Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)C1C=CC=CC=1.C(O)=O>C(O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To a stirring solution of 110 mg (0.17 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 15 mL of a 10% solution of formic acid in absolute ethanol is added 100 mg of 10% palladium on carbon. The resulting black suspension is heated at reflux for 24 h, then cooled to RT. The reaction mixture is filtered through Celite to remove the catalyst and the solvent removed in vacuo. Purification of the residue by gradient silica gel flash column chromatography using hexane/EtOAc 3/2 up to 2/3 as eluent followed by further purification via reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2O as eluent and lyophilization afforded 62 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.81 (d, 1H, J=8.0), 7.41-6.90 (m, 17H), 5.00 (m, 1H), 4.23 (m, 3H), 3.84 (s, 3H), 3.79 (d, 1H, J=7.9), 3.61 (dd, 1H, J=5.8, 16.1), 1.06 (m, 6H); low resolution MS (FAB)m/e 588 (MH+), 423, 223; Anal. (C35H33N5O4.H2O) Calcd. C, 70.45; H, 5.91; N, 11.74 Found C, 70.62; H, 5.76; N, 11.78.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](=O)[CH3:12].C[S-].[Na+].IC>C(O)C>[Br:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[CH:10][C:11]([CH3:12])=[N:1]2)=[CH:4][N:5]=1
Reactant: CC(=O)/C=C/c1cnc(Br)cc1N
Agent: C[S-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: Cc1ccc2cnc(Br)cc2n1
Reaction time: 0.75 h
Yield: 90 %

Procedure:
(E)-4-(4-Amino-6-bromopyridin-3-yl)but-3-en-2-one (Preparation 66, 331 mg 1.37 mmol) and sodium thiomethoxide (97.5 mg 1.39 mmol) were stirred in ethanol (2.9 mL) at 20° C. for 50 minutes. Iodomethane (86 uL, 1.38 mmole) was added and the reaction stirred for another 45 minutes. The reaction was concentrated in vacuo and diluted with ethyl acetate (30 mL) and washed with water (10 mL). The aqueous was back extracted with ethyl acetate (5 mL) and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound (275 mg, 89%).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([I:29])=[N:23][C:24]=3Cl)[O:7]1)(=O)C.[NH3:30]>>[NH2:30][C:24]1[N:23]=[C:22]([I:29])[N:21]=[C:20]2[C:25]=1[N:26]=[CH:27][N:19]2[C@H:8]1[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@@H:6]([CH2:5][OH:4])[O:7]1
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@H](O)[C@H]1O
Reaction time: 6 h
Yield: 80 %

