Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1CC1c1ccc(Cl)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: N[C@@H]1C[C@@H]1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[2-(4-chloro-phenyl)-cyclopropyl]-isoindole-1,3-dione (320 mg, 1.07 mmol) and hydrazine hydrate (0.5 ml) in ethanol (8 ml) was stirred for 0.5 hour at 50° C. The solution was evaporated under reduced pressure. The resulting amine (compound Z1.001) was used in example P1 without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[N:3]=1.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].CC([N:40]=C=NC(C)C)C>CN(C)C=O>[NH2:40][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:34](=[O:36])[CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[CH:19][CH:18]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)N=C=NC(C)C
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(CO)cc2)n1
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(COC(=O)CNC(=O)OC(C)(C)C)cc2)n1
Reaction time: 12 h
Yield: 105.2 %

Procedure:
A mixture of the title compound of Example 41 (0.684 g, 2.0 mmol), N-tert-butoxycarbonyl glycine (0.368 g, 2.1 mmol), N,N-dimethylaminopyridine (0.049 g, 0.4 mmol), dimethylformamide (15 ml), and N,N-diisopropylcarbodiimide (0.278 g, 2.2 mmol) was stirred for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 40% ethyl acetate-hexane to provide 2-tert-butoxycarbonylamino-acetic acid 4-[4-amino-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazin-2yl-amino]-benzyl ester (1.05 g, 100% yield). 1H NMR (CDCl3) δ 7.74 (s, 1H), 7.63-7.74 (d, 1H), 7.6 (br s, 2H), 7.31-7.36 (m, 4H), 7.20-7.22 (d, 1H), 5.3-5.6 (br s, 2H), 5.17 (d, 2H) 4.95-5.1 (br s, 1H), 3.965 (d, 2H), 2.55 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: O[C:2]1[C:19]([OH:20])=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([OH:22])=[C:14]([OH:21])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([OH:24])=[C:8]([OH:23])[CH:9]=3)[C:4]=2[CH:3]=1.[H-].[Na+].C1(C)C=CC(S(OCC[CH2:39][CH2:40][CH2:41][CH2:42][C:43](F)(F)[C:44]([F:47])(F)F)(=O)=O)=CC=1.CN(C)[CH:53]=[O:54]>C(Cl)(Cl)Cl.O>[F:47][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:24][C:7]1[C:8]([O:23][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][F:47])=[CH:9][C:10]2[C:11]3[C:16](=[CH:15][C:14]([O:21][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][F:47])=[C:13]([O:22][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][F:47])[CH:12]=3)[C:17]3[C:4](=[CH:3][CH:2]=[C:19]([O:20][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][F:47])[CH:18]=3)[C:5]=2[C:6]=1[O:54][CH2:53][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][F:47]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCC(F)(F)C(F)(F)F)cc1
Reactant: CN(C)C=O
Reactant: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: FCCCCCCOc1ccc2c(c1)c1cc(OCCCCCCF)c(OCCCCCCF)cc1c1cc(OCCCCCCF)c(OCCCCCCF)c(OCCCCCCF)c21
Temperature: 25 °C
Yield: 36.6 %

Procedure:
0.30 g (0.925 mmol) of 2,3,6,7,10,11-hexa-hydroxytriphenylene (3) was dissolved with 3 ml of DMF (dimethylformamide) in a 30 ml round-bottomed flask, and under stirring at room temperature, 0.27 g (6.75 mmol) of sodium hydride (60% in oil) was added little by little thereto. After the addition, the system was stirred for 10 minutes at room temperature and heated to ca. 80° C. on an oil bath, and 2.56 g (6.84 mmol) of 6-(perfluoroethyl)hexyl p-toluenesulfonate (2) dissolved in 2 ml of DMF was gradually added dropwise thereto. After the dropwise addition, the system was stirred for 5 hours under heating at the same temperature. After the reaction, the system was cooled to room temperature and stirred while adding chloroform and water thereto. The chloroform layer was condensed and purified by silica gel column chromatography with a chloroform eluent. After distilling off the chloroform, the resultant crystal was further purified by silica gel column chromatography with a toluene eluent and recrystallized from an acetone-methanol mixture solvent to obtain 0.52 g (yield=36.6%) of 2,3,6,7,10,1-hexakis[6-(perfluoro)hexyloxy]-triphenylene (1-5). The compound exhibited the following phase transition series.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8](OS(C)(=O)=O)[CH2:9][CH:3]1[CH2:4][CH2:5]2.C([O:17][C:18]([S-:20])=[S:19])C.[Na+].C1(C)C=CC=CC=1>O>[CH3:1][N:2]1[C@@H:3]2[CH2:9][CH:8]([S:19][C:18]([SH:20])=[O:17])[CH2:7][C@H:6]1[CH2:5][CH2:4]2
Reactant: CCOC(=S)[S-]
Reactant: CN1C2CCC1CC(OS(C)(=O)=O)C2
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC[C@H]1CC(SC(=O)S)C2
Temperature: 30 °C

