Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](I)[CH3:2].[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([C:26]4[CH:27]=[N:28][C:29]5[C:34]([CH:35]=4)=[CH:33][C:32]([O:36][CH3:37])=[CH:31][CH:30]=5)=[O:25])[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1>CN(C)C=O.[Ag]=O>[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][N:15]([CH2:1][CH3:2])[C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([C:26]4[CH:27]=[N:28][C:29]5[C:34]([CH:35]=4)=[CH:33][C:32]([O:36][CH3:37])=[CH:31][CH:30]=5)=[O:25])[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)cc2c1
Reactant: CCI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCN(Cc1ccc2c(c1)OCCO2)[C@H]1CC[C@H](COC(=O)c2cnc3ccc(OC)cc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl iodide (51 μL, 0.63 mmol, 8.0 eq) is added at room temperature to a stirred solution of 6-methoxy-quinoline-3-carboxylic acid trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethyl ester (37 mg, 0.08 mmol, 1.0 eq) in N,N-dimethylformamide (0.5 mL), followed by silver oxide (73 mg, 0.31 mmol, 4.0 eq). After 4 hours stirring at room temperature, the reaction mixture is filtered through decalite and the mother liquid is concentrated to give a residue that is purified by preparative HPLC to afford 6-methoxy-quinoline-3-carboxylic acid trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-ethyl-amino]-cyclohexylmethyl ester as an off-white lyophilizated solid (9 mg, 14% yield)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=4[F:33])[CH:24]=3)[N:19]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:18]=2)[CH:14]=[N:13][CH:12]=1>CN(C=O)C>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[N:18]=[C:17]2[C:15]1[CH:14]=[N:13][CH:12]=[C:11]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[N:16]=1
Reactant: Oc1cccnc1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Cl)n1)nn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Oc3cccnc3)n1)nn2C1CCCCO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.9 %

Procedure:
To a solution of 3-hydroxypyridine (40 mg, 0.42 mmol) in DMF (1.2 mL) at 0° C. was added NaH (60% in mineral oil) (28 mg, 0.70 mmol). The heterogenous mixture was stirred for 10 min at 0° C., 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Ex. 16a, 150 mg, 0.35 mmol) was added. The mixture was warmed to RT and stirred overnight. The mixture was then heated at 60° C. for 6 h. Ice was added and the mixture was extracted with EtOAc (3×) and CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-75% EtOAc in hexanes, to provide 5-(2,6-difluorophenyl)-3-(6-(pyridin-3-yloxy)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (74 mg, 0.15 mmol, 43% yield) as a white solid. MS (ESI, pos. ion) m/z: 486.0 (M+1).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[H][H].[C:15]1([CH2:21][C:22]([NH:24][CH:25]2[C:56](=[O:57])[N:27]3[C:28]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:29](OS(C(F)(F)F)(=O)=O)[CH2:30][S:31][C@H:26]23)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>ClCCl>[C:15]1([CH2:21][C:22]([NH:24][CH:25]2[C:56](=[O:57])[N:27]3[C:28]([C:40]([O:42][CH:43]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[O:41])=[C:29]([S:1][C:2]4[S:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)[CH2:30][S:31][C@H:26]23)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: Sc1nc2ccccc2s1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3nc4ccccc4s3)CS[C@H]12
Temperature: -30 °C
Reaction time: 16 h

Procedure:
2-Mercaptobenzothiazole (0.59 g, 0.00353 mole) was dissolved in dry dichloromethane (5 mL), and the resulting mixture was treated at 0° C. with sodium hydride (0.141 g of a 1:1 mineral oil dispersion, 0.00294 mole). Evolution of hydrogen was complete in 15 min, and, after cooling to -30° C., the mixture was treated with a solution of diphenylmethyl 7- phenylacetamido-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate (IVa, 1.858 g, 0.00294 mole) in dichloromethane (25 mL) over a 1-2 min period. The mixture was stirred 16 h at -15° C. and then 4 h at 0° C. in order to consume all of compound IVa (the reaction was monitered by HPLC). (Reaction at higher temperature induces formation of the Δ2 -isomer of compound IIc.) Dilute hydrochloric acid (0.5N, 10 mL) was added to the reaction mixture, followed by extracting the mixture with dichloromethane and drying (sodium sulfate) to yield the title product as a crude product which was recrystallized from dichloromethane/ether at 0° C. overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH2:13].O.[C:15]1([CH3:25])C=CC(S(O)(=O)=O)=C[CH:16]=1.C(OCC)(OCC)(OCC)CC>CO>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:16]([CH2:15][CH3:25])[N:13]([CH3:12])[C:4]2=[O:6]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN
Agent: CCOC(CC)(OCC)OCC
Solvent: CO
Solvent: O
Product: CCc1nc2ccc(Br)cc2c(=O)n1C
Temperature: 25 °C
Yield: 39.9 %

