Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Yield: 47.4 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (241 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 148 mg (47.5%) of the desired product as a solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH3:20]>C(O)C.O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12]([N:19]([CH3:20])[CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1cc(Br)nc(Br)c1
Reactant: CNC
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)c1cc(S(=O)(=O)c2ccccc2)cc(Br)n1
Yield: 88 %

Procedure:
0.113 g (0.0003 mol) of 4-benzenesulphonyl-2,6-dibromopyridine and 0.54 ml of 5.6 M dimethylamine in ethanol were stirred at room temperature in a mixture of 3 ml of ethanol and 3 ml of dioxan for 5 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:10. There was obtained 0.09 g (88%) of (4-benzenesulphonyl-6-bromopyridin-2-yl) -dimethylamine as white crystals; m.p. 128-130° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[N:11]([C:12]([C:14]2[N:15]=[C:16]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[N:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)[CH:18]=2)=[O:13])[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)(=[O:3])[CH3:2].C(OC1C=C(N2C=C(C(N3CCN(C(OCC4C=CC=CC=4)=O)C[C@@H]3CO)=O)N=C2C2C=CC(C)=CC=2)C=CC=1)C.C(N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[C:12]([C:14]1[N:15]=[C:16]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=2)[CH:18]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Agent: CCOc1cccc(-n2cc(C(=O)N3CCN(C(=O)OCc4ccccc4)C[C@@H]3CO)nc2-c2ccc(C)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cccc(-n2cc(C(=O)N3CCNC[C@@H]3COC(C)=O)nc2-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step, C: Benzyl (3R)-3-[(acetyloxy)methyl]-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate To a stirred solution of 3.40 g (6.13 mmol) of benzyl (3R)-4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-3-(hydroxymethyl)-piperazine-1-carboxylate from Step B in 60 mL of anhydrous dichloromethane was added 2.30 mL (13.4 mmol) of N,N-diisopropylethylamine, 1.20 ml (12.2 mmol) of acetic anhydride and 4.0 mg (0.30 mmol) of 4-(dimethylamino)-pyridine. The resulting solution was stirred at ambient temperature overnight, quenched with a saturated aqueous ammonium chloride solution (20 mL). The aqueous layer was separated and extracted with dichloromethane (2×75 mL), and the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 50 to 75% ethyl acetate in hexanes gradient) to yield the title compound as a colorless foam. LC/MS 597.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)(=[O:36])=[O:35])(=[O:27])=[O:26])[CH:5]=[C:6]([CH:23]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11]C1C=CC=C2C(NC(=O)C=12)=O.C[NH2:45]>O1CCCC1.C(O)C.C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([O:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)(=[O:36])=[O:35])(=[O:27])=[O:26])[CH:5]=[C:6]([CH:23]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][NH2:45]
Reactant: CN
Reactant: Cc1cc(OCCCOc2cccc3c2C(=O)NC3=O)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCN(C)CC2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture 3-[5-methyl-3-(2-(4-methylpiperazinylsulfonyl)phenylsulfonyloxy)phenoxy]propoxyphthalimide (156 mg, 0.25 mmol), as prepared in the previous step, and 40% aqueous methylamine (1.50 mL, 21.5 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 4 hours. The solution was concentrated and the residue was purified by flash chromatography (10% methanol in dichloromethane) giving a slurry that was twice dissolved in diethyl ether, filtered, and concentrated giving the title compound as a clear oil (113 mg, 91%). 1H NMR (300 MHz, CDCl3/CD3OD) δ8.22 (dd, 1H, J=7.9, 1.3 Hz), 8.18 (dd, 1H, J=7.9, 1.4 Hz), 7.83 (td, 1H, J=7.7, 1.4 Hz), 7.70 (td, 1H, J=7.7, 1.3 Hz), 6.60 (br s, 1H), 6.56 (br s, 1H), 6.53 (t, 1H, J=2.1 Hz), 3.93 (t, 2H, J=6.3 Hz), 3.80 (t, 2H, J=6.2 Hz), 3.41 (m, 5H), 2.50 (br t, 4H, J=4.9 Hz), 2.30 (s, 3H), 2.24 (s, 3H), 2.00 (pentet, 2H, J=6.2 Hz).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].Br[CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH2:21]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12])[CH2:22][CH3:23]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O