Procedure:
To a flask containing 6.0 g (11.1 mmol) [(2R,3R,4R,5R)-3,4-diacetyloxy-5-(6-chloro-2-iodopurin-9-yl)oxolan-2-yl]methyl acetate (6.4) was added 100 ml of liquid NH3 at −78° C. and the solution was allowed to stir for 6 hours. After which time it was allowed to come to r.t. overnight with concurrent evaporation of the NH3 to yield a brown oil. The product was crystallized from hot isopropanol to give 6.5 (80%), m.p. 143-145° C., r.f.=0.6 in 20% MeOH/CHCl3. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.68 (s, 2H), 5.75 (d, J=6.16, 1H), 5.42 (d, J=5.40 Hz, 1H), 5.16 (d, J=4.62 Hz, 1H), 4.99 (t, J=5.39 Hz, 1H), 4.67 (d, J=4.81 Hz, 1H), 4.06 (d, J=3.37 Hz, 1H), 3.89 (m, 1H), 3.54 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1)(=[O:19])[CH3:18]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-piperidin-4-yl-1,3-dihydro-benzimidazol-2-one (0.2 g, 0.9 mmol) and acetic anhydride (0.2 ml, 2 mmol) was dissolved in acetic acid (5 ml) and stirred at room temperature for 30 minutes, then added water (10 ml) and evaporated to and oil. This was crystallized from ethanol (96%). Yield 0.18 g (0.7 mmol, 77 %). M.p. 212-214° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
12.2 g of 1,3-benzodioxole were placed in 75 ml of glacial acetic acid in a 250 ml sulfonation flask equipped with stirrer, thermometer and dropping funnel and then nitrated at 15°-25° C. by the dropwise addition of 9 ml of nitric acid (d=1.4) in 30 ml of glacial acetic acid. The mixture was stirred at room temperature overnight, the precipitated crystals were removed by filtration under suction, washed with water and recrystallized from alcohol. There were obtained 14.0 g of 5-nitro-1,3-benzodioxole of melting point 149°-150° C. and from the mother liquor an additional 2.0 g of melting point 148°-149° C. Total yield: 90.6% of theory.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]2[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]1=[O:11].C1C(=O)N([Br:19])C(=O)C1>C(#N)C>[Br:19][C:6]1[C:5]2[CH2:8][CH2:9][CH2:10][C:4]=2[C:3](=[O:11])[N:2]([CH3:1])[CH:7]=1
Reactant: Cn1ccc2c(c1=O)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cn1cc(Br)c2c(c1=O)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
The title compound of step 6 (140 mg, 1.04 mmol) was dissolved in ACN (5 mL) and NBS (188 mg, 1.06 mmol) was added. After stirring at rt for 1.5 h, purification by silica gel chromatography (PE/EtOAc=1:1) gave the title compound (196 mg, 89.5%) as a white solid. 1H NMR (CD3Cl, 300 MHz): δ 7.33 (s, 1H), 3.53 (s, 3H), 2.85-2.97 (m, 4H), 2.05-2.13 (m, 2H). LCMS: 228, 230 (M+1)+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:11]1([C:10]2[CH:9]=[N:8][N:6]3[CH:7]=[C:2]([C:22]4[CH:23]=[CH:24][C:19]([CH:17]=[O:18])=[CH:20][CH:21]=4)[CH:3]=[N:4][C:5]=23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1cnc2c(-c3ccccc3)cnn2c1
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: [Na+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1

Procedure:
A deoxygenated solution of 6-bromo-3-phenylpyrazolo[1,5-a]pyrimidine (1-3, 2.00 g, 7.30 mmol, 1 equiv), 4-formylphenylboronic acid (1-4, 1.65 g, 11.0 mmol, 1.51 equiv), aqueous sodium carbonate solution (6.00 mL, 12.0 mmol, 1.64 equiv), and tetrakis(triphenylphosphine)palladium (0.420 g, 0.363 mmol, 0.0500 equiv) in dioxane (100 mL) was heated at reflux for 20 hours. The reaction mixture was partitioned between aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was suspended in methanol (100 mL) and filtered to give 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde (1-5) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ10.11 (s, 1H), 8.93 (d, 1H, J=2.4 Hz), 8.87 (d, 1H, J=2.2 Hz), 8.51 (s, 1H), 8.07 (m, 2H), 7.81 (br d, 2H, J=7.8 Hz), 7.49 (br t, 2H, J=7.7 Hz), 7.32 (t, 1H, J=7.5 Hz).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14]1[O:18][C:17]([C:19]([NH:21][C:22]2[CH:39]=[CH:38][C:25]([O:26][C@@H:27]3[CH2:32][CH2:31][C@H:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]3)=[CH:24][CH:23]=2)=[O:20])=[N:16][N:15]=1.O.CO>C1COCC1>[F:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14]1[O:18][C:17]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][C@@H:27]3[CH2:28][CH2:29][C@H:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[CH:38][CH:39]=2)=[O:20])=[N:16][N:15]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1)c1nnc(Nc2cc(F)c(F)cc2F)o1
Temperature: 35 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
Lithium hydroxide monohydrate (184 mg, 4.38 mmol) was added in one portion to a solution of ethyl cis-4-{4-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]-phenoxy}cyclohexanlecarboxylate (Example 645, 221 mg, 0.44 mmol) in a mixture of THF (4 mL), H2O (4 mL) and MeOH (8 mL) and the reaction mixture was stirred at 35° C. for 3 h. The reaction mixture was concentrated in vacuo and citric acid (40 mL) was added. The resulting mixture was filtered, washed with H2O and recrystallised from ethanol/H2O to give the title compound as a pale yellow solid (118 mg, 56%); 1H NMR δ 1.66-1.70 (4H, m), 1.75-1.83 (4H, m), 2.33-2.40 (1H, m), 4.50 (1H, s), 6.96 (2H, d), 7.67-7.74 (3H, m), 8.17 (1H, q), 10.95 (1H, s), 11.10 (1H, s), 12.05 (1H, s); MS m/e (M−H)− 475. The compound may be further recrystallised from EtOH, melting point 251-253° C.
Reaction SMILES: C([C:5]1[C:6](=O)[NH:7][CH2:8][C:9](=[O:20])[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=12)(C)(C)C.O=P(Cl)(Cl)Cl.[CH3:27][O:28][CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1>ClCCCl.C(Cl)Cl>[C:12]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH2:19][N:10]1[C:9](=[O:20])[CH2:8][N:7]=[C:6]([N:33]3[CH:34]=[C:30]([CH2:29][O:28][CH3:27])[N:31]=[CH:32]3)[CH:5]=[C:11]12)([CH3:17])([CH3:13])[CH3:11]
Reactant: COCc1c[nH]cn1
Reactant: CC(C)(C)C1=C2c3ccccc3CCN2C(=O)CNC1=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCc1cn(C2=NCC(=O)N3CCc4c(cccc4C(C)(C)C)C3=C2)cn1
Temperature: 110 °C
Yield: 33.7 %

