Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].C(O[C:24]1[CH:25]=C(C=C[C:31]=1C)C=O)C>CN(C=O)C>[CH:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:24]([CH3:25])[CH3:31])[CH:5]=[O:6])([CH3:14])[CH3:13]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: CC(C)Br
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1OC(C)C

Procedure:
The title compound was prepared by reaction of 3,4-dihydroxybenzaldehyde with 2-bromopropane in DMF using K2CO3 as base in analogy to the preparation of 3-ethoxy-4-methyl-benzaldehyde (intermediate D2).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][NH:13][NH2:14]>C(O)(=O)C.O>[OH:6][C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[N:13]([CH3:12])[N:14]=1
Reactant: CNN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(O)c2ccccc2c1=O

Procedure:
Phthalic anhydride (7.4 g) was dissolved in hot acetic acid (50 ml) and a solution of methylhydrazine (2.7 ml) in water (50 ml) was added. The mixture was heated under reflux for 15 minutes and left to cool overnight. The precipitate that formed was filtered off, washed with water and dried under reduced pressure at 65° C. to yield 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalazine (7.6 g) as a white solid. m.p. 243-244° C.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[NH2:3].[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>CO>[NH2:17][C:16]1[N:2]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[N:3]=[C:14]([C:13]([CH3:20])([CH3:19])[CH3:12])[CH:15]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Yield: 82.1 %

Procedure:
A flask was charged with 4-hydrazinylbenzonitrile hydrochloride (0.70 g, 3.8 mmol.), 4,4-dimethyl-3-oxopentanenitrile (0.48 g, 3.8 mmol) and MeOH and the reaction was heated at refluxed overnight. The reaction was cooled, and the solids which formed upon cooling were filtered off and discarded. Additional solids formed upon further standing (product) along with product material in solution. The solution containing, the solids was concentrated to yield 0.75 g of solid product (92%). MS M+1 (241).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:10](=[O:13])[CH2:11][CH3:12])[OH:9].[H-].[Na+].[CH3:16]I>CN(C)C=O.O>[CH3:16][O:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)N(O)c1ccccc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N(OC)c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 25 to 30° C., a solution of 22.7 g (0.127 mol) (Example 6a) of N-(2-methylphenyl)-N-propionyl-hydroxylamine in 50 ml of dimethylformamide is dripped into a stirred mixture of 3.4 g (0.14 mol) of NaH in 150 ml of dimethylformamide. After completion of gas evolution (15 mins) 18.4 g (0.13 mol) of methyl iodide is added and the mixture is stirred overnight at room temperature. The reaction mixture is then diluted with water and the aqueous phase is extracted three times with methyl tert-butyl ether. The combined organic phases are extracted with water, dried over MgSO4 and evaporated down. The residue is purified by column chromatography with mixtures of cyclohexane and ethyl acetate. There is obtained 18 g (0.081 mol=64%) of the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[O:12][C:11](=[O:13])[CH:10]=[C:9]2[OH:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:29][NH:30]2)=[CH:26][CH:25]=1>>[CH:1]1([CH2:7][CH:8]2[O:12][C:11](=[O:13])[C:10]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:29]3[NH:30][C:31]4[C:27]([C:28]=3[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:26][CH:25]=[C:24]([F:23])[CH:32]=4)=[C:9]2[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1C=C(O)C(CC2CCCCC2)O1
Reactant: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Reactant: O=Cc1ccccc1
Product: CC(=O)NCCc1c(C(C2=C(O)C(CC3CCCCC3)OC2=O)c2ccccc2)[nH]c2cc(F)ccc12

