Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[F:34][C:30]1[CH:29]=[C:28](/[C:26](/[CH3:27])=[CH:25]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(=CBr)c1cccc(F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol) L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 6 mg as the TFA salt. 1H NMR (CDCl3, TFA salt) δ (ppm): 7.40 (m, 1H), 7.30 (d, 1H), 7.22 (m, 2H), 7.10 (m, 3H), 6.90 (s, 1H), 4.80 (d, 1H), 4.20 (d, 1H), 3.90 (m, 1H), 3.40 (m, 1H), 3.30 (m, 1H), 3.10 (s, 3H), 2.95 (m, 1H), 2.45 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19](Cl)=[O:20]>>[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([N:1]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:20]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: C1COCCOCCOCCOCCN1
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13-tetraoxacyclopentadecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[S:7][C:6]([NH:8][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[O:10])=[N:5][N:4]=1.OO.[CH3:17]C(O)=O>>[CH3:17][CH2:1][CH2:2][C:3]1[S:7][C:6]([NH:8][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[O:10])=[N:5][N:4]=1
Reactant: CCc1nnc(NC(=O)CN(C)C)s1
Reactant: CC(=O)O
Agent: OO
Product: CCCc1nnc(NC(=O)CN(C)C)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To solution of AK-2 (3.3 g, 13.1 mmol) in AcOH (10 mL) is slowly added H2O2 (1.37 mL, 13.7 mmol). The reaction mixture is stirred at rt for 3 h and is then quenched with saturated Na2SO3(aq) and neutralized with 1N NaOH(aq). The mixture is extracted with EtOAc and concentrated to yield AK-3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:18])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[C:12]([O:16]C)[CH:11]=[CH:10][CH:9]=3.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:18])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[C:12]([OH:16])[CH:11]=[CH:10][CH:9]=3
Reactant: COc1ccc2c(c1)-c1c(OC)cccc1C2=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2ccc(O)cc2-c2c(O)cccc21

Procedure:
In a manner analogous to Example 1D, prepare a solution of 3,5-dimethoxy-fluoren-9-one (4.0 g, 16.6 mmole) in 25 mL glacial acetic acid and react with 75 mL hydrogen bromide to obtain the title compound. (m.p. 301-3030° C. (dec.) (54%)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:16])[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[C:3]1=[O:17].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][C:23]=2[CH:31]=1.[Cl-].[NH4+]>C(#N)C.N1C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([S:27]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C@@H:7]([CH3:16])[C:8]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[O:9])[C:3]3=[O:17])(=[O:29])=[O:28])=[CH:24][C:23]=2[CH:31]=1
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N)C1=O
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CC#N
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2cc3cc(Cl)ccc3o2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
To a solution of (3S)-3-amino-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]pyrrolidin-2-one (0.077 g) in anhydrous acetonitrile (2ml) were added 5-chloro-1-benzofuran-2-sulfonyl chloride (0.043 g) in acetonitrile (2 ml) and pyridine (0.057 ml), and the mixture was stirred at room temperature for 72 h. Saturated ammonium chloride solution (2 ml) was added and the resultant mixture stirred at room temperature for 20 min. The mixture was concentrated under reduced pressure and the residue partitioned between chloroform and hydrochloric acid (2M). The organic layer was washed with saturated sodium bicarbonate and brine. The organic layer was isolated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.043 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O1CCOCC1>CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccccc3)n2n1
Temperature: 110 °C
Yield: 25.3 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 49 mg, 0.142 mmol), phenylboronic acid (23 mg, 0.189 mmol), and [1,1′-bis[1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (9.3 mg, 13 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.76 mL of 1,4-dioxane and 0.38 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (65-75% MeCN/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (13.9 mg, 25%). Decomposition observed at 199.8° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H), 2.40 (s, 3H), 5.20 (br. s., 1H), 6.40 (s, 1H), 7.58-7.66 (m, 5H), 7.97 (s, 1H), 8.02 (d, J=8.59 Hz, 2H), 8.06 (dd, J=6.57, 3.03 Hz, 2H), 11.20 (s, 1H); ESI-MS: m/z 387.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[C:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=1.[Cl-].[NH4+].C(O)C>[Fe].O.C(OCC)(=O)C.CN(C)C=O>[CH3:1][C:2]1[C:3]([C:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc([N+](=O)[O-])c1C1=CC(C)(C)CC(C)(C)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cccc(N)c1C1=CC(C)(C)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A mixture of the 1-methyl-3-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (1 g, 3.66 mmol) produced in Example (71a), iron powder (631 mg, 11.0 mmol), ammonium chloride (783 mg, 14.6 mmol), ethanol (15 mL), water (6 mL) and dimethylformamide (1 mL) was stirred for 3 hours and 30 minutes at an external temperature of 90° C. under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture, and it was filtered through Celite. The filtrate was then extracted with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 663 mg of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]#[C:18][CH3:19])[CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.[CH2:22]([N:29]([CH2:33][CH2:34]Cl)[CH2:30][CH2:31]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:33][CH2:34][C:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]#[C:18][CH3:19])[CH:10]=2)(=[O:7])=[O:8])([C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC#CCOc1cccc(S(=O)(=O)CC(=O)OCC)c1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Product: CC#CCOc1cccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)c1
Yield: 63 %

