Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[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[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[CH2:27]([O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[OH:45])[CH3:28]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]([CH3:25])[CH3:26])[CH2:21][CH2:22]2)=[CH:3][C:2]([C:34]2[CH:33]=[CH:32][C:31]([OH:45])=[C:30]([O:29][CH2:27][CH3:28])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CCOc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN(C)C)CC4)c3c2)ccc1O
Yield: 41.9 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (30 mg, 0.072 mmol) was reacted with 2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (40 mg, 0.150 mmol) to afford the desired product (14.3 mg, 42%) as a yellow solid: NMR (500 MHz, CD3OD) δ 8.73 (s, 1H), 8.31 (d, J=1.7 Hz, 1H), 8.03 (m, 2H), 7.30 (d, J=2.1 Hz, 1H), 7.22 (dd, J=8.2, 2.1 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.22 (q, J=7.0 Hz, 2H), 3.54 (d, J=12.6 Hz, 2H), 3.26-3.12 (m, 2H), 2.59-2.50 (m, 1H), 2.44 (s, 2H), 2.37 (s, 6H), 2.02-1.83 (m, 3H), 1.68-1.53 (m, 2H), 1.49 (t, J=7.0 Hz, 3H), 1.35-1.26 (m, 2H), 1.26-1.15 (m, 2H); ESI MS m/z 474 [C29H35N3O3+H]+; HPLC 96.9% (AUC), tR=10.59 min.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[CH:3]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1)=[O:8])=[O:2]
Reactant: CCOC(=O)c1cnc(SC)nc1C(=O)c1cccc(C(OC)OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnc(SC)nc1C(=O)c1cccc(C=O)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of Example 215A (500 mg, 1.32 mmol) in dichloromethane (20 ml) was added TFA (5 mL). The mixture was stirred at 40° C. overnight. The reaction mixture was concentrated and the crude product was used in the next step without further purification. MS (DCI/NH3) m/z 331 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[CH2:18][CH3:19].[BH4-].[Na+]>CO>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCC=O
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,3-diphenylpropan-1-amine 1 (4.22 g, 20.0 mmol) in MeOH (100 mL) at room temperature was added propionaldehyde (1.16 g, 20.0 mmol) (1.45 mL). The reaction mixture was stirred at room temperature for 3 h and sodium borohydride (1.20 g, 31.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with 5 M NaOH, partially concentrated, and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 8% MeOH (2 M NH3) in DCM) gave 3,3-diphenyl-N-propylpropan-1-amine 7 as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH:7](O)[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: COC(=O)[C@@H]1COCC(O)N1C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1COCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of example 1109C (522 mg, 2.0 mmol) in 4 mL of methylene chloride was cooled in an ice/acetone bath and triethylsilane (1.6 mL, 10.0 mmol) was added. The solution was then treated with a solution of boron trifluoride etherate (0.27 mL, 2.2 mmol) in 1 mL of methylene chloride. After stirring 30 minutes, the bath was removed and stirring continued for 30 minutes and the mixture was quenched by the addition of 2M aqueous sodium carbonate. The mixture was diluted with water and methylene choride and the layers separated. The aqueous layer was extracted with 2 portions of methylene chloride and the combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (40 g, 20% ethyl acetate/hexanes) to provide 200 mg (41%) of the title compound. MS (DCI, NH3): 246 (MH+); 263 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd].[Br-].[Zn+2].[Br-]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a solution of (E)-3-(4-chloro-phenyl)-acrylic acid ethyl ester (0.37 g, 1.73 mmol) in ethyl acetate (10 ml) were added palladium on activated charcoal (18 mg) and zinc bromide (80 mg, 0.35 mmol). The reaction vessel was then pressurized with hydrogen gas to a pressure of 1 atmosphere and the mixture was stirred for 18 h. The catalyst was then removed by filtration, washing with ethyl acetate, and the filtrate was concentrated in vacuo to yield a colourless oil which was used for the next step without further purification; MS (ISP): 214.2, 212.1 ([M+H]+.).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([OH:9])[C@@H:7]([OH:10])[CH2:6][O:5][CH:3]1[OH:4].Cl>>[F:1][C@@H:2]1[C@@H:8]([OH:9])[C@H:7]([CH2:6][OH:5])[O:10][CH:3]1[OH:4]
Reactant: OC1OC[C@H](O)[C@H](O)[C@H]1F
Agent: Cl
Product: OC[C@@H]1OC(O)[C@H](F)[C@H]1O

