Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: Oc1ccc(S)cc1
Reactant: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[(2-bromo-ethyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03031, 146 mg, 0.50 mmol), 4-hydroxythiophenol (126 mg, 1.0 mmol) and potassium carbonate (138 mg, 1.0 mmol) in DMF (10 mL) was stirred overnight at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was crystallised from methanol. Yield: 116 mg (69%) colourless crystals. 1H-NMR (400 MHz, d6-DMSO) δ=2.99 (t, J=7.0 Hz, 2H), 3.93 (t, J=7.0 Hz, 2H), 6.48 (d,=9.0 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 7.68 (d, J=9.0 Hz, 2H), 8.89 (s, 2H), 9.66 (s, 1H, —OH). 13C-NMR (100 MHz, d6-DMSO) δ=30.62, 53.07, 102.92, 113.36, 116.86, 119.59, 122.71, 134.07, 134.49, 144.07, 151.17, 157.83. LRMS (FAB+): 338.2 (100, [M+H]+). Found: C 60.6, H 4.57, N 20.6%; C17H15N5OS (337.4) requires C 60.52, H 4.48, N 20.76%.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O>[S:21]([O:8][CH2:7][C:3]1([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC1(CO)COC1
Solvent: c1ccncc1
Solvent: O
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Temperature: 0 °C

Procedure:
3-ethyl-3-hydroxymethyloxetane (trade name of product, OXT-101®, manufactured by To a Gosei Co.; 116 g) was added to pyridine (500 mL) and cooled to 0° C. while stirring. p-Toluene sulfonyl chloride (190 g) was added divisionally for several times. After stirring for 5 hours while keeping at 0° C., the reaction mixture was poured to iced water (1 L). It was extracted with diethyl ether (500 mL), the pH was rendered acidic with 3% hydrochloric acid, and extracts were washed with water. Then, the extracts were washed with a saturated solution of sodium carbonate and water successively and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3-[(tosyloxy) methyl]3-ethyloxetane (243 g).
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].[Br-].[N+:7]([C:10]1[CH:35]=[CH:34][CH:33]=[CH:32][C:11]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:9])=[O:8].[OH-].[Na+]>C1C=CC=CC=1>[CH3:4][C:3](=[CH2:5])[CH:2]=[CH:12][C:11]1[CH:32]=[CH:33][CH:34]=[CH:35][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: C=C(C)C=O
Reactant: O=[N+]([O-])c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C=C(C)C=Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.0 ml of methacrolein was dissolved in 100 ml of benzene. Thereto were added 31.5 g of 2-nitro-benzyltriphenylphosphonium bromide and 100 ml of a 5 N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 5 hours. The organic layer was separated and washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene) to obtain 2.7 g of 1-(3-methyl-1,3-butadienyl)-2-nitrobenzene (containing about 2.2 g of o-nitrotoluene) as a light yellow oily material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2O[C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:5][CH:4]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C1(C)C(C)=CC=CC=1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:26]1[C:15](=[O:17])[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[C:11]1[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: CN(C)CCN
Reactant: COc1ccc(CCc2nc3ccccc3c(=O)o2)cc1
Solvent: Cc1ccccc1C
Product: COc1ccc(CCc2nc3ccccc3c(=O)n2CCN(C)C)cc1
Yield: 74 %

Procedure:
A mixture of 295 mg (1 mmol) of 2-{2-(4-methoxyphenyl)ethyl}-4H-3,1-benzoxazin-4-one synthesized in the same manner as in Synthesis example 2 and 88 mg (1 mmol) of 2-dimethylaminoethylamine in xylene (5 ml) was heated under reflux for 2 hours. After the xylene was distilled off under reduced pressure, the crude crystals obtained were purified by silica gel column chromatography (eluent; 3% methanol/methylene chloride) to obtain 260 mg (76%) of 3-(2-dimethylaminoethyl)-2-{2-(4-methoxyphenyl)ethyl}- 4(3H)-quinazolinone.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH:8]=[CH:7]1)C.O.[NH2:15][NH2:16]>C(O)C>[O:12]=[C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])[CH:7]=[CH:8]1
Reactant: CCOC(=O)Cn1ccc(=O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)Cn1ccc(=O)cc1

