Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH:6]1[CH2:9][CH2:8][C:7]1=[O:10].[BH4-].[Na+]>CO>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][C@H:6]1[CH2:9][CH2:8][C@H:7]1[OH:10]
Reactant: O=C1CCC1Oc1ccccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Compound C4 (3.00 g, 13.0 mmol) was dissolved in methanol (100 mL) and cooled to −78° C. Sodium borohydride (1.48 g, 39.1 mmol) was added portion-wise over 10 minutes, and the mixture was stirred at −78° C. for an additional 30 minutes before being allowed to warm to room temperature and stir for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (2×150 mL). The organic layers were combined, washed with saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Two purifications via silica gel chromatography [Gradients: 1) 0% to 50% ethyl acetate in heptane; 2) 0% to 50% dichloromethane in heptane] provided the title compound as a colorless oil. The product was tentatively assigned cis stereochemistry on the basis of NOE studies. Yield: 650 mg, 2.80 mmol, 22%. 1H NMR (400 MHz, CDCl3) δ 7.60 (br dd, J=7.8, 1.2 Hz, 1H), 7.47 (br ddd, J=8.2, 7.8, 1.2 Hz, 1H), 7.04 (br dd, J=7.6, 7.6 Hz, 1H), 6.87 (br d, J=8.4 Hz, 1H), 4.86-4.91 (m, 1H), 4.45-4.53 (m, 1H), 2.75 (d, J=9.2 Hz, 1H), 2.27-2.36 (m, 1H), 2.02-2.22 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:21]=1)([O-:19])=[O:18]>COCCOCCOC>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:29][CH2:28][CH2:27][NH:26][C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)[CH:3]=1
Reactant: NCCNc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)nc(OS(=O)(=O)C(F)(F)F)c1
Solvent: COCCOCCOC
Product: Cc1cc(C)nc(NCCNc2ccc([N+](=O)[O-])cc2)c1
Temperature: 165 °C
Yield: 56.5 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 4,6-dimethyl-pyridin-2-yl ester (0.6 g, 2.35 mmol) in diglyme (2 mL) was added N*1*-(4-nitro-phenyl)-ethane-1,2-diamine (0.51 g, 2.82 mmol). The reaction mixture was heated to 165° C. for 24 h. The resulting reaction mixture was concentrated under reduced pressure and the residue diluted with chloroform. The organic layer was washed with brine and water and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by column chromatography (60-120 mesh) using 20% ethyl acetate/petroleum ether as eluent to afford N-(4,6-dimethyl-pyridin-2-yl)-N′-(4-nitro-phenyl)-ethane-1,2-diamine (0.38 g, 55%) as a cream solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(F)cc1
Reaction time: 6 h
Yield: 97 %

Procedure:
A mixture of 3-(4-fluorobenzoyl)propanoic acid (42.3 g, 0.22 mol) and 10% Palladium on carbon (3 g) in acetic acid (250 mL) was hydrogenated at 50 psi and 25° C. for 6 h. The mixture was filtered and concentrated in vacuo. The residue was distilled at 0.02 mm Hg and the product crystallized to give 4-(4-fluorophenyl)butyric acid as a white solid (97%). m.p., 44-46.2° C. (lit. J. Am. Chem. Soc. 89, 386, 1967; m.p., 45.5-46.5° C.).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:14]1[C:13](=[C:22]3[C:17](=[CH:16][CH:15]=1)[CH:18]=[CH:19][CH:20]=[N:21]3)[NH:12][S:9]2(=[O:11])=[O:10]
Reactant: Nc1ccc(F)cc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2ccc(F)cc21
Yield: 9 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-5-fluoro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 297) (250 mg, 0.78 mmol), t-butyl nitrite (121 mg, 1.18 mmol), AcOH (2.5 ml) and THF (2.5 ml) gave the title compound (21 mg, 8%) after purification by column chromatography (×2) with n-hexane/DCM (50:50) as the eluent followed by recrystallisation.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][C:12]([F:15])([F:14])[C:11]([F:17])([F:16])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:1].[F:16][C:11]1([F:17])[C:12]([F:15])([F:14])[CH2:13][NH:9][CH2:10]1
Reactant: [H][H]
Reactant: FC1(F)CN(Cc2ccccc2)CC1(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: FC1(F)CNCC1(F)F

Procedure:
A solution of 1-benzyl-3,3,4,4-tetrafluoro-pyrrolidine hydrochloride (23.8 g, 88 mmol) in ethanol (300 mL) containing 10% palladium on carbon was treated with hydrogen in a Parr shaker at 45 psi for 3 hours. The mixture was filtered through Celite®, the filtrate was concentrated to dryness. The residue was triturated with ether and the solid was collected and dried (13.4 g, 85%, (mp 193-196° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:22]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:22][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: C[C@@H]1CC[C@H](C(=O)N2CCCC2)CN1c1ccc([N+](=O)[O-])c(N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CC[C@H](C(=O)N2CCCC2)CN1c1ccc(N)c(N)n1

Procedure:
A solution of cis-(1-(6-amino-5-nitropyridin-2-yl)-6-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (500 mg, 1.50 mmol) in ethanol (20 mL) was added to a suspension of 10% palladium-on-carbon (250 mg) in ethanol under a nitrogen atmosphere. The suspension was hydrogenated using a balloon filled with hydrogen gas for 2 h at room temperature. The mixture was filtered through Celite and the filtrate was used for the next step without further purification.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 74.1 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 3.3 g.), conc.hydrochloric acid (2.80 g.), tetrahydrofuran (20 ml.) and methanol (50 ml.) were treated in a similar maner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.3 g.).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Product: O=C(O)c1c(N2CCCC2)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and pyrrolidine. Yellow solid. MS (ESI): 387.2 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:18])[C@@H:6]([NH2:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:2]([O:4][C:5](=[O:18])[C@@H:6]([NH:17][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
(S)-Ethyl-2-amino-3-(4-nitrophenyl)propionate hydrochloride (1.23 g, 4.47 mmol) was suspended in dichloromethane (25 mL) and to this suspension was added benzoyl chloride (0.628 g, 4.47 mmol) and triethylamine (1.36 g, 13.4 mmol). The mixture was stirred overnight at room temperature under nitrogen. The crude reaction was washed with 5% HCl, water, brine, dried (Na2SO4), concentrated and purified by flash chromatography (silica gel, 2:1 hexanes:EtOAc) to afford the title compound as a white powder (0.865 g, 57%): MS(ES+) m/e 343 [M+H]; mp 99-101° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH:21]([O:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CCCCO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=[C:2]([NH:30][C:27]3[CH:26]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[NH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccc(F)cc1
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2ccc([N+](=O)[O-])c(N[C@@H](C)c3ccc(F)cc3)n2)n[nH]1
Temperature: 115 °C
Yield: 21.6 %

Procedure:
A mixture of (S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 19, 1.08 g, 3.7 mmol), 5-isopropoxy-1H-pyrazol-3-amine (0.57 g, 4.0 mmol), and DIEA (0.80 ml, 4.6 mmol) in n-BuOH (10 ml) was heated in a sealed tube at 115° C. for 72 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc=3:1) to give the title compound as a yellow solid (0.32 g, 22%). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [CH:1]([CH:4]([C@H:14]1[CH2:17][C@H:16](CS([O-])(=O)=O)[CH2:15]1)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[O:6][SiH3:7])([CH3:3])[CH3:2].[N:23]1[C:31]([NH2:32])=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[N:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]([CH:4]([C@@H:14]1[CH2:15][C@H:16]([N:27]2[CH:28]=[N:29][C:30]3[C:26]2=[N:25][CH:24]=[N:23][C:31]=3[NH2:32])[CH2:17]1)[C:5]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[O:6][SiH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)C([C@H]1C[C@H](CS(=O)(=O)[O-])C1)C(O[SiH3])(C(C)C)C(C)C
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C([C@H]1C[C@@H](n2cnc3c(N)ncnc32)C1)C(O[SiH3])(C(C)C)C(C)C
Temperature: 120 °C

Procedure:
In a 25 mL three-neck flask with trans-3-(triisopropyl-siloxyethyl)cyclobutyl -mesylate (0.27 g, 7.7 mmol), adenine (0.16 g, 1.18 mmol) and Cs2CO3 (0.38 g, 1.17 mmol) inside, dry DMF 5 mL was added under argon. Then began to heat to 120° C. and after 24 hr, the solvent was removed and directly applied to silica gel flash chromatography to give 0.14 g (47%) the desired product. 1H NMR (CDCl3, 400 MHz): δ 0.99-1.05 (m, 21H), 1.72-1.78 (m, 2H), 2.15-2.23 (m, 2H), 2.60-2.79 (m, 3H), 3.67-3.70 (t, J=6.0, 2H), 4.81-4.90 (m, 1H), 6.37-6.39 (bs, 2H), 7.88 (s, 1H), 8.31 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 12.08, 18.17, 26.60, 37.03, 39.84, 45.86, 61.64, 138.76, 140.09, 150.07, 152.91, 155.93. MS (FAB): expected for C20H35N5OSi (M+H)+ 390.61. Found 390.26828. IR (neat) νmax 2942, 2865, 1670, 1604, 1571, 1463, 1415, 1308, 1246, 1108, 882, 681, 658.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[Li].O>CO>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(Cc2ccccc2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 1-benzyl-1H-pyrazole-4-carboxylate (1.05 g, 3.56 mmol) was dissolved in MeOH (20 ml). Water (10 ml) and LiOH.H2O (0.299 g, 7.11 mmol) were added and the suspension was stirred for 3 h at rt. The reaction mixture was evaporated in vacuum to remove the MeOH. The water phase was washed with AcOEt, then treated with 1N HCl until pH3, and extracted with AcOEt. The organic phase was dried over MgSO4 and evaporated in vacuum to give the title compound which was used in the next step without any further purification. HPLC/MS (Method A) RtA=1.3 min, MS [M+H]+=203.1.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]1[NH2:10].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:22][N:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:26][C:25]([C:36](Cl)=[O:37])=[N:24]1>C(Cl)Cl>[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]1[NH:10][C:36]([C:25]1[CH:26]=[C:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[N:23]([CH2:22][C:21]2[CH:39]=[CH:40][C:41]([CH3:42])=[C:19]([Cl:18])[CH:20]=2)[N:24]=1)=[O:37]
Reactant: Cc1ccc(Cn2nc(C(=O)Cl)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Reactant: CC1CCCC(C)C1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(C(=O)NC3C(C)CCCC3C)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Yield: 32.8 %

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 36 from 0.605 g of 2,6-dimethylcyclohexylamine hydrochloride, 1 ml of triethylamine in 15 ml of DCM and 1.5 g of the compound obtained in step A of EXAMPLE 36 in 15 ml of DCM. 0.6 g of the expected product is obtained; m.p.=59.9° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:25]([F:31])=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1>>[F:31][C:25]1[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cc1cnc(F)c(Br)c1
Product: Cc1cnc(F)c(N2CCC3(CC2)CCN(c2ccc(OC(F)(F)F)cc2)C3=O)c1

