Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=C12.O.[NH2:13]N>CO.ClCCl>[NH2:13][CH2:10][CH2:9][C:8]1[C:1](=[O:11])[NH:5][CH:4]=[CH:3][CH:7]=1
Reactant: NN
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: NCCc1ccc[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a suspension of 1.2 g (2.5 mmol) of phthalimide 4 in 100 ml of methanol was added 6 ml of hydrazine monohydrate. This was stirred at room temperature overnight upon which the suspension turned into a clear yellow solution. The mixture was concentrated and residue was diluted with water and extracted with chloroform. The organic solution was washed with brine and dried (MgSO4), and the residue was purified by column chromatography with silica eluting with 10% methanol in dichloromethane affording 0.48 g of the aminoethyl-pyridone 5 (55% yield).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:3]([C:5]1[O:6][CH:7]=[CH:8][N:9]=1)[OH:4].[CH:18]1([CH2:24][CH:25]([CH2:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:24][C@H:25]([CH2:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[C:26]([NH:1][C@H:2]([C:3]([C:5]2[O:6][CH:7]=[CH:8][N:9]=2)=[O:4])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC(CCc1ccccc1)[C@H](O)c1ncco1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Product: O=C(N[C@@H](CCc1ccccc1)C(=O)c1ncco1)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1

Procedure:
It is similarly prepared according to the general procedure for example 10 but using (S)-2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol and 2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid.
Reaction SMILES: C(NC1SC(S(Cl)(=O)=O)=C(C)N=1)(=O)C.C[O:16][C:17](=[O:81])[C@@H:18]([NH:34][C:35]([CH:37]1[CH2:46][C:45]2[CH:44]=[C:43]3[O:47][CH2:48][C@H:49]([C:51]4[CH:56]=[CH:55][C:54]([NH:57][C:58](=[O:67])[C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=5)=[CH:53][CH:52]=4)[O:50][C:42]3=[CH:41][C:40]=2[CH2:39][N:38]1[S:68]([C:71]1[S:75][C:74]([NH:76]C(=O)C)=[N:73][C:72]=1[CH3:80])(=[O:70])=[O:69])=[O:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[NH2:76][C:74]1[S:75][C:71]([S:68]([N:38]2[CH:37]([C:35]([NH:34][C@@H:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)[C:17]([OH:81])=[O:16])=[O:36])[CH2:46][C:45]3[CH:44]=[C:43]4[O:47][CH2:48][C@H:49]([C:51]5[CH:56]=[CH:55][C:54]([NH:57][C:58](=[O:67])[C:59]6[CH:64]=[CH:63][C:62]([Cl:65])=[C:61]([Cl:66])[CH:60]=6)=[CH:53][CH:52]=5)[O:50][C:42]4=[CH:41][C:40]=3[CH2:39]2)(=[O:70])=[O:69])=[C:72]([CH3:80])[N:73]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: Cc1nc(N)sc1S(=O)(=O)N1Cc2cc3c(cc2CC1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The methyl ester hydrochloride (10 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (7 mg) according to General Procedure E. The resulting (S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzoylamino)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (8 mg) was hydrolyzed according to General Procedures N and B to give the title compound. LCMS: (m/z) 924.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9](OC)=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH:9]=[O:10])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: COC(=O)c1nccnc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1nccnc1C=O
Reaction time: 0.17 h

Procedure:
To an cooled solution (−78° C. internal temp) of 1 g of methyl 3-methoxypyrazine-2-carboxylate in 50 mL of toluene was added 6 mL of 1 M diisobutyl aluminum hydride in toluene. After stirring 10 min the reaction was quenched with 5 mL of methanol and concentrated under reduced pressure. To a stirred solution of the residue in 100 mL of dichloromethane was added 10 mL of water, then 10 g of MgSO4. The mixture was filtered and 1.5 g of activated MnO2 was added. The mixture was heated to reflux under nitrogen for 5 h, then cooled and filtered. Concentration under reduced pressure gave the product as an odiferous solid: MS (m+1)=139.1; 1H NMR (400 MHz, CDCl3) 10.25 (s, 1H), 8.4 (m, 2H), 4.15 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:23][CH2:24][CH2:25][CH2:26][Br:27])=[CH:15][CH:14]=1)(=[O:3])C.Br[O-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:27][CH2:26][CH2:25][CH2:24][O:23][C:16]1[CH:15]=[CH:14][C:13]2=[C:22]3[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]3[C:1](=[O:3])[C:4]1[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=12
Reactant: CC(=O)c1c(-c2ccc(OCCCBr)c3ccccc23)oc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: O=C1c2c(oc3ccccc23)-c2ccc(OCCCBr)c3cccc1c23

