Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1>[O:12]=[C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:10][N:9]1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 1A (1.0 g, 4.21 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 6.3 mL, 6.3 mmol) via syringe under nitrogen followed by ethyl 2-bromoacetate (0.47 mL, 4.21 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (20:80) gave the title compound. MS (DCI+) m/z 324.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[O:28][CH2:29][C:30]#[N:31])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[O:28][CH2:29][C:30]#[N:31])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile to yield an off-white solid (3.3%). mp 253° C.; LCMS: m/z=491.16 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.41 (d, 1H, J=7.8 Hz), 8.31 (s, 1H), 7.65 (m, 2H), 7.28 (m, 2H), 7.18 (m, 1H), 7.07 (m, 3H), 4.91 (s, 2H), 3.76 (m, 2H), 2.34 (m, 2H), 2.04 (m, 2H), 1.36 (s, 6H), 1.24 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][C:12](=[O:14])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Br[C:16]1C=C(C=CC=1C)C(=N)NO.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:16])[C:12](=[O:14])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=N)NO)cc1Br
Reactant: Cc1ccc(-c2noc(=O)[nH]2)cc1Br
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2noc(=O)n2C)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step-2: 3-(3-Bromo-4-methylphenyl)-1,2,4-oxadiazol-5(4H)-one: To a 0° C. cooled solution of 3-bromo-N-hydroxy-4-methylbenzimidamide (500 mg, 2.18 mmol, 1.0 eq) in DCM (10 mL) was added triphosgene (250 mg, 0.87 mmol, 0.4 eq) followed by diisopropylethylamine (0.76 mL, 4.46 mmol, 2 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction was cooled back down to room temperature and quenched with water (5 mL) followed by dilution with DCM. The layers were separated and the organic layer was washed with brine (10 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum to afford 250 mg of the title product as white solid. 1HNMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H, D2O exchangeable), 8.01 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.0, 1.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H) 2.42 (s, 3H); ESI-MS (m/z) 255, 257 [(MH)+, Br79,81]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[H-].[Na+].[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
A solution of 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide(0.20 g, 0.52 mmol) in tetrahydrofuran(3 mL) was added to a suspension of 60% sodium hydride(21.8 mg, 0.55 mmol) in tetrahydrofuran (3 mL) under ice bath, and the mixture was stirred for 5 minutes. Then, pivaloyl chloride(71 μ L, 0.57 mmol) was added and the mixture was stirred for 10 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was washed with isopropyl ether/n-hexane under suspension to give the title compound (195 mg, 80.2%) as a white crystal.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH2:19][OH:20])[CH:16]([N:21]=[N+:22]=[N-:23])[C:15]1=[O:24])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]=[O:20])[CH:16]([N:21]=[N+:22]=[N-:23])[C:15]1=[O:24])([C:10]([CH3:12])([CH3:13])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chromium trioxide (0.06 mol) is added to a solution of pyridine (0.12 mol) in methylene chloride (150 ml) and the mixture is stirred at room temperature for 15 min. A solution of N-(t-butyldimethylsilyl)-3-azido-4-(2-hydroxyethyl)-azetidin-2-one (0.01 mol) in methylene chloride (10 ml) is then added all at once. After stirring at room temperature for 5 min, the mixture is decanted and the dark, gummy residue is washed with more methylene chloride. The combined methylene chloride supernatant is concentrated under vacuum to a residue which is taken up in ether and filtered through celite. The filtrate is washed with 5% hydrochloric acid, 5% sodium bicarbonate solution, and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to yield N-(t-butyldimethylsilyl)-3-azido-4-(2-oxoethyl)azetidin-2-one.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][CH:10]([C:16]1[CH:17]=[C:18]([CH:40]=[CH:41][CH:42]=1)[O:19][C@@H:20]1[CH2:24][N:23]([C:25]([N:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH2:28][CH3:29])=[O:26])[C@H:22]([C:37]([OH:39])=[O:38])[CH2:21]1)[NH:9][C:8]2=[O:43])(=[O:4])=[O:3].[OH-].[Na+].Cl>O1CCCC1>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][CH:10]([C:16]1[CH:17]=[C:18]([CH:40]=[CH:41][CH:42]=1)[O:19][C@@H:20]1[CH2:24][N:23]([C:25]([N:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:28][CH3:29])=[O:26])[C@H:22]([C:37]([OH:39])=[O:38])[CH2:21]1)[NH:9][C:8]2=[O:43])(=[O:4])=[O:3]
