Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[NH:3][CH2:2]1.[H-].[Na+].Cl[C:11]([CH3:15])([CH3:14])[C:12]#[CH:13]>CN(C)C=O>[CH3:14][C:11]([N:3]1[CH2:2][CH2:1][CH2:7][S:4]1(=[O:6])=[O:5])([C:12]#[CH:13])[CH3:15]
Reactant: C#CC(C)(C)Cl
Reactant: O=S1(=O)CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)N1CCCS1(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a stirred solution of 1,3-propanesultam (2.000 g, 16.5 mmol) in anhydrous N,N-dimethylformamide (30 mL) at 0° C. was added 60% sodium hydride in mineral oil (1.981 g, 49.5 mmol) and the mixture was stirred at 0° C. for 1 hr. 3-Chloro-3-methyl-1-butyne (2.300 g, 22.4 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hr and then slowly warmed to room temperature and stirred for 16 hrs. The reaction was carefully quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography (0-70% ethyl acetate/hexanes) to afford the desired product as a yellow oil (1.35 g, 44%). 1H NMR (300 MHz, CDCl3) δ 3.52 (t, 2H, J=6.6 Hz), 3.23 (t, 2H, J=7.5 Hz), 2.46 (s, 1H), 2.42-2.28 (m, 2H), 1.74 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([N:7]1[CH2:12][CH2:11][C:10]([F:15])([CH2:13][OH:14])[CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[C:5]([N:7]1[CH2:12][CH2:11][C:10]([F:15])([CH:13]=[O:14])[CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC(F)(CO)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1(F)CCN(C(=O)c2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
2.48 g of pyridine-SO3 complex (15.5 mmol) are added in a single portion to a solution of 1.5 g of 1-(3-Chloro-4-fluorobenzoyl)-4-fluoro-4-piperidine-methanol (5.18 mmol), 2.16 ml of triethylamine (15.5 mmol) and 15 ml of anhydrous DMSO. After stirring for 3 hours at room temperature, the yellow solution obtained is poured into an ice-water mixture and extracted twice with ethyl acetate. The organic phases are washed with aqueous 5% citric acid solution and then with salt water, dried over MgSO4 and filtered and the solvent is removed under vacuum. 1.49 g (quantitative yield) of a yellow oil are obtained, this product being used without further purification in the following step.
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[N:22]=[C:23]=[O:24].CCOCC>C1COCC1>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:23]([NH:22][C:13]2[CH:14]=[C:15]([C:18]([F:19])([F:21])[F:20])[CH:16]=[CH:17][C:12]=2[F:11])=[O:24])=[C:4]([F:10])[CH:3]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cc1cc(N)c(F)cc1Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c(F)cc1Br

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylaniline (500 mg, 2.45 mmoL) in THF (3 mL) was added the 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (625 mg, 3.0 mmol). The reaction generated a white solid within 10 min. An additional portion of THF (3 mL) was added and the mixture dissolved. TLC analysis (1:1 Et2O:Hex) indicated that the reaction was complete. The product was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O). 1H-NMR (DMSO-d6) δ 9.37 (d, J=2.8 Hz, 1H), 9.17 (d, J=2.4 Hz, 1H), 8.61 (dd, J=7.2, 2 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.55 (d, J=10.8 Hz, 1H), 7.49 (dd, J=10.8, 8.8 Hz, 2H), 7.39 (m, 1H), 2.29 (s, 3H); MS [M+H]+=409.3, LCMS RT=3.91 min.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:34][CH:35]=[CH:36][C:37]=1[CH3:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:37]1[CH:36]=[CH:35][S:34][C:33]=1[CH2:32][N:7]1[C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:2]1=[O:1]
Reactant: Cc1ccsc1CCl
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccsc1Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2sc(-c3ccccc3)cc21

