Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[NH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)=[O:7])C.O.Cl>C1COCC1.CO.O>[C:13]1([C:10]2[NH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
LiOH (27.5 mg, 0.65 mmol) was added to a stirred solution of 5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (67 mg, 0.31 mmol) in THF:MeOH:H2O (3:1:1, 3 mL), and the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with 10% aqueous HCl, filtered the solid precipitated to afford 37 mg (63.79% yield) of 5-Phenyl-1H-pyrrole-2-carboxylic acid. LCMS Purity: 92.24%.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:21][C:22]1[CH:43]=[CH:42][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]4[CH2:41][CH2:40]4)=[O:38])[N:35]=3)[CH:32]=2)=[C:24]([F:44])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:22]([NH:21][C:7]([C:6]5[C:2](=[O:1])[N:3]([C:15]6[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=6)[N:4]([CH2:10][C:11]([F:12])([F:13])[F:14])[CH:5]=5)=[O:8])=[CH:23][C:24]=4[F:44])=[CH:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: O=C(O)c1cn(CC(F)(F)F)n(-c2ccccc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1)c1cn(CC(F)(F)F)n(-c2ccccc2)c1=O
Yield: 77.6 %

Procedure:
Using 3-oxo-2-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid (210 mg, 0.72 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (170 mg, 0.52 mmol), HATU (280 mg, 0.72 mmol), diisopropylethylamine (200 mg, 1.6 mmol) and N,N-dimethylformamide (6 mL) as starting materials and in the same manner as in Example 35, the title compound (240 mg, 77%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:20]([OH:29])(=[O:28])[C@@H:21]([C@H:23]([C:25]([OH:27])=[O:26])[OH:24])[OH:22]>>[OH2:22].[OH2:22].[C:25]([CH:23]([CH:21]([C:20]([OH:29])=[O:28])[OH:22])[OH:24])([OH:27])=[O:26].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CC(C)(NCCCn1ccnc1)c1ccc(Cl)cc1
Product: O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
N-[1-(4-Chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)propylamine (2.57 g) and L-(+)-tartaric acid (1.39 g) were dissolved in warm IMS (10 ml) and allowed to cool. On scratching a salt crystallised. The salt was collected by filtration and recrystallised from IMS to give N-[1-(4-chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)propylamine (+)tartrate dihydrate, m.p. 76°-78° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])[C@H:17]([CH3:35])[O:16][C:15]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:14]1=3)=[C:7]([O:41][CH3:42])[CH:6]=[CH:5]2.CC1(C)C2[C:65](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:64][C:46]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C[OH:86]>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:28]([O:27][C:26]([N:25]([CH3:33])[C@@H:23]([CH3:24])[C:22]([NH:21][C@H:18]1[C@H:17]([CH3:35])[O:16][C:15]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:14]=2[N:13]([CH2:12][C:8]2[C:7]([O:41][CH3:42])=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([C:46]([O:64][CH3:65])=[O:86])=[CH:3]3)[C:19]1=[O:20])=[O:34])=[O:32])([CH3:29])([CH3:31])[CH3:30]
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)Oc2cc(C)ccc21
Reactant: CO
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)Oc4cc(C)ccc43)c(OC)ccc2c1
Temperature: 70 °C
Yield: 316.8 %

Procedure:
A mixture of tert-butyl (S)-1-((2S,3S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-2,8-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (70 mg, 109 μmol, Eq: 1.00), Pd(OAc)2 (2.45 mg, 10.9 μmol, Eq: 0.1), Xantphos (12.6 mg, 21.9 μmol, Eq: 0.2), MeOH (35.0 mg, 44.2 μl, 1.09 mmol, Eq: 10), and TEA in a microwave tube was purged with CO and heated at 70° C. under CO overnight. The mixture was diluted with EtOAc, water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford methyl 5-(((2S,3S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2,8-dimethyl-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)methyl)-6-methoxy-2-naphthoate (43 mg, 63%)
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:40]([N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(N[C@H](Cc1ccccc1)CN(Cc1ccccc1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)OCc1cncs1
Yield: 39.3 %