Procedure:
Ethyl 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}4-piperdine carboxylate was prepared according to the general method as outlined in example 1 (step 6), starting from ethyl{[3-(2-butynyloxy)phenyl]sulfonyl}acetate (3 g, 10.1 mmol) and Benzyl-bis-(2-chloro-ethyl) amine hydrochloride (2.88 g, 10.7 mmol); 2.91 g yellow oil. Yield 63%; MS: 456.3 (M+H)+.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[CH:12]1([C:17]2[C:26]3[C:25](=[O:27])[CH2:24][C:23]([CH3:29])([CH3:28])[CH2:22][C:21]=3[N:20]=[C:19]([CH:30]([CH3:32])[CH3:31])[C:18]=2[C:33](=[O:44])[C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1.CO>C1COCC1>[CH:12]1([C:17]2[C:26]3[C@@H:25]([OH:27])[CH2:24][C:23]([CH3:28])([CH3:29])[CH2:22][C:21]=3[N:20]=[C:19]([CH:30]([CH3:32])[CH3:31])[C:18]=2[C:33]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=2)=[O:44])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)c1nc2c(c(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)C2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)C2
Temperature: 0 °C

Procedure:
140 mg (0.96 mmol, 0.08 eq.) of (1R,2S)-1-aminoindan-2-ol are initially charged in 440 ml of THF, and 7.80 g (47.8 mmol, 4.0 eq.) of borane N,N-diethylaniline complex are added at room temperature. After the evolution of gas has ceased, the mixture is cooled to 0° C. and 5.47 g (12 mmol, 1 eq.) of the compound from Example 2A, dissolved in 40 ml of THF, are added. With stirring, the mixture is allowed to warm to room temperature over a period of 28 h. After the reaction has ended, 20 ml of methanol are added to the reaction mixture and the mixture is concentrated. The residue is partitioned between 150 ml of water and 150 ml of ethyl acetate. The aqueous phase is extracted twice with in each case 100 ml of ethyl acetate. The combined organic phases are washed with 50 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is then purified by chromatography (silica gel, mobile phase: isohexane/ethyl acetate 4:1).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:24]=[CH:23][C:12]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCOCC1.CO.C(OCC)(=O)C>[CH2:3]([O:10][C:11]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:24]=[CH:23][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)c1ccc(-c2ccccn2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccccn2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.69 mL) was added to a solution mixture of the obtained benzyl 2-(benzyloxy)-4-(pyridin-2-yl)benzoate (0.18 g) in dioxane (0.9 mL) and methanol (0.9 mL), followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture. After adjusting the pH to 4 with 6 mol/L hydrochloric acid, ethyl acetate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid substance was collected by filtration to obtain 0.12 g of 2-(benzyloxy)-4-(pyridin-2-yl)benzoic acid as a white solid.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:42])[O:11][CH2:12][C@@H:13]([N:28]([CH3:41])[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[Cl:40])=[O:30])[CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[N:7][CH:8]=1.NN>CO>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:42])[O:11][CH2:12][C@@H:13]([N:28]([CH3:41])[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[Cl:40])=[O:30])[CH2:14][CH2:15][CH2:16][NH2:17])=[N:7][CH:8]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN1C(=O)c2ccccc2C1=O)COC(=O)Nc1ccc(C(F)(F)F)cn1
Agent: NN
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(1,3-dioxoisoindolin-2-yl)pentyl 5-(trifluoromethyl)pyridin-2-ylcarbamate (150 mg, 0.24 mmol) in MeOH (5.0 mL) was added NH2NH2 (0.2 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated, dissolved in MeOH, filtered, and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 5-(trifluoromethyl)pyridin-2-ylcarbamate (91 mg, 76%). LRMS (M+H+) m/z 506.1.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][N:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].C(N(CC)CC)C>C(O)(C)C>[CH2:1]([N:8]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]([OH:20])[CH2:21][N:23]([CH2:24][CH2:25][N:26]2[N:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH3:22])=[CH:17][CH:18]=1)[S:9]([CH3:12])(=[O:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1ccc(C2CO2)cc1
Reactant: CNCCn1ncc2ccccc2c1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(N(Cc2ccccc2)S(C)(=O)=O)cc1

