Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([S:9]([C:12]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[C:16](=[CH:17][C:18]([S:27]([N:30]5[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32]([CH3:37])[CH2:31]5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=S)[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH2:3]1.[CH3:39][N:40]([CH2:42][CH2:43][CH2:44][NH2:45])[CH3:41]>N1C=CC=CC=1>[CH3:36][CH:34]1[CH2:33][CH:32]([CH3:37])[CH2:31][N:30]([S:27]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH3:26])[C:23]4[C:14](=[CH:13][C:12]([S:9]([N:4]5[CH2:3][CH:2]([CH3:1])[CH2:7][CH:6]([CH3:8])[CH2:5]5)(=[O:11])=[O:10])=[CH:25][CH:24]=4)[C:15](=[N:45][CH2:44][CH2:43][CH2:42][N:40]([CH3:41])[CH3:39])[C:16]=3[CH:17]=2)(=[O:28])=[O:29])[CH2:35]1
Reactant: CN(C)CCCN
Reactant: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=S)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Solvent: c1ccncc1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=NCCCN(C)C)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
A mixture of 2,7-bis(3,5-dimethylpiperidin-1-ylsulfonyl)-10-methylacridine-9(10H) thione (145 mg, 0.25 mmole), pyridine (5 mL) and dimethylaminopropylamine (0.125 mL, 1 mmole) was stirred at 100° C. for 4 hrs. Solvent was partially evaporated and reaction product was precipitated by addition of methanol. Precipitate was collected by filtration, washed with methanol and dried to give 137 mg (85%) of the title compound. MS 644 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2ccccc2cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c([N+](=O)[O-])cccc2cn1
Reaction time: 0.5 h

Procedure:
3-Methylisoquinoline (2.14 g, 14.9 mmol) was added portionwise to ice-cooled concentrated H2SO4 (10 ml) keeping the internal temperature below 10° C. A nitrating mixture of concentrated H2SO4 (2 ml) and fuming nitric acid (2 ml) was then added dropwise keeping the internal temperature below 15° C. After stirring for 30 minutes, TLC indicated reaction was complete. The acid was neutralized by adding the mixture to an excess of 4N aqueous NaOH (180 ml) with ice-cooling. The mixture was extracted with dicbloromethane (2×150 ml), then dried (Na2SO4) and evaporated to give the crude product (2.69 g) as a yellow solid. Flash column chromatography using as eluant 5% methanol in dicbloromethane gave a pure sample of the title compound (660 mg) and a further sample (1.95 g) containing ca. 10% of the isomer 3-methyl-8-nitroisoquinoline.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[N:32]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[N:32]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Example 6 was prepared from diphenylacetyl chloride and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, 1H, J=8.0 Hz), 7.71–7.63 (m, 3H), 7.42–7.23 (m, 10H), 6.89 (d, 1H, J=7.6 Hz), 4.96 (s, 1H), 3.41 (dd, 2H, J=5.6, 7.6 Hz), 3.00 (d, 2H, J=11.6 Hz), 2.60 (m, 1H), 2.47 (t, 2H, J=6.4 Hz), 2.45 (m, 1H), 2.06–2.01 (m, 2H), 1.89–1.64 (m, 6H), 1.13 (d, 6H, J=6.8 Hz); ESMS m/e: 499.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].CC([O-])(C)C.[K+].[CH3:32][N:33]([CH3:36])[CH:34]=O.S(OC)(OC)(=O)=O.CCOCC>COCCOC>[CH3:1][C:2]1[C:3]([C:21](=[CH:32][N:33]([CH3:36])[CH3:34])[C:22]([O:24][CH3:25])=[O:23])=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1c(C)ncnc1Oc1cccc(-c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: COC(=O)C(=CN(C)C)c1c(C)ncnc1Oc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
Methyl [6-methyl-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate (60 g, 0.18 mol) is added in one portion to a solution of t-BuOK (60 g, 0.53 mol) in 1,2-dimethoxyethane (0.51) at -40° C. After 1 hour dimethylformamide-dimethyl sulfate (1:1 adduct, 120 ml) is added at -50° C. The reaction mixture is allowed to warm to room temperature to give a yellow suspension. Addition of ether, washing repeatedly with brine and drying gives the crude methyl α-[4-methyl-6-(3-phenylphenoxy)-5-pyrimidinyl]-β-dimethylaminoacrylate (67 g, 95%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:47]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:48][CH2:49][NH2:50])[CH2:44][CH2:45][CH3:46]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:50][CH2:49][CH2:48][N:47]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:51][CH2:52][CH2:53][CH3:54])=[O:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCN(CCN)CCCC
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (134 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dibutyl-1,2-ethanediamine (78 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (69 mg, yield 43%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[Cl:20][C:21]1[C:25]([Cl:26])=[C:24]([CH3:27])[NH:23][C:22]=1[C:28](NC1CCN(C2C=C(SCC(NC)=O)C=C(Cl)N=2)CC1)=[O:29]>>[C:18]([C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:28]([C:22]3[NH:23][C:24]([CH3:27])=[C:25]([Cl:26])[C:21]=3[Cl:20])=[O:29])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13])#[N:19]
Reactant: N#Cc1cc(C(N)=O)cc(N2CCC(N)CC2)n1
Reactant: CNC(=O)CSc1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(C#N)n3)CC2)c(Cl)c1Cl

