Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][C@@H:23]2[C@@H:27]([CH2:28][OH:29])[O:26][C@@H:25]([N:30]3[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]3=[O:32])[CH2:24]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H:43]([OH:44])C1.C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:22][C@@H:23]2[C@@H:27]([CH:28]([CH:43]=[O:44])[OH:29])[O:26][C@@H:25]([N:30]3[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]3=[O:32])[CH2:24]2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: COc1ccc(C(O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)O[C@@H]2CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C(O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)O[C@@H]2C(O)C=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a stirred, cold solution of 3′-O-(4,4′-dimethoxytrityl)thymidine (prepared from thymidine by the common procedures, 40.4 g, 0.072 mol) in anhydrous DMSO was added a solution of DCC (45.86 g, 0.224 mol) in DMSO (180 ml). The resulting solution was stirred at 5° C. for 5 min. pyridine (2.94 g, 3.0 ml, 0.0371 mol) was added and after stirring for another 5 min. a solution of trifluorocaetic acid (2.11 g, 1.43 ml, 0.0185 mol) in DMSO (2 ml) was added dropwise. The resulting reaction mixture was stirred at 5° C. for 10 min. and at room temperature for 6 h. Water (20 ml) was added dropwise under cooling and the mixture stirred at room temperature for 1 h. Precipitates were filtered and washed with DMSO. The combined DMSO solution was poured onto crashed ice (4 L) with stirring. After standing for 1 h, the precipitates were filtered and washed thoroughly with water. The cake was dissolved in methylene chloride (500 ml), and the organic layer separated, dried (Na2SO4), and concentrated. The crude was purified by chromatography on silica (3% methanol in methylene chloride) to give 32.6 g (81%) of 3′-O-(4,4′dimethoxytrityl)-5′-formylthymidine as a colorless powder.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:24]3[CH2:26][CH2:25]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH:24]3[CH2:26][CH2:25]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC(c1cn(-c2ccc(C(F)(F)F)cn2)nc1C1CC1)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2C2CC2)C2CCCCC2)cc1
Yield: 19.9 %

Procedure:
Using cyclohexyl{3-cyclopropyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.32 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.15 g, 21%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([CH2:29]O)[CH:25]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11](=[O:22])[N:12]([CH2:29][C:26]3[CH:25]=[C:24]([CH3:23])[O:28][N:27]=3)[C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Reactant: Cc1cc(CO)no1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3cc(C)on3)C2=O)cc1
Temperature: 130 °C
Yield: 21.1 %

Procedure:
To a solution of 3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione (0.17 mmol, 50 mg), 5-methylisoxazole-3-methanol (0.19 mmol, 21 mg) and diethyl azodicarboxylate (0.19 mmol, 33 mg) in dry THF (1 mL) was added triphenylphosphine (0.19 mmol, 49 mg) in dry THF (1 mL). The mixture was heated in a microwave reactor at 130° C. for six min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 14 mg (21%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.23 (bs, 1H), 7.16-7.06 (m, 3H), 7.01-6.96 (m, 2H), 6.63-6.53 (m, 4H), 6.03 (d, J=0.7 Hz, 1H), 4.82 (s, 2H), 3.70 (s, 3H), 2.39 (d, J=0.7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16].[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:13])[CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)c1cn(C)c2c(C(=O)O)cc(Br)cc12
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a stirred suspension of 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid (300 mg, 1.013 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (280 mg, 1.484 mmol) and HOAt (200 mg, 1.469 mmol) in DMF (15 mL) was added N-methylmorpholine (170 μL, 1.546 mmol) and EDC free base (310 mg, 1.997 mmol). The reaction was stirred for 18 h at RT. LCMS showed that the reaction was complete. The reaction was evaporated to near dryness under vacuum. Water (˜15 mL) was added and the solids which precipitated out were triturated, filtered and dried under vacuum. LCMS indicated that the solids were only 87% pure. The solid was partially dissolved in CH2Cl2. Noticed that the product began to crystallize out. Slowly added an equal volume of hexanes, triturated, filtered and dried under vacuum to give the product 5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxamide (188 mg, 0.437 mmol, 43.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.50 (br. s., 1H), 8.54 (t, J=4.8 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.14 (s, 1H), 7.09 (d, J=2.0 Hz, 1H), 5.87 (s, 1H), 4.31 (d, J=5.1 Hz, 2H), 3.65 (s, 3H), 3.11 (dt, J=6.9, 13.5 Hz, 1H), 2.22 (s, 3H), 2.12 (s, 3H), 1.26 (d, J=6.8 Hz, 6H). MS (ES)+ m/e 429.9 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCC(=O)Cl
Reactant: NCc1ccc(N2CCN(C3CCCC3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCc1ccc(N2CCN(C3CCCC3)CC2)nc1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 26 mg (0.1 mmol) C-[6-(4-cyclopentyl-piperazin-1-yl)-pyridin-3-yl]-methylamine, 20 mg (0.2 mmol) triethylamine and 12 mg (0.11 mmol) butyryl chloride in DCM was stirred at room temperature. After evaporation acetonitrile/DMF was added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 20.3 mg (61%) of the title compound. (m/e): 331.3
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH3:12]O.S(=O)(=O)(O)O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Cl)cc1O

