Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].[ClH:17]>C(OCC)(=O)C.CCOCC>[NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].[ClH:17]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1.6 g (7 mmoles) of BOC-HPro-NH2 are dissolved in 10 ml of warm ethyl acetate. The solution is cooled to room temperature, and 10 ml of a 6 n hydrochloric acid solution in ethyl acetate are added. The reaction mixture is allowed to stand for one hour, thereafter it is diluted with ether, the separated precipitate is triturated and filtered off. 1.05 g (91%) of H-HPro-NH2.HCl are obtained; m.p.: 178°-180° C., Rf6 =0.32, [α]D25 =+26.2° (c=1%, in methanol).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[OH:12][C:7]1([CH2:16][N+:13]([O-:15])=[O:14])[C:6]2[C:10](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]1=[O:11]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2c(I)cccc2C1=O
Solvent: O
Product: O=C1Nc2c(I)cccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
7-iodoisatin (0.136 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1>>[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: c1ccc2c(c1)CCNC2
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1N1CCc2ccccc2C1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([C:21](O)=[O:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[C:28]1([NH:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)C(C)C)C>>[C:28]1([N:34]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:21]([C:15]2[CH:14]=[C:13]3[C:18]([CH:19]=[N:20][C:11]([CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[O:22])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)CCNc1ccccc1
Reactant: N#Cc1ccc(CCc2ncc3ccc(C(=O)O)cc3n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COC(=O)CCN(C(=O)c1ccc2cnc(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.4 g (1.3 mmol) of 2-[2-(4-cyanophenyl)ethyl]quinazoline-7-carboxylic acid and 5 mL of thionyl chloride were stirred for 60 minutes at 50° C. Then the thionyl chloride was distilled off, the residue was dissolved in methylene chloride, mixed with 0.24 g (1.3 mmol) of methyl 3-(N-phenylamino)propionate and 0.22 mL of (1.3 mmol) of N-ethyldiisopropylamine and stirred for 18 hours at ambient temperature. After evaporation of the solvent in vacuo, the residue was chromatographed on silica gel and eluted with methylene chloride containing 1% methanol. Yield: 230 mg (37% of theory); Rf value: 0.64 (silica gel, methylene chloride/methanol=9:1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9]C)=O)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:13]I.[BH4-].[Na+]>O1CCCC1.CO>[OH:9][CH2:7][C@H:5]1[N:6]([CH3:13])[C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: CI
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)CC[C@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of (S)-methyl 5-oxo-pyrrolidine-2-carboxylate (Aldrich, 2.86 g, 20 mmol) in tetrahydrofuran (50 mL) at 0° C. was added in portions 60% oil dispersion NaH (720 mg, 30 mmol). Methyl iodide (1.88 mL, 30 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was concentrated under reduced pressure and residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was redissolved in anhydrous tetrahydrofuran (50 mL), sodium borohydride (946 mg, 25 mmol) was added followed by dropwise addition (˜20 min) of methanol (20 mL) at 50° C. The reaction mixture was stirred for an additional 1 h at a range from 45° C. to 50° C., then cooled to room temperature and concentrated under reduced pressure. Citric acid (10%) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, ethyl acetate-ethanol 4:1) to afford 1.3 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.77 (m 1H), 1.95 (m, 1H), 2.18 (m, 2H), 2.69 (s, 3H), 3.43 (m, 2H), 3.55 (m, 1H), 4.77 (t, J=6 Hz, 1H); MS (DCI/NH3) m/z 130 (M+H)+, 147 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[CH:12][C:3]=12.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:11]=[CH:12][C:3]=12
Reactant: CSc1nc(Cl)c2cn[nH]c2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2cnn(COCC[Si](C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.7 %

Procedure:
4-Chloro-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (497 mg, 2.477 mmol) was dissolved in 5 mL dry DMF, and the reaction mixture was cooled to 0° C. Sodium hydride (109 mg of 60% suspension in mineral oil) was added, and the reaction mixture was stirred for five minutes. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.52 mL, 2.922 mmol) was then aded, and the reaction mixture was stirred for 10 minutes. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography using 5% EtOAc in hexanes to give 391 mg of 4-Chloro-6-methylsulfanyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[NH4+:28]>CO.C(OCC)(=O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Yield: 26 %

