Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH2:13][CH2:12]3)=[CH:5][CH:4]=1.[Br:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1.Cl>ClCCl>[Br:20][C:21]1[S:25][C:24]([S:26]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cc1
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)s1)N1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.25 g commercially available 5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-1H-indole were dissolved in 10 ml dichloromethane. Then 2.5 ml diidopropylethylamine were added. Then 1.37 g of commercially available 5-Bromo-thiophene-2-sulfonyl chloride dissolved in 5 ml dichloromethane were at 0° C. The mixture was stirred at room temperature for three hours. Then the mixture was poured on 100 ml 1M HCl and extracted five times with portions of 50 ml dichloromethane. The combined organic extracts were washed with 100 ml saturated NaHCO3 solution. The organic layer was then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by chromatography on silica gel to obtain 2.1 g of 1-(5-Bromo-thiophene-2-sulfonyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole.
Reaction SMILES: C(O)(=O)C(O)=[O:3].[CH3:7][N:8]([CH2:10][C@H:11]1[O:32][N:14]2[C:15]3[CH:27]=[C:26]([C:28]([O:30]C)=[O:29])[CH:25]=[CH:24][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@@H:13]2[CH2:12]1)[CH3:9].[OH-].[Na+]>C(O)C.O>[OH2:3].[CH3:9][N:8]([CH2:10][C@H:11]1[O:32][N:14]2[C:15]3[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@@H:13]2[CH2:12]1)[CH3:7].[CH3:9][N:8]([CH2:10][C@H:11]1[O:32][N:14]2[C:15]3[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@@H:13]2[CH2:12]1)[CH3:7]
Reactant: O=C(O)C(=O)O
Reactant: COC(=O)c1ccc2c(c1)N1O[C@H](CN(C)C)C[C@H]1c1ccccc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)C[C@@H]1C[C@H]2c3ccccc3Oc3ccc(C(=O)O)cc3N2O1
Yield: 41.6 %

Procedure:
(±)-Methyl cis-2-[(dimethylamino)methyl]-3,3a-dihydro-2H-dibenz[b,f]isoxazolo-[2,3-d][1,4]oxazepine-11-carboxylate ethanedioate(1:1)(1.53g), prepared following the procedure in example 7, in ethanol (60 ml) was added dropwise to a mixture of sodium hydroxide (0.3 g) in water (7.5 ml) and the mixture was stirred and refluxed for 2 hours. The solvent was evaporated in vacuo and the residue was acidified with HCl (4N) to a pH of 3.6. The precipitate was filtered off, dried with P2O5 and purified by short pad column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 7/3). The pure fractions were collected and evaporated and the residue (1 g) was treated with CH2Cl2 /C2H5OH/H2O 25ml/5ml/5ml. The precipitate was filtered off and dried, yielding 0.5 g (38%) of (±)-cis-2-[(dimethylamino)methyl]-3,3a-dihydro-2H-dibenz[b,f]isoxazolo[2,3-d][1,4]oxazepine-11-carboxylic acid hemihydrate; mp. 229.8° C. (comp. 4).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].[C:8](Cl)([Cl:10])=[O:9]>C1C=CC=CC=1>[Cl:10][C:8]([O:7][CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][CH3:1])=[O:9]
Reactant: CCCC(O)CC
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: CCCC(CC)OC(=O)Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
20.4 G. (0.2 moles) of 3-hexanol is added dropwise under anhydrous conditions to 345 ml. (0.4 moles) of 12.5% phosgene in benzene with stirring and cooling in an ice bath. The addition is complete in 2 hours and 15 minutes and the temperature is allowed to warm to room temperature and the reaction mixture is stirred overnight. Gaseous nitrogen is passed through the solution for several hours to remove the excess phosgene and hydrogen chloride. The reaction mixture is then evaporated to dryness in vacuo affording 28.3 g. (86%) of a colorless oil which infrared analysis indicates to have a strong carbonyl band and no hydroxy band. The oil is used as is in subsequent reactions.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[C:20]1=O>>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH:21]1[C:20]2[N:17]=[C:15]([NH:14][C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:2]([F:1])[CH:3]=3)[S:16][C:19]=2[CH2:24][CH2:23][CH2:22]1
Reactant: O=C1C(Br)CCCC1c1ccc(Cl)cc1Cl
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccc(Cl)cc3Cl)cc2F)cn1

