Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2].[I-].[Na+].[C-:30]#[N:31].[K+].O>CS(C)=O>[C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([C:30]#[N:31])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOCn1c(C#N)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 25 °C
Reaction time: 58 h
Yield: 60.3 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (1.83 g, 4.11 mmol) and sodium iodide (123 mg, 0.82 mmol) in anhydrous dimethylsulfoxide (40 ml) was added potassium cyanide (294 mg, 4.52 mmol). After stirring at room temperature for 58 hours, the mixture was treated with water (200 ml) and extracted with ethyl acetate (4x 25 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (25 ml) and then dried over magnesium sulfate. After the solvent was evaporated under reduced pressure, the product was purified by flash chromatography on silica get eluting with ethyl acetate-hexane (1:3) to provide (R)-1-(5-Acetoxyhexyl)-8-cyano-7-ethoxymethyl-3-methylxanthine (970 mg, 60% yield) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.CS(C)=O.[Cl-].[Na+]>O>[Cl:1][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1nccnc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1nccnc1Cl
Temperature: 140 °C
Reaction time: 0.58 h
Yield: 85.9 %

Procedure:
2.42 g of diethyl (3-chloro-2-pyrazinyl)malonate and 15 ml of dimethyl sulfoxide were mixed. To the mixture was added 0.62 g of sodium chloride and 0.32 g of water. The mixture was stirred for about 35 minutes at an inner temperature of 127 to 153° C. The reaction mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 1.53 g of ethyl (3-chloro-2-pyrazinyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:19])=[CH:11][C:12]=2/[CH:14]=[CH:15]/[C:16](O)=[O:17])[C:7]([CH3:20])=[CH:6]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.C(N(C(C)C)CC)(C)C.[Cl:57][C:58]1[CH:59]=[C:60]([S:64]([NH2:67])(=[O:66])=[O:65])[S:61][C:62]=1[Cl:63].Cl>ClCCl.O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:19])=[CH:11][C:12]=2/[CH:14]=[CH:15]/[C:16]([NH:67][S:64]([C:60]2[S:61][C:62]([Cl:63])=[C:58]([Cl:57])[CH:59]=2)(=[O:65])=[O:66])=[O:17])[C:7]([CH3:20])=[CH:6]1
Reactant: Cc1cn(Cc2ccc(Cl)cc2Cl)c2c(/C=C/C(=O)O)cc(F)cc12
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1cn(Cc2ccc(Cl)cc2Cl)c2c(/C=C/C(=O)NS(=O)(=O)c3cc(Cl)c(Cl)s3)cc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of (E)-3-[1-(2,4-dichloro-benzyl)-5-fluoro-3-methyl-1H-indol-7-yl]-acrylic acid (10.0 g, 26.4 mmol) in dichloromethane (100 mL) was added EDCI (7.9 g, 41.2 mmol), HOBt hydrate (0.71 g, 5.3 mmol), and diisopropylethylamine (10.6 g, 81.8 mmol), and the mixture was stirred for 20 mm. To the reaction was added 4,5-dichlorothiophene-2-sulfonamide (6.43 g, 27.2 mmol), and the mixture was stirred at room temperature for 15 mm, then at reflux for 16 h. The reaction was cooled to room temperature then diluted with 25 mL water followed by 25 mL 2 M HCl. The mixture was stirred for 5 mm, then the phases were split. The organic phase was diluted with 25 mL of 2 M HCl and stirred, which induced precipitation of the product. The temperature was reduced to 0° C., and stirring was continued for 1 h. The product was collected via vacuum filtration, washed with water (3×25 mL) and heptanes (2×25 mL), then vacuum dried at 60° C. to afford 9.3 g (60% yield) of the title compound. The product could be further purified via recrystallization from ethanol: 1H-NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 5.53 (s, 2H), 6.12 (d, 1H, J=8.4 Hz), 6.21 (d, 1H, J=15.4 Hz), 7.04 (dd, 1H, J=10.0, 2.4 Hz), 7.22 (dd, 1H, J=8.4, 2.0 Hz), 7.37 (s, 1H), 7.38 (d, 1H, J=2.0 Hz), 7.46 (dd, 1H, J=9.2, 2.4 Hz), 7.74 (d, 1H, J=15.4 Hz), 7.90 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.CO.C([O-])=O.[NH4+:22]>[Pd].O>[NH2:22][CH:5]1[CH2:6][CH2:7][C:2]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(=O)CC1
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCC(N)CC1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a mixture of tert-butyl (1-methyl-4-oxocyclohexyl)carbamate (4.00 g) and methanol (50 mL), ammonium formate (10.2 g) and water (5 mL) were added and stirred for 1 hour until they were completely dissolved. Then, 10% palladium on carbon (2.0 g) was added and stirred at room temperature for 65 hours. After insoluble materials were separated by filtration through celite, the solvent was distilled off, and chloroform was added to the resulting residue, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off to give tert-butyl (4-amino-1-methylcyclohexyl)carbamate (3.73 g) as a colorless syrup.
Reaction SMILES: C(=O)(O)[O-].[Na+:5].Cl.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:29][O:30][CH3:31])[C:14]([NH:16][CH:17]2[C:27](=[O:28])[N:19]3[C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1>O>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:29][O:30][CH3:31])[C:14]([NH:16][CH:17]2[C:27](=[O:28])[N:19]3[C:20]([C:24]([O-:26])=[O:25])=[CH:21][CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1.[Na+:5]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C