Procedure:
Tropine-3-mesylate (25 g, 0.114 mol) and sodium ethylxanthate (19.7 g, 0.137 mol) were added to stirred toluene (0.075 L) under nitrogen. The stirred mixture was maintained at 30° C. for 6 h. Water (0.05 L) was added and after 15 min stirring the phases were separated. The toluene phase, containing the title compound, was used directly in the preparation of tropine-3-thiol as in Step 4b.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=[S:32])[NH2:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:24]
Reactant: S
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile (8.44 g) and triethylamine (3.5 cc) in anhydrous pyridine (60 cc) is saturated by bubblin9 in hydrogen sulphide for 5 hours at 25° C. The clear solution obtained is kept stirred for 12 hours at 25° C., and the mixture is then outgassed by bubbling through nitrogen for 90 minutes. The reaction mixture i diluted with ethyl acetate (500 cc) and washed with distilled water (8×200 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is purified by chromatography on a column of basic alumina (0.05-0.16 mm) (height: 31 cm; diameter: 2.6 cm), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (5 liters) and 50:50 (5 liters) and collecting 100-cc fractions. Fractions 4 to 90 are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (8.54 g) in the form of an orange-yellow product of honey-like consistency.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][N:37]=[N+]=[N-])=[O:10])=[CH:5][CH:4]=1.CO.[C:44]([OH:47])(=[O:46])[CH3:45]>C(OCC)(=O)C.[Pd]>[C:44]([OH:47])(=[O:46])[CH3:45].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][NH2:37])=[O:10])=[CH:40][CH:41]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN)cc1
Yield: 94.5 %

