Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1[C:10]([N:11]2[C:16]3[N:17]=[C:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[CH:24][C:23]=4[O:34][CH3:35])[N:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]2=[O:36])=[CH:9][CH:8]=[CH:7][C:6]=1[N:37](C1C=CC=C(N2C3N=C(NC4C=CC(N5CCOCC5)=CC=4OC)N=CC=3C=CC2=O)C=1C(C)(C)C)C(=O)[O-])(C)(C)C.[C:77]([OH:83])([C:79]([F:82])([F:81])[F:80])=[O:78]>C(Cl)Cl>[F:80][C:79]([F:82])([F:81])[C:77]([OH:83])=[O:78].[NH2:37][C:6]1[CH:5]=[C:10]([N:11]2[C:16]3[N:17]=[C:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[CH:24][C:23]=4[O:34][CH3:35])[N:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]2=[O:36])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N(C(=O)[O-])c4cccc(-n5c(=O)ccc6cnc(Nc7ccc(N8CCOCC8)cc7OC)nc65)c4C(C)(C)C)c3C(C)(C)C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCOCC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
Crude bis(tert-butyl (3-(2-((2-methoxy-4-morpholinophenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl))carbamate (2a) was treated with DCM (5 mL) and TFA (3 mL) and stirred at RT for 15 min. The reaction mixture was concentrated and purified on a Gilson preparatory HPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5 u, 5-95% 0.1% TFA/CH3CN in 0.1% TFA/water) affording 8-(3-aminophenyl)-2-((2-methoxy-4-morpholinophenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one 2,2,2-trifluoroacetate (2b, 74 mg, 0.13 mmol, 41% yield) as a brown amorphous solid after drying in a genevac overnight. m/z (ESI, +ve ion) 446.1 (M+Na)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.86 (1H, s), 8.05 (1H, d, J=9.6 Hz), 7.51-7.58 (1H, m), 7.32 (1H, dt, J=7.6, 1.3 Hz), 7.15-7.21 (2H, m), 6.90 (1H, d, J=8.6 Hz), 6.71 (1H, d, J=9.6 Hz), 6.67 (1H, d, J=2.5 Hz), 6.53 (1H, dd, J=8.7, 2.6 Hz), 3.87-3.93 (5H, m), 3.68 (3H, s), 3.18-3.24 (4H, m).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].I[C:16]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][C:23]=2[NH2:25])[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=[C:16]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=3)[C:24]=12
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(NS(C)(=O)=O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 2.6 %

Procedure:
A solution of 4-Methanesulfonylaminophenylboronic acid (24 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA40 (0.9 mg, 3% yield). ESI-MS (M+H)+ m/z calcd 347.1, found 347.0.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH:15]3[CH3:17])[C:7]=12.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:24][C:2]2[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]4[CH2:16][CH:15]4[CH3:17])[C:7]=23)=[CH:21][CH:20]=1
Reactant: Cc1c(C)n(CC2CC2C)c2c(Cl)nncc12
Reactant: OCc1ccc(F)cc1
Product: Cc1c(C)n(CC2CC2C)c2c(OCc3ccc(F)cc3)nncc12
Yield: 91.6 %

Procedure:
The title compound (trans) was prepared as a white powder in 91.60% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine and 4-fluorobenzyl alcohol.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH:8]=[O:9]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)c(Cl)c1
Temperature: 150 °C

