Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O.[OH-].[Na+]>ClCCl>[CH2:5]([O:4][C:2]([N:12]1[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]1)=[O:3])[CH:6]=[CH2:7]
Reactant: C=CCOC(=O)Cl
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N1CCN(C)CC1
Reaction time: 0.5 h

Procedure:
A solution of allyl chloroformate (15 ml) in dry dichloromethane was added at -20° C. under stirring to a solution of N-methylpiperazine (10 g) in the same solvent. After 30 minutes the temperature was let rise to +15° C. and the reaction mixture was poured into water. The organic layer was discarded, 1N NaOH was added to a pH≥7, and the mixture was extracted with dichloromethane. The CH2Cl2 extracts were dried (MgSO4), evaporated, and the resulting oil distilled 118° C. (at 18 mmHg) to yield 4-allyloxycarbonyl-1-methylpiperazine (15.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][CH2:19][C@H:20]([NH:28][S@@](C(C)(C)C)=O)[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][CH2:19][C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[NH2:28])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: CC(C)(C)[S@@](=O)N[C@@H](CNc1cc(-c2ccc(C(F)(F)F)c(Cl)c2)ncn1)c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: N[C@@H](CNc1cc(-c2ccc(C(F)(F)F)c(Cl)c2)ncn1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A solution of (R,R)-2-methyl-propane-2-sulfinic acid [2-[6-(3-chloro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-1-(4-fluoro-phenyl)-ethyl]-amide (0.172 g, 0.337 mmol) in MeOH (5 mL) was added HCl (4 N in dioxane, 0.34 mL) at rt. After 30 min, the reaction mixture was purified directly via reverse phase chromatography. The desired fractions were then free-based by washing with sat. aq. NaHCO3 (2×30 mL) and extracting with EtOAc (2×25 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (75 mg, 54%) as a white solid. MS (ESI+): calcd for C19H15ClF4N4 m/z 410.09. found 411.1 (M+H)+. 1H NMR (CDCl3): 8.60 (s, 1H), 8.05 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.35 (dd, J=8.6, 5.3 Hz, 2H), 7.05 (t, J=8.6 Hz, 2H), 6.66 (s, 1H), 5.89 (s, 1H), 4.27 (s, 1H), 3.76-3.64 (m, 1H), 3.59-3.50 (m, 1H), 3.03-2.85 (m, 2H).
Reaction SMILES: Cl.N=[C:3]1[NH:9][CH:8]([CH2:10][CH:11]=[CH:12][C:13]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.BrC1C=CC(OC)=CC=1C(OC)=[O:29].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:29]=[C:3]1[NH:9][CH:8]([CH2:10][CH:11]=[CH:12][C:13]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1cc(OC)ccc1Br
Reactant: COC(=O)c1cc(OC)ccc1C=CCC1CCCCC(=N)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(OC)ccc1C=CCC1CCCCC(=O)N1

Procedure:
methyl 2-[3-(hexahydro-7-imino-1H-azepin-2-yl)-1-propenyl]-5-methoxybenzoate, monohydrochloride ##STR201## 200 A) The Isomer B title material of Example 18 in acetonitrile is coupled to methyl 2-bromo-5-methoxybenzoate in the presence of palladium acetate, tri-o-tolylphosphine, and triethylamine by the method of Example 32 to provide methyl 2-[3-(hexahydro-7-oxo-1H-azepin-2-yl)-1-propenyl]-5-methoxybenzoate as primarily its E isomer.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:45]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:46].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:45]([O:47][C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:12](=[O:14])[C@@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:54][CH2:55]1)=[O:49])[CH3:46]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
To a solution of 220 mg of (S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyric acid, 327 mg of NEM and 233 mg of TOTU in 1.6 ml of DMF, 112 mg of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 16 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][C:21](=O)[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].Cl.[NH2:33][OH:34].O.CO>C1COCC1>[Cl:1][C:2]1[C:3]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:4]2[C:18]3[CH2:19][CH2:20]/[C:21](=[N:33]/[OH:34])/[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]
Reactant: NO
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCC(=O)C4)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CC/C(=N/O)C4)cc1

