Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4].[C:19]([O-:22])(=O)[CH3:20].[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:24](=[O:26])[CH3:25])=[C:13]([O:18][C:19](=[O:22])[CH3:20])[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4]
Reactant: CCCN1CCCC(c2ccc(O)c(O)c2)C1
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: [Na+]
Product: CCCN1CCCC(c2ccc(OC(C)=O)c(OC(C)=O)c2)C1

Procedure:
A suspension of 3.5 g of N-propyl-3-(3',4'-dihydroxyphenyl)-piperidine hydrobromide in 40 ml of acetic acid anhydride was stirred with 3.5 g of sodium acetate for 3 hours at 20° C and the mixture was then filtered. The filtrate was evaporated to dryness and the residue was taken up in a water-ethyl acetate mixture. The mixture was made alkaline with sodium bicarbonate addition and the organic phase was recovered by decanting. The organic phase was washed with water, dried and evaporated to dryness to obtain 3.3 g of N-propyl-3-(3',4'-diacetoxyphenyl)-piperidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][N:20](C)[CH3:21])#[N:2].[Cl:23][C:24]([Cl:31])([Cl:30])[CH2:25][O:26][C:27](Cl)=[O:28]>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[CH:17][CH2:18][CH2:19][N:20]([CH3:21])[C:27]([O:26][CH2:25][C:24]([Cl:31])([Cl:30])[Cl:23])=[O:28])#[N:2]
Reactant: CN(C)CCC=C1c2ccccc2CCn2cc(C#N)cc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN(CCC=C1c2ccccc2CCn2cc(C#N)cc21)C(=O)OCC(Cl)(Cl)Cl

Procedure:
2-Cyano-6,11-dihydro-11-(3-dimethylaminopropylidene)-5H-pyrrolo[2,1-b][3]benzazepine (5 g., 17.2 mmoles) and 2,2,2-trichloroethylchloroformate (4 g., 18.8 mmoles) in 100 ml. benzene were refluxed for 18 hours. The mixture was poured onto water, washed with dilute hydrochloric acid and then with water, dried over sodium sulfate and concentrated under vacuum to yield 7.1 g. of dark red oil. It was adsorbed on 250 g. silica gel and eluted with 2 liters benzene. The eluate was discarded.
Reaction SMILES: C(OC([C:11]1[NH:12][C:13]2[CH2:14][CH2:15][C:16]([CH3:23])([CH3:22])[C:17](=[O:21])[C:18]=2[C:19]=1[CH3:20])=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:20][C:19]1[C:18]2[C:17](=[O:21])[C:16]([CH3:23])([CH3:22])[CH2:15][CH2:14][C:13]=2[NH:12][CH:11]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)[nH]c2c1C(=O)C(C)(C)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2c1C(=O)C(C)(C)CC2
Reaction time: 0.5 h

Procedure:
3,5,5-trimethyl-4-oxo-4,5,6,7-tetrahydroindole-2-carboxylic acid benzyl ester from the previous step, 6.60 g (21.20 mmol) and 2.0 g of 10% Pd—C was suspended in ethyl acetate 150 mL and hydrogenated under balloon of hydrogen for 3 hours. The reaction mixture was diluted with methanol 0.5 L and the mixture was stirred under Ar for 30 min to dissolve the precipitated carboxylic acid intermediate. The catalyst was then removed by filtration and the filtrates were evaporated to dryness and dried on highvac. The residue was dissolved in trifluoroacetic acid 40 mL, the solution was stirred on a 45° C. bath for 30 min, then evaporated to dryness. The residue was dried on highvac. The crude material was applied onto a column of silica (60 g) in dichloromethane and eluted with 10:1 dichloromethane-ethyl acetate mixture. Y=3.17 g (84% overall) of 3,5,5-trimethyl-4-oxo-4,5,6,7-tetrahydroindole as a white solid that gradually turns pink on air and light. 1H-NMR (d6-DMSO, 400 MHz): 10.89 (br s, 1H), 6.44 (s, 1H), 2.72 (t, 6.3 Hz, 2H), 2.12 (s, 3H), 1.85 (t, 6.3 Hz, 2H), 1.04 (s, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc21
Yield: 50 %

