Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])[C:16]([C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)([CH3:18])[CH3:17].CI.[C:36](OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([CH3:36])[C:15](=[O:33])[C:16]([C:19]1[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1)([CH3:18])[CH3:17]
Reactant: CCOC(C)=O
Reactant: CC(C)(C(=O)Nc1ccccc1-c1ccccc1N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1-c1ccccc1N
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 151 mg (0.32 mmol) N-(2′-amino-biphenyl-2-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-isobutyramide in 1 ml N,N-dimethylformamide under argon 130 mg (0.65 mmol) potassium hexamethyldisilazide were added at 0°. Stirring was continued for 1 h at room temperature and the reaction mixture was cooled to 0° again. At this temperature, 115 mg (0.81 mmol) methyl iodide were added. After stirring for 3 hrs at room temperature, ethyl acetate was added and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/CH2Cl2 1:1) to give 56 mg (36%) N-(2′-amino-biphenyl-2-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as colorless oil, MS (ISP): 481.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:19]([NH2:24])[CH2:20][CH2:21][CH2:22]N.C(Cl)Cl.C[N:29]1CCCC1=O>CO>[NH2:29][CH:20]([CH2:21][CH3:22])[CH2:19][NH:24][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)ccc2c1=O
Reactant: CN1CCCC1=O
Reactant: NCCCCN
Solvent: ClCCl
Solvent: CO
Product: CCC(N)CNc1ccc2c(=O)c(C(=O)O)cn(C3CC3)c2c1
Temperature: 130 °C

Procedure:
To a solution of 7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (1.0 g) in 1-methyl-2-pyrrolidinone (10 mL) was added butylenediamine (1.7 g). The mixture was heated at 130° C. for 16 h. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH and filtered to give the title compound (450 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[C:9](=[O:15])[NH:10][C:11](S)=[N:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].C(O)C>C(OCC)(=O)C.ClCCl.[Ni]>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[C:9](=[O:15])[NH:10][CH:11]=[N:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2cnc(S)[nH]c2=O)cc1
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1ccc(Oc2cnc[nH]c2=O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of 5-(4-ethylphenoxy)-2-(mercapto)pyrimidine-4(3H)-one (2.49 g, 10.28 mmoles), ethanol (250 mL) and wet Raney Ni (50% slurry in water, active catalyst) (Aldrich) (10.9 g) was refluxed with stirring for 3 hours. The reaction was cooled to about 40° C. and filtered through a pad of Celite 545 (Fisher). The pad was washed with hot ethanol (2×75 mL), and the pad was placed in a beaker of water. The combined filtrates were spin evaporated in vacuo to a syrup. The syrup was dissolved in ethyl acetate and reevaporated to give a gray solid. The solid was dissolved in ethyl acetate (40 mL) and applied to a column (4.2×9.5.cm) of Silica Gel 60 (E.M. Science, 230-440 mesh) that was equilibrated with ethyl acetate. The column was eluted with ethyl acetate by flash chromatography, and twelve 100 mL fractions were collected. Fractions 4-10 were combined and spin evaporated in vacuo. The residual oil was dissolved in ethyl acetate and evaporated to give a mixture of light green and white crystals. The crystals were dissolved in dichloromethane and spin evaporated in vacuo to give 1.37 g (63% yield) of 5-(4-ethylphenoxy)pyrimidine-4(3H)-one. Recrystallization of a sample form ethyl acetate gave analytically pure 5-(4-ethylphenoxy)-2-(mercapto)pyrimidine-4(3H)-one as white needles, mp 144-146° C.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[C:14]2[O:13][C:12]3[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[C:11]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl>C(O)C.CN(C)C=O.O>[OH:19][CH:18]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[C:14]=3[O:13][C:12]=2[CH2:15][CH2:16][CH2:17]1
Reactant: O=C1CCCc2oc3c([N+](=O)[O-])cccc3c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c3c(oc12)CCCC3O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