Procedure:
Treatment of 3-acetyl-2-[4-(3-bromopropoxy)naphthyl]-benzofuran with sodium hypobromite followed by cyclization of the product with aluminum chloride as described above, gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:23][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NC1CCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(cyclobutyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.34 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.42 mmol of cyclobutylamine. LC/MS [9.86 min; 412 (M+1)]
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH3:20])=[O:4].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20][Br:21])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(CC2CCCCC2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCCCC2)c1CBr
Yield: 73.5 %

Procedure:
A mixture of 5-bromo-1-cyclohexylmethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (4.95 g, 14.5 mmol), N-bromosuccinimide (2.83 g, 15.9 mmol), and benzoyl peroxide (0.35 g, 1.45 mmol) in CCl4 (140 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (10% EtOAc/hexanes) to give 4.49 g of the title compound as a white solid. MS: (+) m/z 422.09 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[C:7]([OH:14])=[N:6]2)#[N:2].[N+:15]([O-])([OH:17])=[O:16]>>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:15]([O-:17])=[O:16])[N:9]=[C:8]([OH:13])[C:7]([OH:14])=[N:6]2)#[N:2]
Reactant: N#Cc1ccc2nc(O)c(O)nc2c1
Reactant: O=[N+]([O-])O
Product: N#Cc1cc2nc(O)c(O)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
1 g 6-Cyano-2,3-dihydroxyquinoxaline is added gradually to 10 ml of ice-cooled fuming nitric acid. The mixture is stirred at 25° C. for 1 h. The reaction mixture is poured into ice-water giving 1 g of a crude product. Recrystallization (DMF-water) gives 0.9 g (75%) of 6-cyano-2,3-dihydroxy-7-nitroquinoxaline, m.p. >300° C. IR: peak at 2240 cm-1,
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[N:25]1[CH:29]=[N:28][CH:27]=[N:26]1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[N:25]1[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-n2cncn2)c1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-n1cncn1

Procedure:
7-Bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was coupled with 4-fluoro-3-([1,2,4]triazol-1-yl)phenylboronic acid as described in Example 3, step f, final paragraph, to give the title compound: 1H NMR (360 MHz, DMSO-d6) δ 7.82 (1H, dd, J 8.7, 10.5 Hz), 8.34-8.39 (1H, m), 8.39 (1H, s), 8.71 (1H, dd, J 2.4, 7.4 Hz), 9.02 (1H, s), 9.13 (1H, d, J 2.4 Hz); MS (ES+) m/z 350 [M+H]+.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18].[F:19][C:20]([F:26])([F:25])[C:21](=[O:24])[CH2:22][CH3:23]>C1COCC1>[F:19][C:20]([F:26])([F:25])[C:21]([C:17]1[S:13][C:14]([SH:18])=[N:15][CH:16]=1)([OH:24])[CH2:22][CH3:23]
Reactant: CCC(=O)C(F)(F)F
Reactant: Sc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(O)(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
iPr2NH (2.0 g, 19.9 mmol) was dissolved in THF (23 mL) and cooled to −78° C. n-Butyllithium (2.5M, 8.0 mL, 19.9 mmol) was added dropwise, followed by thiazole-2-thiol (0.9 g, 7.9 mmol) in THF (5 mL). After 10 minutes, trifluoro-2-butanone (0.5 g, 4.0 mmol) was added and the reaction was stirred at −78° C. for 6 hours. The reaction was warmed to room temperature and quenched with 5% aqueous NH4Cl (20 mL). The aqueous layer was acidified and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% EtOAc in hexanes) to give the desired product, 10b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([I:15])=[C:11](I)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.[OH-].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([I:15])=[C:11]([O:25][CH2:24][C:21]3[CH:22]=[N:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c(I)c(I)cnn1-c1ccc(Cl)cc1
Reactant: OCc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(I)c(OCc2ccc(Cl)nc2)cnn1-c1ccc(Cl)cc1
Yield: 61.5 %