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide to yield an off-white solid, 2-[5-Chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide (50%). LCMS: m/z=543.51 (M+H+), 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.52 (d, 1H, J=8.6 Hz), 8.17 (s, 1H), 7.88 (d, 1H, J=8.1 Hz), 7.68 (s, 1H), 7.50 (m, 1H), 7.28 (m, 4H), 3.68 (m, 2H), 2.76 (s, 6H), 2.34 (m, 2H), 2.05 (m, 2H), 1.35 (s, 2H), 1.16 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[Br:44][C:45]1[CH:46]=[C:47]([C@H:51]([NH2:53])[CH3:52])[CH:48]=[CH:49][CH:50]=1>C(Cl)(Cl)Cl>[Br:44][C:45]1[CH:46]=[C:47]([C@H:51]([NH:53][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([CH3:24])[C:18]=2[CH3:23])=[O:42])[CH3:52])[CH:48]=[CH:49][CH:50]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](N)c1cccc(Br)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4cccc(Br)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (79 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (34 mg, yield 26%).
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[O:13][CH:14]=[C:15]([C:17]2([OH:20])[CH2:19][CH2:18]2)[N:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>N1C=CC=CC=1.CC(=O)OCC>[C:21]([O:20][C:17]1([C:15]2[N:16]=[C:12]([CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4])[O:13][CH:14]=2)[CH2:18][CH2:19]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(C2(O)CC2)co1
Reactant: CC(C)(C)C(=O)Cl
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OC1(c2coc(CO[Si](C)(C)C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-4-yl)cyclopropanol (509 mg, 1.89 mmol) in pyridine (2.0 mL) was treated with pivaloyl chloride (0.28 mL, 2.27 mmol) and the reaction mixture was stirred at rt overnight. Sat. aq. NH4Cl (10 mL) was added followed by EA (10 mL). The org. layer was washed with a CuSO4 sol. (2×15 mL) followed by brine (10 mL). The layers were separated and the org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (9:1 hept-EA) gave the title compound as a colorless oil: TLC: rf (9:1 hept-EA)=0.35. LC-MS-conditions 06: tR=1.19 min, [M+H]+=354.18.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH3:8])(=O)C.[C:9]([O:12][CH2:13]C=C)(=[O:11])[CH3:10]>>[CH2:5]([OH:4])[CH:6]=[CH:7][CH3:8].[C:9]([O:12][CH3:13])(=[O:11])[CH3:10]
Reactant: CC=CCOC(C)=O
Reactant: C=CCOC(C)=O
Product: CC=CCO
Product: COC(C)=O
Yield: 88 %
Yield: 85 %

Procedure:
The tube, catalyst and general procedure described in Example I were employed, with 57.0 g of crotyl acetate substituted for the allyl acetate. The effluent in this case was composed of 12.5 g of unconverted crotyl acetate (22% recovery), 24.7 g of crotyl alcohol (88% yield based on 78% conversion), 24.5 g of methyl acetate (85% yield) and the excess methanol.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]1[C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19][CH3:20])[CH:17]=2)[CH:12]=[C:11]1[C:21](=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CSc1ccc2cc(C(=O)C(C)C)n(CCNC(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1ccc2cc(C(=O)C(C)C)n(CCN)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 143.4 %