Sodium borohydride (38 mg) was added to a solution of 6-nitro-1-oxo-1,2,3,4-tetrahydrodibenzofuran (231 mg) in a mixture of ethanol (1.5 ml) and N,N-dimethylformamide (1.5 ml). The mixture was stirred at ambient temperature for 20 minutes, diluted with water and acidified with 3.6% hydrochloric acid. The separated oil was extracted with ethyl acetate and the extract was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give 1-hydroxy-6-nitro-1,2,3,4-tetrahydrodibenzofuran (175 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](Cl)[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=2)O1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:32]3[CH:33]=[N:34][N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=3)[N:11]3[CH:15]=[CH:16][N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: Clc1nc(-c2ccc(Br)cc2)cc2nccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2nc(-c3ccc(Br)cc3)cc3nccn23)cn1
Temperature: 70 °C
Yield: 39.8 %

Procedure:
To a flask charged with 7-(4-bromophenyl)-5-chloroimidazo[1,2-c]pyrimidine (2.68 g, 8.685 mmol), potassium carbonate (3.601 g, 26.06 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E; 6.628 g, 17.37 mmol) were combined in a glass bomb and the vessel was evacuated and backfilled with argon. To the reaction was added 100 mL of DME and then water (1.252 mL, 69.48 mmol) and argon was bubbled through the reaction for 20 minutes before tetrakis(triphenylphosphine)palladium (0) (1.004 g, 0.8685 mmol) was added in one portion. The reaction was fitted with a septum and argon was bubbled through for 10 minutes before the reaction was sealed and heated to 70° C. for 4 hours 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation E; 3.3 g, 8.6 mmol) was added. Argon was bubbled through for 10 minutes before the reaction was sealed and heated to 70° C. for 3 hours. The reaction was diluted with 10% methanol in DCM (300 mL), dried with MgSO4, filtered, and then concentration under reduced pressure. The resultant crude was purified by silica gel chromatography eluting with a gradient of 30-75% ethyl acetate in hexanes to afford the title compound (1.625 g, 3.454 mmol, 39.77% yield). MS (apci) m/z=470.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:29])[CH:23]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)CCc1cccc(N)c1
Product: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Yield: 67.7 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (280 mg, 0.91 mmol) was reacted with 3-[2-(dimethylamino)ethyl]aniline (150 mg, 0.91 mmol) to afford the desired product (270 mg, 68%) as a yellow solid: ESI MS m/z 438 [C23H24BrN3O+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[C:20]2[N:19]=[C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:45]1([CH2:51][CH2:52][CH2:53]Br)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O>[CH:8]([O:11][C:12]1[C:20]2[N:19]=[C:18]([CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]3[CH2:34][CH2:35][N:36]([CH2:53][CH2:52][CH2:51][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:37][CH2:38]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: CC(C)Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][CH2:17][OH:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][CH2:17][O:18][CH2:22][CH:23]1[CH2:25][CH2:24]1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=CCO)C2
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(=CCOCC1CC1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
A reaction flask was charged with 3-(2-hydroxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (0.380 g, 1.5 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil, 0.060 g, 1.5 mmol) was added in portions and the mixture was stirred at 50° for 1 h. The mixture was cooled to rt and bromomethylcyclopropane (0.202 g, 1.5 mmol) was added followed by stirring at rt for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 1:1) to give the title compound (0.115 g, 25%). 1H NMR (CDCl3) δ 5.38-5.32 (m, 1H), 4.36-3.96 (m, 2H), 3.88-3.75 (m, 2H), 3.09 (d, 2H), 2.48-1.66 (m, 6H), 1.48-1.36 (m, 2H), 1.30 (s, 9H), 0.94-0.33 (m, 1H), 0.40-0.33 (m, 2H), 0.05-0.00 (m, 2)
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([Br:18])=[CH:13][C:12]=2[CH3:19])[C:4](=[O:10])[CH:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:20](OC(=O)C)(=O)[CH3:21].C(O)(=[O:29])C>>[Br:18][C:14]1[CH:13]=[C:12]([CH3:19])[C:11]([N:3]2[C:2]3[N:1]=[C:20]([CH3:21])[N:8]=[C:7]([OH:29])[C:6]=3[CH:5]([CH3:9])[C:4]2=[O:10])=[C:16]([CH3:17])[CH:15]=1
Reactant: Cc1cc(Br)cc(C)c1N1C(=O)C(C)C(C#N)=C1N
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Product: Cc1nc(O)c2c(n1)N(c1c(C)cc(Br)cc1C)C(=O)C2C
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-1-(4-bromo-2,6-dimethylphenyl)-4-methyl-5-oxo-4,5-dihydro-1H-pyrrole-3-carbonitrile (100 g) in acetic acid (100 mL) was added acetic anhydride (38.3 g) and the mixture was heated at reflux for 8 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure, and water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropylether to give 7-(4-bromo-2,6-dimethylphenyl)-4-hydroxy-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (56.6 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[S:5])[CH3:2].[CH3:19][I:20]>CC(C)=O>[IH:20].[CH3:19][S:5][C:4](=[N:3][CH2:1][CH3:2])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CCNC(=S)Nc1ccccc1N1CCOCC1
Reactant: CI
Solvent: CC(C)=O
Product: CCN=C(Nc1ccccc1N1CCOCC1)SC
Product: I

Procedure:
A mixture of 1-ethyl-3-(2-morpholinophenyl) thiourea (3.2 g) and methyliodide (2 g) in acetone (25 ml) was heated at reflux for 4 hours to yield 2-methyl-3-ethyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide as a pale yellow solid (m.p. 170°-172° C.) which was recrystallised from acetone.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[N:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.[OH-].[Na+]>CN(C=O)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[N:12]=[N:13][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(-c2ccc(Nc3ccccc3)nn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(-c4ccc(Nc5ccccc5)nn4)cc3)c2cc1OC
Temperature: 120 °C

Procedure:
A mixture of 4-(6-phenylamino-pyridazin-3-yl)-phenol (Step 3, 0.25 g, 0.95 mmol), 4-chloro-6,7-dimethoxy-quinoline (0.212 g, 0.95 mmol), Cu powder 0.1 g) and NaOH pellet (0.1 g) in DMF/pyridine (1.5 mL/1.5 mL) was heated in a microwave (CEM Discover, 60 W, 120° C., ramp 12 min, hold 18 min). The reaction mixture was then diluted with 50 mL of EtOAc and washed with 20 mL of water followed by brine (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column (50% EtOAc/hexane to EtOAc) to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 451.2(M+H). Calc'd Exact Mass for C27H23N4O3: 450.49.
Reaction SMILES: [C:1]([N:8]([CH3:10])[OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]O.[C:18]([O-])([O-])=[O:19].[K+].[K+]>CN(C=O)C.[Li+].[Br-]>[OH:19][CH2:18][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:9][N:8]([CH3:10])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: OCCOCCCl
Reactant: O=C([O-])[O-]
Reactant: CN(O)C(=O)OC(C)(C)C
Agent: [Br-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CN(OCCOCCCO)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A mixture of N-Boc-N-methyl hydroxylamine (132 mg, 0.898 mmol), 2-(2-chloroethoxy)ethanol (168 mg, 1.35 mmol), K2CO3 (372 mg, 2.69 mmol) and LiBr (2 mg, 0.018 mmol) in DMF (3 mL) was heated at 100° C. and stirred for 16 h. The resulting mixture was cooled down to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography using 50% EtOAc/hexanes as eluent to afford the desired product as colorless oil (152 mg, 0.647 mmol, 72%). 1H NMR (CDCl3, 400 MHz): 8 (ppm) 1.45 (s, 9H), 2.68 (br s, 1H), 3.08 (s, 3H), 3.57-3.60 (m, 2H), 3.66-3.72 (m, 4H), 3.96-3.99 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 62A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.02 (d, J=8.48 Hz, 1H) 7.76 (d, J=1.36 Hz, 1H) 7.45 (d, J=7.80 Hz, 1H) 7.40 (dd, J=8.31, 1.86 Hz, 1H) 7.07 (d, J=7.80 Hz, 1H) 3.95-4.07 (m, 1H) 3.25-3.45 (m, 1H) 2.59 (s, 3H) 2.50 (s, 3H) 2.43-2.78 (m, 6H) 1.77-2.00 (m, 4H) 1.47-1.68 (m, 2H). MS: (M+H)+=364.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
