Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH:17][C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:15][CH:16]=1.[Br:28]CC(C1C=C(C(OC)=S)SC=1C)=O.NC(NC1C=NC2C(C=1)=CC=CC=2)=S>>[BrH:28].[CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH:17][C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:15][CH:16]=1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Agent: COC(=O)c1cc(-c2csc(Nc3cnc4ccccc4c3)n2)c(SC)s1
Agent: NC(=S)Nc1cnc2ccccc2c1
Product: Br

Procedure:
Methyl 5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28 mmol) was allowed to react with amino(3-quinolylamino)methane-1-thione (59.1 mg) as described in Example 154, step (a) to give 107.5 mg (78% yield) of methyl 5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ 2.75 (s, 3H), 3.84 (s, 3H), 7.52 (s, 1H), 7.92-8.05 (m, 2H), 8.22 (s, 1H), 9.22 (m, 2H); Mass Spectrum (ESI) m/z calcd. for C19H15N3O2S3, 413.54 (M+H), found 414. 1.
Reaction SMILES: C[O:2][C:3]([C@:5]1([CH2:11][O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH2:9][CH2:8][CH2:7][N:6]1[CH3:10])=[O:4].O.[OH-].[Li+].Cl>CO.O>[CH3:10][N:6]1[CH2:7][CH2:8][CH2:9][C@@:5]1([CH2:11][O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:20]([CH3:22])[CH3:21])[C:3]([OH:4])=[O:2]
Reactant: COC(=O)[C@]1(CO[Si](C(C)C)(C(C)C)C(C)C)CCCN1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)[Si](OC[C@@]1(C(=O)O)CCCN1C)(C(C)C)C(C)C
Yield: 88.3 %

Procedure:
A solution of Intermediate 85f (2.50 g, 7.93 mmol) and lithium hydroxide monohydrate (3.33 g, 79.3 mmol) in MeOH and water (50 mL) was stirred at reflux for 2 h. The cooled solution was acidified with 1M HCl to pH 5. The MeOH was removed in vacuo and the resulting aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the title compound as a white foam (2.21 g, 92%). 1H NMR (400 MHz, CDCl3): 1.00-1.21 (21H, m), 1.93-2.04 (2H, m), 2.32-2.42 (1H, m), 2.43-2.56 (1H, m), 2.96-3.09 (4H, m), 3.90-4.00 (1H, m), 4.20 (1H, d, J 10.9), 4.22 (1H, d, J 10.9).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[CH3:29][C:30](C)([O-:32])[CH3:31].[Li+].C(C1OC1)Br>CN(C)C(=O)C>[CH2:29]([CH2:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1])[CH:30]1[O:32][CH2:31]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: BrCC1CO1
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CCC1CO1
Temperature: 10 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Cholesterol (5.80 g; 15 mmol; Sigma, St. Louis, Mo.) was dissolved in 76 ml dry N,N-dimethylacetamide (DMAc) under a flow of dry argon. The solution was cooled to 10° C. and 15 ml (15 mmol) of a 1.0 M solution of lithium tert-butoxide in hexanes (Sigma) was added. After further cooling to 5° C., 10 ml (117 mmol) of freshly distilled epibromohydrin was added and the mixture was stirred at 3-5° C. for 2 hours. The temperature was allowed to slowly rise to 21-23° C. and the reaction was allowed to continue for another hour. The reaction mixture was then diluted with 500 ml of 0.5% aqueous KHCO3 and extracted with 350 ml n-heptane and then twice more with 100 ml n-heptane. The combined organic layers were dried over Na2SO4. After filtration from the desiccant, the solvent was removed in vacuo. The syrupy residue (7.3 g) was purified by flash-chromatography on silica gel employing elution with hexane, hexane/toluene (1:1 mixture), and toluene. The fractions containing pure glycidyl-cholesterol (thin layer chromatography (TLC)-monitoring) were pooled and dried in vacuo until crystallization occurred. The procedure yielded 4.25 g glycidyl-cholesterol (64%). The product displayed an Rf of 0.38 by TLC (silica gel, n-heptane/ethyl acetate, 85:15 by volume). The signals (only those produced by the glycidyl group not present in the starting cholesterol) obtained by 1H NMR analysis of the product are as follows: 2.62 and 2.87 (both m, 1H and 1H, two non-equivalent H of oxirane CH2), 3.15 (m, 1H, CH), and 3.47 and 3.72 (both m, 1H and 1H, diastereotopic H of CH2O).
Reaction SMILES: C12([OH:11])CC3CC(CC(C3)C1)C2.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[C:26]12([OH:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH:27]1[OH:36])[CH2:33]2>ClC1C=CC=CC=1.C(O)(=O)C>[C:26]12([OH:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[C:27]1([OH:11])[OH:36])[CH2:33]2
Reactant: OC1C2CC3CC(C2)CC1(O)C3
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: OC12CC3CC(CC(C3)C1(O)O)C2
Temperature: 85 °C
Reaction time: 20 h
Yield: 50.5 %

