Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=O)[NH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:16])=O.N1C=CC=CC=1.O>C(#N)C>[Cl:16][C:5]1[O:6][C:2]([CH3:1])=[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1oc(=O)[nH]c1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: Cc1oc(Cl)nc1-c1ccccc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a suspension of 5-methyl-4-phenyl-1,3-oxazol-2(3H)-one (430 mg, 2.45 mmol) in phosphorus oxychloride (2.36 g, 14.7 mmol) was added pyridine (194 mg, 2.45 mmol) and the mixture was stirred at 120° C. for 2 hr. The reaction mixture was diluted with acetonitrile and added dropwise to water (about 30° C.). The organic materials were extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to give the title compound (233 mg, yield 49%) as a yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:30]=[CH:31][CH:32]=2)O1>>[CH3:18][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH:28]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCC1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCOCC5)c4)nc23)CCCC1

Procedure:
(1-Methyl-cyclopentyl)-[2-(3-morpholin-4-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclopentyl)-methanone and 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine following general procedures as described in these Examples. M+H=391.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cc(-c3ccc4cc[nH]c4c3)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 22 %

Procedure:
6-bromo-1H-indole (28.8 mg, 0.147 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (109.2 mg, 0.288 mmol), Fibercat palladium catalyst (Johnson-Matthey, 55.5 mg), and K2CO3 (2 M in water, 0.50 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (10 ml; 2×5 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via HPLC (10%->95% MeCN/water with 0.1% TFA), silica gel (4:1->3:1->2:1->1:1 hexanes/EtOAc) to afford crude product. This crude material was then purified again via HPLC (same conditions as above) to afford title compound (11.9 mg, 22%). MS (ESI pos. ion) m/z: 369 (M+H). Calc'd Exact Mass for C23H16N2OS: 368.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH:14]=[CH:15][C:16](OCC)=[O:17])=[C:9]([OH:21])[CH:8]=[CH:7]2)#[N:3]>>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH:14]=[CH:15][C:16](=[O:17])[NH2:1])=[C:9]([OH:21])[CH:8]=[CH:7]2)#[N:3]
Reactant: N
Reactant: CCOC(=O)C=Cc1c(O)ccc2cc(C#N)ccc12
Product: N#Cc1ccc2c(C=CC(N)=O)c(O)ccc2c1
Reaction time: 32 h

Procedure:
2.0 Liters of 25% aqueous ammonia was added to 25.2 g of 6-cyano-1-(2-ethoxycarbonylvinyl)-2-naphthol, followed by stirring at 40°-45° C. for 32 hours. After cooling, the reaction mixture was concentrated to 300 ml under reduced pressure, and the residue was stirred for 30 minutes under cooling with water. The precipitate was collected by filtration and washed with a small amount of water and acetone to obtain 9.55 g of the desired product.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:28]=[CH:27][C:19]4[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=4[C:17]=3[CH2:29][CH2:30][CH3:31])=[C:9]([CH2:34][CH2:35][CH3:36])[C:8]=2[O:37][CH3:38])=[CH:4][S:3]1.[N+](C)([O-])=O.C1COCC1.[CH2:48](Br)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CCCCCC.C(OCC)(=O)C.C(OCC)C.O>[CH3:38][O:37][C:8]1[C:9]([CH2:34][CH2:35][CH3:36])=[C:10]([CH:32]=[CH:33][C:7]=1[C:5]1[N:6]=[C:2]([S:1][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[S:3][CH:4]=1)[O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:28]=[CH:27][C:19]2[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=2[C:17]=1[CH2:29][CH2:30][CH3:31]
Reactant: BrCc1ccccc1
Reactant: CCCc1c(OCCCOc2ccc(-c3csc(=S)[nH]3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(-c3csc(SCc4ccccc4)n3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Yield: 71.7 %

Procedure:
The compound of Example 26 (30 mg, 53.7 μmol) was added to 1.5 ml of nitromethane, 0.5 ml of THF, and 30 ml (0.25 mmol) benzyl bromide. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was poured into ethyl ether/water, and the ether layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. Flash chromatography of the residue on silica gel using 10:1 to 7:1 hexane/ethyl acetate (1% acetic acid) gave the product (25 mg, 38.5 μmol, 72% yield). High resolution mass spectrum, m/e 648.2490 (calculated for C36H42NO6S2 (M+H), 648.2453).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.N1C=CC(C(O)=O)=C1.Cl.CN.[CH3:21][N:22]([C:24]([O:28]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:21][NH:22][C:24]([C:9]1[CH:6]=[CH:4][NH:3][CH:7]=1)=[O:28]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc[nH]c1
Reaction time: 0.33 h

Procedure:
DIPEA (284 mg, 381 uL, 2.2 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (111 g, 1.0 mmol) and methylamine hydrochloride (222 mg, 3.3 mmol) in DMF (10 mL) at 0° C. Stirring for 20 min, HATU (570 g, 1.5 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (100 mL), washed with H2O (3×10 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc on silica gel. Yield: 57 mg (46%). 1H NMR (400 MHz, CHLOROFORM-D) δ 2.89 (s, 3 H), 5.89 (s, 1 H), 6.36-6.44 (m, 1 H), 6.75-6.79 (m, 1 H), 7.34-7.40 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@@H:8]1[C@H:12]([CH2:13][F:14])[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>CO.[Pd]>[CH2:36]([O:35][C:33]([N:10]1[CH2:11][C@@H:12]([CH2:13][F:14])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH2:9]1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(Cc2ccccc2)C[C@H]1CF
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1CF

Procedure:
A solution of ((3R,4R)-1-Benzyl-4-fluoromethyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (1 g, 3.24 mmol) in methanol (20 mL) was hydrogenated at 1 atm with 10% palladium on carbon (100 mg) for 24 hours. He crude reaction mixture was filter through celite then concentrate to an oil. The crude amine was dissolved in dichloromethane (8 ml) then cooled to 0 C and diisopropylethylamine (619 ul, 3.57 mmol) was added followed by benzyl chloroformate (507 ul, 3.57 mmol, 1.1 equiv.). The crude reaction was concentrated to an oil then purified by silica gel chromatography eluting with 0-20% EtOAc in Heptane which gave the title compound IXa of as a colorless oil (811 mg). 1H NMR (400 MHz, CHLOROFORM-d) 1.45 (s, 9H) 2.67 (br. s., 1H) 3.24-3.49 (m, 2H) 3.63-3.80 (m, 2H) 4.27-4.53 (m, 2H) 4.53-4.66 (m, 1H) 4.70 (dd, J=9.73, 4.93 Hz, 1H) 5.14 (br. s., 2H) 7.37 (br. s., 5H); LCMS: M+1−Boc=253.
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@H:9]2[C@@H:14]([N:15]([CH3:17])[CH3:16])[CH2:13][C@H:12]([O:18][C@@H:19]3[C:24]4[C:25]([OH:40])=[C:26]5[C:33](=[O:34])[C:32]6[C:35]([OH:39])=[CH:36][CH:37]=[CH:38][C:31]=6[C:29](=[O:30])[C:27]5=[CH:28][C:23]=4[C@@H:22]([C:41]([O:43][CH3:44])=[O:42])[C@@:21]([OH:46])([CH3:45])[CH2:20]3)[O:11][C@H:10]2[CH3:47])C[C@@H]2O[C@@H]3[C@H](O[C@H]12)O[C@@H](C)C(=O)C3.Cl.[OH-].[Na+].O>CC(C)=O>[CH3:47][CH:10]1[O:11][CH:12]([O:18][CH:19]2[C:24]3[C:25]([OH:40])=[C:26]4[C:33](=[O:34])[C:32]5[C:35]([OH:39])=[CH:36][CH:37]=[CH:38][C:31]=5[C:29](=[O:30])[C:27]4=[CH:28][C:23]=3[CH:22]([C:41]([O:43][CH3:44])=[O:42])[C:21]([OH:46])([CH3:45])[CH2:20]2)[CH2:13][CH:14]([N:15]([CH3:17])[CH3:16])[CH:9]1[OH:8]
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@@H]5O[C@H]6CC(=O)[C@H](C)O[C@H]6O[C@@H]5[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2CC(N(C)C)C(O)C(C)O2)CC1(C)O)C(=O)c1c(O)cccc1C3=O
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of 100 mg of auramycin B in 15 ml of acetone was added 0.3 ml of concentrated hydrochloric acid and hydrolysed at room temperature for 120 minutes. The reaction mixture was neutralised by dilute sodium hydroxide solution and 20 ml of water was added and extracted with 20 ml of chloroform twice. The extracts were combined and concentrated to a small volume in vacuo. The concentrate was chromatographed by a column packed with silica gel (chloroform:methanol, 95:5). The fractions containing auramycin D were concentrated in vacuo to give 38 mg of auramycin D.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[OH:21][C@@H:22]([CH2:40][OH:41])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([O:38][CH3:39])[CH:31]=2)[CH2:26][CH2:25]1>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([CH:27]4[CH2:26][CH2:25][N:24]([CH2:23][C@@H:22]([OH:21])[CH2:40][OH:41])[CH2:29][CH2:28]4)=[CH:31][C:32]=3[O:38][CH3:39])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cc(C2CCN(C[C@@H](O)CO)CC2)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cc(C2CCN(C[C@@H](O)CO)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 9.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (63.4 mg, 0.216 mmol) and 4-[1-((R)-2,3-Dihydroxy-propyl)-piperidin-4-yl]-2-methoxy-benzaldehyde (69.6 mg, 0.469 mmol) were reacted to produce 12 mg (10%) of the title compound. mp: 209-211° C., 1H NMR (300 MHz, CDCl3): 10.67 (s, 1H), 8.35 (d, J=8 Hz, 1H), 8.04 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.94 (s, 1H), 6.39-6.35 (m, 3H), 5.51 (d, J=8 Hz, 1H), 5.19 (t, J=8 Hz, 1H), 5.07 (s, 1H), 4.08 (s, 3H), 3.89 (m, 1H), 3.19 (s, 2H), 2.98 (d, 1H), 2.91 (s, 1H), 2.88 (d, J=8 Hz, 1H), 2.62 (m, 1H), 2.46-2.22 (m, 5H). MS: 567 (M+H), HPLC: 1.83 min (G method).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([O:17]C)=O)=[C:13]([CH2:19]Br)[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:26].CO>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:17])[NH:26][CH2:19][C:13]=3[NH:12][C:11]3[CH2:21][O:22][CH2:23][C:24](=[O:25])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: COC(=O)C1=C(CBr)NC2=C(C(=O)COC2)C1c1ccc(F)c(Br)c1
Solvent: CO
Product: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CNC1=O)N2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The product from Example 25B (0.22 g, 0.46 mmol) was treated with a 1:1 ammonia/methanol mixture (60 mL) in a metal Parr stirred reactor for 2.5 days at ambient temperature. The solvent was allowed to evaporate and the residue was purified by chromatography on silica gel (5% and then 10% methanol in methylene chloride) to provide the title compound (0.026 g) as a solid.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C([O:19][C:20](=[O:31])[C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=1)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([F:30])[CH:24]=2)=[C:21]([C:20]([OH:31])=[O:19])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C#Cc1ccc(Cl)c(F)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1=C(c2ccc(Cl)c(F)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (61.3 g, 0.26 mol) in CH2Cl2 (120 ml) was added dropwise over 90 minutes to a stirred solution of (4-chloro-3-fluoro-phenyl)-propynoic acid ethyl ester (39.0 g, 0.17 mol) and trifluoroacetic acid (1.30 ml, 0.02 mol) in CH2Cl2 (170 ml). The reaction mixture was stirred at 25° C. for 72 h and afterward evaporated to dryness. The residue was dissolved in dioxane (390 ml). An aqueous solution of NaOH (45.0 ml, 0.48 mol, 2.8 eq.) was added, and the resulting emulsion was stirred at r.t. for 18 h. The low boiling organic solvent was removed under vacuum. Water (100 ml) was added, the aqueous layer was separated and washed with TBME (2 times 100 ml). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was stirred overnight and the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 42.0 g (75%) of IId as a white solid.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl-:2].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH2+:16][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: [NH3+]CCOc1ccc2ccccc2c1Cl
Reactant: Cc1ccc(C=O)o1
Agent: [Cl-]
Product: Cc1ccc(C[NH2+]CCOc2ccc3ccccc3c2Cl)o1
Yield: 70 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)oxy]ethanaminium chloride and 5-methylfuran-2-carbaldehyde in 70% yield as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)=[C:4]([NH2:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1.C(Cl)(Cl)=O.[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43]>C(Cl)(Cl)Cl.C(O)C.O>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]\[C:42]([OH:44])=[O:43].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)=[C:4]([NH:17][C:32]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[O:33])[CH:3]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: Nc1cc(Br)ccc1N1CCc2ccccc21
Agent: Cl
Agent: O=C(Cl)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCc3ccccc32)CC1
Reaction time: 0.25 h
Yield: 39.8 %

