Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:27](=[O:28])[CH2:26][N:25]([CH3:29])[C:24]2=[O:30])[CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@:26]32[N:25]([CH3:29])[C:24](=[O:30])[N:23]([C:18]2[CH:17]=[C:16]([Cl:15])[CH:21]=[C:20]([Cl:22])[CH:19]=2)[C:27]3=[O:28])=[CH:4][CH:3]=1
Reactant: BrCCCCC(Br)c1ccc(Br)cc1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCCC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(1,5-dibromopentyl)benzene (4.2 g, 10.9 mmol) (Preparation 14) and 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (2.59 g, 10 mmol), the above titled compound was obtained as a white solid (3.1 g, mp=118° C.). 1H NMR (CDCl3): 7.41 (2H, d, J=8.4 Hz), 7.30 (1H, m), 7.00 (2H, d, J=8.4 Hz), 6.90 (2H, m), 3.03 (3H, s), 2.91 (1H, dd, J1=12.9 Hz, J2=3.6 Hz), 2.55 (1H, dq), 2.1–2.3 (1H, m), 1.8–2.05 (5H, m), 1.3–1.6 (1H, m).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.CN(C)[CH2:14][CH2:15]CN=C=NCC.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][N:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(I)nc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(I)nc1
Temperature: 50 °C

Procedure:
To a suspension of 6-iodonicotinic acid (23.38 g, 94.20 mmol) in dichloromethane (100 ml) was added a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.86 g, 103.6 mmol) in dichloromethane (250 ml). To this mixture was added ethanol (12.40 g, 269.27 mmol) followed by dimethylaminopyridine (1.15 g, 9.41 mmol). The mixture was heated at 50° C. for 24.5 hours, concentrated in vacuo, and diluted with water (200 ml) then extracted with ethyl ether (550 ml). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to a yellow solid. Purification by flash chromatography (silica, 10% EtOAc-hexane) afforded the title compound as white needles: mp 48°-49° C.; 1H NMR (CDCl3): δ 8.94 (1H, d, J=2.1 Hz), 7.91 (1H, dd, J=2.1, 8.2 Hz), 7.85 (1H, d, J=8.2 Hz), 4.41 (2H, q, J=7.1 Hz), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[S:38][C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[S:38][C:34]([CH3:33])=[CH:35][N:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)s5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 1 eq), 1-(5-methylthiazol-2-yl)cyclopropanamine (0.07 g, 1 eq), EDCI.HCl (0.13 g, 1.5 eq), HOBT (0.094 g, 1.5 eq) and TEA (0.19 ml, 3 eq) were dissolved in dichloromethane and the above solution was stirred at room temperature for 18 h. Then water was added to the mixture and the organic layer was separated. The organic layer was washed with water and the product was purified by Prep. HPLC. Yield: 65 mg (25%)1HNMR (400 MHz, CDCl3): δ 1.43-1.46 (m, 2H), 1.74-1.77 (m, 2H), 2.32 (s, 3H), 2.37 (s, 3H), 3.01-3.03 (d, J=5.2 Hz, 3H), 4.04 (s, 3H), 5.89 (m, 1H), 6.91 (s, 1H), 7.16 (t, 2H), 7.27 (m, 2H), 7.51 (d, J=4 Hz, 1H), 7.66 (s, 1H), 8.00 (m, 2H), 8.13 (s, 1H), 8.7 (s, 1H). LCMS: (ES+) m/z=570.2 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14]([C:16]1[CH:17]=[C:18]([S:23]([N:26]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[C:27]2[S:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:19]=[CH:20][C:21]=1F)#[N:15]>>[C:14]([C:16]1[CH:17]=[C:18]([S:23]([N:26]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])[C:27]2[S:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:19]=[CH:20][C:21]=1[O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[I:1])#[N:15]
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3I)c(C#N)c2)c(OC)c1