Procedure:
2-{4-(N-Benzylmethanesulphonamido)phenyl]oxirane (1.5 g), N-methyl-2-(phthalazin-1-on-2-yl)ethylamine (1.4 g) and triethylamine (1.4 g) in isopropanol (50 ml) were stirred at reflux temperature for 5 hours. The solvent was evaporated, the residue dissolved in methylene chloride and washed three times with sodium carbonate solution and three times with brine. The organic layer was dried and evaporated to give an oil which was purified by column chromatography on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methylene chloride containing methanol (0% up to 2%). Combination and evaporation of the appropriate fractions gave a foam which was chromatographed a second time on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methyl isobutyl ketone (MIBK) containing acetone (0% up to 20%). The appropriate fractions were combined and evaporated then re-evaporated from diethyl ether to give the title compound as a foam, yield 450 mg.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:13]=1[CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([O:22]CC)=[O:21])=[O:17])=[O:11])(=[O:5])[CH3:4]>O1CCCC1>[C:3]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:13]=1[CH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[O:11])(=[O:5])[CH3:4]
Reactant: CCOC(=O)CNC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 ml of 2N sodium hydroxide solution are added to a solution of 1.50 g (0.004 mol) of ethyl N-[2-(4-acetamidobutyryl) -5-chlorohydrocinnamoyl]glycinate in 15 ml of tetrahydrofuran and the mixture is stirred at room temperature for 1 hour. After acidification with 17 ml of 2N hydrochloric acid, the mixture is extracted with ethyl acetate/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Recrystallization from ethyl acetate/ether yields N-[2-(4-acetamidobutyryl) -5-chlorohydrocinnamoyl]glycine as white crystals with melting point 88-89°.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8]C)=[O:6].S(=O)(=O)(O)O.[CH3:16][C:17]1[C:22]([OH:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[OH:25].[OH-].[Na+].Cl>CO.O>[CH3:8][O:7][C:5](=[O:6])[CH2:4][C:3]1[C:21]2[C:20]([CH3:24])=[CH:19][C:18]([OH:25])=[C:17]([CH3:16])[C:22]=2[O:23][CH:2]=1
Reactant: Cc1cc(O)c(C)c(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1coc2c(C)c(O)cc(C)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethyl 4-chloro-3-oxobutanoate (3.08 mL) was added sulfuric acid (8.10 mL) at 0° C., then was added 2,5-dimethylbenzene-1,3-diol (3.0 g) in several portions at 0° C. The mixture was warmed to room temperature and stirred at room temperature for 2 h. The reaction mixture was poured into water under stirring at 0° C. The precipitate was collected by filtration and washed with hexane to give a solid. The solid was added to 1N NaOH (40 mL) at room temperature. The mixture was stirred at 100° C. for 1 h. After cooling, the reaction mixture was acidified with 6 N HCl (7.0 mL). The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give the crude product. To a mixture of the crude product and MeOH (50 mL) was added H2SO4 (0.057 mL). The mixture was stirred at 60° C. for 2 h. The mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (865 mg).
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:29][CH2:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=O)=[C:7]([CH:28]=1)[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O-]CC.[Na+].O>C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:29][CH2:30][C:31]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)=[CH:8][C:7]=2[CH:28]=1
Reactant: Cc1ccc(C(=O)COc2ccc(Br)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C2=Cc3cc(Br)ccc3OC2)cc1
Reaction time: 24 h
Yield: 85.6 %