Procedure:
Sodium bicarbonate (1.04 g.) was added to a solution of 7-{2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 2.6 g.) in water (100 ml.) under ice-cooling and stirred at room temperature. The resultant solution was lyophilized to give sodium 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=S)[CH2:2][CH3:3].C(O)(=[O:31])C>O.C(OCC)(=O)C>[CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:31])[CH2:2][CH3:3]
Reactant: CC(=O)O
Reactant: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Solvent: O
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 0.5 h

Procedure:
Mercuric acetate (0.38 g) is added with stirring to a solution of N-propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (0.6 g) in acetic acid (10 cc), and stirring is continued for 4 hours 30 minutes at a temperature in the region of 20° C. The black reaction mixture is diluted with distilled water (25 cc) and ethyl acetate (50 cc) and then filtered and alkalinized with stirring with 4N aqueous sodium hydroxide solution to pH 13. After settling has taken place, the organic phase is separated and the aqueous phase is extracted with ethyl acetate (20 cc). The combined organic phases are washed successively with saturated aqueous sodium chloride solution (50 cc). After drying over magnesium sulphate, filtration and concentration to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C., N-propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (0.43 g) is obtained in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:35][C@H:34]([CH2:36][O:37]CC4C=CC=CC=4)[C@@H:25]([O:26]CC4C=CC=CC=4)[C@@H:16]3[O:17]CC3C=CC=CC=3)[C:4]=2[N:5]=[C:6](S(C)(=O)=O)[N:7]=1.C([O:48]CC=C)C=C.[Na].[NH3:53]>>[NH2:53][C:6]1[NH:7][C:2](=[O:48])[C:3]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:25]([OH:26])[C@@H:16]3[OH:17])[C:4]=2[N:5]=1
Reactant: CS(=O)(=O)c1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reactant: N
Reactant: C=CCOCC=C
Agent: [Na]
Product: Nc1nc2c(ccn2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1

Procedure:
4-Chloro-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine reacted sequentially with sodium allyloxide and liquid ammonia and deblocked by hydrogenation in the presence of a catalyst provides 2-amino-7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-one. Treatment with phosphoryl chloride and triethyl phosphate provides the corresponding 5'-phosphate compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@@H:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@H:30]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: N[C@H](CO)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@@H](c5ccccc5)CO4)c3)cc12
Yield: 24.2 %

