Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(C1OC(C2C=CC=CC=2)=NN=1)C1C=CC2C=C(C(O)=O)SC=2C=1.[C:26]([NH:34][NH:35][C:36](=[O:53])[CH:37]([C:39]1[CH:52]=[CH:51][C:42]2[CH:43]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[S:45][C:41]=2[CH:40]=1)[F:38])(=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[F:38][CH:37]([C:36]1[O:53][C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:34][N:35]=1)[C:39]1[CH:52]=[CH:51][C:42]2[CH:43]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[S:45][C:41]=2[CH:40]=1
Reactant: CCOC(=O)c1cc2ccc(C(F)C(=O)NNC(=O)c3ccccc3)cc2s1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C(O)c1cc2ccc(C(F)c3nnc(-c4ccccc4)o3)cc2s1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(F)c3nnc(-c4ccccc4)o3)cc2s1
Temperature: 120 °C

Procedure:
Dehydration/Saponification; 6-[Fluoro-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-benzo[b]thiophene-2-carboxylic acid. A solution of ethyl 6-[2-(2-benzoylhydrazino)-1-fluoro-2-oxoethyl]-1-benzothiophene-2-carboxylate (51 mg, 0.13 mmol) in THF (2.0 mL) was treated with Burgess reagent (45 mg, 0.19 mmol). The reaction vessel was sealed and heated to 120° C. in the microwave reactor for 20 minutes. The reaction was evaporated in vacuo and purified by flash chromatography (10-40% ethyl acetate/hexanes) to give ethyl 6-[fluoro(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1-benzothiophene-2-carboxylate as a white solid. ESIMS calcd 383.1 (M++H), found 383.0 (M++H). To a solution of ethyl 6-[fluoro(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1-benzothiophene-2-carboxylate in THF (2.5 mL) was added 1M sodium hydroxide (5.0 mL, 5.0 mmol) and the resulting solution was stirred at ambient temperature for 1 hour. The reaction was partitioned between ethyl acetate and 1M HCl solution. The organics were dried over sodium sulfate, filtered and evaporated to give 6-[fluoro(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-1-benzothiophene-2-carboxylic acid as a white solid. ESIMS calcd 355.1 (M++H), found 355.0 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:31][CH2:32][CH2:33][O:34]C2CCCCO2)=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:10]=[C:9]2/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:5])[CH3:2].Cl.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:31][CH2:32][CH2:33][OH:34])=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[N:10]=[C:9]2/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c(/C=C/c3ccc(F)cc3)nn2C(=O)OC(C)(C)C)c1OCCOC1CCCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c(/C=C/c3ccc(F)cc3)nn2C(=O)OC(C)(C)C)c1OCCO
Temperature: 25 °C
Reaction time: 19 h
Yield: 69.8 %

Procedure:
To a solution of 147 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-[2-(tetrahydropyran-2-yloxy)-ethoxy]-1H-indazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-ethyl ester in 1.5 mL of tetrahydrofuran was added 1.5 mL of 2N hydrochloric acid, and stirred at room temperature for 19 hours. Thereafter, the reaction solution was added with water and extracted twice ethyl acetate, and the resultant organic layer was washed once with saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography, to afford 87.1 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:8]=2[CH2:26][N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:26][N:27]2[CH:35]=[N:34][C:33]3[C:28]2=[N:29][CH:30]=[N:31][C:32]=3[NH2:36])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(Cn3cnc4c(N)ncnc43)c(-c3ccccc3)c3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncnc2c1ncn2Cc1[nH]c2ccccc2c1-c1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
A mixture of 9-[3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-ylmethyl]-9H-purin-6-ylamine from Example 22 (330 mg, 0.667 mmol) and 2M KOH (1.3 mL) in MeOH (20 mL) was stirred at 70° C. for 5 h. Volatiles were removed under reduced pressure and the resulting residue was diluted with water. The pH of the solution was adjusted to 1 by addition of 1M HCl and then to 8 by addition of a saturated solution of NaHCO3. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-9% MeOH in DCM) affording 162 as a white solid (102 mg, 45%). LCMS: RT 3.79 min [M+H]+ 341.2. 1H NMR (DMSO, 400 MHz): δ 11.31 (1H, s), 8.16 (1H, s), 8.02 (1H, s), 7.64-7.59 (2H, m), 7.57 (1H, d, J=7.96 Hz), 7.50 (2H, t, J=7.96 Hz), 7.43-7.33 (2H, m), 7.24 (2H, s), 7.16 (1H, t, J=7.50 Hz), 7.07 (1H, t, J=7.50 Hz), 5.59 (2H, s)
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:10])[CH2:6][CH2:7][C:8]#[CH:9].[N:12]#[C:13][NH2:14]>>[ClH:1].[CH2:6]([C:5]1[N:10]=[C:13]([NH2:14])[NH:12][CH:4]=1)[CH2:7][C:8]#[CH:9]
Reactant: C#CCCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCCc1c[nH]c(N)n1
Yield: 48 %

