Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17][S:18]([O-:20])=[O:19].[Na+].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.[Cu]I>[CH3:17][S:18]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:20])=[O:19]
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 150 °C

Procedure:
A mixture of 250 mg (0.764 mmol) of the compound of Example 15A, 86 mg (0.841 mmol) of sodium methanesulphinate, 19 mg (0.168 mmol) of (S)-proline and 23 mg (0.168 mmol) of potassium carbonate in 3 ml of DMSO/water (4:1) was initially degassed, 16 mg (0.084 mmol) of copper(I) iodide were then added and the mixture was finally, under an argon atmosphere, heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 150° C. for 30 min. After cooling to RT, the reaction mixture was filtered through a little Celite and then separated into its components by preparative HPLC (Method 9). Concentration of the product fractions and drying of the residue under high vacuum gave 83 mg (33% of theory) of the title compound.
Reaction SMILES: Cl.C([O:6][C:7](=[O:37])[CH2:8][N:9]([S:19]([C:22]1[CH:31]=[C:30]2[C:25]([C:26]([Cl:36])=[CH:27][N:28]=[C:29]2[NH:32][C:33]([NH2:35])=[NH:34])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(C)(C)C>C(C(O)=O)(F)(F)F.C1(C)C=CC=CC=1>[Cl:36][C:26]1[C:25]2[C:30](=[CH:31][C:22]([S:19]([N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[CH2:8][C:7]([OH:37])=[O:6])(=[O:20])=[O:21])=[CH:23][CH:24]=2)[C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[N:28][CH:27]=1
Reactant: COc1cccc(CN(CC(=O)OC(C)(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(CN(CC(=O)O)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-methoxybenzyl)glycine t-butyl ester hydrochloride (95 mg, 0.167 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 1 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo. The residue was dissolved in EtOAc and stirred at room temperature for 1 h. The resulting precipitate was collected by filtration, washed with Et2O and dried to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-methoxybenzyl)glycine (65 mg, 0.128 mmol) as a white powder.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[CH3:15])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: CCOC(=O)C=Cc1ccc(C)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C)c(O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.4 %

Procedure:
To a solution of ethyl 3-(3-(benzyloxy)-4-methylphenyl)acrylate (2.50 g) in ethanol (50 mL) was added 10% palladium-activated carbon (250 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 15 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.50 g) as a colorless oil.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[NH2:9][CH:10]=[C:11]([CH3:14])[CH:12]=O.C(N(CC)CC)C>Cl.C([O-])(=O)C.[NH2+]1CCCCC1>[CH3:14][C:11]1[CH:10]=[N:9][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:12]=1
Reactant: CC(C=O)=CN
Reactant: O=C1CCCC(=O)C1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cnc2c(c1)C(=O)CCC2
Temperature: 120 °C
Reaction time: 24 h
Yield: 52.7 %

Procedure:
A mixture of cyclohexane-1,3-dione (22.4 g., 0.2 mol.), 3-amino-2-methylacrolein (17 g., 0.2 mol.), triethylamine (10 ml.) and piperidinium acetate (0.25 g.) was heated with stirring in an oil bath at 120° C for 24 hours. The cooled reaction mixture was dissolved in 2N HCl (50 ml.) and extracted with ethyl acetate (3 × 50 ml.) and the organic extracts discarded. The aqueous solution was adjusted to pH 10 with sodium carbonate and extracted with chloroform (3 × 50 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo. The residual oil was distilled to give the title compound as a colorless oil (17 g., 52%) b.p. 79°/0.2 mm Hg which solidified.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[CH:12]([N:15]1[C:19]([C:20]2[CH:21]=[C:22]3[N:28]([N:29]=2)[C:27]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:26]=2[O:25][CH2:24][CH2:23]3)=[N:18][CH:17]=[N:16]1)([CH3:14])[CH3:13]>C(OCC)C>[OH:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:34][C:31]2[CH:32]=[CH:33][C:26]3[O:25][CH2:24][CH2:23][C:22]4[N:28]([N:29]=[C:20]([C:19]5[N:15]([CH:12]([CH3:14])[CH3:13])[N:16]=[CH:17][N:18]=5)[CH:21]=4)[C:27]=3[CH:30]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: O=C(CO)N1CCNCC1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C=O)ccc1OCC2
Agent: Cl
Solvent: CCOCC
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(CN3CCN(C(=O)CO)CC3)ccc1OCC2

Procedure:
Following the procedure for 128 without the use of HCl in diethyl ether, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehyde was reacted with 2-hydroxy-1-piperazin-1-yl-ethanone to give 132 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.95 (s, 1 H); 7.86 (d, J=2.0 Hz, 1 H); 7.28-7.23 (m, 1 H); 7.17 (d, J=8.2 Hz, 1 H); 6.86 (s, 1 H); 5.73-5.60 (m, 1 H); 4.55 (t, J=6.0 Hz, 2 H); 4.15 (s, 2 H); 3.69 (t, J=4.8 Hz, 2 H); 3.64-3.55 (m, 3 H); 3.29 (t, J=4.8 Hz, 2 H); 3.16 (t, J=6.0 Hz, 2 H); 2.55-2.46 (m, 4 H); 1.58 (d, J=6.6 Hz, 6 H). LCMS: RT=5.70 min, M+H+=452
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][OH:36].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][CH2:34][CH2:35][OH:36])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCO
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCO)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 6 %

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.021 g (0.33 mmole) of 2-amino-ethanol, 0.102 g (0.27 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.195 mL (1.12 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) to give 0.0065 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-hydroxy-ethyl)-3-methoxy-benzamide (I-30) as a white solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=[NH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[P:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31]>>[CH:30]([P:29]([CH:33]([CH3:35])[CH3:34])[N:22]=[C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:32])[CH3:31]
Reactant: CC(C)P(Cl)C(C)C
Reactant: N=C(Nc1ccccc1Sc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: CC(C)P(N=C(Nc1ccccc1Sc1ccccc1)c1ccccc1)C(C)C

Procedure:
Procedure as described for NP Amidine I using the following amounts and modifications: 1.52 g of N1-(2-(phenylthio)phenyl)benzamidine (Amidine XIV, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (2.07 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][O:9]2)[N:5]=[CH:4][C:3]=1[C:11]#[N:12].[OH:13][C@H:14]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CCO>[OH:9][CH:8]([C:6]1[N:5]=[CH:4][C:3]([C:11]#[N:12])=[C:2]([CH3:1])[CH:7]=1)[CH2:10][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C@H:14]([OH:13])[C:22]2[CH:31]=[CH:30][C:25]3[C:26](=[O:29])[O:27][CH2:28][C:24]=3[C:23]=2[CH3:32])[CH2:17][CH2:18]1
Reactant: Cc1cc(C2CO2)ncc1C#N
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1cc(C(O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ncc1C#N
Temperature: 140 °C

Procedure:
To a microwave tube were added 4-methyl-6-(oxiran-2-yl)pyridine-3-carbonitrile (40 mg, 0.25 mmol), 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one (69 mg, 0.25 mmol, as a free base), and EtOH (3.0 mL). The mixture was heated in the microwave for 60 min at 140° C. The solvent was evaporated and the crude product was purified by chiral prep SFC (30% MeOH (0.1% DEA)/CO2 on OJ column) to provide 6-(1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methylpyridine-3-carbonitrile as individual isomers. Further, the products were treated with 1 M HCl in diethyl ether to give the final products as HCl salts.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)/C=C/c1cnccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)/C=C/c1cnccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
900 mg (3.23 mmol) of the Boc-protected aminopyridine from Example 7A are dissolved in 3 ml of trifluoroacetic acid at 0° C. The reaction mixture is then stirred at room temperature for 1 h, the mixture is introduced into ice-cold sodium bicarbonate solution and stirred for 30 min, and the resulting precipitate is filtered off, washed with water and dried. 242 mg (42% of theory) of the title compound are obtained.
Reaction SMILES: [Br-:1].C1(C(O)(C2C=CC=CC=2)C(O[CH:12]2[CH2:17][CH2:16][N+:15]([CH3:28])([CH2:18][C:19](=[O:27])[NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:14][CH2:13]2)=O)CCCCC1.[CH:36]1([C:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([OH:45])[C:42]([OH:44])=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[Br-:1].[CH:36]1([C:41]([OH:45])([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:42]([O:44][CH:14]2[CH2:13][CH2:12][CH2:17][CH2:16][N+:15]2([CH3:28])[CH2:18][C:19](=[O:27])[NH:20][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C[N+]1(CC(=O)Nc2cnccn2)CCC(OC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2cnccn2)CCCCC1OC(=O)C(O)(c1ccccc1)C1CCCC1

