Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C@H:16]([CH2:20][CH3:21])[C@H:17]([OH:19])[CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[CH2:8]([N:15]([C@H:16]([CH2:20][CH3:21])[C@H:17]([OH:19])[CH3:18])[C:24](=[O:25])[CH2:23][Cl:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC[C@@H](NCc1ccccc1)[C@@H](C)O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]([C@@H](C)O)N(Cc1ccccc1)C(=O)CCl
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.43 mL, 3.4 mmol) was added to a −40° C. solution of (2R,3R)-3-(benzylamino)pentan-2-ol (220 mg, 1.1 mmol) in dichloromethane (100 mL), followed by the addition of 2-chloroacetyl chloride (0.10 mL, 1.1 mmol) dropwise. The reaction mixture was stirred at −40° C. for 1 hour and then quenched with saturated NaHCO3 solution. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded N-benzyl-2-chloro-N-((2R,3R)-2-hydroxypentan-3-yl)acetamide. MS APCl calc'd for C14H20ClNO2 [M+H]+ 270. found 270.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[Br:1][C:2]1[N:3]=[N:4][C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nn1
Reactant: OB(O)c1ccccc1F
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: COCCOC
Product: Fc1ccccc1-c1ccc(Br)nn1

Procedure:
300 mg (1.26 mmol) of 3,6-dibromopyridazine, 176.5 mg (1.26 mmol) 2-fluoro-phenylboronic acid, 34.7 mg (0.038 mmol) of tetrakis(triphenylphosphine)palladium and 1.26 ml of an aqueous 1 M sodium carbonate solution in 15 ml of DME were heated under reflux for 3 h. After cooling, the reaction mixture was poured onto water and extracted with ethyl acetate. The combined organic phases were dried, evaporated, and the product purified by RP18 chromatography. Yield: 62 mg.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[CH2:21]([O:23][C:24](=[O:37])[C:25]([O:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][C:30]=1[CH3:36])([CH3:27])[CH3:26])[CH3:22].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH2:21]([O:23][C:24](=[O:37])[C:25]([CH3:27])([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:10][CH2:9][CH2:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:5][CH:6]=2)=[CH:31][C:30]=1[CH3:36])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
0.181 g (0.642 mmol) of the above prepared 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol and 0.153 g (0.642 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) were dissolved in 8 ml of abs. THF and treated successively at 0° C. with 0.156 g (0.771 mmol) of tributylphosphine and 0.133 g (0.770 mmol) of N,N,N′,N′-tetramethylazodicarboxamide. The cooling bath was then removed and stirring continued for one night. Filtration over a pad of Celite, evaporation of the solvent, followed by flash chromatography (SiO2, hexane/AcOEt=85/15), delivered 0.070 g of the title compound as colorless oil.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[ClH:11].[CH2:12]([OH:14])[CH3:13]>>[ClH:11].[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1](=[NH:10])[O:14][CH2:12][CH3:13])=[CH:3][CH:4]=1
Reactant: CCO
Reactant: COc1ccc(C#N)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1

Procedure:
Ethyl 4-methoxybenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, anisonitrile (25.6 g, 0.199 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 40.5 g (94%) of the target compound as pale-red crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]#[N:22])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=2)=O)C.[H][H]>CCO.O=[Pt]=O>[CH2:18]([O:17][C:15]([C:10]1[CH:11]=[CH:12][C:13]2[CH:14]=[C:6]3[C:4](=[O:3])[NH:22][CH2:21][CH2:20][N:7]3[C:8]=2[CH:9]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC#N)c2c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)c1ccc2cc3n(c2c1)CCNC3=O
Yield: 109.2 %

