Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].C(NCC)C.Cl>CC(C)=O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[N:17]([CH2:18][CH3:19])[CH2:15][CH3:16]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCNCC
Solvent: CC#N
Product: CCN(CC)S(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: -10 °C

Procedure:
7.6 g of 2-chloro-5-nitrophenylsulfonyl chloride was dissolved in 50 g of acetone, and the obtained solution was then cooled to -10° C. A solution obtained by dissolving 3.03 g of triethylamine and 2.2 g of diethylamine in 20 g of acetonitrile was added dropwisely to the obtained solution. During the addition, the mixture was agitated under cooling so that the temperature did not exceed 0° C. The temperature was gradually raised to room temperature, and the mixture was poured into a dilute solution of hydrochloric acid at pH of about 2. The produced crystals were filtered off and washed with water (yield: 7.8 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([S:11][CH3:12])=[N:9][N:10]=1)=O)C.[NH3:13]>C(O)C>[CH3:12][S:11][C:8]1[S:7][C:6]([C:4]([NH2:13])=[O:3])=[N:10][N:9]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(SC)s1
Solvent: CCO
Product: CSc1nnc(C(N)=O)s1

Procedure:
11.8 g of 5-methylthio-1,3,4-thiadiazole-2-carboxylic acid ethylester which is the compound obtained in Example 10, were mixed with 50 ml ethanol and 50 ml of a 25% aqueous ammonia solution whereupon the mixture was heated for 15 minutes on a steam bath. After cooling part of the reaction product precipitated. The precipitation was completed by adding ice water. The precipitate was then removed by suction and dried in a vacuum.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1.Cl>ClCCl>[NH2:25][C@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: ClCCl
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](N)CC(C)C)ccc21
Reaction time: 1 h
Yield: 14.2 %

Procedure:
An ambient temperature solution of (R)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (102 mg, 0.232 mmol) in dichloromethane (1 mL) was treated with HCl (1.160 mL, 4.64 mmol) and stirred for 1 h. The resulting mixture was concentrated to an oil and purified by reverse phase high performance liquid chromatography (Phenomenex Luna C18 30×100 mm 10 micron; water/methanol/0.1% TFA gradient elution). Fractions containing product were neutralized with saturated aqueous sodium bicarbonate and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine and the layers were separated. The aqueous was extracted twice more with ethyl acetate and the pooled organics were washed once with brine, dried over magnesium sulfate, filtered, and concentrated to afford (R)-8-((2-amino-4-methylpentyl)oxy)-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (11.5 mg, 0.033 mmol, 14% yield) as a milky oil. LC/MS, (ESI) m/z 340.2 [(M+H)+, calcd for C20H26N3O2 340.2]; HPLC retention time (method C): tR=13.02 min; HPLC retention time (method D): tR=13.05 min; 1H NMR (500 MHz, METHANOL-d4) δ 8.68-8.63 (m, 2H), 8.58 (d, J=9.0 Hz, 1H), 7.22 (dd, J=9.0, 2.3 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 4.52 (dd, J=10.5, 3.3 Hz, 1H), 4.34 (dd, J=10.7, 6.6 Hz, 1H), 3.82 (s, 3H), 3.80-3.75 (m, 1H), 3.25 (s, 3H), 1.91-1.81 (m, 1H), 1.80-1.73 (m, 1H), 1.72-1.64 (m, 1H), 1.07 (d, J=5.8 Hz, 3H), 1.06 (d, J=5.8 Hz, 3H).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1S(O)(=O)=O.C(NCCNC1C=CC(N)=CC=1S(O)(=O)=O)(=O)C.Cl>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(S(=O)(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: CC(=O)NCCNc1ccc(N)cc1S(=O)(=O)O
Agent: Cl
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-4-bromoanthraquinone-2-sulfonic acid and 4-(β-acetylaminoethylamino)aniline-3-sulfonic acid were subjected to Ullmann condensation in the presence of cuprous chloride as a catalyst, followed by hydrolysis of the acetyl group under an acid condition of hydrochloric acid, thereby obtaining an anthraquinone intermediate compound of the following formula (2) in the free acid form. ##STR244##
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12]>>[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)C1CCNCC1
Reactant: Clc1cccnc1Cl
Product: COC(=O)C1CCN(c2ncccc2Cl)CC1

