Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:10](=[O:14])[CH2:9]2)=[CH:15][CH:16]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CN(CCc2ccc(Cl)cc2)CCN1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(Cl)cc5)CC4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-(4-chlorophenethyl)piperazin-2-one (90 mg, 0.38 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (130 mg, 0.344 mmol), Cs2CO3 (123 mg, 0.378 mmol), CuI (131 mg, 0.688 mmol) and trans-1,2-bis(methylamino)cyclohexane (24 mg, 0.17 mmol) in dioxane (10 mL) was degassed by bubbling N2 through the suspension for 45 min. The suspension was put under N2 and heated at reflux for 5 d. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded tert-butyl 8-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate as a tan solid. 2 N HCl in Et2O (100 mL) was added to a solution of the tan solid in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 16 h. The suspension was concentrated, and the resulting residue was dissolved in MeOH (1 mL). Et2O (100 mL) was added, the resulting suspension was filtered, and the solid was washed with Et2O and put in a vacuum oven at 40° C. for 1 h to afford 22 mg (13%) of the title compound as a tan solid: 1H NMR (500 MHz, DMSO-d6) δ 11.54 (br s, 1H), 9.16 (br s, 2H), 7.54-7.32 (m, 6H), 6.96 (d, J=8.0 Hz, 1H), 4.21-3.44 (m, 9H), 3.42-3.05 (m, 12H); ESI MS m/z 437 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[C:17]([NH:9][CH:8]([C:10]([OH:12])=[O:11])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=1)(=[O:19])[CH3:18]
Reactant: COc1ccc(CC(N)C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CC(NC(C)=O)C(=O)O)cc1

Procedure:
O-Methyl-DL-tyrosine, 114 g., is dissolved in 500 ml. of a solution of 46 g. of sodium hydroxide in water with cooling. Acetic anhydride, 80 ml., and 50% sodium hydroxide to maintain pH 9-11 are added with continued cooling. The reaction is stirred for twenty minutes at pH 11 and is then acidified to pH 1 with continued cooling. The precipitated solid is collected by filtration, washed with a small amount of water and dried to give the above named compound, mp. 144°-146° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])([CH3:33])([CH3:32])[CH3:31].IC1C=CC(NC(C2C=CC(N3CCC(C(NS(C(C)(C)C)(=O)=O)=O)CC3)=NC=2)=O)=CC=1C>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:14])[C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([NH:37][S:34]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:36])=[O:35])=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2]
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCC(C(=O)O)CC4)cc3)cc21
Agent: Cc1cc(NC(=O)c2ccc(N3CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC3)nc2)ccc1I
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC4)cc3)cc21

Procedure:
N-(1-Ethyl-1H-indol-6-yl)-4-[4-(2-methyl-propane-2-sulfonylaminocarbonyl)-piperidin-1-yl]-benzamide was prepared form 1-[4-(1-ethyl-1H-indol-6-ylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid and t-butyl sulfonamide in a manner similar to the one described in the synthesis of 4-(2-methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (4-iodo-3-methyl-phenyl)-amide. The product was isolated after a silica gel column purification with 50-100% Et2O in hexanes to 50-100% EtOAc in hexane gradient. HRMS m/z calcd for C27H34N4O4S [M+H]+: 511.2374. Found: 511.2372.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[C:6]([I:9])[C:5]([CH3:10])=[C:4]([I:11])[C:3]=1[CH3:12].C([O:16][C:17](=[O:19])[CH3:18])(=O)C.S(=O)(=O)(O)O.[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(=O)C>[I:1][C:2]1[C:3]([CH2:12][O:19][C:17](=[O:16])[CH3:18])=[C:4]([I:11])[C:5]([CH2:10][O:19][C:17](=[O:16])[CH3:18])=[C:6]([I:9])[C:7]=1[CH2:8][O:16][C:17](=[O:19])[CH3:18]
Reactant: Cc1c(I)c(C)c(I)c(C)c1I
Reactant: CC(=O)OC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1c(I)c(COC(C)=O)c(I)c(COC(C)=O)c1I
Reaction time: 16 h