Procedure:
A solution of the 9-[(phenyl)methyl]-4-hydroxy-5-Carbomethoxy carbazole (200 mg, 0.6 mM) in 4 mL MeOH and 40 mL concentrated aqueous ammonium hydroxide was sonicated for 30 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 50 mg (26%) of the 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=1 and 8 Hz), 7.5-7.1 (m, 9H), 6.6 (d, 1H, J=8 Hz), and 5.8 (s, 2H). IR (KBr, cm−1) 3428, 3198, 3063, 1631, 1599, 1579, 1562, 1496, 1442, 1330, 1261, 1215, 775, and 697. MS (ES) m/e 315, 317.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:29].[Na+]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[Si:11]([O:10][C@@H:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([CH2:1][CH:2]=[O:29])[CH2:5]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@H]1CCC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](O[C@@H]1CCC[C@H](CC=O)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenylsilane are dissolved in 100 ml of diethyl ether, and 9.4 g of sodium periodate, dissolved in 100 ml of water, are added. At 0° C., 15 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 5 hours, a further 5 g of sodium periodate are added, and the mixture is stirred at room temperature for another 3 hours. The reaction mixture is then diluted by addition of 300 ml of methyl tert-buthyl ether and washed with saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 6 g of [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde as a yellow-brown oil. C24H32O2Si (380.61), MS(ESI): 381 (M+H+), Rf(n-heptane:ethyl acetate=5:1)=0.44.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>CN(C=O)C>[CH3:14][N:15]([CH:17]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3])[CH3:16]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C=CN(C)C)cc1OC
Temperature: 150 °C
Reaction time: 35 h
Yield: 77.4 %

Procedure:
A mixture of 3,4-dimethoxy acetophenone 11 (5 g, 27.47 mmol) and DMF-DMA (3.9 g, 111.1 mmol) in DMF (10 mL) was heated to 150° C. under an atmosphere of N2. After stirring for 35 h 150° C., the reaction mixture was concentrated in vacuo. The resulting residue was triturated with diethylether and dried under high vacuum to afford compound 12 (5.0 g, 77%) as a yellow solid. TLC Rf=0.5 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 7.8 (d, J=12.2 Hz, 1H), 7.56-7.51 (m, 3H), 6.86 (d, J=8.1 Hz, 1H), 5.71 (d, J=12.2 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.03 (br, 6H); MS (ES) m/z 236 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].OS(O)(=O)=O>>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccc(Br)cc1C(=O)O
Temperature: 100 °C
Yield: 93.3 %

Procedure:
To a mixture of 2-hydroxy-5-bromo-benzoic acid (5.0 g, 23.0 mmol) in acetic anhydride (7.1 mL, 75.4 mmol) was added conc. H2SO4 (0.35 mL) at rt. Resulting suspension was heated in a 100° C. oil bath for 25 min. After cooled to about 50° C., the reaction mixture was poured onto ice (100 g) with stirring. The precipitated product was collected, rinsed with water, and dried in vacuo to give the title compound (5.56 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=8.21 (d, J=2.3 Hz, 1H), 7.71 (dd, J=8.6, 2.3 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 2.34 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Reactant: CCc1ccc(O)c(Oc2ccccc2)c1
Product: CCc1ccc(Oc2cc(F)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(Oc2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethyl-2-phenoxy-phenol as in Example 18 to afford 0.139 g (52%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C30H27O5F 487.1921, found 487.1906.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CC1(CC2)OCCO1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Yield: 40.2 %