Procedure:
A solution of 4-chloro-2-hydroxybenzoic acid (100 g, 0.58 mol), methanol (500 mL) and concentrated sulfuric acid (50 mL) was refluxed for 20 hr. Benzene (100 mL) was added and the solvent was slowly distilled off from the mixture until 300 mL of distillate was collected. The residue was taken up in diethyl ether, the aqueous phase was separated, the organic phase was washed with sodium bicarbonate solution, dried and evaporated to give 100 g of the title compound as an oil which crystallized on cooling; mp 27°-30° C., and IR (mineral oil) 3150, 1660 and 1600 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=4)[C:22]([OH:24])=[O:23])[N:14]([CH3:28])[C:13]=3[CH:29]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32][OH:33]>C(O)C.O>[CH3:32][O:33][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=4)[C:22]([OH:24])=[O:23])[N:14]([CH3:28])[C:13]=3[CH:29]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cn1c(COc2cccc(C(=O)O)c2)nc2ccc(Oc3ccc(Cl)nc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Oc2ccc3nc(COc4cccc(C(=O)O)c4)n(C)c3c2)cn1
Yield: 79 %

Procedure:
A solution of 3-({6-[(6-chloropyridin-3-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid produced in Example (18e) (0.40 g, 0.98 mmol) and sodium hydride (63%, 0.372 g, 9.76 mmol) in methanol (9.8 mL) was heated under reflux under microwave irradiation for two hours. After leaving to cool, water was added to the reaction mixture. This aqueous solution was washed with hexane five times and neutralized by adding 1 M hydrochloric acid. The precipitated solid was collected by filtration to obtain the crude title compound. A suspension of the crude title compound in ethanol (5 mL) and water (5 mL) was heated under reflux for two hours and left to cool. Then, the precipitated solid was collected by filtration to obtain the title compound (0.312 g, 79%) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1cccc(Br)c1
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (0.3 mL) was added to a stirred mixture of 3-bromophenol (26.2 g) and acetic anhydride (15 mL). An exothermic reaction took place, after which the mixture was allowed to cool to RT. Acetic acid and excess acetic anhydride were evaporated, and the residue was poured onto ice. The mixture was extracted with ether, and the combined ether extracts were washed with brine, then dried over magnesium sulfate and concentrated to afford 3-bromophenyl acetate (compound 6a, 31.6 g) as an amber oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:35]([O-:38])([O-])=[O:36].[K+].[K+].Br[N:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH2:43]1>CN(C=O)C.CO>[F:22][C:21]([F:24])([F:23])[C:35]([OH:38])=[O:36].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:46]4[CH:47]=[N:42][CH:43]=[N:44][CH:45]=4)=[CH:18][CH:19]=3)=[N:11][N:10]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: BrN1C=CC=NC1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)ccc1Cl
Product: O=C(O)C(F)(F)F
Temperature: 80 °C

