.15 g, 75%). 1H-NMR (300 MHz, DMSO-d6) 8.25-8.31 (m, 2H), 7.73 (s, 1H), 7.67-7.73 (m, 2H), 6.71 (br s, 2H), 4.12 (q, J=7.1 Hz, 2H), 1.16 (t, J=7.1 Hz, 3H); HPLC RT (Method A) 2.91 min; TLC Rf=0.30 (95:5 v/v CH2Cl2-EtOAc).