Procedure:
A solution of (2S, 4S)-1-p-methoxybenzyloxycarbonyl-2-azidomethyl-4-tritylthiopyrrolidine (17.27 g: 30.64 mmole) in a mixture of ethyl acetate (150 ml), methanol (200 ml), and acetic acid (2.63 ml: 46 mmole) is subjected to conventional hydrogenation over 5% palladium on carbon (5 g). After the reaction, the catalyst is filtered off and the filtrate is concentrated in vacuo to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-aminomethyl-4-tritylthiopyrrolidine acetate (17.33 g) as a residue. The residue is dissolved in dichloromethane, washed with aqueous sodium hydrogen carbonate, and concentrated to give (2S,4S)-2-aminomethyl-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine (16.82 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH3:11][Mg]Br.C1(C)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.O>[OH:10][C:8]1[CH:9]=[C:4]([C:2]([CH3:11])([CH3:1])[OH:3])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cccc(O)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 1088 grams (8 moles) of 3-hydroxyacetophenone in 13.25 liters of tetrahydrofuran was added in a nitrogen atmosphere, over 40 minutes, a solution of 10,000 grams (20 moles) of a commercially prepared 2 M solution of methylmagnesium bromide in a mixture of equal weights of tetrahydrofuran and toluene. The mixture was stirred with a turbine stirrer during the addition. Stirring was continued as the mixture was heated under reflux (70° C.) for three hours. A solution of 5.6 liters of saturated aqueous ammonium chloride solution in 2.4 liters of water was then added and the mixture was stirred for one hour at room temperature. It was allowed to stand for one hour, the aqueous and organic layers were separated and the organic layer was washed with 7.5 liters of water, after which the tetrahydrofuran was removed by distillation. There was added 7600 ml. of a 10% aqueous solution of sodium hydroxide, and the mixture was again distilled until all tetrahydrofuran and toluene had been removed. The aqueous residue was filtered and acidified with concentrated hydrochloric acid. The precipitated solids were filtered, washed with cold water and dried to yield the desired 3-hydroxyphenyldimethylcarbinol. The yield was 976 grams, or 80% of theoretical.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:34])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[F:32][C:30]([F:31])([F:33])[O:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:34])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(OC(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1Oc1ccc(OC(F)(F)F)cc1)C1CCNCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-[2-(4-Trifluoromethoxy-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (HVB01064, 0.3 g, 0.62 mmol) was dissolved in anhydrous DCM (7 ml), cooled to 0° C. and to this was added TFA (2.8 ml), and the reaction mixture was stirred under nitrogen for 1.5 h. The reaction mixture was poured onto solid potassium carbonate (6 g), and water (25 ml) added. Extracted with DCM and the organic layers dried over anhydrous magnesium sulphate, and evaporated in-vacuo, 0.21 g, 87%. Rf: 0.35 (DCM), 1HNMR: (CDCl3, 270 MHz) δ 1.64 (2H, m, CH2), 1.79 (2H, dd, J=2.7, 12.9 Hz, CH2), 2.32 (1H, m, CH), 2.61 (2H, td, J=2.7, 12.3 Hz, NCH2), 2.94 (1H, s, NH), 3.10 (2H, td, J=3.3, 12.6 Hz, NCH2), 6.79 (1H, dd, J=1.2, 8.1, ArHD), 6.95 (2H, m, ArHE), 6.95 (1H, m, ArHE), 7.08 (1H, td, J=1.5, 7.8 Hz, ArHc), 7.13 (2H, d, J=8.4 Hz, ArHF), 7.62 (1H, s, NH), 8.34 (1H, dd, J=1.2, 8.1 Hz, ArHA).
Reaction SMILES: [CH2:1]([C:5]1[CH:61]=[CH:60][C:8]([CH2:9][N:10]([C:18]2[CH:19]=[C:20]([CH:38]=[C:39]([N:41](C(OC(C)(C)C)=O)[CH2:42][C:43]3[CH:48]=[CH:47][C:46]([CH2:49][CH:50]([CH3:52])[CH3:51])=[CH:45][CH:44]=3)[CH:40]=2)[C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:24]=2)=[O:22])C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[ClH:62].CCCCCC>C1(C)C=CC=CC=1.O1CCOCC1>[ClH:62].[ClH:62].[CH2:49]([C:46]1[CH:45]=[CH:44][C:43]([CH2:42][NH:41][C:39]2[CH:38]=[C:20]([CH:19]=[C:18]([NH:10][CH2:9][C:8]3[CH:60]=[CH:61][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)[CH:40]=2)[C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:24]=2)=[O:22])=[CH:48][CH:47]=1)[CH:50]([CH3:52])[CH3:51]
Reactant: CC(C)Cc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)c2)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)Cc1ccc(CNc2cc(NCc3ccc(CC(C)C)cc3)cc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[3-[3,5-bis[N-(4-isobutylbenzyl)-N-tert-butoxycarbonylamino]benzoyl]indol-1-yl]butyric acid (1.02 g) in toluene (10 ml) was added 4N solution of hydrogen chloride in 1,4-dioxane (30 ml) at 25° C. The mixture was stirred at 25° C. for 1 hour, and then hexane (30 ml) was added. The precipitates were filtered and washed with isopropyl ether and hexane to give 4-[3-[3,5-bis[(4-isobutylbenzyl)amino]benzoyl]indol-1-yl]butyric acid dihydrochloride (688 mg) as white powder.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[CH3:27][O:28][C:29]([C@@H:31]1[CH2:35][C@H:34](OS(C)(=O)=O)[CH2:33][N:32]1[S:41]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)(=[O:43])=[O:42])=[O:30]>CN(C=O)C>[CH3:27][O:28][C:29]([C@@H:31]1[CH2:35][C@@H:34]([S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:33][N:32]1[S:41]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)(=[O:43])=[O:42])=[O:30]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
64.2 g (167 mmol) of triphenylmethanthiol was slowly added at RT to a solution of 17.9 g (160 mmol) of potassium tert-butylate in 300 ml DMF and stirred mechanically for 30 min. Then 63 g (152 mmol) of (4S,2S)-4-Methanesulfonyloxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methylester in 300 ml DMF were added at 20° C. by cooling at the end with an ice bath. The reaction was heated for 1.3 h at 100° C., cooled, evaporated to 400 ml and extracted with 250 ml aqueous saturated NH4Cl/EtOAc (3×300). The organic phases were washed with aq. 10% NaCl, dried over Na2SO4 and evaporated. Flash chromatography (CH2Cl2/MeOH 99:1) gave 58.6 g (65%, (2S,4R)/(2R,4R)-isomer ca 4:1, 1H-NMR) and 9.2 g (10%), (2S,4R)/(2R,4R)-isomer ca 1:1, 1H-NMR) of (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid methyl ester, MS: 594 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:8]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1[nH]ccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1[nH]ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3-chloro-1H-pyrrole-2-carboxylic acid (15 g, 0.1 mol) in N,N-dimethylformamide (300 mL) and triethylamine (72 mL, 0.52 mmol) under argon atmosphere was added benzyl bromide (61 mL, 0.52 mmol) at 0-5° C. and the reaction was stirred mechanically overnight at room temperature. Next day, the reaction mixture was concentrated in vacuum and the residue was suspended in 4% aqueous solution of sodium bicarbonate (300 mL) and extracted with ethyl acetate (2×250 mL). The organic layers were mixed and washed with more 4% aqueous solution of sodium bicarbonate, water and brine, and were dried (magnesium sulphate, MgSO4) and concentrated under reduced pressure to give 21.4 g of a residue corresponding to the title compound (88% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#N.[CH2:12]([Mg]Br)[CH3:13].C1C[O:19]CC1>>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:19])[CH2:12][CH3:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: C1CCOC1
Reactant: COc1ccc(C#N)cc1F
Reactant: CC[Mg]Br
Product: CCC(=O)c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzonitrile (350 mg, 2.32 mmol) in 15 mL anhydrous THF was added ethylmagnesium bromide (1 M in Et2O, 4.63 mL) at 0° C. The reaction mixture was stirred at rt overnight, then quenched with sat. NaHCO3, extracted with EtOAc, washed with brine, dried and evaporated. The residue was purified by column chromatography (eluent: petroleum ether/EtOAc=5/1) over silica gel to give the product (239 mg, 57% yield) as a yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]2[CH:35]=[CH:34]C(N)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>>[CH:17]1([C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:34]=[CH:35][C:30]([N:26]5[CH2:27][CH2:28][CH2:29][N:23]([CH3:22])[CH2:24][CH2:25]5)=[CH:31][CH:32]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1sc(C(=O)C2CCCC2)cc1N=CN(C)C
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Product: CN1CCCN(c2ccc(-n3cnc4cc(C(=O)C5CCCC5)sc4c3=O)cc2)CC1