Reactant: CCOC(=O)CCN(CC)C(=O)N1C[C@@H](Oc2cccc(C3NC(=O)c4cc(S(N)(=O)=O)c(Cl)cc4N3)c2)C[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CCC(=O)O)C(=O)N1C[C@@H](Oc2cccc(C3NC(=O)c4cc(S(N)(=O)=O)c(Cl)cc4N3)c2)C[C@H]1C(=O)O

Procedure:
The product from Example 11 is dissolved in aqueous tetrahydrofuran and treated with a molar excess of aqueous sodium hydroxide. After the reaction is complete, the solution is acidified with dilute hydrochloric acid to precipitate out (cis)-4-[3-[6-(aminosulfonyl)-7-chloro-1,2,3,4-tetrahysro-4-oxo-2-quinazolinyl]phenoxy]-1-[[(2-carboxyethyl)ethylamino]carbonyl]-L-proline.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]([OH:29])=[O:28]>CO>[OH:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]([O:29][CH3:1])=[O:28]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1c(O)ccc2ccccc12
Solvent: CO
Product: COC(=O)c1c(O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dicyclohexyicarbodiimide (1.20 Kg, 5.8 mol, 1.1 eq) was added portionwise over 4.5 hours to a cooled, mechanically-stirred slurry of 2-hydroxy-1-naphthoic acid (1.00 Kg, 5.3 mol) in methanol (3 L) under nitrogen. The internal temperature was maintained between 10 and 15° C. during the addition. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 hours. The methanol was removed under reduced pressure and the residue taken up in ethyl acetate (5 L) and heated with stirring to 64° C. (internal temperature) and then allowed to cool once again to ambient temperature. The mixture was filtered, and the solid washed with ethyl acetate (0.7 L). The ethyl acetate solutions were combined and concentrated under reduced pressure. The residue (2.5 Kg) was recrystallised from ethanol-water (9:1, 3.3 L) and dried under vacuum at ambient temperature. Yield 0.92 Kg, 85%
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:28][N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14]
Reactant: CNc1ccccc1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 47b), using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1 b) and N-methylaniline 2,2,2-trifluoroacetate (CAS 29885-95-8) as starting materials and isolated as colorless oil. MS (EI): m/e=374.5 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[OH-].[Na+].CCOCC>C1COCC1>[NH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(C2(c3ccccc3)CCN(CCC#N)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2(c3ccccc3)CCN(CCCN)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a stirred solution of 3-[4-(4-methoxyphenyl)-4-phenylpiperidin-1-yl]propionitrile (1.41 g, 4.40 mmol, 1.0 equiv) in anhydrous THF (10 mL) under argon was added a solution of BH3 in THF (1.0 M, 11.0 mL, 2.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 15 mL) was added and stirring was continued for 2 hours at 55-60° C. The mixture was basified to pH 9 by addition of 6 N aq. NaOH and extracted with CH2Cl2 (3×75 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (10 mL) and treated with HCl in ether (1.0 M, 9.0 mL, 2.0 equiv). The solvents wore removed, ether (30 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×10 mL). Water (20 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1 M NaOH, and the aqueous phase was extracted with CH2Cl2 (3×40 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 610 mg (43%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([O:21]CC2C=CC=CC=2)[CH:20]=1)[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9])[CH3:3]>[Pd].C(O)C.C1COCC1>[OH:21][C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:20]=1)[C:8]([NH:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1)=[O:9]
Reactant: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc(O)cc(OC(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