Procedure:
2-Amino-hex-5-ynoic acid methyl ester hydrochloride (2.53 g, 14.2 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (1.17 g, 48%) as a pale yellow oil (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.52 (s, 1H), δ 2.61 (t, 2H), δ 2.42 (m, 2H), δ 2.27 (t, 1H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.4, 126.2, 109.4, 81.9, 69.9, 23.8, 17.4 ppm; HRMS (ESI) calcd for C7H10N3 (M+) 136.0869. found 136.0865.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH:34]=[N:33][C:32]([C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][C:38]3([CH3:44])[CH3:43])=[O:36])=[N:31]2)[CH:27]=[CH:28][CH:29]=1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:40]2[CH2:41][CH2:42][N:37]([C:35]([C:32]3[N:33]=[CH:34][N:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=4)[N:31]=3)=[O:36])[C:38]([CH3:44])([CH3:43])[CH2:39]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CNCCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Reactant: O=C(O)c1cccc(Br)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)CN(C(=O)c2cccc(Br)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 394 mg (1.94 mmol) 6-bromo-pyridine-2-carboxylic acid in 30 mL THF was added 369 mg (2.28 mmol) 1,1′-carbonyldiimidazole. After stiffing at 60° C. for 4 h, 520 mg (1.63 mmol) [1-(3-chloro-phenyl)-1H-[1,2,4]triazol-3-yl]-(2,2-dimethyl-piperazin-1-yl)-methanone was added. The resulting mixture was stirred at 50° C. for 12 h. The solvent was evaporated. The residue was taken up in DMF and purified by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([C:16](=[O:24])[NH:17][C:18]1[S:19][C:20](Br)=[CH:21][CH:22]=1)[CH2:7][CH2:6]2.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=C(B(O)O)C=1>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[NH:17][C:16]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([C:12]([F:13])([F:14])[F:15])[CH:10]=2)[CH2:6][CH2:7]1)=[O:24]
Reactant: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(Br)s1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccnc1
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccs1)CC2
Yield: 27 %

Procedure:
A mixture of 5-methoxy-6-trifluoromethyl-1-(5-bromo-2-thienyl) carbamoyl indoline (E48) (0.64 g, 1.5 mmol), sodium carbonate (1.1 g), pyridine-3-boronic acid (0.55 g, 4.5 mmol) and tetrakis triphenylphine palladium(0) (0.1 g) in dimethoxyethane/water (20 ml/5 ml) was heated to reflux overnight under argon. Extraction workup and chromatography afforded the title compound in 27% yield as a white solid, m.p. 240-244° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[O:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]=[C:32]1B(O)O>>[O:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]=[C:32]1[C:7]1[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: OB(O)c1cc2ccccc2o1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2cc3ccccc3o2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 1-benzofuran-2-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C23H20NO4 (M+H): 374.1372. Found 374.1387
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:11]2)(=O)=O.C(OC1C=CC(CN)=CC=1)C1C=CC=CC=1.[CH2:44]([O:51][C:52]1[CH:78]=[CH:77][C:55]([CH2:56][NH:57][C:58]2C=C(OC)C=C3C=2CC(C2C=CC(OC)=CC=2)C3)=[CH:54][CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:44]([O:51][C:52]1[CH:53]=[CH:54][C:55]([CH2:56][NH:57][CH2:58][C:7]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:11]3)=[CH:77][CH:78]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: COc1ccc(C2Cc3cc(OC)cc(OS(=O)(=O)C(F)(F)F)c3C2)cc1
Reactant: COc1ccc(C2Cc3cc(OC)cc(NCc4ccc(OCc5ccccc5)cc4)c3C2)cc1
Agent: NCc1ccc(OCc2ccccc2)cc1
Product: COc1ccc(C2Cc3cc(OC)cc(CNCc4ccc(OCc5ccccc5)cc4)c3C2)cc1

Procedure:
Synthesized from 6-methoxy-2-(4-methoxyphenyl)indan-4-yl trifluoromethanesulfonate and 4-benzyloxybenzylamine according to an analogous synthetic method to Example 116, (4-benzyloxybenzyl)[6-methoxy-2-(4-methoxyphenyl)indan-4-yl]amine (1.2 g) was used according to an analogous synthetic method to Preparation Example 18 to provide the title compound (1.0 g).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[S:7]1[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: O=C(O)CCSc1ccccc1
Solvent: O
Product: O=C1CCSc2ccccc21
Temperature: 60 °C
Reaction time: 96 h