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (109 mg, 0.44 mmol) and crude 2-bromo-6-(2,4-dichloro-phenyl)-cyclohexanone (350 mg, ca. 0.5 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-brown solid (118 mg, 57%). MS ISP (m/e): 473.1 [(M+H)+]. mp 136-139° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([S:24](Cl)(=[O:26])=[O:25])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:26])=[O:25])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(C(=O)O)c(Cl)cc2F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-chloro-5-chlorosulfonyl-4-fluorobenzoic acid as described in the synthetic METHOD B to give a white solid (26.5 mg) with purity >90%. MS (pos) m/z 421.4, 423.4.
Reaction SMILES: [OH-].[Na+].O.[C:4]1([C:10]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:18]3[C@@H:14]([CH2:15][N:16]([C:19](=[O:31])[C@@H:20]([O:27]C(=O)C)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17]3)[C@@:13]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])([OH:32])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:41]1([C:10]2([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C@@H:18]3[C@@H:14]([CH2:15][N:16]([C:19](=[O:31])[C@@H:20]([OH:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17]3)[C@@:13]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])([OH:32])[CH2:12][CH2:11]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)[C@@H](OC(C)=O)c3ccccc3)C[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)[C@@H](O)c3ccccc3)C[C@H]21
Yield: 80.9 %