Procedure:
As described for example 112a, (4-oxo-4H-pyridin-1-yl)-acetic acid ethyl ester (Bambury, Ronald E.; Edwards, Michael Louis; Miller, Laird Foulis. 4-Oxo-1-pyridinylpeniclliin and -cephalosporin derivatives. Ger. Offen. (1975)) in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the title compound was obtained as a yellow solid (yield: 98%). MS: m/e=168.3 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17].[C:18](OCC)(OCC)(OCC)[CH2:19][CH3:20].Cl.N1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:18]1[CH2:19][CH3:20]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCCCCl
Yield: 72.9 %

Procedure:
Using the general method of Example 1 Part D, N4-(4-chlorobutyl)quinoline-3,4-diamine (˜35.75 mmol) was cyclized using triethyl orthopropionate (7.56 g, 42.9 mmol) in the presence of pyridine hydrochloride (0.41 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.5 g of 1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as a white powder.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5](O)=[O:6])=[CH2:3].[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14]>CO>[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][N:14]1[C:5](=[O:6])[CH2:4][CH:2]([C:1]([OH:9])=[O:8])[CH2:3]1
Reactant: CN(C)CCN
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CO
Product: CN(C)CCN1CC(C(=O)O)CC1=O
Temperature: 160 °C
Yield: 56 %

Procedure:
A mixture of commercially available itaconic acid and N,N-dimethylethylenediamine was heated up to 160° C. for about 20-25 minutes. The mixture was allowed to cool to 100° C. and then diluted with MeOH to prevent solidification. The product was obtained in a 56% yield after crystallization from MeOH/EtOAc. 1H-NMR (300 MHz, D2O): δ 2.63 (dd, 1H), 2.80 (dd, 1H), 2.95 (s, 6H), 3.15-3.25 (m, 1H), 3.32-3.44 (m, 1H), 3.44-3.76 (m, 4H), 3.82-3.94 (m, 1H). Retention Time (LC, method: ammonium acetate standard): 0.13 min. MS (M+H+): 201.0.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:47](Cl)(=[O:49])[CH3:48].C(OCC)(=O)C>ClCCCl>[C:47]([N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)Cl
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(=O)N(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 2 h
Yield: 60 %

Procedure:
The product from Example 26D (50 mg, 0.088 mmol) in 1,2-dichloroethane (2 mL) was treated with triethylamine (14 μl, 0.097 mmol) and acetyl chloride (6.3 μl, 0.088 mmol) at ambient temperature. After stirring for two hours, the mixture was treated with ethyl acetate (8 mL), wash with aqueous 10% NaHCO3 (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified on a silica gel cartridge eluting with (chloroform:methanol, 99:1) to provide the title compound (32.1 mg, 60%). 1H NMR (CDCl3) δ 8.78 (d, 2H), 7.83 (d, 2H), 7.32-7.01 (m, 10H), 5.42 (d, 1H), 5.21 (d, 4H), 4.71 (br s, 1H), 4.01 (br s, 1H), 3.85 (m, 2H), 3.35 (m, 1H), 3.22 (dd, 1H), 3.00-2.55 (m, 5H), 1.57 (s, 3H); MS (ESI+) m/z 608 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([C:21](N(OC)C)=[O:22])=[CH:12][C:13]([Cl:20])=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:6]1)(=[O:3])[CH3:2].[CH3:27][Mg]Br>O1CCCC1>[C:21]([C:11]1[C:10]([N:7]2[CH2:8][CH2:9][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]2)=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[C:13]([Cl:20])[CH:12]=1)(=[O:22])[CH3:27]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](NC(C)=O)C1
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a mixture of 8-[(3S)-3-(acetylamino)pyrrolidin-1-yl]-5-chloro-N-methoxy-N-methylquinoline-7-carboxamide (75 mg, 0.20 mmol) in tetrahydrofuran (0.3 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.85 mL, 1.2 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (22 mg, 33%). LCMS calculated for C17H19ClN3O2(M+H)+: m/z=332.1; found: 332.1.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[CH:24][CH:25]=4)[NH:20][C:19]3=S)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-:35].[K+].O.OO>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:35])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=S)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred mixture of 36 parts of 3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-2,3-dihydro-7-nitro-2-thioxo-4(1H)-quinazolinone, 700 parts of a potassium hydroxide solution in ethanol 5% and 150 parts of water were added 500 parts of a hydrogen peroxide solution 3% at room temperature. The whole was stirred overnight at room temperature. The mixture was neutralized with acetic acid. The product was filtered off, washed with water and 2-propanol and stirred in 2,2'-oxybispropane and thrichloromethane. The product was filtered off and dried, yielding 31 parts (88%) of 3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-7-nitro-2,4(1H,3H)-quinazolinedione; mp. 188° C. (24).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[C:40]([O-])(=[O:42])[CH3:41].[Na+].O>CN(C=O)C>[C:40]([O:11][CH2:12][C@H:13]1[O:18][C@@:17]2([C:26]3[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]4[CH:35]=[CH:34][C:31]([CH2:32][CH3:33])=[CH:30][CH:29]=4)[CH:25]=3)[CH2:20][O:19]2)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]1[OH:39])(=[O:42])[CH3:41]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COC(C)=O)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 80 °C
Yield: 38.1 %