Procedure:
Triiodomesitylene (19.5 g, 39 mmol) was added to glacial acetic acid (200 ml) containing acetic anhydride (400 ml) and concentrated sulfuric acid (40 ml). Solid potassium permanganate (24.6 g, 156 mmol) was then added in small portions over a period of 3 h. After stirring for 16 h, the solvent was evaporated and water (200 ml) was added. The aqueous suspension was extracted with dichloromethane (250 ml) and the organic phase was washed with water (3×50 ml), dried (MgSO4) and evaporated. The solid residue was suspended in acetone and the white crystalline product was collected by filtration. Yield: 9.3 g (35%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[F:9][C:10]([F:38])([F:37])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](Cl)=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>O1CCCC1.O>[OH:3][NH:2][C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:20]2[CH2:21][CH2:22][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:38])([F:37])[F:9])[CH:12]=3)[CH2:18][CH2:19]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: NO
Reactant: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.24 g, 3.4 mmol) in tetrahydrofuran (5.0 mL) a solution of NaHCO3 (0.40 g, 4.8 mmol) in water (6 mL) was added and the resultant mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was added to a suspension of (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10a) (0.31 g) in tetrahydrofuran (5 mL) and the mixture was stirred at ambient temperature for 0.5 hours. The mixture was poured into water (25 mL), the precipitate was filtered, washed with water, ether, and dried to give the title compound (0.23 g, 73%). M.p. 178-179° C. 1H NMR (DMSO-d6, HMDSO), δ: 2.95-3.10 (4H, m); 3.23-3.40 (4H, m, overlapped with a signal of water); 6.62 (1H, d, J=15.9 Hz); 7.09 (1H, d, 3=7.7 Hz); 7.16 (1H, s); 7.19 (1H, d, J=8.0 Hz); 7.40 (1H, t, 3=7.7 Hz); 7.54 (1H, d, J=15.9 Hz); 7.80 (2H, d, J=8.4 Hz); 7.83 (2K, d, J=8.4 Hz); 9.35 (1H, br s); 10.72 (1H, br s). HPLC analysis on Omnispher 5 C18 column: impurities 3.5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1M acetate buffer (pH 5.0), 50:50; sample concentration 1 mg/ml; flow rate 1.3 mL/min; detector UV 254 nm). Anal. Calcd for C20H20F3N3O4S, %: C, 52.74; H, 4.43; N, 9.23; S, 7.04. Found, %: C, 52.04; H, 4.29, N, 8.86; S, 7.20.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:32])=[C:20]([NH:22][S:23]([C:26]3[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=3)(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][S:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[F:32][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][CH2:37][CH2:36][CH2:35][S:34][CH3:33])[N:7]=2)=[CH:21][C:20]=1[NH:22][S:23]([C:26]1[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=1)(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cn(C)cn3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CSCCCN
Product: CSCCCNc1nccc(-c2sc(C(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3cn(C)cn3)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-imidazole-4-sulfonamide (75 mg, 0.152 mmol) and [3-(methylthio)propyl]amine (86 mg, 0.817 mmol) the title compound of Step B was obtained as a golden oil (76 mg, 89% yield). MS (ESI): 561.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:7]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12]2[S:13][CH2:14][CH2:15][C:11]=2[C:10]2[C:16]([OH:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:9]=2[O:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BrH:28].[N:29]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:28].[CH2:22]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:12]2[S:13][CH2:14][CH2:15][C:11]=2[C:10]2[C:16]([O:21][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:17][C:18]([CH3:20])=[CH:19][C:9]=2[O:8]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCC1(CCCCCC)Oc2cc(C)cc(O)c2C2=C1SCC2
Reactant: O=C(O)CCCN1CCCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCC1(CCCCCC)Oc2cc(C)cc(OC(=O)CCCN3CCCC3)c2C2=C1SCC2

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexyl magnesium bromide, using the procedure described in Example 8, there is obtained 4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-7-methyl-4H-thieno [2,3-c][1]benzopyran. The benzopyran is then reacted with γ-pyrrolidinobutyric acid, hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:15]1[N:24]=[C:23]([NH:25][C@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.[CH3:38][C:39]1[CH:40]=[CH:41][C:42]([O:48][CH3:49])=[C:43](B(O)O)[CH:44]=1>O.C(O)CCC>[CH3:49][O:48][C:42]1[CH:43]=[CH:44][C:39]([CH3:38])=[CH:40][C:41]=1[C:15]1[N:24]=[C:23]([NH:25][C@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)nc3ccccc23)C1
Reactant: COc1ccc(C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: COc1ccc(C)cc1-c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Yield: 88 %