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 3-bromo-2-fluoro-5-methylpyridine. Light yellow solid. MS (ESI): 424.1 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cn2)CC1
Yield: 56.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (380 mg) described in Preparation Example 151 and oxazolidin-2-one (91 mg), the title compound (217 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].CN(C=O)C>>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.3 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (501 mg, 3.16 mmol, 1.00 eq) and 4-tert-butylphenol (611 mg, 4.07 mmol, 1.29 eq) were dissolved in DMF (6.0 mL) Anhydrous K2CO3 (654 mg, 4.73 mmol, 1.50 eq) was added and the reaction mixture was stirred at room temperature for 14 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100 to 1:50) to afford the title compound as colourless solid (820 mg, 3.01 mmol, 95% yield). Rf=0.40 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C15H17N2O3+[M+H]+ 273.1234. found: 273.1229. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J=2.8 Hz, 1H, aromatic H), 8.46 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.53-7.42 (m, 2H, aromatic H), 7.17-7.05 (m, 2H, aromatic H), 7.01 (d, J=9.1 Hz, 1H, aromatic H), 1.35 (s, 9H, C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 167.20, 150.49, 148.98, 145.26, 140.29, 134.95, 126.99, 120.84, 111.38, 34.72, 31.57.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]#[N:5].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25]>CC(N(C)C)=O>[I:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:2]3[C:3]=2[C:4]([NH2:5])=[N:25][C:24]([NH2:26])=[N:23]3)=[CH:17][CH:16]=1
Reactant: N=C(N)N
Reactant: N#Cc1c(F)cccc1OCc1ccc(I)cc1
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCc3ccc(I)cc3)cccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
2-Fluoro-6-(4-iodobenzyloxy)benzonitrile (176.6 mg, 0.5 mmol) and guanidine carbonate (110 mg; 0.66 mmol) were heated at 140° C. in dimethyl acetamide for 7 hours. The mixture was cooled to room temperature and stored in the freezer overnight. The precipitate was collected by filtration and the filtrate was diluted with dichloromethane. The filtrate was stored in the freezer for 3 hours. The resulting precipitate was collected by filtration and all the solids were combined and crystallized from 50% ethanol/water to yield 114 milligrams of 5-(4-iodobenzyloxy)quinazoline-2,4-diamine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:19][C@H:20]4[CH2:22][C:21]4([F:24])[F:23])[C:13]3=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[F-].[Cs+].C[Si](C)(C)[C:32]([F:35])([F:34])[F:33]>CN(C=O)C.CO>[F:24][C:21]1([F:23])[CH2:22][CH:20]1[CH2:19][N:18]1[C:13]2[C:14](=[N:15][C:10]([C:8]3[CH:9]=[C:4]([C:1]([OH:3])([CH3:2])[C:32]([F:35])([F:34])[F:33])[CH:5]=[CH:6][C:7]=3[CH3:27])=[CH:11][CH:12]=2)[N:16]([CH3:26])[C:17]1=[O:25]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3C[C@H]2CC2(F)F)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(C(C)(O)C(F)(F)F)cc1-c1ccc2c(n1)n(C)c(=O)n2CC1CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a microwave vial, 5-(5-acetyl-2-methylphenyl)-1-{[(1R)-2,2-difluorocyclopropyl]methyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (9-4) (25 mg, 0.067 mmol) and Cesium fluoride (21 mg, 0.135 mmol) were dissolved in DMF (0.35 mL). Trimethyl(trifluoromethyl)silane (54 uL, 0.34 mmol) was added dropwise and allowed to stir at room temperature for 30 minutes. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce racemic 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-[2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10-1). HRMS (M+H)+: observed=442.1543, calculated=442.1548.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)c1

Procedure:
Carboxylic acid (145)(57 mg, 0.26 mmol) was coupled to aniline (64)(50 mg, 0.26 mmol) using Method C to give the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:18]([O-])=[O:19].[Na+]>Cl.O>[N:1]1([CH2:7][CH:8]2[N:13]([N:18]=[O:19])[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][CH2:9]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: c1ccc2c(c1)NC(CN1CCOCC1)CO2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1c2ccccc2OCC1CN1CCOCC1

Procedure:
Similarly 10.9 g (0.047 mole) of racemic 3-(4-morpholinylmethyl)-3,4-dihydro-2H-1,4-benzoxazine in 250 ml of 2N aqueous hydrochloric acid was treated with 3.9 g (0.057 mole) of sodium nitrite in 50 ml of water at 0° C. to produce racemic 3-(4-morpholinylmethyl)-4-nitroso-3,4-dihydro-2H-1,4-benzoxazine, which was used as such in the next synthetic step without further purification or characterization.
Reaction SMILES: [I:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[OH:33]>N1C=CC=CC=1>[OH:33][C:24]1[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:23]=1[NH:22][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[I:1]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1I
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1I
Temperature: 50 °C
Yield: 68.3 %

Procedure:
A mixture of 1.78 g of 3-iodo-isonicotinic acid, 1.38 g of WSC and 12 ml of pyridine was stirred while heating at 50° C. for 15 minutes. Then, 1.15 g of 2-amino-4-(trifluoromethyl)phenol was added to the reaction mixture. The reaction mixture was stirred while heating at 80° C. for two hours. The reaction mixture was returned to room temperature, and concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1.81 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3iodo isonicotinamide.