Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[CH3:23][CH:24]([CH3:27])[CH2:25][NH2:26]>CN1C(=O)CCC1.CO>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=[C:2]([NH:26][CH2:25][CH:24]([CH3:27])[CH3:23])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)S1
Reactant: CC(C)CN
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)CNc1cc(NC2CC2)n2ncc(C=C3SC(=O)NC3=O)c2n1
Temperature: 130 °C

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione (30 mg, 0.09 mmol) in NMP was added 2-methylpropan-1-amine (20 mg, 0.268 mmol). The reaction was heated at 130° C. overnight. The reaction mixture was diluted with MeOH and purified by prep HPLC to yield 5-((7-(cyclopropylamino)-5-(isobutylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=373)
Reaction SMILES: C[O:2][C:3]([C@@:5]1([CH3:9])[CH2:8][CH2:7][NH:6]1)=[O:4].[OH-].[Na+].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(O)(=O)C>O>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:6]2[CH2:7][CH2:8][C@:5]2([CH3:9])[C:3]([OH:2])=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)[C@@]1(C)CCN1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C[C@]1(C(=O)O)CCN1C(=O)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-methyl-azetidine-2-carboxylic acid methyl ester (1 eq.) in water were added aqueous NaOH (1M) (3 eq.) then 4-bromo-benzoyl-chloride (1 eq.) dropwise. The reaction was stirred for 4 h at 20° C. The reaction was neutralised with acetic acid. The solvent was partially removed under reduced pressure and the crude was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH/AcOEt/AcOH/iPr2O: 95/5/98/2/300) to afford (R)-1-(4-bromo-benzoyl)-2-methyl-azetidine-2-carboxylic acid.
Reaction SMILES: [C:1](#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:10][O:11][CH2:12][CH3:13].[OH2:14]>>[CH3:10][O:11][C:12]1[CH:13]=[C:1]([C:1](=[O:14])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: N#Cc1ccccc1
Reactant: CCOCC
Reactant: O
Product: COc1cccc(C(=O)c2ccccc2)c1
Reaction time: 16 h
Yield: 60 %

Procedure:
To the mixture then were added dropwise 103 grams (1 mole) of benzonitrile in 500 ml. of ether. A vigorous reaction occurred. The mixture was stirred for 16 hours, and then 500 ml. of water were gradually added. The reaction mixture then was filtered through a glass wool plug to remove excess magnesium. The ether was evaporated, and to the resulting aqueous layer were added 300 ml. of concentrated hydrochloric acid. The resulting mixture was heated on a steam bath for one hour. The product was extracted into ether, and the ether layer was washed with water, dried, and distilled to obtain 127 grams (60 percent) of m-methoxybenzophenone as a pale green liquid, b.p. 135°-139°/0.05 mm.