Procedure:
To a solution of ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (20 mg, 0.034 mmol) in 1 mL of DMF, was added sodium acetate (36 mg, 0.44 mmol). The solution was warmed to 80° C. and kept at the same temperature overnight. 5 mL of water was added and the solution was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 6 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.37 (s, 1H), 7.19 (s, 1H), 7.11 (s, 4H), 5.12 (d, J=13.0 Hz, 1H), 5.08 (d, J=13.0 Hz, 1H), 4.32 (dd, J=11.6, 2.0 Hz, 1H), 4.17-4.09 (m, 3H), 3.99-3.94 (m, 1H), 3.77-3.68 (m, 2H), 3.43 (dd, J=9.8, 8.6 Hz, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.99 (s, 3H), 1.20 (t, J=7.6 Hz, 3H); MS ESI (m/z) 485 (M+Na)+, calc. 462.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].CS(C)=O.Br[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: ClCCCBr
Reactant: Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: ClCCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A mixture of 4-hydroxyindole (0.100 g, 0.75 mmol, 1.0 eq), powdered potassium hydroxide (0.042 g, 0.75 mmol, 1.0 eq), and DMSO (3 mL) was stirred at room temperature for 1 hour before 1-bromo-3-chloropropane (0.118 g, 0.75 mmol, 1.0 eq) was added. The above mixture was then stirred at room temperature for another 0.5 hour and then 15 mL of water was added to it. The resultant mixture was extracted with ethyl acetate (2×30 mL). The organic layer was collected, combined, washed with water (6×25 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel using hexane/ethyl acetate (95/5) as an eluant to afford 4-(3-chloropropoxy)-1H-indole (0.130 g, yield: 83%).
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].[CH2:5]([N:7]1[C:19]2[CH:18]=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([C:23]([OH:25])=[O:24])[CH:12]=2)[CH3:6].[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][Cl:32])[CH3:27]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CCOCC>[ClH:32].[ClH:32].[CH2:5]([N:7]1[C:19]2[CH:18]=[CH:17][C:16]([C:20]([O:22][CH2:2][CH2:1][CH2:3][N:7]([CH2:8][CH3:9])[CH2:5][CH3:6])=[O:21])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([C:23]([O:25][CH2:31][CH2:30][CH2:29][N:28]([CH2:33][CH3:34])[CH2:26][CH3:27])=[O:24])[CH:12]=2)[CH3:6]
Reactant: CCn1c2ccc(C(=O)O)cc2c2cc(C(=O)O)ccc21
Reactant: CC(C)O
Reactant: CCN(CC)CCCCl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CCOCC
Product: CCN(CC)CCCOC(=O)c1ccc2c(c1)c1cc(C(=O)OCCCN(CC)CC)ccc1n2CC
Product: Cl