Procedure:
Cytidine (16.5 g, 0.068 mol) was treated with sodium hydride (4.5 g) and bromopropane (15 ml) in DMF (150 ml) at room temperature for three days. The resulting reaction mixture was used directly in the next step (see Example 83).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.[CH2:17]([S:23](Cl)(=[O:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>N1C=CC=CC=1.CN(C=O)C>[CH3:15][C:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:4][NH:3][S:23]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:25])=[O:24]
Reactant: Cc1c(CN)[nH]c2ccccc2c1=O
Reactant: CCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCS(=O)(=O)NCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.5 %

Procedure:
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (212 mg) in pyridine-DMF (8:1, 9 mL) was added hexanesulfonyl chloride (180 mg) under ice-cooling, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added to the residue, followed by extraction with ethyl acetate (100 mL). The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]hexane-1-sulfonamide (56 mg).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[NH:8][C:9]1[N:14]=[C:13]([C:15]2[N:19]([CH2:20][CH2:21][N:22]3C(=O)C4=CC=CC=C4C3=O)[CH:18]=[N:17][CH:16]=2)[CH:12]=[CH:11][N:10]=1>CCO>[NH2:22][CH2:21][CH2:20][N:19]1[C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:7]3[CH:33]=[CH:34][CH:35]=[C:5]([Cl:4])[CH:6]=3)[N:14]=2)=[CH:16][N:17]=[CH:18]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Yield: 59.2 %

Procedure:
Hydrazine hydrate (54 ml, 1.73 mmol) was added to a suspension of 2-(3-chloroanilino)-4-[1-(2-phthalimidoethyl)imidazol-5-yl]pyrimidine (Example 10; 163 mg, 0.37 mmol) in EtOH (5 ml) and the mixture was heated at reflux for 2 hours. The mixture was allowed to cool, the volatiles removed by evaporation and the residue purified by column chromatography eluting with DCM and 7M methanolic ammonia solution (90:10) to give the title compound 69 mg, (59%) as a solid product. NMR: 1.41 (brs, 2H), 2.99 (t, 2H), 4.55 (t, 2H), 7.00-7.09 (m, 2H), 7.22-7.35 (m, 3H), 7.65-7.70 (m, 2H), 7.73-7.78 (m, 1H), 8.39 (d, 1H); m/z: 315.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[N:40]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:46])[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCCC1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino-4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure D using 1-pyrrolidinecarbonyl chloride. The final product was obtained in 57% yield.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]3[CH:10]=[CH:9][C:8]([C:24]#[N:25])=[CH:7][C:6]=3[C:5]=2[CH2:4]1.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>>[C:24]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:13]1[CH2:14][CH2:15][CH:3]([NH:2][C:28](=[O:29])[N:27]([CH3:31])[CH3:26])[CH2:4][C:5]2=1)#[N:25]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(N)C1
Agent: Cl
Product: CN(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Yield: 69 %

Procedure:
Prepare the title compound by essentially following the procedures as described in Example 162, using 6-amino-9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile hydrochloride (Preparation 54) and dimethylcarbamyl chloride. Purify by silica gel chromatography (30-70% (4% (2M NH3/MeOH)/CH2Cl2)/hexanes) to give the title compound in 69% yield as a white solid. MS (ES): m/z 391 (M+1), 389 (M−1); HPLC (Method B): Rt=4.11 min (99%).
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:22])[NH:8][C:9]2[C:10]([CH3:21])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH3:5])[CH2:3][CH2:2]1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:17]3[CH:18]=[CH:19][C:14]([C:13]4[O:12][N:11]=[C:10]([CH3:21])[C:9]=4[NH:8][C:7]([O:6][CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:5])=[O:22])=[CH:15][CH:16]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)C1CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)C4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-cyclopropyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester; the isolated material was then purified by preparative HPLC, using a Chiracel OD column (97:3 hexanes:EtOH) to provide enantiomer A and enantiomer B. Enantiomer A had a retention time of 27 minutes, enantiomer B had a retention time of 33 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCBr
Product: CCCCCCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Yield: 22.3 %