Procedure:
The title compound was synthesised by an analogous method to Example 18 starting from 2-(4-aminopiperidin-1-yl)-6-cyanoisonicotinamide hydrochloride salt (Intermediate 198) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=O)[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:32][NH2:33]>C(O)C>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[N:32][NH2:33])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NN
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: CCO
Product: COc1cc(C(C)=NN)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 381.4 %

Procedure:
A stirred mixture of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone (4.3 g, 10 mmol), prepared as in Example 3 above, hydrazine (0.8 g, 2.5 mmol), and ethanol (40 ml) was refluxed for 16 hours. The cooled solution was concentrated to yield an oily residue. The residue was triturated with water and the resultant solid was collected to afford 4.2 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 -piperidinyl]propoxy]-3-methoxyphenyl]-ethanone hydrazone as a yellow solid. The compound was recrystallized from isopropanol and then from toluene to afford 1.7 g (39%), m.p.=106°-108° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([F:8])([F:19])[F:20])[C:17]1=[S:18])[CH3:2]
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2ccccc2C(F)(F)F)C1=S
Yield: 18.7 %

Procedure:
The tide compound was prepared by the procedure described in Example 4 using 9.2 g of N-ethyl glycine, 10.2 g of 2-(trifluoromethyl)-phenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. The residue was further purified by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (2.7 g), m.p. 82°-85° C. Anal. Calcd. for. C12H11F3N2O S: C, 50.00; H, 3.85; N,9.72. Found: C, 50.00; H, 3.61; N, 9.61. Mass spectrum (EI, M.+) m/z 288.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:11](=[O:20])[C:10]1([CH3:22])[CH3:21])=[O:8].[Cl:27][C:28]1[C:29]([Cl:37])=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1.C1COCC1>C(OCC)(=O)C>[C:23]([C:4]1[S:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[C:11](=[O:20])[C:10]2([CH3:21])[CH3:22])=[O:8])=[C:2]([NH:1][C:35]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[C:29]=2[Cl:37])=[O:36])[CH:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2N)C(C)(C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)c2sc(C(C)(C)C)cc2NC(=O)Nc2cccc(Cl)c2Cl)C(C)(C)C1=O
Temperature: 75 °C
Yield: 66.9 %

