Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:14]([NH2:25])[C:15]1[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[C:17]([O:18][CH3:19])[CH:16]=1>C(N(CC)CC)C>[CH3:19][O:18][C:17]1[CH:16]=[C:15]([CH:24]=[CH:23][C:20]=1[O:21][CH3:22])[CH2:14][NH:25][C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:12]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(CN)cc1OC
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)C23CC4CC(CC(C4)C2)C3)cc1OC

Procedure:
Subject 4.0 g. (20 mmoles) of adamantane carboxylic acid chloride, 3.3 g. (20 mmoles) of veratrylamine and 10.0 ml. of triethylamine to the process of Example 11 and obtain thereby the title product, m.p. 120°-122° C.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].C(OC([N:12]1[CH2:17][C@@H:16]([CH2:18]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:15]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][O:37][CH2:38][C@H:39]([O:41][CH2:42][CH3:43])[CH3:40])=[CH:32][CH:31]=2)[C@@H:14]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]3[O:54][CH2:53][CH2:52][N:51]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[C:50]=3[CH:60]=2)[CH2:13]1)=O)(C)(C)C>CN1CCCN(C)C1=O.CC(OC)(C)C>[CH2:42]([O:41][C@H:39]([CH3:40])[CH2:38][O:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:15]2[C@@H:14]([O:44][CH2:45][C:46]3[CH:47]=[CH:48][C:49]4[O:54][CH2:53][CH2:52][N:51]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[C:50]=4[CH:60]=3)[CH2:13][NH:12][CH2:17][C@H:16]2[CH2:18][NH2:1])=[CH:31][CH:32]=1)[CH3:43]
Reactant: [N-]=[N+]=[N-]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](COS(=O)(=O)c3ccc(C)cc3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN1CCCN(C)C1=O
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.57 mmol of sodium azide are added to a solution of 0.91 mmol of (3R,4R,5S)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (example 5d) in 5 ml of 1,3-dimethyl-tetrahydro-pyrimidin-2-one (DMPU) under argon at 50° C. After 2 h, the reaction mixture is cooled to RT, diluted with TBME, washed successively with H2O (2×) and brine, dried over Na2SO4 and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a pale yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.27 (EtOAc/heptane 1:1); Rt=5.98 (gradient I).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl[C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(O)C>Cl.O>[Br:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:6])[N:22]3[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]3=[N:1]2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: COC(=O)c1ccc(Br)cc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccn2c(=O)c3ccc(Br)cc3nc12
Temperature: 0 °C

Procedure:
A solution of methyl 2-amino-4-bromo-benzoate (460 mg; 2 mmol), 2-chloronicotinic acid (315 mg; 2 mmol), concentrated hydrochloric acid (5 drops), ethanol (5 ml) and water (25 ml) was heated at reflux for 18 hours, cooled to 0° C. and filtered. The solid filter cake obtained was dried in vacuo and used directly in the next example.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].C(O)=O.[CH3:15][NH:16][NH2:17]>C(OC)(C)(C)C>[F:1][CH:2]([F:11])[C:3]1[CH:4]=[C:5]([OH:6])[N:16]([CH3:15])[N:17]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(F)F
Solvent: COC(C)(C)C
Solvent: O=CO
Product: Cn1nc(C(F)F)cc1O
Temperature: 5 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
166 g (1 mol) of ethyl 4,4-difluoro-3-oxobutanoate were charged in 500 ml of methyl tert-butyl ether and treated with 140 g of formic acid. After cooling of the mixture to 5° C., 119 g (as 40% aqueous solution) of monomethylhydrazine were added. The mixture was then stirred for 20 h at 22° C. The phases were separated, and the organic phase was washed with 200 ml of water and dried over MgSO4. After the removal of the solvent under reduced pressure, 148 g of the product was obtained as an yellow solid having an m.p. of 133° C. and a purity of 95%. Yield 95%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([OH:11])[CH2:13]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnccc1N1CCC[C@@H](O)C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, (R)-3-hydroxypiperidine and triethylamine in DMF yielding (R)-1-(3-nitropyridin-4-yl)piperidin-3-ol, LCMS (m/z): 224.1 (MH+); LC Rt=1.06 min.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:27][CH3:28])=[C:10]([O:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>O1CCOCC1.C(O)(C)C>[NH:17]1[CH2:16][CH2:15][CH:14]([O:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][C:9]=2[O:27][CH3:28])[N:6]=[CH:5][N:4]=[C:3]3[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:30]([Cl:29])[C:31]=2[F:37])[CH2:19][CH2:18]1
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Temperature: 100 °C

