Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.[H-].[Na+].[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCOC(C)=O>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2]([NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[S:29])=[N:3][C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1nc(NC(=S)Nc2ccccc2)c(F)cn1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 8.4 %

Procedure:
To a suspension of 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidin-2-one (0.20 g, 0.74 mmol) in anhydrous tetrahydrofuran (THF; 3 mL) was added sodium hydride (NaH; 0.044 g of 60 wt % suspension in mineral oil, 1.11 mmol) at 0° C. After gas evolution had subsided, the mixture was transferred via cannula to an ice-cold mixture of phenyl isothiocyanate (1.0 g, 7.4 mmol) in anhydrous THF (5 mL) and stirred for 6 h. The reaction mixture was diluted with EtOAc (25 mL), and the resulting solution was washed with satd aq ammonium chloride (NH4Cl; 15 mL) and brine (15 mL). The organic phase was dried over Na2SO4, filtered, and the solvent evaporated. The residue was purified by precipitation from methanol (MeOH) and Et2O to give (1-benzenesulfonyl-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-3-phenylthiourea as a light yellow solid (0.025 g, 8%): mp 205-208° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.26 (dd, J=3.7, 1.1 Hz, 1H), 10.87 (m, 1H), 8.65 (m, 1H), 8.10 (d, J=7.5 Hz, 2H), 7.85 (t, J=7.5 Hz, 1H), 7.71 (m, 2H), 7.45 (m, 2H), 7.34 (m, 2H), 7.10 (m, 1H); ESIMS m/z 405 ([M+H]+).
Reaction SMILES: [OH:1][CH:2]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[C:3]1[CH:4]=[C:5]([C:16]([O:18]C)=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.[OH-].[Li+].[NH4+].[Cl-]>O1CCOCC1.O>[OH:1][CH:2]([C:20]1[S:21][CH:22]=[CH:23][N:24]=1)[C:3]1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2nccs2)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3nccs3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 5-(hydroxy(thiazol-2-yl)methyl)-4′-methylbiphenyl-3-carboxylate (170 mg, 0.50 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL) was added lithium hydroxide (42 mg, 1.8 mmol). After being stirred at rt for 4 h, the reaction mixture was treated with aq. NH4Cl and extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous MgSO4 and purified by silica gel column to afford the title compound. 1H NMR (CDCl3, 400 MHz): 8.19 (s, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.24 (m, 1H), 7.14 (d, J=7.6 Hz, 2H), 6.21 (s, 1H), 5.28 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([NH:32][C:33]([CH2:35][O:36]C(=O)C)=[O:34])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:27][CH2:28][CH:29]([NH:32][C:33](=[O:34])[CH2:35][OH:36])[CH2:30][CH2:31]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(=O)OCC(=O)NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(CO)NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Yield: 70 %

Procedure:
Acetoxyacetyl chloride (46 mg, 2 equiv) was added dropwise to a solution of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (47 mg, 0.1 mmole) (80 mg, 0.17 mmole) and triethylamine (71 μL, 3 equiv.) in dry DCM (3 mL) at 0° C. under nitrogen. After stirring at 0° C. for 3 hr and at RT for 1 hr, it was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 2% MeOH) afforded acetic acid (1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidin-4-ylcarbamoyl)-methyl ester as a solid (73 mg, 75%). A solution of this ester in THF (0.4 mL) was treated with aq. NaOH (IN, 0.38 mL, 3 equiv.). After 2 hr at RT it was diluted with DCM, washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 0 to 3% MeOH) afforded the title compound as a solid (47 mg, 70%). MS: 529 (M+H)+; HPLC Ret Time: 1.37 min (YMC Xterra ODS S7 3.0×50 mm column, 2 min gradient, 5 ml/min).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:3][CH:2]=1.[Br:16]Br>C(Cl)(Cl)Cl.ClCCl>[Br:16][C:15]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12
Reactant: c1cnc2cc(-c3ccncc3)nn2c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Brc1c(-c2ccncc2)nn2cccnc12
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To 2-(pyridin-4-yl)pyrazolo[1.5-a]pyrimidine (0.30 g) in 15 mL chloroform was added dropwise a solution of 86 μL bromine in 1 mL chloroform. After 1.5 hours. at ambient temperature, the mixture was diluted with dichloromethane, washed with 10% aqueous potassium carbonate, dried over sodium sulfate, filtered, and evaporated to afford 386 mg (92% yield) product as a tan solid. MS showed a M+1 molecular ion of m/z 277.4 by positive APCI.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:18][C:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OC(=Cc1ccncc1)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 152.9 %

