Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(-c3cccc(F)c3)csc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2csc3c2OCCNC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
tert-Butyl 8-(3-fluorophenyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (209 mg) was dissolved in ethyl acetate (2 ml), and 4 N hydrogen chloride-ethyl acetate solution (2 ml) was added. The mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of MeOH and Et2O to give 8-(3-fluorophenyl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (142 mg, 83.0%) as a solid.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[C:3]2[C:6]3[C:12](=[CH:13][C:2]=12)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH3:14][C:15]1C=CC=C2C(=CC3C2=CSC=3)[CH:16]=1.C1SC=C2C3C(=CC=12)C=CC=CC=3>>[CH:15]([C:8]1[CH:7]=[C:6]2[C:12]([CH:11]=[CH:10][CH:9]=1)=[C:13]1[C:4]([S:5][CH:1]=[CH:2]1)=[CH:3]2)([CH3:16])[CH3:14]
Reactant: Cc1cccc2c3cscc3cc-2c1
Reactant: c1ccc2cc3cscc3c-2cc1
Product: CC(C)c1cccc2c3ccsc3cc-2c1

Procedure:
The position numbering system of the following azuleno[1,2-c]thiophene derivatives is ##STR12## Azuleno[1,2-c]thiophene 7-Methylazuleno[1,2-c]thiophene
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][CH:12]1[CH:17]([O:18][CH2:19][CH:20]([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15][CH:14]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:13]1.C(N(C(C)C)CC)(C)C>ClCCl>[F:11][CH:12]1[CH:17]([O:18][CH2:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:16][CH2:15][CH:14]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(OCC(O)c2ccccc2)C(F)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(OCC(=O)c2ccccc2)C(F)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
A solution of oxalyl chloride (0.054 mL, 0.623 mmol) in dichloromethane (10 mL) was cooled to −78° C. Dimethylsulfoxide (0.088 mL, 1.36 mmol) was added dropwise and the reaction mixture was stirred for 5 min. (−) tert-Butyl 3-fluoro-4-(2-hydroxy-2-phenylethoxy)cyclohexylcarbamate (200 mg, 0.567 mmol) was then added as a solution in dichloromethane (1 mL). After 5 min of stirring, diisopropylethylamine (0.494 mL, 2.84 mmol) was added in one portion, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was then poured saturated sodium bicarbonate, the layers were separated and the aqueous extracted (4×) with dichloromethane. The combined organic layers were dried with anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (hexane: ethyl acetate) gave tert-Butyl 3-fluoro-4-(2-oxo-2-phenylethoxy)cyclohexylcarbamate (175 mg, 88% yield) as a white solid.
Reaction SMILES: C([CH:5]([NH:9][C:10]1[CH:15]=[C:14]([I:16])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18][CH3:19])[C:6]([OH:8])=[O:7])(C)(C)C.O=S(Cl)Cl.[CH3:24]O>>[Cl:17][C:13]1[C:14]([I:16])=[CH:15][C:10]([NH:9][CH2:5][C:6]([O:8][CH3:24])=[O:7])=[C:11]([O:18][CH3:19])[CH:12]=1
Reactant: COc1cc(Cl)c(I)cc1NC(C(=O)O)C(C)(C)C
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CNc1cc(I)c(Cl)cc1OC

Procedure:
A mixture of tert-butyl 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetic acid (3.0 g, 8.7 mmol), SOCl2 (3 mL) in MeOH (20 mL) was stirred at reflux for 2 h. The mixture was concentrated in vacuo to yield the crude product (3.1 g) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][C@@H:12]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][N:11]3[CH2:10]2)=[CH:5][C:4]=1[O:26][CH3:27])#[N:2].[ClH:28]>O1CCOCC1>[ClH:28].[CH3:27][O:26][C:4]1[CH:5]=[C:6]([C@@H:9]2[O:14][CH2:13][C@@H:12]3[CH2:15][NH:16][CH2:17][CH2:18][N:11]3[CH2:10]2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: COc1cc([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc([C@H]2CN3CCNC[C@H]3CO2)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (3S,9aS)-3-(4-cyano-3-methoxyphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (38.0 mg, 0.102 mmol) was dissolved in 10 mL of 4 M HCl in dioxane and stirred at room temperature for 8 h. The mixture was concentrated to ¼ the original volume and diluted with 5 mL of diethyl ether. The precipitate was filtered and dried under high vacuum to afford the title compound: 1H NMR (DMSO-d6, Z (cis) isomer, 500 MHz) δ 7.77 (d, J=7.9 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J=7.9 Hz, 1H), 4.95 (bs, 1H), 4.08 (bs, 2H), 3.96 (s, 3H), 3.85-3.60 (bs, 3H), 3.58-3.34 (m, 6H); LC/MS: (IE, m/z) [M+1]+=274.
Reaction SMILES: [Na].Cl[C:3]1[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=1.[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([CH3:20])[CH:14]=1>>[CH3:20][C:15]1[CH:14]=[CH:13][C:18]([O:19][C:3]2[N:4]=[N:5][C:6]([S:9][CH2:10][CH:11]=[CH2:12])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: C=CCSc1ccc(Cl)nn1
Reactant: Cc1ccc(O)cc1
Agent: [Na]
Product: C=CCSc1ccc(Oc2ccc(C)cc2)nn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of dry p-cresol. To the resulting solution was added 1.87 g(0.01 mol) of 3-chloro-6-allylthiopyridazine and then the reaction solution was stirred for 5 hours at 100±5° C. After the reaction was allowed to stop, the reaction solution was cooled and adjusted to alkaline (pH 14) with 150 ml of 2N--NaOH, thereby precipitating the crystals. The precipitated crystal was extracted with diethyl ether, washed twice with purified water, dried over anhydrous magnesium sulfate and then concentrated to remove diethyl ether. The resulting oily residue was slowly cooled to obtain the title compound as a pale white amorphous crystal.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH:21][S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Product: O=S(=O)(Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2)c1ccccc1
Yield: 74.6 %

