Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].I[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[C:28]1[CH:37]=[CH:36][C:35]2[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=2[CH:29]=1>C(O)C>[CH2:1]([NH:5][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:22]=2)=[CH:13][C:12]=1[C:28]1[CH:37]=[CH:36][C:35]2[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=2[CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: CCCCN
Solvent: CCO
Product: CCCCNCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 54.4 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 1.9 ml (19.3 mmol) of n-butylamine and 750 mg (1.29 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 380 mg of ethyl 4′-(3-butylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=175° C., yield=59%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.C(O)C.C1(C)C=CC(S([CH2:24][N+:25]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:24]#[N:25])[CH2:8]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77.1 %

Procedure:
To a solution of 2-adamantanone (6.24 g, 41.50 mmol) in anhydrous 1,2-dimethoxyethane (150 mL) was added anhydrous ethanol (3.6 mL, 61.00 mmol) and p-toluenesulfonylmethyl isocyanide (10.0 g, 51.50 mmol) at 0° C. Potassium tert-butoxide (7.03 g, 62.70 mmol) was added in portions over 35 minutes under nitrogen atmosphere. The reaction mixture was stirred for 3.5 hours at ambient temperature. The mixture was filtered through a pad of diatomaceous earth that was washed with ethyl acetate (200 mL). The filtrate was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound (5.16 g, 77% yield) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 2.88 (s, 1H), 2.15-2.11 (m, 4H), 1.92-1.85 (m, 4H), 1.75-1.70 (m, 6H); MS (ES−) m/z 162.2 (M+1).
Reaction SMILES: [C:1]([C:9]1[C:10]([CH:14]=O)=[CH:11][S:12][CH:13]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([C:9]1[C:10](/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:11][S:12][CH:13]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1cscc1C=O
Reactant: O=C(O)CC(=O)O
Product: CCCCCCC#Cc1cscc1/C=C/C(=O)O
Yield: 41.5 %