Procedure:
A mixture of 25 g (164 mmol) of adamantanol, 5.36 g (32.8 mmol) of N-hydroxyphthalimide, 0.11 g (0.328 mmol) of vanadiumacetylacetonato [V(acac)3], 150 mL of acetic acid and 150 mL of chlorobenzene was stirred for 20 hours at 85° C. and 1 atm (0.101 MPa) in an atmosphere of oxygen. After completion of reaction, the reaction mixture was analyzed by gas chromatography and high performance liquid chromatography, and, as a result, the conversion of adamantanol was 95.6%, adamantanediol and adamantanetriol were formed in yield 50.5% (selectivity 52.8%) and yield 40.7% (selectivity 42.6%), respectively. Moreover, in the reaction mixture, 1.85 g of N-hydroxyphthalimide used as a catalyst, 1.51 g of phthalimide, and 0.40 g of phthalic anhydride were contained.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].[OH-].[K+]>C(O)C>[CH3:17][C:16]([CH3:18])=[CH:15][CH2:14][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: CC(C)=CCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=CCON1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a stirring solution of N-hydroxyphthalimide (Aldrich, 1.63 g, 10.0 mmol) in anhydrous ethanol (50 mL) was added 1-bromo-3-methyl-but-2-ene (Aldrich, 1.4 mL, 12.0 mmol) and potassium hydroxide (0.67 g, 12.0 mmol). After the reaction was allowed to stir at 50° C. for 4 hours, it was concentrated in vacuo and then dissolved in ethyl acetate and partitioned with water. The organic layer was washed twice with water, twice with saturated sodium chloride solution, collected and dried over Na2SO4, filtered and concentrated in vacuo, affording a white solid. The collected solid was purified via silica column in 10% methanol in dichloromethane to afford 2-(3-methyl-but-2-enyloxy)-isoindole-1,3-dione (0.53 g, 23%): 1H NMR (400 Mz; DMSO-d6) δ 7.81 (s, 4H), 5.38 (t, 1H, J=1.5), 4.57 (d, 2H, J=7.6) 1.67 (s, 3H), 1.62 (s, 3H); MS (APCI+)=232.0
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:28][C:29](Cl)=[O:30]>>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[C:5]([C:29](=[O:30])[CH3:28])=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1
Reactant: CC(=O)Cl
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1c(I)c(C(C)=O)c(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I