Procedure:
A mixture of the compound obtained in Example 33 (2.0 g), hydroxylamine hydrochloride (673 mg), water (5 ml), methanol (5 ml), and THF (40 ml) was heat under reflux for 2 hours and then evaporated under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride and the resulting solution was washed with a saturated, aqueous solution of sodium hydrogen carbonate and water, dried (MgSO4), and then evaporated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel to obtain (Z)-1-{[3-chloro-7-(hydroxyimino)-4-(4-methoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-2-yl]methyl}-2,5-pyrrolidinedione:
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C@@H:9]([CH2:12][NH:13][CH2:14][CH3:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+].[I-]>C(#N)C>[CH2:22]([N:13]([CH2:12][C@@H:9]1[O:8][C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:10]1)[CH2:14][CH3:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCNC[C@H]1COc2cccc(F)c2O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCN(Cc1ccccc1)C[C@H]1COc2cccc(F)c2O1
Yield: 83 %

Procedure:
A mixture of N-{[(2S)-8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}ethanamine (1.95 g, 9.2 mmol), K2CO3 (2.55 g, 18.5 mmol), benzylbromide (1.3 ml, 11.1 mmol), a spatula of NaI (<5 mg) and acetonitrile was heated under microwave radiation at 120° C. for 20 min. The solution was filtered and evaporated, Na2CO3 (10%) was added and the solution was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to dryness. Purification on flash column chromatography (isooctane/EtOAc) yielded 2.3 g of the title compound. MS m/z (rel. intensity, 70 eV) 149 (10), 148 (86), 92 (8), 91 (bp), 65 (7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](O)=O>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccncc1N
Reactant: O=C(O)c1cccs1
Product: c1csc(-c2nc3cnccc3[nH]2)c1
Temperature: 160 °C
Yield: 24.6 %

Procedure:
A mixture of 1.1 g (10 mM) of 3,4-diaminopyridine, 1.3 g (10 mM) of thiophene-2-carboxylic acid, and 50 g of polyphosphoric acid was heated at 160° C. for four hours. The reaction mixture was added to 100 g of ice and stirred for fifteen minutes. The precipitated solid was collected by filtration and dried to give 500 mg of 2-(2-thienyl)-1H-imidazolo[4,5-c]pyridine; mp 265°-268° C.
Reaction SMILES: C([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)CCC.CCCCCC.C([Li])CCC.[Cl:21][Si:22](Cl)([CH2:24][Cl:25])[CH3:23]>C1COCC1>[Cl:21][Si:22]([CH2:24][Cl:25])([CH:9]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:23]
Reactant: C[Si](Cl)(Cl)CCl
Reactant: CCCCC1=CC=CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](Cl)(CCl)C1C=CC=C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
THF in a volume of 100 ml was added to 6 g (49 mmol) of n-butylcyclopentadiene, and the mixture was cooled to −78° C. A 1.65 M hexane solution of n-butyllithium in a volume of 29.6 ml (48.8 mmol) was added thereto dropwise. The mixture was stirred at room temperature for 2 hours and was cooled again to −78° C. Dichloro(chloromethyl)(methyl)silane in an amount of 8.0 g (49 mmol) dissolved in 50 ml of THF was added dropwise. The mixture was stirred at room temperature for 3 hours and was concentrated under reduced pressure. Hexane was added, and the mixture was filtered. The filtrate was distilled under reduced pressure to give 3.43 g of target chloro(chloromethyl) (cyclopentadienyl)(methyl) silane.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]2.[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C(O)(C)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][CH2:2][C:3]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=2[O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Solvent: CC(C)O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1
Temperature: 37.5 °C
Reaction time: 5 h

