Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.[F:12][C:13]1[CH:14]=[C:15]([CH:20]2CCC(=O)[CH2:22][CH2:21]2)[CH:16]=[C:17]([F:19])[CH:18]=1>O>[F:12][C:13]1[CH:14]=[C:15]([CH:20]2[CH2:9][CH2:8][CH:7]([CH:11]=[O:10])[CH2:22][CH2:21]2)[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: C1CCOC1
Reactant: O=C1CCC(c2cc(F)cc(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=CC1CCC(c2cc(F)cc(F)c2)CC1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To dried MTP 10.0 g (29.2 mmol), THF 100 ml was added, and potassium-t-butoxide 3.30 g (29.4 mmol) was added. The mixture was stirred for about one hour. To the reactant, a THF solution (50 ml) of the above 4-(3,5-difluorophenyl)cyclohexanone 5.0 g (23.8 mmol) was added dropwise, and the mixture was stirred for 2 hours. Water 150 ml was added to the reactant, the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene). The resulting purified material was stirred in mixture solvent of 3N-hydrochloric add 200 ml and acetone 200 ml for 5 hours at room temperature, and the product was extracted with toluene. The extract was washed with a saturated sodium bicarbonate aqueous solution and then with water, and dried over anhydrous magnesium sulfate. Toluene was distilled off to obtain 4-(3,5-difluorophenyl)cyclohexanecarboaldehyde 5.0 g (22.3 mmol). The yield was 93.7% from 4-(3,5-difluorophenyl) cyclohexanone.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[C:3]=1[O:4][CH2:5][CH2:6][C@H:7]([NH2:9])[CH3:8].[F:15][C:16]([F:25])([F:24])C1C=CC=CC=1O>>[F:15][C:16]([F:25])([F:24])[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C@H:7]([NH2:9])[CH3:8]
Reactant: C[C@@H](N)CCOc1c(Cl)cccc1Cl
Reactant: Oc1ccccc1C(F)(F)F
Product: C[C@@H](N)CCOc1ccccc1C(F)(F)F
Yield: 88 %

Procedure:
Intermediate 14 (55 mg, 0.250 mmol, 88% yield) was prepared as a white powder following the procedure described for Intermediate 13 by replacing 2,6-dichlorophenol with 2-trifluoromethylphenol. LC-MS (ESI) 221 (M+H), RT=1.48 min (Method B).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][S:6]([C:9]1[CH:29]=[CH:28][C:12]([O:13][CH:14]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:15]([O:17]C)=[O:16])=[C:11]([CH2:30][CH2:31][CH3:32])[CH:10]=1)(=[O:8])=[O:7])=[O:4].[OH-].[Na+].C(Cl)(Cl)Cl.CO.C(O)(=O)C.Cl>CO.O>[CH3:1][NH:2][C:3]([NH:5][S:6]([C:9]1[CH:29]=[CH:28][C:12]([O:13][CH:14]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:15]([OH:17])=[O:16])=[C:11]([CH2:30][CH2:31][CH3:32])[CH:10]=1)(=[O:7])=[O:8])=[O:4]
Reactant: CCCc1cc(S(=O)(=O)NC(=O)NC)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCCc1cc(S(=O)(=O)NC(=O)NC)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 69.3 %

Procedure:
To a stirred solution of 570 mg (1.23 mmol) of the product of Step A in 6 mL of methanol was added 540 μL (2.71 mmol) of 5N sodium hydroxide. The reaction mixture was allowed to stir overnight after which TLC analysis (90:10:1 chloroform/methanol/acetic acid) indicated the saponification had proceeded to completion. The reaction mixture was acidified to pH=2 using 6N HCl, poured into water, and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated in vacuo to give the crude product. Purification of the crude product by silica-gel flash chromatography using (92:7:1 chloroform/methanol/acetic acid) afforded 384 mg (70%) of the title compound as an amorphous solid.
Reaction SMILES: C([NH:4][C:5]1[N:10]([O:11]C(=O)C)[C:9](=[NH:15])[N:8]=[C:7]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:6]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[N:10]([OH:11])[C:9](=[NH:15])[N:8]=[C:7]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:6]=1
Reactant: CC(=O)Nc1cc(N2CCCCC2)nc(=N)n1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=c1nc(N2CCCCC2)cc(N)n1O

