Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[N:6]=[CH:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>CCCCCC.CCOC(C)=O>[C:47]1(=[O:57])[N:51]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=3[N:6]=[CH:5]2)[C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12
Reactant: O=[N+]([O-])c1ccc2c(c1)ncn2CCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2C(=O)N1CCn1cnc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-5-nitrobenzimidazole (0.27 g, 1.3 mmol) was added triphenylphosphine (0.38 g, 1.4 mmol), DEAD (0.25 ml, 1.4 mmol) and phthalimide (0.21 g, 1.4 mmol) in a portion and resulting mixture was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo, yielding an oil which was subjected to column chromatography (40% Hexane/EtOAc) to provide 0.36 g (1.1 mmol, 82%) of 1-(2-phthalimidylethyl)-5-nitrobenzimidazole. The nitrobenzimidazole was subsequently subjected to hydrogenation, bromination and coupling with ISA to produce 0.41 g of 1-(2-phthalimidylethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole which was refluxed with 0.3 ml of hydrazine in 20 ml of MeOH for 0.5 h to yield the desired product (0.31 g, 0.96 mmol, 68% overall). The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.21 g (24%) of the product as a white foamy solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][N:33]=2)[CH2:28][CH2:27]1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:35]4[CH:34]=[N:33][C:32]([N:29]5[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]5)=[N:37][CH:36]=4)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cnc(N4CCN(C)CC4)nc3)ccc1-2

Procedure:
Following Example 267, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide and 2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine to give 270. MS: (ESI+)=509.2
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-])=O.[C:14](OCC)(=[O:16])[CH3:15]>[C].[Pd].CO>[N:6]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:4]([NH:1][C:14](=[O:16])[CH3:15])[CH:5]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)CCCC2
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cnc2c(c1)CCCC2
Reaction time: 16 h

Procedure:
10% Palladium-carbon (200 mg) was added to a methanol solution (68 ml) of 3-nitro-5,6,7,8-tetrahydroquinoline (2.41 g], 13.5 mmol) obtained in 2), which was stirred under hydrogen atmosphere for 16 hours. After a catalyst was filtered off, the solvent was distilled out under reduced pressure. The resulting residue was dissolved in pyridine (35 ml). Anhydrous ethyl acetate (1.91 ml, 20.3 mmol) was added to the solution, which was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled out under reduced pressure. Diisopropyl ether-n-hexane (1:8) was added to the resulting residue, to give the titled compound (2.48 g) as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:26])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10](OS(O)(=O)=O)=[CH:9][C:8]=2[O:24][CH3:25])(=[O:3])[CH3:2].[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29]>>[C:1]([C:4]1[C:5](=[O:26])[NH:6][C:7]2[C:12]([C:13]=1[NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=[CH:9][C:8]=2[O:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CC(C)CN
Reactant: COc1cc(OS(=O)(=O)O)c(C(F)(F)F)c2c(C)c(C(C)=O)c(=O)[nH]c12
Product: COc1ccc(C(F)(F)F)c2c(NCC(C)C)c(C(C)=O)c(=O)[nH]c12
Yield: 69 %

Procedure:
3-Acetyl-5- trifluoromehyl-8-methoxy-4-methylsulfoxy-2-quinolinone (3.4 7g, 0.01 mol) and isobutylamine (0.73g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.46g, yield: 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([F:25])=[CH:18][C:17]=1F.CC(OC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:17]2[CH:18]=[C:19]([F:25])[C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[F:15])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a solution of 2-chloropyridin-4-ol (100 g, 772 mmol) in anhydrous DMF (2 L) was added K2CO3 (128 g, 926 mmol) in one portion at RT. The mixture was stirred for 10 min at RT, and was then treated with 1,2,4-trifluoro-5-nitrobenzene (88 mL, 772 mmol) slowly over 10 min. The internal temp of the reaction mixture was maintained below 24° C. during the addition. The reaction was stirred at RT for 1 h and then it was stopped by adding ice/water (10 L). The mixture was stirred for 2 h and then filtered to remove the solids. The solids were washed with water (5 L), hexanes (3 L) and then dried under vacuum at 50° C. to give 194.7 g of crude material. The solids were treated with MTBE (200 mL), stirred for 2 h, collected by filtration, washed with MTBE (50 mL) and dried under vacuum at 40° C. for 3 h to afford 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (164.6 g, 74.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (dd, J=10.2, 7.0 Hz, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.90 (dd, J=11.6, 6.7 Hz, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.26 (dd, J=5.6, 2.4 Hz, 1H); MS (ESI): m/z 287.0 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl[C:17]1([C:41]2[C:42]([O:47][CH2:48][CH3:49])=[N:43][CH:44]=[CH:45][CH:46]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([I:26])[CH:24]=2)[N:19]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=2[O:38][CH3:39])(=[O:29])=[O:28])[C:18]1=[O:40]>ClCCl>[CH3:39][O:38][C:31]1[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]=1[S:27]([N:19]1[C:20]2[C:25](=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)[C:17]([C:41]2[C:42]([O:47][CH2:48][CH3:49])=[N:43][CH:44]=[CH:45][CH:46]=2)([NH:15][C:12]2[CH:13]=[CH:14][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)[C:18]1=[O:40])(=[O:29])=[O:28]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOc1ncccc1C1(Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Solvent: ClCCl
Product: CCOc1ncccc1C1(Nc2ccc(N3CCN(CC)CC3)cc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 11.3 %