Procedure:
A reactor was charged with 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol (12.13 kg, 40.27 mol) and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (14.00 kg, 40.07 mol). The solids were suspended in isopropanol (172.8 kg, 220 L). The suspension was heated from 20° C. to 35° C. and stirred at 35-40° C. for 5 hours to form 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea. The solution was cooled to 25° C. and subsequently polish filtered. To the filtered solution of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea in isopropanol was added HCl (4.80 kg of 32% aqueous HCl, 1.05 eq.) through a polish filter at 22-23° C., and the mixture was stirred at 18-23° C. overnight (14 hours). The bulk solution was seeded with 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride Form B by adding 20.0 g 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride Form B suspended in 300-400 mL of isopropanol to the bulk solution. The mixture was stirred for 3 days (convenience). Analysis showed complete crystallization, at which time 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride From B was isolated by filtration. The product was washed with isopropanol (64 kg, 81.4 L) added via polish filter in portions and dried under vacuum at 55° C. for about 28 hours to provide 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride Form B (92.3% yield). Methods used to characterize this material are described in Examples 2-F and 2-G. Form B prepared according to this method was anhydrous, as confirmed by single X-ray crystallography.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:15])[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(O)(c2ccc(F)nc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](O)[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[F:30]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:30])[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@@H](O)C1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@H](F)C1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Process B: (3S,4R)-1-Benzyloxycarbonyl-3-bromomethyl-4-hydroxypyrrolidine (492 mg) was dissolved in toluene (1 mL). To this solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) was added and perfluoro-1-octanesulfonylfluoride (0.42 mL) was subsequently added dropwise while the mixture was chilled in an ice water bath. The reaction mixture was stirred at 2° C. for 30 min and then at room temperature for 5 hours. Subsequently, the mixture was poured on a silica gel pad and was eluted with ethyl acetate (80 mL). The eluate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-1-benzyloxycarbonyl-3-bromomethyl-4-fluoropyrrolidine as a milky white syrup (421 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:28].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:28])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
A solution of (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (5.00 g, 14.95 mmol) in dry DMF (50 mL) was added dropwise to a suspension of sodium hydride 60% in mineral oil (0.7176 g, 17.94 mmol) in dry DMF (10 mL). The mixture was stirred at 0° C. for 1 hour and allowed to stir at room temperature for 2 hours. Then the mixture was cooled to 0° C. and treated dropwise with iodomethane (1.024 mL, 16.45 mmol). The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature over 18 hours. Water (40 mL) was added, and the mixture was extracted into EtOAc (3×50 mL). The organic layers were combined, washed with water (3×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 20% EtOAc/hexane (1.25 L) to provide (R)-benzyl 3-(tert-butoxycarbonyl(methyl)amino)piperidine-1-carboxylate (4.10 g, 79% yield) as an oil. LCMS (APCI+) m/z 349 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN1CCCC1=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Product: CC1Cc2c(N3CCCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 33.8 %

Procedure:
7-Amino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.5 g) and pyrrolidine (0.7 g) are suspended in N-methylpyrrolidone (10 ml), and the mixture is heated at 110°-120° C. for 5 hours in a sealed tube. The reaction mixture is concentrated to dryness under reduced pressure, and to the residue is added ethyl acetate. The resulting crystals are separated by filtration and recrystallized from N,N-dimethylformamide to give 7-amino-8-fluoro-2-methyl-6-oxo-9-(1-pyrrolidinyl)-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.2 g) as yellow cubic crystals. m.p. 296°-299° C. (decomp.)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:19][CH:18]=3)[C:12]([CH2:14][CH3:15])=[N:13][C:8]2=[C:7]([CH3:34])[CH:6]=1.[C:35](Cl)([CH3:37])=[O:36].C(N(CC)CC)C>C1COCC1>[C:35]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:21][CH:22]=3)[C:12]([CH2:14][CH3:15])=[N:13][C:8]2=[C:7]([CH3:34])[CH:6]=1)(=[O:36])[CH3:37]
Reactant: CCc1nc2c(C)cc(NCCN)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc2c(C)cc(NCCNC(C)=O)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h