Procedure:
The product from Example 26D (87.5 mg, 0.155 mmol), benzaldehyde (19 μl, 0.186 mmol), acetic acid (11 μl, 0.181 mmol), and sodium triacetoxyborohydride (53 mg, 0.248 mmol) were processed as described in Example 27 to provide the title compound (40 mg, 39%). 1H NMR (CDCl3) δ 8.72 (s, 2H), 7.80 (s, 2H), 7.32-6.95 (m, 15H), 5.21 (s, 4H), 4.65 (br s, 2H), 3.93 (br s, 2H), 3.56 (s, 2H), 2.78 (dd, 2H), 2.66 (br s, 2H), 2.45 (d, 4H); MS (ESI+) m/z 656 (M+H)+.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([CH:27]=[CH2:28])[NH:22]2)=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].[CH:29]([CH2:31][C:32](O)=[O:33])=[CH2:30].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([CH:27]=[CH2:28])[N:22]2[C:32](=[O:33])[CH2:31][CH:29]=[CH2:30])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: C=CCC(=O)O
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(C(=O)OC)cc2)N1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl cyanophosphonate (0.78 mL) was added to a solution of (2R*,6S*)-2-(4-carbomethoxyphenyl)-6-vinylpiperidine (422 mg), vinylacetic acid (0.44 mL), and triethylamine (1.44 mL) in DMF (5 mL), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 281 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([S:20]([OH:23])(=[O:22])=[O:21])[CH:14]=1>>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:20]([C:15]2[CH:16]=[CH:17][C:18]([OH:19])=[CH:13][CH:14]=2)(=[O:22])=[O:21])[CH:5]=1.[CH:5]1[CH:6]=[C:1]([OH:7])[C:2]([S:20]([C:15]2[CH:14]=[CH:13][C:18]([OH:19])=[CH:17][CH:16]=2)(=[O:22])=[O:23])=[CH:3][CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Product: O=S(=O)(c1ccc(O)cc1)c1ccccc1O

Procedure:
A reaction mixture comprising 4,4′-dihydroxydiphenylsulfone and 2,4′-dihydroxydiphenylsulfone can be obtained by mixing phenol and sulfuric acid and/or phenolsulfonic acid, followed by heating the resultant mixture and removing formed water by distillation as an azeotrope. It is preferable that the reaction is conducted under a reduced pressure. It is preferable that, where necessary, phenol is added during the reaction to supplement phenol removed to the outside of the system by the azeotropic distillation with water. In general, 4,4′-dihydroxydiphenylsulfone is formed in a greater amount than 2,4′-dihydroxydiphenylsulfone.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2]O.O[CH2:6][CH:7]([CH2:9][OH:10])O>>[C:9]([O:10][CH3:1])(=[O:10])[C:7]1[CH:6]=[CH:7][C:2]([C:1]([O:4][CH3:2])=[O:4])=[CH:9][CH:6]=1
Reactant: OCCO
Reactant: OCC(O)CO
Product: COC(=O)c1ccc(C(=O)OC)cc1
Yield: 490.7 %

Procedure:
A polyester is produced in known manner from 388 g of dimethyl terephthalate, 112 g of ethylene glycol and 75 g of glycerin, and mixed with 204 g of the reaction product of Example A at a temperature of 180°-215° C. in two portions. After the diimidodicarboxylic acid (of Example A) is completely taken up in the terephthalate resin, 1.0 g of cadmium acetate is added thereto and the reaction mixture is further condensed for 3 hours at 215° C., finally under vacuum. The obtained resin is dissolved in 450 g of technical cresol while still hot, and mixed with a solution of 9 g of butyl titanate in 27 g of cresol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:25]4[CH:26]=[CH:27][C:28](Br)=[CH:29][C:24]=4[O:23][C:22]=3[CH:31]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44]1[NH:48][C:47]2[CH:49]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:51]=[CH:52][C:46]=2[N:45]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:25]4[CH:26]=[CH:27][C:28]([C:50]5[CH:51]=[CH:52][C:46]6[N:45]=[C:44]([CH:40]7[CH2:41][CH2:42][CH2:43][N:39]7[C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[NH:48][C:47]=6[CH:49]=5)=[CH:29][C:24]=4[O:23][C:22]=3[CH:31]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)oc2cc(Br)ccc23)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)oc2cc(-c4ccc5nc(C6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)ccc23)[nH]1
Temperature: 90 °C
Yield: 46.3 %