Procedure:
The title compound (1.2 g, 22%) was prepared as an oil from ethyl 3-(4-benzyloxyphenyl)-2-hydroxypropanoate (4.2 g, 14.0 mmol) and 1-bromohexane (3.4 g, 21.0 mmol) by an analogous procedure to that described in preparation 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[C:11]([OH:26])=[C:10]([C:27](OCC)=[O:28])[C:9]2=[O:32])=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38]>>[C:37]([NH:36][CH2:35][CH2:34][NH:33][C:27]([C:10]1[C:9](=[O:32])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:17]2[C:12]([C:11]=1[OH:26])=[N:13][CH:14]=[C:15]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH:16]=2)=[O:28])(=[O:39])[CH3:38]
Reactant: CC(=O)NCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Product: CC(=O)NCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(F)cc2)c1=O
Yield: 56.7 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.043 mmol) and N-(2-aminoethyl)acetamide (60 mg, 0.595 mmol), was prepared N-[2-(acetylamino)ethyl]-1-(4-fluorophenyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (12 mg, 57% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.17 (br s, 1 H), 8.54 (s, 1 H), 7.32-7.27 (m, 2 H), 7.22-7.18 (m, 2 H), 7.03-6.93 (m, 4 H), 6.74 (s, 1 H), 6.03 (br s, 1 H), 3.96 (s, 2 H), 3.58 (m, 2 H), 3.46 (m, 2 H), 1.97 (s, 3 H); MS m/z 493 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([NH:40][C:41](OC2C=CC=CC=2)=[O:42])[C:27](=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:19]([NH:22][C:41]([NH:40][C:26]2[CH:25]=[C:24]([Cl:23])[CH:39]=[CH:38][C:27]=2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:42])(=[O:20])=[O:21])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)c2ccccc2c1O
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)c2ccccc2c1O
Yield: 73.2 %

Procedure:
323 mg (1.00 mmol) of 3-t-butoxycarbonyl-4-hydroxy-1-naphthalenesulfonamide and 381 mg (1.00 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 447 mg (yield 73%) of 4-({[(2-benzyloxycarbonyl-5-chloroanilino)carbonyl]amino}sulfonyl)-1-hydroxy-2-naphthalenecarboxylic acid t-butyl ester. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 1.66 (9H, s), 5.34 (3H, s), 6.98 (1H, d), 7.35-7.48 (5H, m), 7.66 (1H, m), 7.81 (1H, m), 7.89 (1H, d), 8.37 (2H, m), 8.44 (1H, s), 8.71 (1H, d), 10.02 (1H, br), 12.52 (1H, br).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[N:3]=1.[NH2:24][C@@H:25]([CH2:29][OH:30])[CH:26]([CH3:28])[CH3:27].C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1.O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:24][CH:25]([CH:26]([CH3:28])[CH3:27])[CH2:29][OH:30])=[N:3][C:4]=2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(Nc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Reactant: CC(C)[C@@H](N)CO
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: CC(C)C(CO)Nc1nc(Nc2cccc([N+](=O)[O-])c2)c2ncn(C(C)C)c2n1
Yield: 3.1 %

Procedure:
(2-Chloro-9-isopropyl-9H-purin-6-yl)-(3-nitro-phenyl)-amine (333 mg, 1 mmol), D-valinol (310 mg, 3.0 mmol), and DBU (457 mg, 3.0 mmol) were stirred in NMP (5 mL) overnight at 150° C. under N2. After cooling, the mixture was diluted with H2O (40 mL) and was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with brine, treated with decolourising charcoal and MgSO4, filtered, and evaporated. The residue was redissolved in DMSO/H2O and chromatographed (Vydac 218TP1022; 9 mL/min, 27.5-37.5% MeCN in 0.1% aq CF3COOH over 40 min). Appropriate peak fractions were pooled and lyophilized to afford the title compound as an orange solid (12.3 mg). Anal. RP-HPLC (Vydac 218TP54; 1 mL/min): tR=15.8 min (27.5-37.5% MeCN in 0.1% aq CF3COOH over 20 min); purity>95% (λ=214 nm). DE-MALDI-TOF MS: [M+H]+=398.5 (C19H25N7O3=399.5).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].ICCC>O>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]1[CH:20]([CH3:22])[CH3:21]
Reactant: Cc1ccc2c(c1)NC(C)CC2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCI
Product: Cc1ccc2c(c1)N(C(C)C)C(C)CC2
Yield: 57.6 %