Procedure:
Polyphosphoric acid (110 g) was admixed with 3-phenylsulfanylpropionic acid (13.54 g, 74 mmol) and the reaction mixture was stirred at 60° C. for 96 h. After cooling to RT, the reaction mixture was admixed with water (250 ml) and extracted with diethyl ether (3×100 ml). The combined organic phases were washed with 5% eq. NaHCO3 solution (50 ml), washed with water (50 ml) and dried over sodium sulfate, and the solvent was removed under reduced pressure. After column chromatography purification of the residue (silica gel, 8:1 cyclohexane/MTBE), the desired product was obtained as a greenish oil (8.0 g, 66% of theory).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(C(C)(C)C)n3)CC2)cc1

Procedure:
60 mg (66%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(4-methoxyphenyl)piperazine (40 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[O:29])[CH2:22][CH:23]2[C:26]([Cl:28])=[O:27])=[CH:19][CH:18]=1>C(N(CC)CC)C>[ClH:28].[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[O:29])[CH2:22][CH:23]2[C:26]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:8][N:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:27])=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)C(C(=O)Cl)CC2=O
Reactant: C1CCC(CN2CCCC2)NC1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(C(=O)N1CCCCC1CN1CCCC1)CC2=O
Yield: 36.5 %

Procedure:
From 1.21 g of 2-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride. 1.35 g of 6-methoxy-3-oxoindan-1-carbonyl chloride and 2.79 ml of triethylamine. 0.72 g of the title compound was obtained, melting at 210°-228° C. (dec) using a procedure similar to that in Example 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N)[CH2:27][NH2:28].Cl>CN(C)C=O>[C:27]([C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:28]
Reactant: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1Br
Reactant: NCCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1C#N
Temperature: 25 °C

Procedure:
A mixture of S 3'-bromo-4'-(1-methylheptyloxy)-4-biphenylcarboxylic acid (56.7 g), cuprous cyanide (16.3 g) and dimethylformamide (140 ml) was heated for 12 hours under reflux, followed by cooling the resulting material to room temperature, treating with 10 wt. % ethylenediamine aqueous solution (700 ml), acidifying with 6N hydrochloric acid, collecting the precipitates by filtration, washing with boiling water, dry-sucking and recrystallizing from acetic acid to obtain S 3'-cyano-4'-(1-methylheptyloxy)-4-biphenylcarboxylic acid (40.8 g) (C-S, 100.0° C., S-I, 138.7° C.).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:13])[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=2[O:22]C)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:13])[C:6]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[OH:22])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(-c2ccc(OC)cc2OC)c2cccc(F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc(-c2ccc(O)cc2O)c2cccc(F)c21
Yield: 92 %

Procedure:
Prepared according to Method D step C from 1-allyl-3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.187 g, 0.6 mmol), boron tribromide (0.362 mL, 3.80 mmol) and 1.0 mL of cyclohexene to give the product (0.157 g) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]([NH2:25])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].CCN(CC)CC>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:25][C:19]4[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([Br:16])[CH:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(N)cc1Br
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reaction time: 16 h

Procedure:
To a solution of the crude 1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl chloride (3.0 mmol) in CH2Cl2 (30 mL) at ambient temperature was added a solution of 3-bromo-4-methoxybenzenamine (3.3 mmol), Et3N (15 mmol), and CH2Cl2 (90 mL) dropwise. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 (500 mL). The solution was washed with 1N HCl (2×250 mL), sat. aq. NaHCO3 (2×250 mL), then brine (250 mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuo to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methoxyphenyl)cyclopropane-carboxamide (B-10) with suitable purity to be used without further purification.
Reaction SMILES: CC1(C)[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:54])[CH2:13][NH:14][CH2:15][CH2:16][C:17]3[CH:53]=[CH:52][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:27]=[C:28]([S:32]([N:35](COCC[Si](C)(C)C)COCC[Si](C)(C)C)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=4)=[CH:19][CH:18]=3)=[CH:11][C:5]=2[CH2:4][O:3]1>C(O)(=O)C.O>[OH:54][C@H:12]([C:10]1[CH:9]=[CH:8][C:6]([OH:7])=[C:5]([CH2:4][OH:3])[CH:11]=1)[CH2:13][NH:14][CH2:15][CH2:16][C:17]1[CH:53]=[CH:52][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]2[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)=[CH:19][CH:18]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(OCCOCc4cccc(S(=O)(=O)N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c4)cc3)ccc2O1
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cccc(COCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(CO)c3)cc2)c1
Yield: 39 %