Procedure:
The title compound was prepared according to Preparation 255 using 2-iodo-4-(trifluoromethoxy)phenol (Preparation 226) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzene sulfonamide (Preparation 68).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:17])=[CH:11][CH:10]=1
Reactant: NC1CCOCC1
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: O=C(Cc1ccc(Br)cc1)NC1CCOCC1
Yield: 100 %

Procedure:
The title compound was prepared in substantially the same way as intermediate (iv) by coupling of tetrahydropyran-4-yl amine with (4-bromo-phenyl)-acetic acid to give 0.65 g (100% yield) as a thick oil which solidified on standing.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[CH3:11])=[N+:2]=[N-:3].[Br:12]N1C(=O)CCC1=O>C1C=CC=CC=1>[N:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[CH2:11][Br:12])=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(I)cc1N=[N+]=[N-]
Solvent: c1ccccc1
Product: [N-]=[N+]=Nc1cc(I)ccc1CBr
Yield: 67.4 %

Procedure:
A mixture of the azide from step 1 (9.1 g, 0.035M), N-Bromosuccinimide (6.8 g, 0.039M) and 1,1azobis(cyclohexanecarbonitrile) (0.85 g, 3.5 mmol) in benzene (40 ml) was heated at reflux overnight. The solvent was evaporated under vacuum and the residue was diluted EtOAc (100 ml) and washed with water (50 ml) and brine, dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography (silica, hexanes) to give the azide as a white solid (8 g, 67%). 1H NMR (500 MHz, CDCl3): δ 4.30 (2H, s), 6.98 (1H, d, J 8.0), 7.35 (2H, t, J 7.0).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC(Cl)(Cl)[C:13]([N:15]=C=O)=[O:14].[OH-].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:13]([NH2:15])=[O:14])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)CCN2
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)N1CCc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2.5 g, 12.6 mmol) in DCM (30 mL) is added a trichloroacetyl isocyanate (1.6 mL, 13.2 mmol). After stirring for 1 h at 0° C., a solution of methanolic KOH (1M, 10 mL) is added. The resulting mixture is allowed to warm and stir at room temperature for 16 h. The reaction is concentrated and purified by silica gel column (0-100% EtOAc in heptane) to afford the title compound (2.6 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[OH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](O)=[O:19])[CH2:14][CH2:13]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:18]([C@H:15]2[CH2:16][CH2:17][C@@H:12]([OH:11])[CH2:13][CH2:14]2)=[O:19])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-aminomethyl-3-chloropyrazine hydrochloride (content 76%, 69.4 mmol, 16.43 g), cis-4-hydroxycyclohexanecarboxylic acid (69.4 mmol, 10 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mmol, 19.95 g), 4-dimethylaminopyridine (6.94 mmol, 0.847 g) in dichloromethane (200 ml) was added N,N-diisopropylethylamine (173 mmol, 30.3 ml, 22.41 g) until pH became eight and the reaction mixture was stirred at room temperature for 18 hours. Then it was concentrated in vacuo, ethyl acetate and water were added and the organic layer separated. The water layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient of 0% to 7% methanol). All fractions that contained product were combined and concentrated in vacuo. The residue was dissolved in dichloromethane (400 ml) and washed with 2 M sodium hydroxide (aq) (three times 100 ml), washed with brine, dried (MgSO4) and concentrated in vacuo to give (cis)-N-((3-chloropyrazin-2-yl)methyl)-4-hydroxycyclohexanecarboxamide (15.47 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>CN(C)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=3)[CH2:11][C:5]=2[CH:4]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc2c(c1)CNc1ccccc1C2=O
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: COc1ccc2c(c1)CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1C2=O
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 8-methoxy-11-oxo-6,11- dihydrodibenz[b,e]azepine (150 mg) in N,N-dimethylaniline (1 ml) was added 4-nitrobenzoyl chloride (140 mg) at 110° C. The mixture was stirred for 1 hour at the same temperature and diluted with ethyl acetate. The solution was washed successively with diluted hydrochloric acid and brine. The organic phase was dried over magnesium sulfate, and evaporated in vacuo to give crude 8-methoxy -5-(4-nitrobenzoyl)-11-oxo-6,11-dihydrodibenz[b,e]azepine (240 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCC1
Temperature: 25 °C