Procedure:
Prepared from N2-(2-phenoxy-ethyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 108, step B) (155 mg, 0.50 mmol, HPLC 0.691 min) and benzenesulfonyl chloride (70 ul, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (158 mg, 75%, HPLC 1.452 min), MS (ISP) m/e=424.1 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([CH2:16][CH2:17][C:18](OCC)=[O:19])[CH2:14][CH2:13][C:12](=O)[NH:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([CH2:16][CH2:17][CH2:18][OH:19])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCC1(c2ccc(OC)nc2)CCC(=O)NC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(C2(CCCO)CCCNC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
2.321 g (7.58 mmol) of ethyl 3-[3-(6-methoxypyridin-3-yl)-6-oxopiperidin-3-yl]propanoate obtained in stage 1.2, in solution in 128 ml of anhydrous tetrahydrofuran, are introduced at ambient temperature into a 250 ml round-bottomed flask. 2.876 g (75.8 mmol) of lithium aluminum hydride are added portionwise and the resulting mixture is subsequently stirred at ambient temperature for 3 hours. The mixture is subsequently hydrolyzed with a saturated aqueous sodium sulfate solution, filtered through celite and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 90/10/1, to provide 1.80 g of the desired compound in the form of a yellow wax.
Reaction SMILES: CC1(C)CCN(C2C=CC(SC(F)(F)F)=CC=2)C(=O)N1CC1C2C(=NC=CC=2)NC=1.O[CH2:32][C:33]([NH:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:47]([F:50])([F:49])[F:48])=[CH:42][CH:41]=1)=[O:38])([CH3:35])[CH3:34]>>[CH3:32][C:33]1([CH3:35])[CH2:34][N:39]([C:40]2[CH:45]=[CH:44][C:43]([O:46][C:47]([F:50])([F:49])[F:48])=[CH:42][CH:41]=2)[C:37](=[O:38])[NH:36]1
Reactant: CC(C)(CO)NC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: CC1(C)CCN(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1c[nH]c2ncccc12
Product: CC1(C)CN(c2ccc(OC(F)(F)F)cc2)C(=O)N1

Procedure:
4,4-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazolidin-2-one was prepared similar to procedure for compound 5, using 1-(1-hydroxy-2-methylpropan-2-yl)-3-[4-(trifluoromethoxy)phenyl]urea. 1H NMR (399 MHz, CDCl3): δ 7.26 (s, 2 H); 7.12 (d, J=8.3 Hz, 2 H); 4.09 (s, 2 H); 1.37 (s, 6 H). LCMS [M+H]+=275.1.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9](=[CH:17][C:18]1[CH:23]=[C:22]([C:24]2[C:28]([Cl:29])=[C:27]([O:30][CH:31]([F:33])[F:32])[N:26]([CH3:34])[N:25]=2)[C:21]([Cl:35])=[CH:20][C:19]=1[Cl:36])[C:10]([O:12]C(C)(C)C)=[O:11]>ClCCl>[Cl:8][C:9](=[CH:17][C:18]1[CH:23]=[C:22]([C:24]2[C:28]([Cl:29])=[C:27]([O:30][CH:31]([F:32])[F:33])[N:26]([CH3:34])[N:25]=2)[C:21]([Cl:35])=[CH:20][C:19]=1[Cl:36])[C:10]([OH:12])=[O:11]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)OC(C)(C)C)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
85 ml of trifluoroacetic acid were added dropwise to a solution of 34.4 g (70 mmol) of tert-butyl 2-chloro-3-(2,4-dichloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)phenyl)-propenoate in 85 ml of dichloromethane. After 3 hours the mixture was concentrated. The residue was triturated with n-hexane, then filtered off and dried. Yield: 19.9 g.
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].I[CH2:14][C@@H:15]1[CH2:19][N:18]([C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17](=[O:28])[CH2:16]1.O>CS(C)=O>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:1])([CH2:14][C@H:15]1[CH2:16][C:17](=[O:28])[N:18]([C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[CH2:19]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](CI)CC1=O
Reactant: COC(=O)C(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)(C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1)C(=O)OC
Yield: 67.1 %