Procedure:
A mixture of 2,7-dimethyl-1,2,3,4-tetrahydroquinoline (32.2 g, 0.2 m), potassium carbonate (15.0 g, 0.11 m), and 2-iodopropane (51 g, 0.3 m) was heated at 90°-95° C. for 5.5 hr. Progress of the reaction was slow. An additional quantity (34.0 g) of iodopropane was added and the mixture refluxed for 24 hrs. longer. Starting material was still evident by thin-layer chromatography. The reaction mixture was drowned into 200 ml water and extracted with chloroform (50 ml). The organic layer was treated with 10 ml of acetic anhydride for 1 hr. at 90°-95° C. to convert the 2,7-dimethyl-1,2,3,4-tetrahydroquinoline into N-acetyl-2,7-dimethyl-1,2,3,4-tetrahydroquinoline, which enables the recovery of the pure product by distillation. The organic layer was distilled under vacuum to give 23.4 g (55% yield) of product which boiled at 85° C. at 0.21.1 mm Hg.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][C:32]#[N:33])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 92.6 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (1.05 g 3.49 mmol) in DMF (15 mL) is added potassium carbonate (2.4 g, 17.4 mmol) and bromoacetonitrile (1.2 mL, 17.4 mmol). The mixture is heated at 85° C. for 1.5 h. The mixture is cooled and partitioned between water and Et2O. The organic layer is washed twice with water (200 mL), dried over magnesium sulfate and concentrated. Column chromatography (60 g silica gel) using CH2Cl2 as eluent gave 1.1 g (92%) of 2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]1([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)[CH:32]=[O:33]>C1COCC1>[F:29][C:24]1[C:23]([O:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:28][CH:27]=[CH:26][C:25]=1[CH:32]=[O:33]
Reactant: Fc1ccccc1Oc1ccccc1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Oc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Cool a solution of 2,2,6,6-tetramethylpiperidine (5.1 mL, 30.0 mmol) in THF (40 mL) to −78° C. Add dropwise n-Butyllithium (18.7 mL, 30.0 mmol, 1.6 M in hexanes) and stir for 10 min at −78° C. Add dropwise 2-fluorophenyl phenyl ether (4.7 g, 25.0 mmol), stir 2 h at −78° C. Add N,N-dimethylformamide (2.3 mL, 30.0 mmol) dropwise over 15 min. Stir the resulting mixture for 3 h at −78° C. and allow to warm to ambient temperature over 16 h. Quench the reaction mixture with water (50 mL), extract with ethyl acetate, dry over Na2SO4, filter and concentrate under reduced pressure to give an oil. Crystallize the oil with hexanes to give a solid, collect and recrystallize from hexanes/ethyl acetate/methylene chloride to give the title compound: mp 75–77° C.; MS(m/e): 216 (M+); Calculated for C13H9FO2: Calcd: C, 72.22; H, 4.20. Found: C, 72.41; H, 4.23. Purification of the mother liquors by silica gel chromatography (2–3% ethyl acetate/hexanes) gives an additional amount of the title compound: MS(m/e): 216 (M+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:40])[S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:34][N:35]([CH3:40])[S:36]([N:13]1[CH2:14][C:5]2[CH:4]=[C:3]([Cl:2])[CH:26]=[CH:25][C:6]=2[N:7]2[C:11](=[N:10][N:9]=[C:8]2[C@H:15]2[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]2)[CH2:12]1)(=[O:38])=[O:37]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(S(=O)(=O)N(C)C)C3)CC1
Reaction time: 65 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.070 g, 0.18 mmol) and triethylamine (0.037 ml, 0.26 mmol) in dichloromethane (3 ml) was added N,N-dimethylsulfamoyl chloride (0.028 ml, 0.26 mmol) at room temperature. After stirring for 65 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.063 g, 77%) as white solid. MS m/e: 468 (M+H+).