Procedure:
1.0 g (3.4 mmoles) of 6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-piperidinopyrimidine prepared as described in Example 7 is dissolved in a mixture containing 20 ml of ethanol and 5 ml of 1N aqueous sodium hydroxide solution, the mixture is refluxed for 30 minutes, then evaporated under reduced pressure. Taking up the residue in 10 ml of water, the crystals are filtered, washed with water and dried to give the aimed compound in a yield of 0.54 g (76%), which shows no melting point depression when mixed with the product of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:30]([F:33])([F:32])[F:31])[CH:27]=2)[O:22][C:21]([CH3:35])([CH3:34])[C@H:20]1[OH:36].C(N(CC)CC)C.C(N)(=O)C1C=CC=CC=1>C1C=CC=CC=1.ClCCl>[OH:36][C@H:20]1[C@H:19]([NH:18][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:30]([F:33])([F:31])[F:32])[CH:27]=2)[O:22][C:21]1([CH3:35])[CH3:34]
Reactant: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: NC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(C(=O)N[C@@H]2c3cc(OC(F)(F)F)ccc3OC(C)(C)[C@H]2O)c1
Yield: 76.5 %

Procedure:
5-Methyl-2-nitrobenzoic acid (1.81 g, 10 mmol) was converted to the corresponding acid chloride by refluxing in benzene (30 mL) with thionyl chloride (1.66 g, 14 mmol) for 0.5 hours. The crude mixture was concentrated in vacuo and diluted with dichloromethane (10 mL). This solution was added to a cooled solution of (3S, 4R)-4-amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol (2.75 g, 10 mmol), triethylamine (1.39 mL, 10 mmol) and dichloromethane (25 mL). The crude benzamide was worked-up in a method similar to that in Example 1 to afford 3.37 g (82%) of a white solid: m.p. 185°-187° C., 1H NMR (DMSO-d6): δ 9.12 (d, 1H), 7.96 (d, 1H), 7.60 (s, 1H), 7.51 (d, 1H, 7.38 (s, 1H), 7.16 (d, 1H), 6.86 (d, 1H), 5.84 (d, 1H), 5.00 (t, 1H), 3.66 (m, 1H), 2.45 (s, 3H), 1.43 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=O.C([NH2:18])=O.C[O-].[Na+]>Cl>[CH3:15][C:11]1[CH:12]=[N:13][C:14]2[CH:5]([C:3]([NH2:18])=[O:2])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: NC=O
Reactant: COC(=O)C1CCCc2cc(C)cnc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cnc2c(c1)CCCC2C(N)=O
Yield: 90 %

