Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:31])[C:9](=O)[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[C:23]([CH2:28][CH3:29])=[N:24][O:25][C:26]=1[CH3:27])=[O:11]>O1CCCC1.C(OCC)C>[CH3:31][N:8]([CH2:9][CH:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[C:23]([CH2:28][CH3:29])=[N:24][O:25][C:26]=1[CH3:27])[OH:11])[CH3:7]
Reactant: CCc1noc(C)c1-c1c(C(=O)C(=O)N(C)C)c2ccccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1noc(C)c1-c1c(C(O)CN(C)C)c2ccccc2n1C

Procedure:
A suspension of 9.24 g (0.243 mole) of lithium aluminum hydride and 500 ml tetrahydrofuran under nitrogen is heated to reflux and is treated by rapid addition with 18.47 g (0.054 mole) of N,N,1-trimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylamide in 350 ml of tetrahydrofuran. The resulting mixture is heated an additional 15 minutes, cooled, diluted with 350 ml of diethylether and is quenched by the dropwise addition of 60 ml of saturated magnesium sulfate solution. The mixture is then filtered through celite and the filter cake is washed with tetrahydrofuran methylene chloride and methanol. The filtrate is evaporated in vacuo and the residue chromatographed on silica gel using acetone as an eluant to give α-(dimethylaminomethyl)-2-(3-ethyl-5-methyl-4-isoxazolyl)-1-methyl-indole-3-methanol m.p. 119° to 121° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:29]1[C:33]([C:34]([Cl:36])=[O:35])=[CH:32][CH:31]=[N:30]1>>[ClH:36].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:4]=[C:3]([NH:2][C:34]([C:33]5[O:29][N:30]=[CH:31][CH:32]=5)=[O:35])[CH:8]=[CH:7][CH:6]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: O=C(Cl)c1ccno1
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: O=C(Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1)c1ccno1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 31.8 mg (0.24 mmol) of isoxazole-5-carbonyl chloride are reacted together by general method F. 44.4 mg (72.6% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[C:2]=[S:3].[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.CC1C=CC=CC=1>[CH3:15][N:16]([C:2]([NH:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)N1CCC(N=C=S)CC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(NC(=S)N(C)c2ccccc2)CC1
Yield: 42 %

Procedure:
A mixture of 107 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate, 53.5 parts of N-methylbenzenamine, 1 part of N,N-dimethyl-4-pyridinamine and 450 parts of methylbenzene was stirred and refluxed overnight. After cooling, the reaction mixture was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 68 parts (42%) of ethyl 4-[[(methylphenylamino)thioxomethyl]amino]-1-piperidinecarboxylate; mp. 95.2° C. (14).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]([F:22])([F:21])[F:20])=[CH:11][C:5]=2[N:4]=1.[NH2:25][C:26]1([CH2:32][OH:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>O1CCOCC1>[F:20][C:19]([F:22])([F:21])[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3]([C:2]3[O:33][CH2:32][C:26]4([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[N:25]=3)=[N:4][C:5]=2[CH:11]=1
Reactant: NC1(CO)CCCCC1
Reactant: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C3=NC4(CCCCC4)CO3)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
2-Trichloromethyl-5-(2-trifluoromethoxy-phenyl)-1H-benzimidazole (241 mg, 0.610 mmol, as prepared in step B of this Example) and (1-amino-cyclohexyl)-methanol (315 mg, 2.44 mmol, as prepared in the previous step) were placed in a 40 mL vial equipped with a magnetic stir bar. Water (8 mL) was added, and the mixture was cooled to 0° C. and stirred at that temperature for 1 h. Complete dissolution of starting materials did not occur, so the mixture was warmed to rt, treated with dioxane (8 mL), and stirred at rt for 14 h. The mixture was extracted three times with EtOAc (20 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography using a 12-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 2:5, v/v over 30 min. The column was repeated under these conditions, yielding 24.6 mg (10%) of the desired compound. 1H-NMR (400 MHz, d6-DMSO) δ: 7.78 (br. s., 1H), 7.46-7.64 (m, 5H), 7.27-7.46 (m, 1H), 4.27 (s, 2H), 1.60-1.82 (m, 6H), 1.47-1.58 (m, 1H), 1.33-1.46 (m, 3H).
Reaction SMILES: Cl[SiH:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[CH:10]([CH3:12])[CH3:11].[CH:13]([NH2:16])([CH3:15])[CH3:14]>CCCCCC>[CH:10]([N:3]1[CH:4]=[CH:5][N:6]([CH:7]([CH3:9])[CH3:8])[SiH:2]1[NH:16][CH:13]([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)N1C=CN(C(C)C)[SiH]1Cl
Reactant: CC(C)N
Solvent: CCCCCC
Product: CC(C)N[SiH]1N(C(C)C)C=CN1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
In an argon atmosphere, 4.24 g (20.7 mmol) of Si(iPrNCHCHNiPr)(H)Cl was dissolved in 20 mL of hexane and after adding 2.51 g (42.4 mmol) of isopropylamine, the mixture was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 75° C./3.7×102 Pa) to obtain 1,3-diisopropyl-2-isopropylamino-1,3-diaza-2-silacyclopent-4-ene (Si(iPrNCHCHNiPr)(H)NHiPr) as a colorless liquid (yielded amount: 4.10 g, yield: 87%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][C:5]1[C:13]2[C:12]([OH:14])=[CH:11][C:10]([F:15])=[CH:9][C:8]=2[N:7]([CH2:16][CH3:17])[CH:6]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[CH2:16]([N:7]1[C:8]2[C:13](=[C:12]([O:14][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=[C:10]([F:15])[CH:9]=2)[C:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])=[CH:6]1)[CH3:17]
Reactant: CCn1cc(CCN(C)C)c2c(O)cc(F)cc21
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1cc(CCN(C)C)c2c(Oc3ccccc3)cc(F)cc21
Temperature: 25 °C
Yield: 2.9 %

Procedure:
A mixture of 1-9b (80 mg, 0.32 mmol), bromobenzene (100 mg, 0.64 mmol), K2CO3 (110 mg, 0.8 mmol) and CuI (152 mg, 0.8 mmol) in 10 mL of dioxane was stirred at reflux overnight. After cooled to room temperature, the volatiles were evaporated under vacuum and the resulting residue was partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×15 mL). The organic layers were combined, washed with brine (2×30 mL), dried over MgSO4 and evaporated. The resulting brown residue was purified by preparative HPLC (acid condition, water/CH3CN, 25-30% CH3CN in 7.5 min, RT=6.5 min) to give 32-2 (3 mg, 3%) as a white solid. 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.34 (t, J=8.0 Hz, 2H), 7.13-7.09 (m, 2H), 7.02 (d, J=8.0 Hz, 2H), 6.85 (d, J=11.2 Hz, 1H), 6.10 (d, J=11.2 Hz 1H), 4.05 (q, 2H), 3.33-3.28 (m, 2H), 3.11-3.07 (m, 2H), 2.74 (s, 6H), 1.33 (t, J=7.2 Hz, 3H). LRMS: calc 326.2 and found: 327.1 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][N:25]=1.[F-].[Cs+]>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]([C:12]([NH:14][CH:15]3[CH2:16][CH2:17][N:18]([C:24]4[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][N:25]=4)[CH2:19][CH2:20]3)=[O:13])=[CH:21][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCNCC1)c1ccc(-c2cccc(F)c2)nc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)nc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Temperature: 100 °C
Yield: 97 %