Procedure:
To a solution of tert-butyl(2-(2-isobutyryl-6-(methylthio)-1H-indol-1-yl)ethyl)carbamate (200 mg, 0.53 mmol) in CH2Cl2 (9 mL) at 0° C. was added TFA (1 mL). The reaction mixture was stirred at rt for 1 h. The mixture was concentrated (T<25° C.), treated with water (5 mL), adjusted to pH=11 with sat. NaHCO3 and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated to afford 1-(1-(2-aminoethyl)-6-(methylthio)-1H-indol-2-yl)-2-methylpropan-1-one (210 mg, 100% yield) as a colorless oil. LC-MS MS (ESI) m/z 258.8 [M-18+H]+.
Reaction SMILES: CC(C)=O.C(OCC)C.[CH3:10][C@H:11]1[CH2:94]O[C@@:14]2(O[C@H:17]3[C@@H:19](O)[C@H:20]4[C@@H:25]5[CH2:26][CH2:27][C@H:28]6[CH2:33][C@@H:32]([O:34][C@@H]7O[C@H](CO)[C@H](O[C@@H]8O[C@H](CO)C(O)[C@H](O[C@@H]9OC[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O[C@@H]8O[C@H](CO)[C@H](O)[C@H](O[C@@H]9O[C@H](CO)[C@@H](O)[C@H](O)[C@H]9O)[C@H]8O)[C@H](O)[C@H]7O)[C@H:31](O)[CH2:30][C@:29]6([CH3:89])[C@H:24]5[CH2:23][CH2:22][C@:21]4([CH3:90])[C@H:16]3[C@@H:15]2[CH3:92])[CH2:13][CH2:12]1>C(O)C>[CH3:94][CH:11]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:16]1[C@:21]2([CH3:90])[C@H:20]([C@H:25]3[C@H:24]([CH2:23][CH2:22]2)[C@:29]2([CH3:89])[C:28]([CH2:33][C@H:32]([CH2:31][CH2:30]2)[OH:34])=[CH:27][CH2:26]3)[CH2:19][CH2:17]1)[CH3:92])[CH3:10]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1[C@@H](O)[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[C@@H]6O[C@H](CO)[C@H](O[C@@H]7O[C@H](CO)C(O)[C@H](O[C@@H]8OC[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O[C@@H]7O[C@H](CO)[C@H](O)[C@H](O[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The whole mixture was incubated at 37° C. for 90 minutes, then the reaction was terminated by adding 1 mM of 15%-KOH (a 95% ethanol solution), next 2 mg of cholesterol was added thereto, saponified at 75° C. for 1 hour, and cholesterol was extracted with petroleum ether, the extract was concentrated to dryness. To the residue thus obtained was added with 2.5 ml of a mixture of acetone-diethyl ether (1:1) and 2.5 ml of 1%-digitonin (a 50% ethanol solution), then this solution was allowed to stand for 1 hour in cooling condition by using ice-water to precipitate cholesterol. The precipitate was washed with acetone, a mixture of acetonediethyl ether (1:1) and diethyl ether in this order, then the radioactivity of the residue was measured by using a liquid scintillation counter.
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[NH:17][C:18]1[CH:19]=[N:20][N:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([NH:29][CH3:30])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][N:21]([C@H:23]4[CH2:28][CH2:27][C@H:26]([NH:29][CH3:30])[CH2:25][CH2:24]4)[CH:22]=2)=[CH:3][C:2]([C:36]2[CH:37]=[C:32]([Cl:31])[C:33]([OH:48])=[C:34]([Cl:47])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1