Reaction SMILES: [C:1]([O:23]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].N(CCCC)(CCCC)CCCC.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:21][O:20][C:18]([CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:23])=[O:19]
Reactant: COC(=O)CCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)C1CCCCCCC=CCCCCCCCC1=O
Yield: 48.6 %

Procedure:
Under an argon stream, CH2Cl2 solvent (0.5 ml) was placed in a two-necked flask beforehand, and thereto were added dropwise, at 0 to 5° C., a mixed solution of dimethyl cis-9-octadecenedioate (170 mg, 0.50 mmol) and Bu3N (278 mg, 1.50 mmol) in CH2Cl2 (2.1 ml) and a solution of TiCl4 (159 μl, 1.45 mmol) in CH2Cl2 (2.5 ml) at the same time over a period of about 1 hour by means of a microfeeder. The whole was further mixed at the same temperature for 15 minutes. Water was added to the reaction mixture and the resulting mixture was stirred and then extracted with ether. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the evaporation of the solvent under reduced pressure, the crude product was purified by silica gel chromatography (hexane/ethyl acetate=20/1→10/1) to obtain the aimed product (75 mg, 49%) and a by-product (34-membered ring; 26 mg, 18%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:15])[C:10]([O:12]CC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:16][CH2:17]C([O-])=O.[Na+].C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.Cl>C1COCC1>[Cl:16][CH2:17][C:10](=[O:12])[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:15]
Reactant: O=C([O-])CCl
Reactant: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A mixture of 5.00 g (21.52 mmol) of ethyl (S)-2-(tert-butyldimethylsilyloxy)propionate, 3.76 g (32.3 mmol) of sodium chloroacetate, 2.18 g (21.5 mmol) of triethylamine, and 50 mL of THF was cooled in ice, and 37 mL (64.6 mmol) of a 1.75 M solution of tert-butylmagnesium chloride was added dropwise thereto over a period of 1 hour. After the completion of the dropwise addition, reaction was performed at 0° C. for another 3 hours, and 6 M hydrochloric acid (about 20 mL) was added to the reaction solution to adjust the pH to 6.0. Subsequently, stirring was performed at 25° C. for 2 hours. A product was extracted with ethyl acetate (100 mL×2). The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5.01 g of the title compound as a colorless oil (yield: 98%). 1H-NMR (400 MHz, CDCl3) δ: 0.10 (s, 6H), 0.92 (s, 9H), 1.24 (d, 3H, J=6.8 Hz), 4.35 (q, 1H, J=6.8 Hz), 5.50 (q, 2H, J=17.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1F)[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1[NH:31][CH:28]1[CH2:30][CH2:29]1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Reactant: NC1CC1
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Yield: 83 %

Procedure:
A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3,5-trifluorobenzoic acid ethyl ester (Example 2a, 1.95 g, 5.01 mmol) and cyclopropylamine (14.0 mL, 201 mmol) in dimethyl sulfoxide (5 mL) is heated in a sealed glass tube for 44.5 hours at 100° C. Compressed air is blown into the black solution to remove excess cyclopropylamine. The solution is concentrated under high vacuum and purified by flash column chromatography (1:9 ethyl acetate/hexanes) to afford the title compound (1.77 g). 1H NMR (CDCl3): δ 7.32 (dd, 1H), 4.81–4.67 (bs, 1H), 4.35–4.16 (m, 3H), 3.95–3.40 (m, 4H), 2.92–2.80 (m, 1H), 2.25–2.08 (m, 1H), 1.97–1.77 (m, 1H), 1.46 (s, 9H), 1.34 (t, 3H), 0.72–0.63 (m, 2H), 0.57–0.49 (m, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15]2)([O-:11])=[O:10].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:26]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)[C:15]([Br:1])=[C:16]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Br)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
A solution of N-bromosuccinimide (0.83 g, 4.7 mmol) in DMF (5 mL) was added dropwise to a stirred solution of ethyl 5-nitro-1H-indole-2-carboxylate (1.0 g, 4.27 mmol) in DMF (5 mL) at 0˜5° C. After the addition was completed, the reaction was warmed to room temperature and stirring was continued for an additional 1.5 h. The reaction mixture was poured over ice water and the resulting precipitate was collected and dried. The dried solid was re-dissolved in DMF (10 mL) and benzyl bromide (0.68 g, 4.0 mmol) and Cs2CO3 (6.56 g, 20 mmol) were added successively. The reaction was stirred for overnight and then diluted with water. The product was extracted with ethyl acetate, dried over magnesium sulfate. Recrystalization from ethyl acetate and hexane gave 0.99 g (57%) of ethyl 1-benzyl-3-bromo-5-nitro-1H-indole-2-carboxylate as an off-white solid: 1H NMR (DMSO-d6) δ 1.28 (t, J=7.0 Hz, 3 H), 4.35 (q, J=7.0 Hz, 2 H), 5.90 (s, 2 H), 7.00-7.10 (m, 2 H), 7.20-7.35 (m, 3 H), 7.95 (d, J=9.3 Hz, 1 H), 8.25 (dd, J=9.3, 2.0 Hz, 1 H), 8.48 (d, J=2.0 Hz, 1 H); MS (ESI) m/z 403/405 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].Cl[CH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([O:39][C:40]4[C:41]5[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][C:42]=5[N:43]=[CH:44][N:45]=4)=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.CC[O:59]C(C)=O>C(Cl)Cl>[CH3:10][S:11]([O:13][CH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([O:39][C:40]4[C:41]5[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][C:42]=5[N:43]=[CH:44][N:45]=4)=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)(=[O:59])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CCl)cc(C(F)(F)F)c3)c2)C1
Reactant: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(COS(C)(=O)=O)cc(C(F)(F)F)c3)c2)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(1-(3-(hydroxymethyl)-5-(trifluoromethypphenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8 H)-carboxylate (0.211 g, 0.361 mmol) in 6 mL of DCM with DIEA (0.19 mL, 1.08 mmol) at 0° C., methanesulfonyl chloride (0.037 mL, 0.469 mmol) is added and the reaction stirred for 3 h. At that point the reaction is diluted with EtOAc, washed with saturated sodium bicarbonate, brine and the organic layer is dried over sodium sulfate. Concentration provides a mixture of the title compound and tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8 H)-carboxylate (3:7), which is carried on to next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][C@H:17]([CH3:20])[CH2:18][OH:19].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:16]([C@H:17]([CH3:20])[CH2:18][OH:19])[CH:6]=[CH:5]2
Reactant: C[C@@H](N)CO
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Reaction time: 0.5 h

Procedure:
A microwave vial was charged with 6-chloro-5-nitro-1H-isochromen-1-one (80.0 mg, 0.000355 mol), (2R)-2-aminopropan-1-ol (29 mg, 0.00039 mol), triethylamine (0.15 mL, 0.0011 mol) and methanol (4 mL, 0.1 mol) and subjected to microwaves at 100° C. for 30 minutes. The reaction went to completion with 10% of cyclized product in addition to the required product. The solvent was removed and the residue purified by flash chromatography to obtain the product as a light yellow solid. MS m/z=283.2 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 8.43 (d, J=8.86 Hz, 1H), 7.80 (d, J=8.86 Hz, 1H), 7.75 (d, J=7.98 Hz, 1H), 6.36 (d, J=7.09 Hz, 1H), 5.03-4.86 (m, 2H), 3.63-3.52 (m, 2H), 1.30 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1]/[C:2](=[N:28]\[OH:29])/[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23].[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:25]1([NH:24][C:22]([C:7]2[N:8]=[N:9][N:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=3)[C:6]=2[CH2:5][CH2:4][CH2:3][C:2]2[NH:1][C:30](=[O:31])[O:29][N:28]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC/C(N)=N/O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCc2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a solution of 5-[(4Z)-4-amino-4-(hydroxyimino)butyl]-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (240 mg, 0.6 mmol) obtained in Example 1209 and 1,1′-carbonyldiimidazole (97 mg, 0.6 mmol) in THF (5 ml) was added DBU (91 mg, 0.6 mmol) at room temperature and the mixture was stirred at 50° C. for 3 hr and concentrated. The residue was dissolved in water (10 ml), adjusted to pH 4-5 with 1N hydrochloric acid and liberated oil was extracted with ethyl acetate (30 ml×2). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (150 mg, 59%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][CH:5]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39]Br>O1CCCC1>[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39][N:2]([CH3:1])[C:3](=[O:23])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][CH:5]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1cnc(N2CCOCC2)cc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 0.27 g (0.87 mmol) N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide in 15 ml tetrahydrofuran, 1.12 ml of a 1 M solution (1.12 mmol) of potassium hexamethyldisilazide in tetrahydrofuran was added at 0° C. After 30 min, 0.16 ml (0.87 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added dropwise and the reaction mixture was allowed to warm to room temperature over night. Quenching with water was followed by extraction with ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography gave 0.20 g (44%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:28][CH2:29][CH2:30][CH3:31].BrC1N(COCC[Si](C)(C)C)C2C=NN(COCC[Si](C)(C)C)C(=O)C=2C=1C.[CH:60]1([O:63][C:64]2[CH:65]=[C:66](B3OC(C)(C)C(C)(C)O3)[CH:67]=[CH:68][C:69]=2[O:70][CH3:71])[CH2:62][CH2:61]1.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[CH2:28]([C:3]1[C:4]2[C:9](=[O:10])[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:2]=1[C:66]1[CH:67]=[CH:68][C:69]([O:70][CH3:71])=[C:64]([O:63][CH:60]2[CH2:61][CH2:62]2)[CH:65]=1)[CH2:29][CH2:30][CH3:31]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC1CC1
Reactant: CCCCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: Cc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CCCCc1c(-c2ccc(OC)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 87.6 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(a) except for using 530 mg (0.999 mmol) of 2-bromo-3-butyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 22-(b) in place of 2-bromo-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, and using 435 mg (1.50 mmol) of 2-(3-cyclopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference Example 1-(e) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 537 mg of the title compound was obtained as a brownish oil. (Yield: 88%)
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CCOC(C)=O>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[C:3](/[CH:8]=[N:16]/[S@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ncccc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1ncccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-fluoropicolinaldehyde (300 g, 2400 mmol), copper sulfate (572 g, 3600 mmol) and (S)-2-methylpropane-2-sulfinamide (319 g, 2640 mmol) in DCM (3 L) in a 10 L 3-neck round bottom flask was stirred for 3 h at rt. The progress of the reaction was monitored by TLC (30% EtOAc in petroleum ether). After completion of reaction, the solid was filtered off and the filtrate was concentrated under vacuum. The initially obtained product was purified by column chromatography using silica (60-120 mesh) with 20% EtOAc in n-hexane as eluent to give the title compound sulfinamide as yellow oil. 1H-NMR (400 MHz, CDCl3): δ ppm 8.89 (s, 1H), 8.64 (s, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.46 (d, J=3.6 Hz, 1H), 1.29 (s, 9H). MS (ESI pos. ion) m/z: 155.0 (M-O and t-Bu).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.F[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+]>CN1CCN(C)C1=O>[F:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:1]([O:20][C:17]2[CH:15]=[CH:10][CH:11]=[C:12]([F:16])[CH:13]=2)[CH:3]=1
Reactant: Fc1cccc(F)c1
Reactant: Oc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: Fc1cccc(Oc2cccc(Oc3cccc(F)c3)c2)c1
Temperature: 220 °C
Yield: 52.7 %

Procedure:
In a nitrogen atmosphere, 76.4 g (0.693 mole) of resorcinol, 382 g (3.34 mole) of m-difluorobenzene, 500 g (3.62 mole) of potassium carbonate and 1 liter of 1,3-dimethyl-2-imidazolidinone (abbreviated to DMI hereinafter) were placed in a 3-liter SUS autoclave, and the autoclave was closed. Then, the reaction vessel was purged with nitrogen, and the internal temperature was raised up to 220° C. with stirring. The contents in the reaction vessel were stirred for 20 hours under heating at 220° C. During the stirring, the internal pressure was not more than 0.7 MPa. The progress of the reaction was confirmed by high performance liquid chromatography (HPLC). The intermediate product, 3-(3-fluorophenoxy)phenol almost disappeared at this time. After cooling to room temperature, the reaction mixture was filtered to separate a salt. To the resulting filtrate, 1 liter of toluene and 2 liters of water were added. Then, liquid separation was carried out to obtain an organic phase. The organic phase was washed with 1 liter of a 5% sodium hydroxide aqueous solution and then washed with 1 liter of water. The solvent and the starting difluorobenzene were distilled off under reduced pressure, and then quantitative determination was made by HPLC. As a result, the reaction yield of 1,3-bis(3-fluorophenoxy)benzene was 63%. The resulting crude compound was purified by vacuum distillation (bp 190° C./6.5 hPa) to obtain 109 g (0.365 mole, purity (HPLC): 99%, yield: 53%) of 1,3-bis(3-fluorophenoxy)benzene as a colorless oily product. The structure and the properties of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl-].[Na+]>CC(N(C)C)=O>[CH2:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=3[N:7]=2)[CH2:18][CH2:17]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Sc1nc2cc(Cl)ccc2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Nc2nc3cc(Cl)ccc3o2)CC1
Yield: 39 %

Procedure:
A mixture of 5-chloro-benzooxazole-2-thiol (4.00 g, 21.5 mmol, 1.0 equiv; commercially available from Aldrich) and ethyl 4-amino-1-piperidine carboxylate (4.9 g, 28.0 mmol, 1.3 equiv) in anhydrous DMAc (5 mL) was heated to 200° C. under microwave irradiation for 20 min. To the crude reaction mixture was added a conc. solution of sodium chloride (100 mL), the solution extracted with ethyl acetate (3×100 mL) and the combined organic phases dried over MgSO4. Purification of the crude material with column chromatography on silica eluting with hexane/ethyl acetate (2:1→1:1) yielded 2.7 g (39%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.19 (t, J=7.1 Hz, 3H), 1.39-1.45 (m, 2H), 1.93-1.97 (m, 2H), 2.98 (br s, 2H), 3.77-3.78 (m, 1H), 3.91-3.95 (m, 2H), 4.04 (q, J=7.1 Hz, 2H), 7.00 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 8.19 (d, J=7.6 Hz, 1H). 13C NMR (100 MHz, DMSO): δ 14.53, 31.11, 42.07, 49.60, 60.63, 109.45, 115.10, 119.65, 127.78, 144.86, 146.71, 154.56, 162.50. MS (ISP): 324.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[C:23]([OH:24])=[N:22][C:21]2[C:16]1=[N:17][CH:18]=[N:19][C:20]=2[NH2:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[CH2:8]([N:15]1[C:23]([O:24][C:27]([O:29][CH3:30])=[O:28])=[N:22][C:21]2[C:16]1=[N:17][CH:18]=[N:19][C:20]=2[NH2:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)Cl
Reactant: Nc1ncnc2c1nc(O)n2Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1nc2c(N)ncnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Triethylamine (202 mg, 2 mmol) and N,N-dimethylaminopyridine (111 mg 0.5 mmol) were added to 9-benzyl-8-hydroxyadenine (241 mg, 1 mmol) dissolved in anhydrous THF (20 ml). After stirring at room temperature for 1 h, methyl chloroformate (113 mg, 1.2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The resulting reaction mixture was extracted by ethyl acetate (50 ml) and water (50 ml), and the resulting organic layer was concentrated under vacuum followed by addition of ether (20 ml) to obtain the desired compound as crystals (300 mg, Yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16]=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:10]=[CH2:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C(=O)N(N)c1ccc(F)c(Cl)c1
Reactant: C=O
Solvent: c1ccccc1
Product: C=NN(C(=O)N(C)C)c1ccc(F)c(Cl)c1
Reaction time: 18 h
Yield: 7.9 %

Procedure:
To a solution of 54.3 g of 2-(3-chloro-4-fluorophenyl)-4,4-dimethylsemicarbazide in 300 ml of benzene was added rapidly 40.5 g of 37% formaldehyde, followed by 240 g of Mg2SO4 at ambient temperature. After several days, an additional 40 g of 37% formaldehyde was added and the mixture was stirred for 18 hours. The resulting product was filtered and the filtrate was concentrated to dryness leaving an amber syrup which was purified by silica chromatography to yield 4.5 g of formaldehyde 2-(3-chloro-4-fluorophenyl)-4,4-dimethylsemicarbazone as a viscous oil.