Procedure:
1.4 cm 3 of an aqueous 1N solution of sodium hydroxide and then 10 cm3 of water are added to a solution of 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2- methoxyphenyl)-2-[(S)-2-acetyloxy-2-phenylacetyl]perhydroisoindol-4-ol in 30 cm3 of ethanol. The reaction mixture is refluxed for 1 hour and concentrated to dryness under reduced pressure (2.7 kPa), and the residue is taken up in 50 cm3 of water and then 1.5 cm3 of an aqueous 1N solution of hydrochloric acid and extracted with 40 cm3 of ethyl acetate (3 times). The organic phases are combined, washed with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.5 cm, height 27 cm) by eluting under a pressure of 0.4 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting fractions of 30 cm3. Fractions 2 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in isopropyl ether. 0.6 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-hydroxy-2-phenylacetyl]perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 256° C.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:5][C:4]([CH3:16])([C:6]([O:8]CC2C=CC=CC=2)=[O:7])[CH2:3]1.[OH-].[Na+]>C(O)C>[F:1][C:2]1([F:17])[CH2:5][C:4]([CH3:16])([C:6]([OH:8])=[O:7])[CH2:3]1
Reactant: CC1(C(=O)OCc2ccccc2)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C(=O)O)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
To a solution of Intermediate 296A (1.2 g, 4.99 mmol) in ethanol (5 mL) was added a 5N aq. solution of NaOH (4.99 mL, 24.97 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure; the residue was dissolved in water and extracted with diethyl ether (3×5 mL) The pH of the aqueous solution was adjusted to 7.0 using a 2N aq. solution of HCl and extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford Intermediate 296B as a pale yellow liquid (500 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.73-12.70 (m, 1H), 3.03-2.89 (m, 2H), 2.49-2.41 (m, 2H), 1.40 (s, 3H).
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7].ClC1C=[C:16](C=CC=1O)[C:17](O)=[O:18].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[C:17]([O:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:2])(=[O:18])[CH3:16]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
3-Chloro-4-hydroxybenzoic acid hemihydrate (10.16 g, 56 mmol) was dissolved in 20 ml of acetic anhydride, followed by the addition of 0.5 ml of concentrated sulfuric acid. The resulting mixture was stirred at 100° C. for 3 hours and was then allowed to stand overnight at room temperature. The precipitate was collected by filtration and then washed with benzene, whereby 8.95 g of 4-acetoxy-3-chlorobenzoic acid were obtained (yield: 75%, melting point: 149-151° C.). A mixture of 8.95 g (41.7 mmol) of 4-acetoxy-3-chlorobenzoic acid and 22.23 g (167 mmol) of aluminum chloride was then heated at 180° C. for 3 hours. Subsequent to the addition of ice and 1N hydrochloric acid, the resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and was then dried over MgSO4. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate, whereby 2.97 g of the title compound were obtained as yellow powder (yield: 33%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1.CN(C=O)C>[Cl-].[Na+].O>[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:25])([F:24])[C:20]([F:23])([F:21])[F:22])=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)C(F)(F)F
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)C(F)(F)F
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To flask containing the title compound from Example 8 Step C (415 mg, 0.971 mmol) were added cesium carbonate (791 mg, 2.43 mmol), 4-bromobenzyl bromide (316 mg, 1.26 mmol), and DMF (6 mL), and the resulting mixture was stirred at 45° C. After 3 h, the reaction mixture was allowed to cool to room temperature, then was poured into brine and extracted with EtOAc. The organic phase was separated and concentrated in vacuo. Purification by chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 597.7 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.82 (dd, J=8.0, 2.0 Hz, 1H), 7.49-7.47 (m, 2H), 7.38-7.35 (m, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.11-7.08 (m, 1H), 7.02 (d, J=8.5 Hz, 1H), 5.09 (s, 2H), 4.37 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1.CS(C)=[O:17]>F[B-](F)(F)F.[Ag+]>[CH:2]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1)=[O:17]
Reactant: CS(C)=O
Reactant: N#Cc1ccc2ccc(CBr)cc2c1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: N#Cc1ccc2ccc(C=O)cc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Silver tetrafluoroborate (1,168 mg) was suspended in 6 ml of dimethyl sulfoxide, 1,230 mg of 7-Bromomethyl-2-naphthalenecarbonitrile was added to the suspension, and the mixture was stirred at room temperature for 14 hours. The reaction solution was filtered, water was added to the mother liquid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate as the eluent to give 543 mg of 7-formyl-2-naphthalenecarbonitrile in the form of white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:22])[CH2:17][CH2:16]2)[N:3]=1.[OH-:35].[Na+]>>[OH:35][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:22])[CH2:17][CH2:16]2)[N:3]=1
Reactant: CN1CCN(c2nc(Cl)nc(N3CCC(C(=O)NCc4ccccc4C(F)(F)F)CC3)n2)CC1
Reactant: [OH-]
Agent: [Na+]
Product: CN1CCN(c2nc(O)nc(N3CCC(C(=O)NCc4ccccc4C(F)(F)F)CC3)n2)CC1
Temperature: 80 °C

Procedure:
To ⅕ of the suspension prepared in step b (0.542 mmol, 1.00 equiv) was added 6 N NaOH. The resulting mixture was heated to 80° C. for 1 h. The final solution was directly purified by reverse-phase HPLC (Sunfire, 20-40% CH3CN, H2O, 0.1% TFA, 12 min) to afford 21.2 mg of the title compound. MS (ES+): m/e 480.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:29])[CH2:27][CH3:28])[CH:23]=[CH:24][CH:25]=1>CN(C)C=O>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:29])[CH2:27][CH3:28])[CH:23]=[CH:24][CH:25]=1)[CH3:9]
Reactant: CCC(=O)c1cccc(CBr)c1
Reactant: CNCC=CC#CC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 26.7 %

Procedure:
N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine (trans:cis=about 3:1) (0.80 g; 5.29 mmol) and sodium carbonate (0.80 g; 7.56 mmol) were added to N,N-dimethylformamide (20 ml). While the mixture was stirred at room temperature, 3′-bromomethylpropiophenone (1.14 g; 5.04 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. The mixture was stirred for 2.5 hours at room temperature, and poured into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.40 g of the target compound as orange oily matter (yield: 26.7%).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 19.5 %