Procedure:
To 1-cyanomethyl-1H-indole-2,6-dicarboxylic acid diethyl ester (500 mg, 1.66 mmol) in 20 mL of absolute EtOH was added PtO2 (Adams' catalyst). The reaction mixture was hydrogenated at 50 psi of hydrogen overnight. The reaction mixture was filtered through a pad of diatomaceous earth, the solid cake was washed with dichloromethane several times. The solvent was evaporated to dryness to give 468 mg of 1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid ethyl ester as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.O.[SH-:19].[Na+]>C(O)C>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[N:7]=[C:2]([SH:19])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: Fc1ccccc1-c1nnc2ccc(Cl)nn12
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccccc1-c1nnc2ccc(S)nn12

Procedure:
A solution of 6-chloro-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 mmol) and sodium hydrosulfide hydrate (1.5 equiv.) in ethanol was refluxed for 2-6 hours. The solvent was removed under reduced pressure, water (2 ml) was added, and the pH adjusted to 9 with sodium hydroxide solution. After removing the resulting precipitate, the filtrate was acidified with 6M HCl to a pH of 3, and the formed precipitate was collected, washed with cold water, and dried to give 3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-thiol. This compound is taken on to the next step without purification
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:6][CH:5]=1)([O-])=O>C(O)C.O.C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:30][CH2:31][O:32][C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1ccc(CCN(CCCCCCN2C(=O)c3ccccc3C2=O)CCOc2ccc(N)cc2)cc1
Reaction time: 12 h
Yield: 100.1 %

Procedure:
2-[6-([2-(4-nitrophenyl)ethyl]{2-[(4-nitrophenyl)oxy]ethyl}amino)hexyl]-1H-isoindole-1,3(2H)-dione (0.35 g) was dissolved in a mixture of ethanol (40 ml), water (5 ml) and acetic acid (5 ml) and the resulting solution degassed under reduced pressure. 10% Palladium on carbon (56% paste, 0.27 g) was added and the resulting mixture stirred vigorously under a hydrogen atmosphere (atmospheric pressure) for 12 h. The reaction mixture was filtered through Celite™ and washed with ethanol. The filtrate and washings were evaporated to dryness to give the title compound (0.313 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C1(C)C=CC=CC=1.CCCCCC>[C:20]([C:14](=[CH:13][NH:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:21]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CCc1cccnc1N
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C(C#N)=CNc1ncccc1CC

