Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[F:11].Br.CS(C)=[O:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[O:15])=[CH:4][C:3]=1[F:11]
Reactant: CS(C)=O
Reactant: CC(=O)c1ccc(Br)c(F)c1
Agent: Br
Product: O=CC(=O)c1ccc(Br)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-bromo-3-fluorophenyl)ethanone (4, 890.8 g, 4.1 mol) in DMSO (4 L) was slowly added a solution of 48% aqueous hydrogen bromide (HBr, 1420 ML, 12.5 mol, 3.0 equiv). The reaction temperature was gradually increased from 20° C. to 50° C. during the course of the addition. The reaction mixture was subsequently heated to 60° C. and stirred at 60° C. overnight. The resulting dimethyl sulfide was removed by distillation and the residue was poured into ice water (28 L). The resulting yellow precipitate was collected by filtration (save the filtrate) and washed with water (5 L). The yellow solid was dissolved in ethyl acetate (EtOAc, 5 L), washed with brine (1 L) and dried over anhydrous sodium sulfate (Na2SO4). The solution was then concentrated under the reduced pressure and the resulting solid was dried in a vacuum oven at 45° C. to give the desired product, 2-(4-bromo-3-fluorophenyl)-2-oxoacetaldehyde, as its hydrate (hydrate of 5, 730.6 g, 1020.9 g theoretical, 71.6% yield). The aqueous phase (filtrate) was extracted with ethyl acetate (3×5 L) and the combined organic phase was washed with water (2×2 L), brine (2 L) and dried over anhydrous sodium sulfate (Na2SO4). The solution was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45° C. to give the second crop of 2-(4-bromo-3-fluorophenyl)-2-oxoacetaldehyde hydrate (hydrate of 5, 289.4 g, 1020.9 g theoretical, 28.3% yield; total 1020 g, 1020.9 g theoretical, 99.9% yield) which was used in the subsequent reaction without further purification. For hydrate of 5: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00-7.70 (m, 3H), 6.69 (br s, 2H), 5.59 (s, 1H).
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:19]([O:26][C:27]([N:29]1[C@@H:33]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:32]([CH:38]=O)[O:31][C:30]1([CH3:41])[CH3:40])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1COCC1>[CH2:19]([O:26][C:27]([N:29]1[C@@H:33]([CH2:34][CH:35]([CH3:36])[CH3:37])[C@H:32]([CH:38]=[C:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:31][C:30]1([CH3:40])[CH3:41])=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CC
Yield: 88.1 %

Procedure:
71.6 mg of lithium chloride was suspended in 5 ml of dry THF under an argon atmosphere, and 426 mg of ethyl 2-diethylphosphonobutanoate dissolved in 0.6 ml of dry THF was added thereto under stirring. The mixture was stirred at room temperature for 5 minutes, and then 323 mg of 1,8-diazabicyclo{5,4,0]-7-undecene (hereinafter referred to simply as DBU) was added thereto in the form of a 50° dry THF solution, and the mixture was stirred at room temperature for 10 minutes. Then, 450 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine dissolved in 1.0 ml of dry THF was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was cooled to 0° C. and neutralized with 1N hydrochloric acid. Then, the solution was extracted three times with ethyl acetate. The organic layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 518 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-ethyl-2-propenoate as colorless oily substance.
Reaction SMILES: [F:1][C:2]1([F:29])[C@@H:19]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:18][CH2:17][C@@:16]2([CH3:27])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=O.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CO>[CH:30]1([N:33]=[C:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:27])[C:3]([C:2]([F:1])([F:29])[C@@H:19]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: C[C@]12CC[C@H](OC3CCCCO3)C(F)(F)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CO
Product: C[C@]12CC[C@H](OC3CCCCO3)C(F)(F)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NC3CC3)CC[C@@H]12
Temperature: 25 °C

Procedure:
To a solution of 21 g of 4,4-difluoro-3β-(2-tetrahydropyranyloxy)androst-5-en-17-one in a mixture of 175 ml of cyclopropylamine and 150 ml of methanol there is added 5 g of molecular sieves. The reaction mixture is refluxed for 48 hours, cooled to room temperature, and filtered through magnesium sulfate. The magnesium sulfate is washed with ethyl acetate and the solvent is removed from the combined filtrates under reduced pressure to give 17-(cyclopropylimino)-4,4-difluoro-3β-(2-tetrahydropyranyloxy)androst-5-ene.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC(C)=CC=2)(=O)=O)=[C:4]([C:21]2[O:22][C:23]([CH3:26])=[N:24][N:25]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1.O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[NH:39]1[C:40]2[C:36](=[C:35]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[C:4]([C:21]4[O:22][C:23]([CH3:26])=[N:24][N:25]=4)[CH:3]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(C)o4)cc(Br)cc32)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 150 °C
Yield: 52.9 %