Procedure:
Using general procedure C, 5-cyclohexylmethyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-acetamide (Example 18.1.) to give the title compound as pale red solid. MS: 503.0 ([M−H]−).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[S:29][CH:30]=[CH:31][C:32]=1B(O)O)(=[O:27])[CH3:26]>>[C:25]([C:28]1[S:29][CH:30]=[CH:31][C:32]=1[C:5]1[CH:6]=[CH:7][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:24])(=[O:27])[CH3:26]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: CC(=O)c1sccc1B(O)O
Product: CC(=O)c1sccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 20 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-acetyl-3-thienylboronic acid (available from Aldrich Chemical Company, Inc.; 68 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2-(2-acetyl-thiophen-3-yl)-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid (19 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 13.12 (br s, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.94 (d, J=5.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.10 (d, J=5.0 Hz, 1H), 2.08 (s, 3H).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:14]2[O:18][C:17](=[N:19][NH2:20])[C:16](=C=O)[CH2:15]2)[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11].[C:23](O)(=[O:25])C>CN(C)C=O>[OH:25][CH2:23][CH:15]1[C:14]([C:6]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=2)=[N:20][NH:19][C:17](=[O:18])[CH2:16]1
Reactant: COc1cc(C2CC(=C=O)C(=NN)O2)cc(OC)c1OC
Reactant: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C2=NNC(=O)CC2CO)cc(OC)c1OC

Procedure:
7.0 g (0.222 mol) of the compound prepared in section (a) are stirred in 20 ml of dimethylformamide and 1 ml of acetic acid at 80° C. for 5 hours. After the mixture has been concentrated, the residue is taken up in methylene chloride, the methylene chloride mixture is washed with potassium carbonate solution and concentrated and the residue is recrystallised from ethanol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.[BH4-].[Na+]>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:18][CH:19]=1)=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)OCc2ccc(C=O)cc2)cc1C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)OCc2ccc(CO)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 g (5 mmol) of the aldehyde obtained in Example 45, 50 ml of THF and 50 ml of methanol are introduced into a round-bottomed flask. 100 mg (2.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:23])=[C:9]([CH:22]=1)[CH2:10][N:11]([CH3:21])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:4]>CCO>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:6]=[CH:7][C:8]([F:23])=[C:9]([CH:22]=1)[CH2:10][N:11]([CH3:21])[CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15]
Reactant: NO
Reactant: CN(CCC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1F
Solvent: CCO
Product: CN(CCC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Hydroxylamine (50% in water) (513.54 μL; 8.55 mmol; 5 eq.) was added to a solution of tert-butyl N-(5-cyano-2-fluorobenzyl)-N-methyl-beta-alaninate, obtained in step 1 (500 mg; 1.71 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at RT for 24 hours. Solvent was evaporated in vacuo and the resulting oily residue was freeze-dried to afford the title compound as a colourless oil (560 mg; quantitative). 1H NMR (CDCl3) δ 7.74 (dd, J=6.6, 2.2 Hz, 1H), 7.58-7.53 (m, 1H), 7.03 (t, J=9.1 Hz, 1H), 5.10 (s, 2H), 3.59 (s, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.44 (t, J=6.9 Hz, 2H), 2.28 (s, 3H), 1.46 (s, 9H). LC/MS (Method B): 326.2 (M+H)+. HPLC (Method A) Rt 2.18 min (Purity: 86.2%).
Reaction SMILES: [H-].[Li+].CN(P(N(C)C)(N(C)C)=O)C.CC(S)(C)C.C[O:20][C:21](=[O:50])[C:22]([CH3:49])([CH3:48])[CH2:23][C:24]1[N:25]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[C:26]2[C:31]([C:32]=1[S:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:29]([O:38]C)=[CH:28][CH:27]=2>CN(C=O)C>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:25]2[C:26]3[C:31](=[CH:30][C:29]([OH:38])=[CH:28][CH:27]=3)[C:32]([S:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:24]2[CH2:23][C:22]([CH3:49])([CH3:48])[C:21]([OH:50])=[O:20])=[CH:46][CH:45]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)(C)S
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of LiH (12.6 g) and HMPA (105 mL) in DMF (1050 mL) at 0° C. was added 2-methyl-2-propanethiol (178 mL). The mixture was stirred at room temperature for 30 min, then 3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid methyl ester (150 g) (EP 419,049, Example 1, Step A) in DMF (450 mL) was added slowly. The mixture was slowly heated to 150° C. and kept at that temperature for 18 hours. After cooling to room temperature, the supernatant layer was decanted and the residue dissolved in H2O and acidifed with 1N HCl, extracted twice with Et2O, washed twice with brine, dried over MgSO4, filtered and evaporated to dryness to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:28](=[O:30])[CH3:29])[N:12]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2N)co1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCc1nc(-c2ccccc2NC(C)=O)co1
Temperature: 25 °C