Procedure:
A solution of 2-amino-3-ethylpyridine (13.0 g., 0.1063 mole) and ethyl ethoxymethylenecyanoacetate (18.0 g., 0.1063 mole) in toluene (50 ml.) was heated on a steam bath for 20 minutes. The solution was cooled and the resulting mixture diluted with Skellysolve B. The title compound (19.0 g.), m.p. 122°-125° C., was collected by filtration. From the mother liquors, after recrystallization from cyclohexane, was obtained a further crop (7.0 g.) of product, m.p. 122°-125° C. Total yield of title compound, 26.0 g. (99.6%). The material from cyclohexane was recrystallized twice from methanol to give analytical material, m.p. 123°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@@:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.[H-].[Na+].[CH2:27]([O:34][C@H:35]1[C@H:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:39]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:38][C@@H:37]2[O:58][C@H:36]12)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:27]([O:34][C@@H:35]1[C@@H:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:39]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[O:38][C@@H:37]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[C@@:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:23][CH3:24])([F:22])[C:9]2=[O:21])[C@@H:36]1[OH:58])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)Nc2cc(C(F)(F)F)ccc21
Reactant: c1ccc(COC[C@H]2O[C@@H]3O[C@@H]3[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N([C@@H]2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-II) (0.200 g, 0.55 mmol) was added anhydrous tetrahydrofuran (3 mL) and 95% sodium hydride (0.018 g, 0.7 mmol). The yellow solution was allowed to stir at room temperature for 30 minutes. 1,2-Anhydro-3,4,6-tri-O-benzyl-α-D-glucopyranose (prepared by the method of Halcomb and Danishefsky J. Am. Chem. Soc. 1989, 111, 6661) (0.480 g, 1.1 mmol) was then dissolved in anhydrous tetrahydrofuran (2.5 mL) and added dropwise to the reaction mixture over 15 minutes. The reaction was allowed to stir at reflux overnight. Once complete, the reaction was cooled and then poured into saturated sodium bicarbonate. The solution was extracted with ethyl acetate (3×). The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The crude mixture was purified via flash chromatography (silica gel, 30% ethyl acetate in hexanes). The title product was obtained as a yellow oil (0.287 g, 65%). 1H NMR (CDCl3, 400 MHz): δ 7.79 (dd, 1H, J=1.8 Hz, 0.68 Hz), 7.45 (s, 1H), 7.39-7.20 (m, 18H), 6.69 (dd, 1H, J=7.6 Hz, 1.1 Hz), 5.43 (d, 1H, J=9.5 Hz), 4.93 (m, 3H), 4.67 (m, 1H), 4.55 (dd, 2H, J=12.3 Hz, 5.7 Hz), 4.3 (ddd, 1H, J=4.9 Hz, 4.2 Hz), 3.87 (d, 1H, J=9.3 Hz), 3.79-3.70 (m, 4H), 3.42 (s, 3H), 2.54 (d, 1H, J=4.3 Hz).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1.[Br-].[CH3:14][S+](C)C.[OH-].[K+].O>C(#N)C>[O:12]1[CH2:14][CH:11]1[C:9]1[O:10][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(C2OCCO2)o1
Reactant: C[S+](C)C
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: c1cc(C2OCCO2)oc1C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
5-[1,3]Dioxolan-2-yl-furan-2-carbaldehyde (2.03 g, 12.1 mmol), trimethylsulfonium bromide (1.90 g, 12.1 mmol) and potassium hydroxide (779 mg, 13.9 mmol) were suspended in acetonitrile (75 mL), and the solution was stirred overnight at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, 2-(5-oxiranyl-furan-2-yl)-[1,3]dioxolane (2.25 g) was obtained as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(OCC)(=O)C.O>CS(C)=O>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CN)cc1
Reactant: COCCOc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COCCOc1cc(NCc2ccc(OC)cc2)ccc1[N+](=O)[O-]

Procedure:
To a solution of 2-methoxy-ethanol in 4 ml dry THF, was added tert-butoxide (378 mg, 3.37 mmol) at 0° C. The resulting mixture was added dropwise to the solution of 2,4-difluoro-1-nitro-benzene (536 mg, 3.37 mmol) in 5 ml dry THF at 0° C. The mixture was stirred at 0° C. for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give 4-Fluoro-2-(2-methoxy-ethoxy)-1-nitro-benzene. 4-Fluoro-2-(2-methoxy-ethoxy)-1-nitro-benzene (1.35 g, 6.3 mmol) was treated with p-methoxybenzylamine (1.64 mL, 12.6 mmol) in dimethyl sulfoxide at 80° C. in a sealed tube for 4 hr. After work up with ethyl acetate and water isolated N-(4-methoxybenzyl)3-(2-methoxyethoxy)-4-nitrobenzenamine intermediate. RP-HPLC: 2.13 min; ES-MS (M+H)+=346; To this intermediate added trifluoroacetic acid and heated the reaction mixture at 80° C. for 1 hr to deprotect the p-methoxybenzyl functionality to give final product 3-(2-methoxyethoxy)-4-nitobenzenamine. RP-HPLC: 1.14 min; ES-MS (M+H)+=213; 1H-NMR (MeOH-d4) δ (ppm): 3.4 (s, 3 H), 3.8 (t, 2 H), 4.10 (t, 2 H), 6.2 (dd, 1 H), 6.26 (d, 1 H), 7.76 (d, 1 H).
Reaction SMILES: [CH2:1]1[C@:6](O)([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1[NH2:13].O=[CH:15][C@@H:16]([C@H:18]([C@@H:20]([C@@H:22]([CH2:24][OH:25])[OH:23])[OH:21])[OH:19])[OH:17].C[O-].[Na+]>CO>[CH:1]1[C@H:2]([NH2:13])[C@H:3]([OH:12])[C@@H:4]([OH:11])[C@H:5]([OH:10])[C:6]=1[CH2:7][OH:8].[CH2:24]1[O:25][C@@H:15]2[O:23][C@H:22]1[C@@H:20]([OH:21])[C@H:18]([OH:19])[C@H:16]2[OH:17]
Reactant: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O
Product: O[C@@H]1[C@@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Reaction time: 4 h
Yield: 87.6 %

