Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].O[NH2:4].Cl.C[O:7][C:8](=O)/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[CH:13][CH:12]=1.ON.C(=O)=O>CO>[OH:1][NH:4][C:8](=[O:7])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: NO
Reactant: COC(=O)/C=C/c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: CO
Product: O=C(/C=C/c1ccc(CNCCc2c[nH]c3ccccc23)cc1)NO
Reaction time: 8 h

Procedure:
4-formylcinnamic acid methylester is produced by adding 4-formylcinnamic acid (25 g, 0.143 mol) in MeOH and HCl (6.7 g, 0.18 mol). The resulting suspension is heated to reflux for 3 hours, cooled and evaporated to dryness. The resulting yellow solid is dissolved in EtOAc, the solution washed with saturated NaHCO3, dried (MgSO4) and evaporated to give a pale yellow solid which is used without further purification (25.0 g, 92%). To a solution of tryptamine (16.3 g, 100 mmol) and 4-formylcinnamic acid methylester (19 g, 100 mmol) in dichloroethane, NaBH(OAc)3 (21 g, 100 mmol) is added. After 4 hours the mixture is diluted with 10% K2CO3 solution, the organic phase separated and the aqueous solution extracted with CH2Cl2. The combined organic extracts are dried (Na2SO4), evaporated and the residue purified by flash chromatography to produce 3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (29 g). A solution of KOH (12.9 g 87%, 0.2 mol) in MeOH (100 mL) is added to a solution of HONH2.HCl (13.9 g, 0.2 mol) in MeOH (200 mL) and a precipitate results. After 15 minutes the mixture is filtered, the filter cake washed with MeOH and the filtrate evaporated under vacuum to approximately 75 mL. The mixture is filtered and the volume adjusted to 100 mL with MeOH. The resulting solution 2M HONH2 is stored under N2 at −20° C. for up to 2 weeks. Then 3-(4-{[2-(1H-indol-3-yl)-ethlamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester (2.20 g, 6.50 mmol) is added to 2 M HONH2 in MeOH (30 mL, 60 mmol) followed by a solution of KOH (420 mg, 6.5 mmol) in MeOH (5 mL). After 2 hours dry ice is added to the reaction and the mixture is evaporated to dryness. The residue is dissolved in hot MeOH (20 mL), cooled and stored at −20° C. overnight. The resulting suspension is filtered, the solids washed with ice cold MeOH and dried under vacuum, producing N-Hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 336 [MH+]).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(CC)CC)C>C(Cl)Cl.CCCCCC>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:17]=[C:18]([NH:19][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Nc1cccc(C(F)(F)F)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.0 g. of adamantane carboxylic acid chloride, 1.60 (10 mmoles) of m-trifluoromethylaniline and 5.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from a methylene chloride-hexane mixture to obtain the title product, m.p. 171°-174° C.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2([C:30]#N)[CH2:29][CH2:28][CH2:27]2)=[CH:21][C:20]=1[F:32].C[OH:35].Cl>CN(C=O)C.O>[CH3:16][NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:2](=[S:3])[N:1]([C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=3)[C:30](=[O:35])[C:26]32[CH2:29][CH2:28][CH2:27]3)=[CH:21][C:20]=1[F:32]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Reactant: CO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 80 °C
Yield: 57 %