Procedure:
2,3-Dichloropyridine (1.48 g, 10 mmol, Aldrich) and piperidine-4-carboxylic acid methyl ester (1.43 g, 10 mmol, Aldrich) were reacted under the conditions of Example 3a to give the title compound as a colorless viscous oil. MS (ESI, pos. ion) m/z: 256 (M+1).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH3:20])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:19][CH3:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCC[C@@H](O)[C@H](CC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 6 (660 mg, 2.47 mmol) and 1-bromotetradecane (1.71 g, 6.17 mmol), alcohol 53 was obtained as a colorless oil (535 mg, 47% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].CO.[CH3:36]CN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O:12][CH3:36])=[O:11]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (652 mg, 1.4424 mmol) was dissolved in methylene chloride (20 ml), then anhydrous methanol (231 mg, 7.2187 mmol), 4-dimethylaminopyridine (264 mg, 2.1639 mmol) and WSC-HCl (830 mg, 4.3296 mmol) were added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (490 mg, 1.0515 mmol, 73%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:31](I)=[CH:30][N:29]([S:33]([C:36]5[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=5)(=[O:35])=[O:34])[C:26]4=[N:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43][C:44]1[CH:45]=[C:46]([CH:64]=[CH:65][CH:66]=1)[CH2:47][N:48]1[C:52]([CH3:53])=[C:51](B2OC(C)(C)C(C)(C)O2)[C:50]([CH3:63])=[N:49]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:31]([C:51]5[C:50]([CH3:63])=[N:49][N:48]([CH2:47][C:46]6[CH:64]=[CH:65][CH:66]=[C:44]([F:43])[CH:45]=6)[C:52]=5[CH3:53])=[CH:30][N:29]([S:33]([C:36]5[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=5)(=[O:35])=[O:34])[C:26]4=[N:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(CCOCc6ccccc6)CC5)cc4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCOCc6ccccc6)CC5)cc4)cnc32)cc1
Yield: 99.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-(4-(4-(2-(benzyloxy)ethyl)piperazin-1-yl)phenyl)-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 42) (130 mg, 0.203 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (101 mg, 0.305 mmol) in sodium carbonate (65 mg, 0.602 mmol), Pd(PPh3)2Cl2 (7 mg, 0.0101 mmol), Toluene/ethanol/water (5/2.5/1 ml) to give 155 mg of the crude titled compound. MS: m/z=769.3 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[NH:8][C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.0 g), phenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.28 g, 100%).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:20][CH:19]=3)[C:11](=[O:30])[CH:10]=2)=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH2:15][CH2:16][CH3:17])[N:12]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:22][CH:23]=2)[C:11](=[O:30])[CH:10]=1
Reactant: CCCc1nc(NCc2ccc(OC)cc2)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc(N)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Yield: 92.3 %

Procedure:
A solution (3 mL) of 6-[(4-methoxybenzyl)amino]-2-propyl-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one (400 mg) in trifluoroacetic acid was stirred with microwave irradiation at 100° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to aminopropylsilane-bonded silica gel column chromatography (ethyl acetate/hexane) to give the title compound (270 mg) as a solid.
Reaction SMILES: BrC1SC([C:7]2[C:15]3[C:11](=NSN=3)[C:10]([C:16]3[S:17][C:18](Br)=[CH:19][CH:20]=3)=CC=2Cl)=CC=1.BrC1SC(C2C3C(=NSN=3)C(C3SC(Br)=C(CCCCCCCCCCCC)C=3)=CC=2Cl)=CC=1CCCCCCCCCCCC.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>>[S:17]1[C:16]2[CH:10]=[CH:11][CH:15]=[CH:7][C:20]=2[CH:19]=[CH:18]1
Reactant: Clc1cc(-c2ccc(Br)s2)c2nsnc2c1-c1ccc(Br)s1
Agent: CCCCCCCCCCCCc1cc(-c2cc(Cl)c(-c3cc(CCCCCCCCCCCC)c(Br)s3)c3nsnc23)sc1Br
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: c1ccc2sccc2c1
Temperature: 135 °C