Procedure:
To a stirred solution of 2-amino-5-bromo-benzoic acid (10.00 g, 46.38 mmol) in methanol (25 mL) was added methylamine (100 ml of 2 M solution in methanol), p-toluenesulfonic acid monohydrate (8.82 g, 46.38 mmol), and triethyl orthopropionate (40.87 g, 231.9 mmol). The reaction was refluxed for 18 hours, at which time it was allowed to cool to room temperature. The solution was concentrated under reduced pressure. The residue was partitioned between sodium carbonate aqueous (50 ml) and dichloromethane (50 ml). The organic layer was then washed with saturated brine (2×30 ml). The combined organic phase was dried over magnesium sulfate and filtered. The solvent was removed under vacuum. The resulting residue was purified by silica gel chromatography with 100% dichloromethane. The product was collected and was dried under reduced pressure to give 6-Bromo-2-ethyl-3-methyl-3H-quinazolin-4-one (Yield 4.92 g, 39.9%). 1H NMR (400 MHz, CDCl3): □ 1.42 (t, 3H, J=7.33 Hz), 2.86 (dd, 2H, J=14.65, 7.58 Hz), 7.45 (d, 1H, J=8.5 Hz), 7.80 (dd, 1H, J=8.50, 2.02 Hz), 8.40 (d, 1H, J=2.05 Hz). MS m/z calc. 266.01, found (ESI); 267.0 (M+1)+. Retention time 2.44 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)[S:7](=[O:24])(=[O:23])[C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C.[Pd]>[O:30]1[C:29]2[CH:33]=[CH:34][C:26]([CH2:25][N:6]3[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([C:39]4[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:37]([O:36][CH3:35])[CH:38]=4)[C:9]4[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=4[S:7]3(=[O:23])=[O:24])=[CH:27][C:28]=2[O:32][CH2:31]1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(c2cc(OC)c(OC)c(OC)c2)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
2-Benzo[1,3]dioxol-5-ylmethyl-1,1-dioxo-4-(trifluoromethanesulfonyloxy)-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester was taken up in toluene/DMF (10 mL/2 mL) and treated with (3,4,5-trimethoxy)phenylboronic acid (0.35 g, 1.65 mmol), potassium carbonate (0.23 g, 1.67 mmol), and Pd° (PPh3)4 (0.19 g, 0.16 mmol). The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with sat. aq. NaHCO3, brine, dried over magnesium sulfate, and the solvent evaporated. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate 1:1. The resulting oil was treated with diethyl ether, the precipitated solid collected, and dried to give the product as an off-white solid;
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].[CH3:10]O>>[OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Product: COC(=O)[C@H]1NCC[C@@H]1O

Procedure:
To a stirred solution of trans-3-hydroxy-L-proline (15 g, 0.114 moles) in methanol (200 mL) was added borontrifluoride diethyl ether (42 mL, 0.343 moles) and the reaction mixture was refluxed for 48 h. Once the starting material had disappeared (monitored by TLC) the reaction mixture was concentrated to get the title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.CS(C)=O.O.[NH2:25][NH2:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:25][NH2:26])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: NN
Solvent: CS(C)=O
Solvent: CCO
Solvent: O
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 24 h