Procedure:
Treatment of unprotected 2-deoxy-2-fluoro-L-arabinopyranose with one equivalent of either sulfuric or hydrochloric acid at room temperature failed to give the desired furanoside. Only unreacted starting material was detected. Using nine equivalents of hydrochloric acid gave the desired product 2-deoxy-2-fluoro-L-arabinofuranose, which was contaminated with starting material (2:1 ratio). The best result, so far, was achieved by refluxing 2-deoxy-2-fluoro-L-arabinopyranose with 1 equivalent of sulfuric acid in dry methanol. After 6 hours all of the starting material had disappeared affording 2-deoxy-2-fluoro-L-arabinofuranose as an oil in 80% yield. 1H—, 13C- and 19F-NMR indicated a 3:1 α:β mixture of anomers, with some minor impurities. L-ribo- and L-arabinopyranoside as well as L-ribofuranoside are the possible side products. The D-isomer of 2-deoxy-2-fluoro-L-arabinofuranose was previously made by two different groups, but in less efficient ways (Wright, J. A.; Taylor, N. F.; Fox, J. J. J. Org. Chem 1969, 34, 2632. and Wysocki, R. J.; Siddiqui, M. A.; Barchi, J. J.; Driscoll, J. S.; Marquez, V. E. Synthesis 1991, 1005).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=2)[CH:21]=[C:20]([N:33]2[C@H:38]([CH3:39])[CH2:37][O:36][C@H:35]([CH2:40][NH2:41])[CH2:34]2)[N:19]=1>C1COCC1>[NH2:17][C:18]1[N:19]=[C:20]([N:33]2[C@H:38]([CH3:39])[CH2:37][O:36][C@H:35]([CH2:40][NH:41][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:34]2)[CH:21]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=2)[N:23]=1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112 %

Procedure:
Triethylamine (48 μL, 0.34 mmol) and benzoyl chloride (31 μL, 0.27 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (77 mg, 0.23 mmol) in THF (5 mL), and the mixture was stirred at room temperature under nitrogen for 30 minutes. The mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (115 mg) as a yellow glass. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]#[C:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:43]#[C:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C#Cc2ccccc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(C#Cc2ccccc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 90 °C

Procedure:
In a 30 mL glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), 4,4,5,5-tetramethyl-2-(phenylethynyl)-1,3,2-dioxaborolane (75 mg, 0.329 mmol) and PdCl2(PPh3)2 (105 mg, 0.150 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The vessel was sealed with a cap and the reaction mixture was heated to 90° C. in an oil bath for 2 hours. The reaction mixture was subsequently diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-(phenylethynyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL), TFA (3 mL) was added, and the mixture was stirred for 1 hour. The volatiles were subsequently evaporated and the residual material was dissolved in DMSO (5 mL) and purified by preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give the TFA salt of the title compound as a pale yellow solid (14.5 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 1H), 2.05-2.12 (m, 1H), 3.49-3.66 (m, 2H), 3.76 (d, J=11.62 Hz, 1H), 3.84-4.04 (m, 2H), 4.31-4.51 (m, 3H), 7.16-7.29 (m, 1H), 7.42-7.53 (m, 3H), 7.53-7.67 (m, 2H), 7.92 (br s, 3H), 8.50 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H19FN4O2, 367. found, 367.
Reaction SMILES: [CH2:1]([C:11]1[C:15]2[S:16][C:17]3[C:21]4[S:22][C:23](C(O)=O)=[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:20]=4[S:19][C:18]=3[C:14]=2[S:13][C:12]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(=O)=O.CCCCCC>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:25]([C:24]1[C:20]2[S:19][C:18]3[C:14]4[S:13][CH:12]=[C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:15]=4[S:16][C:17]=3[C:21]=2[S:22][CH:23]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c3sc(C(=O)O)c(CCCCCCCCCC)c3sc21
Agent: [Cu]
Agent: O=C=O
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCCCc1csc2c1sc1c3scc(CCCCCCCCCC)c3sc21
Temperature: 255 °C
Yield: 62.5 %

Procedure:
Compound 75 (13.5 g, 0.021 mol) was mixed with copper powder (0.9 g) in quinoline (80 mL), and the mixture was heated to 250-260° C. in a Woods-metal bath. When no further bubbles of carbon dioxide gas could be detected (about 2 hours), the mixture was allowed to cool to room temperature and hot hexane (400 mL) was added. This mixture was then repeated washed by HCl (2N, 4×50 mL). The hexane was partially removed by evaporation, and the resultant solid was collected by filtration and re-crystallized from hexane to afford compound 70 (7.0 g, 60.6% yield). M.p. 111.0-113.3° C. 1H NMR (C6D6) δ 6.53 (s, 2H), 2.51 (t, 4H), 1.64 (m, 4H), 1.27 (m, 28H), 0.89 (t, 6H). 13C NMR: 141.26, 136.42, 133.17, 132.04, 120.73, 32.31, 30.03, 29.96, 29.90, 29.79, 29.66, 29.04, 23.07, 14.28.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 93.3 %

Procedure:
A solution of 8a (0.05 g, 0.13 mmol), benzoyl chloride (0.09 g, 0.92 mmol) and a catalytic amount of DMAP in CH2Cl2 (20 mL) was stirred at room temperature for 2 h. Absolute MeOH (15 mL) was added and the solvent was removed under reduced pressure. CH2Cl2 (25 mL) was added to the residue and the solution was washed with 10% HCl (3×20 mL) and saturated NaCl (3×20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded 13 (0.06 g, 98%) as a white solid, mp 165-170° C.; 1H NMR (CDCl3): δ 1.18 (3H, s, H-19); 1.47 (3H, s, H-20); 1.50-1.75 (4H, m, H-6β, H-7α,β and H-11β); 1.84 (1H, ddd, J=3.0, 3.0, 9.9 Hz, H-6α); 2.11 (1H, dd, J=2.4, 10.8 Hz, H-8); 2.26 (1H, s, H-10); 2.47 (2H, m, H-3α,β); 2.55 (1H, dd, J=5.1, 13.5 Hz, H-11α); 2.84 (1H, dd, J=6.9, 9.9 Hz, H-4); 3.75 (3H, s, CO2CH3); 5.40 (1H, dd, J=9.6, 10.5 Hz, H-2); 5.52 (1H, dd, J=2.1, 11.7 Hz, H-12); 6.39 (1H, dd, J=0.9, 1.8 Hz, H-14); 7.40 (1H, dd, J=1.5, 1.8 Hz, H-15); 7.42 (1H, dd, J=0.9, 1.5 Hz, H-16); 7.48 (2H, dt, J=7.2, 7.5 Hz, Ar-meta-H); 7.60 (1H, tt, J=1.2, 7.5 Hz, Ar-para-H); 8.09 (2H, dt, J=1.2, 7.2 Hz, Ar-ortho-H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(CCC2CCCO2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(CCC2CCCO2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
To an acetic acid (10 mL) solution of 4-(2-(tetrahydrofuran-2-yl)-ethyl)-benzaldehyde (565 mg, 2.77 mmol) described in Manufacturing Example 82-1-3 were added nitromethane (1.69 g, 27.7 mmol) and ammonium acetate (427 mg, 5.54 mmol) under nitrogen atmosphere at room temperature, which was stirred for 4 hours at 120° C. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (646 mg, 94%) as a crude product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH2:25])[N:9]=2)=[CH:4][CH:3]=1.F[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.C(O[K])(C)(C)C>CS(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:25][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3cccc(N)c3nc2-c2ccc(C)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: Cc1ccc(-c2nc3cccc(Nc4ccc([N+](=O)[O-])cc4)c3nc2-c2ccc(C)cc2)cc1
Reaction time: 20 h

Procedure:
While agitating 3.0 g (9.2 mmol) of 2,3-di(4-methyl-phenyl)-5-aminoquinoxaline, 1.4 g (9.9 mmol) of 4-fluoronitrobenzene and 100 ml of dimethylsulfoxide, 3.4 g (30.3 mmol) of t-butoxy potassium was gently added. After completion of the addition, the reaction container was purged with nitrogen, followed by agitation at room temperature for 20 hours. After completion of the reaction, 100 ml of water was added while cooling, and an organic phase was extracted by use of a chloroform solvent, followed by concentration to obtain the intended product.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([NH2:40])[CH:34]=1)(=O)C.Cl>O.C(O)(C)C>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:40][C:35]2[CH:34]=[C:33]([NH2:32])[CH:38]=[CH:37][C:36]=2[CH3:39])=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: Nc1c(S(=O)(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(N)cc1Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
38.2 Parts 1-amino-4-bromoanthraquinone-2-sulphonic acid are dissolved in 200 parts water/100 parts i-propanol and the pH adjusted to 8.5-9.0 with sodium carbonate. After addition of 18 parts 4-acetylamino-2-aminotoluene the mixture is warmed to 80° C. and treated with 1 part cuprous chloride and 12 parts sodium carbonate. After 4 hours the reaction is over. Finally 25 parts 30% hydrochloric acid are added to the reaction mixture, which is then heated to reflux. After 18 hours the suspension is cooled to room temperature, filtered and washed with 1% hydrochloric acid, to give 1-amino-4-(5'-amino-2'-methylphenylamino)-anthraquinone-2-sulphonic acid.
Reaction SMILES: C([NH2:4])(C)C.Cl.[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:21][CH:22]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:27]=1[F:34])[C:23](=O)[CH3:24])[C:15](OC(C)C)=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]>O.CS(C)=O>[CH3:24][C@H:23]1[NH:4][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[O:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:21][C@H:22]1[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:27]=1[F:34]
Reactant: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1cc(F)cc(F)c1F
Reactant: CC(C)N
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1NC(=O)C(NC(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1F
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of NaBO3.4H2O (1.5 g, 3.9 mmol) in H2O (18.2 g) was charged isopropylamine (1.16 g, 19.6 mmol) dropwise at 20° C. After the mixture was stirred for 30 min, the pH was adjusted to 10.2-10.3 by 6N HCl. PLP (0.042 g, 0.27 mmol) and ATA-412 (1.0 g) was charged to the solution at 20° C. After the above mixture was stirred for 1 h, a solution of 45 (2 g, 4.7 mmoL) in DMSO (10 mL) was added slowly at 20° C. The solution was heated to 55° C. and stirred for 24 h. After the reaction was complete, the reaction was quenched by isopropyl alcohol (10 mL), and then partitioned with water and IPAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-20% EtOAc/PE) to give 46 (1.45 g, 85% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.95-7.78 (m, 1H), 6.95 (m, 1H), 3.01 (t, 1H), 1.36 (s, 9H), 1.17-1.10 (br, 4H), 1.12 (m, 3H); MS (ESI) m/e [M+H]+: 359.15.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[C:18]([O:20][CH2:21][CH3:22])=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c1)=N2

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.3) (200 mg, 0.50 mmol) and commercially available 4-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 208516-15-8] (144 mg, 0.55 mmol) according to the general procedure II. Obtained as a white solid (164 mg, 63%). MS (ISP) 559.7 [(M+H)+]; mp>260° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O.[I-].[K+]>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: BrCCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCBr)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 34.6 %

Procedure:
2', 4'-dihydroxy-3'-(n-propyl)acetophenone (19.1 g), 1,4-dibromobutane (48 ml, 0.4 moles), potassium carbonate (13.8 g), and potassium iodide (50 mg) were combined in MEK (300 ml). The reaction mixture was stirred and heated to reflux temperature overnight then cooled to room temperature. The cooled solution was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The concentrate was chromatographed on a preparatory-scale HPLC (silica column) eluted with a gradient of 1 to 20% ethyl acetate in hexane to yield 11.2 g of the title product: n.m.r. (300 MHz, CDCl3) δ: 12.8 (s, 1H); 7.6 (d, 1H); 6.45 (d, 1H); 4.1 (t, 2H); 3.55 (t, 2H); 2.7 (t, 2H); 2.65 (s, 3H); 2.25 (m, 2H); 2.05 (m, 2H); 1.58 (m, 2H); 0.98 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23](Br)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[CH:25][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1OC

Procedure:
Synthesized using 3,4-dimethoxyphenylboronic acid (610 mg, 3.36 mmol) and 1a (400 mg, 1.68 mmol) according to Method C. Yellow solid. Yield: 470 mg, 1.58 mmol, 94%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.93 (s, 3H), 3.98 (s, 3H), 5.16 (s, 2H), 6.92 (br, s, 1H), 6.94 (d, J=8.5 Hz, 1H), 7.11 (bs, 1H), 7.46 (dd, J=8.5, 2.2 Hz, 1H), 7.47 (dd, J=8.5, 2.2 Hz, 1H), 7.58 (bs, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 56.0, 56.0, 113.3, 110.0, 111.1, 119.0, 119.5, 120.0, 129.4, 130.3, 131.4, 135.7, 148.4, 149.4, 150.3, 157.3; MS (ESI): m/z=296.17 [M+H]+.