Procedure:
To the solution of 2-[5-(7-Bromo-dibenzofuran-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (124 mg, 0.26 mmol) and 2-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (107 mg, 0.26 mmol) in DME (2.25 ml) and water (0.75 ml) was added potassium carbonate (72 mg, 0.52 mmol), followed by Pd(PPh3)4 (15 mg) and PdCl2(dppf)CH2Cl2 (15 mg). The mixture was heated at 90° C. for 6 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 2-(5-{7-[2-(1-t-butoxycarbonyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-dibenzofuran-3-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (83 mg). m/z: 689.1 (M+1), 687.3 (M−1), 345.0 (M+2)/2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][CH2:7][C:8]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=1)[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C.[Sn](Cl)(Cl)(Cl)Cl>ClCCl.C(O)C>[NH2:13][C:12]1[C:8]([CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[N:9][N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1
Reactant: CCOC(=O)CNCc1nn(Cc2ccccc2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1nn(Cc2ccccc2)cc1N)C(=O)c1ccc(Cl)cc1

Procedure:
1.5 g (4.7 mol) of ethyl[((1-benzyl-4-nitro-1H-pyrazol-3-yl)methyl)amino]acetate was dissolved in 50 ml of dichloromethane: 0.71 ml (5.6 mmol) of 4-chlorobenzoyl chloride and 0.85 ml (6.1 mmol) of triethylamine were added to the obtained solution under cooling with ice, and they were stirred under cooling with ice for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 100 ml of ethanol. 5.3 g (23.5 mmol) of tin chloride was added to the obtained solution, and they were stirred at 70° C. overnight. The solvent was evaporated. Sodium carbonate and ethyl acetate were added to the residue, and they were vigorously stirred at room temperature. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccccc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by recrystallization from methanol afforded 1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a beige solid, m.p. 203–204° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:21]=1[C:22]#[N:23]>>[NH2:19][C:20]1[C:21]([C:22]#[N:23])=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)(CO)C(=O)NCCOCc1ccccc1
Product: CC(C)(COc1cccc(N)c1C#N)C(=O)NCCOCc1ccccc1
Yield: 82 %

Procedure:
Prepared as in Example 197b (Method B) from N-(2-(benzyloxy)ethyl)-3-hydroxy-2,2-dimethylpropanamide (Example 199c) and 2-amino-6-fluorobenzonitrile in 82% yield. MS 368 (MH+).
Reaction SMILES: [N:1]([CH:4]([CH3:23])/[CH:5]=[CH:6]/[C:7]1[S:11][C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[N:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[C:45](OC(=O)C)(=[O:47])[CH3:46]>O1CCCC1>[CH:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[S:11][C:7](/[CH:6]=[CH:5]/[CH:4]([NH:1][C:45](=[O:47])[CH3:46])[CH3:23])=[CH:8][N:9]=2)=[CH:14][CH:15]=1)([CH3:22])[CH3:21]
Reactant: CC(/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1)N=[N+]=[N-]
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)NC(C)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
To a solution of the product of Example 7F (85 mg, 0.26 mmole) in tetrahydrofuran (3 mL)) was added triphenylphosphine (75 mg, 0.29 mmole) and stirred at 50° C. for 3.5 hours. The reaction mixture was added an aqueous solution of 2N NaOH (0.3 mL) and stirring was continued at 50° C. for additional 40 minutes. The reaction mixture was cooled down to room temperature, added acetic anhydride (200 μL, 2.1 mmole), stirred for 45 minutes, quenched with methanol and stirred at room temperature, overnight. The reaction mixture was diluted with methylene chloride and washed with water (×3) and brine. The product was purified via silica column, using a gradient of 25-100% ethyl acetate in hexane and yielded 40 mg (44.9%) of light yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.11-7.22 (m, 2H) 7.04 (s, 1H) 6.85-6.95 (m, 2H) 6.48 (dd, J=15.44, 1.10 Hz, 1H) 5.72 (dd, J=15.63, 5.70 Hz, 1H) 5.37 (d, J=8.46 Hz, 1H) 4.60-4.76 (m, 1H) 4.44-4.59 (m, 1H) 2.00 (s, 3H) 1.34 (d, J=6.25 Hz, 6H) 1.28 (d, J=6.62 Hz, 3H). Mass spectrum DCI 347 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C@H:10]([C@H:28]([OH:33])[CH2:29][CH2:30][CH2:31][CH3:32])[C:11]([NH:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:12])=[CH:4][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:40](I)[CH3:41]>CN(C)C=O.C(OCC)(=O)C>[CH2:40]([O:26][C:25](=[O:27])[C@H:14]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[NH:13][C:11](=[O:12])[C@H:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[C@H:28]([OH:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH3:41]
Reactant: CCI
Reactant: CCCC[C@@H](O)[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC[C@@H](O)[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of Nα-[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan (300 mg) in N,N-dimethylformamide (10 ml) were added potassium carbonate (69 mg) and ethyl iodide (155 mg) and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.5N hydrochloric acid (20 ml×2), saturated sodium bicarbonate aqueous solution (20 ml×2) and brine (20 ml) successively and the organic layer was dried over magnesium sulfate. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give N [(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan ethyl ester as an amorphous powder (260 mg).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][S:26]([NH2:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: NS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-aminophenylmethane sulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.1 (d,1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.5 (q, 4H), 7.2 (d, 1H), 6.9 (s, 2H), 4.2 (s, 2H); APCI−MS m/z 387 (M+H)+.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12](=[O:29])[CH2:13][N:14]([C:24](=[O:28])[C@H:25]([CH3:27])[NH2:26])[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)([CH3:10])([CH3:9])[CH3:8].[CH2:30]([N-:34][C:35](=[O:46])[C:36](=O)[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH3:33]>>[C:7]([O:11][C:12](=[O:29])[CH2:13][N:14]([C:24](=[O:28])[C@H:25]([CH3:27])[NH:26][CH:36]([C:35]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[O:46])[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CCCC[N-]C(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: O=C(O)C(=O)O
Product: CCCCNC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 19.1 %

