Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][CH2:4][C@H:3]1[C:9]([OH:11])=[O:10].N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:1][C@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][CH2:4][C@H:3]1[C:9]([OH:11])=[O:10])(=[O:20])[CH3:19]
Reactant: C[C@@H]1CC[C@@H](C(=O)O)[C@@H](O)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](C)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
To a solution of (1R,2S,4R)-2-Hydroxy-4-methyl-cyclohexanecarboxylic acid (162 mg, 1.02 mmol) in dichloromethane (5 ml) was added pyridine (495 ul, 6.12 mmol) followed by acetic anhydride (385 ul, 4.08 mmol). The reaction mixture was stirred for 20 h at room temperature. Then, the solvents were removed and 10 ml of 3N HCl solution was added. This mixture was stirred for 30 minutes and then a saturated solution of NaHCO3 was slowly added until PH=9-10. This solution was then extracted with ethyl acetate (2×5 ml). The aqueous phase was then acidified with a 10% HCl solution and extracted with ethyl acetate (3×5 ml). The following ethyl acetate layers were combined, dried (Na2SO4) and concentrated to obtain 109 mg (53%) of (1R,2S,4R)-2-Acetoxy-4-methyl-cyclohexanecarboxylic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=Cc1cc2ccccc2o1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cc2ccccc2o1

Procedure:
A mixture of 1-benzofuran-2-carbaldehyde and propanedioic acid was treated with piperidine to give (2E)-3-(1-benzofuran-2-yl)prop-2-enoic acid. The resulting acid was converted to the acyl azide, then cyclized to [1]benzofuro[3,2-c]pyridin-1(2H)-one with tri-n-butylamine at 180° C. Treatment with phosphorus oxychloride provided 1-chloro[1]benzofuro[3,2-c]pyridine, which was converted to the requisite 2-aminoethanol according to the method of footnote 32.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH3:10][Mg]Br.CCOCC.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:9])[CH3:10]
Reactant: O=Cc1ccncc1Br
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccncc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 3-bromo-pyridine-4-carbaldehyde (2.0 g, 10.8 mmol) in dry THF (45 mL) is added methyl magnesium bromide solution in Et2O (3M; 3.9 mL, 11.8 mmol). The mixture is stirred at 0° C. for 1 h then warmed and stirred at room temperature for 1 h. Saturated aqueous NH4Cl solution is added and the mixture is extracted with EtOAc. The organic layers are combined and concentrated to afford 2.1 g of 1-(3-bromo-pyridin-4-yl)-ethanol.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].Br[CH2:15][CH2:16][C:17]([F:21])=[C:18]([F:20])[F:19]>C(OCC)C.[Ag]>[F:1][C:2]([F:12])([F:13])[C:3]([F:10])([F:11])[C:4]([F:8])([F:9])[C:5]([O:7][CH2:15][CH2:16][C:17]([F:21])=[C:18]([F:20])[F:19])=[O:6]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: FC(F)=C(F)CCBr
Agent: [Ag]
Solvent: CCOCC
Product: O=C(OCCC(F)=C(F)F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 3.2 grams (0.01 mole) of the silver salt of heptafluorobutyric acid in 40 ml of diethyl ether was added dropwise 1.9 grams (0.01 mole) of 4-bromo-1,1,2-trifluoro-1-butene in 10 ml of diethyl ether. Upon completion of addition the reaction mixture was stirred for two hours at ambient temperature, then was heated under reflux for one hour. The ether solvent was removed by distillation and the residual oil distilled under reduced pressure to give 1.0 gram of (3,4,4-trifluoro-3-butenyl) heptafluorobutyrate; b.p. 25° C./4.0 mm Hg. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3Br)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[C:38]1([C:44]#[CH:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[C:45]#[C:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(Br)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(C#Cc4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 75 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of (2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-yl acetate (1.26 g, 2.67 mmol), CuI (0.102 g, 0.534 mmol), and Pd(PPh3)2Cl2 (0.187 g, 0.267 mmol) in DMF was added DIPEA (0.930 mL, 5.34 mmol) and phenylacetylene (1.17 mL, 10.69 mmol). The mixture was stirred at 75° C. for 1 hour then concentrated. The residue was dissolved in CH2Cl2 (70 mL) and washed with saturated aq EDTA.Na2 (3×50 mL). The combined organics were dried (Na2SO4) and concentrated. The dark crude oil was purified by flash chromatography (40% EtOAc/hexanes) to afford the title compound (1.2 g, 91%).
Reaction SMILES: [NH3:1].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[S:12](Cl)(=[O:14])=[O:13]>O1CCCC1>[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[S:12]([NH2:1])(=[O:14])=[O:13]
Reactant: N
Reactant: O=S(=O)(Cl)c1sccc1C1OCCO1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sccc1C1OCCO1