Procedure:
This compound is prepared by an analogous method to 4-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-piperidinium bromide (Example 4) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with cyclopentyl-mandelic acid.
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:22]([C:23](=[O:25])[CH:24]=1)=[C:21]([O:26]C)[CH:20]=[C:19]([O:28]C)[C:18]=2[C@@H:30]1[CH2:34][CH2:33][N:32]([CH3:35])[C@H:31]1[CH2:36][OH:37].C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:22]([C:23](=[O:25])[CH:24]=1)=[C:21]([OH:26])[CH:20]=[C:19]([OH:28])[C:18]=2[C@@H:30]1[CH2:34][CH2:33][N:32]([CH3:35])[C@H:31]1[CH2:36][OH:37]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1CO
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
Molten pyridine hydrochloride (2.5 g, 21 mmol, 10×w/w) was added to compound of example 7 (0.25 g, 0.58 mmol) and heated at 180° C. for 1.5 h. The reaction mixture was cooled to 25° C., diluted with MeOH (10 mL) and basified using Na2CO3 to pH 10. The mixture was filtered and the organic layer was concentrated. The residue was suspended in water (10 mL), stirred for 30 min., filtered and dried to obtain the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]2[OH:29])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1NC1CCCCC1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1ccc2cc(SCc3ccccc3)ccc2n1[C@@H]1CCCC[C@H]1O
Temperature: 70 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A 25-mL pressure vessel was charged with (E)-ethyl 3-(5-(benzylthio)-2-((2-hydroxycyclohexyl)amino)phenyl)acrylate (2.36 g, 5.73 mmol), methanol (10 ml), and a solution of sodium methoxide in methanol (25 wt. %, 2.64 mL, 11.47 mmol). The reaction vessel was sealed with a Teflon cap and the yellow reaction mixture was warmed to 70° C. After 16 h, additional solution of sodium methoxide in methanol (25 wt. %, 1.9 mL, 8.25 mmol) was added and the reaction vessel was sealed and warmed to 100° C. After 20 h, the reaction mixture was allowed to cool to ambient temperature and concentrated under reduced pressure to furnish a yellow residue which was purified by flash column chromatography (50-g Biotage column, eluent: gradient, 20 to 70% EtOAc in heptane) to afford 6-(benzylthio)-1-((1R,2R)-2-hydroxycyclohexyl)quinolin-2(1H)-one (469 mg, 1.283 mmol, 22.38% yield) as a yellow syrup. m/z (ESI) 366.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.N[C@@H:32]([C:36]1C=CC=C[CH:37]=1)[CH2:33][C:34]#N>>[C:12]([CH2:11][C@@H:10]([NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[C:9]1[CH:37]=[CH:36][CH:32]=[CH:33][CH:34]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: N#CC[C@@H](N)c1ccccc1
Product: N#CC[C@@H](NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (3R)-3-amino-3-phenylpropanenitrile (Organic Synthesis 2008, 85, 219-230) instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 388 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.24 (1H, s) 8.79 (1H, d, J=8.44 Hz) 8.02 (1H, d, J=5.42 Hz) 7.85 (1H, d, J=5.47 Hz) 7.51 (1H, d, J=5.47 Hz) 7.44 (2H, d, J=7.18 Hz) 7.22-7.39 (4H, m) 6.84 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.47, 1.22 Hz) 5.46 (1H, td, J=8.63, 6.47 Hz) 3.01-3.22 (2H, m)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:22](=[O:23])[CH:16]([CH3:15])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccc(F)cc1

Procedure:
Prepared according to general Procedure A using 4-fluoroaniline (18 g, 162 mmol), pyridine (13 mL, 162 mmol) and diethyl methylmalonate (28 mL, 162 mmol). After purification ethyl 3-(4-fluorophenylamino)-2-methyl-3-oxopropanoate was obtained. Mass Spectrum (ESI) m/e=240.1 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[C:14]1([NH:20][OH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N+:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O-:21])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-c2ncco2)cc1
Reactant: ONc1ccccc1
Solvent: CCO
Product: [O-][N+](=Cc1ccc(-c2ncco2)cc1)c1ccccc1
Temperature: 5 °C
Yield: 70.9 %

Procedure:
A mixture of 4-(2-oxazolyl)-benzaldehyde (1 eq., 6.3 gm) and N-phenyl-hydroxyamine (1 eq., 3.9 gm) was refluxed in ethanol (100 ml) for 30 minutes and concentrated to a volume of 50 ml. An equal amount (50 ml) of water was added and the mixture was cooled in a refrigerator at 5° C. overnight. White crystals were obtained, which were isolated by filtration and dried, producing 6.7 gm of 4-(2-oxazolyl)-phenyl-N-phenylnitrone.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@@H:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[CH2:5][CH2:4][C@@H:3]1[NH:13][C:14](=[O:25])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)=[O:16].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][N:39]1[CH2:44][CH2:43][C:42]2[N:45]=[C:46]([C:48](O)=[O:49])[S:47][C:41]=2[CH2:40]1.Cl.CN(C)CCCN=C=NCC>CC(N(C)C)=O.O.C(N(CC)CC)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C:14]([NH:13][C@H:3]2[CH2:4][CH2:5][C@H:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[CH2:7][C@H:2]2[NH:1][C:48]([C:46]2[S:47][C:41]3[CH2:40][N:39]([CH3:38])[CH2:44][CH2:43][C:42]=3[N:45]=2)=[O:49])=[O:25])=[N:19][CH:20]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)C(=O)Nc2ccc(Cl)cn2)[C@H](N)C1
Reactant: CN1CCc2nc(C(=O)O)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)C(=O)Nc3ccc(Cl)cn3)sc2C1
Yield: 81.8 %