Procedure:
To acetonitrile (15.0 mL) were added 3-chloro-4-hydroxy-benzaldehyde (556, 0.6 g, 4 mmol), 4-chlorobenzyl bromide (557, 1.2 g, 6 mmol), and potassium carbonate (0.9 g, 7 mmol). The reaction was heated to 150° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate: hexanes) (558, 0.85 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[NH:6][C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[Cl:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([S:9][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:6][C:5]=2[CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc(Cl)c(Cl)cc3[nH]2)o1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
5,6-Dichloro-1H-benzimidazole-2-thiol (1.0 g, 4.56 mmol) is suspended into 50 mL of tetrahydrofuran under argon. Then, 0.33 g (6.85 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (0.64 g, 4.57 mmol) is then added and the reaction mixture is stirred at room temperature for 1 h, upon which it is poured on ice and extracted 3 times with ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 200 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate/cyclohexane 50/50 v/v; rate: 50 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is triturated in diisopropyl ether, filtered and dried under reduced pressure. 0.93 g of 5-(5,6-dichloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a yellow powder. mp: 170° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH:20]([CH3:22])[CH3:21].O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a mixture of 6-hydroxy-2,3-dihydro-1H-inden-1-one (5.0 g, 33.8 mmol) in DMF (170 mL) was added K2CO3 (9.33 g, 67.5 mmol) and 1-bromo-2-methylpropane (5.50 mL, 50.6 mmol). The resulting orange mixture was stirred at r.t. overnight and was then heated to 60° C. for 2 days. The mixture was cooled to r.t., water was added and the mixture was extracted with EtOAc (×4). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography using 0-20% EtOAc in heptane as eluent afforded 4.98 g (72% yield) of the title compound: 1H NMR (500 MHz, CDCl3) δ ppm 1.03 (d, 6 H), 2.10 (dt, 1 H), 2.69-2.75 (m, 2 H), 3.04-3.11 (m, 2 H), 3.75 (d, 2 H), 7.17-7.22 (m, 2 H), 7.37 (d, 1 H); MS (ES+) m/z 205 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([N:21]=[C:22]=[O:23])=[CH:15][C:14]=2[O:13]1>>[O:20]1[C:19]2[CH:18]=[CH:17][C:16]([NH:21][C:22]([NH:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][CH:6]=[CH:5]4)=[O:23])=[CH:15][C:14]=2[O:13][CH2:12]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccc2c(c1)OCO2)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 3,4-(methylenedioxy)phenyl isocyanate. m/z (ES+) 308 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)(=[O:15])=[O:14].Cl[CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)(=[O:15])=[O:14])[CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(C)(C)O)ccc2Cl)cc1OC
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CN(c1cc(C(C)(C)O)ccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
To a solution of N-[2-chloro-5-(1-hydroxy-1-methyl-ethyl)-phenyl]-3,4-dimethoxy-benzenesulfonamide (0.98 g, 2.5 mmol) in DMF (7.5 mL) was added 2-Chloro-N,N-diethyl-acetamide (0.418 g, 1.1 eq) and K2CO3 (0.35 g, 1 eq). The mixture was heated at 80° C. over night, cooled and partitioned between EA and water. The organic layer was washed several times with water and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (hex/EA 1:1, EA) to give the product as a colourless foam (1.15 g, 92%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]2)[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[N+](C1C=CC=CC=1)([O-])=O>C1(C)C(C)=CC=CC=1.[C].[Pd]>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C1C=CCCC1
Agent: [Pd]
Solvent: Cc1ccccc1C
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2c1ccccc1
Yield: 83.5 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (500 mg) was suspended in xylene (20 ml), nitrobenzene (831 mg) and 10% palladium carbon (250 mg) were added therto, and the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool, filtrated, and the filtrate was concentrated under reduced pressure. Diisopropyl ether was added to the residue, crystals so precipitated were collected by filtration, to thereby obtain 413 mg of the titled compound (Yield: 83%).
Reaction SMILES: C[Si]([C:5]#[C:6][Si:7]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])Br)(C)C.[CH2:15]([Mg]Cl)[CH:16]=[CH2:17]>C1COCC1>[CH2:15]([Si:7]([C:6]#[CH:5])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])[CH:16]=[CH2:17]
Reactant: CC(C)[Si](Br)(C#C[Si](C)(C)C)C(C)C
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C#C[Si](CC=C)(C(C)C)C(C)C
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
The (trimethylsilylethynyl)diisopropylbromosilane intermediate was transferred to an oven-dried flask, dissolved in anhydrous THF, treated with 1.2 equivalents of allylmagnesium chloride (2.0 M in THF) dropwise, and heated to 45° C. for 12 hrs. The reaction was quenched by the slow addition of ice water, then dilute sulfuric acid to dissolve magnesium salts, followed by the addition of pentane. The organic layer was separated, and the aqueous layer was extracted with pentane one additional time. Organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under rotary evaporation. Removal of the trimethylsilyl substituent is effected by treatment with 6-8 drops of 15% NaOH in 1:1 THF:MeOH, followed by stirring for 1-2 hours. Analysis by GC-MS was helpful to ascertain completion of the deprotection, since thin layer chromatography (hexanes, visualization by potassium permanganate stain) revealed no appreciable difference between the trimethylsilyl-protected and deprotected acetylene. The product was isolated by extraction into hexanes (2×50 mL). The organic layer was washed with 10% HCl (10 mL) and water (2×10 mL), then dried over magnesium sulfate, filtered, and concentrated under rotary evaporation to yield 11.3 g of crude (allyldiisopropylsilyl)acetylene.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[Br:11]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:6]([Br:11])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(N)no1
Product: CC(C)(C)c1onc(N)c1Br
Yield: 91 %