Procedure:
To a solution of pyrrolidine (8.25 g, 116 mmol) in dichloromethane (120 mL) were added triethylamine (19.0 mL, 139 mmol) followed by addition of methanesulfonyl chloride (9.0 mL, 116 mmol) at 0° C. The reaction was allowed to stir while warming up to rt. overnight, which was transferred to a separatory funnel and washed twice with 1.0N HCl and brine once. Organic phase was dried over magnesium sulfate, filtered and solvent was removed to leave a pure title product as a white solid. Step B: 1-(Pyrrolidin-1-ylsulfonyl)propan-2-one
Reaction SMILES: [CH:1]([CH2:3][C:4](O)=[O:5])=[CH2:2].Cl.[NH2:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12]>C(Cl)Cl>[C:4]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:5])[CH2:3][CH:1]=[CH2:2]
Reactant: COC(=O)CC(N)c1ccccc1
Reactant: C=CCC(=O)O
Agent: Cl
Solvent: ClCCl
Product: C=CCC(=O)NC(CC(=O)OC)c1ccccc1
Temperature: -10 °C
Reaction time: 15 h
Yield: 95.4 %

Procedure:
To a solution of vinylacetic acid (861 mg, 10.0 mmol), methyl 3-amino-3-phenylpropionate hydrochloride (2.37 g, 11.0 mmol) and TEA (1.6 mL, 12 mmol) in DCM (20 mL) at -10° C. was added DEC (2.11 g, 11.0 mmol). The resulting mixture was stirred at -10° C. for 15 hours. The mixture was then washed with water, 0.1M HCl, sat. NaHCO3, sat. NaCl and dried over anhydrous MgSO4. Concentration in vacuo followed by pumping until constant weight gave 2.36 g (95%) of the desired amide as a golden oil of suitable purity for further reaction; 1H NMR (300 MHz, CDCl3) 87.28 (m, 5H), 6.78 (bd, J=7.7 Hz, 1H), 5.95 (m, 1H), 5.43 (dt, J=8.4, 5.9 Hz, 1H), 5.25 (m, 2H), 3.61 (s, 3H), 3.04 (d, J=7.0 Hz, 2H), 2.88 (dq, J=15.0, 5.9 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[N:8]([C:19]([N:16]3[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]3)=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Reactant: CC1CCN(C(=O)Cl)CC1
Product: CC1CCN(C(=O)n2c(=O)oc3cc(Br)cnc32)CC1

Procedure:
100 mg (0.46 mmol) of 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one were reacted in analogy to Example 6 with 150 mg (0.93 mmol) of 4-methylpiperidin-1-carbonyl chloride. Yield: 78 mg (50%), M+H+: 340.09.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)[CH3:2].[CH:14](O)=[O:15]>C(OC(C)C)(C)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH:14]=[O:15])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=CO
Solvent: CC(C)OC(C)C
Product: CCOC(=O)Cc1cccc(NC=O)c1
Yield: 88 %

Procedure:
A solution of 3-aminophenylacetic acid ethyl ester (3.0 g; 0.017 mol; from Example T(i) above), and formic acid (1.5 g; 0.034 mol) in diisopropylether (150 mL) was refluxed with a Dean-Stark trap overnight. The solution was concentrated to dryness, dissolved in ether and washed with diluted HCl to remove remaining starting material. Drying (Na2SO4) and concentration yielded the sub-title compound (3.1 g; 89%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:20]1[CH:25]=[C:24]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCCc2ccc(-c3cccc(F)c3)cc21
Temperature: 80 °C
Yield: 54.4 %