Procedure:
3-({2-[4-(2-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}ethyl)phenoxy]ethoxy}methyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.015 g) was heated at 75° for 6 h in acetic acid (1.5 ml) and water (0.75 ml). The solution was evaporated to dryness and re-evaporated twice with methanol to give crude product (0.012 g). This was purified by preparative layer chromatography on a silica plate (20×20 cm) which was developed twice in dichloromethane:ethanol: 0.880 ammonia solution, 25:8:1. After elution of the required band using methanol in dichloromethane, the eluate was evaporated to dryness and re-evaporated successively with acetic acid in methanol and then methanol to give the title compound (0.0037 g) LCMS RT=2.19 min. ES+ve 517 (MH)+
Reaction SMILES: C[C@@H](NC)[C@H]1O[C@H](O[C@H:10]2[C@H:15]([OH:16])[C@@H:14]([O:17][C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H:13]([NH2:29])[CH2:12][C@@H:11]2N)[C@H](N)CC1.OC1O[C@H](CO)[C@@H](O)[C@@H]1O.N1C=CC(N)=NC1=O.C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@@]2(O)O[C@H]([C@H](C(O)=O)[C@@H](O)C2)C[C@@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C=CC=CC=CC=CC=CC=CC=C1.CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.N[C@H](C(O)=O)CCC(=O)N>>[C:15]1([CH:10]=[CH:11][CH:12]=[C:13]([NH2:29])[C:14]=1[OH:17])[OH:16]
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)NC)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Product: Nc1cccc(O)c1O
Reaction time: 132 h

Procedure:
Chromaffin cells were prepared from bovine adrenal glands by protease perfusion using the method described by Livett in Physiol. Rev. 64:1103 (1984). The cells were plated at 1×106 cells/well in 24-well plates in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum, 8 μM fluorodoxyurine, 50 μg/ml gentamicin, 10 μM cytosine arabinofuranoside, 2.5 μg/ml fungizone, 25 international units/ml penicillin, 25 μg/ml streptomycin and 2 mM glutamine. Experiments were performed 3-8 days after plating. Ca2+-evoked catecholamine release was measured fluorometrically.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:20])[CH:14]([CH3:19])[CH:15]([CH3:18])[CH2:16][CH3:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26].O>CN(C)C=O>[CH3:19][CH:14]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])=[O:20]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: CCC(C)C(C)C(=O)Nc1ccc2ncnc(N)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)C(C)C(=O)Nc1ccc2ncnc(NC=C(C(=O)OC)C(=O)OC)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A mixture of 4-amino-6-(2,3-dimethylpentanamido)quinazoline (6.75 g) and dimethyl methoxymethylene-propanedioate (6.48 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 1 hour and cooled to ambient temperature. Water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water, and dried. There was obtained dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (6.58 g). A portion of the crude product was chromatographed on silica gel with chloroform and ethyl acetate (3:1) and recrystallized from ethyl acetate to give analytically pure dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (0.45 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13]([CH2:16][CH2:17][OH:18])(=[O:15])=[O:14])([O-:3])=[O:2].O.[S:20](=O)(=[O:23])([OH:22])[OH:21].[Cl-].[Na+]>>[S:20]([O:18][CH2:17][CH2:16][S:13]([C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14])([OH:23])(=[O:22])=[O:21]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)CCO)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)CCOS(=O)(=O)O)c([N+](=O)[O-])c1
Reaction time: 14 h

Procedure:
105 parts of 2[2,4-dinitrophenylsulfonyl]ethanol are gradually added at 0°-5° C. to 380 parts of sulfuric acid monohydrate and the mixture is stirred at that temperature for 14 hours. The resulting brown solution is then gradually discharged onto a mixture of ice and 20% sodium chloride solution, the result being a yellowish suspension. The precipitate is filtered off and washed initially with 1000 parts of cold 20% sodium chloride solution and then with 200 parts of ice-water. Drying leaves 2-[2,4-dinitrophenylsulfonyl]ethyl hydrogensulfate in very good yield and purity.
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[OH:13][C:14]([CH:16]([C:18]1[CH:27]=[CH:26][C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:19]=1)[CH3:17])=[O:15].[ClH:28].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[ClH:28].[OH:15][C:14]([CH:16]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]([CH3:24])[CH3:25])=[CH:26][CH:27]=1)[CH3:17])=[O:13]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(N)O
Temperature: 25 °C

Procedure:
In 1 ml of dichloromethane, 636 mg (1.75 mmol) of the Boc-aminopropanol-ibuprofen obtained above was dissolved, and 4 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring under ice-cooling for 10 minutes and at room temperature for 3 hours. After confirming disappearance of Boc-aminopropanol-ibuprofen by TLC, diethyl ether was added thereto, followed by decantation three times. Thereafter, the residue was dried under reduced pressure to give the titled substance at a yield of 406 mg (77%). The structure was identified by 1H-NMR (CDCl3).