Procedure:
To dimethyl methylmalonate (1.06 g, 7.29 mmol) in DMSO (7 mL) at room temperature was added NaH (291 mg of a 60% dispersion in oil). After the effervescence had ceased the lactam 85 (2 g, 7.29 mol) in DMSO (5 mL) was added. After 1 hour water was added and the aqueous solution extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/acetone) of the residue gave the product as an oil (1.7 g, 81%). MS m/z 348 (M+H, 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[C:32]([O:39][CH3:40])(=[O:38])[CH2:33][CH2:34][C:35]([O-])=[O:36]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:35](=[O:36])[CH2:34][CH2:33][C:32]([O:39][CH3:40])=[O:38])[CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)[O-]
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Product: COC(=O)CCC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 86.5 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 202 mg; 0.46 mmol) and monomethyl succinate (165 mg; 0.92 mmol), 220 mg (86%) of the title compound was obtained as a yellow oil after purification by reverse phase flash chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:16])[NH:6]2.[CH2:17]([O:19][C:20](=[O:33])[CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][CH:26]=1)=[O:24])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20](=[O:33])[CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[C:10]([S:11](=[O:12])(=[O:13])[NH:14][CH3:15])[C:2]=3[CH3:1])[NH:6][C:5]2=[O:16])[NH:27][CH:26]=1)=[O:24])[CH3:18]
Reactant: CNS(=O)(=O)c1ccc2c(c1C)CC(=O)N2
Reactant: CCOC(=O)CNC(=O)c1c[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)CNC(=O)c1c[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)NC)c(C)c32)c1C
Yield: 51.7 %

Procedure:
4-Methyl-5-methylaminosulfonyl-2-oxindole (50 mg, 0.21 mmol) was condensed with [(5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino]-acetic acid ethyl ester (100 mg, 0.42 mmol) and piperidine (0.1 mL) in ethanol (2 mL) to give 50 mg (52%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH2:40])[C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:36][CH2:35][CH2:34][C@H:17]4[S:18](=[O:33])(=[O:32])[C:19]([CH3:31])([CH3:30])[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:21][C@:16]4([CH3:37])[C:15]=3[CH:38]=2)=[O:9])=[N:6][CH:7]=1.[H][H]>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:39][CH3:40])[C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:36][CH2:35][CH2:34][C@H:17]4[S:18](=[O:32])(=[O:33])[C:19]([CH3:31])([CH3:30])[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:21][C@:16]4([CH3:37])[C:15]=3[CH:38]=2)=[O:9])=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: C=Cc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Agent: [Pd]
Solvent: ClCCl
Product: CCc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2

Procedure:
A mixture of tert-butyl ((4aR,11bR)-10-(5-chloro-3-vinylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.11 g, 0.19 mmol) and palladium, 10% wt. on activated carbon (0.060 g, 0.056 mmol) in DCM (1.0 ml) was stirred under a balloon of hydrogen at room temperature for 12 h. The reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10% to 60% EtOAc in hexane, to provide tert-butyl ((4aR,11bR)-10-(5-chloro-3-ethylpicolinamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate as white solid. To a solution of this compound in 1 mL of DCM was added trifluoroacetic acid (0.56 ml, 7.47 mmol). The mixture was stirred at room temperature for 30 min. The solvent was evaporated and the residue was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 5% MeOH in DCM to give N-((4aR,11bR)-2-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-chloro-3-ethylpicolinamide (0.010 g, 0.020 mmol, 10.9% yield) as an off-white solid. m/z (ESI) 491.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[O:11])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
4-Methoxyphenyl isocyanate (0.4 g, 2.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and triethylamine (0.3 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was stirred with 1N HCl (30 mL) for one hour and then filtered. The solid was slurried with hot ethanol (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-urea (0.5 g, 59%) as a white solid: mp 205-207° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.49-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.68 (s, 3H, OCH3), 4.70 (d, J=5.7 Hz, 2H, CH2), 5.13-5.20 (dd, J=5.2 and 12.4 Hz, 1H, CH), 6.66 (t, J=5.7 Hz, 1H, NH), 6.79 (d, J=9.0 Hz, 2H, Ar), 7.27 (d, J=9.0 Hz, 2H, Ar), 7.75-7.88 (m, 3H, Ar), 8.59 (a, 1H, NH), 11.65 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.94, 48.86, 55.10, 113.86, 119.50, 121.82, 127.15, 131.59, 133.38, 133.62, 134.70, 140.46, 154.03, 155.45, 167.02, 167.60, 169.84, 172.22; Anal. calcd. for C22H20N4O6: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.43; H, 4.42; N, 12.58.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C=C(C(O)=[O:26])C(C(OO)=O)=CC=1.[OH-].[K+]>C(OCC)(=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:1](=[O:5])[C:2]2([CH3:4])[O:26][CH2:3]2)=[CH:8][C:9]=1[C:15]([F:16])([F:17])[F:18])#[N:14]
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=C(O)c1ccccc1C(=O)OO
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 77.3 %

