Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[NH:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)=[CH:13][CH:12]=1>CC#N>[Br:1][C:21]1[N:20]=[C:19]([CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[NH:23][C:22]=1[C:24]([F:25])([F:26])[F:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCc2nc(C(F)(F)F)c[nH]2)cc1
Solvent: CC#N
Product: COc1ccc(CCc2nc(Br)c(C(F)(F)F)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Bromosuccinimide (5.4 g, 0.03 mole) was added to a solution of VI (8.1 g, 0.03 mole) in CH3CN (150 mL) and the mixture stirred at room temperature. After 18 hours, the solution was evaporated to dryness in vacuo. The residue was partitioned between CHCl3 and H2O. Evaporation of the washed and dried CHCl3 extract under reduced pressure left 10.5 g (quant.) of VII; m.p. 104°-106° C. (CHCl3 --C6H14).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]([N+:15]([O-:17])=[O:16])=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(F)cc(Cl)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
The Method of Cheeseman, supra. was adapted. 5-Chloro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione (30 mg, 0.14 mMol) was dissolved in concentrated H2SO4 (0.5 ml) at 0° C. for 30 min, and KNO3 (17 mg, 0.17 mmole, Baker) was added in one portion to this solution. The mixture was stirred at 0° C. for 3 h, then at room temperature for 30 h. It was poured into ice water (5 g) and the precipitate was collected by filtration. The precipitate was dissolved in 1N NaOH (5 mL), then was acidified to pH=2 with 4N HCl to give a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h, affording the pure (by NMR) title compound 5-chloro-6-nitro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione (31 mg, 85.4%), as a white amorphous solid. mp: decomposed from 280° C. IR (KBr, cm-1): 3600, 3462, 3131, 1712, 1612, 1550. NMR (1H, DMSO-d6): δ7.106 (d, J=10.2 Hz, 1H), 11.800 (s, 1H), 12.371 (s, 1H). HRMS: calcd. for C8H3N3O4ClF (M+) m/z: 258.9795, found: 258.9790.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)ccc1Br
Reactant: Nc1cccnc1
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cccnc1

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 3-Amino-pyridine was performed in accordance with the general method of Example 78, step 3 to yield the title compound as a light yellow crystalline solid, MS (ISP): m/e=258.1 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([N:4]1[CH:3]=[CH:2][CH:6]=[N:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2cccn2)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-iodopyrazole (400 mg, 2 mmol) in DMF(4 mL) at 0 C. was added sodiumhydride (80 mg, 60% dispersion in mineral oil, 2 mmol) followed by benzyl bromide (342 mg, 2 mmol) and reaction micture was allowed to stir for 2 h. Reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give N-benzylpyrazole in almost quantitative yield. IH NMR 5.29 (s, 2H), 7.18-7.28 (m,2H), 7.28-7.40 (m, 4H), 7.53 (s, 1H).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28]1[CH:51]=[CH:50][C:31]([CH2:32][N:33]2[C:37]([NH:38][CH:39]=[C:40]3[C:45](=[O:46])OC(C)(C)OC3=O)=[CH:36][CH:35]=[N:34]2)=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[C:37]3[N:38]=[CH:39][CH:40]=[C:45]([OH:46])[C:36]=3[CH:35]=[N:34]2)=[CH:50][CH:51]=1
Reactant: COc1ccc(Cn2nccc2NC=C2C(=O)OC(C)(C)OC2=O)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Temperature: 240 °C

Procedure:
2,2-dimethyl-1,3-dioxane-4,6-dione 1 (meldrum's acid) (20 g, 139 mmol), 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (2) (28.2 g, 139 mmol, 1 eq) (prepared according to the procedure described by Misra, R. N., et al. Bioorg. Med. Chem. Lett. (2003), 13, 1133-1136) in presence of triethoxymethane (30.8 g, 208 mmol, 1 eq) was heated to 85° C. for 1 hr, subsequently worked up and treated with diethyl ether, and provided the pure 5-(((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3) as yellow solid (39.3 g). To a stirred solution of DOWTHERM™ (80 mL) was added compound 3 (39.3 g at 200° C. under N2 in portions over a 30 min). After completion of additions, the RM was heated at 240° C. for 1 hr. After completion of the reaction from TLC, the mixture was diluted with hexanes (300 mL) to separate the DOWTHERM™ from the crude RM. The resulting crude mixture on treatment with DCM and diethyl ether provided the off-white solid of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (4) (24.56 g). Chlorination of compound 4 (24 g, 94 mmol) on treatment with phosphoryl trichloride (43 g, 282 mmol) in dichloroethane (10 mL) at 40° C. for 4 hr yielded 19 g of 4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine 5.
Reaction SMILES: BrBr.[F:3][C:4]([F:18])([F:17])[O:5][C:6]1[CH:15]=[C:14]2[C:9]([NH:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[S-:19][C:20]#[N:21].[K+]>C(O)(=O)C>[NH:21]=[C:20]1[N:10]2[CH2:11][C:12](=[O:16])[NH:13][C:14]3[CH:15]=[C:6]([O:5][C:4]([F:3])([F:17])[F:18])[CH:7]=[C:8]([C:9]=32)[S:19]1
Reactant: N#C[S-]
Reactant: O=C1CNc2ccc(OC(F)(F)F)cc2N1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N=c1sc2cc(OC(F)(F)F)cc3c2n1CC(=O)N3
Yield: 15.1 %