Procedure:
Into a suspension of [5-bromo-2-[2-(4-methylphenyl)-2-oxoethoxy]benzyl](triphenyl)phosphonium bromide (5.53 g) in ethanol (20 ml) was added at room temperature a 20% solution of sodium ethoxide in ethanol (2.85 g), and the resulting mixture was stirred for 24 hours. After addition of water (15 ml) to the reaction mixture, a solid material was collected by filtration and was washed with water. The solid material were purified by recrystallization (ethanol) to obtain 6-bromo-3-(4-methylphenyl)-2H-1-benzopyran (2.16 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)Cc1csc(Br)n1
Product: CCOC(=O)Cc1csc(N(C)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 2-bromo-4-thiazolylacetate (2.5 g) and N-methylaniline (2.1 g) is stirred at 150°-155° C for 30 minutes. The resultant solution is treated in the same manner as in Example 1 to give ethyl 2-(N-methylanilino)-4-thiazolylacetate (2.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:28][C:27]([CH3:30])([CH3:29])[CH:26]=[CH:25][C:6]2=[C:7]2[C:16]=1[C:15](=[O:17])[C:14]1[CH:13]=[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]3=[C:10]([N+:22]([O-:24])=[O:23])[C:9]=1[NH:8]2.[H-].[Na+].I[CH3:34]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:28][C:27]([CH3:30])([CH3:29])[CH:26]=[CH:25][C:6]2=[C:7]2[C:16]=1[C:15](=[O:17])[C:14]1[CH:13]=[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]3=[C:10]([N+:22]([O-:24])=[O:23])[C:9]=1[N:8]2[CH3:34]
Reactant: CI
Reactant: COc1cc2c(c3[nH]c4c([N+](=O)[O-])c5ccccc5cc4c(=O)c13)C=CC(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4c([N+](=O)[O-])c1n3C)C=CC(C)(C)O2

Procedure:
To a solution of 300 mg of the compound obtained in Step 5 in 30 ml of dimethylformamide there are added 1.48 g of sodium hydride and then 1.8 ml of iodomethane. The reaction mixture is refluxed, under argon, for 3 days, and is then slowly hydrolysed by the addition of ice. The precipitate formed is filtered off and then dried and is chromatographed over silica gel (dichloromethane/methanol: gradient from 0.1 to 0.5%), allowing the expected product to be isolated.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Br)([O:3][CH2:4][CH3:5])=[O:2].[NH3:14]>C(#N)C>[C:1]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:14])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: N
Reactant: CCOC(=O)c1cccc(CBr)c1
Solvent: CC#N
Product: CCOC(=O)c1cccc(CN)c1
Temperature: -30 °C

Procedure:
3-Carboethoxybenzyl bromide (1 ml; Heterocycles, 1977, 6, 5) was added to a saturated solution of ammonia in acetonitrile (30 ml) which had been cooled to -30° C. The mixture was stirred and allowed to warm to laboratory temperature. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column using a 10:1 v/v mixture of ethyl acetate and methanol as eluent. There was thus obtained as an oil 3-carboethoxybenzylamine (0.4 g) which was used without further purification as the appropriate amine in the process described in Example 1.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH2:28][CH3:29])=[C:20]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[CH2:31]([N:33]=[C:34]=[S:35])[CH3:32]>>[CH2:1]([C:3]1[C:4](=[O:30])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH2:28][CH3:29])=[C:20]([S:23]([NH:24][C:34]([NH:33][CH2:31][CH3:32])=[S:35])(=[O:25])=[O:26])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)N1CC(C)=C(CC)C1=O)CCO2
Reactant: CCN=C=S
Product: CCNC(=S)NS(=O)(=O)c1cc2c(cc1OCC)OCCC2CNC(=O)N1CC(C)=C(CC)C1=O

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-ethoxychroman ##STR55## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-ethoxychroman is synthesized analogously to Example 14, starting from 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-ethoxychroman and ethyl isothiocyanate. Melting point: 178°-180° C.