Procedure:
N-Methacryloyl-4-cyano-3-trifluoromethylaniline (13.8 g, 54 mmol) and ethyl acetate (40 ml) were charged in a 300 ml four-neck flask, and the mixture was heated at 50° C.-55° C. A solution of mono-perphthalic acid in ethyl acetate (108.05 g, net 19.82 g, 110 mmol) was added dropwise at a temperature in the range of 50° C.-55° C. over 3.9 hr. After stirring at the above-mentioned temperature for 4.5 hr, a solution of mono-perphthalic acid in ethyl acetate (10.36 g, net 1.90 g, 10.4 mmol) was further added dropwise over 10 min. Then the mixture was stirred for 1 hr and left standing overnight at room temperature. The mixture was adjusted to pH=8 (universal test paper) with 20% aqueous KOH solution and partitioned. The organic layer was washed with deionized water (20 ml) in which Na2S2O5 (5.0 g) had been dissolved, dried over MgSO4, decolorized with activated carbon (carborafine 0.5 g), and concentrated under reduced pressure. Toluene (60 ml) was added to the residue and the mixture was heated to 80° C. After cooling to 25° C., the mixture was filtrated to give 4-cyano-N-(2,3-epoxy-2-methylpropionyl)-3-trifluoromethylaniline (11.37 g, yield 77.3%). Purity 98.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>ClCCl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:31]4[CH2:32][CH2:33][CH:28]([CH3:27])[CH2:29][CH2:30]4)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Reactant: CC1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(Cc2ccc(/C=C/C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 4.30.c. from (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-formylphenyl)acrylamide and 4-methylpiperidine. Yield: 80 mg (21.7% of theory); melting point: 207° C.-208° C.; C28H29ClN2O (M=445.00); calc.: molecular ion peak (M+H)+: 445/447; found: molecular ion peak (M+H)+: 445/447; Rf value: 0.76 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](I)[C:6]=1[CH3:12])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.[Cu]Cl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[C:6]=1[CH3:12])[CH3:2]
Reactant: CCOC(=O)c1cccc(I)c1C
Reactant: Oc1ccc(F)cc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cccc(Oc2ccc(F)cc2)c1C
Temperature: 130 °C
Yield: 54.5 %

Procedure:
A mixture of 3-iodo-2-methyl-benzoic acid ethyl ester (6.29 g, 0.02 mol), para-fluorophenol (4.86 g, 0.04 mol), cesium carbonate (14.14 g, 0.04 mol), 2,2,6,6-tetramethylheptane-3,5-dione (447 μL, 2 mmol) and copper (I) chloride (1.07 g, 0.01 mol) in anhydrous N-methyl-2-pyrrolidone (38 mL) was heated at 130° C. for 3 days before it was cooled to room temperature, quenched with water and filtered. The filtrate was extracted with ethyl acetate. The organic layer was washed twice with 0.5 N sodium hydroxide, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a pale green oil (2.99 g): 1H NMR (CDCl3, 200 MHz): δ=7.63 (m, 1H), 7.18 (m, 2H), 6.98 (m, 2H), 6.85 (m, 2H), 4.37 (q, J=7.0 Hz, 2H), 2.45 (s, 3H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(O)C.[CH2:4]([N:7]1[C:13]2[CH:14]=[CH:15][C:16](Br)=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]([O:21][CH3:22])=[O:20])[CH2:9][CH2:8]1)[CH:5]=[CH2:6].B([O-])([O-])O[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH2:4]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]([O:21][CH3:22])=[O:20])[CH2:9][CH2:8]1)[CH:5]=[CH2:6]
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: C=CCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C=CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In toluene (20 ml), ethanol (2 ml) and water (2 ml) were suspended methyl 1-allyl-7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (274 mg), 4-propoxyethoxyphenyl borate (248 mg) and potassium carbonate (307 mg), and the suspension was stirred under argon atmosphere for 30 minutes, Then, tetrakistriphenylphosphinepalladium (69 mg) was added thereto, and the mixture was heated under argon atmosphere at 100° C. for 8 hours. After allowing to cool, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=4:1) to give methyl 1-allyl-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (269 mg) as yellow oil.