Procedure:
A mixture of 4-isothiocyanato-2-trifluoromethylbenzonitrile (1a) (2.16 g, 9.47 mmol) and N-methyl-4-(1-cyanocyclobutylamino)-2-fluorobenzamide (52c) (1.303 g, 5.27 mmol) in DMF (20 ml) was heated under microwave irradiation at 80° C. for 16 hours. To this mixture was added methanol (50 ml) and aq. 2N HCl (20 ml). The second mixture was refluxed for 3 hours. After being cooled to room temperature, the reaction mixture was poured into cold water (100 ml) and extracted with ethyl acetate (150 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield N-methyl-4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]-2-fluorobenzamide (52d) [RD162] (1.43 g, 3.0 mmol, 57%), the structure of which is illustrated in Formula 28, as a yellow powder.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[S:12][CH:13]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2Cl)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2cccc(Cl)c2Cl)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(2,3-dichlorophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 25, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12]([O:17][C@@H:18]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]3[OH:20])=[N:13][NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)[CH3:2].[C:29](O)(=[O:31])[CH3:30].C(OC(=O)C)(=O)C>O1CCCC1>[C:29]([N:14]1[C:15]([CH3:16])=[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:12]([O:17][C@@H:18]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]2[OH:20])=[N:13]1)(=[O:31])[CH3:30]
Reactant: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)=O)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole (0.41 g) in tetrahydrofuran (10 mL) were added acetic acid (0.11 mL) and acetic anhydride (0.18 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. The resulting precipitated crystal was collected by filtration to give 1-acetyl-4-[(4-ethylthiophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole (0.36 g).
Reaction SMILES: C([N:4]1[C:12]2[CH:7]([N:8](C(=O)C)[CH:9]([Cl:17])[N:10](C(=O)C)[C:11]=2Cl)[N:6]([C@@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]2[OH:23])[CH2:5]1)(=O)C.[C:30]1([CH:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>COCCOC>[C:39]1([CH:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:37][NH:38][C:11]2[C:12]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[C:9]([Cl:17])[N:10]=2)[C@@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]2[OH:23])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(=O)N1CN([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C2C1=C(Cl)N(C(C)=O)C(Cl)N2C(C)=O
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2.75 g of triacetyl-2,6-dichloro-9-(β-D-ribofuranosyl)purine (M. J. Robins and B. Uznanski Can. J. Chem., 59, 2601 (1981), J. F. Gerster and R. K. Robins, J. Org. Chem., 31, 3258 (1966)), 1.34 g of 2,2-diphenylethylamine and 0.748 g of triethylamine is stirred at room temperature, under a nitrogen atmosphere for four hours in 50 ml of 1,2-dimethoxyethane (distilled over NaH). The precipitate of Et3N+HCl is filtered and the solvent is evaporated from the filtrate to dryness. The residue is dissolved in 50 ml of methanol saturated with ammonia and stirred at room temperature for three hours. The mixture is evaporated to dryness and the residue is purified by medium pressure liquid chromatography on silica gel using 5% methanol in chloroform as the eluent. Evaporation of the solvent from the pure fractions affords a solid material which is crystallized from a mixture of chloroform-2-propanol (10:1) and hexane yielding N6 -(2,2-diphenylethyl)-2-chloroadenosine, mp 120°- 123° C.
Reaction SMILES: C([O:8][C:9](=[O:48])[CH2:10][C@@H:11]([N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[CH:30]1)[C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.C(O)=O>[Pd].CO>[CH:9]([OH:48])=[O:8].[C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:37]2[CH:38]=[CH:39][C:34]([C:31]3[CH:32]=[CH:33][N:29]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:28])[NH:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[CH2:10][C:9]([OH:48])=[O:8])[CH:30]=3)=[CH:35][CH:36]=2)=[CH:45][CH:44]=1)#[N:47]
Reactant: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(=O)Nc1ccncc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 89.9 %

Procedure:
A mixture of palladium on carbon and 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid benzyl ester (72 mg, 0.112 mmol) in MeOH with formic acid afforded 30 mg(49%) of 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid formate salt as a solid, mp 134-6° C. 1H NMR (DMSO-d6): δ 8.39-8.35 (m, 3H), 7.81 (d, 2H, J=5.9 Hz), 7.63 (s, 2H), 7.34-7.23 (m, 4H), 7.28 (d, 2H, J=10.3 Hz), 7.24 (s, 1H), 6.96-6.92 (m, 1H), 6.52 (dddd, 1H, J=1.8, 2.9, 4.8, 7.4 Hz), 5.35-5.29 (m, 1H), 3.39-3.18 (bm, 1H), 3.09-2.91 (bm, 1H), 1.06 (s, 9H). IR (KBr): 2966, 2225, 1719, 1654, 1594, 1560, 1507, 1396, 1196 cm1. HRFABMS: Calculated for C28H31N4O4 (M+H+): 550.2454. Found: 550.2450. Anal. Calculated for C32H31N5O4.1.0HCO2H.2.5CH3OH: C, 63.10; H, 6.41; N, 10.36. Found: C, 63.03, H, 6.75; N. 10.38.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:7]2[CH:19]=[CH:20][C:21](N)=[CH:22][C:6]=2[N:5]=1.COCC1N(S(C2C=CC(C)=CC=2)(=O)=O)C2C=CC([N+]([O-])=O)=CC=2[N:28]=1>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[C:7]2[CH:19]=[C:20]([NH2:28])[CH:21]=[CH:22][C:6]=2[N:5]=1
Reactant: COCc1nc2cc(N)ccc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: COCc1nc2cc([N+](=O)[O-])ccc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: COCc1nc2ccc(N)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h