Procedure:
To a solution of 2.9 parts of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione in a mixture of 2.5 parts by volume of dimethylsulfoxide and 100 parts by volume of ethanol is added 5 parts by volume of 80% hydrazine hydrate, and the mixture is allowed to stand for 24 hours. After evaporation of the solvent under reduced pressure, the residue is diluted with water, followed by extraction with methylene chloride. The methylene chloride layer is dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with benzene gives 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine. Recrystallization from a mixture of methylene chloride and benzene gives crystals melting at 205° C to 207° C (decomposition) which are confirmed to be identical with the product prepared in Examples 1 and 9.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([C:24]1[N:25]=[CH:26][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]=1[CH3:29])[CH:10]1[C:22](=[O:23])[N:14]2[C:15]3[C:20]([CH:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]([O:8][CH:9]([C:24]1[N:25]=[CH:26][N:27]([C:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:28]=1[CH3:29])[CH:10]1[C:22](=[O:23])[N:14]2[C:15]3[C:20]([CH:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(O)C2CCc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2cc3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (1.26 g) was added to a solution of 8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.34 g, a mixture of the isomers A and B) in pyridine (20 ml). After being stirred at 60° C. for 2 hours, the solution was evaporated in vacuo. The residue obtained was diluted with chloroform and neutralized with an aqueous sodium hydrogencarbonate solution. The separated organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one as an oil, which was used in the next reaction without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[CH:17][C:16]([O:24][CH3:25])=[C:15]2[C:10]=1[CH:11]1[CH2:27][CH2:26][CH:14]2[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:38][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O:22][CH2:21][CH:20]([OH:23])[CH2:19][C:18]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=2)[CH:14]2[CH2:13][CH2:12][CH:11]3[CH2:27][CH2:26]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: COc1cc(CC(O)CO)c(OCc2ccccc2)c2c1C1CCC2CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1cc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c(OCc2ccccc2)c2c1C1CCC2CC1
Yield: 89.5 %

Procedure:
Treatment of (±)-3-[5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-6-yl]propane-1,2-diol (15.82 g, 0.043 mol) with p-toluenesulfonyl chloride (9.00 g, 0.047 mol) in anhydrous pyridine (400 mL) generally according to the procedure described for Intermediate 18 gave 20.12 g (90%) of (±)-3-[5-(benzyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-6-yl]-2-hydroxypropyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C30H34O6S.0.5H2O: C, 67.77; H, 6.64. Found: C, 67.86; H, 6.55.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17](=[O:45])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:44])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[CH:30][C:29]=3[C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])[CH:19]=2)[NH:11]1.[Br:46]Br.O>C(O)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([Br:46])=[C:12]([NH:16][C:17](=[O:45])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:44])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[CH:30][C:29]=3[C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])[CH:19]=2)[NH:11]1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3cc(=O)n(-c4c(Cl)cc(Cl)cc4Cl)[nH]3)c2)c(C(C)(C)CC)c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3Br)c2)c(C(C)(C)CC)c1

Procedure:
In 200 ml of acetic acid, 33 g of 1-(2,4,6-trichlorophenyl)-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-5-pyrazolone was dissolved. 7.5 g of bromine was dropwise added to the solution with stirring. After the completion of the reaction, the reaction mixture was added to water, and the thus obtained crystals recovered by filtration and washed were recrystallized, after drying, from 150 ml of a mixture of ethyl acetate and ligroin (1:10 by volume) to obtain 26 g of 1-(2,4,6-trichlorophenyl-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-4-bromo-5-pyrazolone having a melting point of 139° to 141° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].O1CC[CH2:34][CH2:33]1.C(I)C>CN(C)C=O>[CH2:33]([O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2)[CH3:34]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To an ice-cooled and stirred solution of methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.2 g) and potassium carbonate (0.50 g) in N,N-dimethylformamide (10 mL)-tetrahydrofuran (30 mL) was added ethyl iodide (0.28 mL), and the mixture was stirred at room temperature for 18 h and then at 55° C. for 15 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=25:75 to 40:60, volume ratio) to give the title compound (0.65 g, 50%) as light yellow crystals. MS 391 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[N:15]([C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:17])[C:14]([O:28]C)=[N:13][C:12]([CH3:30])=[C:11]2[C:31](=[O:33])[CH3:32])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[N:15]([C:16]([O:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[O:17])[C:14](=[O:28])[NH:13][C:12]([CH3:30])=[C:11]2[C:31](=[O:33])[CH3:32])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a well-stirred solution of 6-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (4.0 g, 8.63 mmol) in THF (100 mL) at 0-5° C., 6 N aqueous HCl (4 mL) was added and the mixture was allowed to warm to room temperature. After 2 h, solvent was evaporated and the product dried under vacuum. The title compound was obtained as a pure single component and used un the next step without further purification (3.88 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=O.C([O:14][C:15](=O)[CH2:16][C:17]1[N:18]=[N:19][NH:20][N:21]=1)C.N1CCCCC1.C(O)(=O)C>CN(C=O)C>[OH:11][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[OH:10])[O:1][C:15](=[O:14])[C:16]([C:17]1[N:18]=[N:19][NH:20][N:21]=1)=[CH:4]2
Reactant: CCOC(=O)Cc1nn[nH]n1
Reactant: O=Cc1cc(O)c(O)cc1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=c1oc2cc(O)c(O)cc2cc1-c1nn[nH]n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4,5-trihydroxybenzaldehyde (1.23 g), (2H-tetrazol-5-yl)-acetic acid ethyl ester (1.25 g), piperidine (1.36 g) and acetic acid (0.06 g) in DMF (10 ml) was stirred at 90° C. under nitrogen for two hours. After ice water treatment and acidification to pH 2 the product was filtered and triturated with hot ethanol. Yield: 0.55 g.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Yield: 10 %