Procedure:
Example 125. A solution of -(tert-butyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (370 mg, 1.30 mmol) in DCE (20 mL) was treated with POCl3 (0.24 mL, 2.60 mmol) and the mixture was heated to 110° C. for 1 h. The mixture was then allowed to cool to RT, diluted with DCM and washed with H2O. The org. phase was then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (20 mL) and 4-(methoxymethyl)-1H-imidazole (438 mg, 3.90 mmol) was then added. The mixture was heated to 110° C. for 1 h, and then allowed to cool to RT, diluted with DCM and washed with H2O. The org. layer was then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) and SFC (column: PPU 5 μm, 250×30 mm, 60 A, Princeton; eluent: isocratic 5% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) gave the title compound (83 mg). UPLC-MS: MS 379.2 (M+H+); UPLC rt 1.04 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.38 (s, 9 H); 3.10-3.20 (m, 2 H); 3.22 (br s, 3 H); 3.63 (m, 2 H); 4.25 (m, 4 H); 6.86 (d, J=1.96 Hz, 1 H); 7.31 (s, 1 H); 7.49 (d, J=8.21 Hz, 1 H); 7.54-7.69 (m, 2 H); 8.17 (d, J=1.56 Hz, 1 H).
Reaction SMILES: [Cl: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[CH2:14][C:15]#[N:16].[NH2:17][OH:18]>C(O)C>[Cl: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[CH2:14][C:15]([NH:17][OH:18])=[NH:16]
Reactant: NO
Reactant: N#CCc1ccccc1-c1ccccc1Cl
Solvent: CCO
Product: N=C(Cc1ccccc1-c1ccccc1Cl)NO
Temperature: 60 °C
Yield: 91.7 %

Procedure:
To a stirred solution of (2′-chloro-biphenyl-2-yl)-acetonitrile (15) (2 g, 8.78 mmol) in ethanol (20 mL) was added aqueous hydroxylamine (50%) (1.16 g, 17.8). The mixture was heated to 60° C. for 16 h. After completion of the reaction, the reaction mixture was evaporated, extracted with ethyl acetate and concentrated to get 2-(2′-chloro-biphenyl-2-yl)-N-hydroxy-acetamidine (16) (2.1 g, 91.7%) as an off-white solid which was directly used in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13]C1N=CC=CC=1C#N.C(O)(=O)C(C)(C)C.OS(O)(=O)=O>[N+]([O-])([O-])=O.[Ag+]>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:13])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C#N)cn1
Reactant: Cc1ncccc1C#N
Agent: [Ag+]
Agent: CC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1nc(C(C)(C)C)ccc1C#N