Procedure:
A mixture of 4-(4-amino-2-tert-butylthiophene-5-carbonyl)-1-(2-(dimethylamino)ethyl)-3,3-dimethylpiperazin-2-one (0.035 g, 0.092 mmol), dichlorophenyl isocyanate (0.019 g, 0.10 mmol), and THF (2 mL) was heated at 75° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried, the solvent eliminated under vacuum and the crude product was purified by preparative thin layer chromatography (dichloromethane:methanol, 95:5) to afford 0.035 g of 1-(5-tert-butyl-2-(1-(2-(dimethylamino)ethyl)-3,3-dimethyl-2-oxopiperazine-4-carbonyl)thiophen-3-yl)-3-(2,3-dichlorophenyl)urea. 1H NMR (400 MHz, acetone-d6): δ (ppm) 9.57 (bs, 1H); 8.86 (bs, 1H); 8.17 (d, 1H); 7.65 (s, 1H); 7.30 (m, 2H); 3.90 (m, 2H); 3.60 (m, 2H); 3.50 (t, 2H); 2.43 (t, 2H); 2.20 (s, 6H); 1.70 (s, 6H); 1.40 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH3:21])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(C)C2=O)cn1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (50 mg, 0.182 mmol) and cesium carbonate (60 mg, 0.185 mmol) were mixed in DMF (1 mL) for 15 minutes under a nitrogen atmosphere at room temperature. Then, iodomethane (14 mg, 0.185 mmol) was added and the reaction continued to stir for an addition 2 hours. H2O (2 mL) was added and the product was extracted with ethyl acetate (1 mL, 2×). The organic phase was collected and washed with saturated sodium bicarbonate solution (2 ml, 2×), dried, and filtered. Solvent was removed under a stream of nitrogen and then further dried under high vacuum to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methylimidazolidine-2,4-dione as a white solid (42 mg, 80%). Yield: 80%. 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.41 (s, 3H), 3.06 (s, 3H), 3.95 (s, 2H), 5.05 (s, 2H), 7.89 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.58 μM.
Reaction SMILES: O1CCC[CH2:2]1.C[Mg]I.CON(C)[C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.Cl>O>[Cl:21][C:16]1[CH:15]=[C:14]([CH2:13][C:12](=[O:22])[CH3:2])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)Cc1ccc(Cl)c(Cl)c1
Agent: C[Mg]I
Agent: Cl
Solvent: O
Product: CC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran, 75 mL, was cooled to 0° C., and 10.3 mL of methylmagnesium iodide (3.0M in diethyl ether) was added dropwise during a 30 minute period. The reaction mixture was maintained at <2° C. during the addition. Upon completion of addition, 7.0 grams (0.028 mole) of N-methoxy-N-methyl-3,4-dichlorophenylacetamide was added dropwise during a 45 minute period. The reaction mixture temperature was maintained between -2° C. and +2° C. throughout the addition. Upon completion of addition, the reaction mixture was stirred at about 0° C. for 1.5 hours. After this time, 50 mL of aqueous 2N hydrochloric acid was added dropwise to the reaction mixture. The reaction mixture temperature was maintained at <4° C. throughout the addition. The reaction mixture was then taken up in 100 mL of water and extracted with two 150 mL portions of diethyl ether. The combined extracts were washed with 100 mL of an aqueous solution saturated with sodium chloride. The extracts were then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which weighed 6.6 grams. The 6.6 grams isolated here was combined with 3.2 grams of the same material prepared in an analogous manner. The combination was subjected to column chromatography on silica gel. Elution was accomplished using 50% methylene chloride in petroleum ether, then gradually increasing to 75% methylene chloride in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of (3,4-dichlorophenyl)acetone. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)[CH2:3][CH2:2]1.BrCCCCBr.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[C:26]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=4)[CH2:30][CH2:29][N:28]3[C:41]=2[CH3:42])[CH:22]=[CH:23][CH:24]=1>CN(C=O)C>[CH3:40][O:39][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][C:34]=1[O:37][CH3:38])[C:27]1=[C:26]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:18]4[CH2:3][CH2:2][CH2:1][CH2:11]4)[CH:20]=3)=[C:41]([CH3:42])[N:28]1[CH2:29][CH2:30]2
Reactant: CCOC(=O)c1c(-c2cccc(N)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Reactant: C1CCC2=NCCCN2CC1
Solvent: BrCCCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2cccc(N3CCCC3)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Temperature: 120 °C
Reaction time: 20 h

Procedure:
168.5 mg (1.11 mmol) of DBU and 79.9 mg (0.37 mmol) of 1,4-dibromobutane were added to a solution of 150 mg (0.37 mmol) of ethyl 2-(3-aminophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate obtained as described above in 3 mL of DMF. The mixture was stirred at 120° C. for 20 hours, the solvent was evaporated under reduced pressure, and the residue was taken up in an ethyl acetate/water mixture. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with water, dried over Na2SO4 and the solvent was evaporated under reduced pressure. Chromatography on a short silica gel column using a dichloromethane/ethyl acetate 10:1 mixture as eluant, followed by crystallization from diethyl ether gave the title compound.
Reaction SMILES: C12CC1CNC2.C12CC1CNC2C(O)=O.[C@@H:16]1([C:22]([OH:24])=O)[CH2:18][C@@H:17]1[C:19](O)=[O:20].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:22](=[O:24])[CH:16]2[CH:17]([CH2:18]2)[C:19]1=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H]1C[C@H]1C(=O)O
Agent: C1NCC2CC12
Agent: O=C(O)C1NCC2CC21
Product: O=C1C2CC2C(=O)N1Cc1ccccc1