Procedure:
Using a procedure similar to that of Example 282 (step 2) with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 1-methyl-piperazine as starting materials, 25 mg (10%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.00 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.50 (s, 2 H), 2.50 (m, 4 H), 2.30 (s, 4 H), 2.10 (s, 3 H); ES-MS m/z 529.05 [M+H]+, HPLC RT (min) 2.27.
Reaction SMILES: ClCCl.[F:4][CH:5]([F:35])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:22](COCC[Si](C)(C)C)[C:16]3[CH:17]=[N:18][NH:19][C:20](=[O:21])[C:15]=3[CH:14]=2)=[CH:9][C:8]=1[O:31][CH:32]([CH3:34])[CH3:33].N>CO>[F:35][CH:5]([F:4])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:22][C:16]3[CH:17]=[N:18][NH:19][C:20](=[O:21])[C:15]=3[CH:14]=2)=[CH:9][C:8]=1[O:31][CH:32]([CH3:33])[CH3:34]
Reactant: CC(C)Oc1cc(-c2cc3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)ccc1OC(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)Oc1cc(-c2cc3c(=O)[nH]ncc3[nH]2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.2 %

Procedure:
To 2 ml of dichloromethane solution containing 99 mg (0.21 mmol) of 2-(4-difluoromethoxy-3-isopropoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 39-(a) was added 0.1 ml of boron trifluoride diethyl ether complex under ice-cooling, and the mixture was reacted at room temperature for 3 hours. After completion of the reaction, methanol and 28% aqueous ammonia were added to the solid obtained by filtrating the reaction suspension, and the mixture was stirred at room temperature for 12 hours. Then, the solution was concentrated under reduced pressure, and the obtained solid was washed with chloroform and dried under reduced pressure to obtain 29 mg of the title compound as a white solid. (Yield: 42%)
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])=[CH:20][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCOc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCCOc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Succinic anhydride (62.4 g) mashed by a mortar and pestle was placed in a 1 l three-necked flask, followed by adding heptyloxybenzene (100 g) and nitrobenzene (300 ml), portion-wise adding anhydrous aluminum chloride (150 g) under ice cooling, heating the mixture up to 50° C., agitating for 2 hours, allowing to stand overnight, after which the resulting reaction solution was poured in water, and subjected to steam distillation to distil off excess nitrobenzene, followed by ice-cooling, filtering off the resulting solids, heating under reflux together with toluene to remove water by means of Dien-Stark type drain tube, filtering off the solution while hot, recrystallizing from the filtrate, and further filtering off the resulting crystals, to obtain 3-(4-heptyloxybenzoyl)propionic acid (114.5 g). m.p.: 103.5°-105.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>CS(C)=O>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ccc(N)nc1
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Amino nicotinamide 13.7 g (0.1 mole) is dissolved in 100 ml of dimethylsulfoxide and acetic anhydride 14.2 ml (0.15 mole) is added to the above solution. The mixture is stirred at room temperature for 16 hours. White crystals which are formed during the reaction are isolated by filtration and are purified by washing with 0.2 N HCl and ethanol. 6-Acetylamino nicotinamide 9.5 g thus synthesized is practically pure as shown by infrared spectroscopy and thin-layer chromatography.