Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([S:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)(=[O:21])=[O:22])[CH2:18][CH2:19]1)=[O:13]
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(COc1ccc(F)cc1F)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 73.8 %

Procedure:
2,4-difluoro phenol (110 mg, 0.85 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.352 g, 2.55 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by re-crystallization to yield the title compound (280 mg, 73.87% yield) as an off-white solid.
Reaction SMILES: [C:1](#N)C.Cl.[CH3:5][O:6][NH2:7].[CH2:8]([N:15]([CH:24]1[CH2:28][CH2:27][O:26][CH:25]1O)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.C(OCC)(=O)C.CCCCCC>[CH2:8]([N:15]([CH:24]([CH2:28][CH2:27][OH:26])[CH:25]=[N:7][O:6][CH3:5])[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][C:20]([CH3:1])=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1ccccc1)N(Cc1ccccc1)C1CCOC1O
Reactant: CON
Reactant: CC#N
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CON=CC(CCO)N(Cc1ccccc1)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.2 mL of acetonitrile, 0.6 mL of water and 0.1 g of O-methylhydroxylamine hydrochloride were added to 0.2 g of N-benzyl-N-(2-hydroxyoxolan-3-yl)benzamide, and the obtained mixture was then stirred at room temperature for 0.5 hours. The reaction mixture was then left at rest for 11 hours. Thereafter, hexane, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40 to 30/70), so as to obtain 99 mg of N-benzyl-N-(4-hydroxy-1-(methoxyimino)butan-2-yl)-4-methylbenzamide in the form of a colorless oily product.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)(=[O:18])=[O:17])[C@@H:12]([C:31]([NH:33][O:34]C(C)(C)C)=[O:32])[CH2:11]1)(=[O:9])=[O:8])(=[O:3])[CH3:2]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.O>[C:1]([NH:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)(=[O:17])=[O:18])[C@@H:12]([C:31]([NH:33][OH:34])=[O:32])[CH2:11]1)(=[O:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCS(=O)(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(F)cc3)s2)[C@@H](C(=O)NOC(C)(C)C)C1
Solvent: O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCS(=O)(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(F)cc3)s2)[C@@H](C(=O)NO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of (2R)-4-[2-(acetylamino)ethanesulfonyl]-N-tert-butoxy-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide (130 mg) in anisole (1 ml), trifluoroacetic acid (1 ml) and H2O (0.02 ml) was stirred at ambient temperature overnight, and then at 50° C. for 5 hours. The mixture was concentrated in vacuo, and the residue was purified by SiO2 column chromatography, eluted with MeOH in CHCl3=2% then 5%. The fractions containing the desired product were combined and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 88 mg of (2R)-4-[2-(acetylamino)ethanesulfonyl]-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:15]1[C:20]([Br:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[C:30][CH2:31][NH:32]C(OC(C)(C)C)=O)=[CH:25][CH:24]=2)[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH:8]([C:15]1[C:20]([Br:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][CH2:31][NH2:32])=[CH:27][CH:28]=2)[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reaction time: 3 h
Yield: 105.7 %

Procedure:
Trifluoroacetic acid (0.25 ml) was added to a solution of 4-anilino-5-bromo-2-{4-[3-(t-butoxycarbonylamino)-1-propynyl]anilino}pyrimidine (Method 25; 30 mg, 0.06 mmol) in DCM (1 ml). The solution was left to stand for 3 hours and volatile material was removed by evaporation. The residue was triturated with diethyl ether to give the product as a trifluoroacetate salt (25 mg, 81%). NMR: 4.0 (m, 2H), 7.2 (m, 2H), 7.4 (m, 2H), 7.5-7.7 (m, 4H), 7.8 (m, 1H), 8.2 (br s, 2H), 8.7 (s, 1H), 9.6 (s, 1H); MS (MH+): 394.3, 396.3.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)=[CH:10][C:9]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=2)=[C:8]([Cl:61])[C:3]=1[O:4][CH2:5]CO.[C:62]([Cl:66])(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C>[CH2:35]([O:34][C@H:15]1[C@H:16]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@H:12]([C:11]2[CH:10]=[C:9]([CH2:51][C:52]3[CH:53]=[CH:54][C:55]([O:58][CH2:59][CH3:60])=[CH:56][CH:57]=3)[C:8]([Cl:61])=[C:3]([O:4][CH2:5][CH2:62][Cl:66])[C:2]=2[Br:1])[O:13][C@@H:14]1[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCO)c2Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCCl)c2Cl)cc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a solution of alcohol 79 (2.68 g, 2.95 mmol) in acetonitrile (30 mL) were added CCl4 (3.4 mL, 35.41 mmol) and PPh3 (1.9 g, 7.38 mmol) at 0° C. The mixture was stirred at 55° C. for 3 hours. The mixture was filtrated and concentrated in vacuo. The resultant was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 80 (2.59 g, 95%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O1CCCC1.