Procedure:
Reaction of 4-(octynyl)-3-thiophenecarboxaldehyde (550 mg, 2.5 mmole) with malonic acid by the method described in Example 2 yielded the title compound 272 mg (41.5%) mp °C.; νmax (mull) 2600(vb), 1790, 1615, 940, 865, 835, 760; δ(CDCl3) 0.90(3H, distorted t), 1.40(8H, m), 2.37(2H, t, J=6 Hz), 6.23(1H, d, J=16 Hz), 7.22(1H, bs), 7.37(1H, bs), 7.77(1H, d, J=16 Hz), 10.3(1H, bs).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=1)[C:20](O)=[O:21])=[O:14].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[CH3:56][N:57]1[CH2:62][CH2:61][N:60]([C:63]2[CH:68]=[CH:67][C:66]([NH:69][C:70]3[N:75]=[CH:74][C:73]([NH2:76])=[CH:72][N:71]=3)=[CH:65][CH:64]=2)[CH2:59][CH2:58]1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([C:20]([NH:76][C:73]2[CH:74]=[N:75][C:70]([NH:69][C:66]3[CH:65]=[CH:64][C:63]([N:60]4[CH2:59][CH2:58][N:57]([CH3:56])[CH2:62][CH2:61]4)=[CH:68][CH:67]=3)=[N:71][CH:72]=2)=[O:21])[CH:23]=1
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2F)cc1C(=O)O
Reactant: CN1CCN(c2ccc(Nc3ncc(N)cn3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2F)cc1C(=O)Nc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 16×100 mm vial was charged with 5-((2-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-2-methylbenzoic acid 36 (0.100 g, 0.293 mmol), dichloromethane (3 mL), diisopropylethylamine (0.200 ml, 1.15 mmol), 1-hydroxybenzotriazole (0.0396 g, 0.293 mmol), EDC.HCl (0.0562 g, 0.293 mmol), and N2-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,5-diamine (0.0875 g, 0.308 mmol), and the mixture stirred at room temperature for 24 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane) to afford N1-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methyl-N3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)isophthalamide 37 as a light yellow solid. MS m/z found 608 [MH+]; calc. for C31H29F4N7O2=607.60.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Cl)c(Cl)c1
Reaction time: 3.5 h
Yield: 27.3 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and 4.17 g (25.6 mmol) 3,4-dichloroaniline was heated to reflux under N2. At 3.5 hours, removed head and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids and washed with water. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving 2.106 g of yellow solid: mass spectrum (electrospray m/e): M+H=359.1, 361.0.
Reaction SMILES: C(N(CC)CC)C.CN(C1C=CC=CN=1)C.C(O[C:21](=[O:23])[CH3:22])(=O)C.[NH2:24][C:25]1[CH:45]=[CH:44][C:28]([CH2:29][C:30]2[NH:31][C:32](=[O:43])[C:33]3[N:38]([CH3:39])[N:37]=[C:36]([CH2:40][CH2:41][CH3:42])[C:34]=3[N:35]=2)=[CH:27][CH:26]=1>ClCCl>[CH3:39][N:38]1[C:33]2[C:32](=[O:43])[NH:31][C:30]([CH2:29][C:28]3[CH:44]=[CH:45][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:26][CH:27]=3)=[N:35][C:34]=2[C:36]([CH2:40][CH2:41][CH3:42])=[N:37]1
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(C)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (160 μl, 0.0011 mol), dimethylaminopyridine (10 mg), and acetic anhydride (50 μl, 0.0005 mol) were added to a solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (110 mg, 0.00037 mol) in dichloromethane (9 ml). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was then partitioned between 2M aqueous hydrochloric acid solution (15 ml) and dichloromethane (15 ml) and the aqueous phase extracted with dichloromethane/methanol (30 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give, after crystallisation from ethyl acetate/methanol, the title compound as an off white solid (105 mg), m.p.272-275° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][NH2:13])=[O:9].[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]=[CH:38][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][C:29]2[NH:30][CH:31]=[CH:32][N:28]=2)=[CH:41][CH:40]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1cccc([N+](=O)[O-])c1
Reactant: O=Cc1ccc(Cc2ncc[nH]2)cc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN=Cc2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
506 mg (1.35 mM) of 2-aminoethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine -3,5-dicarboxylate was mixed with 251 mg (1.35 mM) of 4-(1-imidazolylmethyl)benzaldehyde and the mixture was stirred for 15 hours at room temperature, whereby the captioned compound was obtained. The yield was 544 mg (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][C:18]([OH:27])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+]>CO.C(#N)C>[NH2:34][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([OH:27])[CH2:17][CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-hydroxy-4-phenylpiperidin-1-yl) quinolin-7-yl]ethanone (37 mg, 0.097 mmol) and ammonium acetate (74.9 mg, 0.971 mmol) in methanol (0.55 mL) and acetonitrile (0.55 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (12.2 mg, 0.194 mmol). The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (35 mg, 94%). LCMS calculated for C22H25ClN3O (M+H)+: m/z=382.2; Found: 382.1.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1)=O.N1CCCCC1.[CH2:17]([N:21]1[C:26]([NH:27][N:28]=[CH:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([Cl:39])[CH:37]=3)[NH:32][CH:31]=2)=[CH:25][C:24](=[O:40])[N:23]([CH3:41])[C:22]1=[O:42])[CH:18]([CH3:20])[CH3:19]>CN(C)C=O>[Cl:39][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH2:29][N:28]1[C:1]([C:3]2[N:7]([CH3:8])[CH:6]=[C:5]([C:9]#[N:10])[CH:4]=2)=[C:25]2[C:26]([N:21]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:22](=[O:42])[N:23]([CH3:41])[C:24]2=[O:40])=[N:27]1
Reactant: Cn1cc(C#N)cc1C=O
Reactant: CC(C)Cn1c(NN=Cc2c[nH]c3ccc(Cl)cc23)cc(=O)n(C)c1=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C#N)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Temperature: 50 °C
Yield: 59 %

Procedure:
5-formyl-1-methyl-1H-pyrrole-3-carbonitrile (0.032 g) and piperidine (0.05 ml) was added to a solution of 5-chloro-1H-indole-3-carbaldehyde (3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (0.075 g) in dimethylformamide (1.5 ml). The solution was heated at 50° C. for 5 hours. Reaction cooled to room temperature and purified on preparative HPLC to give the title compound (0.058 g). Mass: 490.16 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:2][CH3:1])[N:8]=1)(=[O:22])=[O:21]
Reactant: CNc1cccc(CCO)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1cccc(CCOS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A mixture of 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol (300 mg, 1.9 mmol), triethylamine (0.3 ml, 2.2 mmol), methanesulfonyl chloride (0.17 ml, 2.2 mmol), and dichloromethane (15 ml) was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried with sodium sulfate, filtered, and evaporated under vacuum to give a yellow oil. The crude product was chromatographed over silica gel to yield 300 mg (69%) of 2-[6-(Methylamino)-2-pyridyl]ethyl methylsulfonate. NMR 1H Cl3CD δ: 7.45 (dd, 1H, J=7.2, 8.4 Hz), 6.51 (d, 1H, J=7.2 Hz), 6.33 (d, 1H, J=8.4 Hz), 4.65 (t, 2H, J=6.4 Hz), 3.06 (t, 2H, J=6.4 Hz), 2.92 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1.C(O)(=O)C.CO[CH:30]1[CH2:34][CH2:33][CH:32](OC)O1>Cl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH:30]=[CH:34][CH:33]=[CH:32]5)=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1
Reactant: COC1CCC(OC)O1
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(N)cc4)[nH]c3cc21
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(-n5cccc5)cc4)[nH]c3cc21
Reaction time: 20 h