Procedure:
To 250 ml. of isopropanol was added 10.0 g. (0.035 mole) of 9-ethylcarbazole-3,6-dicarboxylic acid, 21.2 g. (0.14 mole) of 3-diethylaminopropylchloride and 0.5 ml. of 60% aqueous benzyltrimethylammonium chloride. The solution was heated at reflux for 2 hours with stirring and then allowed to stir overnight at room temperature. Addition of ether to the reaction mixture gave the crystalline product which was recrystallized twice from methanol-acetone, m.p. 233°-234°, λmaxEtOH 252, E1 cm1% 865.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:4])=[O:3].C([Li])CCC.[CH3:35][OH:36]>>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([O:36][CH3:35])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:4])=[O:3].[CH3:35][O:36][C:5]1[N:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Reactant: CO
Agent: [Li]CCCC
Product: COc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Product: COc1nc(S(C)(=O)=O)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2,4-Bis(methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine from Reference Example 5 (2.0 g, 4.1 mmol) was reacted with 1.0 equivalent each of n-butyl lithium and methanol by the procedure described in Reference Example 6 and 7 to afford 2-(methylsulfonyl)-4-methoxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine and 2-methoxy-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichloro-phenyl)pyrimidine as a mixture: HPLC/MS: m/e=443 (M++1); Rt=3.57-3.89 min.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7](O)[CH2:6][C@H:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2].CS(Cl)(=O)=O.O>ClCCl.C(N(CC)CC)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)C[C@H]1c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C=CC1c1ccccc1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
6.0 g (17.9 mmol) of rel-(7S,9S)-10-acetyl-7-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (racemic) are dissolved in 100 ml of dichloromethane and 20 ml of triethylamine. A solution of 2.9 g (25 mmol) of methanesulfonyl chloride in 5 ml of dichloromethane is then added dropwise with ice cooling in the course of 30 min. After 2 h, the mixture is hydrolyzed with water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated. The residue is crystallized using diethyl ether. 4.8 g (85%) of the title compound are isolated as a slightly brown solid (m.p. 170° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH2:16][O:17][CH3:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].CN(C=O)C.C1(S(NN)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:8][CH2:9]1)=[O:5]
Reactant: COCC=Cc1ccc(Cl)c(C(=O)NC2CC2)c1
Agent: NNS(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCCCc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 110 °C
Yield: 78.5 %

Procedure:
2-Chloro-N-cyclopropyl-5-(3-methoxy-propenyl)-benzamide (12.6 g, 47.6 mmol) was dissolved in dry toluene (650 mL). Dry DMF (70 mL) was added, and the mixture was heated to 110° C. Benzensulfonyl hydrazine (24.5 g, 143 mmol) was added in three portions over 3 h. The mixture was heated for a total time of 3 h, and allowed to cool to rt. The solvents were removed under reduced pressure, and the residue was diluted with Et2O. The mixture was washed with water, and the aq. phase was extracted back with Et2O (3×). The combined org. extracts were washed with water, and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:9→1:4→1:3→1:1) yielded the title compound (10.0 g, 78%). LC-MS: tR=0.83 min; ES+: 268.19.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[C:14](Cl)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC=CC=1>CC(C)=O.O>[C:14]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: O=C(C=Cc1ccccc1)Oc1ccc2ccccc2c1
Reaction time: 0.12 h
Yield: 80.5 %

Procedure:
In 70 ml of acetone was dissolved 6.4 g of 2-naphthol. A 25% queous sodium hydroxide solution was added to the solution. A solution of 8.1 g of cinnamoyl chloride in 10 ml of acetone was dropwise added to the mixture over 4 minutes while stirring. After the stirring was continued for 7 minutes, benzene and water were added to the system to effect liquid separation. After the organic phase was washed with an aqueous hydrogen sodium carbonate solution, the system was dried over anhydrous potassium carbonate and the solvent was distilled off. The residue was treated with n-hexane and benzene to give crystals of the product. The product was recrystallized from a solvent mixture of n-hexane and benzene to give 9.8 g of the product.
Reaction SMILES: CC1C(C)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14].[C:20](O)(=[O:22])[CH3:21]>>[C:20]([NH:4][C:3]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][CH:7]=[C:14]2[C:13]([O:16][C:17](=[O:19])[C:18]=12)=[O:15])(=[O:22])[CH3:21]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1C
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Product: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)OC2=O

Procedure:
2,3-Dimethyl-6-nitroaniline was acetylated in acetic acid by using 1 equivalence of acetic anhydride, and the product was recrystallized from ethanol. The resulting 3-acetamido-4-nitroxylene was dissolved in boiled water containing magnesium sulfate. To the solution, 6 equivalences of potassium permanganate suspended in water was added in several portions, and the solution was refluxed until purple color disappeared. The hot reaction mixture was filtered and cooled, and then the filtrate was made acidic with hydrochloric acid and extracted with ethyl acetate. The resulting 3-acetamido-4-nitrophthalic acid was dehydrated in acetic anhydride using acetyl chloride. The reaction mixture was concentrated under reduced pressure, and then a small quantity of anhydrous methylene chloride was added to the residue and the deposited solid was collected by filtration to obtain 3-acetamido-4-nitrophthalic anhydride.