Procedure:
4-(4-Ethylpiperazin-1-yl)phenylamine (44 mg, 0.21 mmol) was added to a solution of 3-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-5-iodo-1,3-dihydro-indol-2-one (110 mg, 0.18 mmol) in dichloromethane (15 ml). The reaction mixture was agitated in a Biotage microwave vial at 120° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. Purification by chromatography (silica gel, 0-8% methanol in dichloromethane) resulted in 16 mg of the title compound (11% yield).
Reaction SMILES: [OH-].[K+].Br[CH:4]([CH3:22])[C:5]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)=[O:6].Cl.O.[CH2:25]([OH:27])[CH3:26]>CN1CCCC1=O>[C:18]([C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH:4]([O:27][CH2:25][CH3:26])[CH3:22])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[OH:17])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCO
Reactant: CC(Br)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(C)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1 h
Yield: 45 %

Procedure:
6.6 g (117 mmol) of potassium hydroxide are dissolved in 130 ml of ethanol and stirred for one hour. Then 10.0 g (29.3 mmol) of 2-bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-propan-1-one dissolved in 20 ml of n-methylpyrrolidone is added at room temperature while stirring. After stirring for 20 hours the reaction mixture is cooled with an ice bath and 5 ml of concentrated hydrochloric acid and 150 ml of water is added. Then ethanol is evaporated, 200 ml of ethylacetate added and the water phase split off. The organic phase is washed with 100 ml of brine, dried over sodium sulfate and evaporated. The residue is purified by column chromatography and crystallisation of the pure fractions from hexane to give 4.1 g (45%) of compound 115; m.p. 64° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)[C:15](=[O:25])[O:14][N:13]=2)=[N:10][O:9][N:8]=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[N:26]([CH2:6][C:7]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=3)[C:15](=[O:25])[O:14][N:13]=2)=[N:10][O:9][N:8]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 65.3 %

Procedure:
4-[4-(3-Chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-ylmethyl methanesulfonate (400 mg, 1.02 mmol) was dissolved in anhydrous DMF (10 mL) followed by addition of sodium azide (133 mg, 2.04 mmol). Reaction was stirred for 3 hrs. Consumption of starting material was monitored by TLC and HPLC. The reaction mixture was added to a mixture of (400 μL) bromine/water and stirred for 10 min. DCM was added and the layers were separated. The combined organics were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (225 mg, 65%). MF=C11H5ClFN7O3; LCMS calculated for C11H6ClFN7O3(M+H)+: m/z=338.020.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:27])[C:14]3[N:15]([CH3:26])[C:16]4[CH:17]=[CH:18][C:19]([OH:25])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7].[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:24]2[C:12](=[C:13]([CH3:27])[C:14]3[N:15]([CH3:26])[C:16]4[CH:17]=[CH:18][C:19]([O:25][C:29]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)=[O:36])=[CH:20][C:21]=4[C:22]=3[CH:23]=2)[CH:11]=[CH:10][N:9]=1)=[O:7]
Reactant: O=C(O)c1cccnc1
Reactant: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(O)ccc3n(C)c12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1c2ccnc(C(=O)NCCN(C)C)c2cc2c3cc(OC(=O)c4cccnc4)ccc3n(C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
A mixture containing 3 g of 1-[(2-dimethylaminoethyl)aminocarbonyl]-5,6-dimethyl-9-hydroxy-6H-pyrido[4,3-b]carbazole, 1.5 g of nicotinic acid, 3.7 g of dicyclohexylcarbodiimide and 1.5 g of dimethylaminopyridine dissolved in 100 ml of pyridine is stirred at room temperature for 16 hours. At the end of 16 hours, a further 2 g of dicyclohexylcarbodiimide and 0.75 g of nicotinic acid are added and the mixture is stirred for a further 24 hours and concentrated to dryness. The residue is taken up in dichloromethane and washed with sodium hydrogen carbonate, and the dichloromethane phase is concentrated to remove by filtration as much as possible of the dicyclohexylurea formed, and the filtrate is concentrated to dryness. The residue is chromatographed on silica using a mixture of toluene, ethanol and triethylamine (100:10:05) as eluant. 3.5 g of the desired product are obtained, m.p. (cap): 190-192° C.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:15][S:16]([O:2][C@H:3]1[CH2:7][CH2:6][N:5]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCNC1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 62.9 %