Procedure:
6-Bromo-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazole (70 mg, 0.162 mmol) was dissolved in 1,4-dioxane (1.2 ml) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (47.1 mg, 0.194 mmol, available from Frontier Scientific Europe), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (5.91 mg, 8.08 μmol), water (0.8 ml) and 2M aqueous sodium bicarbonate (0.242 ml, 0.485 mmol) were added. The reaction mixture was heated under microwave irradiation at 150° C. for 15 mins. The solution was loaded onto a silica cartridge (0.5 g) and eluted with methanol. The eluant was concentrated, the residue dissolved in methanol and absorbed onto Florisil. This was placed on top of a silica cartridge (10 g) and eluted with 25-50% ethyl acetate/cyclohexane. Appropriate fractions were evaporated to give the title compound as a yellow solid (27 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.CC(C)([O-])C.[Na+].[NH2:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)C>[CH3:31][C:29]1[CH:30]=[C:26]([NH:25][C:16]2[CH:17]=[CH:18][C:13]([N:4]3[N:3]=[CH:2][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]3=[O:12])=[CH:14][CH:15]=2)[NH:27][N:28]=1
Reactant: O=c1c2ccccc2c(Br)nn1-c1ccccc1
Reactant: Cc1cc(N)n[nH]1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Product: Cc1cc(Nc2ccc(-n3ncc4ccccc4c3=O)cc2)[nH]n1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
Degassed toluene (6 ml) and ethanol (3 ml) were added in one portion to a mixture of 4-bromo-2-phenyl-2H-phthalazin-1-one (0.750 g, 2.5 mmol), sodium t-butoxide (0.337 g, 3.5 mmol), 3-amino-5-methyl pyrazole (0.291 g, 3 mmol), tris-(dibenzylideneacetone)-dipalladium (0.115 g, 0.125 mmol) and 2-(di-t-butylphosphino)-biphenyl (0.075 g, 0.25 mmol) under nitrogen. The reaction mixture was heated to 100° C. for 20 hours with stirring and then cooled to room temperature. Diethyl ether (10 ml) was added and the precipitated solid was filtered to give the crude product as a grey solid (0.6 g, 76% yield). A 0.06 g portion of the crude product was triturated with acetonitrile (2 ml) and water (2 ml) to give the target compound (0.045 g, 58% yield based on recovered materials). 1H-NMR: (400 MHz, D6-DMSO) 11.96 (1H, s), 9.33 (1H, s), 8.53 (1H, d), 8.38 (1H, d), 7.92–7.99 (2H, m), 7.88 (2H, d), 7.77 (2H, t) 7.34 (1H, t) 6.24 (1H, s) 2.18 (3H, s) MS (ESI+)=(M+H)+ 318.29.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:20]=[C:8]2[C:9]([C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH3:4].[C:21]([O:24][CH2:25][CH2:26]Br)(=[O:23])[CH3:22].[Cl-].[NH4+]>CN(C)C=O>[CH2:3]([C:5]1[CH:20]=[C:8]2[C:9]([C:13](=[O:19])[CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:22][C:21]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH3:4]
Reactant: CC(=O)OCCBr
Reactant: CCc1cc2c(C(=O)CC(=O)OC)cccn2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C(=O)OC)C(=O)c1cccn2nc(CC)cc12