Procedure:
Using cyclohexyl{1-ethyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}methanol (0.6 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.42 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.18 g, 20%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7]/[C:8](=[N:33]\[OH:34])/[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:20][C:21]([C:23]2[NH:27][C:26]3[S:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]=2)=[O:22])[C:11]1=[O:32].C1COCC1.Cl>N1C=CC=CC=1.CCOC(C)=O>[NH2:7]/[C:8](=[N:33]\[O:34][C:2]([O:4][CH2:5][CH3:6])=[O:3])/[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:20][C:21]([C:23]2[NH:27][C:26]3[S:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]=2)=[O:22])[C:11]1=[O:32]
Reactant: CCOC(=O)Cl
Reactant: N/C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21)=N\O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)O/N=C(\N)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Temperature: 100 °C

Procedure:
Ethyl chloroformate (60 μL, 0.63 mmol) was added to a suspension of N-{1-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 31; 200 mg, 0.48 mmol) in dry pyridine (1 mL) under an inert atmosphere then stirred heated to 100° C. for 30 minutes. On cooling THF (10 mL) and added followed by EtOAc (50 mL) and 1M HCl aq. (20 mL). The organic was separated and dried (Na2SO4), filtered and evaporated to give a clear orange oil. This was used in the next stage without characterization or purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:9](=[O:30])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[C:13]([F:29])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:9](=[O:30])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[C:13]([F:29])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)c(F)c1
Reaction time: 0.12 h
Yield: 83.9 %

Procedure:
Methyl 2-[(4-{2-[benzyl(hexyl)amino]-2-oxoethyl}-2-fluorophenoxy)methyl]benzoate (109 mg, 0.222 mmol) was dissolved in THF (2 ml). Lithium hydroxide (10.6 mg, 0.444 mmol) solved in water (1 ml) was added. The mixture was put in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes. It was then acidified with 1% hydrochloric acid, pH˜3, and extracted with ethyl acetate. The organic extract was washed with brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM and then MeOH/DCM (0.5: 99.5, then 1:99) as eluant gave 89 mg the desired product, yield 84%.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=2[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=1.C(OC(=O)C)(=O)C>>[CH3:34][N:33]([CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=[CH:31][C:30]=1[C:7]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:24])[CH3:1])=[CH:23][CH:22]=2)[C:9]2[C:10](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])[C:11](=[O:13])[O:8]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Temperature: 95 °C
Yield: 73.6 %

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (20.3 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (88%, 9.3 g.) and acetic anhydride (74 ml.) was heated (to 95° C.) during one hour, then cooled, affording 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X = Y4 = (CH3)2N, Y2 = H, Z4 = Z5 = Z6 = Z7 = Cl) (20.3 g., m.p. 227°-229° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]([C:10]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC)=O)=C(C)[NH:14][C:15]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1>C(O)C>[CH3:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16])=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(C)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(C)cc1

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 4-methylbenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-methylbenzyl ester of melting point 112° C (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:14][C:15]([C:17]1[CH:26]=[CH:25][C:24]2[NH:23][C:22](=[O:27])[C:21]3[NH:28][CH:29]=[CH:30][C:20]=3[C:19]=2[CH:18]=1)=O.[CH2:31]([C:33]([O-:35])=[O:34])[CH3:32]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:24]4[NH:23][C:22](=[O:27])[C:21]5[NH:28][CH:29]=[CH:30][C:20]=5[C:19]=4[CH:18]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:31]([C:33]([O-:35])=[O:34])[CH3:32]
Reactant: NC(=S)Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=c1[nH]c2ccc(-c3csc(Nc4ccc(Cl)c(Cl)c4)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 6 h
Yield: 13.9 %

Procedure:
87 mg (1.2 mmol) of (3,4-dichlorophenyl)-thiourea is added to a suspension of 124 mg (0.33 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3.5 mL of ethanol. The mixture is stirred at 90° C. for 6 hours then the mixture is cooled to room temperature. The solvent is evaporated, then the product is purified by preparative LCMS. After drying, 23 mg (14%) of 8-[2-(3,4-dichlorophenylamino)-thiazol-4-yl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.