Procedure:
A mixture of methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate (25 g. 0.13 m), formamide (11.6 g., 0.26 m) and sodium methoxide (from 2.99 g., 0.13 m sodium) was heated on a steam bath for 1 hour while bubbling nitrogen through the mixture, to blow off the methyl formate produced in the reaction. The cooled reaction mixture was diluted with 2N HCl and worked up as described in Example 21 to give the title compound in 90% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@@H:45]([C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=4)[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:53][C:49]1[CH:48]=[C:47]([C@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]2[C@@H:25]2[C@@:20]([CH3:54])([CH2:21][CH2:22]3)[C@@:19]3([CH3:55])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH3:46])[CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2cccc(Cl)c2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@H](C)c2cccc(Cl)c2)CC1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((R)-1-(3-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (400 mg, 0.489 mmol) in DCM (10 mL) that was stirred at room temp was then added TFA (5 mL, 64.9 mmol). The reaction mixture was stirred at 30° C. for 2 h. The mixture was evaporated to dryness then diluted with 200 mL DCM. The organic phase was washed with saturated NaHCO3, water and brine. The organics were dried and concentrated under reduced pressure to afford crude product which was purified by preparative-HPLC to afford the title compound (100 mg, 27%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.38-7.14 (m, 4H), 6.96 (d, J=15.8 Hz, 1H), 6.25 (d, J=7.8 Hz, 1H), 5.73 (d, J=15.6 Hz, 1H), 5.23-5.08 (m, 1H), 4.50 (dd, J=5.4, 10.7 Hz, 1H), 3.27-3.11 (m, 1H), 2.82-2.49 (m, 3H), 2.33-2.19 (m, 1H), 2.19-2.00 (m, 2H), 2.00-0.71 (m, 47H); LC/MS: m/z calculated 761.4. Found 762.2 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.Cl>CC(O)C>[ClH:11].[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(Br)cc43)c2cc1OC
Yield: 88 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 88% yield from 6-bromo-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to a procedure analogous to that given in Example 2. (M.P. 245°-248° C.(dec); LC-MS: 386, 388 (MH+); anal. RP18-HPLC RT: 4.95 min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][CH2:25][C:26](O)=[O:27])(=[O:16])[NH2:15]>C(Cl)(Cl)Cl>[C:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][CH2:25][C:26]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:27])(=[O:16])[NH2:15]
Reactant: NC(=O)c1ccc(Cl)cc1NCC(=O)O
Reactant: COc1ccc(CCN)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(=O)CNc2cc(Cl)ccc2C(N)=O)cc1OC
Reaction time: 6 h
Yield: 56.5 %

Procedure:
To 0.36 g of 3,4-dimethoxyphenethylamine was added 0.46 g of N-(2-carbamoyl-5-chlorophenyl)glycine and the mixture was stirred at 175° to 185° C. for 6 hours under nitrogen atmosphere. After cooling, the mixture was dissolved in 50 ml of chloroform and the chloroform solution was filtered to remove insoluble materials. The filtrate was washed with 5% hydrochloric acid, a 5% aqueous sodium carbonate solution and water and then dried. The solvent was evaporated in vacuo, and the residue was subjected to column chromatography on silica gel (15 g) and eluted with a mixture of chloroform and methanol (50:1 by volume). The eluate was concentrated to give 0.44 g of 2-(2-carbamoyl-5-chlorophenylamino)-N-(3,4-dimethoxyphenethyl)acetamide as colorless needles having a melting point of 167.5°-169° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(NC(=NC(C)C)O[C:19]([CH3:22])([CH3:21])[CH3:20])(C)C>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Reaction time: 25 h
Yield: 59.3 %

Procedure:
Indole-5-carboxylic acid (1.00 g, 6.21 mmol) and tert-butyl N,N′-diisopropylcarbamimidate 2.29 g) were combined in 15 mL of THF and the reaction mixture was stirred for 25 hours. The reaction mixture was concentrated and the residue was purified on a silica gel column eluting with a gradient of 5% ethyl acetate/hexane to 100% ethyl acetate to provide tert-butyl 1H-indole-5-carboxylate (0.800 g, 3.68 mmol, 59%.)
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[I:13]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO.ClCCl>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: II
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(-n2ccnc2)cc1I
Temperature: 25 °C
Reaction time: 192 h
Yield: 13.8 %

Procedure:
4-(Imidazol-1-yl)phenol (500 mg) was dissolved in water (6 ml), methanol (18 ml), and dichloromethane (6 ml) to prepare a solution. Iodine (1.58 g) was added to the solution, and the mixture was stirred at room temperature for 8 days. An aqueous sodium thiosulfate solution and methanol were added to the reaction solution, and the mixture was stirred and was then concentrated. The concentrate was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 4-(imidazol-1-yl)-2-iodophenol (123 mg, yield 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[N:17][CH:18]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Br)cn1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-amino-5-bromopyridine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:20](B(O)O)=[CH:21][S:22][CH:23]=1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[C:19]([CH3:18])=[CH:23][S:22][CH:21]=2)=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1cscc1B(O)O
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: Cc1cscc1-c1ccc(C(C)(C)C(=O)NCC(C)C)cc1
Yield: 67 %