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 6-tert-butylnicotinonitrile starting from 2-methyl-nicotinonitrile (intermediate 30) (216 mg, 1.7 mmol), pivalic acid (868 mg, 8.5 mmol), AgNO3 (38.5 mg, 0.23 mmol), (NH4)2S2O8 (504 mg, 2.2 mmol) and 3.75 ml 10% H2SO4. Purification by normal phase chromatography with 100% heptane to 90/10 Heptane/EA yielded 240 mg of a mixture of both mono and di-t-butylated pyridines. Material used crude in the preparatin of [1-(6-tert-butyl-2-methylpyridin-3-yl)ethyl]amine (intermediate 32) below.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH2:15])[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH:15][CH:18]([CH:20]2[CH2:22][CH2:21]2)[CH3:17])[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)C1CC1
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)C)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NC(C)C1CC1)C(=O)Nc1ncc(C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide (150 mg, 0.54 mmol) and cyclopropyl methyl ketone(45 mg, 0.54 mmol)in 10 mL of methylene chloride and 5 drops of acetic acid was treated with sodium triacetoxyborohydride (172 mg, 0.8 mmol) and stirred at room temperature overnight. The mixture was quenched with dilute ammonium hydroxide and extracted with methylene chloride. The organic layer was separated and concentrated to dryness. The residue was purified by HPLC to give 2-(S)-(1-cyclopropyl-ethylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide as a colorless oil, LC-MS RT=1.4 min, M+1=310.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[C:6]1[CH:45]=[CH:44][C:9]([CH2:10][N:11]([CH2:25][C:26]2[CH:43]=[CH:42][C:29]3[N:30]([CH2:40][CH3:41])[C:31](=[O:39])[C:32]([CH3:38])([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:28]=3[CH:27]=2)[CH2:12][CH2:13][N:14]2[CH:19]=[CH:18][C:17]3[O:20][C:21]([CH3:23])=[CH:22][C:16]=3[C:15]2=[O:24])=[CH:8][CH:7]=1)C.[OH-].[Na+]>C1COCC1>[CH2:40]([N:30]1[C:31](=[O:39])[C:32]([CH3:38])([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:28]2[CH:27]=[C:26]([CH2:25][N:11]([CH2:10][C:9]3[CH:44]=[CH:45][C:6]([CH:5]=[O:4])=[CH:7][CH:8]=3)[CH2:12][CH2:13][N:14]3[CH:19]=[CH:18][C:17]4[O:20][C:21]([CH3:23])=[CH:22][C:16]=4[C:15]3=[O:24])[CH:43]=[CH:42][C:29]1=2)[CH3:41]
Reactant: CCOC(OCC)c1ccc(CN(CCn2ccc3oc(C)cc3c2=O)Cc2ccc3c(c2)N(C)C(=O)C(C)(C)C(=O)N3CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccc(C=O)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A 2N-hydrochloric acid (5 ml) was added to an THF solution (5 ml) of 7-({N-(4-diethoxymethylbenzyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)-1-ethyl-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.52 g), and the mixture was stirred at room temperature for 1 hour. 2N-Sodium hydroxide solution(5 ml) was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. The residue was recrystallized from ethyl acetate and ether, and dried to give the title compound(0.35 g) as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].CCN(CC)CC.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21](=[O:22])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCO)C(=O)OCc1ccccc1
Yield: 75.6 %

Procedure:
A solution of 20.0 g (266.3 mmol) of 2-(methylamino)ethanol was dissolved in 100 mL of CH2Cl2 and treated first with 74.23 mL (532.54 mmol, 2 eq) of Et3N then with 33.8 mL (239.64 mmol, 0.9 eq) of benzylchloroformate within a period of 1.5 h at RT. The reaction was partitioned between Et2O (×3)/aqueous 10% KHSO4 (×2), dried over Na2SO4 and evaporated to yield 37.93 g (68%) of (2-hydroxy-ethyl)-methyl-carbamic acid benzyl ester, MS: 210 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=2O)[N:5]=[CH:4][CH:3]=1.[OH-].[NH4+].P(Cl)(Cl)([Cl:22])=O>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=2[Cl:22])[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Cl
Yield: 69 %