Procedure:
Freidel-Crafts acylation is performed on 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13) in the presence of AlCl3 and CH3COCl to yield 2′,4′,6′-triiodo-3′-ethyl-5′-acetyl-3-nitrobiphenyl-4-carboxylic acid (17). 2′,4′,6′-triiodo-3′-ethyl-5′-acetyl-3-nitrobiphenyl-4-carboxylic acid (17) is then reacted with a zinc mercury amalgam and hydrochloric acid and heated to yield 2′,4′,6′-triiodo-3′,5′-bis(ethyl)-3-nitrobiphenyl-4-carboxylic acid (18)
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:11]1.Cl>CCOCC.O1CCCC1>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([OH:19])=[O:18])[CH2:11]1
Reactant: O=C(O)CC1CCCC(=O)C1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CC1CCCC(O)(c2ccccc2)C1
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 80 mmol of phenyl magnesium bromide (from 24.2 ml of a 3.3 M solution of phenyl magnesium bromide in ether) in 100 ml of tetrahydrofuran at 10° C. was slowly added 5.0 g (32.1 mmol) of 3-oxocyclohexane-1-acetic acid (prepared by the method of Bartlett and Woods, J.A.C.S. 62, 2933 (1960)) in 25 ml of tetrahydrofuran. The reaction was stirred 1 hr. longer at 25° and then added to 250 ml 1 N hydrochloric acid and 250 ml ether. The organic extract was extracted with 150 ml of 1 N sodium hydroxide. The base extract was reacidified with 200 ml of 1 N hydrochloric acid and extracted with 300 ml of ether. This ether extract was dried over magnesium sulfate and evaporated to an oil. Crystallization from ether gave 3.25 g (43%) of the title compound, MP, 152°, as a pure diastereomer. The mother liquor (4.0 g, 53%) was pure by PMR analysis and contained the other diastereomer. Crystallization of the mother liquor in cyclohexane followed by several recrystallizations gave the other diastereomer of the title compound, MP, 114°-115°.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][C:44]([CH2:48]C)([OH:47])[CH2:45][CH3:46].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:48][C:44]([CH2:45][CH3:46])([OH:47])[CH2:43][CH3:42])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(O)(CC)CCBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(CC)CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 121.1 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (82.8 mg, 0.143 mmol), 5-bromo-3-ethyl-3-pentanol (139 mg, 0.715 mmol), tetrahydrofuran. (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane : ethyl acetate=8:1, developed once) to give 99.6 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from 5-bromo-3-ethyl-3-pentanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[NH:26][C:25]([CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[ClH:36].C(O)C>O1CCCC1>[ClH:1].[ClH:36].[NH2:28][CH2:27][C:25]1[NH:26][C:19]2[C:18]([NH:17][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methylcarbamate (500 mg) in tetrahydrofuran (12 mL) was added 2N hydrochloric acid (6.0 mL) at room temperature. The mixture was stirred at 60° C. for 2 hrs, ethanol was added to the reaction system and the mixture was concentrated under reduced pressure. The resultant crystals were collected by filtration and washed with diisopropyl ether to give the title compound (481.4 mg) as pale-yellow powder crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])(C)(C)C.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].O>CCOCC>[F:18][C:19]([F:26])([F:25])[C:20]([C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1)=[O:21]
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: O=C(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
5.00 g (20.57 mmol) of 3-bromo-5-fluorobenzotrifluoride were stirred in 60 ml of dry ether and admixed dropwise at −78° C. under a protective gas atmosphere (argon) with 1.33 ml (20.75 mmol) of tert-butyllithium solution [cf. also trifluoroacylation: H. K. Nair, D. M. Quinn Bioorganic & Medicinal Chemistry Letters 3(12), 2619-22 (1993); G. J. Pork et al., J. Org. Chem. 22, 993 (1957)]. Subsequently, the reaction mixture was stirred at −78° C. for 45 minutes and then added dropwise, with the aid of a syringe, in portions at −78° C., to a solution of 3.71 g (26.17 mmol) of ethyl trifluoroacetate in 40 ml of dry ether. Thereafter, the entire reaction mixture was stirred first at −78° C. for 10 minutes and then at room temperature for one hour. For workup, the entire reaction mixture was added to water and extracted with ether. The organic phase was removed and dried at 40° C. under reduced pressure (not less than 10 mbar owing to the high volatility of the compound). This gave 4.06 g (75.9% of theory) of 2,2,2-trifluoro-1-[3-fluoro-5-(trifluoromethyl)phenyl]-ethanone, which was isolated as the hydrate.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:48][CH3:49])=[C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[C:20]4[CH:25]=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[OH-].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:48][CH3:49])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)[nH]c2nccc1-2
Reaction time: 6 h
Yield: 72.1 %