Procedure:
This compound was prepared from 3-amino-5-tert-butylisoxazole and N-bromosuccinimide as described in Example 25a in 91% yield, Rf 0.27 (3:1 hexanes/ethyl acetate).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1.[H-].[Na+].Cl>CN(C)C=O.O>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([NH:19][C:20]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CC(=O)C2CCC1C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.27 g, 2.0 mmole), 3-(trifluoromethyl) phenyl isocyanate (0.55 ml, 4.0 mmole), and 60% sodium hydride in mineral oil (0.088 g, 2.2 mmole) in dimethylformamide (100 mL) was stirred at 0° C. for 1 hour and then heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N aqueous HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified with by chromatography on silica gel (40% dichloromethane/hexane) to give a clear oily liquid as the expected product. The oily product was crystallized with ethyl acetate/hexane in a dry ice bath to afford the title compound as a white solid, mp=68–69° C.; MS (−) ESI m/z=324 (M−H)−.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>C1(C)C(C)=CC=CC=1>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[NH:23][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4]
Reactant: Nc1nc2ccccc2s1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nc3ccccc3s2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 70 %

Procedure:
N-(2-Benzothiazolyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-benzothiazole. Yield: 70% of theory, m.p. 262° C (decomp.; from xylene).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](N)[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]=[CH2:13])([O-:3])=[O:2].ClC1C=CC([C:20]([OH:22])=[O:21])=CC=1[N+]([O-])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]=[CH2:13])[C:20]([OH:22])=[O:21])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C=CCNc1ccc(N)cc1[N+](=O)[O-]
Product: C=CCNc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Synthesis and working up as for compound 1, but with 4-chloro-3-nitrobenzoic acid instead of 4-fluoro-3-nitroaminobenzene. Yellow crystals, melting point 195°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1.CO>C1COCC1>[Br:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:38])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N(C(=O)c2ccc(Br)cc2)c2ncccc2Cl)C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Preparation 1 tert-Butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (214.4 g, 687.7 mmol) was dissolved in 260 mL of THF and the resulting suspension was cooled to −10° C. Lithium bis(trimethylsilyl)amide (1 mol/L in THF, 687.7 mL, 687.1 mmol) was added over 25 min followed by warming to 20° C. and stirring for 1 h before cooling back to −10° C. 4-Bromobenzoyl chloride (140.0 g, 625.2 mmol) was added as a solution in 230 mL of THF over 1.5 h, maintaining the internal temperature at less than −7° C. After complete addition, the reaction mixture was warmed to 0° C. at which point HPLC indicated the reaction was complete. MeOH was added (101 mL), then the reaction was warmed to room temperature and concentrated in vacuo to a low volume. The solvent was then exchanged to 2-MeTHF. The crude product solution (700 mL in 2-MeTHF) was washed with 700 mL of half-saturated aqueous NaHCO3, followed by 200 mL of half-saturated brine. The 2-MeTHF solution was concentrated to a low volume followed by addition of 400 mL of heptane resulting in precipitation of solids which were collected via filtration. The collected solids were dried to afford the title compound as a tan powder (244 g, 79% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].[F:34][C:35]([F:40])([F:39])[CH2:36][CH2:37]I>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([CH2:37][CH2:36][C:35]([F:40])([F:39])[F:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: FC(F)(F)CCI
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)CCC(F)(F)F)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
The reaction was carried out under argon. Sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (66 mg, 44 μmol; purity 32%) was suspended in DMF (600 μl). 1,1,1-Trifluoro-3-iodopropane (144 mg, 643 μmol; 14.6 eq.) was then added, and the mixture was heated in a closed tube at 120° C. overnight. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (7.4 mg, 30% of theory).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:31]([O:33]CC1C=CC=CC=1)=O)[CH3:30])=[O:27])[CH2:22][C:23](=[O:25])[NH2:24])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:48][NH2:49]>CO>[NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:31]([NH:48][NH2:49])=[O:33])[CH3:30])=[O:27])[CH2:22][C:23](=[O:25])[NH2:24])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: NN
Solvent: CO
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)C(=O)NN