Procedure:
To 5 ml of liquified ammonia gas dissolved in 50 ml of tetrahydrofuran was added dropwise with stirring and cooling 12.7 g of 3-(1,3-dioxolan-2-yl)thiophene-2-sulfonyl chloride. After stirring overnight at ambient temperature, the tetrahydrofuran was removed in vacuo, water was added to the residue and the mixture was extracted twice with 75 ml of methylene chloride. After washing the combined methylene chloride extracts with water, drying over magnesium sulfate, filtering off the drying agent and evaporation of the methylene chloride, an oily solid residue was obtained. This was chromatographed through silica gel using 1:1 ethyl acetate-hexanes as eluant (Rf 0.35). Evaporation of the solvent mixture yielded 2.2 g of the desired product, as a waxy solid. Infrared absorption spectra showed peaks at 3360, 3260, 1340 and 1140 cm-1, consistent for a primary sulfonamide. Mass spectrum analysis: calc. 235, found 234 (Mass-1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:24])[NH:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:38][C@@H:39]1[C@@H:44]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:43]([O:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[C@@H:42]([CH2:59][O:60][C:61](=[O:66])[C:62]([CH3:65])([CH3:64])[CH3:63])[O:41][C@@H:40]1Br)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:40]3[O:41][C@H:42]([CH2:59][O:60][C:61](=[O:66])[C:62]([CH3:65])([CH3:64])[CH3:63])[C@@H:43]([O:52][C:53](=[O:58])[C:54]([CH3:55])([CH3:56])[CH3:57])[C@H:44]([O:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])[C@H:39]3[O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCc2ccccc2)cc1OC1CCOCC1
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccc(OCc2ccccc2)cc1OC1CCOCC1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-{[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide instead of 4-{[4-(3-benzyloxypropoxy)phenyl]Methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[CH2:11]>>[Cl:8][C:6]1[CH:7]=[C:2](/[CH:11]=[CH:10]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C=Cc1ccccn1
Reactant: Nc1ncc(Cl)cc1Br
Product: Nc1ncc(Cl)cc1/C=C/c1ccccn1

Procedure:
The title compound was prepared from 3-bromo-5-chloro-2-pyridinamine and 2-vinylpyridine. Purification by column chromatography on silica gel eluting with methylene chloride—methanol (95:5) and repeated using hexane—EtOAc (70:30 to 50:50) as eluant gave a yellow solid:
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[CH3:59][S:60]([NH2:63])(=[O:62])=[O:61].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28]([NH:63][S:60]([CH3:59])(=[O:62])=[O:61])=[O:29])[N:27]=4)[CH:21]=3)[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:34][C:33]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)co2)c(=O)[nH]c1=S
Reactant: CS(N)(=O)=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)NS(C)(=O)=O)co2)c(=O)[nH]c1=S

Procedure:
The product of example 37(0.2 g), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.38 g), 4-dimethylaminopyridine (0.07 g), methanesulphonamide (0.095 g) and N,N-diisopropylethylamine (0.43 ml) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 16 h. The mixture was partitioned between aqueous tartaric acid and ethyl acetate. The organic solution was dried (MgSO4) and evaporated. Purification was by reverse phase silica gel chromatography (C18-sep-pak) eluting with 50% methanol in 0.1% aqueous ammonium acetate. Yield 0.032 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=1.C([Li])CCC.[CH3:19][S:20]SC>C(OCC)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:20][CH3:19])[CH:4]=1
Reactant: CSSC
Reactant: COc1ccnc(-c2cccs2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccnc(-c2sccc2SC)c1
Temperature: 25 °C