Procedure:
3.06 g. 8,8-dimethyl-2-(4-aminophenyl)-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinolin-6-one (see Example 38) were allowed to stand for 20 hours at 25° C. with 30 ml. glacial acetic acid, 5 ml. water, 2 drops of concentrated hydrochloric acid and 1.32 ml. 2,5-dimethoxytetrahydrofuran. The reaction mixture was then washed with 100 ml. water. After crystallization from ethanol, there was obtained 0.8 g. of the title compound; m.p. 329°-350° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)=[O:7]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccc(C(=O)CCC(=O)O)cc2)c1
Yield: 84.3 %

Procedure:
In a manner similar to that described in Example 3, 3-methoxybenzoyl chloride (0.052 g, 0.00030 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.069 g of 4-[4-(3-methoxy-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+328.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[OH:20])(=[O:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][S:22]([CH3:21])(=[O:24])=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
The 5'-O-acetylthymidine obtained in Example 7 was dissolved in 100 ml of pyridine and cooled to 0° C. Then, 11.57 g (2 equivalents) of methanesulfonyl chloride were added thereto. After these were reacted at 0° C. for 1.5 hours, 5.79 g (one equivalent) of methanesulfonyl chloride were added thereto and reacted at 0° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride, and the insoluble substances were removed by filtration. The organic layer was washed with water; aqueous, saturated sodium hydrogencarbonate solution; water; and saturated saline solution in this order, dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 10.4 g of 5'-O-acetyl-3'-O-methanesulfonylthymidine. The product was used in the next reaction, without being isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[O:9][CH:8]2S(C1C=CC=CC=1)(=O)=O.CC(C)([O-])C.[Li+].[C:28]([CH:31]1[CH2:40][CH2:39][CH:38]2[CH:33]([CH2:34][CH:35]=[CH:36][C:37]2=[O:41])[CH2:32]1)(=[O:30])[CH3:29]>C1COCC1>[C:28]([C:31]1[CH:32]=[C:33]2[C:38]([C:37](=[O:41])[C:36]3[CH:10]([OH:12])[CH:11]4[C:7](=[C:8]([OH:9])[C:35]=3[CH2:34]2)[CH2:6][CH2:5][CH2:4][CH:3]4[O:2][CH3:1])=[CH:39][CH:40]=1)(=[O:30])[CH3:29]
Reactant: COc1cccc2c1C(=O)OC2S(=O)(=O)c1ccccc1
Reactant: CC(=O)C1CCC2C(=O)C=CCC2C1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1CCCC2=C(O)C3=C(C(=O)c4ccc(C(C)=O)cc4C3)C(O)C21
Yield: 95 %