Procedure:
To a microwave tube was added 6-(3-fluorophenyl)-N-(piperidin-4-yl)nicotinamide (2.2 g, 7.35 mmol, tert-butyl 6-bromonicotinate (2.85 g, 11 mmol), DMA (5 mL), CsF(6.70 g, 44.1 mmol) and TEA (5 drops). After heating the reaction mixture on CEM microwave at fullpower (100° C. for 45 min), the solution was extracted with ethyl acetate and washed with water. The solvent was removed and the residue purified by chromatography (silica, 50% EtOAc: Hep) to give the desired product, tert-butyl 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinate (3.39 g, 97%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.06 (1H, d, J=1.1 Hz), 8.58 (1H, d, J=1.6 Hz), 8.47 (1H, d, J=7.9 Hz), 8.27 (1H, d, J=8.4 Hz), 8.10 (1H, d, J=8.2 Hz), 7.98 (1H, d, J=8.4 Hz), 7.93 (1H, d, J=10.8 Hz), 7.86 (1H, d, J=9.1 Hz), 7.54 (1H, q), 7.29 (1H, t, J=8.6 Hz), 6.88 (1H, d, J=9.1 Hz), 4.41 (2H, d, J=13.5 Hz, 4.15 (1H, d, J=4.8 Hz), 3.10 (2H, t, J=12.3 Hz), 2.48 (2H, br. s.), 1.91 (2H, d, J=13.4 Hz), 1.50 (9H, s), HRMS (TOF, ES+) calculated 477.2302; observed 477.2515.
Reaction SMILES: [CH2:1]([C@H:7]1[C@@H:12]([OH:13])[CH2:11][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:26]([Si:30]([CH3:33])([CH3:32])Cl)([CH3:29])([CH3:28])[CH3:27].CCOCC>CN(C=O)C>[CH2:1]([C@H:7]1[C@@H:12]([O:13][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:33])[CH3:32])[CH2:11][C@@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCC[C@@H]1C[C@H](O)[C@H](CCCCCC)C(=O)O1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)O1
Reaction time: 48 h
Yield: 63.5 %

Procedure:
M)d) 1.5 g of (3S,4S,6R)-tetrahydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one were dissolved in 8 ml of DMF. 0.85 g of t-butyldimethylchlorosilane in 4 ml of DMF were then added dropwise. The mixture was stirred for 48 hours. The reaction mixtures was poured in to 100 ml of ether and washed with 1N hydrochloric acid. The organic phase was dried, filtered and evaporated. The material obtained was chromatographed on silica gel. There was obtained 1.26 g of (3S,4S,6R)-tetrahydro-3-hexyl-4-[(t-butyldimethylsilyl)oxy]-6-undecyl-2H-pyran-2-one, MS: 411 (M+ -t-butyl).
Reaction SMILES: C1(N2C(=O)C3SC=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C1(N)CCCCCCC1>C(O)(=O)C>[CH:10]1([N:9]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[C:24]=3[N:23]=[CH:8]2)[CH2:16][CH2:17][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2C)c1N
Agent: NC1CCCCCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: Cc1ccccc1-c1csc2c(=O)n(C3CCCCCCC3)cnc12
Yield: 60.6 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(o -tolyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1 ml), cyclooctylamine (0.107 ml, 0.77 mmol), and acetic acid (0.1 ml) were used to give 85.4 mg (0.24 mmol, 60.6% yield) of the title compound.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[NH3:11]>>[C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[NH4+:11].[NH4+:11]
Reactant: O=C(O)CCCCC(=O)O
Reactant: N
Product: O=C([O-])CCCCC(=O)[O-]
Product: [NH4+]