Procedure:
To a solution of 2-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (3.2 g, 4.57 mmol) in 1,4-dioxane (200 ml) was added 1.0M potassium hydroxide (91 ml, 91 mmol) and the resulting reaction was stirred at 80 C for 6 hrs. The reaction was diluted with ethyl acetate (200 ml), washed with brine (200 ml), adsorded to silica gel and purified by LC (DCM to 5% MeOH/DCM) to provide 2-[(2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (1.8 g, 72%). ESIMS (M+H)+=547. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.88 (m, 2 H) 2.07 (br. s., 6 H) 2.59-2.68 (m, 2 H) 2.74 (d, J=4.58 Hz, 3 H) 3.20 ) (s, 2 H) 3.66 (t, J=6.13 Hz, 2 H) 3.80 (s, 3 H) 6.25-6.28 (m, 1 H) 6.78 (s, 1 H) 6.88-6.98 (m, 2 H) 7.32-7.39 (m, 1 H) 7.45 (s, 1 H) 8.20 (d, J=8.42 Hz, 1 H) 8.38 (s, 1H) 8.46-8.59 (m, 1 H) 10.06 (s, 1 H) 11.32 (br. s., 1 H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1>[OH:16][CH:15]([CH:12]1[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1)[CH:17]=[CH2:18]
Reactant: C=C[Mg]Br
Reactant: O=CC1CCN(C(=O)c2ccccc2)CC1
Solvent: C1CCOC1
Product: C=CC(O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 500 mg of 1-benzoylpiperidine-4-carboxaldehyde (Step C) in 10 mL THF at −78° C., was added 2.99 mmol of vinyl magnesium bromide. The solution was warmed to 0° C. and stirred for 1 h. The reaction was quenched with 15 mL of aq. ammonium chloride and extracted with 3×20 mL ether and the combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography with 2:1 hexane:ethyl acetate followed by 1:1 hexane:ethyl acetate followed by hexane:ethyl acetate:methanol, 50:50:5 to give 411 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21]([OH:23])=O)[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)=[C:5]([CH3:19])[CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:47]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1>CN(C=O)C.O>[CH2:47]([N:57]1[CH2:62][CH2:61][N:60]([C:21](=[O:23])[CH2:20][N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=3)=[C:5]([CH3:19])[CH:4]=2)[CH2:59][CH2:58]1)[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1
Reactant: Cc1cc(N(C)CC(=O)O)ccc1Oc1ccc([N+](=O)[O-])cn1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of {methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetic acid (0.93 g, 2.9 mmol) in DMF (40 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol), 1-hydroxybenzotriazole monohydrate (0.54 g, 3.5 mmol), and 1-piperonylpiperazine (0.68 g, 3.08 mmol). The reaction mixture was stirred for 15 hours at room temperature under a nitrogen atmosphere. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→dichloromethane:methanol=100:1), to thereby yield 1.2 g of the title compound.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5Br)=[O:23])[CH2:21][CH2:20]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[NH:30][CH:29]=[C:28]5[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:23])[CH2:21][CH2:20]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: O=C(Nc1ccc2[nH]cc(Br)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(Nc1ccc2[nH]cc(-c3ccccc3)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 130 °C

Procedure:
Phenyl boronic acid (24.6 mg, 0.204 mmol) was added to a solution of 1-(benzo[d][1,3]-dioxol-5-yl)-N-(3-bromo-1H-indol-5-yl)cyclopropanecarboxamide (39.9 mg, 0.100 mmol) in ethanol (1 mL) containing FibreCat 1001 (6 mg) and 1M aqueous potassium carbonate (0.260 mL). The reaction mixture was then heated at 130° C. in a microwave reactor for 20 minutes. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-phenyl-1H-indol-5-yl)cyclopropane carboxamide ESI-MS m/z calc. 396.2, found 397.3 (M+1)+. Retention time of 3.52 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (d, J=1.9 Hz, 1H), 8.66 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.65-7.61 (m, 3H), 7.46-7.40 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 7.25-7.17 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 6.98-6.87 (m, 2H), 6.02 (s, 2H), 1.43-1.39 (m, 2H), 1.06-1.02 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:23])=[C:6]([S:8]([N:11]([CH2:19][O:20][CH2:21][CH3:22])[C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[NH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=2[OH:39])[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[NH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=2[O:39][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([S:8]([N:11]([CH2:19][O:20][CH2:21][CH3:22])[C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)(=[O:10])=[O:9])=[C:5]([F:23])[CH:4]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Nc1cc(-c2cc(Cl)ccc2O)ccn1
Reactant: CCOCN(c1ncc(F)cn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOCN(c1ncc(F)cn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N)c2)cc1F
Temperature: 50 °C
Reaction time: 19 h
Yield: 58.4 %

Procedure:
To a solution of 5-chloro-N-(ethoxymethyl)-2,4-difluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 14, 75 mg, 0.20 mmol) in dimethylsulfoxide (1 mL) was added 2-(2-aminopyridin-4-yl)-4-chlorophenol (Preparation 13, 43.3 mg, 0.20 mmol) and potassium carbonate (40.7 mg, 0.30 mmol). The reaction mixture was stirred at 50° C. for 19 hours, then diluted with ethyl acetate (30 mL) and washed with 1N aqueous sodium hydroxide solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (50% hexanes in ethyl acetate to 100% ethyl acetate gradient elution) to afford the title compound as a white solid (68 mg).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[NH:12]C(=O)C)([O-:5])=[O:4].C(O)C>O>[N+:3]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[CH:10][C:11]=1[NH2:12])([O-:5])=[O:4]
Reactant: CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of potassium hydroxide (2.5 g), 3-nitro-4-acetamido-1,1′-biphenyl (23.5 g), prepared in (A) above, water (6 mL) and ethanol (12 mL) is heated at reflux for one hour. The reaction mixture is cooled to room temperature and then poured into 300 mL of a mixture of water and ice. The solid is collected by filtration and the crude product is recrystallized from methanol (800 mL) to give 14.1 g of the title compound as an orange solid melting at 170–172° C.