Procedure:
Box-Lys(Z)-Asn-Ala-OBzl (XXIV) (2.3g, 3.5 mmol) was dissolved in MeOH (20 ml) with heating and treated with H2NNH2 (1.1 ml) at 4° C for 72 hr. The precipitated product was filtered and washed with MeOH and ether, yield 1.0g (49.3%). The white powder was crystallized from DMF with isopropanol; mp 177°-180° C; [α]D25 -14.9° (c 1.5, DMF). Anal. Calcd for C26H41N7O8 (579.67): C, 53.87; H, 7.13; N, 16.91. Found: C, 53.75; H, 7.19; N, 17.00.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[O:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1>>[O:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)=[CH:11]1
Reactant: OB(O)c1ccoc1
Reactant: O=Cc1ccc(Br)nc1
Product: O=Cc1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 43c (976 mg, 5.25 mmol) and 3-furanboronic acid (881 mg, 7.87 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (10:1) as eluent. White solid. Yield: 770 mg, 85%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=6.94 (dd, J=1.9, 0.9 Hz, 1H), 7.51-7.55 (m, 1H), 7.58 (dd, J=8.2, 0.6 Hz, 1H), 8.11-8.17 (m, 2H), 9.00 (dd, J=2.2, 0.9 Hz, 1H), 10.06 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=108.5, 120.0, 126.5, 129.6, 136.3, 143.2, 144.4, 152.6, 156.8, 190.1; MS (ESI): m/z=174.26 [M+H]+.
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])[NH:9][C:8](=O)[CH:7]=[CH:6]2.P(Br)(Br)([Br:18])=O.O>ClC1C=CC=CC=1>[Br:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2ccc(=O)[nH]c2cc1OC
Reactant: O=P(Br)(Br)Br
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Br)c2cc1OC
Temperature: 150 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
6,7-Dimethoxyquinolone (0.79 g) was dissolved in chlorobenzene (7 ml) to prepare a solution. Phosphorus oxybromide (3.34 g) was added to the solution, and the mixture was stirred at 150° C. for 6 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using acetone-chloroform to give 4-bromo-6,7-dimethoxyquinoline (429 mg, yield 42%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([OH:18])=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([Cl:22])=[O:18])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)O)n2)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reaction time: 2 h

Procedure:
2′-(Acetylamino)-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxylic acid, Compound (4), (100 mg; 0.35 mmol; 1 eq.) is suspended in DCM (6 ml). Oxalyl chloride (92 μl; 1.06 mmol; 3 eq.) is added followed by anhydrous dimethylformamide (5.5 μl; 0.07 mmol; 0.20 eq.). After 2 hours, a sample is quenched with MeOH, showing that the reaction is complete. The solvents are evaporated affording 2′-acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride which is used in the next step without further purification. HPLC (method A), Rt: 1.90 min (purity: 92.0%).