Procedure:
According to the procedure described for compound B71 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1.09 g, compound B50) is reacted with 2-(chloromethyl)-3-methylthiophene (410 mg, compound D28) in the presence of potassium carbonate (778 mg) in dry DMF (14 ml) for 1 h at 100° C. to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6]
Reactant: OCC#CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 90 g (1.07 mol) of 2-butyne-1,4-diol and 9 g of p-toluenesulfonic acid in 1000 ml of tetrahydrofuran, cooled to 0° C., there were added dropwise 104.88 ml (96.69 g, 1.15 mol) of dihydropyran, and thereafter the reaction mixture was stirred for 3 hours at room temperature. It was then neutralized with triethylamine and evaporated in vacuo. The residue was purified by silica gel column chromatography (2000 g) using hexane-ethyl acetate (80:20) as eluant, to yield 2-butyne-1,4-diol monotetrahydropyranyl ether and a small amount of the bis-tetrahydropuranyl ether.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=3)[C:5]=2[N:6]=1.[Br-].[C:23]1([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=4)[C:5]=3[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)COc1ccc2c(c1)CCc1sc(S)nc1-2
Agent: [Br-]
Product: O=C(O)COc1ccc2c(c1)CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Yield: 50 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-7-yl)oxy]acetate and diphenylmethane bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 50%.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1>O1CCCC1>[F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:25]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc(C(F)(F)F)c(F)c1F
Solvent: C1CCOC1
Product: NC(=S)c1ccc(C(F)(F)F)c(F)c1F
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 186.4 %

Procedure:
A suspension of 2,3-difluoro-4-trifluoromethyl-benzamide (1 g, 4.4 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent; 900 mg, 2.2 mmol) in tetrahydrofuran (2 ml) was stirred under microwave irradiation at 130° C. for 15 min. The solvent was removed under reduced pressure to give an orange oil which was purified by column chromatography (silica gel, heptane/AcOEt) to yield 1.0 g (4.1 mmol, 93%) of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[OH:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].S(Cl)(Cl)=O.[CH2:34](Cl)[Cl:35]>>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[O:9][CH2:34][Cl:35])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCCl
Temperature: 70 °C

Procedure:
A solution of 18.5 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate, 50 ml of methylene chloride and 50 ml of thionyl chloride was stirred at 20° to 25° C. for 2 hours and was then evaporated to dryness. The residue was admixed with 1.38 g of paraformaldehyde and 0.15 g of zinc chloride and the suspension was heated at 70° C. for 21/2 hours. After treatment, the product was chromatographed over silica gel and eluted with an 8-2 hexane-ethyl acetate mixture to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-chloromethoxy-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-:3])=[O:2].[NH:14]1[CH2:16][CH2:15]1.O>CS(C)=O>[N:14]1([C:10]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:9]=2)[C:6]([NH2:8])=[O:7])[CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CN1
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(N2CC2)ccc1[N+](=O)[O-]
Temperature: -5 °C
Yield: 47 %