Procedure:
The crude (S)-3-hydroxyl-pyrrolidine hydrochloride 11b (124 mg, 1 mmol) was dissolved in 15 mL of dichloromethane, followed by addition of triethylamine (303 mg, 3 mmol). The reaction solution was cooled down to 0° C., followed by addition of methanesulfonyl chloride (264 mg, 2.30 mmol), then warmed up to room temperature and stirred for another 2.5 hours. The resulting solution was mixed with 10 mL of dichloromethane, 1M citric acid was added dropwise to adjust the pH to 4˜5, the organic phase was dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (S)-1-(methylsulfonyl)pyrrolidin-3-yl methanesulfonate 11c (153 mg) as a yellow solid, which was directly used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7](=[CH2:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[C:1]1([C:7](=[CH2:10])[CH2:8][O:9][S:19]([CH3:18])(=[O:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: C=C(CO)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(COS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
To a well stirred solution of 2-phenyl-prop-2-en-1-ol (700 mg, 5.22 mmol) in dichlorometane (10 mL) at 0° C. is added triethylamine (0.945 mL, 6.78 mmol) and methylsulfonyl chloride (0.424 mL, 5.48 mmol). The reaction is allowed to stir for 10 min, warmed to room temperature and is stirred for 30 min. The reaction is quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted several times with ethyl acetate. The organic layers are combined, washed with 1 N hydrochloric acid, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified via silica gel chromatography (10% ethyl acetate in hexanes) to yield the title compound (1.07 g, 4.95 mmol).
Reaction SMILES: CO.[CH3:3][C:4]1([CH3:15])[CH2:9][CH2:8][CH2:7][C:6]([C:10]#[C:11][CH2:12][CH:13]=[CH2:14])=[CH:5]1>O>[CH3:3][C:4]1([CH3:15])[CH2:9][CH2:8][CH:7]=[C:6]([C:10]#[C:11][CH2:12][CH:13]=[CH2:14])[CH2:5]1
Reactant: C=CCC#CC1=CC(C)(C)CCC1
Solvent: O
Solvent: CO
Product: C=CCC#CC1=CCCC(C)(C)C1
Yield: 70 %

Procedure:
(c') 7 g of the above prepared carbinol were heated in a distillation apparatus in the presence of 2 g of H3BO3 at 12 Torr until no further formation of water was observed. The temperature was then slowly increased to 120°-130° and a 2:3 mixture of 1-(3,3-dimethyl-cyclohex-1-en-1-yl)-pent-4-en-1-yne and 1-(3,3-dimethyl-cyclohex-6-en-1-yl)-pent-4-en-1-yne was obtained (5.3 g; 70% yield). The subsequent conversion to the desired cyclohexenic ketones is effected according to the procedure given above (pathway I) paragraph d)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14]O)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:20])=O>O1CCCC1>[Cl:20][CH2:14][C:11]1[S:12][CH:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=2)[N:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(-c2csc(CCl)n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound (4.14 g) obtained in Example 103a was dissolved in tetrahydrofuran (100 mL), and thionyl chloride (3.5 mL) was added. The reaction mixture was stirred at room temperature for 24 hr, and heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (3.19 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:21]Br>C(Cl)Cl.O>[Br:21][C:10]1[C:11](=[O:20])[C:12]2[C:17]([C:9]=1[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2
Reactant: BrBr
Reactant: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=CC2=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C(c1cc(F)cc(F)c1)=C(Br)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-5-methoxy-1H-inden-1-one (810 mg, 2.98 mmol) obtained in Step 2 in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of Br2 (571 mg, 3.57 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 3 h at room temperature. The reaction was diluted with H2O (10 mL) and extracted with CH2Cl2. The extracts were washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/hexanes) to afford the desired product (1.0 g, 95%).
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[Cu](C#N)[C:16]#[N:17]>CN(C)C=O>[C:16]([C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: COC(=O)c1cc(F)c(F)c(Br)c1F
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(F)c(C#N)c1F
Yield: 66.2 %

Procedure:
269 g of methyl 3-bromo-2,4,5-trifluoro-benzoate and 108 g of copper cyanide are heated to reflux for 5 hours in 400 ml of dimethylformamide. All volatile constituents of the reaction mixture are then removed by distillation in vacuo. The distillate is then fractionated on a column. 133 g of methyl 3-cyano-2,4,5-trifluoro-benzoate of boiling point 88-89° C./0.01 mbar are obtained.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][S:2][CH:3]=1)=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(=O)c1ccsc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccccc1)c1ccsc1
Yield: 95.1 %

Procedure:
4 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride, 8 g of sodium bicarbonate and 3.6 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(3). 5.25 g of N-benzoyl-N-[(3-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[N:13][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH2:25]Br)=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2=[CH:12][N:13]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([C:20](=[O:21])[C:19]4[CH:30]=[CH:31][C:16]([Cl:15])=[CH:17][CH:18]=4)[CH:23]=3)[N:14]=[C:8]2[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reactant: CC(C)(C)n1ncc2[nH]ncc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc2nn(Cc3cccc(C(=O)c4ccc(Cl)cc4)c3)cc2c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (5 ml) was dissolved 5-t-butyl-1H-pyrazolo-[3,4-d]pyridazin-4(5H)-one (288 mg) followed by addition of 3-(4-chlorobenzoyl)benzyl bromide (712 mg) and potassium carbonate (318 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with ethyl acetate and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=1:1), washed with the following solvent, and dried. As the washing solvent, diethyl ether was used for 5-t-butyl-1-[3-(4-chlorobenzoyl) benzyl]-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one and n-hexane-diethyl ester was used for 5-t-butyl-2-[3-(4-chlorobenzoyl)benzyl]-2H-pyrazolo [3,4-d]pyridazin-4(5H)-one.
Reaction SMILES: [Si:1]([C:8]#[C:9][CH2:10][N:11]1[C:16]([I:17])=[CH:15][C:14]([CH:18]([OH:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH3:27])[C:12]1=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl[Si:37]([CH3:47])([CH3:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:1]([C:8]#[C:9][CH2:10][N:11]1[C:16]([I:17])=[CH:15][C:14]([CH:18]([O:26][Si:37]([CH3:46])([CH3:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([CH3:27])[C:12]1=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(C(O)Cc2ccccc2)cc(I)n(CC#C[Si](C)(C)C(C)(C)C)c1=O
Reactant: CCCCCCCC[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC[Si](C)(C)OC(Cc1ccccc1)c1cc(I)n(CC#C[Si](C)(C)C(C)(C)C)c(=O)c1C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
To a solution of 1-[3-(tert -butyldimethylsilanyl)prop-2-ynyl]-4-(1-hydroxy-2-phenylethyl)-6-iodo-3-methyl-1H-pyridin-2-one 4a (60 mg, 0.12 mmol) and 4-dimethylaminopyridine (2 mg, 1.2 μmol) in CH2Cl2 (2 mL) was added NEt3 (49 mg, 66 μL, 0.48 mmol) and chlorodimethyloctylsilane (62 mg, 77 μL, 0.3 mmol). The resulting mixture was stirred for 12 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes-EtOAc 15:1) to afford 5a (41 mg, 51%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ7.32-7.24 (m, 3H), 7.15-7.12 (m, 2H), 7.08 (s, 1H), 5.14 (d, J=17.0, 1H), 5.09 (d, J=17.0, 1H), 4.79 (t, J=6.4 Hz, 1H), 2.79 (d, J=6.4 Hz, 2H), 1.98 (s, 3H), 1.39-1.11 (m, 14H), 0.94 (s, 9H), 0.90-0.87 (m, 3H), 0.10 (s, 6H), −0.17 (s, 3H), −0.18 (s, 3H); 13C NMR (75 MHz, CDCl3) δ162.3, 152.0, 137.8, 129.7, 129.1, 128.3, 127.5, 127.2, 126.6, 118.6, 88.4, 44.6, 33.5, 32.0, 29.4, 29.3, 26.1, 23.2, 23.0, 22.7, 17.9, 16.5, 14.2, 12.0, −0.19, −2.05, −4.78.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][CH3:13])[CH2:10][CH3:11].[CH3:15][C:16]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:20])[CH2:17][CH:18]=O>>[CH2:10]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[NH:1][CH2:18][CH2:17][C:16]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:20])[CH3:15])([OH:14])[CH2:12][CH3:13])[CH3:11]
Reactant: CCC(O)(CC)c1ccc(F)cc1N
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Product: CCC(O)(CC)c1ccc(F)cc1NCCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
The product is obtained analogously to intermediate product 1b starting from 3-(2-amino-4-fluorophenyl)pentan-3-ol and tert-butyl (1,1-dimethyl-3-oxopropyl)carbamate. The crude product is purified by column chromatography (silica gel, dichloromethane/MeOH 100:0→98:2). Yield: 7.70 g (99%).