Procedure:
The procedures in Synthesis Example 2 were repeated by using 3.3 g (7.2 m mol) of 2-(4-chlorophenyl)-4,5-diiodo-3(2H)-pyridazinone, 1.1 g (7.7 m mol) of 6-chloro-3-pyridine-methanol, 0.4 g of potassium hydroxide and 80 ml of N,N-dimethylformamide to give 2.1 g of the intended product. (recrystallized from benzene)
Reaction SMILES: OC1C(=O)C2C(C(=O)C=1)=CC=CC=2.[CH2:14]([NH:18][CH:19]([C:31]1[C:32](=[O:43])[C:33]2[C:38]([C:39](=[O:42])[C:40]=1[OH:41])=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])CCC.C(NC(C1C(=O)C2C(C(=O)C=1)=CC=CC=2)CCCCCCCCCCC)CCC>>[CH3:14][NH:18][CH:19]([C:31]1[C:32](=[O:43])[C:33]2[C:38]([C:39](=[O:42])[C:40]=1[OH:41])=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCC(NCCCC)C1=C(O)C(=O)c2ccccc2C1=O
Agent: CCCCCCCCCCCC(NCCCC)C1=CC(=O)c2ccccc2C1=O
Agent: O=C1C=C(O)C(=O)c2ccccc21
Product: CCCCCCCCCCCC(NC)C1=C(O)C(=O)c2ccccc2C1=O

Procedure:
The yield relative to 2-hydroxy-1,4-naphthoquinone used for the preparation of 2-(1-butylaminododecyl)-3-hydroxy-1,4-naphthoquinone, was 80.1 mol %. Further, the yield relative to the starting material 2-(1-butylaminododecyl)-1,4-naphthoquinone, was 81.7 mmol %.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C@@H:17]([NH:19][C:20]1[N:25]3[N:26]=[CH:27][CH:28]=[C:24]3[N:23]=[C:22](S(C)(=O)=O)[N:21]=1)[CH3:18])=[CH:7]2.[BH4-].[Na+].O>CCO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C@@H:17]([NH:19][C:20]1[N:25]3[N:26]=[CH:27][CH:28]=[C:24]3[N:23]=[CH:22][N:21]=1)[CH3:18])=[CH:7]2
Reactant: COCCNc1nc2c(Cl)cccc2cc1[C@H](C)Nc1nc(S(C)(=O)=O)nc2ccnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCCNc1nc2c(Cl)cccc2cc1[C@H](C)Nc1ncnc2ccnn12
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
To a solution of Example 20 (60 mg, 0.12 mmol) in EtOH/CHCl3 (1:1; 1.2 mL) was added portionwise NaBH4 (9.6 mg, 0.25 mmol). After 10 minutes of stirring, water (1 mL) was added and the reaction mixture was concentrated in vacuo. The residue was partitioned between DCM and water. The organic layer was washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and concentrated in vacuo. The resulting gum was freeze-dried to give the title compound (30 mg, 60%) as an off-white solid. δH (CDCl3) 8.28 (1H, s), 7.96 (1H, d, J=2.14 Hz), 7.90 (1H, s), 7.65 (1H, dd, J 7.56, 1.39 Hz), 7.52 (1H, dd, J 7.97, 1.41 Hz), 7.12 (1H, t, J=7.76 Hz), 6.59 (1H, br d, J=9.42 Hz), 6.48-6.46 (2H, m), 5.75-5.66 (1H, m), 3.94-3.85 (1H, m), 3.83-3.74 (1H, m), 3.65-3.51 (2H, m), 3.18 (3H, s), 1.86 (3H, d, J=6.80 Hz). LCMS (ES+) 398 (M+H)+, RT 19.67 minutes (Method 6).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:18]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)=[N+:13]([O-])[CH:14]=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[N:5][N:6]2[CH3:35].O=P(Cl)(Cl)[Cl:43]>>[Cl:43][C:14]1[N:13]=[C:12]([C@@H:18]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[N:6]([CH3:35])[N:5]=[C:4]3[NH:36][S:37]([CH3:40])(=[O:38])=[O:39])=[CH:16][CH:15]=1
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc[n+]([O-])c3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
(S)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-(2-(3,5-difluorophenyl)-1-(2,2,2-trifluoroacetamido)ethyl)pyridine 1-oxide (57C, 1.0 g, 1.66 mmol) was treated with POCl3 (2.32 mL, 24.84 mmol). The reaction mixture was stirred at 115° C. for 2 hours. Upon cooling, the reaction was concentrated in vacuo, taken in DCM, and vigorously stirred with saturated aqueous NaHCO3 for 1 hour. The organic layer was collected, and the aqueous layer was extracted an additional time with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column chromatography, eluting with 0-100% EtOAc in hexanes to give the title compound. MS (m/z) 622.13 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]([CH2:15][CH2:16][O:17][CH3:18])[CH3:14])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1COCC1.ClCCl>[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:13]([CH2:15][CH2:16][O:17][CH3:18])[CH3:14])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: COCCN(C)c1ccc(OC)c2nc(N)sc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccc(CCl)cc3)sc12
Reaction time: 16 h
Yield: 42.5 %