Procedure:
Exceptions to this generalization are provided by the reactions of adipic acid with ammonia and with tert.butylamine. When adipic acid is reacted with two or more moles of ammonia, diammonium adipate is obtained in quantitative yield. However, if one reacts adipic acid with one mole of ammonia one can obtain ammonium hydrogen adipate as a pure crystalline salt. When adipic acid is reacted with two or more moles of tert.butylamine, bis-tert.butylammonium adipate is obtained in quantitative yield, but in this case it is not possible to obtain the mono-tert.butylammonium adipate as a pure crystalline compound. When one reacts 0.5 mole of adipic acid with 0.5 mole of tert.butylamine in methanol one obtains first 0.19 mole of the bis-salt, m.p. 185°-187° d. The second crop, 35.4 g, m.p. 91°-135°, might represent 0.17 mole of the crude mono-salt, but on recrystallization to effect purification the only pure compound isolated is the bis-salt. When one reacts 0.50 mole of adipic acid with 0.27 mole of tert.butylamine the product is 61.2 g of salt having m.p. 91°-101°, which cannot be pure mono-salt since this weight of product would represent a yield greater than 100%. Analysis for nitrogen gave 5.52% whereas the pure mono-salt would have 6.76% nitrogen. The product is, therefore, a mixture of mono-salt and adipic acid. Again all attempts to purify this product by crystallization gave only the bis-salt, and it is clear that in this case the bis-salt is so much less soluble than any other possible product that recrystallization always results in its precipitation except when a large excess of adipic acid is present. For a more detailed discussion of the amine salts of dibasic acids, both normal and anomalous, see J. E. Barry, M. Finkelstein and S. D. Ross, J. Org. Chem. 47, 64 (1982).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.CC#N.N1C=CC=CC=1.[C:18]1([O:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[Cl:8][C:4]1[N:3]=[C:2]([NH:1][C:25](=[O:26])[O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Nc1cncc(Cl)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(Nc1cncc(Cl)n1)Oc1ccccc1
Reaction time: 18 h
Yield: 51.9 %

Procedure:
A solution of 2-amino-6-chloropyrazine (2.0 g, 15.44 mmol) in a mix of 1:1 THF:MeCN (20 mL), and pyridine (1.28, 16.2 mmol) was treated dropwise with phenylchloroformate (2.54 g, 16.2 mmol) in THF (10 mL). After stirring for 18 h, the resulting solid was collected and dried to provide the title compound (2 g, 53%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]([NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])=O)=[CH:12][CH:11]=1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]2[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[N:16]=2)=[CH:12][CH:11]=1
Reactant: CC(C)(CO)NC(=O)c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc(OCCCCl)cc2)=N1
Reaction time: 3 h
Yield: 99 %

Procedure:
Thionyl chloride (1.55 g, 13.09 mmol, 1.1 equiv.) is added dropwise to 4-(3-chloropropoxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide ax53 (3.18 g, 11.9 mmol, 1 eq) in dry dichloromethane (100 ml), under a nitrogen atmosphere over 30 min. The solution is then stirred for 3 h. Water and potassium carbonate are finally added and the mixture is stirred until no more bubbles are formed (pH=10). The layers are separated and the dichloromethane layer is washed with brine, dried over sodium sulfate and evaporated under vacuum to give 3.18 g of 2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=1[OH:5].[C:11](O)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].B(F)(F)F.CCOCC.O.O.O.C([O-])(=O)C.[Na+]>ClC(Cl)C.O>[OH:10][C:8]1[CH:9]=[C:3]([O:2][CH3:1])[C:4]([OH:5])=[CH:6][C:7]=1[C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COc1cc(O)ccc1O
Reactant: O=C(O)CCCCC(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: COc1cc(O)c(C(=O)CCCCC(=O)O)cc1O