Procedure:
The procedure is carried out as in Example 23, but starting with 1.1 g of bromine in 3.5 ml of acetic acid, 1.6 g of 7-trifluoromethoxy-3,4-dihydro-1H-quinoxalin-2-one and 1.54 g of potassium thiocyanate in 20 ml of acetic acid. The product obtained (1.8 g) is purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and methanol (99-1 by volume). 0.3 g of 2-imino-8-trifluoromethoxy-2H,4H-thiazolo[3,4,5-de]quinoxalin-5(6H)-one is thus obtained in the form of-a yellow solid melting at 255° C. [Analysis C10H6F3N3O2S, % calculated C: 41.53, H: 2.09, F: 19.71, N: 14.53, O: 11.06, S: 11.09, % found C: 41.00, H: 1.7, F: 19.2, N: 14.50, S: 11.6].
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]([C:23]([NH:25][C:26]4[CH:27]=[C:28](/[CH:32]=[CH:33]/[C:34]([O:36]CC)=[O:35])[CH:29]=[CH:30][CH:31]=4)=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O[Li].O>>[N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]([C:23]([NH:25][C:26]4[CH:27]=[C:28](/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35])[CH:29]=[CH:30][CH:31]=4)=[O:24])[C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)c2cc(-c3cccc(N4CCNCC4)c3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)/C=C/c1cccc(NC(=O)c2cc(-c3cccc(N4CCNCC4)c3)cc3ccccc23)c1
Yield: 74.7 %

Procedure:
Compound 25b (107 mg, 75%) was synthesized from 24c (150 mg, 0.3 mmol) and LiOH.H2O (38 mg, 0.89 mmol) using procedure according to the Method E described above.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(P(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][C:12]2[C:2]3[N:27]=[CH:26][CH:25]=[CH:24][C:3]=3[C:4](=[O:5])[N:6]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:7]=2[CH:8]=1
Reactant: COc1ccc(CN(C(=O)c2cccnc2Cl)c2cccc(OC)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cccnc3c3ccc(OC)cc32)cc1
Temperature: 120 °C
Yield: 24.4 %

Procedure:
To a stirred solution of the compound (873 mg, 2.28 mmol) prepared in step 2 in N,N-dimethylformamide (6.0 ml), were added sequently palladium(II) acetate (153.6 mg, 0.684 mmol), 1,3-bis(diphenylphosphino)propane (282 mg, 0.684 mmol), tributylphosphine (0.563 ml, 2.28 mmol), and potassium carbonate (630 mg, 4.56 mmol) and the mixture was refluxed for four hours at 120° C. Once the reaction was completed, the reaction mixture was cooled to a room temperature and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate:dichloromethane=1:1:1) to obtain the title compound (192.4 mg, yield: 24%, white solid).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[N:25][CH:26]=1.O>CN(C)C=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)=[CH:26][N:25]=2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccc(COc3ccc(CCCCn4ccnn4)cc3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
A solution of 91 mg (0.42 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 18 mg (0.44 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 5-Chloromethyl-2-(4-chloro-phenyl)-pyridine (GB 1147068) were added and stirred continued over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 121 mg (69%) of the title compound as light brown powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([NH:34][C:6]1[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=[C:2]([Cl:1])[N:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
2,4-Dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (0.500 g, 1.89 mmol) was dissolved in THF (10 mL) then was added DIPEA (1.65 mL, 9.47 mmol), followed by benzylamine (0.406 g, 3.79 mmol). Then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to remove THF. To this residue, water (10 mL) was added and the aqueous solution was extracted with CH2Cl2 (25×3 mL). The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 11% EtOAc/hexanes) to afford N-benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.400 g, 63.1%). LCMS Condition B-47: retention time 2.70 min, [M+1]=335.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[C:9]([Cl:20])[S:8][C:7]=1[NH:21][C:22](=[O:26])[CH2:23][C:24]#[N:25])=[O:5])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[C:9]([Cl:20])[S:8][C:7]=1[NH:21][C:22](=[O:26])[CH2:23][C:24]#[N:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(=O)CC#N)sc(Cl)c1-c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(NC(=O)CC#N)sc(Cl)c1-c1ccc(N)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(2-cyano-acetylamino)-4-(4-nitrophenyl)-5-chloro-thiophene-3-carboxylic acid ethyl ester (1.00 g, 2.54 mmol), Fe (432 mg, 7.71 mmol), and NH4Cl (110 mg, 2.03 mmol) in EtOH (20 mL) and H2O (10 mL) was heated to 85 C for 2 h. The reaction was cooled to room temperature and filtered through a plug of celite, eluting with hot MeOH. The eluent was concentrated under reduced pressure to give a solid that was used in the next step without further purification. MS (ESI) m/e 362 (M−H)−.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:12][CH:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][NH2:15])[CH2:8][CH2:9][CH2:10][CH3:11]>>[CH2:17]([O:16][CH:13]([O:12][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][NH:15][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCOC(CN)OCCCCC
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)NCC(OCCCCC)OCCCCC