Procedure:
2,6-bis(Trimethylstannyl)-benzo[1,2-b:4,5-b′]dithiophene-4,8-(5-(2-hexyldecyl)-2-thiophenecarboxylic acid) ester (101.0 mg (81.0%), 0.672 mmol), 4,7-bis(5-bromo-2-thienyl)-5-chloro-2,1,3-benzothiadiazole (16.56 mg, 0.0336 mmol), 4,7-bis(5-bromo-4-dodecyl-2-thienyl)-5-chloro-2,1,3-benzothiadiazole (27.87 mg, 0.0336 mmol), Pa2dba3 (2.46 mg, 0.0027 mmol), P(o-tol)3 (3.27 mg, 0.0108 mmol) were placed in a 100 mL schlenk flask. The flask was degassed and backfilled with argon three times. Dry chlorobenzene (11 mL) was injected and the reaction was heated in a 135° C. heat bath for 18 hr. The reaction was cooled to room temperature and the contents of the flask were poured into methanol (100 mL). The precipitates were collected by filtration. The solid was subjected to Soxhlet extraction and washed with methanol (4 h), then ethyl acetate (16 h). The final product was extracted out with dichloromethane and weighed 35.0 mg after drying under vacuum (37.0%). Elemental Analysis: Calcd. C, 67.51; H, 7.46; N, 1.99. Found: C, 67.73, H, 7.23, N, 1.67. FIG. 2 shows the UV-vis spectra of the polymer in thin film form and as a solution in chloroform.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[N:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: Cc1ccc(N=C=O)cc1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(C)cc3)c(=O)n(C3CCCC3)c12
Yield: 64.8 %

Procedure:
1-Cyclopentyl-7-methoxy-3-p-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (26 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-4-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 402 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.49 (s, 1H), 7.84 (d, 1H), 7.61 (t, 1H), 7.38 (m, 1H), 7.34 (m, 1H), 7.32 (m, 1H), 7.24 (d, 1H), 7.08 (d, 1H), 5.03 (p, 1H), 4.16 (s, 3H), 2.43 (m, 2H), 2.29 (s, 3H), 2.08 (m, 4H), and 1.24 (m, 2H) ppm.
Reaction SMILES: N([O-])=O.[Na+].Cl.Cl.[CH3:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14](N)=[CH:13][C:11]=2[N:12]=1.O.[OH-].[NH4+].[BrH:21]>[Cu]Br>[CH3:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([Br:21])=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: Br
Agent: [Cu]Br
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: Cc1nc2cc(Br)ccc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium nitrite (0.9 g, 13 mmol) was added portionwise to a suspension of 2-methyl-5-aminobenzothiazole dihydrochloride (2.0 g, 8 mmol) in hydrobromic acid (24 ml) at 0° C. The resulting mixture was added dropwise to a solution of copper(I) bromide (4.0 g, 14 mmol) in hydrobromic acid (50 ml) at 0° C. After stirring at 0° C. for 2 hours, water was added. The reaction mixture was basified to pH 9 using aqueous ammonium hydroxide and was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate to give 2-methyl-5-bromobenzothiazole (1.0 g, 52%, 82% AUC GC) after chromatography (9:1 heptane/ethyl acetate): 1H NMR (300 MHz, DMSO-d6) δ 8.12 (d, J=1.8 Hz, 8.02 (dd, 1H) J=8.4, 1.5 Hz, 1H), 7.56 (dd, J=8.7, 2.1 Hz, 1H), 2.81 (s, 3H).
Reaction SMILES: C([O:5]C1C=CC(SC(C2C=CC=C(Cl)C=2)C(NO)=O)=CC=1)C#CC.[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])=[O:37])=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28]>>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])(=[O:5])=[O:37])=[CH:34][CH:35]=1)[C:26]#[C:27][CH3:28]
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2cccc(Cl)c2)cc1
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2cccc(Cl)c2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)c2cccc(Cl)c2)cc1
Yield: 27 %