Procedure:
Following general procedure F, {6-bromo-4-[1-(trans-4-(methylamino)cyclohexyl)-1H-pyrazol-4-ylamino]quinolin-3-yl}(cyclopropyl)methanone (60 mg, 0.128 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (55 mg, 0.192 mmol) to afford the desired product (17 mg, 24%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6+TFA-d) δ 8.95-8.65 (br s, 1H), 8.63-8.51 (m, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.02-7.97 (m, 1H), 7.54 (s, 1H), 4.26 (m, 1H), 3.11-3.02 (m, 1H), 2.60 (s, 3H), 2.20-2.08 (m, 4H), 1.88-1.76 (m, 2H), 1.58-1.46 (m, 2H), 1.00-0.76 (m, 4H); ESI MS m/z 550 [C29H29Cl2N5O2+H]+; HPLC 98.4% (AUC), tR=11.56 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:6][CH2:7][CH2:8][CH2:9]Br.[H-].[Na+]>C1COCC1>[Br:6][CH2:7][CH2:8][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: BrCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a stirred solution of imidazole (500 mg, 7.35 mmol) and 1,3-dibromopropane (2.2 mL, 22.0) in THF (35 mL) was added 60% NaH (356 mg, 8.82 mmol), and the resultant mixture was refluxed for 1 h and stirred at room temperature overnight. The mixture was quenched with H2O (25 mL) and diluted with CH2Cl2 (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 97:3) provided 1-(3-Bromo-propyl)-1H-imidazole (410 mg, 30%) as a colorless oil. 1H NMR (CDCl3) δ 2.20-2.34 (m, 2H), 3.31 (t, 2H, J=6.3 Hz), 4.16 (t, 2H, J=6.2 Hz), 6.93 (s, 1H), 7.08 (s, 1H), 7.51 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.F[C:43]1[C:51]([N+:52]([O-:54])=[O:53])=[C:50]([N+]([O-])=O)[C:49]([N+:58]([O-:60])=[O:59])=[CH:48][C:44]=1[C:45]([OH:47])=[O:46].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:30]1[C@H:31]2[O:32][CH2:33][CH2:34][C@H:35]2[C@@H:28]([O:27][C:26]([NH:25][C@H:16]([C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:48]3[C:49]([N+:58]([O-:60])=[O:59])=[CH:50][C:51]([N+:52]([O-:54])=[O:53])=[CH:43][C:44]=3[C:45]([OH:47])=[O:46])=[CH:20][CH:19]=2)=[O:36])[CH2:29]1
Reactant: O=C(O)c1cc([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c1F
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(Oc2c(C(=O)O)cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 59 mg (0.1 mMol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate, 50 of 2-fluoro-3,5-dinitronitrobenzoic acid and 65 mg (0.2 mMol) of cesium carbonate in 0.5 mL of dimethyl formamide was stirred at rt for 2 h. The mixture was diluted with ethyl acetate and extracted with 1N HCl. Evaporation of the solvent and chromatography on silica gel (5% methanolic ammonia in dichloromethane) gave the title compound (25 mg) as a yellow foam. H NMR: 0.82(6H,dd), 1.42(1H,m), 1.63(1H,m), 1.90(2H,m), 2.46(1H,dd), 2.8(1H,dd), 2.82-3.02(5H,m), 3.2(1H,m), 3.6-3.95(6H,m), 4.94(1H,q), 5.58(1H,d), 6.02(2H,s), 6.61(1H,d), 6.75(2H,d), 6.82(1H,d), 7.05(2H,d), 7.3(1H,d), 7.45(1H,s), 8.6(2H,ss).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][N:21]([CH3:37])[C:22]2[N:31]=[C:30]([NH2:32])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:33][CH3:34])[CH:28]=3)[N:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O.[Pd]>[CH3:34][O:33][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:35][CH3:36])[N:23]=[C:22]([N:21]([CH2:20][C:11]1([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:37])[N:31]=[C:30]2[NH2:32]
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(Cc4ccccc4)CC3)nc(N)c2cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Yield: 75.1 %

Procedure:
To a solution of N2-(1-Benzyl-4-phenyl-piperidin-4-ylmethyl)-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine 10, (1.3 g) and ammonium formate (2.2 g) in 24 ml methanol and 6 ml water was added 10% Pd-C (250 mg). After stirring under reflux for two hours, the reaction mixture was cooled and filtered through celite®. The filtrate was concentrated to a small volume, made basic with potassium carbonate, and extracted with dichloromethane. The extract was dried over potassium carbonate, filtered, and evaporated. The residue was chromatographed on silica gel to provide 800 mg of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 as a white powder, MS: 407 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([O:26][CH2:27][O:28][CH3:29])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:30]=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([O:26][CH2:27][O:28][CH3:29])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[C:10]([CH2:30][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C=O
Reactant: C1CCNC1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5cnn(C)c5)cc34)s2)CCC1
Solvent: CC(=O)O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5cnn(C)c5)c(CN5CCCC5)c34)s2)CCC1
Temperature: 75 °C