Procedure:
A stirred solution of 2-nitro-5-fluorobenzamide (Orrin, Eur. Pat. Appl. 19,388; Chem. Abstr. 1981, 94, 156538h) (480 mg, 2.61 mmol) in dry DMSO (2 mL) was treated with aziridine (0.54 mL, 10.4 mmol) at room temperature under N2 for 48 h, then poured into cold water (50 mL). Prolonged cooling at −5° C. gave a crystalline product that was collected and filtered throuhg a column of silica gel in EtOAc to give 11 (256 mg, 47%), mp (EtOAc) 172-174° C. 1H NMR [(CD3)2SO] δ8.01 & 7.61 (2xs, 2H, CONH2), 7.93 (d, J=8.9 Hz, 1H, H-3), 7.17 (dd, J=8.8, 2.4 Hz, 1H, H-4), 7.09 (d, J=2.3 Hz, 1H-6), 2.24 (s, 4H, aziridine-H ). Anal. Calcd. for C9H9N3O3: 52.17;H, 4.38; N, 20.29 Found: C, 52.29;H, 4.27; N, 20.25%.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:30]1[CH:31]=[C:32]([C:40]2[CH:41]=[C:42]([CH3:48])[C:43](=[O:47])[N:44]([CH3:46])[CH:45]=2)[CH:33]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:35]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:46][N:44]1[CH:45]=[C:40]([C:32]2[CH:31]=[C:30]([O:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[CH:35]=[C:34]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:33]=2)[CH:41]=[C:42]([CH3:48])[C:43]1=[O:47]
Reactant: C[C@H](O)c1ccccc1
Reactant: Cc1cc(-c2cc(O)cc(S(C)(=O)=O)c2)cn(C)c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(O[C@H](C)c3ccccc3)cc(S(C)(=O)=O)c2)cn(C)c1=O
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of (1S)-1-phenylethan-1-ol (14 mg, 0.11 mmol) in THF (1 mL) stirred at rt under an atmosphere of nitrogen was treated with triphenylphosphine (38 mg, 0.15 mmol) and 5-(3-hydroxy-5-methylsulfonylphenyl)-1,3-dimethylpyridin-2-one (33 mg, 0.11 mmol). After 30 min, the reaction mixture was treated with DIAD (29 mg, 0.15 mmol). The nitrogen inlet was removed and the mixture was stirred (closed system) for 18 h. After the reaction mixture was diluted with EtOAc (10 ml), it was washed with water, saturated sodium bicarbonate solution (aq), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was diluted with ACN (1 mL) and was purified by prep-HPLC to afford the title compound (21 mg, 48%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (d. J=6.4, 3 H) 2.08 (s, 3H) 3.20 (s, 3H) 3.52 (s, 3H) 5.70-5.80 (q. J=6.4, 1H) 7.23-7.31 (m, 2H) 7.35-7.41 (m, 2H) 7.44-7.51 (m, 3H) 7.56-7.63 (m, 1H) 7.73-7.80 (m, 1H) 8.08-8.15 (m, 1H). LCMS (M+H)+=398.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:12][CH:13]([F:43])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[N:26]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)[C:29]([CH3:31])=[CH:30][C:25]2=[N:24][C:23]=1[CH3:42]>C(Cl)Cl>[F:43][CH:13]([F:12])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]1[N:26]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([NH:41][C:1](=[O:3])[CH3:2])(=[O:39])=[O:40])=[CH:34][CH:33]=3)[C:29]([CH3:31])=[CH:30][C:25]2=[N:24][C:23]=1[CH3:42]
Reactant: Cc1cc2nc(C)c(Cc3ccccc3OC(F)F)n2cc1-c1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cn3c(Cc4ccccc4OC(F)F)c(C)nc3cc2C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 14.6 %

Procedure:
Acetyl chloride (24 μL, 0.34 mmol) and triethylamine (47 μL, 0.34 mmol) were added to a solution of Example 78 (154 mg, 0.34 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2.5 h. Further acetyl chloride (12 μL, 0.17 mmol) and triethylamine (23 μL, 0.17 mmol) were added, and the mixture was stirred at room temperature for 24 h. Further acetyl chloride (49 μL, 0.68 mmol) and triethylamine (94 μL, 0.34 mmol) were added, and the mixture was stirred for 3 days. The solvent was removed and the mixture was purified by silica gel chromatography, eluting with a 0-5% gradient of 7M ammonia/methanol in DCM, to afford the title compound (24.8 mg, 14%) as a white solid. δH (250 MHz, CDCl3) 8.09 (d, J 8.4 Hz, 2H), 7.64 (d, J 19.1 Hz, 2H), 7.42 (s, 1H), 7.35 (d, J 8.3 Hz, 2H), 7.26 (m, 1H), 7.07 (td, J 8.4, 2.1 Hz, 2H), 6.94-6.24 (m, 2H), 4.24 (s, 2H), 2.49 (s, 3H), 2.25 (s, 3H), 2.09 (s, 3H). Method A HPLC-MS: MH+ m/z 500, RT 1.96 minutes (100%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][NH:4][C:3]1=[O:7].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1>Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:1][N:2]2[CH:6]=[N:5][NH:4][C:3]2=[O:7])[CH:9]=1
Reactant: O=Cc1cccnc1
Reactant: Nn1cn[nH]c1=O
Agent: Cl
Product: O=c1[nH]ncn1N=Cc1cccnc1