Procedure:
4.0M HCl in Dioxane (4.0 ml) was added to a suspension of tert-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate (2.62 g) and 3-chloro-2-fluoroaniline (1.08 g) in iso-propanol (50 ml). The reaction mixture was stirred and heated at 100° C. for 2 hours. The yellow precipitate was filtered hot and washed with iso-propanol followed by diethylether and dried under vacuum to give 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline as a di-hydrochloride salt (2.38 g); 1H NMR Spectrum: (DMSO d6) 1.84-1.99 (m, 2H), 2.22-2.33 (m, 2H), 3.12-3.33 (m, 4H), 4.00 (s, 3H), 5.08 (m, 1H), 7.34 (t, 1H), 7.40 (s, 1H), 7.50 (t, 1H), 7.62 (t, 1H), 8.80 (s, 1H), 8.84-8.94 (m, 2H), 8.99-9.11 (m, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@H:28]2[CH2:32][C@@H:31]([CH2:33][OH:34])[NH:30][CH2:29]2)=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:44](N1C=CN=C1)(N1C=CN=C1)=[O:45]>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@@H:28]2[CH2:29][N:30]3[C:44](=[O:45])[O:34][CH2:33][C@@H:31]3[CH2:32]2)=[CH:4][N:3]=1
Reactant: Nc1ncc([C@@H]2CN[C@H](CO)C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncc([C@H]2C[C@H]3COC(=O)N3C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reaction time: 1 h
Yield: 9.5 %

Procedure:
A solution of 4-(2-amino-5-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (20 mg, 0.041 mmol) (Example 7) and DIEA (72 μL, 0.412 mmol) in acetonitrile (0.5 mL) was treated with carbonyldiimidazole (8.0 mg, 0.049 mmol). After 1 h, the starting material was completely consumed. The reaction mixture was quenched with 1.0 N aqueous NaOH solution (1.0 mL) and the mixture was stirred vigorously for 5 min, then, diluted with DCM (10 mL). The organics were washed with brine (2 mL) and dried over Na2SO4 and concentrated. The crude material was purified by reverse phase prep HPLC yielding 4-(2-amino-5-((6R,7aS)-3-oxohexahydropyrrolo[1,2-c]oxazol-6-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (2.0 mg, 7% yield). LCMS (m/z): 511.3, 513.3 (MH+), 0.61 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.92-7.84 (m, 2H), 7.46 (s, 1H), 7.44-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.34-7.28 (m, 1H), 5.19 (t, J=5.87 Hz, 1H), 4.61-4.56 (m, 1H), 4.34 (dd, J=3.52, 9.00 Hz, 1H), 4.24-4.15 (m, 1H), 3.92-3.80 (m, 1H), 3.74-3.62 (m, 1H), 2.41 (td, J=5.72, 11.64 Hz, 1H), 1.84-1.71 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([NH2:14])[CH:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21].[N-]=C=O>CO>[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([NH:22][C:23]([NH:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[O:13][N:12]=1)=[O:24])=[O:21]
Reactant: Nc1cc(-c2ccc(C(F)(F)F)cc2)on1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Agent: [N-]=C=O
Solvent: CO
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1cc(-c2ccc(C(F)(F)F)cc2)on1

Procedure:
5-(4-(Trifluoromethyl)phenyl)-3-aminoisoxazole (500 grams) in 6 l. 1,2-dichloromethane was reacted in a reaction vessel with 2,6-dichlorobenzoyl isocyanate (567 grams). The isocyanate was added in rapid dropwise fashion over one hour keeping the temperature between 20°-40° C. The reaction mixture was allowed to react at 40° C. for three hours and was then stripped and slurried in 1 l. methanol. A white solid product formed which was filtered, dried in an air dryer, and then identified by NMR analysis as the desired compound, yield, 881 grams, m.p.=227°-230° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[C:19]([F:24])[CH:18]=1
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2c1

Procedure:
The method of Example 281 was used with 218.6 mg (1 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile, 174.7 mg (1.2 mmol) of 4-chloro-2-fluoro-aniline and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol. This afforded 319.8 mg of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 325.9, 327.9
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][S:34]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=3)(=[O:36])=[O:35])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)NCC2Cc3c(sc(N)c3C(=O)OC(C)(C)C)CO2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (101 mg, 0.35 mmol) in dichloromethane (1 ml) was added pyridine (32 μl, 0.39 mmol) and 4-methoxybenzenesulfonyl chloride (82 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with dichloromethane (2 ml) and subjected to preparative TLC (1:1 hexanes/ethyl acetate) affording 10 mg, (10% ) of 2-amino-5-((4-methoxy-benzenesulfonylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1COCC1>[CH2:20]([CH:3]([C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH2:2][NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCC(Cc1ccccc1)C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(NCC(Cc1ccccc1)C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1)c1ccc(Cl)cc1

Procedure:
2-(Aminomethyl)-1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3-phenylpropan-1-one (40 mg, 0.1 mmol) was dissolved in THF and then TEA (10.3 mg, 0.1 mmol) followed by 4-chlorobenzoyl chloride (0.1 mmol) were added. Upon completion of addition, the reaction mixture was allowed to stir for several hours and then concentrated. The resulting concentrate was subjected to silica gel chromatography (100% EtOAc) to provide Example 7. MS Found 532.1 (M+H).
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].BrCCO.[CH2:10]1[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[O:11]1.O>C(O)C>[CH2:10]1[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH:15][CH2:2][CH2:1][OH:3])=[CH:13][C:12]=2[O:11]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CC(=O)[O-]
Agent: OCCBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCNc1ccc2c(c1)OCO2

Procedure:
27 mmol of sodium acetate and 15 mmol of 2-bromoethanol are added to 10 mmol of 3,4-methylenedioxyaniline dissolved in ethanol. After 24 hours of heating at reflux, the reaction mixture is brought to ambient temperature, water is added, and then the aqueous phase is extracted with dichloromethane. The organic phases are combined, the solvent is evaporated off and the crude residue is purified by chromatography on silica, using a 10:90 dichloromethane/ethyl acetate mixture as eluant, to yield the expected product in the form of an oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(N(CC)CC)C>ClCCl>[N+:18]([C:21]1[CH:22]=[C:23]([S:27]([O:1][C@@H:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 39.5 mmol, Eq: 1.00) was combined with dichloromethane (75 ml) to give a colorless solution. Then at 0° C., 3-nitrobenzene-1-sulfonyl chloride (9.58 g, 41.9 mmol, Eq: 1.06) was added. Also at 0° C., triethylamine (12.0 g, 16.5 ml, 119 mmol, Eq: 3.00) was added dropwise to the reaction mixture. The reaction was stirred for 1.5 h at 0° C. and then for 2 days at room temperature. The reaction mixture was diluted in dichloromethane (200 ml) and then extracted with 2×50 ml HC10.5N, 70 ml satd. NaHCO3 solution and 50 ml satd. NaCl solution. The organic layer was stirred over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a brown gum (17.25 g, quant., MS (m/e)=431.3 [M+H+]. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:58])(=[N:54][CH:55]2[CH2:57][CH2:56]2)=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:58])(=[N:54][CH:55]7[CH2:57][CH2:56]7)=[O:53])=[CH:47][CH:46]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CS(=O)(=NC1CC1)Nc1ccc(Br)cc1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(NS(C)(=O)=NC5CC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N-(4-bromophenyl)-N′-cyclopropyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.11 min; Mass spectrum (ESI+): m/z=712 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:12]1([C:9]2[CH:10]=[CH:11][C:5]3[O:4][C:3]([CH2:2][O:21][C:18](=[O:20])[CH3:19])=[N:7][C:6]=3[CH:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)[O-]
Reactant: BrCc1nc2cc(-c3ccccc3)ccc2o1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2cc(-c3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromomethyl-5-phenyl-benzoxazole 49 (440 mg, 1.53 mmol) and cesium acetate (585 mg, 3.06 mmol) in 5 ml DMF was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, dried, filtered and concentrated to yield acetic acid 5-phenyl-benzoxazole-2-ylmethyl ester 50.
Reaction SMILES: [N:1]([N+]([O-])=O)=[O:2].[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[NH:13][CH2:14][CH2:15][Cl:16])[CH2:7][CH:8]([CH3:10])[CH3:9]>O1CCCC1.C(O)(=O)C>[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[N:13]([CH2:14][CH2:15][Cl:16])[N:1]=[O:2])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O
Yield: 60.4 %

Procedure:
Dinitrogen trioxide gas (0.6 g) was introduced into a solution of 3-isopentyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (2.15 g, 5.23 mmol), synthesized in the above-mentioned way, in a mixture of tetrahydrofuran (50 ml) and acetic acid (8 ml) with well stirring at 0° to 5° C. After continuation of stirring for 2 hours, the resulting solution was vacuum-concentrated at 25° C. and purified by column chromatography (packing: Kiesel gel 60; eluent: chloroform/methanol 10:1), giving 1.44 g of 3-isopentyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 62.6%, m.p. 66°-68° C., [α]D20 +65.2° (C 1.0, methanol).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH:31]1([N:36]2[CH2:41][CH2:40][NH:39][C:38](=[O:42])[CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([N:36]2[CH2:41][CH2:40][N:39]([C:19]3[CH:20]=[CH:21][C:9]4[C:8](=[O:30])[C:7]5[C:6]6[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=6)[NH:13][C:12]=5[C:11]([CH3:16])([CH3:17])[C:10]=4[CH:18]=3)[C:38](=[O:42])[CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: O=C1CN(C2CCCC2)CCN1
Product: CC1(C)c2cc(N3CCN(C4CCCC4)CC3=O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound B1 and 4-cyclopentylpiperazin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:26])([F:25])[F:24])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH2:22])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:27][C:28]([F:34])([F:33])[CH2:29][C:30](O)=[O:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:23]([F:24])([F:25])[F:26])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([NH:22][C:30](=[O:31])[CH2:29][C:28]([F:34])([F:33])[F:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: O=C(O)CC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NN1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline-1-amine (0.1 g, 0.247 mmol) in CH2Cl2 (10.0 ml) was added 3,3,3-trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIPEA (0.047 g, 0.370 mmol) and the reaction was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2, and the separated CH2Cl2 layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400 MHz, CDCl3) δ 7.32, (d, J=6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J=8.0, 1H), 7.14 (d, J=8.8, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z 514.86 ([M+H]+); IR (thin film) 3428, 1112, 857 cm−1.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][N:44]1[C:52]2[CH:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][NH:62][CH3:63])=[C:55]([C:64]([F:67])([F:66])[F:65])[CH:54]=3)[N:49]=[C:48]([C:68]#[N:69])[C:47]=2[N:46]=[CH:45]1>ClCCl>[C:68]([C:48]1[C:47]2[N:46]=[CH:45][N:44]([CH3:43])[C:52]=2[CH:51]=[C:50]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][N:62]([CH3:63])[C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])=[O:9])=[C:55]([C:64]([F:67])([F:65])[F:66])[CH:54]=2)[N:49]=1)#[N:69]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 50.1 %

Procedure:
To a solution of (S)-1-methylpyrrolidine-2-carboxylic acid (16 mg), DIPEA (60 ul) and HBTU (51.7 mg) in dichloromethane (2 ml) was added 1-methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (51.1 mg). The reaction was left stirring at room temperature for 60 hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)—N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N,1-dimethylpyrrolidine-2-carboxamide (30.2 mg).