Procedure:
Cesium carbonate (869 mg, 2.67 mmol) was added to a solution of 7-bromo-3,4-dihydronaphthalen-1(2H)-one (300 mg, 1.33 mmol), (3-fluorophenyl) boronic acid (372 mg, 2.67 mmol) and toluene (20 mL) in a 50 mL Schlenk tube. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3×), then tetrakis(triphenylphosphine)palladium (0) (15 mg, 0.013 mmol) was added to the reaction. The flask was sealed and heated in a 80° C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (40 g column, hexanes→100% ethyl acetate/hexanes, gradient), to afford 174 mg (54%) of 7-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]([S:16][CH3:17])=[N:12][N:11]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]([N:9]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:8])[C:10]1[N:14]([CH3:15])[C:13]([S:16][CH3:17])=[N:12][N:11]=1)=[O:21]
Reactant: CSc1nnc(Nc2c(C)cccc2C)n1C
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CSc1nnc(N(C(=O)CCl)c2c(C)cccc2C)n1C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a stirred solution of 6.1 g (0.0232 mol) 3-(2,6-dimethylphenylamino)-4-methyl-5-methylthio-1,2,4-triazole in 150 ml toluene was added quickly 2.7 g (0.024 mol) chloroacetyl chloride. An exotherm ensued and the temperature rose to 100° C., followed by separation of an oil which solidified. The reaction mixture was stirred at 100°-105° C. for 1 hour, cooled and diluted with 50 ml saturated sodium bicarbonate and 20 ml dichloromethane. The clear organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give a clear oil. The oil was crystallized from ethyl ether to give 7.4 g of product, as a pale yellow solid, m.p. 145°-147° C. The product is tabulated in Table I as Compound No. 14-B.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[O:2]2.C(O)(=O)C>N1C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[O:2]2
Reactant: O=C(OCc1ccccc1)N1OC2C=CC1C2
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1OC2CCC1C2
Temperature: 25 °C
Yield: 83.4 %

Procedure:
Azodicarbonamide (5.0 g) was stirred with a solution of potassium hydroxide (7.0 g) in water (12 ml) at 4°. After stirring in the ice bath for 1 h the mixture was diluted with ice/water (30 ml) and the solution was filtered. The filtrate was diluted with cool (2°) ethanol (100 ml) and the resultant solid was filtered off, washed with ethanol, methanol and ether to give potassium azodicarboxylate (6.9 g). This was then mixed with 3-aza-2-oxabicyclo[2.2.1]hept-5-ene-3-carboxylic acid, (phenylmethyl) ester (0.82 g) in dry pyridine (60 ml), and acetic acid (2.02 g) was added with stirring at room temperature. After one hour a further portion of glacial acetic acid (2.02 g) was added and the reaction mixture was stirred for 15.5 h. The mixture was evaporated to dryness under reduced pressure. Further acetic acid was then added to quench the remaining yellow colour of the diimide precursor. The residue was partitioned between 0.5M citric acid (75 ml) and ethyl acetate (75 ml) and the organic phase was separated, dried, and concentrated in vacuo. The residue was purified by FCC eluting with ethyl acetate:cyclohexane (1:2) to give the title compound (0.69 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28](OC)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([NH:39][CH2:38][CH2:36][OH:37])=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: NCCO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)NCCO
Yield: 80.9 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with ethanolamine (0.15 mL, 2.5 mmol) to give the title compound as a white solid (170 mg, 80%); NMR Spectrum 1.65 (d, 3H), 3.22 (q, 2H), 3.41-3.45 (m, 2H), 4.75 (t, 1H), 5.22 (q, 1H), 5.70 (s, 2H), 7.01-7.12 (m, 4H), 7.36 (dd, 2H), 7.72-7.76 (m, 3H), 8.17 (s, 1H), 8.47 (m, 1H), 8.53 (s, 1H), 8.56 (s, 1H), 10.73 (br s, 1H); Mass spectrum MH+ 501.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9](O)=O)[C:5](C)=[N:6][CH:7]=1.C1C(=O)[N:16](Br)[C:14](=O)[CH2:13]1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[O-]CC>C(O)C.N1C=CC=CC=1>[N:16]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:7][N:6]=2)[CH:9]=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncc(I)cc1C(=O)O
Agent: CC[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: c1ccncc1
Product: c1cnc2ncccc2c1