Procedure:
N1-{(1S,2R,4S)-2-Amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N2-(5-chloropyridin-2-yl)ethanediamide (553.4 mg) was dissolved in dimethylacetamide (7 mL), and to the solution were added 1-hydroxybenzotriazole monohydrate (245.1 mg), 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (386.0 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (345.0 mg) at room temperature. The resultant mixture was stirred for 13 hours, and triethylamine and water were added thereto. The precipitated crystals were collected by filtration, and were dried, to thereby give 674.1 mg of the title compound.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10](=[O:44])[NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]#[N:27])=[C:21]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-])=O)[CH:36]=3)[CH:34]=2)[N:20]=1)([CH3:8])([CH3:7])[CH3:6]>[Pd].CO>[C:5]([O:9][C:10](=[O:44])[NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[NH:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]#[N:27])=[C:21]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[CH:36]=3)[CH:34]=2)[N:20]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Nc2cncc(-c3cccc([N+](=O)[O-])c3)c2)c(C#N)cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Nc2cncc(-c3cccc(N)c3)c2)c(C#N)cc1F
Temperature: 25 °C
Yield: 109.4 %

Procedure:
Ammonium formate (0.2 g) and 10% Pd/C (0.2 g) were added to a methanol (10 ml) solution containing tert-butyl((1S,2R)-2-((5-cyano-3-fluoro-6-((5-(3-nitrophenyl)pyridin-3-yl)amino)pyridin-2-yl)amino)cyclohexyl)carbamate (87 mg), followed by reflux with heating for 30 minutes. The reaction mixture was cooled to room temperature and filtered with Celite, the solvent was distilled away under reduced pressure, and a yellow solid of tert-butyl((1S,2R)-2-((6-((5-(3-aminophenyl)pyridin-3-yl)amino)-5-cyano-3-fluoropyridin-2-yl)amino)cyclohexyl)carbamate (90 mg) was thus obtained.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[CH:27][CH:28]=4)[O:23][CH2:22][C:21]=3[C:38]3[CH:43]=[CH:42][C:41]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])=[CH:40][C:39]=3O)([OH:19])[CH3:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:34]([Si:31]([CH3:32])([CH3:33])[O:30][C:26]1[CH:27]=[CH:28][C:29]2[C:20]3[C:17]([C:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]5)=[CH:12][CH:13]=4)([CH3:18])[O:19][C:39]4[CH:40]=[C:41]([O:44][Si:45]([C:48]([CH3:50])([CH3:51])[CH3:49])([CH3:47])[CH3:46])[CH:42]=[CH:43][C:38]=4[C:21]=3[CH2:22][O:23][C:24]=2[CH:25]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(O)(C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O)COc2cc(O[Si](C)(C)C(C)(C)C)ccc21)c1ccc(OCCN2CCCCCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2ccc(OCCN3CCCCCC3)cc2)Oc2cc(O[Si](C)(C)C(C)(C)C)ccc2C2=C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-[4-{1-[4-(2-azepan-1-yl-ethoxy)-phenyl]-1-hydroxy-ethyl}-7-(tert-butyl-dimehyl-silyloxy)-2H-chromen-3-yl]-5-(tert-butyl-dimethyl-silyloxy)-phenol, prepared as in STEP A above, was dissolved in toluene (8 mL) and treated with diluted HCl (0.4 mL of concentrated HCl:H2O=1:2 v/v). The reaction mixture was vigorously stirred at room temperature for 1.5 h, then diluted with water and ethyl acetate. The resulting layers were separated and organic layer washed successively with saturated NaHCO3, brine and dried over MgSO4. The desiccant was filtered off, and the filtrate concentrated. Flash chromatography with ethyl acetate:hexane:CH3OH (containing 1% NH4OH)=49:49:2 as the eluent yielded the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18]C2CCCCO2)[CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(Cl)c21
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a solution of the crude ethyl 2-(4-chloro-1-hydroxy-6-(tetrahydro-2H-pyran-2-yl-oxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in THF (3 mL) was added concentrated HCl (1.5 mL) at 0° C. and the mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EtOAc/PE=1:1) to give the title compound as a yellow oil (580 mg. Yield: 60.2%). 1H NMR (400 MHz, DMSO-d6) δ9.94 (d, J=2.8 Hz, 1H), 9.39 (s, 1H), 7.07-7.08 (d, J=2.0 Hz, 1H), 6.92-6.92 (d, J=2.0 Hz, 1H), 5.40-5.48 (m, 1H), 3.19-3.23 (m, 1H), 2.34-2.40 (m, 1H), 1.31-1.50 (m, 5H); MS (ESI) m/z=271 [M+H]+.