[CH2:29]([O:36][C:37]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:70][CH2:69][CH:68]([O:71][Si](C(C)(C)C)(C)C)[CH2:67][CH2:66]2)=[CH:61][C:38]=1[C:39]([NH:41][C:42]1[CH:54]=[C:53]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:52]=[CH:51][C:43]=1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(Cl)(Cl)Cl>[CH2:29]([O:36][C:37]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:70][CH2:69][CH:68]([OH:71])[CH2:67][CH2:66]2)=[CH:61][C:38]=1[C:39]([NH:41][C:42]1[CH:54]=[C:53]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:52]=[CH:51][C:43]=1[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:40])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)ccc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCC(O)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A 1.0 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (0.56 mL) was added to a tetrahydrofuran (3.2 mL) solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)benzamido)-4-phenylbenzoate (0.32 g), followed by stirring at room temperature for 1 hour. A 1.0 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (0.28 mL) was added to the reaction mixture, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture under ice-cooling, and chloroform was added thereto at room temperature. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 90-40% hexane/ethyl acetate] to obtain 0.23 g of tert-butyl 2-(2-(benzyloxy)-5-(4-hydroxypiperidin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[N:8][C:7]([O:10]C)=[C:6]2[NH:12][CH:13]=[CH:14][C:5]=12.CN1CCCC1=O>O>[OH:10][C:7]1[N:8]=[CH:9][C:4]([O:3][CH3:2])=[C:5]2[C:6]=1[NH:12][CH:13]=[CH:14]2
Reactant: COc1cnc(OC)c2[nH]ccc12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cnc(O)c2[nH]ccc12
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To 4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridine hydrochloride (50 g) taken in 2 L 3-necked round bottom flask, 250 ml N-methyl-2-pyrrolidinone was added followed by 8 ml of water, and was heated to 90° C. for about 4 hrs. The reaction mixture was cooled to room temperature, diluted with water (1 L) and the whole mixture was kept in cold room for about one hour. The resulting solid was collected by filtration, washed with cold water and dried in vacuum oven at 50° C. for 4 hrs to afford 7-hydroxyl-4-methoxy-6-azaindole as white solid.
Reaction SMILES: C([C@H]([C@@H](C(OCC)=O)O)O)(OCC)=[O:2].O.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1.C(OO)(C)(C)C.C1(C)C=CC=CC=1>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:25][S@@:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:2]
Reactant: CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC
Reactant: COc1ccc(SC)cc1
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc([S@](C)=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To titanium tetraisopropoxide (1.49 ml) in dichloromethane (50 ml) were added diethyl (S,S)-tartrate (1.71 ml) and water (90 μl), and the mixture was stirred at room temperature for 20 minutes. After 1-methoxy-4-(methylthio)benzene (0.69 ml) was dropwise added, the reaction mixture was cooled to -20° C., dropwise added with 3.07M t-butylhydroperoxide-toluene solution (1.8 ml), and stirred at -20° C. for 15 hours. Water (0.9 ml) was added, and the mixture was stirred at -20° C. for 1 hour, and then at room temperature for 1 hour. A small amount of alumina was added, and the reaction mixture was suction-filtered with celite and washed well with dichloromethane. The filtrate and the washing were combined, added with 5% sodium hydroxide-saturated brine and stirred at room temperature for 1 hour. The organic layer was separated, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluate; ethyl acetate), and the residue (730 mg) was recrystallized from ether-pentane to give 586 mg of the title compound, [α]D -103° C. (c=1.98, acetone).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:23])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])=[O:13])[CH2:7][CH2:6]1.C(N(CC)CC)C.[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Cl.C([OH:42])C>>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[NH:14][C:12](=[O:13])[CH2:11][N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH:3]([OH:23])[CH2:2][NH:1][C:34]([C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[F:31])=[O:42])[CH2:6][CH2:7]1