Procedure:
A mixture of 4 g of 4-amino-1,2,4-triazol-3-one and 100 ml of alcohol is heated to the reflux temperature and 4.3 g of pyridine-3-carbaldehyde and 2 drops of 6N hydrochloric acid are added thereto. After 30 minutes under reflux the reaction mixture is cooled to 20°. The product that has precipitated is then filtered off with suction and dried under a high vacuum. 4.6 g of the title compound having a melting point of 264°-265° are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)nc(N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)c([N+](=O)[O-])c(N)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
6.0 g(0.04911 mole) of 2-amino-4,6-dimethyl pyridine was dissolved in 20 ml of conc. sulfuric acid. The reaction solution was cooled to 0° C. in an ice bath and thereto was added dropwise 2.3 ml(0.04911 mole) of conc. nitric acid diluted with 5 ml of conc. sulfuric acid over 10 minutes. The resultant was stirred for 30 minutes at 0° C. and then added into ice water slowly to terminate the reaction. The reaction solution was neutralized to pH 7-8 with 20% aqueous sodium hydroxide solution and extracted with ethyl acetate(100 ml×3). The organic layer was dried over sodium sulfate anhydride and concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to obtain 4.26 g of the title compound as a yellow solid(yield 52%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C@H:5]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[N:29][N:28]=2)=[CH:17][CH:16]=1)[C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:6]=O.N1C=CC=CC=1>O>[OH:3][N:2]=[CH:4][C@@H:5]([N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:30]=[N:29][N:28]=2)=[CH:19][CH:20]=1)[C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH3:6]
Reactant: NO
Reactant: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=NO
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
Hydroxylamine hydrochloride (25.4 mg, 0.4 mmol) was added to a solution of intermediate (5c) (174 mg, 0.3 mmol), pyridine (3 mL, 37 mmol) and water (1.5 mL, 83 mmol) at room temperature. After 15 minutes, water (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated aqueous NaCl (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography gave intermediate (5d) as a white solid (148 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[NH2:7].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15]>CO>[CH3:12][O:11][C:9]1[CH:10]=[C:4]([O:3][CH3:2])[CH:5]=[C:6]2[C:8]=1[C:13](=[O:17])[C:14](=[O:15])[NH:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(N)cc(OC)c1
Agent: Cl
Solvent: CO
Product: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Temperature: 25 °C

Procedure:
A mixture of 3,5-dimethoxyaniline hydrochloride (54.7 g), oxalyl chloride (54 ml) and methanol (500 ml) was stirred and heated to reflux for 1.5 hours. The mixture was cooled to ambient temperature. The precipitate was isolated, washed in turn with methanol and diethyl ether and dried under vacuum to give 4,6-dimethoxy-2,3-dioxoindoline (55 g); NMR Spectrum: (DMSOd6) 3.85 (s, 3H), 3.9 (s, 3H), 6.0 (s, 1H), 6.2 (s, 1H), 10.9 (s, 1H); Mass Spectrum: M+Na+ 230.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:33]([NH2:36])(=[O:35])[CH3:34].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[C:33]([NH:36][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1)(=[O:35])[CH3:34]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: CC(N)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 110 °C

