Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3.[CH2:29]([O:31][CH:32](OCC)[O:33][CH2:34][CH3:35])[CH3:30]>B(F)(F)F.CCOCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:29]([O:31][CH:32]([O:33][CH2:34][CH3:35])[C@@H:21]1[CH2:22][C@@:23]2([CH3:24])[C@@H:18]([CH2:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:11])[C@H:12]3[CH2:13][CH2:14][C@@H:9]2[OH:8])[CH2:19][C:20]1=[O:28])[CH3:30]
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(OCC)[C@@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)CC1=O
Yield: 71 %

Procedure:
By the method of part A of Example 20 (5α,17β)-17-hydroxyandrostan-3-one trifluoroacetate (ester) (0.344 mole) was diethoxymethylated using triethylorthoformate (126 ml.) and boron trifluoride etherate (140 ml.). The product was crystallized from methanol, affording (2α,5α,17β)-2-(diethoxymethyl)-17-hydroxyandrostan-3-one trifluoroacetate (ester) (118.7 g., 71% yield, m.r. 122°-123° C.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH:12]=[O:13])=[C:5]([CH3:23])[O:4][N:3]=1.Cl.NO.N1C=CC=CC=1.Cl>C(O)C.C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH2:12][OH:13])=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: COc1ccc(-c2nn(C)c(C=O)c2-c2c(C)noc2C)cc1
Agent: Cl
Agent: NO
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1CO
Temperature: 100 °C

Procedure:
A mixture of 4-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (45.0 mg, 0.14 mmol), hydroxylamine hydrochloride (100 mg, 1.45 mmol) and pyridine (129 μL, 1.59 mmol) in ethanol (1 mL) was heated at 100° C. for 3 minutes in the microwave. 1 mL 2 M HCl and 5 mL DCM were added. A precipitate was formed, which was found to be the desired product. The remaining solution was extracted with DCM (5×3 mL). The DCM layer was filtered through a phase separator and concentrated together with the precipitate to give the raw product. To this was added thionyl chloride (3 mL) and the mixture was stirred at room temperature for 2 h and concentrated. Dry DCM (1 mL) and BF3.Me2S (1 M solution in DCM, 0.5 mL, 0.5 mmol) were added and stirred at room temperature over night. The mixture was concentrated and MeOH was added to quench the reaction The crude product was purified on silica gel to give 4-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (30.5 mg, 0.01 mmol, 68%), and 3-(3-chloro-4-hydroxyphenyl)-4-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-pyrazole-5-carbonitrile (6.0 mg, 0.018 mmol, 13%).
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33])C>C(Cl)(Cl)Cl>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: CCCCC#CC(=O)OCC
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Solvent: ClC(Cl)Cl
Product: CCCCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 20) and hept-2-ynoic acid ethyl ester employing the procedure described in Example 95. [α]D25 −14.60 (c 0.5, CHCl3).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][O:29]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@@H:16]3[O:17]C(=O)C)[C:6]=2[CH:5]=[C:4]([Cl:33])[C:3]=1[Cl:34].C(=O)([O-])[O-].[Na+].[Na+].O.CO>C(O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:15]3[O:27][C@@H:26]([CH2:28][OH:29])[C@H:21]([OH:22])[C@@H:16]3[OH:17])[C:6]=2[CH:5]=[C:4]([Cl:33])[C:3]=1[Cl:34]
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Br)c(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC(C)Nc1nc2c(Br)c(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 70.3 %

Procedure:
4Bromo-5,6-dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (1.16 g, 2.0 mmol), sodium carbonate (0.28 g, 2.64 mmol), water (4 mL), methanol (6 mL), and ethanol (8 mL) were used according to general procedure III. The product was purified by silica gel chromatography using 10:1 dichloromethane/methanol to afford 0.64 g (70%) of a white powder, m.p. 221-222° C. Anal. Calcd for C15H18BrCl2N3O4: C, 39.59; H, 3.99; N, 9.23. Pound: C, 39.42; H, 4.20; N, 9.05.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OC=O)(=O)C.CN1C2C(O)=CC=CC=2N=C1.CN1C2C(O)=CC=CC=2N=N1>C1COCC1.C(Cl)(Cl)Cl>[CH3:12][NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(=O)OC=O
Agent: Cn1cnc2cccc(O)c21
Agent: Cn1nnc2cccc(O)c21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CNc1c(O)cccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
The title compound was prepared from 2-amino-3-nitrophenol according to a procedure adapted from Tet. Lett. 23, 3315 (1982). 2-Amino-3-nitrophenol (7.7 g, 50 mmol) in dry THF (20 mL) was treated dropwise with formic-acetic anhydride (130 mmol) in THF (10 mL) at about -5° C. under N2 (g). After stirring 3 hours the mixture was concentrated in vacuo to a viscous oil which was redissolved in THF (12 mL) and treated dropwise with 2M borane-dimethylsulfide in THF (63 mL) at about -5° C. When the addition was complete the mixture was heated to reflux (2 hours), cooled in ice and quenched with MeOH (20 mL). After stirring for 1 hour at about 22° C., anhydrous HCl was bubbled into the solution to acidity it to about pH 2. The mixture was refluxed for 1 hour and concentrated in vacuo. The residue was dissolved in H2O, neutralized with conc. NH4OH and cooled (16 hours) to produce a dark brown solid. This wet material was dissolved in CHCl3, dried over Na2SO4 and concentrated in vacuo to afford a red-brown solid (6.72 g; >95% purity) which was used directly in the syntheses of 3-methylbenzimidazol-4-ol and 3-methylbenzotriazol-4-ol (below).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]2[O:14][C:15](=[O:24])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:10]2[CH2:9]1.[NH2:25][C:26]1[C:27]([C:40](O)=[O:41])=[N:28][C:29]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])=[CH:30][CH:31]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH2:25][C:26]1[C:27]([C:40]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]3[O:14][C:15](=[O:24])[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@@H:10]3[CH2:9]2)=[O:41])=[N:28][C:29]([C:32]2[C:33]([F:39])=[CH:34][CH:35]=[CH:36][C:37]=2[F:38])=[CH:30][CH:31]=1
Reactant: Nc1ccc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3N)C[C@H]21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3NC(=O)c3nc(-c4c(F)cccc4F)ccc3N)C[C@H]21
Reaction time: 15 h
Yield: 46 %

Procedure:
To a solution of (3aR,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate (1.0 equiv.) in DMF (0.3 M) was added 3-amino-6-(2,6-difluorophenyl)picolinic acid (1.2 equiv.), EDC (1.2 equiv.) and HOAt (1.2 equiv.). The solution was stirred for 15 h. To the mixture was added water and the precipitate was filtered. To the filtrate was added EtOAc, and the organic solution was extracted (3 times), dried with Na2SO4, and concentrated to give an orange syrup. The crude was triturated with EtOAc and hexanes mixture and the precipitate was filtered off to give pure product in 46% yield. LCMS (m/z): 567.0 (MH+), LC Rt=3.03 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH:22]([CH3:24])[CH3:23])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:25]=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2].O.P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH:22]([CH3:24])[CH3:23])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:25]([OH:32])=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2]
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OC(C)C)c(OC)cc23)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC(C)C)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.7 %