Procedure:
The product of step (b) above (5 g) dissolved in dry diethyl ether (100 ml) was cooled to -50° and treated with butyl lithium in hexane (2.2M, 13 ml) dropwise during 0.5 hour. The mixture was warmed to -10° for 10 minutes, then cooled to -30°. Dimethyl disulphide (3.5 ml) was then added dropwise. The mixture was maintained at -30° for 0.5 hour then warmed up to room temperature during several hours. Aqueous work-up and ethyl acetate extraction gave the sub-title compound as an oil.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][CH2:16][C:17]1[N:18]([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:19]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=[C:21]([NH2:27])[C:20]=2[N:28]=1)[CH3:14]>>[NH2:27][C:21]1[C:20]2[N:28]=[C:17]([CH2:16][O:15][CH2:13][CH3:14])[N:18]([CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][N:34]([C:11]([NH:10][C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:12])[CH2:33][CH2:32]3)[C:19]=2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)N[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
Using the method of Examples 54-65, trans-2-phenylcyclopropyl isocyanate was reacted with 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 491.3139.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:4][C:3]1([CH3:16])[CH3:15].[C:17]([O:21][C:22](NC(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([NH:1][CH:2]1[CH2:6][N:5]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:4][C:3]1([CH3:15])[CH3:16])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC(C#N)c1ccccc1
Reactant: C[C@H](c1ccccc1)N1CC(N)C(C)(C)C1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(NC(=O)OC(C)(C)C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To an ice cooled solution of 3.69 g of 4-amino-3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolidine in 40 ml of anhydrous tetrahydrofuran there was added 4.92 g of 2-(tert-butoxycarbonylamino)-2-phenylacetonitrile and the mixture was stirred at room temperature for 1 hr. Solvent was removed under reduced pressure, and to the residue there was added ethyl acetate. The mixture was washed with a 1N sodium hydroxide aqueous solution three times and then dried. Solvent was then removed under reduced pressure. The residue was purified through column chromatography using 200 g of silica gel in a column with chloroform as the eluant containing from 1% to 5% methanol to yield 4.32 g of the titled compound.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]=2S[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O:23][CH:24](OCC)[C:25]#[CH:26])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(=O)CCCCC1>[O:2]=[C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:26][C:25]([CH:24]=[O:23])=[C:6]2[N:7]1[CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=12
Reactant: C#CC(OCC)OCC
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccsc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [OH-]
Solvent: O=C1CCCCC1
Product: O=Cc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
A mixture of 0.855 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo[3,2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) and 0.65 ml of 3,3-diethoxypropyne in 30 ml of cyclohexanone was stirred with a few crystals of p-toluenesulfonic acid at 130° for 3 hours under an inert gas and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with 10 percent potassium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, concentrated and chromatographed on silica gel with toluene/acetonitrile (19:1). By crystallization from dioxane, there is obtained 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxaldehyde of m.p. 213°-215°.
Reaction SMILES: [N:1]1([OH:6])[CH:5]=[CH:4][CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1>C(Cl)Cl>[CH2:22]([O:6][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: On1cccn1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(COn2cccn2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.4 %

Procedure:
To a mixture of pyrazol-1-ol (1 g, 11.9 mmol) and i-Pr2NEt (2.02 mL, 11.9 mL) in DCM (15 mL) at 0° C. was added BnBr (4.09 mL, 23.8 mmol). The mixture was allowed to warm up to r.t. and stirred at this temperature for 22 h. The mixture was concentrated in vacuo to afford a yellow paste. The crude product was purified by flash chromatography (silica gel, hexanes/DCM/Et2O (100:0:0 to 80:10:10), Rf 0.23 in hexanes/DCM/Et2O (34:3:3)) to provide the title product as a yellow oil (1.17 g, 56%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[C:25]([CH3:37])[CH:24]=1)=[O:10])=[O:4].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:37][C:25]1[CH:24]=[C:23]([NH:22][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:13]=3)[N:18]=[CH:17][N:16]=2)[CH:28]=[CH:27][C:26]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCNC(=O)CCl)cc34)cc2C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCCNC(=O)CN5CCOCC5)cc34)cc2C)cn1
Temperature: 100 °C
Yield: 38 %