Procedure:
To a stirred solution, under nitrogen of 43.5 g (0.15 mole) of 1-(4-bromo-2-aminophenyl)indoline of Example 3b and 82.8 g (0.60 mole) of milled potassium carbonate in 1000 ml of chloroform was added 44.7 g (0.225 mole) of 4-methyl-1-piperazinecarbonyl chloride hydrochloride in portions over 10 minutes. The reaction was refluxed for 6 hours when an additional charge of 10.4 g (0.075 mole) of potassium carbonate and 14.9 g (0.075 mole) of the carbonyl chloride reagent was added. After refluxing overnight (about 16 hours), the reaction was cooled, treated with 500 ml of water, and stirred vigorously for 15 minutes. The layers were separated and the organic phase was washed thrice with water, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in 200 ml of toluene and adsorbed on a tall chromatography column containing 1.5 kg of silica gel packed in toluene. Elution first with toluene, then with increasing percentages of dichloromethane in toluene, (25% per step), followed by dichloromethane alone, and finally with 1% methanol in dichloromethane brought forth 24 g (overall 39% yield) of fairly pure urea. This was dissolved in 100 ml of ethanol and treated with a solution of 6.96 g (0.06 mole) of maleic acid dissolved in 50 ml of ethanol. The maleate salt was collected, dried, and found to weigh 17.3 g (22% overall), m.p. 175°-177° C. dec. Recrystallization from methanol (charcoal) afforded 12.7 g (16% overall yield) of N-[5-bromo-2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-methyl-1-piperazinecarboxamide maleate, m.p. 175°-177° C. dec.
Reaction SMILES: CN(C)C=O.[C:6]([NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]2[C:12](=[N:13][CH:14]=[C:15]([CH:21]=O)[N:16]=2)[N:11]=1)(=[O:8])[CH3:7].[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.B.CNC>C(O)(=O)C>[C:6]([NH:9][C:10]1[NH:19][C:18](=[O:20])[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:16]=2)[CH2:21][NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=2)[N:11]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1nc(O)c2nc(C=O)cnc2n1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: B
Agent: CNC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NCc2cnc3nc(NC(C)=O)[nH]c(=O)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.07 g (10 mmole) of the dimethylformamide solvate of 2-acetamido-4-hydroxypteridine-6-aldehyde, 3.30 g (20 mmole) of ethyl p-aminobenzoate and 50 ml of glacial acetic acid is stirred at ambient temperature for 30 minutes. To the resulting suspension is added dropwise 1.00 g of dimethylamine borane in 15 ml of acetic acid. The mixture is stirred for an additional 20 minutes, heated to 60° C for 10 minutes and cooled to 25° C. The precipitate is collected by filtration, washed with acetic acid and ether and then dried. The crude product is crystallized from 50 ml of dimethylformamide, with dilution by 20 ml ether, to yield ethyl N2 -acetylpteroate.
Reaction SMILES: [Br-].[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[K].CC(C)([O-])C.[CH:38]1([NH:44][C:45]2[CH:54]=[C:53]3[C:48]([C:49](=[O:62])[C:50]([CH:60]=O)=[CH:51][N:52]3[CH:55]([CH2:58][CH3:59])[CH2:56][CH3:57])=[CH:47][C:46]=2[F:63])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.[Cl-].[NH4+]>C1COCC1>[CH2:2]([O:9][CH2:10][CH2:11][CH:12]=[CH:60][C:50]1[C:49](=[O:62])[C:48]2[C:53](=[CH:54][C:45]([NH:44][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[C:46]([F:63])[CH:47]=2)[N:52]([CH:55]([CH2:56][CH3:57])[CH2:58][CH3:59])[CH:51]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCC(CC)n1cc(C=O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(CC)n1cc(C=CCCOCc2ccccc2)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a 20 ml THF suspension of 1081 mg of (3-benzyloxypropyl)triphenylphosphonium bromide was added 258 mg of potassium, tert-butoxide followed by stirring for 1.5 hours. A 10 ml THF solution of 358 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde was added thereto, followed by stirring for 1 hour. To the reaction mixture was added aqueous saturated ammonium chloride, followed by extraction with ethyl acetate and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent concentration under a reduced pressure, the residue was purified by silica gel column chromatography to obtain 488 mg of 3-[4-(benzyloxy)but-1-en-1-yl]-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:9]([OH:22])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>ClCCl>[CH2:1]([C@H:8]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:9]([OH:22])[CH:10]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[S:48]([C:45]1[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:47][CH:46]=1)(=[O:50])=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCCCCC1(C)OCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(NCCCCC2(C)OCCO2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1

Procedure:
To a solution of the product of Step 2 (0.63 g, 149 mmol) in anhydrous dichloromethane (7 mL) at 0° C. was added N-ethyldiisopropylamine (0.38 g, 0.51 mL, 2.98 mmol) and a solution of 4-methoxybenzenesulfonyl chloride (0.32 g, 1.56 mmol) in anhydrous dichloromethane (2 mL) and the mixture was stirred at ambient temperature under nitrogen atmosphere for 18 hours. The mixture was washed sequentially with 1M hydrochloric acid, sodium bicarbonate/water, brine, dried (sodium sulfate) and concentrated. The residue was chromatographed (silica gel, dichloromethane/methanol, 97:3) to provide the title compound as a thick oil.
Reaction SMILES: FC1C=C2C(=CC=1)C(=O)N(CC1C=CC(OC)=CC=1)C=C2.C(C1(N)CCC(O)CC1)C=C.[CH2:33]([C:36]1([NH2:64])[CH2:41][CH2:40][CH:39]([O:42][C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][C:52]=2Cl)[C:49](=[O:54])[N:48]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)[CH:47]=[CH:46]3)[CH2:38][CH2:37]1)[CH:34]=[CH2:35]>>[CH2:33]([C:36]1([NH2:64])[CH2:41][CH2:40][CH:39]([O:42][C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[C:49](=[O:54])[N:48]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)[CH:47]=[CH:46]3)[CH2:38][CH2:37]1)[CH:34]=[CH2:35]
Reactant: C=CCC1(N)CCC(Oc2cc3ccn(Cc4ccc(OC)cc4)c(=O)c3cc2Cl)CC1
Agent: C=CCC1(N)CCC(O)CC1
Agent: COc1ccc(Cn2ccc3cc(F)ccc3c2=O)cc1
Product: C=CCC1(N)CCC(Oc2ccc3c(=O)n(Cc4ccc(OC)cc4)ccc3c2)CC1

Procedure:
422 mg of 6-(4-allyl-4-amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (18) were synthesized as diastereomeric mixture starting from 641 mg (2.26 mmol) of 2-(4-methoxy-benzyl)-6-fluoro-2H-isoquinolin-1-one (9) and 370 mg (2.38 mmol) of 4-allyl-4-amino-cyclohexanol (16), following the protocol described for 6-(4-allyl-4-amino-cyclohexyloxy)-7-chloro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (17). Rt=1.07 min, 1.10 min (Method C). Detected mass: 419.2 (M+H+).