Procedure:
To a stirred solution of 300 mg (1.12 mmol) 4-methoxy-N7-(2-methoxy-ethyl)-N7-methyl-benzothiazole-2,7-diamine and 1.12 ml (6.56 mmol) N-ethyldiisopropylamine in 10 ml THF at room temperature was added dropwise a solution of 257 mg (1.36 mmol) 4-(chloromethyl)-benzoyl chloride in 3 ml dichloromethane and stirring continued at room temperature for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether and hexane afforded 200 mg (42%) 4-chloromethyl-N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-benzamide as a light yellow crystalline solid. ES-MS m/e (%): 422 (M{37Cl}+H+, 32), 420 (M{35Cl}+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9]O.[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:20])=O)[CH:15]=[C:14]([CH3:21])[CH:13]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH:9]=[CH:20][C:18]([C:16]1[CH:17]=[C:12]([CH3:11])[CH:13]=[C:14]([CH3:21])[CH:15]=1)=[N:1]2
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: Nc1cccc(Cl)c1CO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3c(Cl)cccc3n2)c1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
(2-Amino-6-chlorophenyl)methanol (16 g, 102 mmol), 3,5-dimethylacetophenone (22.6 g, 152 mmol), RuCl2(PPh3)3 (0.973 g, 1.015 mmol), and KOH (10.25 g, 183 mmol) were refluxed in 270 mL of toluene for 18 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature, filtered through a silica gel plug and eluted with 5% ethyl acetate in hexanes. The product was further purified by Kugelrohr distillation to give 23.5 g of crude product, which was crystallized from 60 mL of MeOH to give 8.6 g (32% yield) of the desired product.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11](=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:9]2.Cl>C(OCC)C>[CH3:1][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH3:4])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C[Mg]Br
Reactant: COC(=O)C=C1CCc2cc(OC)ccc2C1=O
Agent: Cl
Solvent: CCOCC
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1C
Temperature: 180 °C
Reaction time: 1 h