Procedure:
0.07 g of the compound obtained in Example 108 dissolved in 5 ml of N,N′-dimethylformamide was reacted with 0.02 ml of morpholine and 0.04 g of potassium carbonate for 10 hours while heating to 100° C. The reacted solution was diluted with distilled water, extracted with ethylacetate, washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (0.03 g, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:28]([NH2:30])[CH3:29])=[C:18]([F:31])[CH:17]=1.C(N(CC)CC)C>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:28]([NH:30][S:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])(=[O:13])=[O:12])[CH3:29])=[C:18]([F:31])[CH:17]=1
Reactant: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(Cl)cc2F)c(OC)c1

Procedure:
The title compound was prepared from 2,4-dimethoxybenzenesulfonyl chloride (379 mg, 1.6 mmol), 1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethylamine (400 mg, 1.6 mmol), and triethylamine (246 μL, 1.7 mmol) according to the procedure and in the same manner as described in Example 105, step c resulting in the isolation of 480 mg (67%) of a white solid;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 86 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.25-3.29 (m, 4H), 3.73-3.77 (m, 4H), 4.16 (s, 3H), 6.55-6.59 (m, 3H), 7.21-7.43 (m, 3H), 7.78-7.83 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH2:31][CH3:32].ClCCl>N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH2:31][CH3:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2-Thiophenesulfonyl chloride (0.3 g in 10 ml dichloromethane, 1.6 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (0.5 g, 1.6 mmol), dichloromethane (40 ml), and pyridine (0.8 ml). The reaction was maintained at room temperature for a few hours and then an additional portion of 2-thiophenesulfonyl chloride (0.1 g, 0.6 mmol) was added. The reaction was maintained overnight and then concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol) and the fractions containing product were washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, and concentrated to provide 0.2 g of N2-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-thiophenesulfonamide as an off white powder, m.p. 137.5–141.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J=8.0 Hz, 1H), 7.89 (dd, J=5.0, 1.3 Hz, 1H), 7.83 (broad s, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.54 (dd, J=3.7, 1.3 Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.44 (broad s, 2H), 4.47 (t, J=7.4 Hz, 2H), 2.87 (m, 4H), 1.80 (m, 4H), 1.58–1.38 (m, 4H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr) 3467, 3361, 3167, 3091, 2957, 2933, 2870, 1644, 1617, 1585, 1533, 1478, 1405, 1336, 1154, 1095, 1014, 854, 761, 733 cm−1; MS (EI) m/e 457.1606 (457.1606 calcd for C22H27N5O2S2); Anal calcd for C22H27N5O2S2: C, 57.74; H, 5.95; N, 15.30. Found: C, 57.50; H, 5.98; N, 15.15.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.O>CN(C)C=O>[C:13]([C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])=[CH:10][CH:11]=1)([OH:15])=[O:14]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
One molar equivalent of maleic anhydride and p-amino benzoic acid are dissolved in N,N-dimethylformamide (DMF), and the mixture stirred at room temperature for five hours under nitrogen atmosphere. The resulting solution is poured into a sufficient water to precipitate crude N-(4-carboxyphenyl)maleamic acid. This is filtered, dried, and recrystallized three times from water to obtain pure N-(4-carboxyphenyl)maleamic acid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)#[N:2].CCN(CC)CC.[SH2:20]>N1C=CC=CC=1>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[S:20])[NH2:2]
Reactant: S
Reactant: N#CCc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a stirred suspension of 4-cyanomethyl-benzoic acid (1.65 g, 10.24 mmol) and Et3N (5 ml) in pyridine, H2S was bubbled during 3 h. The reaction mixture was stirred 16 h at room temperature. Water was then added to the reaction mixture which was agitated for 1 h before acidifying to pH 6 with 1M HCl. The solvent was evaporated and the residue was triturated 30 min. in water (20 ml) and filtered to obtain the title compound 250 (2.08 g, 83%) as a white solid. 1H NMR (DMSO) δ (ppm): 12.85 (bs, 1H), 9.53 (bs, 1H), 9.43 (bs, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 3.88 (s, 2H).