Procedure:
Starting from a mixture of 2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-(3-chlorophenyl)-N-hydroxyacetamide and 2 {[4-(2-butynyloxy)phenyl]sulfinyl}-2-(3-chlorophenyl)N-hydroxyacetamide (210 mg, 0.56 mmol), and following the procedure as outlined in Example 75, 60 mg of 2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(3-chlorophenyl)-N-hydroxyacetamide was isolated as a white powder. mp: 50° C.; Yield: 27%; MS: 394.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.84 (t, J=2.22 Hz, 3H), 4.86 (d, J=2.31 Hz, 2H), 5.06 (s, 1H), 7.12 (d, J=8.97 Hz, 2H), 7.19-7.39 (band, 2H), 7.48 (m, 4H), 9.33 (d, J=1.2 Hz, 1H), 10.9 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1.C([O-])(=O)C.[K+].Br[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.ClCCl>CN(C=O)C>[F:41][C:37]1[CH:36]=[C:35]([N:5]2[C:4](=[O:28])[CH2:3][C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]2=3)[CH:40]=[CH:39][CH:38]=1
Reactant: Fc1cccc(Br)c1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3ccccc32)C(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccc(F)c3)c3ccccc32)C(C)C)cc1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To a stirring solution of 500 mg (1.3 mmol) 2-(2,4-Dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in 5 mL DMF is added 248 mg (3.9 mmol, 3 equiv) of Cu powder, 255 mg (2.6 mmol, 2 equiv) of potassium acetate, and 289 μL (2.6 mmol, 2 equiv) of 1-bromo-3-fluorobenzene. The reaction is heated to 100° C., and after 3 h an additional 289 μL (2.6 mmol, 2 equiv) of 1-bromo-3-fluorobenzene and 248 mg (3.9 mmol, 3 equiv) of Cu powder were added. The reaction is heated at 100° C. for 20 h then is poured onto ice. Dichloromethane is added, and the mixture is filtered through celite. The filtrate is poured into a separatory funnel, and the layers separated. 2 mL of a 30% solution of NH4OH were added to the aqueous layer, and the resulting blue solution is extracted with dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography (gradient 2:1-1:1 hexanes:ethyl acetate) to afford 497 mg of 2-[5-(3-Fluoro-phenyl)-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ7.45-7.25 (m, 4H), 7.18-6.93 (m, 8H), 5.04 (m, 1H), 4.35 (d, 1H, J=16.3), 4.17 (d, 1H, J=16.1), 3.88 (s, 3H), 3.56 (dd, 2H, J=12.0, 29.8), 1.12 (d, 6H, J=6.8); low resolution MS (FAB)m/e 476 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[O:20][CH2:19][CH2:18][CH2:17]1.Cl>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:13]2[CH2:16][CH2:17][CH2:18][C:19]2=[O:20])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCO1
Agent: Cl
Product: O=C1CCCN1c1ccc(OCc2ccccc2)cc1
Yield: 30.8 %

Procedure:
20.3 g (101.9 mmol) 4-benzyloxyaniline and 9.1 ml (119.2 mmol) gamma-butyro-lactone are treated with 3 ml concentrated hydrochloric acid. The mixture is heated 20 hours to 160° C., then 5.5 hours to 200° C. After cooling, the mixture is extracted with 250 ml ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and dried. Evaporation of the solvent and recrystallisation from diethyl ether yields 8.4 g (31%) of a brownish solid. MS: m/e=267 (M+).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O:14]=[C:15]1[N:21]2[CH2:22][CH2:23][C@H:20]2[C:19]2=[C:24]([C:27]([NH2:29])=O)[N:25]=[CH:26][N:18]2[C:17]2[CH:30]=[CH:31][S:32][C:16]1=2>O1CCOCC1.N1C=CC=CC=1>[O:14]=[C:15]1[N:21]2[CH2:22][CH2:23][C@H:20]2[C:19]2=[C:24]([C:27]#[N:29])[N:25]=[CH:26][N:18]2[C:17]2[CH:30]=[CH:31][S:32][C:16]1=2
Reactant: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 1658.3 %

Procedure:
5.75 ml (41.3 mmol) of trifluoroacetic anhydride were added dropwise at 5°-8° to a suspension of 11.05 g (40.:2 mmol) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxamide in 55 ml of dioxan and 7 ml of pyridine. The beige solution obtained was stirred at 50° for 2.5 hours and subsequently poured into 50 ml of ice-water. Extraction with methylene chloride (four times), drying over sodium sulfate, filtration and evaporation yielded a pale brown residue which was chromatographed (silica gel, methylene chloride/methanol 10:1). There were obtained 8.5 g (82%) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carbonitrile as a white powder of m.p. 211°-213°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([F:34])[C:27]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.[Cl:46][C:47]1[CH:51]=[CH:50][NH:49][C:48]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:46][C:47]1[CH:51]=[CH:50][NH:49][C:48]=1[C:52]([NH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:34])=[O:53]
Reactant: O=C(O)c1[nH]ccc1Cl
Reactant: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
HATU (0.113 g, 0.298 mmol) was added to a solution of {[4-chloro-2-fluoro-3-(1-naphthalenyloxy)phenyl]methyl}amine (0.060 g, 0.199 mmol) and 3-chloro-1H-pyrrole-2-carboxylic acid (0.0289 g, 0.199 mmol) nd diisopropylethylamine (0.052 mL, 0.298 mmol) and diisopropylethylamine (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.018 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.80 (br. s., 1H), 8.29-8.40 (m, 1H), 7.91-8.04 (m, 2H), 7.57-7.69 (m, 3H), 7.51 (dd, 1H), 7.35 (t, 2H), 6.93 (t, 1H), 6.52 (d, 1H), 6.19 (t, 1H), 4.54 (d, 2H). ES MS: m/z 429 (M+1).