Reactant: CCO
Reactant: Fc1ccccc1CCl
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CN)CC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CNC(=O)c2ccccc2F)CC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[4-(3-amino-2-hydroxypropyl)piperazin-1-yl]-N-(2,6-dimethylphenyl)-acetamide (0.312 mmoles) in ethanol (2 mL) was added triethylamine (100 μL) followed by 2-fluorobenzyl chloride (0.312 mmoles), and the solution was stirred at 90° C. for 18 hours. Solvent was removed under reduced pressure, and the residue purified by preparative TLC, eluting with 5% methanol/dichloromethane, to yield N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)-carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide, a compound of Formula I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:5]([NH:7][C:8]1[CH:36]=[CH:35][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]3)=[O:22])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+].O.Cl>C1COCC1.C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][CH2:28]3)=[O:22])=[CH:17][CH:18]=2)=[CH:35][CH:36]=1)=[O:6]
Reactant: CCOC(=O)CN1CCN(C(=O)CCc2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1CCN(C(=O)CCc2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1

Procedure:
To a solution of ethyl 2-[4-(3-{4-[4-(3,4-dichlorobenzoylamino)phenoxy]phenyl}propionyl)piperazin-1-yl]acetate (0.493 g, 0.843 mmol) in THF (5 mL) and ethanol (5 mL) were added 5 M aqueous sodium hydroxide (0.253 mL, 1.27 mmol) and water (1 mL), and the resulting solution was refluxed for 1 hour. This reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50% aqueous ethanol. To the resulting solution was added 5 M hydrochloric acid (0.253 mL, 1.27 mmol), and the obtained solid was collected by filtration. To this solid was dissolved in ethanol (10 mL) and 5 M hydrochloric acid (0.3 mL) by heating. The solvent was then evaporated, and the obtained solid was recrystallized from ethanol-diethyl ether, to thereby yield 0.381 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=O)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>C(#N)C.CO>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH2:21])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(F)c1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1c(C(C)N)cc(Cl)c(F)c1Br
Temperature: 65 °C
Yield: 23 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanone (0.44 g, 1.6 mmol) and ammonium acetate (1.8 g, 23 mmol) in acetonitrile (3.0 mL) and methanol (3.0 mL) was heated at 65° C. for an hour. Sodium cyanoborohydride (0.244 g, 3.88 mmol) was added and the mixture was heated at 65° C. overnight. Purification by preparative LCMS (pH=10) gave the desired compound (23% yield). LCMS calculated for C9H8BrClFO (M−NH2)+: m/z=264.9, 266.9. found: 264.9, 266.9. 1H NMR (300 MHz, CDCl3): δ 8.81 (br s, 2H), 7.80 (s, 1H), 4.80 (m, 1H), 3.97 (s, 3H), 1.69 (m, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[O:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[Cu](C#N)[C:12]#[N:13].CN(C)C=O>C(OCC)C.[Cu](I)I>[O:10]1[C:3]2[C:2]([C:12]#[N:13])=[CH:7][N:6]=[CH:5][C:4]=2[CH:8]=[CH:9]1
Reactant: N#C[Cu]C#N
Reactant: Brc1cncc2ccoc12
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1cncc2ccoc12
Temperature: 25 °C

Procedure:
Combine 7-bromofuro[3,2-c]pyridine (4.673 g, 23.5 mmol), copper cyanide (4.21 g, 47.1 mmol), copper iodide (8.96 g, 47.1 mmol), and anhydrous dimethylformamide (100 mL) and at 130° C. for 30 hours. Cool to room temperature, dilute with diethyl ether and wash with 15% aqueous ammonium hydroxide. Extract combined aqueous layers with diethyl ether, wash combined organic layers with 15% aqueous ammonium hydroxide, and brine, dry over magnesium sulfate, and concentrate. Purification using flash chromatography, eluting with hexane:ethyl acetate gives the title compound as a white solid.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[C:4](O)=O.Cl.Cl.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].[OH-].[Na+]>O>[CH:2]1([C:4]2[NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:16]=2)[CH2:3][CH2:1]1
Reactant: Nc1ccccc1N
Reactant: O=C(O)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2[nH]c(C3CC3)nc2c1
Temperature: 160 °C
Yield: 13 %

Procedure:
2-cyclopropanecarboxylic acid (4 g, 52 mmol) was treated with phenylenediamine bis-hydrochloride (1 eq) and polyphosphosphoric acid (52 mL) and heated to 160° C. for 6 h. The reaction was cooled to 0° C. and diluted with water, then basified with NaOH (50% aqueous) until pH>10. The solution was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated, purified by flash chromatography (100% ethyl acetate) giving 2-cyclopropylbenzimidazole (1.1 g, 13%). MS found: (M+H)+=159.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8](O)[CH2:9][N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=1.C(OC(=O)C)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:7](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:14]([F:15])([F:16])[F:17])[N:3]=1
Reactant: O=[N+]([O-])CC(O)c1ccc(C(F)(F)F)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])/C=C/c1ccc(C(F)(F)F)nc1Cl
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-nitroethanol (Int-18) (27 g, 1.0 eq.) in dichloromethane (270 mL) was added 4-dimethylamino pyridine (13.5 g, 1.1 eq.) followed by drop wise addition of acetic anhydride (13.5 g, 1.3 eq) at 0° C. and stirred for 15 min. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice water and extracted with dichloromethane (2×200 mL). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to get crude 2-chloro-3-[(E)-2-nitrovinyl]-6-(trifluoromethyl)pyridine (Int-19) (22.0 g, 87.6%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:30][OH:31]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][CH2:27][CH3:28])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[N:30][OH:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: NO
Reactant: CCCCCCC(=O)CCCn1c(CCC)nc2c(N)nc3ccccc3c21
Agent: Cl
Product: CCCCCCC(CCCn1c(CCC)nc2c(N)nc3ccccc3c21)=NO

Procedure:
By the general method described in Part F of Example 30, 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one was reacted with hydroxylamine hydrochloride to provide 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one oxime in about a 1 to 1 mixture of E and Z isomers as a white solid after recrystallization from aqueous methanol, mp 113-115° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[NH:23]1[C:24]2[C:20](=[C:19]([NH:18][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:3]=3)[CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(Nc2cccc3[nH]ccc23)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-aminoindole (38 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (6 mg, 9%). 1H NMR (CDCl3): 9.75-9.74 (m, 1H), 8.77-8.73 (m, 1H), 8.69 (dd, J=1.8, 5.1 Hz, 1H), 8.57 (s, 1H), 8.08 (s, 1H), 7.44-7.38 (m, 2H), 7.31-7.23 (m, 3H), 6.85 (s, 1H), 6.50-6.48 (m, 1H).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][C:3]1=[CH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>CO.CC(N(C)C)=O.[Pd]>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH:3]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:4]1
Reactant: COC(=O)c1ccc(C=C2COc3ccccc3C2=O)cc1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COC(=O)c1ccc(CC2COc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
Pd/C 10% was added to a suspension of 260 (200 mg, 0.68 mmol) in MeOH (40 ml) and DMA (10 ml) which was previously purged under vacuum. The reaction mixture was stirred during 4 h at room temperature. After evaporation of the MeOH, water was added to the oily residue and the precipitate obtained was filtered. The crude residue was then purified by flash chromatography on silica gel (5-8% AcOEt/Hex) to afford the title compound 263 (114 mg, 59%) as a white solid. LRMS: 282.1 (Calc.). 283.0 (found).
Reaction SMILES: [H-].C(C1[AlH2+]C=1CC(C)C)C(C)C.[F:13][C:14]1[CH:21]=[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=[CH:18][C:15]=1[C:16]#N.C[OH:40]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:21]=[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:40]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#N)c(F)c1
Reactant: CO
Agent: CC(C)CC1=C(CC(C)C)[AlH2+]1
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Di-isobutylaluminmum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of the 2-fluoro-4-(hexadecylamino)benzonitrile under a nitrogen atmosphere. The temperature rises to 40° C. during the addition which takes 30 minutes and the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) is added during 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (500 ml., 5%). After 10 minutes, diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. Recrystallization from hexane affords 2-fluoro-4-(hexadecylamino)benzaldehyde as a white solid.