Procedure:
60% sodium hydride (135 mg) was added to a solution of the compound of Example 180 (830 mg) in N,N-dimethylformamide (40 mL) in a stream of argon gas while the solution was stirred in an ice bath. The mixture was then stirred at room temperature for 15 min. Subsequently, bromoethyl acetate (374 μL) was added to the mixture under stirring in an ice bath. The mixture was further stirred at room temperature for 3 hours. Subsequently, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water (×2) and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification by silica gel column chromatography (hexane:ethyl acetate=2:1) afforded the title compound as a mixture with o-alkylated form. This product was used in the subsequent reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH2:9].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[C:27]([Cl:29])[CH:28]=1)[CH2:25][N:24]([CH3:30])[CH2:23][CH:22]2[C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH:9][S:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH:22]2[C:21]3[C:26](=[C:27]([Cl:29])[CH:28]=[C:19]([Cl:18])[CH:20]=3)[CH2:25][N:24]([CH3:30])[CH2:23]2)[CH:32]=1)(=[O:39])=[O:38]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: CN(CCCN)CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCN)CCCNS(=O)(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of N1-(3-aminopropyl)-N1-methylpropane-1,3-diamine (560 mg, 3.85 mmol) dissolved in DCM (20 mL), was added triethylamine (300 mg, 2.96 mmol) and 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.77 mmol). The resulting solution was stirred for 3 h at room temperature. After removing the solvent, the resulting residue was diluted with EtOAc (50 mL), washed with water (2×10 mL) and dried over anhydrous sodium sulfate. The crude product was purified by Flash-Prep-HPLC with H2O:MeOH (1:4) to afford 300 mg (74%) of N-(3-((3-aminopropyl)(methyl)amino)propyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.FC(F)(F)C(O)=O.[CH2:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60])[CH2:55][CH2:56][CH3:57]>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH2:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][N:64]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH2:63][CH2:62]1)=[O:60])[CH2:55][CH2:56][CH3:57]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 22.4 g of (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester, 30.7 g of NEM and 21.8 g of TOTU in 75 ml of DMF, 20 g of Piperazine-1-carboxylic acid butyl ester trifluoroacetate was added at RT and stirred for 16 h. The reaction mixture was then diluted with saturated aqueous sodium hydrogen carbonate solution and then extracted with 300 ml of ethyl acetate. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO4. The solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 33.4 g.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.[N+](=[CH2:28])=[N-]>CCOC(C)=O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22][CH3:28])=[O:21])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: COc1ccc2c(c1)c(CCC(=O)O)c(C)n2Cc1ccc(Br)cc1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12

Procedure:
To a solution of the compound from Example 1 (75 mg, 0.19 mmol) in 10 mL EtOAc was added ethereal diazomethane solution until a yellow colour persisted. The solution was concentrated in vacuo and crystalized from ether/hexanes to provide 67 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1)[CH3:3].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:29](Cl)=[N:28][CH:27]=[CH:26][N:25]=1)(=[O:22])=[O:21]>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:29]([O:11][CH2:10][C:8]2[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)=[N:28][CH:27]=[CH:26][N:25]=1)(=[O:21])=[O:22]
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Reactant: CN(C)Cc1ccc(CO)o1
Product: CN(C)Cc1ccc(COc2nccnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1