Procedure:
The monomer (1) was prepared by reaction of methacryloyl chloride and aminoacetaldehyde di-n-pentyl acetal in anhydrous solution.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:28]=3)[CH:15]=[C:16]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:28]=3)[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2cc(C(=O)OCc3ccccc3)c3cnn(Cc4ccccc4)c3n2)ccc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2cc(C(=O)O)c3cnn(Cc4ccccc4)c3n2)ccc1F
Temperature: 50 °C
Yield: 63.7 %

Procedure:
Benzyl 1-benzyl-6-[4-fluoro-3-(methoxycarbonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (12.0 g/24.2 mmol) is dissolved in 100 mL of concentrated sulphuric acid. The solution is heated at 50° C. for 1 hour. The reaction mixture is then slowly run into ice-cold water and extracted with EtOAc. The organic phase is washed with water and then with a saturated aqueous solution of NaCl, dried over sodium sulphate and concentrated to dryness to give 6.25 g of a yellow-orange powder (yield: 82%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:20]1[N:24]=[C:23]([CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:22][N:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOCC>C(Cl)Cl>[C:12]([C:20]1[N:24]=[C:23]([CH2:25][S:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:6])[O:22][N:21]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1noc(CSc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1noc(CS(=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A solution of 5.5 g of m-chloroperoxybenzoic acid (85%) in 125 ml of CH2Cl2 was added dropwise at -70° C. under N2 to a solution of 7.5 g of 3-benzoyl-5-phenylthiomethyl-1,2,4-oxadiazole in 150 ml of CH2Cl2. The temperature of the reaction was maintained below -65° by controlling the rate of addition. After stirring further for 30 minutes, the reaction mixture was added directly to a separatory funnel containing 250 ml of 10% Na2S2O3 and 500 ml of Et2O. The organics were washed with saturated NaHCO3 and dried over MgSO4. Concentration gave an oil which solidified on standing. Recrystallization from acetone/hexane gave 3.7 g (44%) of needles, m.p. 79°-81°.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2C2C=CC=CC=2)[CH:4]1[OH:18])[CH3:2].C(N([CH2:24][CH3:25])CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:3]1([C:25]2[CH:24]=[CH:4][CH:3]=[CH:1][CH:2]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[OH:18])[CH3:2]
Reactant: CCC1Cc2c(-c3ccccc3)cccc2C1O
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCC1(c2ccccc2)Cc2ccccc2C1O
Temperature: 0 °C
Yield: 133.4 %

Procedure:
To a 1-liter four-necked round flask (equipped with a stirrer, a dropping funnel and a thermometer) were fed 29.3 g (123.9 mmol) of 2-ethyl-1-hydroxy-4-phenylindane, 51.6 g (371.4 mmol) of triethylamine, 0.75 g (6.3 mmol) of 4-dimethylaminopyridine and 294 ml of methylene chloride. Then, a solution obtained by dissolving 19.2 ml (247.5 mmol) of methanesulfonyl chloride in 19.5 ml of methylene chloride was dropwise added slowly to the system while cooling with ice in a nitrogen atmosphere. After the addition was completed, the resulting mixture was reacted for another 3.5 hours at the same temperature. The reaction mixture was poured in 500 ml of ice water, then the organic phase was separated, and the aqueous phase was further extracted twice with 150 ml of methylene chloride. The whole organic phase was successively washed with a saturated NaHCO3 solution and a saturated salt solution, and dried with anhydrous Na2SO4. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel chromatography (developed with hexane), to obtain 19.7 g of the aimed product (mixture of two kinds of isomers) as a light yellow liquid (yield: 73%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([NH:8][NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CO.C(OCC)C.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]>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:27])[F:28])[CH:19]=2)=[CH:7][C:6]=1[NH:8][NH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)NNc1cc(Br)ccc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)NNc1cc(-c2cccc(OC(F)(F)F)c2)ccc1Cl