Procedure:
To a suspension of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (100 mg, 0.22 mmol), Cs2CO3 (158 mg), acetamide (20 mg), and xantphos (13 mg) in dry 1,4-dioxane (2 mL) was degassed with bubbling N2. Pd2 dba3 was added and the 10 mL tube was sealed and heated at 110° C. for 8 hr. After cooling to room temp., the mixture was diluted with water and extracted with ethylacetate. The combined organics were concentrated and the crude residue obtained purified by reverse phase HPLC to give 151. 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.65 (m, 2H), 7.62 (m, 2H), 7.35 (m, 2H), 7.17 (m, 1H), 6.51 (br s, 1H), 4.15 (m, 2H), 3.29 (s, 3H), 2.91 (m, 2H), 2.03 (s, 3H) MS: (ESI+) 427.1
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([C:22](OCC)=[O:23])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2].O>O1CCCC1>[CH:27]([C:6]1[C:7]([CH2:22][OH:23])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(F)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
257 ml (0.9 mol) of a 3.5 molar solution of sodium-bis-(2-methoxy-ethoxy)dihydroaluminate is steadily added by drops under nitrogen to a solution of 120 g (0.3 mol) of the compound from Example VIII in 800 ml of dried tetrahydrofuran at room temperature, and the mixture is subsequently stirred for 5 h. After cooling to 0° C., 500 ml of water is carefully added by drops, the phases are separated, and the aqueous phase is extracted three times with 250 ml ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in a vacuum. The residue is mixed with petroleum ether, drawn off by suction, and dried in a desiccator.
Reaction SMILES: [S:1]=[C:2]1[NH:14][C:13](=[O:15])[C:5]2=[CH:6][C:7]3[C:12]([N:4]2[NH:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CI.[C:18]([O-])(O)=O.[Na+]>O1CCCC1>[CH3:18][S:1][C:2]1[NH:14][C:13](=[O:15])[C:5]2=[CH:6][C:7]3[C:12]([N:4]2[N:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C([O-])O
Reactant: O=c1[nH]c(=S)[nH]n2c1cc1ccccc12
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nn2c(cc3ccccc32)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Into a round-bottom flask 2-thioxo-2,3-dihydro-1H-[1,2,4]triazino[1,6-a]indol-4-one (9.25 g, 0.04 mol) and methyl iodide (3.42 mL, 0.0549 mol) were combined in tetrahydrofuran (200 mL). The reaction was stirred at 45° C. for one hour. The solvent was removed under vacuum to give a solid, which was next stirred for 30 minutes with saturated aqueous NaHCO3 (100 mL). The solid was filtered and washed with water, then dried on high vacuum and further by azeotrop distillation with toluene to give 2-methylsulfanyl-3H-[1,2,4]triazino[1,6-a]indol-4-one (7 g, 71%), which was used in the next step without further purification. 1H-NMR (DMSO-d6) δ 12.28 (br s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.43 (m, 1H), 7.28 (m, 1H), 7.18 (s, 1H), 2.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Br:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.Br[CH2:12][C:13](=[C:15]([C:18]#[N:19])[C:16]#[N:17])[CH3:14]>C(O)(C)C.O1CCCC1>[NH2:19][C:18]1[N:8]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([Br:10])=[CH:5][C:6]=2[Br:9])[CH:12]=[C:13]([CH3:14])[C:15]=1[C:16]#[N:17]
Reactant: Nc1c(Cl)cc(Br)cc1Br
Reactant: CC(CBr)=C(C#N)C#N
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1cn(-c2c(Cl)cc(Br)cc2Br)c(N)c1C#N
Yield: 26.3 %

Procedure:
A mixture of 5.3 g of 6-chloro-2,4-dibromoaniline and 3.5 g of 2-(2-bromo-1-methylethylidene)malononitrile was dissolved in a mixed solution of 10 ml of isopropanol and 10 ml of tetrahydrofuran. The reaction mixture was heated for 2 hours while being concentrated at 120° C. Water was poured into the reaction mixture. The reaction mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and was allowed to stand for crystallization to yield 1.9 g of 2-amino-4-methyl-1-(2,4-dibromo-6-chlorophenyl)pyrrole-3-carbonitrile.