Procedure:
Prepared in a similar manner to Example 1 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 4-methylthiophen-3-ylboronic acid. Yield: 67%. 1H NMR (400 MHz, dDMSO): δ 0.73-0.79 (d, 6H), 1.48 (s, 6H), 1.67-1.74 (m, 1H), 2.23 (s, 3H), 2.84-2.87 (m, 2H), 7.26-7.27 (m, 1H), 7.34-7.40 (m, 5H), 7.43-7.44 (d, 1H). MS(M+H, 316).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[N+:9]([CH2:12][CH3:13])([O-:11])=[O:10].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(OC(=O)C)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[CH:7]=[CH:13]/[CH2:12][N+:9]([O-:11])=[O:10]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1sccc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C/C=C/c1sccc1Cl
Temperature: 90 °C

Procedure:
In a sulfonation flask, a mixture containing 11.7 g (0.08 mol) 3-chlorothiophene-2-carbaldehyde, 48 g (0.64 mol) nitroethane, 15.4 g (0.2 mol) ammoniumacetate and 160 ml acetic acid is heated at 90° C. for 5 hours. After cooling ethylacetate is added and the organic phase washed three times with water. The organic phase is dried over sodium sulphate and after filtration the organic solvent is distilled off in a water jet vacuum. The residue is purified by column chromatography over silicagel (eluent: ethylacetate/heptane 1:5). Yield: 10.8 g (67% of theory) of a colourless oil (1H-NMR: 2.57/s/3H, 7.12/d/1H, 7.62/d/1H, 8.45/s/1H).
Reaction SMILES: [C:1]1([S:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([NH2:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[C:9]=2[N:11]([CH2:9][CH2:8][CH2:12][CH3:13])[CH2:6][CH2:1][CH2:2][CH3:3])=[CH:13][CH:14]=1
Reactant: NC(=O)C(Sc1ccccc1)c1ccc(Cl)cc1
Solvent: CO
Product: CCCCN(CCCC)c1c(-c2ccc(Cl)cc2)sc2ccccc12
Reaction time: 9 h

Procedure:
Proceed as in Example 31 starting from the N,N-di(n-butyl) [α-phenylthioα-(4-chlorophenyl] acetamide (yellow oil boiling between 180° and 185° at 0.05 torr). The duration of reaction is 9 hours. 50% of theory of colourless prisms melting between 48° and 50° (methanol) are obtained.
Reaction SMILES: [CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH2:1]([C:7]1[N:8]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][S:26]([CH3:25])(=[O:28])=[O:27])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Product: CCCCCCc1nc2cnc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 92.2 %

Procedure:
Using the general method of Example 232, 4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (1.00 g, 3.1 mmol) was reacted with methanesulfonyl choride (0.48 mL, 6.2 mmol) to provide 1.15 g of N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[CH:28][C:27]([CH3:30])=[N:26]2)[CH:22]=[CH:21][C:20]=1[NH2:31].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.CCN(CC)CC>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:17])[NH:31][C:20]1[CH:21]=[CH:22][C:23]([N:25]2[CH:29]=[CH:28][C:27]([CH3:30])=[N:26]2)=[CH:24][C:19]=1[F:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccn(-c2ccc(N)c(F)c2)n1
Reactant: CO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CO[C@@H]1C[C@H](C(=O)Nc2ccc(-n3ccc(C)n3)cc2F)N(C(=O)OC(C)(C)C)C1