Procedure:
5-Hydroxy-[1,7]naphthyridine-6-carboxamides. Preparation of specific examples of heterocycle W3.6 follows established precedent for 5-hydroxy--[1,7]naphthyridine ring synthesis (Just. Liebigs. 1979, 443-445.), Chart P. 5-Iodo-2-methylpyridine-3-carboxylic acid (P.1) (J. Am. Chem. Soc. 1953, 75, 737) is brominated under radical conditions (e.g. NBS, benzoylperoxide) to afford pyridine P.2. P.2 is treated with ethyl 2-N-toluenesulfonylaminoacetate to provide P.3. Upon treatment of P.3 with ethoxide in ethanol, ring cyclization and elimination occurs to afford naphthyridine P.4. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to afford the corresponding amides of the general formula P.5 or, alternatively, ester P.4 is saponified to afford the corresponding acid which is then coupled with a benzylamine employing standard amide coupling protocols (e.g. HOBT/EDC or other suitable carboxylic acid activating agent) to likewise provide amides of the general formula P.5.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[C:9]1([CH2:15][C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH:4]([CH:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:16]#[N:17])=[O:5]
Reactant: N#CCc1ccccc1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CC(C=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium methoxide (5.56 g) in benzene (200 ml) is added dropwise with stirring a mixture of ethyl formate (8.14 g) and phenylacetonitrile (11.7 g) under ice cooling. After 30 minutes, the ice bath is taken off. After reacting for 3 hours, ice water is added to the reaction mixture, and the aqueous layer is separated. The organic layer is washed with 0.5 N sodium hydroxide solution (50 ml×3), and the aqueous layer and the washings are combined and adjusted to pH 3-4 with conc. hydrochloric acid. The mixture is stirred under ice cooling for 20 minutes, and the resulting precipitate is separated by filtration and washed with water to give α-formylphenylacetonitrile. The product is used in the subsequent procedure without further purification.
Reaction SMILES: CN.C1N=[CH:6][N:5]([C:8]([N:10]2C=N[CH:12]=[CH:11]2)=[O:9])C=1.CCN(C(C)C)C(C)C.NCC[C@@:27]1([C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)[O:32][C:31](=[O:33])[N:30]([C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=3[F:49])=[CH:38][CH:37]=2)[CH3:35])[CH2:29][CH2:28]1>C(Cl)Cl>[F:49][C:43]1[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=1[C:39]1[CH:40]=[CH:41][C:36]([C@@H:34]([N:30]2[CH2:29][CH2:28][C@:27]([CH2:12][CH2:11][NH:10][C:8]([NH:5][CH3:6])=[O:9])([C:50]3[CH:51]=[CH:52][C:53]([F:56])=[CH:54][CH:55]=3)[O:32][C:31]2=[O:33])[CH3:35])=[CH:37][CH:38]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Agent: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
To a solution of methylamine (11 mg, 0.11 mmol) and CDI (20 mg, 0.13 mmol) in anhydrous CH2Cl2 (3 mL) was added DIEA (130 mg, 1.00 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at ambient temperature for 1 h. (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (40 mg, 0.088 mmol) was added to the above mixture, and the mixture was stirred at rt overnight. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC to afford 1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-3-methylurea (5 mg, 12%). 1H NMR (CDCl3): 1.56 (m, 3H), 2.10-2.30 (m, 4H), 2.35 (m, 1H), 2.75 (s, 3H), 3.01 (m, 1H), 3.09 (m, 1H), 3.30 (m, 1H), 5.69 (m, 1H), 6.86-6.96 (m, 2H), 7.08 (m, 4H), 7.25 (m, 2H), 7.30 (m, 3H).