Procedure:
Continuing with a synthesis utilizing the object compound (5) to produce the tetrahydronaphthacene dione intermediate, the anion of 7-methoxy-3-phenylsulfonyl-1(3H)-isobenzofuranone (6) as generated at -78° C. using lithium t-butoxide in THF and reacted with the hexahydronaphthalenone (5) to furnish 9-acetyl-5,12-dihydroxy-4-methoxy-6(11H)-hexahydronaphthacenone (7) in 95% yield. Conversion of (7) to 9-acetyl-6-hydroxy-4-methoxy-7,8,9,10-tetrahydronaphthacene-5,12-dione (8) was achieved by heating (7) in dimethylforamide under oxygen at 45° C. for 18 hours.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[N:20]1[C:24]2[CH:25]=[C:26]([N+:33]([O-:35])=[O:34])[C:27]([N+:30]([O-:32])=[O:31])=[C:28](Br)[C:23]=2[NH:22][S:21]1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[N:20]1[C:24]2[CH:25]=[C:26]([N+:33]([O-:35])=[O:34])[C:27]([N+:30]([O-:32])=[O:31])=[C:28]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)[C:23]=2[NH:22][S:21]1
Reactant: O=[N+]([O-])c1cc2c(c(Br)c1[N+](=O)[O-])NSN2Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(c(-c3cccs3)c1[N+](=O)[O-])NSN2c1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Tributylstannylthiophene (9.06 g, 24.3 mmol) and 1,4-dibromo-5,6-dinitro-2,1,3-benzothiadiazole (3.80 g, 9.90 mmol) were dissolved in anhydrous THF (150 mL). After adding Pd(PPh3)2Cl2 (338 mg, 0.48 mmol), reflux was performed for 16 hours. After the reaction was terminated, the temperature was raised to room temperature and the solvent was removed. The product was extracted with dichloromethane and distilled water, dried, subjected to column chromatography (neutral alumina, hexane) and recrystallized in toluene to obtain yellow solid. 1H NMR (500 MHz, CDCl3, ppm): δ 7.75 (dd, 2H, J=5.0 Hz, J=1.0 Hz), 7.52 (dd, 2H, J=3.5 Hz, J=1.0 Hz), 7.24 (dd, 2H, J=5.0 Hz, J=3.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].[N+:10]([O-])([OH:12])=[O:11].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[S:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccsc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1csc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 3-thiophene carboxylic acid methyl ester (1.8 g, 12.68 mmol) in acetic acid (7.5 ml) was added a mixture of nitric acid (0.67 ml), acetic acid (7.5 ml) and acetic anhydride (4.3 ml) at 0-10° C. The reaction mixture was stirred at 40° C. for 1 hr and then poured into crushed ice. The solid was filtered, washed with cold water and dried. The compound was recrystallised using ether/hexane to give 5-nitro-thiophene-3-carboxylic acid methyl ester (1.0 g, 42%).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6](C)[CH2:5][CH2:4]1)#[N:2].Cl.C(C1(C2C=CC=CC=2SC2C=CC=CC=2)CCN(C)CC1)#N.Cl[C:47]([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:48]>C(Cl)Cl>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([C:47]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:48])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(C#N)(c2ccccc2Sc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Product: N#CC1(c2ccccc2Sc2ccccc2)CCN(C(=O)Oc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2.5 g of 4-cyano-1-methyl-4-(2-phenylthiophenyl)piperidine, free base of Example 3, and 1.7 g of phenyl chloroformate in 50 ml of methylene chloride is permitted to stand for 24 hours before being poured onto 100 g of ice. Thereafter, the mixture is extracted with 50 ml of methylene chloride and the organic solution is successively washed twice with 50 ml portions of water, washed once with 40 ml saturated sodium bicarbonate solution, washed once with 40 saturated sodium chloride solution, dried and evaporated. The residue is chromatographed through a silica gel column, first with an ether eluant and then with an ether-hexane (1:1) mixture eluant, until there is no indication of contamination by thin layer chromatography. Thereafter, the product is chromatographed through the same absorbent, ether eluant to provide 4-cyano-1-phenoxycarbonyl-4-(2-phenylthiophenyl)piperidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[O:16]1[CH2:19][C:18](=[O:20])[CH2:17]1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2([OH:20])[CH2:19][O:16][CH2:17]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(I)ccc1Br
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C2(O)COC2)ccc1Br
Reaction time: 0.17 h

Procedure:
A solution of 1-bromo-4-iodo-2-methoxybenzene (Combi-Blocks, 3.00 g, 9.59 mmol) in 40 mL ether was cooled to −78° C. and was treated with n-butyllithium (4.22 ml, 10.55 mmol). After stirring for 10 minutes, the reaction mixture was quenched with 3-oxetanone (0.967 ml, 13.42 mmol), and the cooling bath was removed. After stirring for an additional hour, LC/MS showed mostly product, so the reaction mixture was washed with 1N citric acid solution, the organics dried over MgSO4 and concentrated. This material was carried on to step two without purification. (M+H)+=240.9.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>CC#N>[Br:15][C:6]1[CH:7]=[C:8]([O:11][C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(OC(C)C)cc1
Solvent: CC#N
Product: CC(=O)Oc1ccc(OC(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of acetic acid 4-isopropoxy-phenyl ester (1.04 g, 5.35 mmol, 1 eq.) in MeCN (22 mL), N-bromsuccinimide (953 mg, 5.35 mmol, 1 eq.) was added. The resulting mixture was stirred at r.t. for 18 hours. The solvent was removed in vacuo. The residue was partitioned between water and Et2O. The org. layer was dried over MgSO4, filtered, and concentrated in vacuo to give acetic acid 3-bromo-4-isopropoxy-phenyl ester as an orange oil. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Cl-:15].[Al+3].[Cl-:17].[Cl-].ClCl>C(Cl)Cl>[Cl:15][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([Cl:17])[C:2]=1[CH3:1])[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)CCC(=O)O)cc1Cl
Yield: 44.2 %

Procedure:
To a mixture of 3-(4-methylbenzoyl)propionic acid (7.5 g) and methylene chloride (250 ml) was added slowly portionwise aluminum chloride (15 g) at 0° C. After the addition was completed chlorine gas was bubbled in slowly at 0° C. After 6 hours the reaction mixture was poured into mixture of hydrochloric acid and ice and extracted with methylene chloride (3×150 ml), the combined organic layers were washed with water, dried and evaporated under vacuum yielding 3-(3,5-dichloro-4-methylbenzoyl)propionic acid as a yellow solid (4.5 g).