Procedure:
A solution of Example 47B (0.034 g, 0.079 mmol) in 0.8 mL acetic acid was treated with formalin (0.035 mL, 0.475 mmol) and pyrrolidine (0.039 mL, 0.475 mmol). The reaction was heated at 75° C. for 1 hour. Additional pyrrolidine (0.163 mL, 1.98 mmol) was added, and the reaction was heated at 75° C. for 6 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The concentrate was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. ESI(+) m/z 513.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:7]1[NH:6][C:5]2[CH:10]=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 90 %

Procedure:
Thoroughly dried 5,6-dichloro-1,3-dihydro-benzoimidazol-2-one (28.4 g, 0.14 mol) was suspended in POCl3 (75 mL). The reaction solution was heated to reflux temperature for 3 hours and cooled to room temperature. The solution was poured into crushed ice/water (1.5 L) slowly with sufficient stirring. The solution was neutralized to pH=7.0 with NaOH. The precipitated solid was collected by filtration, washed with water, and dried to afford the title compound (27.9 g, 90%). The crude product was used in the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([I:12])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([I:12])[C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(I)ccc(Cl)c1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(I)ccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
DMF (one drop) was added to a stirred solution of 2,3-dichloro-6-iodobenzoic acid (1.53 g, 4.83 mmol) and oxalyl chloride (2 ml) in ethyl acetate (20 ml). After 2 hours, the solution was evaporated and the product was used immediately.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([O:18][CH:19]([CH3:21])[CH3:20])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1)C(OO)=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([C:5]1[N:6]([O:18][CH:19]([CH3:20])[CH3:21])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:27])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2cnc3cccnc3c2n1OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3cccnc3c2n1OC(C)C
Temperature: 0 °C
Yield: 99.9 %

Procedure:
A solution of 2-butyl-1-isopropoxy-1H-imidazo[4,5-c][1,5]naphthyridine (0.40 g, 1.4 mmol) in dichloromethane (25 mL) was cooled to approximately 0° C., and 3-chloroperoxybenzoic acid (0.42 g of approximately 77% pure material, 1.9 mmol) was added. The reaction was stirred for ten minutes at 0° C., stirred for 1.5 hours at room temperature, and then stirred with saturated aqueous sodium bicarbonate (25 mL) for 15 minutes. The organic layer was separated and dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 0.42 g of 2-butyl-1-isopropoxy-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:15][O:16][CH3:17]>C1COCC1.CN(C)C=O>[CH3:15][O:16][CH2:17][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Oc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCOc1cccnc1
Temperature: -15 °C

Procedure:
Dissolve 3-hydroxypyridine (7 g, 74 mmol) in THF (20.6 mL) and dimethylformamide (34.4 mL) and cool to −15° C. Add potassium tert-butoxide (8.3 g, 74 mmol) and stir at −15° C. for 30 min. Treat the mixture with chloromethylmethyl ether (5.81 mL, 77 mmol) dropwise over 40 min. After the addition is complete, stir the mixture at −15° C. for an additional hour. Remove the ice bath and allow the mixture to warm slowly to 15° C. Pour the mixture into saturated aqueous sodium chloride and stir vigorously for 10 min. Extract the resulting solution with three portions of ethyl acetate. Combine the organic extracts and wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate in vacuo. Use the resulting product without further purification. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=3 Hz, 1H), 8.28 (d, J=5 Hz, 1H), 7.37-7.42 (m, 1H), 7.21-7.27 (m, 1H), 5.20 (s, 2H), 3.49 (s, 3H).