Procedure:
To a suspension of NaH (0.81 g, 18.6 mmol) in DMF (30 mL) under argon atmosphere and cooled to 0° C., a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (2.00 g, 9.3 mmol, obtained in reference example 1) in DMF (15 mL) was added and stirred to room temperature for 30 minutes. It was then cooled to 0° C. and a solution of 4-fluorobenzoyl chloride (2.95 g, 1.9 mmol) in DMF (10 mL) was added. It was stirred at room temperature overnight. Water was added and the solvent was evaporated off. The residue was dissolved in a mixture of CHCl3 and water and the phases were separated. The aqueous phase was extracted with CHCl3 (×3). The organic phase was washed with water (×2), dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.98 g of the desired compound as a yellow solid (yield: 31%).
Reaction SMILES: [Na].[ClH:2].C([O:10][CH2:11][C@@H:12]1[CH2:14][C@H:13]1[N:15]([CH3:17])[CH3:16])C1C=CC=CC=1.N.Cl>C(O)C.CCOCC>[ClH:2].[CH3:16][N:15]([CH3:17])[C@@H:13]1[CH2:14][C@H:12]1[CH2:11][OH:10]
Reactant: CN(C)[C@@H]1C[C@H]1COCc1ccccc1
Agent: Cl
Agent: N
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)[C@@H]1C[C@H]1CO
Reaction time: 3 h

Procedure:
1.2 g of sodium are added, in portions, to a solution of 4 g of the compound of Example 5 in 200 ml of condensed liquid ammonia. After 3 hours, 100 ml of ether and then 5 ml of ethanol are added. Stirring is carried out for 16 hours and the mixture is then concentrated and taken up in dichloromethane. The organic phase is treated in conventional manner and then evaporated. Chromatography over silica gel (dichloromethane/methanol: 90/10) allows the expected product to be isolated, which is converted into its hydrochloride form.
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:2]#[CH:3].[N:9]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([OH:28])[C@H:19]([NH:22][C:23](=[O:27])[CH:24]([Cl:26])[Cl:25])[CH2:20][F:21])=[CH:14][CH:13]=1)=[N+:10]=[N-:11]>>[Cl:25][CH:24]([Cl:26])[C:23]([NH:22][C@H:19]([CH2:20][F:21])[C@H:18]([OH:28])[C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH:3]=[C:2]([CH2:1][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[N:11]=[N:10]2)=[CH:17][CH:16]=1)=[O:27]
Reactant: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: C#CCNS(C)(=O)=O
Product: CS(=O)(=O)NCc1cn(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)nn1

Procedure:
Following the general procedure of Example 66, Step 3 and making non-critical variations but using the product of step 1, Example 67 with the product of Example 66, Step 2 the title compound is obtained (45 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 2.95 (s, 3H), 4.25-4.26 (m, 1H), 4.30 (s, 2H), 4.33-4.34 (m, 0.5H), 4.42-4.46 (m, 0.5H), 4.58-4.61 (m, 0.5H), 4.69-4.73 (m, 0.5H), 4.95 (t, 1H, J=3.3 Hz), 6.08 (d, 1H, J=3.92 Hz), 6.49 (s, 1H), 7.55 (d, 2H, J=8.56 Hz), 7.84 (d, 2H, J=8.6 Hz), 8.64 (d, 1H, J=9.04 Hz), 8.70 (s, 1H). LC-MS (m/z): [M+H]=453.9.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.S(C1C=CC(C)=CC=1)(O[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:1].[O:22]([CH2:21][CH2:20][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([F:2])[CH:4]=2)[CH2:8][CH2:9]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Fc1cccc(CC2CCNCC2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1cccc(CC2CCN(CCOc3ccccc3)CC2)c1
Yield: 50 %