Procedure:
To a stirred solution of 1-(3-ethoxy-benzoyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde (31 mg, 0.079 mmol) in t-butanol (1 mL) and water (1 mL) solution was added sodium dihydrogenphosphate monohydrate (44 mg, 0.32 mmol), 2-methyl-2-butene (0.053 mL, 0.48 mmol) and sodium chlorite (43 mg, 0.48 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate to afford 1-(3-ethoxy-benzoyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carboxylic acid (8 mg, 23% yield) as a light yellow solid. HR-MS m/e calcd for C23H23N1O6 (M−H+) 410.1598, found 410.1601; 1H NMR (300 MHz) compatible.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[Cl:16][C:17]1[C:22]([C:23](O)=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[CH:19][CH:18]=1.S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>C1COCC1>[Cl:16][C:17]1[C:22]([C:23]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][CH:1]([CH3:3])[CH3:2])=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])=[CH:19][CH:18]=1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC(C)Nc1ncnc2c(N)cccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)Nc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)C)c3F)cccc12
Yield: 17.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-isopropylquinazoline-4,8-diamine (Intermediate-57, 50 mg, 0.25 mmol), 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoic acid (Intermediate-60, 100 mg, 0.37 mmol), thionyl chloride (1 mL), and DIPEA (127 mg, 0.99 mmol) in THF (2 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.70-8.67 (d, J=7.2 Hz, 1H), 8.48 (s, 1H), 8.37 (t, 1H), 8.11-8.08 (d, J=7.8 Hz, 2H), 7.53 (t, 1H), 7.41 (m, 2H), 4.55 (m, 1H), 4.31 (d, 2H), 2.50 (m, 1H), 1.27 (d, J=6.6 Hz, 6H), 1.05-1.03 (d, J=6.9 Hz, 6H); MS [M+H]+: 458.47.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C@@H:7]1(C(O)=O)C[C@H:8]1[C:10]([OH:12])=O.CN(C=O)C.[Cl:21]CCl>>[C@@H:1]1([C:2]([Cl:4])=[O:3])[CH2:7][C@H:8]1[C:10]([Cl:21])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@H]1C(=O)O
Reactant: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)[C@@H]1C[C@H]1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (112.0 mL, 1.153 mol) was added drop-wise to a stirred solution of rel-(1R,2R)-cyclopropane-1,2-dicarboxylic acid (60.0 g, 0.461 mol) in dichloromethane (600 mL) at 0° C. DMF (2 mL) was added to the reaction mixture at 0° C., and then the reaction mixture was allowed to warm to ambient temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure to afford rel-(1R,2R)-cyclopropane-1,2-dicarbonyl dichloride. The material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:11]12[CH2:17][CH:14]([CH:15]=[CH:16]1)[CH:13]1[C:18]([O:20][C:21](=[O:22])[CH:12]21)=[O:19])[CH:9]=[CH2:10]>>[C:2]1([N:1]=[C:21]([CH:12]2[CH:13]([C:18]([OH:20])=[O:19])[CH:14]3[CH2:17][C:11]2([CH2:8][CH:9]=[CH2:10])[CH:16]=[CH:15]3)[OH:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: Nc1ccccc1
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=Nc1ccccc1
Temperature: 150 °C