Procedure:
A solution of the 5-hydroxyquinoline IV (5.25 g, 0.022 mol) in phosphorus oxychloride (75 mL) was heated at 80° for 2 hours. The reaction mixture was poured onto ice and basified with excess ammonium hydroxide. The tan solid was filtered to give 5.8 g of crude product. This material was purified via column chromatography over silica gel and elution with chloroform. The fast-moving yellow band was collected and concentrated to give 3.9 g (69%) of the title compound, mp 167°-169°. Crystallization from ethanol did not raise the melting point. The crude material can also be purified by sublimation.
Reaction SMILES: CN(C=O)C.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:14]([Si](OC)(OC)OC)=[CH2:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O>[C:7]1([CH:6]([OH:13])[CH:14]=[CH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C=C[Si](OC)(OC)OC
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a DMF (0.2 mL) solution of CuF.3PPh3.2EtOH (10 mg, 0.01 mmol) as synthesized according to the method described in the foregoing publication and dppf (8 mg, 0.014 mmol) (this catalyst preparation method is designated as “A”; hereinafter the same), benzaldehyde (0.020 mL, 0.20 mmol) and vinyltrimethoxysilane (62 μL, 0.40 mmol) were added at room temperature under an argon atmosphere, the temperature was then raised to 60° C., and the mixture was stirred for 3 hours. Thereafter, the reaction mixture was allowed to stand for cooling to room temperature, to which was then added tetrabutylammonium fluoride (TBAF) (1M/THF, 0.5 mL), and the mixture was stirred for 10 minutes. After adding water, the mixture was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane: 1/9 to 1/4), thereby obtaining desired 1-phenyl-2-propen-1-ol in a yield of 100%.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)#[N:4].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl.O>CN(C)C=O>[C:3]([C:5]1([CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)#[N:4]
Reactant: CN(C)CCCl
Reactant: N#CC1c2ccccc2COc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCC1(C#N)c2ccccc2COc2ccccc21
Yield: 42 %

Procedure:
Sodium hydride (5.0 g; 0.10 mole) is added portionwise with cooling (5°-10° C.) under a nitrogen atmosphere to a solution of 11-cyano-6,11-dihydrodibenz[b,e]oxepin of Example 1A, (20.0 g; 0.09 mole) in dry DMF (200 ml). After thirty minutes, effervescence ceases and 2-dimethylaminoethyl chloride (10.0 g; 0.09 mole) in dimethyl formamide [DMF] (200 ml) is added dropwise. Stirring is continued at 80° C. for sixteen hours. The reaction is cooled and poured into three liters of water. After extraction with ether, the ether is re-extracted with 1 N HCl, and the combined aqueous extracts are made basic with 50% NaOH. After extracting with ether and drying (K2CO3), the solvent is removed in vacuo to provide an oil which is chromatographed on an alumina column. The resulting oil crystallizes upon standing and trituration with hexane yields 11.0 g (42%) of a solid of 11-cyano-11-[2-(dimethylamino)ethyl]-6,11-dihydrodibenz[ b,e]oxepin (m.p. 63°-65° C.),
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10]>C(O)(=O)C>[Br:1][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([F:3])[CH:9]=1
Reactant: BrBr
Reactant: Oc1ccccc1F
Solvent: CC(=O)O
Product: Oc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Bromine (68.7 ml, 1.339 mol) dissolved in acetic acid (300 ml) was added drop by drop to a cooled solution of 2-fluorophenol (150 g, 1.339 mol) in acetic acid (1300 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with aq. sodium bisulfite solution and extracted with dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded 4-bromo-2-fluorophenol (210 g) as a liquid. This was directly taken for next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[C:8]([CH2:47][CH2:48][CH3:49])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:26]=[N:25][N:24]=4)=[CH:13][CH:12]=3)[C:5]=2[C:4]([CH3:50])=[N:3]1.O>CC(O)=O>[CH3:1][N:2]1[C:6]2[N:7]=[C:8]([CH2:47][CH2:48][CH3:49])[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[NH:24][N:25]=[N:26][N:27]=4)=[CH:15][CH:16]=3)[C:5]=2[C:4]([CH3:50])=[N:3]1
Reactant: CCCc1nc2c(c(C)nn2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2c(c(C)nn2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 2 h
Yield: 67.7 %

Procedure:
The material prepared in Step E (160 mg, 0.24 mmol) was dissolved in glacial HOAc (2.0 mL) at 50° C. and H2O was added dropwise until the solution just became cloudy (approx. 0.7 mL). The mixture was kept at 50° C. for 2 hours and then was evaporated to dryness under a stream of nitrogen. The residue so formed was purified by preparative tlc on 1000μ SiO2 plates developed with CHCl3 /MeOH/NH4OH (80:20:2) to give 67 mg (68%) of the title compound as its ammonium salt.