Procedure:
Dissolve 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (4.05 g, 14.8 mmol) and triethylamine (2.26 mL, 16.2 mmol) in THF (40 mL) and stir at room temperature. Add acetyl chloride (1.16 mL, 16.2 mmol) and allow the mixture to stir overnight at room temperature. Concentrate the mixture and partition the residue between aq NaHCO3 and EtOAc. Dry the combined extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) which allows for the isolation of 5-[4-(2-acetylamino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.51 g, 75%). MS (ES): (M+1)+ 317.2 m/z.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:44][CH:45]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1SC(Cc2ccc(OCCn3ccc4cccnc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(OCCn3ccc4cccnc43)cc2)S1
Yield: 55.8 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 2.50 g of 5-{4-[2-(7-aza-indol-1-yl)ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 19), 50 ml of methylene chloride and 3.1 ml of trifluoroacetic acid were used, to give 0.84 g of the title compound, melting at 200.0°-202.4° C.
Reaction SMILES: O1CCCCC1O[CH:8]([C:12]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:9]([NH2:11])=[O:10].N1C=CC=CC=1.[CH3:39][O:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:43](Cl)=[O:44].[OH2:50]>C(Cl)(Cl)Cl>[OH:50][NH:11][C:9](=[O:10])[CH2:8][C:12]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][N:15]([C:43](=[O:44])[C:42]2[CH:46]=[CH:47][CH:48]=[CH:49][C:41]=2[O:40][CH3:39])[CH2:14][CH2:13]1
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(=O)C(OC1CCCCO1)C1(c2ccc(-c3ccc(Cl)cc3)s2)CCNCCS1(=O)=O
Reactant: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C(=O)N1CCC(CC(=O)NO)(c2ccc(-c3ccc(Cl)cc3)s2)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of N-(2-tetrahydropyranyloxy-2-[7-(5-(4-chlorophenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (90 mg) and pyridine (0.5 ml) in chloroform (3 ml) was added 2-methoxybenzoyl chloride (37 mg) and the mixture was stirred at ambient temperature for 3 hours. The mixture was pertitioned between water and chloroform. The organic layer was separated, washed with 5% citric acid water solution, water, saturated sodium bicarbonate solution and brine. To the reaction mixture were added 4N hydrogen chloride-ethyl acetate solution (0.5 ml), chloroform (1 ml) and methanol (1.5 ml) and the reaction mixture was stirred at ambient temperature for 30 minutes. After evaporation of solvent, the residue was purified by HPLC (0.1% trifluoroacetic acid in 20% acetonitrile-water ˜0.1% trifluoroacetic acid in 80% acetonitrile-water) to give N-hydroxy-2-[7-(5-(4-chlorophenyl)-2-thienyl)-4-(2-methoxybenzoyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (54 mg) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][C@H:17]1[O:22][C@@H:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[CH3:23][C@H:21]1[O:22][C@@H:17]([CH3:16])[CH2:18][N:19]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:20]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2C[C@@H](C)O[C@@H](C)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and cis-2,6-dimethylmorpholine (6.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (9.9 mg). Calcd for C17H20N2O3: 300.1474, found 300.1472.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12](O)[CH2:11][NH:10][C:9]1=[O:16])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:63]=[N+:64]=[N-:65])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:14][CH2:13][C@H:12]([N:63]=[N+:64]=[N-:65])[CH2:11][NH:10][C:9]1=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N=[N+]=[N-])CNC1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 70.3 %