Procedure:
To 5-(2-aminoethyl)amino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (20 mg) in THF (1 mL) at °C. was added AcCl (3.4 μL) and triethylamine (18 μL). After 1 h, the solvent was evaporated and the residue was purified (SiO2, 80:20:1 CHCl3, MeOH, NH4OH) to give 17 mg of the title compound.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)=[O:2].[OH:11][C:12]1[C:21]([CH3:22])=[CH:20][C:15]([C:16]([NH:18]O)=[NH:17])=[CH:14][C:13]=1[CH3:23]>>[OH:11][C:12]1[C:13]([CH3:23])=[CH:14][C:15]([C:16]2[N:17]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)[O:10][N:18]=2)=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Reactant: O=Cc1ccc(C(=O)O)s1
Product: Cc1cc(-c2noc(-c3ccc(C=O)s3)n2)cc(C)c1O
Yield: 15.5 %

Procedure:
The title compound (140 mg) is prepared from 5-formyl-2-thiophene carboxylic acid (468 mg, 3.0 mmol) and 4,N-dihydroxy-3,5-dimethyl-benzamidine (540 mg, 3.0 mmol) according to Method A; LC-MS: tR=1.01 min; [M+1]+=301.04; 1H NMR (D6-DMSO): δ2.24 (s, 6H), 7.64 (s, 2H), 8.17 (s, 2H), 8.99 (s, 1H), 10.06 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@:34]([CH3:41])([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:33][O:32][C:31]4=[O:42])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1.FC1C=C(C2C=NN3C=CC(N4[C@@](C)(C5C=CC=CC=5)COC4=O)=NC=23)C=CC=1C1N(COCC[Si](C)(C)C)N=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@:34]([CH3:41])([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:33][O:32][C:31]4=[O:42])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: C[C@]1(c2ccccc2)COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)c(F)c3)c2n1
Agent: C[C@]1(c2ccccc2)COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4COCC[Si](C)(C)C)c(F)c3)c2n1
Product: C[C@]1(c2ccccc2)COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Yield: 75 %

Procedure:
(S)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-methyl-4-phenyloxazolidin-2-one (17 mg, 75%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-methyl-4-phenyloxazolidin-2-one and (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-methyl-4-phenyloxa-zolidin-2-one. LCMS (APCI+) m/z 456.2 [M+H]+.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH3:18])=O)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][CH2:10][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH3:18])[CH:2]=1
Reactant: CC1CCCCN1C(=O)CCNc1cccc(-c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CCCCN1CCCNc1cccc(-c2ccccc2)c1
Reaction time: 5 h
Yield: 20.9 %

Procedure:
3-(Biphenyl-3-ylamino)-1-(2-methyl-piperidin-1-yl)-propan-1-one 1 g (3.1 mmol) in 10 mL of tetrahydrofuran was added dropwise to a cold solution of lithium aluminium hydride 0.1 g (3.1 mmol) in 10 mL dry tetrahydrofuran. The mixture was stirred for 5 hour then was quenched with saturated solution of sodium sulfate. The compound was purified by silica gel chromatography using chloroform-methanol 9:1, yield to 0.2 g of compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]#[N:21])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>CCOCC>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 114.5 %

Procedure:
A suspension of LiAlH4 (4.84 g, 0.128 mol) in dry Et2O (40 ml) under argon atmosphere at 0° C. was dropwise added a solution of 1-benzyl-4-cyano-piperidine (18.3 g, 91.5 mmol) in dry Et2O (80 ml) and stirred to room temperature for 24 h. The reaction mixture was treated carefully with H2O (10 ml), 10% aqueous NaOH (10 ml) and H2O (30 ml) to give a mineral precipitate. The precipitate was filtered through a pad of kiselguhr, washed with Et2O and the filtrate evaporated in vacuo to leave the product as an oil (21.4 g, 82.3%).