Procedure:
482 mg (0.843 mmol)of 1,6-anhydro-3,4-di-O-acetyl-2-deoxy-2 -[1D(1N,2,4/3)-(2,3,4-tri-O-acetyl-5-C-acetoxymethyl-2,3,4-trihydroxy-5-cyclohexen-1-yl)amino]-β-D-glucopyranose (compound 4) was dissolved in dry methanol (20 ml) and a methanolic solution of sodium methoxide (0.5N, 0.1 ml) was added. After 4 hours, solvent was evaporated and the residue was purified by passing through a column of sephadex using water:ethanol (1:1) as eluent to provide pure 1,6-anhydro-2-deoxy-2-[1D-(1N,2,4/3)-5-C-hydroxymethyl-2,3,4-trihydroxy-5-cyclohexen-1-yl)amino]-β-D-glucopyranose (compound 5) (249 mg, 92.5%) as white powder after lyophilization.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:15][C:14]=2[F:29])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:42][O:43][CH2:44][CH2:45][OH:46]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:15][C:14]=2[F:29])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:42][O:43][CH2:44][CH2:45][OH:46])=[O:7]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCOC2CCCCO2)cc1F
Yield: 69 %

Procedure:
The title compound was prepared from reaction of 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by column chromatography on silica gel (50% EtOAc/PE) as eluant), to give 3,4-difluoro-2-{2-fluoro-4-[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]anilino}-N-(2-hydroxyethoxy)benzamide as a white solid (69%) which was used directly in the next step. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.87 (br s, 1 H), 7.46–7.39 (m, 1 H), 7.31 (dd, J=12.2, 1.8 Hz, 1 H), 7.28–7.20 (m, 1 H), 7.14 (dd, J=8.3, 1.6 Hz, 1 H), 6.79 (ddd, J=8.8, 8.8, 4.7 Hz, 1H), 4.80 (br s, 1H), 4.46 (d, J=16.1 Hz, 1H), 4.36 (d, J=16.0 Hz, 1 H), 3.84 (t, J=4.8 Hz, 2 H), 3.75 (ddd, J=11.5, 8.6, 3.3 Hz, 2 H), 3.55 (t, J=4.8 Hz, 2 H), 3.51–3.44 (m, 2 H), 1.76–1.60 (m, 2 H), 1.55–1.42 (m, 4 H). HRMS (EI+) calcd. for C23H23F3N2O5 464.1559 (M+), found 464.1558.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:15][C:16](=[O:36])[N:17]([CH2:26][C:27]1[C:28]([O:34][CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1)[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][N:19]=1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[C:11]([O:15][C:16](=[O:36])[N:17]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][CH:9]=2)[OH:25])=[CH:20][N:19]=1)[CH2:26][C:27]1[C:28]([O:34][CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ccc(C=O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ccc(C(O)c2c[nH]c3ncnc(Cl)c23)cn1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.121 g, 0.790 mmol), (5-fluoro-2-methoxy-pyridin-3-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (77), 2.5 mL of N,N-dimethylformamide and cesium carbonate (0.751 g, 2.30 mmol) were combined in a round bottom flask. The reaction was stirred at room temperature for 6 days, then neutralized with 0.1N aqueous hydrochloric acid, then extracted 3× with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated. The resulting material was purified by silica gel column chromatography, eluting with methanol and dichloromethane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (78, 0.023 g). MS (ESI) [M−H+]−=513.2, 515.2.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:25])[NH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])=[CH:9][C:8]([C:21]([F:24])([F:23])[F:22])=[CH:7][CH:6]=2.[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34](CO)[C:29]=2[N:28]=[N:27]1.[CH2:37](O)C>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:21]([F:22])([F:24])[F:23])[CH:9]=3)[NH:4][C:3](=[O:25])[C:2]=2[NH:1][CH2:37][N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[N:27]2)[CH:17]=1
Reactant: OCc1cccc2[nH]nnc12
Reactant: COc1ccc(Cl)cc1-c1c(N)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Reactant: CCO
Product: COc1ccc(Cl)cc1-c1c(NCn2nnc3ccccc32)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Yield: 71.6 %

Procedure:
A solution of 3-amino-4-(5-chloro-2-methoxyphenyl)-6-(trifluoromethyl)quinolin-2(1H)-one(500 mg, 1.36 mmol), benzotriazole methanol (202.9 mg, 1.36 mmol) and absolute ethanol (5 mL) was heated to 60° C. overnight (18 hours). The resulting suspension was then cooled and the solids were collected. The solids were then washed with ethanol and air dried affording 4-(5-chloro-2-methoxyphenyl)-3-[[(1H-benzotriazol-1-yl)methyl]amino]-6-(trifluoromethyl)quinolin-2(1H)-one (487 mg, 71.6%).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>C1(C)C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:5]1([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[S:3][C:2]([NH:1][C:27]([NH:26][C:24](=[O:25])[C:23]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:22]=2[F:21])=[O:28])=[N:6]1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) was dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g), and 2,6-difluorobenzoylisocyanate (0.4 g) which is a starting compound was added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [CH3:1][C:2]1C=C(C)C=CC=1S(CCC)(=O)=O.[CH3:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([CH3:25])[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:18][C:17]=1[N+:30]([O-:32])=[O:31]>>[CH3:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([CH3:25])[C:19]([S:26]([CH2:29][CH2:1][CH3:2])(=[O:28])=[O:27])=[CH:18][C:17]=1[N+:30]([O-:32])=[O:31]
Reactant: CCCS(=O)(=O)c1ccc(C)cc1C
Reactant: Cc1c([N+](=O)[O-])cc(S(C)(=O)=O)c(C)c1[N+](=O)[O-]
Product: CCCS(=O)(=O)c1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1C

Procedure:
2,4-Dimethyl-1-propylsulfonylbenzene (Beilstein H 5, page 491) was dinitrated analogously to (a).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33](=O)[NH2:34])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([O:5][C:6](=[O:36])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(C(N)=O)cc1Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
2-[(4-{2-[(5-Carbamoyl-3-chloropyridin-2-yl)(heptyl)amino)ethyl)-1,3-thiazol-2-yl)thio)-2-methylpropionic acid tert-butyl ester (0.85 g) synthesized in Example 281-2 was dissolved in dichloromethane (10 mL), triethylamine (0.26 mL), trifluoroacetic acid anhydride (0.24 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=9:1) to give the title compound (0.37 g).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[CH:23]=[C:24]([CH3:26])[S:25][C:19]=2[N:18]=[C:17]1[CH3:27]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[CH:23]=[C:24]([CH3:26])[S:25][C:19]=4[N:18]=[C:17]3[CH3:27])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1cc2c(=O)n(N)c(C)nc2s1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1cc2c(=O)n(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(C)nc2s1

Procedure:
1-Adamantaneacetyl chloride and 3-amino-2,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54-1.76 (m, 12 H) 1.89-1.99 (m, 3 H) 2.04-2.18 (m, 2 H) 2.37 (s, 3 H) 2.5 (s, 3 H) 7.09 (s, 1 H) 10.83 (s, 1 H); MS (ESI+) m/z 372 (M+H)+.