Procedure:
Zinc chloride (9 mg, 0.067 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.135 mmol) and (S)-2-amino-2-phenylethanol (93 mg, 0.675 mmol) in PhCl (3 mL) rt. It was subjected to two interactions of microwave irradiation at 200° C. for 1 hr. The material was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (16 mg, 23%). 1H NMR (500 MHz, CD3OD) δ ppm 8.33 (1H, s), 7.94-8.00 (4H, m), 7.91 (1H, d, J=7.94 Hz), 7.64-7.73 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.32-7.42 (6H, m), 7.26 (2H, t, J=8.55 Hz), 5.45 (1H, t, J=9.16 Hz), 4.94 (1H, t, J=9.31 Hz), 4.36 (1H, t, J=8.24 Hz), 2.97 (3H, s). LC-MS retention time 1.76 min; m/z (MH+): 491. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: PHENOMENEX® Gemini C-18, 4.6×150 mm, 3 μm, Rt=18.32 min, purity=99%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=18.10 min, purity=99%.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]1([C:25]2=[CH:26][C:27]3[C:28]([CH:33]([O:36][Si](C(C)C)(C(C)C)C(C)C)[CH2:34][CH2:35]2)=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:19]1([C:25]2=[CH:26][C:27]3[C:28]([CH:33]([OH:36])[CH2:34][CH2:35]2)=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)[Si](OC1CCC(c2ccccc2)=Cc2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCC(c2ccccc2)=Cc2cccnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
TBAF (1.041 mL, 1.041 mmol) was added to the THF (5 mL) solution of (E)-6-phenyl-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridine (0.2049 g, 0.521 mmol) at rt. The reaction was stirred at room temperature for 6 hours. The solvent was removed via vacuum to give the crude product. MS (ESI)[M+H+]=238.25.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Br>C1COCC1>[OH:2][CH:1]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:17])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Cc1ccccc1[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)c1cnccc1-c1cccc(C#N)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 2.0 M 2-methylphenylmagnesium bromide in THF (0.15 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(2-methyl-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-:27])=[O:26])=[C:6]([CH:24]=1)[O:7][C@@H:8]1[CH2:12][O:11][C@@H:10]2[C@H:13](OS(C(F)(F)F)(=O)=O)[CH2:14][O:15][C@H:9]12.[F-:28].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C(Cl)Cl>[F:28][C@@H:13]1[C@H:10]2[O:11][CH2:12][C@@H:8]([O:7][C:6]3[CH:24]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N+:25]([O-:27])=[O:26])[C@H:9]2[O:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OS(=O)(=O)C(F)(F)F
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2F

Procedure:
3.7 g (8.9 mmol) [(3R,3aR,6R,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate (prepared as described for III.3 from III.1) in 53.2 ml of a 1M solution of tetrabutylammonium flouride in THF (53.2 mmol) is stirred at RT for 3 h. Water and DCM are added and the organic layer is separated, washed with water, dried and evaporated. The residue was purified by FC.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cn1cccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 49.1 %

Procedure:
Using 1-methyl-1H-pyrrole-2-carboxylic acid (97 mg, 0.78 mmol), tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (135 μL, 1.55 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 119, the title compound (133 mg, 49%) was obtained as a white powder.
Reaction SMILES: [C:1]1([CH:7]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH2:27][C:28](=[CH:32][C:33]([O:35]C)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1.O>[C:1]1([CH:7]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH2:27][C:28](=[CH:32][C:33]([OH:35])=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)C2CCCC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)C2CCCC2)C1
Yield: 60 %