Procedure:
A mixture of toluene (1.8 mL), n-butanol (3 mL) and 2M Na2CO3 (3 mL) was degassed with a stream of nitrogen for 20 minutes. The mixture was transferred onto a degassed mixture of (S)-tert-butyl 3-(2-chloroquinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.300 g, 0.86 mmol), palladium tetrakistriphenyl phosphine (0.0718 g, 0.06 mmol) and 5-methyl-2-methoxyphenylboronic acid (0.143 g, 0.86 mmol) and the solution was heated at reflux. After 17 hours the reaction was cooled, diluted with water (20 mL), and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), and concentrated. Silica chromatography (6:1-1:1 petroleum ether/ethyl acetate) gave the title compound as a colourless solid (0.329 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16].Cl.[CH3:18][C:19]1([NH2:22])[CH2:21][CH2:20]1.CCN(CC)CC.O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:19]1([CH3:18])[CH2:21][CH2:20]1)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16]
Reactant: O=c1c2cccc(Br)c2nc(Cl)n1C1CC1
Reactant: CC1(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(Nc2nc3c(Br)cccc3c(=O)n2C2CC2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A glass microwave reaction vessel was charged with 8-bromo-2-chloro-3-cyclopropylquinazolin-4(3H)-one (723) (200 mg, 0.67 mmol), 1-methylcyclopropanamine hydrochloride (Small Molecules, Inc.; 126 mg, 1.17 mmol) and NEt3 (0.46 mL, 3.34 mmol) in DMSO (0.5 mL). The tube was sealed and heated in an oil bath at 100° C. After 1 h, water and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-50% EtOAc in hexanes), to provide 8-bromo-3-cyclopropyl-2-((1-methylcyclopropyl)amino)-quinazolin-4(3H)-one (492a) (170 mg, 0.51 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (dd, J=8.02, 1.56 Hz, 1H), 7.84 (dd, J=7.63, 1.57 Hz, 1H), 6.96 (t, J=7.73 Hz, 1H), 5.77 (s, 1H), 2.65 (tt, J=6.75, 4.11 Hz, 1H), 1.61 (s, 3H), 1.27-1.34 (m, 2H), 0.85-0.92 (m, 4H), 0.80-0.85 (m, 2H). m/z (ES, +ve) 334.0, 336.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[B-](F)(F)(F)[CH:14]=[CH2:15].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([CH:14]=[CH2:15])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc(Cl)cc1C(=O)OC
Temperature: 25 °C
Yield: 398.4 %

Procedure:
A stirred suspension of methyl 2-bromo-5-chlorobenzoate (10 g, 40.08 mmol), potassium trifluoro(vinyl)borate (8.05 g, 60.12 mmol), Pd(dppf)Cl2 (1.64 g, 2.0 mmol) and sodium carbonate (8.5 g, 80.16 mmol) in dioxane (150 mL) and water (15 mL) was refluxed for 8 hours under a nitrogen atmosphere. After cooling to RT, the mixture was filtered, concentrated, and the crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=100:1-50:1 gradient) to give the title compound (31.4 g, 76.4%). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (d, J=2.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.31-7.39 (m, 2H), 5.57 (d, J=17.6 Hz, 1H), 5.31 (d, J=10.8 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C:19]2[N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][CH:20]=2)[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1>C(Cl)Cl.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([C:19]2[CH2:20][CH2:21][CH2:22][N:23]=2)[C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C1c1cc(F)cc2c1OCCO2
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc2c(c(C3=NCCC3)c1)OCCO2
Reaction time: 3 h

Procedure:
TFA (0.09 mL, 1.18 mmol) was added to a solution of tert-butyl 5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate (0.04 g, 0.117 mmol) in DCM (5 mL) at 0° C. and stirring was continued at 25° C. for 3 h. Reaction mixture was concentrated under reduced pressure to afford the crude, which was diluted with ethyl acetate, washed with saturated NaHCO3 solution, dried over anhydrous sodium sulphate to afford 5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3,4-dihydro-2H-pyrrole (Int-55). MS (ESI) m/z 222 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17].[C:19](Cl)(=O)[CH3:20].C(Cl)(=O)CCC>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][O:14][NH:15][C:16](=[O:18])[CH2:17][CH2:19][CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1ccc2ccccc2c1CONC(C)=O
Agent: CCCC(=O)Cl
Product: CCCC(=O)NOCc1c(OC)ccc2ccccc12

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 7, but replacing, in the acylation step, acetic acid chloride with butyric acid chloride, the title compound is obtained.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(O)C.[O-]CC.[Na+].Cl[CH2:20]/[CH:21]=[CH:22]/[CH2:23]Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:7]([C:6]1([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:23][CH:22]1[CH:21]=[CH2:20])=[O:8])[CH3:11]
Reactant: ClC/C=C/CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115 %