Procedure:
From a mixture of 4-(3-fluorobenzyl)piperidine hydrochloride (229.5 mg, 1.0 mmol), 2-phenoxyethyl tosylate (350.4 mg, 1.2 mmol), potassium carbonate (414 mg, 3.0 mmol) in 15 mL of ethanol was 175 mg (50%) of the title compound, mp 175-177° C. 1H NMR (DMSO-d3) 1.696 (m, 1 H), 1.582 (m, 2 H), 2.096 (m, 2 H), 2.617 (m, 2 H), 2.781 (m, 2 H), 3.395 (m, 2 H), 3.687 (m, 2 H), 4.547 (s, 2 H), 6.756-6.999 (m, 6 H), 7.288 (m, 3 H), 12.556 (s, 1 H). Anal. Calcd for C20H25ClFNO: C, 68.66; H, 7.20; N, 4.00. Found: C, 68.37; H, 7.09; N, 3.98.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([OH:3])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH:25][C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:3]
Reactant: COc1ccccc1CCN
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CCNC(=O)Cc1cccc(CC(=O)O)c1
Yield: 30.5 %

Procedure:
Prepared from (3-carboxymethyl-phenyl)-acetic acid (2.00 g), 2-(2-methoxy-phenyl)-ethylamine (1.60 g), 1-hydroxybenzotriazole (1.40 g), Hunigs base (1.8 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.00 g), using the method of Example 44 (step a), to give 1.03 g of the sub-titled compound as a white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=O)[CH2:10][CH2:11][C:12](O)=O>Cl>[CH2:11]([C:12]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH2:10][C:9]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: O=C(O)CCC(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Product: c1ccc2[nH]c(CCc3nc4ccccc4[nH]3)nc2c1

Procedure:
To a flask were added 3 g of 1,2-phenylene diamine, 1.6 g of succinic acid, and 30 ml of 4M hydrochloric acid. The mixture was heated to reflux under nitrogen for 22 hours, and then cooled to 22 C. The solid was filtered, washed with a little water and dissolved in a warm mixture of 30 ml of acetone and 40 ml of water. Enough ammonium hydroxide was added to basify the mixture, and after cooling to 22 C, the product was filtered and washed with 20 ml of 50% acetone and dried, resulting in a light pink solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.Cl.Cl.[CH3:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][NH2:48].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:48][CH2:47][C:43]1[N:42]([CH3:41])[CH:46]=[CH:45][N:44]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cn1ccnc1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1ccnc1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 1.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), C-(1-methyl-1H-imidazol-2-yl)-methylamine dihydrochloride (13.91 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). The reaction mixture was stirred overnight and then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((1-methyl-1H-imidazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (4.9 mg, 0.001 mmol, 13% yield): LCMS=525.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.24 (2 H, m), 7.70 (4 H, t, J=8.03 Hz), 7.52-7.64 (3 H, m), 7.00 (1 H, d, J=1.25 Hz), 6.88 (1 H, d, J=1.51 Hz), 5.18 (1 H, s), 4.40-4.58 (2 H, m), 3.60 (3 H, s); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.0 min.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][C:4]=2[O:3]1.[Li+].[OH-]>C1COCC1>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:4]=2[O:3]1
Reactant: CCOC(=O)c1ccc2[nH]c(=O)oc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To ethyl 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylate in THF (20 mL) was added LiOH (2 g in 10 mL water). The mixture was stirred at room temperature for 20 hours. The solvent was evaporated. The residue was taken up in water and acidified with 5 N HCl to pH=5. The solid was recovered by filtration, washing with water, to provide the pure product as a tan solid (1.44 g, 80%). LCMS (API-ES) m/z: 180 (M+H+).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][O:9][C:8]([NH:12][C@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-:22]#[N:23].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:13]1([NH:12][C:8]2[O:9][CH2:10][C:11]3[C:2]([C:22]#[N:23])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Brc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: [C-]#N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 160 °C
Yield: 49.2 %