Procedure:
A solution of 7'-bromo-3',4'-dihydrospiro[1,3-dioxolane-2,2'(1H)-naphthalene] (3.40 g, 12.6 mmol), trimethylsilylacetylene (7.0 ml, 50 mmol) (Aldrich), triphenylphosphine (0.66 g, 2.50 mmol), and palladium acetate (0.28 g, 1.25 mmol) in triethylamine (18 ml) was stirred at 70° C. for 18 hours and then concentrated in vacuo. The residue was absorbed onto silica gel from a diethyl ether solution and partially purified by elution through silica gel (15 g) with diethyl ether: hexane (1:9). Further purification by chromatography on silica gel eluting with ethyl acetate:hexane (1:19) gave 3',4'-dihydro-7'[2-(trimethylsilyl)ethynyl]spiro[1,3-dioxolane-2,2'(1'H)-naphthalene] (1.45 g). 1H NMR (CDCl3 200 MHz) δ: 0.23 (s, 9H, SiMe3), 1.93 (t, J=7 Hz, 2 CH2), 2.95 (t, J=7 Hz, 2H, CH2), 4.02 (s, 4H, OCH2CH2O), 7.03 (d, J=8 Hz, 1H, Ar), 7.17 (s, 1H, Ar), 7.21 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1([CH3:26])[C:18](=[O:19])[N:17]([CH2:20][CH2:21][C:22]([OH:24])=O)[C:16](=[O:25])[NH:15]1.[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH2:31]>O1CCCC1>[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH:31][C:22](=[O:24])[CH2:21][CH2:20][N:17]1[C:18](=[O:19])[C:14]([CH3:13])([CH3:26])[NH:15][C:16]1=[O:25]
Reactant: COC(CN)OC
Reactant: CC1(C)NC(=O)N(CCC(=O)O)C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(CNC(=O)CCN1C(=O)NC(C)(C)C1=O)OC
Yield: 53.7 %

Procedure:
Analogously to Example 1, 165.43 g (1.02 mol) of 1,1'-carbonyldiimidazole and 700 ml of tetrahydrofuran are introduced into an apparatus, allowed to react with 202.86 g (1.0 mol) of 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)propionic acid and subsequently reacted with 107.21 g (1.02 mol) of 2-aminoacetaldehyde dimethyl acetal. The reaction mixture is evaporated to dryness at 80° C./0.1 mbar in a rotary evaporator, and the resultant residue is purified analogously to Example 1, giving 154.2 g (54.2% of theory) of N-(2,2-dimethoxyethyl)-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)propionamide, which melts at 123° C.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11])=[O:4].[NH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][CH3:25]>C(OCC)(=O)C>[C:13]([C:7]1[S:6][C:5]([C:3]([NH:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH2:24][CH3:25])=[O:4])=[C:9]([O:10][CH3:11])[C:8]=1[CH3:12])([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1sc(C(=O)OC)c(OC)c1C
Reactant: CCN1CCCC1CN
Solvent: CCOC(C)=O
Product: CCN1CCCC1CNC(=O)c1sc(C(=O)OC)c(C)c1OC

Procedure:
The above compound was prepared by heating dimethyl-3-methoxy-4-methyl-2,5-thiophene dicarboxylate and (±)2-(aminomethyl)-1-ethyl-pyrrolidine at 170° under nitrogen atmosphere. After column chromatography, the title compound was obtained, as its fumarate salt, m.p. 155°-156° ex ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH3:2].[F:13][C:14]([F:30])([F:29])[C:15]1[CH:16]=[C:17]([S:25](Cl)(=[O:27])=[O:26])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:12][S:25]([C:17]2[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:15]([C:14]([F:13])([F:29])[F:30])[CH:16]=2)(=[O:27])=[O:26])=[N:9][C:10]=1[CH3:11])[CH3:2]
Reactant: CCOCc1ccc(N)nc1C
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOCc1ccc(NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-ethoxymethyl-6-methyl-pyridin-2-ylamine (0.07 g) and 3,5-di(trifluoromethyl)-benzenesulfonyl chloride (0.145 g) as an off-white solid (0.032 g). MS (ESI−): 441.1 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:13][C:12](=[O:14])[C:11]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][N:9]=5)[CH:4]=[CH:3][C:2]=4[N:1]=3)=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc2cccnc2c1C(=O)O
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cccnc3c12
Temperature: 0 °C
Reaction time: 48 h
Yield: 15.2 %