Procedure:
Seven grams of 2-methoxyhydroquinone and 13.6 g of the monomethyl ester of adipic acid in 60 ml of dichloroethane are mixed under nitrogen in a three-necked flask. Thirteen milliliters of boron trifluoride etherate is run in at room temperature. After five hours of refluxing, the reaction medium is poured into a mixture of 40 g of sodium acetate trihydrate and 100 ml of water. The product is extracted with 500 ml of ethyl acetate, washed, dried, and concentrated under vacuum. The residue is treated with a mixture of 1.4 ml of concentrated sulfuric acid, 14 ml of water, and 40 ml of acetic acid at 80° C. for three hours, then the solution is poured into 100 ml of ice water. The precipitate is filtered, washed several times with 20 ml of water, and dried. The solid is recrystallized from a mixture of ethyl acetate and isopropyl ether, yielding yellow crystals with the following characteristics:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2([C:44]3=[CH:45][C:46]4[O:50][CH2:49][O:48][C:47]=4[CH:51]=[C:43]3[O:42][CH2:41]2)[C:33]1=[O:52].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]3([C:44]4=[CH:45][C:46]5[O:50][CH2:49][O:48][C:47]=5[CH:51]=[C:43]4[O:42][CH2:41]3)[C:33]2=[O:52])=[CH:18][CH:17]=1
Reactant: COc1ccc(COS(=O)(=O)c2ccc(C)cc2)cn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 10.21, and making non-critical variations using (6-methoxypyridin-3-yl)methyl 4-methylbenzenesulfonate to replace 2-bromomethyl-5-(trifluoromethyl)furan, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (45%): 1H NMR (300 MHz, CDCl3) δ 8.19 (d, 1H), 7.59 (dd, 1H), 7.26-7.12 (m, 2H), 7.02 (t, 1H), 6.83 (d, 1H), 6.74 (d, 1H), 6.50 (s, 1H), 6.07 (s, 1H), 5.89-5.82 (m, 2H), 5.00-4.90 (m, 2H), 4.76 (d, 1H), 4.65 (d, 1H), 3.93 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 163.7, 155.9, 149.0, 145.3, 142.4, 141.6, 138.9, 132.2, 129.0, 124.4, 124.1, 123.7, 119.2, 111.7, 109.0, 102.9, 101.5, 93.7, 80.4, 58.2, 53.9, 41.1; MS (ES+) m/z 403.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: OCCCCCCCBr
Reactant: C1=COCCC1
Product: BrCCCCCCCOC1CCCCO1

Procedure:
7-Bromoheptanol will be treated with dihydropyrane in the presence of acid to give 1-O-(tetrahydropyran-2-yl)-7-bromoheptanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:24]([OH:26])=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[C:21]([F:20])=[C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Reactant: CCCCCCOc1ccc(C(=O)O)cc1F
Product: CCCCCCCC(C)C(=O)c1ccc(-c2c(C(=O)O)ccc(OCCCCCC)c2F)cc1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methyloctanoyl) phenol in Example 20 and 3-fluoro-4-hexyloxy benzoic acid was used instead of 3-fluoro-4-heptyloxy benzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.O=S(Cl)[Cl:14].CN(C=O)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:10]=[C:6]([C:7]([Cl:14])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1O

Procedure:
5-Iodosalicylic acid (2.0 g, 7.58 mmol) in toluene was treated with SOCl2 (1.66 mL, 22.7 mmol) and catalytic DMF at reflux for 1 h. The reaction mixture was evaporated to dryness and the acid chloride used in the next step without purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17].O1CCCC1.[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=[O:26].CN>C(N(CC)CC)C>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:5]2[CH2:4][CH2:3][NH:2][C:25](=[O:26])[NH:27][CH3:28]
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)NCCc1c(C(=O)NC)[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To 3-(2-aminoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide hydrochloride (167 mg) were added tetrahydrofuran (2.00 mL), triethylamine (0.246 mL), and 1,1′-carbonyldiimidazole (143 mg), followed by stirring at room temperature for 15 minutes. Then, methylamine (2 M tetrahydrofuran solution, 1.77 mL) was added thereto, followed by warming to 50° C. and stirring for 1 hour. The reaction mixture was cooled to room temperature, silica gel was added thereto, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 20:1) to obtain 5-methoxy-N-methyl-3-{2-[(methylcarbamoyl)amino]ethyl}-1H-indole-2-carboxamide (144 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([NH2:31])[CH3:30])=[N:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=2)[CH3:30])=[N:27][CH:28]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 7, 0.8 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.4 g) in n-BuOH (10 mL) with diisopropylethylamine (2 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.6 g of desired product. MS (electrospray): 402 (M+1) for C18H20FN7O3. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.3 (s, 1H) 11.0 (s, 1H) 8.80 (m, 1H) 8.50 (m, 1H) 8.15 (m, 1H) 7.80 (m, 1H) 7.30 (m, 1H) 6.20 (d, 1H) 5.80 (m, 1H) 5.35 (m, 1H), 4.60 (m, 1H) 1.50 (d, 3H) 1.20 (d, 6H).