Procedure:
93 g of aniline are added dropwise to 102 g of allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride, while stirring. During this addition, the temperature rises to 80° C. The mixture is heated to 150° C. and the pressure is reduced to 4,266 Pa. 9 ml of water and 46 ml of aniline distil off. Distillation gives 82.37 g (60% of theory) of a viscous yellow oil of boiling point 183° C. under 12 Pa, nD20 1.5738 and η25 105.6 Pa.s.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][CH:24]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].CCN(CC)CC.C(Cl)(OCC1C=CC=CC=1)=O>C1COCC1.[Pd]>[CH2:1]([O:8][C:9](=[O:37])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(CC#Cc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A solution containing compound 24 (2.53 g, 5.15 mmol) dissolved in THF (100 mL) was vacuumed and refilled with nitrogen. The procedure was repeated five times. To the solution was added palladium catalyst (0.5 g, 10% Pd on carbon, 50% wet). The flask was then pressurized with hydrogen gas to 45 psi. The mixture was then shaken overnight at room temperature. The catalyst was filtered under vacuum and washed with ethanol (3×20 mL). The filtrate and washings were combined and concentrated under vacuum. The residue was taken into dichloromethane (25 mL). To the newly formed solution was added Et3N (2.32 mL, 15.45 mmol). The solution was then cooled to 0° C. in an ice bath. CbzCl (1.32 g, 7.730 mmol) was added dropwise over 10 min to the solution, which, after the addition of CbzCl, was allowed to slowly warm to ambient temperature over 3 h and continuously stirred overnight. The reaction was quenched with water (30 mL). Two layers were separated. The organic layer was washed with brine (3×30 mL), dried over anhydrous Na2SO4, and concentrated. The resulting residue was subjected to column chromatography eluting with 0-30% ethyl acetate in hexanes to afford the desired product 25 (0.90 g, 35%) as a colorless, viscous oil: 1H NMR (300 MHz, CDCl3) δ 1.45 (d, 3H), 1.45-1.66 m, 6H), 1.72-1.86 (m, 2H), 2.06-2.16 (m, 2H), 2.55 (m, 4H), 3.20 (m, 2H), 4.38 (m, 1H), 4.80 (br, 1H), 5.08 (s, 2H), 7.04 (s, 4H), 7.34 (m, 5H), 7.69 (dd, 2H), 7.81 (dd, 1H); m/z (ESI) 499 [C31H34N2O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 4-chloro-phenyl isocyanate (0.073 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 45 as a colorless solid (0.097 g, 54%). LCMS m/z (%)=421 M+H+ (37Cl, 53), 419 M+H+ (35Cl, 77) 1H NMR (400 MHz, CDCl3) δ: 7.689 (bs, 2H), 7.617 (s, 1H), 7.460 (d, J=2.62 Hz, 1H), 7.438 (d, J=2.52 Hz, 1H), 7.22-7.28 (m, 3H), 6.947 (d, J=8.93 Hz, 1H) 4.245 (m, 1H), 3.808 (s, 3H), 1.575 (d, J=6.35 Hz, 3H), 1.381 (d, J=6.35 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13](OS(C(F)(F)F)(=O)=O)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N[C:30]1[CH:31]=[CH:32][C:33](=[O:36])[NH:34][CH:35]=1.C[C:38]([N:40](C)C)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([NH:40][CH2:38][C:30]3[CH:31]=[CH:32][C:33](=[O:36])[NH:34][CH:35]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)N(C)C
Reactant: Nc1ccc(=O)[nH]c1
Reactant: COc1ccc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc1OC
Product: COc1ccc(-c2cc3ncccc3c(NCc3ccc(=O)[nH]c3)n2)cc1OC
Temperature: 70 °C
Reaction time: 24 h

Procedure:
100 mg Trifluoromethanesulfonic acid 7-(3,4-dimethoxy-phenyl)-[1,6]naphthyridine-5-yl ester (6.2) was placed in 2 mL dimethylacetamide at ambient temperature before 120 mg 5-amino-1H-pyridine-2-one (2.31) was added. The reaction was heated to 70° C. overnight and then cooled to ambient temperature. After this time, additional 14.9 mg 5-amino-1H-pyridin-2-one (2.31) was added and the reaction was heated to 70° C. for 24 h and then 100° C. for a further 24 h. The solvent was removed under reduced pressure and the crude material was purified twice by silica gel chromatography (ethyl acetate/methanol) and then by preparative chromatography. Finally it was free-based using a SCX column to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.Br[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:20][CH2:19][N:18]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
NaH (60% strength in mineral oil, 709 mg, 29.52 mmol) was added to a mixture of 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (2.5 g, 9.84 mmol) in DMF (50 ml) at 0° C., the mixture was stirred at room temperature for 2 h, 4-(bromomethyl)-pyridine HCl (2.42 mg, 14.76 mmol) was then added and the mixture was stirred at room temperature for 16 h. Finally, ice was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase methanol/methylene chloride). Yield: 35%
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](O)=O)[C:7](=[O:15])[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[C:17]([O:21][C:22]([NH:24][C@@:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:30])[C:26]([NH:28][NH2:29])=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.CN(C)CCCN=C=NCC.[OH:50]N1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:17]([O:21][C:22]([NH:24][C@:25]([CH3:30])([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]([NH:28][NH:29][CH2:12][C:11]([N:8]1[CH2:9][CH2:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:16])[C:7]1=[O:15])=[O:50])=[O:27])=[O:23])([CH3:18])([CH3:19])[CH3:20]
Reactant: On1nnc2cccnc21
Reactant: CCCCN1CCN(CC(=O)O)C(=O)C1=O
Reactant: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN1CCN(C(=O)CNNC(=O)[C@@](C)(Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)C1=O