Procedure:
35.2 g (220 mmol) of malonic acid diethyl esterdiethyl malonate and 400 mL of toluene were added into a three-necked flask (1 L), and thereafter, 82.3 mL (210 mmol) of a 20% sodium ethoxide ethanol solution was added thereto as a base. The obtained mixture was stirred at room temperature for 0.5 hours, and 12.5 g of trans-1,4-dichloro-2-butene (100 mmol; a reagent manufactured by Tokyo Chemical Industry Co., Ltd.) was then added to the reaction solution. The obtained mixture was stirred at room temperature for 5 days, and 240 mL of a 1 M sodium hydroxide aqueous solution was then added to the reaction solution. The mixture was stirred for 1 hour, and an organic layer was then separated. A water layer was re-extracted with 200 mL of toluene, and organic layers were then gathered. The gathered organic layer was washed with 200 mL of water three times, and the resultant was then filtrated, while washing the residue with toluene. The obtained filtrate was concentrated at 45° C. under reduced pressure, so as to obtain 24.4 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane in the form of a crude product of a light yellow oily substance. This crude product contained 19.5 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane (yield: 92%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27](O)=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:27](=[O:28])[NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Yield: 98.7 %

Procedure:
1-Amino-N-phenyl-1H-pyrrole-2-carboxamide (0.65 g, 3.23 mmol) was treated with (S)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanoic acid (1 g, 3.23 mmol), N,N-diisopropylethylamine (1.9 mL, 10.66 mmol) and T3P® (50% in ethyl acetate, 2.7 mL, 4.52 mmol) according to the method of Preparation 5a to give 1.57 g (98% yield) of the desired compound. Purity 97%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:21][C:22]([O:24][CH:25]1[CH2:29][C:28](=[O:30])[N:27]([CH2:31][C:32]2[CH:33]=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[C:26]1=O)=[O:23].C(N(CC)CC)C>C(#N)C>[Cl:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][N:27]2[C:28](=[O:30])[CH2:29][CH:25]3[O:24][C:22](=[O:23])[CH:21]=[C:26]23)=[CH:37][CH:36]=1
Reactant: O=C(CBr)OC1CC(=O)N(Cc2ccc(Cl)nc2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1C=C2C(CC(=O)N2Cc2ccc(Cl)nc2)O1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
569 mg (2.17) of triphenylphosphine are added to 712 mg (1.97 mmol) of 1-[(6-chloropyridin-3-yl)methyl]-2,5-dioxopyrrolidin-3-yl bromoacetate (XI-1) in 40 ml of acetonitrile, and the mixture is stirred at 50° C. for 3 hours. 0.29 ml (2.08 mmol) of triethylamine is added, and the mixture is stirred at 50° C. for about 16 hours. The entire reaction mixture is concentrated under reduced pressure and the residue that remains is then taken up in a little ethyl acetate, the insoluble solid is filtered off and the filtrate is purified by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 305 mg (59% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-6,6a-dihydro-2H-furo[3,2-b]pyrrol-2,5(4H)-dione.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[S:8][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)=[CH:3][CH:4]=1
Reactant: NC(=S)c1ccncc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccncc2)n1
Yield: 53.7 %

Procedure:
A solution of thioisonicotinamide (5.0 g) and ethyl bromopyruvate (7.22 g) in ethanol (90 ml) was heated for 5 hours under reflux and concentrated. To the residue were added sodium bicarbonate solution and ethyl acetate, and the organic layer was separated, washed with water and sodium chloride solution, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give pale yellow solid of ethyl 2-(4-pyridyl)-4-thiazolecarboxylate (4.55 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14](C(OC(C)(C)C)=O)[CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:39])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:39])[CH3:2]
Reactant: CCOC(=O)COc1c(C)cc(N(Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C(=O)OC(C)(C)C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1c(C)cc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reaction time: 0.5 h

Procedure:
0.360 g (0.62 mmol) of the above prepared (4-{tert-butoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2,6-dimethyl-phenoxy)-acetic acid ethyl ester was dissolved in 6.25 ml of CH2Cl2 and treated dropwise with 1.59 ml of TFA (33 eq.). After additional 30 min at RT, the bulk of the solvents was removed i. V. and the residue distributed between cold NaHCO3-solution and EtOAc. Washing of the organic layer with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents left 0.292 g of the title compound as off-white solid which was used as such for the next step, MS: 479.4 (MH)+.