Procedure:
To a mixture of 12 g of methyl magnesium bromide and 200 ml. of diethyl ether, 25 g. of 6-methoxy-2-(methoxycarbonylmethylene)-1-tetralone are added. The alkylating mixture is refluxed for one hour after it has been allowed to stand for one hour; the mixture is made acidic to litmus by the addition of 1N methanolic HCl, filtered, and evaporated. The residue, containing methyl 1-methyl-6-methoxy-3,4-dihydro-2-naphthylacetate, is added to 1 g. of 10% palladium-on-charcoal and the resulting mixture is heated to 180° C for six hours. The mixture is cooled, diluted with 200 ml. of chloroform, filtered, and evaporated to yield methyl 1-methyl-6-methoxy-2-naphthylacetate.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C[Sn](C)(C)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O1CCOCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1-c1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
In a 25 mL pear shaped flask was placed 5-iodo-2'-deoxyuridine (0.354 g, 1.0 mmol), 2-trimethylstannylpyridine (0.84 g, 3.5 mmol), Bis (triphenylphosphine)-palladium (II) chloride (0.070 g, 0.1 mmol), and anhydrous 1,4-dioxane (15 mL). The reaction was heated at 60° C. for 15 hrs then at 90° C. for 1 h. The solvent was evaporated and the residue purified by silica gel chromatography (10% CH3OH in CH2Cl2 (1% NH3)) to yield 0.253 g (83%) of the title compound as a white solid m.p. 201°-203° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([S:32]([N:35]2[C:43]3[CH:42]=[C:41]([Cl:44])[CH:40]=[C:39]4[CH2:45][CH2:46][CH:47]([CH2:48][C:49](O)=[O:50])[C:37]([C:38]=34)=[C:36]2[C:52]([O:54][CH3:55])=[O:53])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:26]1([S:32]([N:35]2[C:43]3[CH:42]=[C:41]([Cl:44])[CH:40]=[C:39]4[CH2:45][CH2:46][CH:47]([CH2:48][C:49](=[O:50])[NH:14][C:13]5[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][C:12]=5[O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:37]([C:38]=34)=[C:36]2[C:52]([O:54][CH3:55])=[O:53])(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)O
Reactant: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 103.1 %

Procedure:
A mixture of 4-tert-butoxycarbonylaminomethyl-2-tert-butoxycarbonylmethoxyaniline (202 mg, 0.574 mmol), methyl 1-benzenesulfonyl-7-chloro-3-carboxymethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (250 mg, 0.574 mmol), triethylamine (0.2 mL, 1.43 mmol), and N,N-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (Bop-Cl, 161 mg, 0.631 mmol) in dichloromethane (5 mL) was stirred for 15 h at room temperature and diluted with ethyl acetate. The mixture was washed successively with 5% potassium hydrogen sulfate, water, saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, and concentrated to give 463 mg of the title compound (quant): 1H NMR (CDCl3) δ8.63 (s, 1H), 8.33 (d, 1H, J=8.6 Hz), 8.03 (d, 2H, J=6.9 Hz), 7.92 (s, 1H), 7.58 (t, 1H, J=6.9 Hz); 7.52 (t, 2H, J=6.9 Hz), 7.06 (s, 1H), 6.94 (d, 1H, J=Hz), 6.80 (s, 1H), 4.82 (br, 1H), 4.35 (s, 2H), 4.12 (d, 2H, J=7.3 Hz), 3.89 (s, 3H), 3.86 (m, 1H), 3.03 (mt, 1H, J=14.7 Hz), 2.81 (m, 1H), 2.81 (dd, 1H, J=14.7, 4.3 Hz), 2.53 (dd, 1H, J=14.7, 10.4 Hz), 2.22 (m, 1H), 1.72 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:16])=[O:4].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][Br:17])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1oc(-c2ccccc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1oc(-c2ccccc2)nc1CBr

Procedure:
4-Methyl-2-phenyl-oxazole-5-carboxylic acid methyl ester (3.2 g, 14.7 mmol, prepared according to Cynkowski, T.; Cynkowska, G.; Ashton, P.; and Crooks, P. A. J. Chem. Soc., Chem. Commun. 1995, 2335), N-bromosuccinimide (2.69 g, 15.1 mmol), and benzoyl peroxide (356 mg, 1.47 mmol) were suspended in 37 mL of benzene and the mixture heated at reflux temperature for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-40% ethyl acetate in hexanes to give 1.88 g of the title compound as a yellow solid. MS: (+) m/z 296.0, 298.0 (M+1, 79Br/81Br).