A stirred solution of 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (52 mg, 0.18 mmol), 5-fluoro-1,3-dihydro-indol-2-one (25 mg, 0.4 mmol) in 0.4 ml of ethanol was added dropwise with anhydrous piperidine (0.04 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered under reduced pressure. The resulting solid was washed with anhydrous ethanol (0.2 ml×5), purified by silica gel column chromatography with dichloromethane:methanol (15:1) as eluents to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 38%) as a yellow solid
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Br-:17].[Br-].[Br-].CN(C)C1C=C[NH+]=CC=1.CN(C1C=C[NH+]=CC=1)C.CN(C1C=C[NH+]=CC=1)C>C(Cl)(Cl)Cl>[Br:17][CH:1]=[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: [Br-]
Reactant: C=C1c2ccccc2CCc2ccccc21
Agent: CN(C)c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: BrC=C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
Dissolve 5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (10.00 g, 48.48 mmol) in CHCl3 (125 mL) and add 4-(dimethylamino)pyridinium tribromide (19.35 g, 53.32 mmol). Stir at room temperature for 2.5 h and quench with saturated aqueous Na2SO3. Separate layers, wash organics with saturated aqueous NaHCO3, then H2O. The dried organics (MgSO4) and concentrated to a yellow oil. Purify crude product by loading onto a 20 g plug of silica gel and eluting with hexanes until eluent shows no UV activity. Combine and concentrate hexane washes to afford 13.01 g (94%) of the title compound as a white solid, mp 73.6° C. HPLC shows 99% purity.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:22]=[C:21]([C:23]2[C:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[S:35][C:31]=3[C:30]([Br:40])=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:20]=[C:19]([Br:41])[C:5]=1[O:6][C@@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10]C)=[O:9].CO>C1COCC1>[Br:3][C:4]1[CH:22]=[C:21]([C:23]2[C:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[S:35][C:31]=3[C:30]([Br:40])=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:20]=[C:19]([Br:41])[C:5]=1[O:6][C@@H:7]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Yield: 62.7 %

Procedure:
Aqueous potassium hydroxide (1 N, 2.40 mL, 2.40 mmol) was added to a stirred solution of (S)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenoxy]-3-phenyl-propionic acid, methyl ester (0.88 g, 1.21 mmol) in THF (12 mL)/methanol (8 mL). After 2 h the solution was concentrated, diluted with water (50 mL) and acidified with 10% aqueous HCl. The reaction mixture was then partitioned between water and ether. The ether phase was concentrated and triturated with ether and pet. ether. It was then recrystalized from methanol to provide the title compound as a white solid (0.54 g, 63%): [a]D25 =-24.81° (10.08 mg/mL CHCl3); NMR (CDCl3); δ8.36 (d, J=8 Hz, 1 H), 7.81 (d, J=8 Hz, 1 H), 7.68 (ddd, J=8, 5, 3 Hz, 1 H), 7.58 (dd, J=10, 2 Hz, 2 H), 7.54-7.48 (m, 2 H), 7.44-7.27 (m, 6 H), 7.16 (ddd, J=8, 7, 1), 6.72 (d, J=8 Hz, 1 H), 5.45 (t, J=7 Hz, 1 H), 3.59 (d, J=7 Hz, 2 H); MS (EI): [M+], 3 bromine isotope pattern, 708 (24%), 710 (80%) 712 (100%) 714 (40%); Anal. Calc. for C31H19Br3O3S: C, 52.35, H, 2.69, N, 0.00. Found: C, 52.05, H, 2.59, N, 0.10. Chiral analytical HPLC determined that this compound had approx. 100% EE [column:Chirobiotic V, 5 micron (4.6 ×250 mm); isocratic, 1:1 ethanol:hexane; flow rate =0.80 mL/min; injection volume =0.3 pL; sample conc. =0.25 mg/mL; retention time, R-enantiomer =21 min; retention time, S-enantiomer =16 min.]
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH3:39][C:40]([CH3:44])([CH3:43])[CH:41]=O>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][C:40]([CH3:44])([CH3:43])[CH3:41])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)(C)C=O
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NCC(C)(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure F using trimethylacetaldehyde. The final product was obtained in 47% yield.