Procedure:
A stirred mixture of (5-bromo-4H-benzo[d][1,3]oxazin-2-yl) -(R)-indan-1-yl-amine (Example 10) (1.03 g, 3.79 mmol), zink cyanide (528 mg, 4.5 mmol) and tetrakis-(triphenylphosphine)-palladium (347 mg, 0.3 mmol) in DMF (9 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (2×40 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as white foam (540 mg, 62%). MS (ISN) m/e=288.2 [(M−H)−].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([N:21](COCC)[C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[C:13]([F:33])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[ClH:39].O>CO>[ClH:17].[ClH:39].[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]([F:28])=[CH:26][N:27]=3)(=[O:20])=[O:19])=[C:13]([F:33])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOCN(c1ncc(F)cn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N)c2)cc1F
Agent: Cl
Solvent: O
Solvent: CO
Product: Nc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncc(F)cn3)cc2Cl)ccn1
Temperature: 60 °C

Procedure:
To a solution of 4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-N-(ethoxymethyl)-2-fluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 15, 67 mg, 0.12 mmol) in methanol (1 mL) was added a 2.0 M solution of hydrogen chloride in water (1 mL, 2.00 mmol). The reaction mixture was heated at 60° C. for 6 hours then concentrated in vacuo. The residue was freeze dried from acetonitrile-water to afford the title compound as a white solid (69 mg).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]([N:5]=[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][NH:7]1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][C:3](=[O:4])[CH:2]([F:1])[F:12])=[CH:18][CH:19]=1
Reactant: O=C(N=c1cccc[nH]1)C(F)F
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)F

Procedure:
100 mg (0.58 mmol) of the 2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide obtained by the aforementioned method was dissolved in 10 ml of anhydrous acetonitrile, 94 mg (0.58 mmol) of 2-chloro-5-chloromethyl pyridine was dissolved in 5 ml of anhydrous acetonitrile and added thereto, and subsequently, 84 mg (0.63 mmol) of potassium carbonate was added thereto and the resulting mixture was heated and refluxed for 140 minutes. After the reaction was completed, the reaction solution was returned to room temperature to filter off insoluble materials, and the filtrate was concentrated under reduced pressure. Ether was added thereto to precipitate a solid, and thus the solid was collected and dried well to obtain the subject material. Amount obtained 63 mg (yield 37%).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:19][C:20]1([CH3:36])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([CH2:32][C:33](Cl)=[O:34])[CH:23]=[CH:22][C:21]1=2>>[OH:1][C:2]1[CH:17]=[C:16]([O:18][C:33](=[O:34])[CH2:32][C:24]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:19])([CH3:36])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]=3[CH:25]=2)[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1O
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)Cl)ccc21
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)Oc3ccc(C(=O)OCc4ccccc4)c(O)c3)ccc21

Procedure:
In a manner similar to Example 1(d), by reaction of 2.44 g (10 mmol) of benzyl 2,4-dihydroxybenzoate with 2.6 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetyl chloride, 3.9 g (83%) of the expected ester are obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22](O)=[O:23])=[CH:20][CH:21]=1)=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=2)=[O:4].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:51]([CH3:53])[CH3:52])C2C=CC=CC=2N=N1.CC(N(C)C)=O.CCN(C(C)C)C(C)C>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22](=[O:23])[N:51]([CH3:53])[CH3:52])=[CH:20][CH:21]=1)=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=2)=[O:4]
Reactant: COC(=O)c1c(Cc2ccc(C(=O)O)nc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(Cc2ccc(C(=O)N(C)C)nc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To 3-(6-carboxy-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (0.095 g) in THF (6 mL) was added BOP (0.11 g), followed by DMA (0.15 mL, 2M in THF) and Hunig's Base (ethyl-diisopropylamine) (0.042 mL). Solids began to precipitate: DCM was added until all solids dissolved, and a homogenous reaction mixture was obtained. The mixture was stirred at RT for 1 h, then an additional aliquot of BOP, Hunig's base, and DMA added, and the mixture stirred at RT overnight. The product was worked up with EtOAc and H2O, washed with NaHCO3 (aq) and H2O, and dried over MgSO4. The product was concentrated, applied to a silica gel column with EtOAc, and eluted with EtOAc/MeOH, and concentrated to yield 3-(6-dimethylcarbamoyl-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (compound 103) (80 mg) as a pale yellow solid. M+H=457; mp=235.0-236.0° C.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:11]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
3,3-Dimethylbutanoyl chloride (617 mg, 0.64 mL, 4.6 mmol) was added to a solution of 4-Bromo-2-trifluoromethyl-phenylamine (1.0 g, 4.16 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.1 g, 79% yield).