Procedure:
Prepared by the method of Example 28 using (5-dimethylaminomethyl-2-furanyl)methanol (0.2 g) and 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.4 g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.2 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:43]=[CH:44][CH:45]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[C:10]([CH3:42])=[N:9]1)[CH3:2].[ClH:46]>CO>[ClH:46].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:43]=[CH:44][CH:45]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]5)=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[C:10]([CH3:42])=[N:9]1)[CH3:2]
Reactant: CCOc1cccc(Cn2nc(C)c(-c3c[nH]c4ncc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)c2C)c1
Agent: Cl
Solvent: CO
Product: CCOc1cccc(Cn2nc(C)c(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)cc5)cc34)c2C)c1
Yield: 4.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-ethoxybenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.139 mmol) was deprotected with HCl in methanol (5 ml) to afford 4 mg (4.8% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.39-8.38 (d, 1H), 7.79-7.78 (d, 1H), 7.48-7.45 (m, 2H), 7.32 (s, 1H), 7.22-7.17 (t, 1H), 7.05-7.02 (d, 2H), 6.78-6.76 (dd, 1H), 6.69-6.67 (d, 1H), 6.59 (s, 1H), 5.27 (s, 2H), 3.95-3.93 (q, 2H), 3.95-3.57 (d, 2H), 3.26-3.19 (m, 4H), 3.05-3.02 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.30-1.26 (t, 3H). MS: m/z=507.3 (M+1), HPLC Purity: 92.87% Method: B.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(N)n(C)n1
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)C(C)(C)C)n(C)n1
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To 15.0 g (131 mmol) N-(2,5-dimethyl-2H-pyrazol-3-yl)-amine in 150 mL pyridine at 0° C. was added 19.3 mL (18.9 g, 158 mmol) of pivaloyl chloride. After stirring at 23° C. for 3.5 hours, the reaction solvent was evaporated, and the residue was evaporated with 2×200 mL toluene. The remaining solid was dissolved in 500 mL EtOAc/200 nmL H2O and extracted. The aqueous layer was extracted with 2×100 mL EtOAc, and the combined organics were washed with 1×200 mL brine, dried over MgSO4, filtered and evaporated to an orange solid. Recrystallization from hot hexanes/EtOAc gave 24.45 g (125 mmol, a 96% yield) of the title compound as an off-white, crystalline solid: mp: 86-88° C.; 1H NMR (300 MHz, CDCl3): δ1.32 (s, 9H), 2.22 (s, 3H), 3.63 (s, 3H). 5.98 (s, 1H), 7.12 (brs, 1H); IR (KBr, cm−1): 3316s, 3274s, 2967m, 2935m, 1673s, 1655m, 1570s, 1514m, 1492m, 1457m; MS (ES) m/z (relative intensity): (196, M+, 100). Anal. Calcd. for C10H17N3O: C, 61.51; H, 8.77; N, 21.52. Found: C, 61.33; H, 8.80; N, 21.23.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1>CC(O)=O.[Fe]>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2o1
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1nc2ccc(N)cc2o1
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
To a solution of 2-methyl-6-nitrobenzoxazole (100 mg, 0.560 mmol) in AcOH (2 mL) was added iron powder (325 mesh, 63.0 mg, 1.12 mmol) at 70° C. in a single portion. After 15 min at 70° C. additional iron powder (325 mesh, 63.0 mg, 1.12 mmol) was added and stirring was continued for 15 min. The mixture was cooled and concentrated under reduced pressure. The resulting residue was taken up into EtOAc and washed with sat. Na2CO3 followed by H2O. The organic layer was dried over MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with a gradient of 0 to 25% EtOAc in CH2Cl2 to yield 69 mg (83%) of compound 479A as a solid. HPLC: 97% at 0.24 min (retention time) (YMC S5 ODS column, 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 min containing 0.2% H3PO4, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 149.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:16][C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1.[BH4-].[Na+].C(Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:22][C:20]3[O:21][C:17]([CH3:16])=[CH:18][CH:19]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1ccc(C=O)o1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)o1
Temperature: -20 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (60 mg, 246 μmol) and 5-methylfuran-2-carbaldehyde (111.2 mg, 1.0 μmol) in MeOH (3 ml) was stirred at 45° C. for two days to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (55.8 mg, 1.47 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. Trituration with DCM afforded an off white solid as desired product (61.3 mg, 74% yield). MS +m/z: 338 (M+H)+
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH3:25][CH:26]([CH3:34])[CH2:27][C:28](=[O:33])[CH2:29][C:30](=O)[CH3:31]>>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[C:4]3[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[N:2]=[C:30]([CH3:31])[C:29]=2[C:28](=[O:33])[CH2:27][CH:26]([CH3:34])[CH3:25])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CC(=O)CC(=O)CC(C)C
Agent: Cl
Product: COc1ccc(-c2c(C(=O)CC(C)C)c(C)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Reference Example 6, 2-amino-3',4',4,5-tetramethoxybenzophenone hydrochloride was reacted with 6-methyl-2,4-heptanedione to give 4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxy-2-methylquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 135°-137° C.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1)=[O:5])[CH2:2][CH3:3].C(O)(=O)C.[CH3:18][O:19][C:20]([NH:22][C:23](=NC(OC)=O)SC)=[O:21].O>CO>[CH2:1]([S:4]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:23]([NH:22][C:20](=[O:21])[O:19][CH3:18])=[N:13][C:8]=2[CH:7]=1)=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)c1ccc(N)c(N)c1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCCS(=O)c1ccc2[nH]c(NC(=O)OC)nc2c1
Yield: 81 %

Procedure:
To 3.56 g (18 mMol) 4-(1-propylsulfinyl)-1,2-diaminobenzene in 45 ml methanol is added 1.03 ml acetic acid and 3.84 g (19.8 mMol) 1,3-bis(methoxycarbonyl)-S-methyl isothiourea. The resulting solution is heated to reflux for 21/2 hours, cooled and the solvent stripped. The white solid is digested with water, filtered, washed with ether and dried to yield 4.1 g of the title compound in the form of a white solid, m.p. 215°-216°, yield 81%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH2:11])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCOc1ccc(CN)cc1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 4-butoxybenzonitrile (4.6 g, 26.25 mmol) in Et2O (50 mL) was added lithium aluminum hydride (1.0 M in THF, 26.2 mL, 26.2 mmol) dropwise. The reaction was heated at reflux for 1 h and was cooled to room temperature. The reaction was carefully poured into water (50 mL) and was diluted with Et2O. The solids were removed by filtration through Celite with the aid of Et2O. The organic solution was washed with water followed by brine, dried (MgSO4), filtered, and concentrated in vacuo to provide 4-butoxybenzylamine (2.68 g). 1H NMR (400 MHz, CDCl3) δ 7.16 (m, 2H), 6.82 (m, 2H), 3.91 (m, 2H), 3.75 (s, 2H), 1.73 (m, 2H), 1.46 (m, 2H), 1.39 (m, 2H), 0.95 (t, 3H).