Procedure:
By reacting L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate (2.0 g) with N-butyl-2-oxo-4-phenylbutyrylamide (4.0 g) in a similar manner to that of Example 2, there is obtained N-(1-butylaminocarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester (0.5 g) as colorless oil.
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[CH2:3][O:4][C:5]([NH:7][C:8]([NH2:10])=[S:9])=[O:6].BrC(Br)C(CBr)=[O:16].CN(C)[C:22]1[CH:27]=CC=C[CH:23]=1>C(O)C>[Cl:12][C:2]([Cl:1])([Cl:11])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][CH:23]=[C:22]([CH:27]=[O:16])[N:10]=1)=[O:6]
Reactant: O=C(CBr)C(Br)Br
Reactant: CN(C)c1ccccc1
Reactant: NC(=S)NC(=O)OCC(Cl)(Cl)Cl
Solvent: CCO
Product: O=Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1

Procedure:
A solution of 10.0 g. of N-(β,β,β-trichloroethoxycarbonyl)thiourea, 12.0 g. of 1,1,3-tribromoacetone and 5.0 g. of dimethylaniline in 100 ml. of ethanol is heated under reflux for 2 hours. After cooling, ethanol is removed under reduced pressure, and the oily residue is dissolved in ethyl acetate. Ethyl acetate layer is washed with water and dried over MgSO4. Ethyl acetate is removed under reduced pressure and the oily residue is dissolved in small quantity of chloroform. From the solution which is allowed to stand at room temperature is obtained 2-(β,β,β-trichloroethoxycarbonyl)amino-4-formylthiazole as a crystalline form. 5.0 g. Melting point: 188°-190° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([N:15]1[C:19](=[O:20])[C:18](Cl)=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:16]1(=[O:29])=[O:28])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([N:15]1[C:19](=[O:20])[C:18]([NH:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:16]1(=[O:28])=[O:29])([CH3:14])([CH3:12])[CH3:13]
Reactant: NCCOc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NCCOc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 13 %

Procedure:
The title compound was prepared as described for Example 24 from (2-phenoxyethyl)amine and 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide. The residue was purified by silica gel column chromatography (Horizons Biotage) using 15-20% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.026 g, 13%). 1H NMR (500 MHz CDCl3): δ 7.60-7.51 (m, 2H), 4.72-7.42 (m, 2H), 7.29 (t, 2H), 6.99 (t, 1H), 6.84 (d, 2H), 5.67 (t, 1H), 3.89 (t, 2H), 3.25 (q, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.7, 158.3, 135.2, 131.7, 129.5, 129.8, 129.0, 125.2, 121.7, 114.7, 108.1, 65.9, 61.8, 43.5, 27.8; Mass Spectrum M+H+ 401.