Procedure:
A solution of N-(2-phenyl-2-cyclopentylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine (159 mg, 0.27 mmol) in MeOH (5 mL), THF (1 mL), H2O (1 mL), and 2.5 N NaOH (2.5 mL) was heated to 50° C. for 1 h. The reaction was cooled, diluted with H2O, acidified to pH=5.5, and extracted with EtOAc. The extracts were washed with H2O, dried, and concentrated to yield the titled compound (93 mg, 70%). MS (ESI) 575 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@H:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:11])=O)=[O:6])([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:19][O:20][C:21]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:9](=[O:11])[C@H:8]([NH:7][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:27]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](NC(=O)OC(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A mixture of (R)-Isopropoxycarbonylamino-phenyl-acetic acid (0.74 g), (L)-proline methyl ester hydrochloride (0.51 g), N-methyl morpholine (1.00 mL) and 1.00 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 10 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. The volatiles were pumped off and water was added followed by extraction with ethyl acetate and concentration of the organic layer. The remaining residue was purified by silica chromatography (ethyl acetate/isohexane=3/1) to give 0.95 g (91%) of the title compound as a colorless oil. (+)-APCI-MS: 349 (MH+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:32][C:31]=4[F:44])=[C:25]([CH2:45][CH2:46][CH3:47])[N:24]=[C:23]3[CH3:48])=[CH:21][C:16]=2[CH2:15][CH2:14]1>O.C(OCC)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]5[NH:3][C:4](=[O:7])[O:5][N:43]=5)=[CH:32][C:31]=4[F:44])=[C:25]([CH2:45][CH2:46][CH3:47])[N:24]=[C:23]3[CH3:48])=[CH:21][C:16]=2[CH2:15][CH2:14]1
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
A mixture of hydroxylammonium chloride (7.80 g), sodium hydrogen carbonate (11.4 g) and dimethyl sulfoxide (55 mL) was stirred at 40° C. for 30 min, 4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (5.41 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (55 mL), N,N′-carbonyldiimidazole (2.74 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (2.57 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.94 g, 48%).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=2[CH:7]=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:3])[CH3:2].[CH2:25]([Li])CCC.IC.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=2[CH:7]=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:5]=1[CH3:24])([CH3:25])([CH3:3])[CH3:2]
Reactant: COc1ccc(Nc2cc3c(c(C(C)C)c2C)OCC3(C)C)cc1
Reactant: [Li]CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A stirred solution of 7-isopropyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 52, 0.2 g, 0.615 mmol) in 5 mL of anhydrous tetrahydrofuran under argon, was cooled to -78° C. and treated with 1.6M solution of n-butyllithium in hexanes (0.77 mL, 1.23 mmol). The resulting green reaction mixture was stirred for 0.5 hour at -78° C. and then treated drop wise with iodomethane (0.5 mL, 6.15 mmol) that was passed through a bed of potassium carbonate. The yellow reaction mixture was allowed to warm to room temperature, recooled to 0° C., quenched with saturated ammonium chloride solution and extracted with diethylether. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to flash column chromatography to afford the title compound (0.11 5 g, 51%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.80 (d, 2H, J=9.1 Hz), 6.74 (s, 1H), 6.45 (d, 2H, J=9.1 Hz), 4.24 (s, 2H), 3.77 (s, 3H), 3.60 (br m, 2H), 3.25 (heptet, 1H, J=7.0 Hz), 2.12 (s, 3H), 1.38 (d, 6H, J=7.0 Hz), 1.32 (s, 6H), 1.24 (t, 6H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH:6]=[N:7]2.P(Br)(Br)([Br:19])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:19][C:4]1[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=2[CH3:1])[N:7]=[CH:6][CH:5]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1N=CCC2=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)c2c(Br)ccnc12
Temperature: 90 °C

Procedure:
A mixture of 5,8-dimethyl-6-nitro-4-quinolone (7.12 g, 32.7 mmol), phosphorus oxybromide (7.47 g, 26.12 mmol), pyridine (5.3 mL), and toluene (90 mL) is heated at 90° C. for 6 hours. The mixture is filtered hot, and the solid is washed with water and methylene chloride. The filtrate is extracted with methylene chloride (3×100 mL), and the combined organic layers are dried (sodium sulfate) and evaporated to afford 4-bromo-5,8-dimethyl-6-nitroquinoline.