Procedure:
2-(Methoxymethyl)-1-tosyl-1H-benzo[d]imidazol-5-amine. 2-(Methoxymethyl)-5-nitro-1-tosyl-1H-benzo[d]imidazole (0.9 g, 2.491 mmol) were dissolved in ethanol and purged with nitrogen. Palladium on activated carbon was added (0.530 g, 0.498 mmol), the nitrogen was evacuated and the reaction was stirred under 1 atmosphere of hydrogen for 16 h. The reaction mixture was filtrated through Celite and washed with ethanol. The organic layer was concentrated on a rotary evaporator to dryness to give desired product as purple solid, which was then crystallized from ethyl acetate in hexane to give the desired compound as a white solid (0.7 g, 85% yield). MS (ESI) m/z 332.2 [M+1]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](Cl)=[O:42].C(N(CC)CC)C>CN(C)C=O>[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)=[O:42]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4cccc(Cl)c4)cc3)cc21
Yield: 53.8 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), 3-chlorobenzoylchloride (123 mg), triethylamine (263 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (232 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][N:6]([CH3:8])[CH3:7].Br[C:14]1[CH:23]=[N:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>>[CH3:7][N:6]([CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:2][NH:1][C:20]1[CH:21]=[N:22][CH:23]=[CH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:8]
Reactant: CN(C)Cc1ccccc1CN
Reactant: COC(=O)c1ccncc1Br
Product: COC(=O)c1ccncc1NCc1ccccc1CN(C)C
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from N-[2-(aminomethyl)benzyl]-N,N-dimethylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.88 (d, 1H, J=5.1 Hz), 7.82 (br s, 1H), 7.61 (d, 1H, J=5.1 Hz), 7.20-7.36 (m, 4H), 4.68 (d, 2H, J=5.8 Hz), 3.87 (s, 3H), 3.46 (s, 2H), 2.22 (s, 6H). [M+H] calc'd for C17H21N3O2, 300. Found 300.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[F:10].[C-:11]#[N:12].[Na+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[CH:4][C:3]=1[F:10]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1
Yield: 56.5 %

Procedure:
A solution of 4-bromo-3-fluorobenzyl bromide (27 g, 0.1 moles) in ethanol (200 ml) is mixed with NaCN (5.4 g, 0.11 moles) and refluxed for 3 hours. The mixture is concentrated under vacuum; the resulting residue is taken up with water and then extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate, and concentrated under vacuum to give a dark oil (12.1 g, 56% yield).
Reaction SMILES: [CH2:1](Cl)CCl.[N:5]1[C:14]2[NH:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:6]=1.C[N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][NH:31][CH3:32].C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC>CN(C=O)C>[CH3:32][N:31]([CH:30]([CH3:1])[C:22]1[NH:21][C:29]2[C:24]([CH:23]=1)=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17](=[O:19])/[CH:16]=[CH:15]/[C:7]1[CH:6]=[N:5][C:14]2[NH:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCCN2
Reactant: CNCc1cc2ccccc2n1C
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(c1cc2ccccc2[nH]1)N(C)C(=O)/C=C/c1cnc2c(c1)CCCN2
Yield: 70 %