Procedure:
4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (100 mg, 0.281 mmol) was dissolved in ca. 2 mL of anhydrous DMF under argon. Solid potassium bis(trimethylsilyl)amide (140.2 mg, 0.702 mmol) was added and the resulting yellow solution was heated at 80° C. for 15 min. Then solid K2CO3 (19.4 mg, 0.140 mmol) was added, followed by 3-bromopyrimidine (89.4 mg, 0.562 mmol). The reaction mixture was microwaved at 200° C. for 15 min. Then it was diluted with 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by preparative reverse-phase chromatography using acetonitrile/water gradient with 0.1% TFA. The major peak having the mass of the product was collected; solvent was removed in vacuo to give the title product as a white fluffy solid (73.0 mg of white crystalline solid).
Reaction SMILES: Br[C:2]1C=CC([N+]([O-])=O)=C[C:3]=1C=O.[C:13](NC(C1CCNCC1)=O)(C)(C)[CH3:14].[C:26]([NH:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2Br)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(B(O)O)C>>[C:26]([NH:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[C:44]([NH2:46])[CH:43]=[CH:42][C:41]=2[CH2:2][CH3:3])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[C:26]([NH:30][C:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[CH2:13][CH3:14])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Reactant: CC(C)(C)NC(=O)C1CCN(Cc2cc([N+](=O)[O-])ccc2Br)CC1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Br
Agent: CCB(O)O
Product: CCc1ccc(N)cc1CN1CCC(C(=O)NC(C)(C)C)CC1
Product: CCc1ccc([N+](=O)[O-])cc1CN1CCC(C(=O)NC(C)(C)C)CC1

Procedure:
The title compound is prepared according to the reactions described above starting from 2-bromo-5-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination 1-(2-bromo-5-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide; LC-MS A: tR=0.62 min; [M+H]+=397.99; followed by alkylation with ethylboronic acid yielding 1-(2-ethyl-5-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide; LC-MS A: tR=0.66 min; [M+H]+=348.34, followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.49 min; [M+H]+=318.21.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[BH4-].[Na+].O>O1CCCC1>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:14][OH:15])=[CH:16][CH:17]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(CO)cc1
Reaction time: 1 h

Procedure:
4-(Phenylsulfonyl)benzaldehyde (prepared according to the method of Ulman et al., J. Org. Chem. (1989), 54 (19), 4691–2; 12.3 g, 50 mmol) was dissolved in tetrahydrofuran and methanol was added, followed by careful addition of sodium borohydride (2.0 g, 52.9 mmol). The reaction was stirred for 1 hour before pouring into water and extracting with ethyl acetate. The organic layer was dried over MgSO4 and evaporated in vacuo to give [4-(phenylsulfonyl)phenyl]methanol. This was treated with phosphorus tribromide and heated to reflux for 16 hours. The cooled reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with dichloromethane, to give 1-(bromomethyl)-4-(phenylsulfonyl)benzene (10.1 g, 65%). δH (500 MHz, CDCl3): 7.96–7.90 (4H, m), 7.59–7.56 (1H, m), 7.52–7.49 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.C[O-].[Na+].[Na].[CH2:21]([N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:24][CH3:25])[CH3:22]>CO.C1(C)C=CC=CC=1>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCN(CC)CCCCl
Reactant: Oc1ccc(-c2cc3ccccc3o2)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCN(CC)CCCOc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
A solution of 4.9 g. (0.023 mol.) of 2-p-hydroxyphenylbenzofuran in 75 ml. of toluene and 5 ml. of methanol was added to a sodium methoxide solution prepared by dissolving 0.54 g. (0.023 g.-atom) of sodium in 25 ml. of methanol. The mixture was refluxed for 15 minutes, then the methanol was removed by distillation and 3.48 g. (0.023 mol.) of diethylaminopropyl chloride was added and the resulting reaction mixture was refluxed for four hours. The mixture was filtered and the filtrate concentrated under reduced pressure to give 2-[4'-(3-diethylaminopropoxy)phenyl]benzofuran, m.p. 86°-88°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:11])=[C:9]2[C:12](=[C:16]=[O:17])[CH:13]=[CH:14][CH:15]=[C:8]2[O:7]1)=[O:5])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Oc2cccc(=C=O)c2=C1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(CO)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 0.123 g (0.530 mmol) of 4-carbonyl-3-methylbenzofuran-2-carboxylic acid ethyl ester in 10 mL of ethanol was added 0.019 g (0.505 mmol) of sodium borohydride. The reaction was stirred at room temperature for 2 h and than diluted wuth water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 0.113 g of 4-hydroxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[N+:12]([O-:14])=[O:13])([CH3:3])[CH3:2].Cl.[CH3:16]O>>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:16])=[O:10])[C:5]=1[N+:12]([O-:14])=[O:13])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Agent: Cl
Product: COC(=O)c1n[nH]c(C(C)C)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 91 %