Procedure:
A solution of 2-(4-butyl-2,3-dioxopiperazin-1-yl)acetic acid (Intermediate F, 142 mg, 0.62 mmol), (R)-2-tert-butoxycarbonylamino-2-benzylpropanehydrazide (Intermediate B, 225 mg, 0.77 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (93 mg, 0.68 mmol) and diisopropylethylamine (0.12 mL, 0.68 mmol) in 6.2 mL DMF was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. Drying, solvent evaporation and flash chromatography (silica gel, 0-10% MeOH/CH2Cl2) gave 1-((2-((R)-2-tert-butoxycarbonylamino-2-methyl-3-phenylpropanoyl)hydrazino)acetyl)-4-butylpiperazine-2,3-dione. 1H NMR (CDCl3) δ 7.26 (m, 3H), 7.17 (m, 2H), 4.25 (A of AB, 1H, J=15.9 Hz), 4.20 (B of AB, 1H, J=15.6 Hz), 3.74 (m, 1H), 3.62 (m, 3H), 3.47 (m, 3H), 3.08 (m, 1H), 1.57 (m, 2H), 1.46 (s, 9H), 1.40 (s, 3H), 1.36 (m, 2H), 0.94 (t, 3H, J=7.2 Hz).
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:35])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:17]([F:34])=[CH:18][C:19]3[C:29](=[O:30])[C:28]([C:31]([OH:33])=[O:32])=[CH:27][N:21]4[C@@H:22]([CH3:26])[CH2:23][O:24][C:25]=2[C:20]=34)[CH2:10]1)=O)(C)(C)C>Cl>[NH2:8][C:9]1([CH3:35])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:17]([F:34])=[CH:18][C:19]3[C:29](=[O:30])[C:28]([C:31]([OH:33])=[O:32])=[CH:27][N:21]4[C@@H:22]([CH3:26])[CH2:23][O:24][C:25]=2[C:20]=34)[CH2:10]1
Reactant: C[C@H]1COc2c(N3CC4(CC4)C(C)(NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Product: C[C@H]1COc2c(N3CC(C)(N)C4(CC4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
(3S)-10-[7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane-5-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (761 mg, 1.56 mmol) was dissolved in concentrated hydrochloric acid (6.5 mL) in an ice bath, and the mixture was stirred at room temperature for 120 minutes. The reaction mixture was washed with chloroform, and saturated aqueous solution of sodium hydroxide was added to the aqueous layer in an ice bath to a pH of 12.0. Hydrochloric acid was then added to adjust pH to 7.4, and the solution was extracted with lower layer of a mixed solution (chloroform:methanol: water, 7:3:1). After combining the organic layers, and drying with anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. Chloroform was added to the residue, and the insoluble content was removed by filtration. The filtrate distilled under reduced pressure. The residue was purified by crystallization from ethanol, and dried under reduced pressure to obtain 260 mg (0.68 mmol, 43%) of the title compound as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH2:17]([O:16][C:14]([C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]([F:19])([F:32])[F:31])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(Br)c2)n1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n1

Procedure:
The titled compound was prepared by reacting ethyl 1-(3-bromophenyl)-5-methyl-1H-pyrazole-3-carboxylate (from Step 1 of EXAMPLE 1) with 2-(Trifluoromethoxy)phenylboronic acid (from Step 3 of EXAMPLE 1) under the reaction condition described in Step 4 of EXAMPLE 1.