Procedure:
EDC (203 mg, 1.06 mmole) was added to a solution (E)-3-(5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (180 mg, 0.88 mmole), 1-methyl-2-(methylaminomethyl)-1H-indole (185 mg, 1.06 mmole), HOBt.H2O (143 mg, 1.06 mmole), and Et3N (0.31 mL, 2.2 mmole) in dry DMF (5 mL) at RT. After. 18 hr the mixture was concentrated. Flash chromatography on silica gel (10% EtOH/EtOAc) gave the title compound (222 mg, 70%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.99-6.82 (m, 8H), 6.40 (s, 1H), 4.82 (s, 2H), 3.67 (m, 2H), 3.29 (m, 3H), 3.07 (m, 3H), 2.73 (m, 2H), 1.77 (m, 2H); for minor rotomer δ 6.16 (s, 1H), 5.00 (s, 2H); MS (ES) m/e 361 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:26][C@H:25]1/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:23])([CH3:20])([CH3:19])[CH3:18].FC(F)(F)C(O)=O.C(Cl)Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32])[CH2:26][C@H:25]1[CH:37]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH:38]1[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (40.2 g, 135.6 mmol, purity: 80%) was added to a solution of ethyl (E)-3-[(2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]acrylate (37.4 g, 93.5 mmol, compound of Reference Example 1-4 of U.S. patent application Ser. No. 07/674,971) in methylene chloride (190 ml) in a nitrogen stream, and a 1M trifluoroacetic acid-methylene chloride solution (9.35 ml, 9.35 mmol) was dropwise added under cooling with ice. The reaction solution was stirred at room temperature for 1.5 hours, and poured into a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed sequentially with water, a 10% citric acid aqueous solution, water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a (2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-benzyl-3-ethoxycarbonylpyrrolidin-4-yl)pyrrolidine diastereomer mixture (50.2 g, yield: 100%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)(=[O:21])[CH3:20]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:16]([O:17][CH2:26][CH2:25][CH2:24][CH2:23][O:22][C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(O)c2cccc(O)c2oc1=O
Reactant: CC(=O)OCCCCBr
Product: CCCCOc1c(O)c2cccc(OCCCCOC(C)=O)c2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-butoxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 4-bromobutyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-butoxy-4-hydroxy-8-(4-acetoxybutoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CO)cc1NC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(COS(C)(=O)=O)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-acetylamino-4-hydroxymethyl-benzoic acid methyl ester (4 g, 17.9 mmol) and Et3N (7.5 mL, 3.0 equiv) in DCM (100 mL) at 0° C. was added MsCl (2.1 mL, 1.5 equiv) dropwise. At the end of the addition, the mixture was stirred 1 h at 0° C. The organic phase was washed with a saturated solution of NaHCO3 and then dried (Na2SO4). The solution was concentrated in vacuo to afford the title compound as a brown paste (5.4 g, 100%) (ES-MS: m/z 302.2 [M+H]+, rt 4.58 min).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[NH2:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH2:8][CH2:7][C:6]([NH:10][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCC(=O)CC1
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=CNC1=CCC(CC)CC1)C(=O)OCC

Procedure:
A mixture of 12.6 g of 4-ethylcyclohexanone, 17.0 g of diethyl aminomethylenemalonate, and 950 mg of p-toluenesulfonic acid in 170 ml of toluene is heated at reflux for 48 hours with a water separator, under nitrogen atmosphere. The solvent is removed under nitrogen atmosphere and under vacuum, and the residue purified by flash column chromatography on a silica gel column eluted with methylene chloride. The desired product, diethyl N-(4-ethylcyclohexen-1-yl)-aminomethylenemalonate is obtained as an oil. The purified product in 90 ml Dowtherm is aded to 300 ml Dowtherm preheated to 250° under nitrogen atmosphere. After heating at 240°-245° for 4 hours the reaction mixture is cooled and allowed to stand at room temperature overnight. The precipitate which formed is filtered off, washed with hexane and air-dried. Recrystallization form isopropanol after treatment with decolorizing carbon affords ethyl 4-hydroxy-6-ethyl-5,6,7,8-tetrahydroquinoline-3-carboxylate m.p. 218°-220°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[OH-].[Na+]>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[C:14]([CH3:13])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Yield: 92 %

Procedure:
A solution of commercially available 2,4,5-trifluoro-nitrobenzene (25a) (5.0 mL, 43.5 mmol), diethyl methylmalonate (6.2 mL, 36.1 mmol), and sodium hydroxide (1.57 g, 39.1 mmol) in DMF (55 mL) was allowed to react in the same manner as in (a) in Production Example 1. The crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (10:1) solution to give 11.0 g (76%) of compound (26a) of interest as clear brown oil.
Reaction SMILES: [CH:1](=[C:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH2:2]C.[Na].[C:11](OC)(=O)[CH2:12]C(C)=O>CO>[CH2:11]=[CH:12][C:5](=[O:9])[CH2:6][CH2:7][CH2:8][CH2:4][CH2:1][CH3:2]
Reactant: CCC=C1CCCC1=O
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Solvent: CO
Product: C=CC(=O)CCCCCC

Procedure:
The procedure of Example 1 is repeated with 19.5 g (0.16 mol) of propylidene cyclopentanone, 0.46 g (0.02 g-atom) of sodium, 21 g (0.18 mol) of methyl acetoacetate and 100 ml of methanol. Fractional distillation yields 14 g (bp 95°-102° C. at 0.5 mm) of 5-ethylbicyclo [4.3.0.] non-1-en-3-one having the structure: ##STR8##