Procedure:
(2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.350 g, 1.427 mmol), aniline 1 (0.273 g, 1.427 mmol) and EEDQ (0.529 g, 2.140 mmol) were dissolved in CHCl3 (30 mL). Et3N (0.6 mL, 4.281 mmol) was added and the reaction mixture was heated at reflux for 18 h. The mixture was allowed to cool and diluted with CHCl3 (100 mL) and washed with 5% HCl, 0.5 N NaOH, water and brine (40 mL each), the organic extract was dried over MgSO4, filtered and the solvent removed to give a pale tan foam. The crude product was used for the next step without purification. MS: APCI (AP+): 419.2 (M)+, (AP−): 417.2 (M)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:23](=[O:26])[NH:24][CH3:25])=[C:6]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)=O)[CH:7]=1.C[Si](C)(C)N[Si](C)(C)C.II.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:23](=[O:26])[N:24]([CH3:25])[C:9]([CH:11]3[CH2:15][CH2:14][CH2:13][NH:12]3)=[N:8]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1ccc(Br)cc1NC(=O)C1CCCN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cn1c(C2CCCN2)nc2cc(Br)ccc2c1=O
Temperature: 25 °C

Procedure:
The mixture of tert-butyl 2-(5-bromo-2-(methylcarbamoyl)phenylcarbamoyl)pyrrolidine-1-carboxylate (0.2 g, 0.47 mmol), hexamethyldisilazane (0.39 mL, 1.88 mmol), I2 (0.24 g, 0.94 mmol), and DCM (10 mL) was refluxed for 5 h under nitrogen atmosphere. Na2S2O3 aqueous solution was added to quench the reaction followed by cooling to room temperature. The organic layer was separated and the water layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to give the desired product, which was directly used for the next step. MS (ESI): 308, 310 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=2)[C:5](=[O:17])[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH3:2].B.[Na].CO.Cl>O1CCCC1>[CH2:1]([CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=2)[C:5](=[O:17])[CH:4]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH3:2]
Reactant: CCC1=C(c2cccc(Cl)c2)C(=O)N(c2cccc(C(C)C)c2)C1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1CN(c2cccc(C(C)C)c2)C(=O)C1c1cccc(Cl)c1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
5.0 g (14.7 mmol) of 4-ethyl-3-(3-chlorophenyl)-1-(3-isopropylphenyl)-3-pyrroline-2-one synthesized in Example 4 and 0.56 g (14.7 mmol) of sodium boron hydride were dissolved in 70 ml of tetrahydrofuran, and 11 ml of methanol were slowly added to the solution over about 1 hour, while the solution was heated under reflux. Reaction was allowed to proceed at the same temperature for further 1 hour, and the reaction mixture was then poured into 1 N hydrochloric acid, followed by extraction with ethyl acetate. The resultant organic layer was washed with water, an aqueous saturated sodium bicarbonate solution and water in this order, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and n-hexane was then added to the resultant residue to achieve crystallization, followed by recrystallization from etherpetroleum ether, thereby obtaining 4.5 g of the desired product in the state of colorless crystals (yield 90%). m.p. 88.5°-90.0° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6](Br)[C:5]=1[F:15].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.COC(=O)C1C=C(C(F)(F)F)C=C(Cl)C=1N1CCCC1=O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])[C:5]=1[F:15]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(Br)c1F
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: COC(=O)c1cc(C(F)(F)F)cc(Cl)c1N1CCCC1=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(F)(F)F)cc(N2CCCC2=O)c1F

Procedure:
3-Bromo-2-fluoro-5-trifluoromethylbenzoic acid methyl ester (500 mg, 1.95 mmol)), caesium carbonate (950 mg, 2.92 mmol), pyrrolidin-2-one (248 mg, 2.92 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (68 mg, 0.117 mmol) and tris(dibenzylideneacetone)dipalladium (0) (36 mg, 0.039 mmol) were refluxed under argon in dioxane (7 ml) for 18 h. After cooling, the mixture was filtered and evaporated in vacuo. Column chromatography on silica gel eluting with a gradient of 20–50% ethyl acetate in hexane gave a mixture of D24 and 3-chloro-2-(2-oxopyrrolidin-1-yl)-5-trifluoromethylbenzoic acid methyl ester (195 mg).