Procedure:
A mixture of methyl 2-(5-bromo-2-chlorophenyl)hydrazine carboxylate (i.e. the product of Step B) (1.27 g, 4.5 mmol), [3-(trifluoromethoxy)phenyl]boronic acid (1.85 g, 9 mmol), cesium carbonate (2.9 g, 9 mmol), tris(dibenzylideneacetone)dipalladium (0.18 g, 0.2 mmol) and triphenylphosphine (1.2 g, 4.5 mmol) in toluene (60 mL) and methanol (60 mL) was heated at refluxed for 24 h. After cooling, the reaction mixture was taken up in diethyl ether and washed with water. After drying over sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by flash chromatography using 25% ethyl acetate in hexanes as eluant to afford a solid matieral (1.3 g), which was a mixture of starting material and the title compound.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1.C(=O)(O)[O-:12].[Na+]>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N+:5]=1[O-:12]
Reactant: Cc1cccc(Cl)n1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc(Cl)[n+]1[O-]
Temperature: 87.5 °C
Yield: 96.5 %

Procedure:
30% Hydrogen peroxide solution (20 mL, 0.176 mol) was added slowly into a solution of 2-chloro-6-methylpyridine (5.0 g, 39.4 mmol) in glacial acetic acid (30 mL) whilst the mixture was kept below 20° C. The reaction mixture was then heated to 85-90° C. overnight. The reaction was cooled and neutralised with cold sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (4×50 mL) and the combined organic layers washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-6-methyl-pyridine-1-oxide (5.43 g, 96.5%) as an oil.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([CH:17]=[O:18])=[CH:6][CH:5]=1.S(=O)(=O)([OH:22])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[F:19][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:8]=2[C:7]([C:17]([OH:22])=[O:18])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)c2oc3ccncc3c12
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccncc3c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a well stirred solution of 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyridine-9-carbaldehyde (500 mg, 1.90 mmol) in acetone (10 mL) was added sulphamic acid (276 mg, 2.85 mmol) at about 10° C. followed by drop wise addition of a solution of sodium chlorite (240 mg, 2.66 mmol) in water (5 mL) at about 0 to 5° C. The mixture was then stirred for about 1-2 hours. Ice cold water (50 mL) was added and the mixture was stirred for about 30 hours. The solid which separated was filtered, washed with water (3×5 mL) and dried at about 60-70° C. to give 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyridine-9-carboxylic acid as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)CCC>C1(C)C=CC=CC=1.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>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccccc2)cc1F
Temperature: 110 °C
Yield: 155.2 %

Procedure:
A solution of 4-bromo-2-fluorobenzaldehyde (0.15 g, 0.74 mmol), tributyl(phenyl)stannane (0.27 mL, 0.81 mmol) and Pd(PPh3)4 (0.043 g, 0.037 mmol) in PhCH3 (2.5 mL) was heated in a sealed reaction tube to 110° C. for 12 h. Additional tributyl(phenyl)stannane (0.20 mL, 0.61 mmol) and Pd(PPh3)4 (0.043 g, 0.037 mmol) were added and the solution was further heated to 110° C. for 2 h. The solvent was removed in vacuo. The residue was purified via column chromatography (SiO2, 5:1 hexanes/EtOAc) to provide 0.23 g (>100% yield) of 3-fluorobiphenyl-4-carbaldehyde, which was used without further purification: MS (EI) for C13H9OF: 201 (MH+).
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5].[H][H]>O.[Ni]>[CH2:2]([OH:1])[CH2:3][C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5]
Reactant: O=CC[C@H](O)[C@H](O)CO
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Product: OCC[C@H](O)[C@H](O)CO
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A 100 g (0.75 mole) portion of 2-deoxy-D-ribose was dissolved in 200 ml of water to form an aqueous solution into which 20 g of Raney nickel were added. The thus prepared reaction mixture in an autoclave was heated under a hydrogen pressure of 40 kg/cm2G up to a temperature of 70° C. taking 30 minutes and kept for additional 1 hour at the same temperature and under the same hydrogen pressure. After cooling, the reaction mixture taken out of the autoclave was filtered to remove the solid catalyst and the filtrate, as combined with the washings of the solid catalyst with water, was subjected to removal of the water to give about 100 g of 2-deoxy-D-erythropentitol. The yield of the product was almost quantitative.