Procedure:
3-Azabicyclo(3.1.0)hexane, a precursor for preparing 3-azabicyclo(3.1.0)hexane-2-carboxylic acid, a plant gametocide, is prepared by (a) treating cis-1,2-cyclopropanedicarboxylic acid with benzylamine, to form 3-(benzyl)-3-azabicyclo(3.1.0)hexane-2,4-dione, (b) selectively reducing the dione to 3-(benzyl)-3-azabicyclo(3.1.0)hexane, and (c) hydrogenolysis of that compound to 3-azabicyclo(3.1.0)hexane.
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2F)=O)[CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.Cl.[CH2:22]([NH:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C(C)=CC=CC=1>[CH2:22]([N:29]1[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([OH:13])[CH:9]=2)[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(c1ccc(O)cc1F)C1CCC1
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Oc1ccc2c(C3CCC3)nn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclobutyl(2-fluoro-4-hydroxyphenyl)methanone (6.967 g) which can be prepared according to the method described in Reference example 9, etc., sodium acetate (14.16 g; manufactured by Kanto Chemical Co., Inc.), and benzylhydrazine-dihydrochloride (10.55 g; manufactured by Sigma-Aldrich Co.) were suspended in xylene (85 mL; manufactured by Wako Pure Chemical Industries, Ltd.). By using a dean-stark apparatus, the mixture was stirred overnight at reflux. After cooling to room temperature, solid obtained after filtering the precipitate was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The organic layer was combined, washed twice with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the title compound was obtained (8.003 g).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8](=[O:11])[C:9]=1[OH:10])(=[O:3])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>O>[C:1]([C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8](=[O:11])[C:9]=1[O:10][CH3:18])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1oc(-c2ccccc2)cc(=O)c1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C(C)=O)oc(-c2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A mixture of 2-acetyl-3-hydroxy-6-phenyl-4H-pyran-4-one (200 mg), potassium carbonate (150 mg), iodomethane (0.0600 mL) and DMF (5.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (90.0 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(N(CC)C(C)C)(C)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C1COCC1>[CH2:34]([S:36]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:38])=[O:37])[CH3:35]
Reactant: CCS(=O)(=O)Cl
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: -78 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
To a stirring suspension of D-phenylalanine (50 g, 300 mmol) in THF (400 mL) was added N,O-bis(trimethylsilyl) acetamide (92 g, 450 mmol). After stirring for 12 h, the solution was cooled to −78° C. and N,N-diisopropylethylamine (58 mL, 330 mmol) was added. To this solution was slowly added ethanesulfonyl chloride (31 mL, 330 mmol) and the cold bath was removed. After stirring for 20 h, the solvents were removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous phase was washed with diethyl ether, acidified with solid citric acid and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 61 g (79%) of a thick colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O>>[CH3:2][C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
nitrating acetanilide using a mixture of nitric acid and sulfuric acid to produce 4-nitroacetanilide and nitrating further using a mixture of nitric acid and sulfuric acid to produce VI;
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=O.[NH2:13][C:14]1[N:23]=[C:22]([C:24]([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[CH2:43][OH:44])[CH:20]=2)[N:15]=1.CN(C)C[CH2:48][OH:49].N12CCCN=C1CCCCC2.Cl.C(=O)(O)[O-]>N1C=CC=CC=1>[CH3:9][N:8]([CH3:1])[CH2:12][CH2:11][C:48]([O:44][CH2:43][C:36]1[CH:37]=[C:38]([F:42])[C:39]([F:41])=[CH:40][C:35]=1[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:13])[N:23]=[C:22]2[C:24]([N:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34]1)=[O:25])=[O:49]
Reactant: CN(C)CCO
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CN(C)CCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
200 mg of 1,1′-carbonyldiimidazole are dissolved in 10 ml of pyridine and cooled to 0° C. A solution of 500 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone dissolved in 10 ml of pyridine is added. The mixture is subsequently stirred at 0° C. for 2 h and at 25° C. for 2 h. 200 mg of 2-(dimethylamino)ethanol and 200 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene are then added, and the mixture is stirred at 25° C. for a further 18 h. The mixture is added to 250 ml of 1 N HCl, neutralised using bicarbonate solution and washed 3 times with 150 ml of dichloromethane each time. The organic phases are washed twice with 50 ml of water each time, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase).