Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:18]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:19]([C:29](ON1C(=O)CCC1=O)=[O:30])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.CO>CN(C=O)C>[NH:18]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:19]([C:29]([NH:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:30])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O

Procedure:
H-Glu(OBzl)-OH (39.4 g, 166 mmol) was stirred with Boc-Ser(Bzl)-OSu (65.0 g, 166 mmol) in 900 ml DMF overnight in the presence of Et3N (2.3 ml, 165 mmol). More Et3N was added during this time in order to maintain the reaction slightly basic. The clear solution was evaporated to dryness and the oily residue partitioned between EtOAc (1.5 liters) and 5% HOAc (2 liters). The organic layer was washed with H2O (2 times), dried over Na2SO4, and concentrated to a clear oil (90.0 g) which was taken up in 3 liters of ether and treated with 25 ml of cyclohexylamine The solid formed was recrystallized from MeOH and ether: yield, 76.2 (74.8%); mp 154°-156.5°; [α]D25 =+6.32° (c 1, MeOH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH3:10]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:10])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: N
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CO
Product: Cc1cc(N)nc(N)n1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of 50.0 grams (0.348 mole) of 2-amino-4-chloro-6-methylpyrimidine (commercially available) and 100 mL of aqueous 30% ammonia in 400 mL of methanol was placed in a high pressure vessel and heated to 130°-165° C. under a pressure of 140°-250 psig, where it was stirred for 13 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. The reaction vessel was then opened and the reaction mixture was removed. The reaction vessel was washed with 200 mL of methanol, and the wash was combined with the reaction mixture. The combination was concentrated under reduced pressure to a residual solid. The solid was then stirred for 2 hours at ambient temperature with 100 mL of aqueous 30% ammonia. The mixture was cooled to 0° C., and the solid was collected by filtration. The solid was dried, yielding 40.8 grams of 2,4-diamino-6-methylpyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][NH:28][CH2:29][CH3:30]>C(#N)C>[CH3:27][N:28]([CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1)[CH2:29][CH3:30]
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCN(C)CC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), N-methylethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 84 (2), 79 (2), 73 (5), 72 (bp).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[O:20][CH3:21])=[O:11].[OH-].[Na+]>CO.O>[CH3:21][O:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[C:10](=[O:11])[CH:9]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(38) To a solution of benzaldehyde (295 mg, 2.77 mmol) and 2,6-dimethoxyacetophenone (500 mg, 2.77 mmol) in 4.1 ml of methanol was added 0.1 ml of 40% sodium hydroxide in water at 10° C. After stirring for 3 hour at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 371 mg (49.9%) of white flakes: mp 125.5-126.6° C. (lit. mp 123-124° C., Kuck and Grutzmacher, Org. Mass. Spect., 1978, 13, 90-102). 1H NMR (250 MHz) δ 7.55-7.51 (m, 2 H), 7.39-7.30 (m, 5 H), 7.00-6.94 (d, 1 H), 6.64-6.61 (d, 2 H), 3.79 (s, 6 H); 13C NMR (62.7 MHz) 213. 176.1, 163.9, 153.4, 149.4, 149.0, 147.4, 147.3, 147.0, 122.6, 74.5 ppm.
Reaction SMILES: [CH:1]1([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:16]([S:19][CH2:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])(=[O:18])[CH3:17].O>CC(N(C)C)=O>[C:16]([S:19][CH2:20][CH:21]([CH3:25])[C:22]([N:10]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: C[C@H](NC1CCc2ccccc21)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)SCC(C)C(=O)N(C1CCc2ccccc21)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
N-(1-Indanyl)alanine (3.0 g) is suspended in 30 ml of dimethylacetamide, then 3.3 g of 3-acetylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and thereafter stirring is continued at room temperature for 2 hours. The reaction mixture is poured into 200 ml of water, and extracted with 200 ml of ethyl acetate. The extract is washed with 10 ml of 10% hydrochloric acid and with water, and dried. The ethyl acetate is distilled off under reduced pressure, and the residue is crystallized from an ethyl ether-petroleum ether mixture, to give 2.3 g of N-(3-acetylthio-2-methylpropionyl)-N-(1-indanyl)alanine, colorless needles having a melting point of 133°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][CH2:17][CH2:18][O:19][CH3:20].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1.C([O-])(=O)C.[NH4+].C(#N)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: COCCNc1cnccc1-c1c(F)cccc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COCCN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1c(F)cccc1OC

Procedure:
The title compound was prepared in analogy to example 223, from [4-(2-fluoro-6-methoxy-phenyl)-pyridin-3-yl]-(2-methoxy-ethyl)-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (example 223, intermediate d) and using preparative HPLC (ammonium acetate/acetonitrile) for purification. Yellow solid (17%). MS (ESI): m/z=527.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15]CC)=O)=[CH:7][N:6]([CH3:18])[C:5]=2[CH:4]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:13]([C:8]2[C:9](=[O:12])[C:10]3[S:11][C:3]([CH2:2][OH:1])=[CH:4][C:5]=3[N:6]([CH3:18])[CH:7]=2)=[O:15])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cn(C)c2cc(CO)sc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)cc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Ethyl 2-(hydroxymethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (250 mg, 0.94 mmol) was suspended in 4-chlorobenzylamine (2.0 mL, 16.4 mmol). The mixture was stirred at 80° C. for 16 hours before it was quenched with a mixture of 1.0 M hydrochloric acid (25 mL) and ice (5 g). The mixture was stirred at room temperature for 1 hr. The solid ppt. was collected by vacuum filtration and washed thoroughly with 50 mL of water. Drying in vacuo left a white solid (0.26 g).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:16]=1)(=[O:14])=[O:13].[C:30](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[Cl:50]CCl>>[ClH:50].[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N:23]2[CH2:28][CH2:27][N:26]([CH3:30])[CH2:25][CH2:24]2)[CH:16]=1)(=[O:13])=[O:14]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C)ccc2OC(F)F)cc1N1CCNCC1
Reactant: ClCCl
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)Nc2cc(C)ccc2OC(F)F)cc1N1CCN(C)CC1
Product: Cl
Reaction time: 0.17 h

Procedure:
0.429 g N-(2-(difluoromethoxy)-5-methylphenyl)-4-methoxy-3-(piperazin-1-yl)benzenesulfonamide (1.004 mmol) were dissolved in 5 mL of dichloromethane. 0.086 mL of acetic acid (1.505 mmol) and 0.319 g of sodium triacetoxyborohydride (3.01 mmol) were added. After stirring for 10 min, 0.083 mL of aqueous formaldehyde solution (3.01 mmol) were added and the reaction stirred for 72 h at room temperature. The solvents were evaporated and the residue purified via preparative silica gel chromatography (Super Flash cartridge (Interchim)) using a dichloromethane (+0.1% triethylamine) and methanol gradient as eluent. Fractions containing the product were combined, the solvents evaporated, and the product converted to the hydrochloride salt by addition of hydrochloric acid in diethyl ether and subsequent evaporation to dryness (yield 0.169 g of product).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1.C.[H][H]>C(O)(=O)C.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCN(CC)C/C=C/Cc1ccc(Cl)cc1
Agent: [Pt]
Solvent: CC(=O)O
Product: CCN(CC)CCCCc1ccc(Cl)cc1

Procedure:
Add 2.0 g (0.0084 mole) of (E)-4-(4-chlorophenyl)-N,N-diethyl-2-buten-1-amine to flask containing 0.20 g platinum (5%) on activated charcoal suspended in 15 ml glacial acetic acid. Stir reaction mixture under one atmosphere hydrogen until hydrogen absorption ceases (41/2 hours). Filter reaction mixture with methylene chloride wash and 50 ml distilled water. Separate layers and extract aqueous with 3×70 ml methylene chloride. Combine methylene chloride extracts and wash with cold 2×75 ml 1N NaOH. Dry organic layer over MgSO4, filter and evaporate to yield the title compound.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C1(C)C=CC=CC=1>ClCCl.CO>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccccc1NC1CCCCC1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
Cyclohexylamine (8.1 ml) was added dropwise to 1-fluoro-2-nitrobenzene (4) (3.7 mg) under a nitrogen atmosphere at 0°. To the resulting orange solid, dry toluene (10 ml) was added and the mixture was stirred at 23 ° C. for 30 min. then diluted with dichloromethane/methanol 1/1 (100 ml) and the organic layer was washed with brine (50 ml), 10 % solution sodium hydroxide (50 ml) and brine (50 ml), dried and concentrated in vacuo to give the title compound as an orange solid (7.45 g). Mp 105°-7° T.l.c. CH-EA (7:3). Rf 0.78
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:22])[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:7]=2[CH:6]=[C:5]([O:23][CH3:24])[CH:4]=1.[S-]CC.[Na+].O>CN(C)C=O>[OH:2][C:3]1[C:8]2[C:9](=[O:22])[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:7]=2[CH:6]=[C:5]([O:23][CH3:24])[CH:4]=1
Reactant: COc1cc(OC)c2c(c1)OCCCCC=CCCCCOC2=O
Agent: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O)c2c(c1)OCCCCC=CCCCCOC2=O
Yield: 38 %

Procedure:
A solution of 1,3-dimethoxy-6,7,8,9,12,13,14,15-octahydro-5,16-dioxa-benzocyclopentadecen-17-one (321 mg, 0.96 mmol) and sodium thioethoxide (97 mg, 1.15 mmol) in dimethyl formamide was heated at 140° C. for 4 h whereby it was poured into water (100 ml). Extraction and chromatography gave 1-hydroxy-3-methoxy-6,7,8,9,12,13,14,15-octahydro-5,16-dioxa-benzocyclopentadecen-17-one (117 mg).
Reaction SMILES: CC1C=NC=C(C=1)C(NC1CCNCC1)=O.ClC1C=CC(C=O)=CC=1OCC.[Cl:29][C:30]1[CH:54]=[CH:53][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([NH:41][C:42]([C:44]3[CH:45]=CC=[C:48]4[C:52]=3[NH:51][CH:50]=[CH:49]4)=[O:43])[CH2:37][CH2:36]2)=[CH:32][C:31]=1[O:55][CH2:56][CH3:57].B.N1C=CC=CC=1>ClCCCl.C(O)(=O)C>[Cl:29][C:30]1[CH:54]=[CH:53][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:43])[C:44]3[CH:45]=[C:49]([CH3:48])[CH:50]=[N:51][CH:52]=3)[CH2:37][CH2:36]2)=[CH:32][C:31]=1[O:55][CH2:56][CH3:57]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cccc4cc[nH]c34)CC2)ccc1Cl
Agent: B
Agent: CCOc1cc(C=O)ccc1Cl
Agent: Cc1cncc(C(=O)NC2CCNCC2)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1Cl
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of 5-methyl-N-(piperidin-4-yl)-nicotinamide (22 mg, 0.10 mmol), 4-chloro-3-ethoxy-benzaldehyde (22 mg, 0.12 mmol) in DCE:EtOH (1:11 mL) was added acetic acid (25 μL) and pyridine-borane complex (25 μL, 8M in pyridine, 0.2 mmol). The reaction was shaken for 16 h, after which time it was concentrated and purified by reversed phase HPLC (MeCN:H2O) affording the title compound (22 mg, 57%). MS: 388.4 (MH+)
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]2[N:12]=[N:13][N:14]=[C:7]2[C:6]=1[N+:15]([O-])=O.CO>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]2[N:12]=[N:13][N:14]=[C:7]2[C:6]=1[NH2:15]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c2nnnn12
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(NCC(C)C)c(N)c2nnnn12
Reaction time: 2 h
Yield: 88.5 %

Procedure:
N-(2-Methylpropyl)-5-methyl-8-nitrotetraazolo[1,5-a]pyridin-7-amine (9.60 g, 43.6 mmol) was dissolved in warm anhydrous toluene (900 mL) and methanol (100 mL) and then added to a 2 L stainless steel Parr vessel. The vessel was flushed several times with nitrogen, and 5% platinum on carbon (2.0 g) was added to the solution. The vessel was flushed multiple times with hydrogen, and then placed under hydrogen pressure (50 psi, 3.4×105 Pa). After two hours, no further hydrogen was consumed. The reaction mixture was filtered through a layer of filter agent (available from Aldrich, Milwaukee, Wis. under the trade name CELITE), and the filter cake was washed with hot toluene (1 L). The filtrate was concentrated under reduced pressure to yield 8.5 g N7-(2-methylpropyl)-5-methyltetraazolo[1,5-a]pyridine-7,8-diamine as a light orange solid, m.p. 159–162° C.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:8](=[O:7])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: CN(C)CCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN(C)C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-dimethyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 446 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.C(N(C(C)C)CC)(C)C.Cl.[CH3:53][O:54][NH:55][CH3:56]>O.CN1C(=O)CCC1>[CH3:53][O:54][N:55]([CH3:56])[C:25]([C:24]1[CH:23]=[N:22][N:10]2[C:11]([CH3:21])([CH3:20])[CH2:12][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=12)=[O:26]
Reactant: CC1(C)CC(c2ccccc2)N(Cc2ccccc2)c2c(C(=O)O)cnn21
Reactant: CNOC
Agent: CN(C)C(O)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CON(C)C(=O)c1cnn2c1N(Cc1ccccc1)C(c1ccccc1)CC2(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a 5 mL NMP solution containing 0.72 g (1.99 mmol) of 2 was added 0.91 g (2.39 mmol) of O-7-azabenzotriazolo-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and 0.416 mL (2.39 mmol) of diisopropylethylamine. After stirring for 30 min, 0.233 g (2.39 mmol) of O,N-dimethyl-hydroxylamine hydrochloride was added and the reaction heated to 50° C. After 1 h, the reaction mixture was poured into water and extracted with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a crude oil. Purification of this oil by flash chromatography eluting with a 60 to 50% hexanes/AcOEt gradient gave 0.65 g (81%) of the title compound as a light golden colored solid. 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.56 (s, 3H), 2.06-2.16 (m, 2H), 3.25 (s, 3H), 3.49 (s, 3H), 3.90 (d, J=16.0 Hz, 1H), 4.45 (dd, J=5.1, 11.3 Hz, 1H), 5.06 (d, J=16.2 Hz, 1H), 6.98 (dd, J=1.8, 6.1 Hz, 2H), 7.20-7.24 (m, 3H), 7.30-7.34 (m, 1H), 7.37-7.41 (m, 4H), 7.74 (s, 1H). MS Calcd.: 404. Found: 405 (M+H).
Reaction SMILES: [C:1]1(=O)[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[NH2:16][NH2:17]>CN(C=O)C.C(O)C>[N:16](=[C:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3)[NH2:17]
Reactant: NN
Reactant: O=C1Nc2ccc3ncccc3c2C1=O
Solvent: CCO
Solvent: CN(C)C=O
Product: NN=C1C(=O)Nc2ccc3ncccc3c21
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of 2.3 g (12 mmol) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione (prepared from 6-aminoquinoline according to Procedure A) and 2.0 ml (0.06 mol) of hydrazine in 50 ml of DMF and 50 ml of ethanol was stirred at reflux for 2 hours. The resulting suspension was allowed to cool to ambient temperature and was then chilled in an ice bath and filtered. The solid was washed with a small volume of ethanol and allowed to air dry to give 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one as an orange solid (1.8 g, 73%): 1H NMR (DMSO-d6): δ7.37 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.71 (dd, J=4.2, 1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 J=14.7 Hz, 1H), 10.89 (br d, J=14.7 Hz, 1H), 10.95 (brs, 1H); ESI−MS m/z 213 (M+H)+. A solution 1.8 g (8.5 mmol) of 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinolin-2-one in 50 ml of freshly prepared 0.5 M sodium ethoxide solution was stirred at reflux for 3 hours. The solution was diluted with 50 ml of water, neutralized with acetic acid, and concentrated on a rotary evaporator until cloudy. The solution was stored in a refrigerator overnight. The solid was filtered off, and the filtrate was extracted with three 80-ml portions of EtOAc. A solution of the solid in MeOH/EtOAc was combined with the extracts and passed through a short pad of silica gel, eluting with EtOAc. The solution was then concentrated to a small volume on a rotary evaporator, and the resulting suspension was diluted with an equal volume of ethanol, sonicated, and filtered to give 3-H-pyrrolo[3,2-f]quinoline-2-one as a light green solid (0.52 g, 33%); 1H NMR (DMSO-d6): δ3.80 (s, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4, 4.2 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.70 (dd, J=4.2, 1.6 Hz, 1H), 10.57 (br s, 1H); APCI−MS m/z 183 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1([CH2:20][CH2:21][OH:22])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.[N+:23]([C:26]1[CH:36]=[CH:35][C:29]([C:30]([N:32]=[C:33]=S)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(Cl)CCl.O>C1COCC1>[Br:19][C:5]1[CH:4]=[C:3]2[C:8]([O:9][C:10]3[C:11]([F:18])=[CH:12][C:13]([O:16][CH3:17])=[CH:14][C:15]=3[C:2]32[CH2:20][CH2:21][O:22][C:33]([NH:32][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:36][CH:35]=2)=[N:1]3)=[CH:7][CH:6]=1
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(F)c2c(c1)C(N)(CCO)c1cc(Br)ccc1O2
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: COc1cc(F)c2c(c1)C1(CCOC(NC(=O)c3ccc([N+](=O)[O-])cc3)=N1)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 2-(9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)ethanol (7.17 g, 19.47 mmol) in THF (100 mL) was added 4-nitrobenzoyl isothiocyanate (4.26 g, 20.45 mmol). The reaction mixture was stirred for 30 min at RT. EDC (5.60 g, 29.2 mmol) and TEA (0.543 ml, 3.89 mmol) were added sequentially and the reaction mixture was heated to 70° C. for 1 hr. The reaction mixture was cooled to RT and water (50 ml) was added. The reaction mixture was stirred for 1 hr, upon which a precipitate formed, which was filtered off and washed with water and MeOH. The solid was dried to afford N-(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2-yl)-4-nitrobenzamide (6.0 g, 11.06 mmol, 56.8% yield).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>[OH-].[Na+].C(OCC)(=O)C>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([O:1][N:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:22])=[O:21])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: On1nnc2ccccc21
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)On2nnc3ccccc32)cc1
Reaction time: 8 h
Yield: 43.8 %

Procedure:
In 1 N aqueous sodium hydroxide (b 98 ml) is dissolved 1-hydroxy-1,2,3-benzotriazole (13.5 g). To the solution is added powdery p-nitrobenzenesulfonyl chloride (22.2 g) with stirring under ice-cooling, and the mixture is stirred at the same temperature for 15 minutes and further at room temperature for 4.5 hours. After allowing to stand overnight, the reaction mixture is extracted with ethyl acetate (150 ml). The extract is washed with water and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off. The resulting powdery residue is washed twice with petroleum ether (30 ml) and recrystallized from benzene (90 ml) to give colorless crystals. The crystals are dissolved in ethyl acetate (100 ml) and the mixture is washed twice with a saturated aqueous sodium hydrogen carbonate (10 ml) and water in order and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under a reduced pressure to give colorless crystals of 1-(p-nitrobenzensulfonyloxy)-1,2,3-benzotriazole (14 g), melting point: 119.5°-121.5° C. Ultraviolet spectrum (methanol): λmax 254 nm, E=234.