Procedure:
5-Isopropyl-4-nitropyrazole-3-carboxylic acid was added to a 4.5M solution of HCl in absolute methanol. The reaction mixture was heated at 60° C. for 7 hours. The title compound was crystallized from ethyl acetate; yield 91%; mp=78-80° C. 1H NMR (300 MHz, CDCl3): 1.39 d (6H, J=7.1 Hz); 3.64 sept (1H, J=7.1 Hz), 3.98 s (3H). CHN required: C=45.07%; H=5.20%; N=19.70%; found: C=45.21%; H=5.23%; N=19.65%.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[N:12]1([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[S:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[C:27]=3[C:35]([C:37]3[CH:42]=[CH:41][C:40](F)=[CH:39][CH:38]=3)=[O:36])=[CH:22][CH:21]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C.[Cl-].[Na+].O>[O:11]=[C:7]1[CH2:8][CH2:9][CH2:10][N:6]1[CH2:5][CH2:4][O:3][C:40]1[CH:41]=[CH:42][C:37]([C:35]([C:27]2[C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[S:30][C:26]=2[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:25][CH:24]=2)=[O:36])=[CH:38][CH:39]=1
Reactant: O=C1CCCN1CCO
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCCN2CCCC2=O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% oil dispersion, 50 mg) was suspended in DMF (2.0 mL) and stirred at ambient temperature for 15 min under argon before 1-(2-hydroxyethyl)-2-pyrrolidinone (87 μL) was added. After stirring for 15 min, 4-fluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophen-3-yl ketone (223 mg) in 1 mL of DMF was introduced and the resulting solution was stirred at ambient temperature for 3.5 h. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5-10:90-85) afforded the product as a colorless oil (210 mg).
Reaction SMILES: [CH:1]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)=[CH:2][CH2:3][CH3:4].[SH:14][CH2:15][C:16]([OH:18])=[O:17]>C(OCC)(=O)C>[O:9]1[C:8]2[CH:12]=[CH:13][C:5]([CH2:1][CH:2]([S:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:3][CH3:4])=[CH:6][C:7]=2[O:11][CH2:10]1
Reactant: O=C(O)CS
Reactant: CCC=Cc1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Product: CCC(Cc1ccc2c(c1)OCO2)SCC(=O)O
Yield: 53.7 %

Procedure:
2.2 g of 5-(1-butenyl)-1,3-benzodioxole and 5.4 g of mercaptoacetic acid were heated at 60° C. for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water and an aqueous common salt solution and dried over magnesium sulfate. The solvent was distilled off and the product was separated according to silica gel column chromatography (chloroform) to obtain 1.8 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[H-].[Na+].[S:12]1[C:16]([C:17]2[C:22]([Br:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=2)=[CH:15][C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]1=2>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[S:12]1[C:16]([C:17]2[C:22]([Br:23])=[CH:21][N:20]=[C:19]([O:1][CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][NH:6][C:5]3=[O:9])[N:18]=2)=[CH:15][C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]1=2
Reactant: Clc1ncc(Br)c(-c2cc3ccccc3s2)n1
Reactant: O=C1NCCN1CCO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NCCN1CCOc1ncc(Br)c(-c2cc3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Hydroxyethyl)imidazolidin-2-one (0.6 g, 4.6 mmol) was taken up in anhydrous THF (5 mL) and added dropwise to a reaction flask containing a suspension of sodium hydride (0.147 g (60% in oil), 3.68 mmol) in anhydrous THF (10 mL) at 0° C. The ice bath was removed and the reaction allowed to warm up to room temperature over a 2 h period. 4-(benzo[b]thiophen-2-yl)-5-bromo-2-chloropyrimidine (0.3 g, 9.2 mmol), dissolved in THF was added dropwise. The reaction was stirred overnight. The reaction was then diluted with ethyl acetate and saturated sodium bicarbonate. The organic layer was then washed with water and brine. The organic portion was dried with sodium sulfate and then purified by flash chromatography on silica gel using a gradient of 0 to 10% methanol in dichloromethane to give a white solid. Yield=0.085 g. MS (M+H)+ 420.