Procedure:
To a stirred solution of ((3S,6R)-6-hydroxy-2-oxo-azepan-3-yl)carbamic acid tert-butyl ester (3 g, 12.3 mmol example 1 f) and triphenylphosphine (3.75 g, 14.1 mmol) in THF (200 mL) at 0° C. is added diethyl azodicarboxylate (2.2 mL, 13.5 mmol) at a rate to maintain a temperature <5° C. followed immediately by addition of diphenylphosphoryl azide (2.9 mL, 13.5 mmol). The reaction is stirred for 60 h at room temperature in the dark, the solvent is removed under vacuum and the residue chromatographed on silica (hexane to ether gradient) to give 2.33 g (70%) of ((3S,6S)-6-azido-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester as a solid. MS (ESI) 270 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH3:12])=[CH:5]2.CN(C)[CH:15]=[CH:16][N+:17]([O-:19])=[O:18]>FC(F)(F)C(O)=O.CCOC(C)=O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH3:12])=[C:5]2/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18]
Reactant: CN(C)C=C[N+](=O)[O-]
Reactant: CCc1cc2cc(Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCc1[nH]c2ccc(Cl)cc2c1/C=C/[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The indole 3 (5 mmol) was added to a stirred ice-cooled solution of 1-(dimethylamino)-2-nitroethylene (0.58 g, 5 mmol) in trifluoroacetic acid (5 mL). The mixture was stirred at room temperature under N2, for 0.5 h and then poured onto ice water. The aqueous solution was extracted with ethyl acetate, the combined organic layers were washed with a saturated NaHCO3 solution and then with water. After drying over Na2SO4, the solvent was evaporated under reduced pressure to give a crude orange solid which was suspended in a mixture of EtOAc-Et2O and filtered, or chromatographed on silica gel (cyclohexane/EtOAc, 1:1, as eluent).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:23]=[C:24]([NH2:35])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1.Cl.N1C=CC=CC=1>C(OCCO)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:21][C:22]1[CH:23]=[C:24]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:19]#[N:20])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1O
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
A mixture of 1.0 g (3.53 mmol) of 4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.93 g (3.88 mmol) of 3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamine and 0.41 g (3.52 mmol) of pyridine hydrochloride in 20 mL of 2-ethoxyethanol is heated at 120° C. for 2 hours, then cooled to room temperature. The product mixture is diluted with a saturated solution of sodium carbonate, stirred for 15 minutes and the solid is collected by filtration. The solid is washed with water and dried in vacuo. The crude product is purified by silica gel chromatography, utilizing a 95:5 to 9:1 gradient of methylene chloride/methanol to give 1.13 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp>300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:15][CH2:16][O:17][CH3:18])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
5-Chloro-2-nitro-pyridine-3-ol (1.15 mmol) is dissolved in DMF (2 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added and the suspension is stirred 45 min at room temperature. 1-Bromo-2-methoxy-ethane (1 eq.) is added and the reaction suspension is heated to 100° C. for 24 hours. The reaction solution is pored into water and extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-Chloro-3-(2-methoxy-1-ethoxy)-2-nitro-pyridine is obtained after column chromatography as beige solid in a yield of 60%; mp. 71.5-72.5°; HPLC (method C): 1.63 min; LC-MS (method A): 1.36 min, 232.95 (M+H+).
Reaction SMILES: [C:1]([O:5]CC(O)C)(=[O:4])[CH:2]=[CH2:3].CC1C(N=C=O)=CC([N:17]=[C:18]=[O:19])=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.COC1C=CC(O)=CC=1.C([C:53]1C=C(C)C=C(C(C)(C)C)[C:54]=1[OH:64])(C)(C)C>>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:17][C:18]([O:64][CH2:54][CH3:53])=[O:19]
Reactant: C=CC(=O)OCC(C)O
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C
Reaction time: 7 h

Procedure:
260 g (2 mol) of 2-hydroxypropyl acrylate (molecular weight 130) was placed in a flask equipped with a stirring blade, and with constant stirring, 174 g (1 mol) of TDI (2,4-tolylene diisocyanate) was added dropwise, with care taken over the generated heat, and the temperature was raised to 70° C. 1 g of dibutyl tin diacetate, 0.2 g of hydroquinone monomethyl ether and 1 g of 2,6-di-t-butyl-4-methylphenol were then added. Reaction was allowed to proceed at this temperature for 7 hours, and once the disappearance of NCO absorption had been confirmed via an infrared absorption spectrum, the reaction mixture was removed, yielding a urethane acrylate (A-X) as the radical polymerizable oligomer (A). The number average molecular weight of the synthesized urethane acrylate (A-X) was 434.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:45][O:44][CH2:43][CH2:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1
Reactant: COCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-(2-methoxyethoxy)phenyl borate (124 mg) and potassium carbonate, (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (40 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-[4-(2-methoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 53) (246 mg).