Procedure:
5-Cyclopentanecarbonyl-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 436.58 (C24H28N4O2S) was obtained in this way; MS (ESI): 437 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1.C(OCC)(=O)C>CN(C)C=O.O1CCCC1>[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1
Reactant: CNc1ccncc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cnccc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 140 mg (0.71 mmol) methyl-(3-o-tolyl-pyridin-4-yl)-amine in 1 ml N,N-dimethylformamide at 0° C. were added dropwise 0.71 ml (0.71 mmol) of 1 M potassium hexamethyldisilazide solution in tetrahydrofuran. Stirring was continued for 1 h at room temperature and the reaction mixture was cooled to 0° C. again. At this temperature, a solution of 270 mg (0.85 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 0.5 ml tetrahydrofuran was added. After stirring for 18 h at room temperature, ethyl acetate was added and the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 211 mg (58%) of the title compound as white foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][OH:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>O1CCCC1>[C:33]([O:12][CH2:11][C:9]1[O:10][C:6]2[C:5]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=2[CH:8]=1)(=[O:35])[CH3:34]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3cc(CO)oc23)c1=O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Yield: 43.6 %

Procedure:
0.4 g (1.1 mmol) of 3-(4-chloro-2-hydroxymethylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 0.13 g (1.2 mmol) of triethylamine were dissolved in 20 ml of tetrahydrofuran, and 0.1 g (1.2 mmol) of acetyl chloride was dropwise added thereto under cooling with ice. After completion of the reaction, the reaction solution was poured into water and washed with ethyl acetate. The organic layer was washed sequentially with a 10% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.2 g (yield: 45.5%) of the desired product as white solid. Melting point: 135-138° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][OH:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH:18]=O.[C:27](#[N:31])[CH2:28][C:29]#[N:30]>>[NH2:31][C:27]1[O:1][C:2]2[C:10]([CH:18]([C:17]3[CH:16]=[C:15]([O:14][CH3:13])[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=3)[C:28]=1[C:29]#[N:30])=[CH:9][CH:8]=[C:7]1[N:6]([CH2:11][OH:12])[CH:5]=[CH:4][C:3]=21
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: OCn1ccc2c(O)cccc21
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2CO)cc(OC)c1OC

Procedure:
The title compound was prepared from 4-hydroxy-1-hydroxymethylindole (30 mg, 0.18 mmol), 3,4,5-trimethoxy-benzaldehyde (36 mg, 0.18 mmol) and malononitrile (12 mg, 0.18 mmol) similar to Example 24 to yield 63 mg (84%) of white solids. 1H NMR (CDCl3): 7.21-7.20 (m, 2H), 6.84 (d, J=8.4 Hz, 1H), 6.64 (d, J=3.0 Hz, 1H), 6.42 (s, 2H), 5.61 (d, J=6.0 Hz, 2H), 4.78 (s, 1H), 4.67 (brs, 2H), 3.82-3.80 (m, 9H), 2.46 (brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]C(=O)[CH2:15][CH2:14]1)(=[O:12])=[O:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CO[CH:44]([O:47][CH3:48])[O:45][CH3:46].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:44]([O:45][CH3:46])([O:47][CH3:48])[CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: COC(OC)OC
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CCOC(=O)C1=CC(OC)(OC)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Yield: 87.8 %

Procedure:
6.1 g (16.2 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 120 ml of methanol and 4.1 g (16.2 mmol) of pyridinium p-toluenesulfonate and 8.86 ml (81.0 mmol) of trimethoxymethane were sequentially added thereto with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 6.0 g of the title compound as a white powder (yield: 88%).