Procedure:
To a suspension of 500 mg (2.66 mmol) of 7-amino-quinoline-8-carboxylic acid in 20 mL of anhydrous tetrahydrofuran at 10° C., is added 775 mg (2.66 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 1.07 mL (13.28 mmol) of pyridine. Then the suspension is cooled to 0° C. and 830 μL (10.63 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is precipitated with a minimum of water. The filtration gave 180 mg of product after drying on high vacuum pump. The filtrate is evaporated and the residue obtained is purified by flash chromatography to afford 100 mg more of product as a solid. The overall yield is 24%; LC/MS:444/446 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[Br:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH2:22]Br>>[Br:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:21]=1[CH2:22][N:3]1[C@@H:2]([CH3:1])[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4]1=[O:13]
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: [Li]CCCC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (0.386 g, 2.13 mmol) in THY (7 mL) at −78° C. under N2 was added n-butyllithium (2.5M in hexanes; 0.94 mL, 2.35 mmol), and the mixture was stirred at −78° C. for 30 minutes. 2-Bromo-5-(trifluoromethyl)benzyl bromide (0.678 g, 2.13 mmol) was added, and the reaction was warmed to room temperature and stirred overnight. Once no starting material was seen by analytical LCMS, the mixture was transferred to a separatory funnel and partitioned between EtOAc and H2O. The organic layer was separated and washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]=[C:16]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][N:17]1[CH2:33][C:34](O)=[O:35].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:7]([NH:8][C:34](=[O:35])[CH2:33][N:17]1[CH2:18][CH2:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]1=[O:15])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diphenylmethanamine (0.18 g, 1.00 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.96 (d, J=8.5 Hz, 1H), 7.21-7.37 (m, 20H), 6.13 (d, J=8.4 Hz, 1H), 4.08 (s, 2H), 3.37 (t, J=6.5 Hz, 2H), 2.71 (t, J=6.4 Hz, 2H); MS (DCI+) m/z 461 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:19])([CH3:18])[C:15](Br)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:19])([CH3:18])[C:15]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(Br)ccc32)C=C1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(Br)ccc32)C=C1N1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of (3E)-6-bromo-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one (2.3 g, 6.0 mmol) and morpholine (1.0 mL, 11.4 mmol) in 10 mL of DMF was heated in 96 C bath for 3 hours. The mixture was cooled to room temperature and poured into 200 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give (3E)-6-bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 2.1 g, 89%.
Reaction SMILES: [NH:1]([CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[NH2:2].[N:18]1[CH:23]=NC=N[CH:19]=1>C(O)C.C(OC)(C)(C)C>[CH3:17][N:15]([CH2:14][CH2:13][C:7]1[C:6]2[CH:5]=[C:4]([CH2:3][N:1]3[N:2]=[CH:23][N:18]=[CH:19]3)[CH:12]=[CH:11][C:10]=2[NH:9][CH:8]=1)[CH3:16]
Reactant: c1ncncn1
Reactant: CN(C)CCc1c[nH]c2ccc(CNN)cc12
Solvent: CCO
Solvent: COC(C)(C)C
Product: CN(C)CCc1c[nH]c2ccc(Cn3cncn3)cc12
Yield: 157.2 %

Procedure:
A solution of [2-(5-Hydrazinomethyl-1H-indol-3-yl)-ethyl]-dimethyl-amine (3.1 g, 85% purity, 11.9 mmol) and 1,3,5-triazine (0.69 g, 8.5 mmol) in ethanol (50 ml) is refluxed over night. The solution is then diluted with tert-butyl methylether (TBME), and the precipitated ammonium salts are filtered off. Removal of the solvent on the rotavapor produces 3.6 g of an oil which is chromatographed on silica (CH2Cl2: MeOH:NH4OH 98:2:1 to 95:5:1 v:v:v) to give 1.75 g (55%) of the product, dimethyl-[2-(5-[1,2,4]triazol-1-ylmethyl-1H-indol-3-yl)-ethyl]amine (Rizatriptan). HPLC retention time: 4.0 min.