10% Palladium on charcoal (550 mg) was added to a solution of 3-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide (5.5 g, 14.6 mmol) in ethanol (75 mL) and THF (50 mL) and the mixture stirred at RT under a hydrogen atmosphere for 24 hours. The catalyst was removed by filtration and the filtrates evaporated in vacuo to a residue which was crystallised from ethyl acetate to give the desired compound (3.42 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[CH3:38]>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31]5[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=5)=[CH:30][C:25]=4[N:24]=[C:23]3[CH3:38])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCN
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCNCC(O)COc1ccc(CCOCC2CC2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)pyridazinone.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[S:19]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:21])=[O:20])(OCC)=O)C.[H-].[Na+].[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([O-:32])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH3:27][C:24]([CH3:25])([CH3:26])[CH2:23][O:22][S:19]([C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[CH:9]=[CH:37][C:36]1[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=1)(=[O:20])=[O:21]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
2-(Diethoxyphosphorylmethyl)-5-nitro-benzenesulfonic acid, 2,2-dimethylpropyl ester Example 55, 1.15 g, 2.72 mmol) was dissolved in 55 mL of anhydrous tetrahydrofuran. Sodium hydride (0.12 g, 2.99 mmol) was added in one portion and the reaction mixture was stirred for twenty minutes. The solution turned a deep red color. After attaching a reflux condenser, 4-nitrobenzaldehyde (0.821 g, 5.43 mmol) was added and the mixture was heated to reflux in an oil bath. After six hours the solution was cooled to room temperature, diluted with ethyl acetate (300 mL), washed with brine (2×), washed with conc. sodium bisulfite (2×), and the organic layer was dried (MgSO4). After concentration on a rotovap the crude material was purified by a gradient flash column using 30 to 60% ethyl acetate in hexanes as the eluant to afford 1.13 g of the title compound as a yellow solid (91%): 1HNMR (CDCl3) δ8.91 (d, J=2 Hz, 1H), 8.51 (dd, J=9 Hz, 2 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 8.09 (d, J=16 Hz, 1H), 8.06 (d, J=9Hz, 1H), 7.74 (d, J=9Hz, 2H), 7.31 (d, J=16 Hz, 1H), 3.75 (s, 2H), 0.88 (s, 9H); MS (ES-NEG): [M−H]− 419; Anal. Calc. for C19H20N2O7S: C, 54.28; H, 4.79; N, 6.66. Found: C, 54.13; H, 4.68; N, 6.54.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][S:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH:29]=2)[C:14]=1[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>ClCCl>[CH3:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][S:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH:29]=2)=[O:9])[C:14]=1[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(CSc2cccc(OCc3ccc4ccccc4n3)c2)c1C(=O)OCC(C)C
Solvent: ClCCl
Product: Cc1cccc(CS(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1C(=O)OCC(C)C
Reaction time: 8 h

Procedure:
m-Chloroperbenzoic acid (<86%, 34 mg, 0.17 mmol) is added to a solution of isobutyl 2-methyl-6-[3-(quinolin-2-ylmethoxy)-phenylsulfanylmethyl]-benzoate (80 mg, 0.17 mmol, example 84) in dichloromethane (1 mL) and the reaction is stirred overnight. The reaction is partitioned between ethyl acetate and sodium bicarbonate and the organic phase is washed with additional bicarbonate solution, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 40% ethyl acetate in hexanes) to provide the title compound. MS (ESD) 488 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[F:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Yield: 230.8 %

Procedure:
In a separate preparation, 2-amino-5-fluorobenzoic acid (15 g, 97 mmol) was dissolved in tetrahydrofuran (250 mL) and triphosgene (10.04 g, 33.8 mmol) was added portion-wise. A thick white precipitate formed with a small exotherm. The slurry gradually became easier to stir and was left stirring at room temperature for 16 h. The mixture was filtered to provide a white solid which was rinsed with diethyl ether then dried at 50° C. in a vacuum over to give 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (14.1 g, 78 mmol). The 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione may be converted to a 7-fluoro-1-(4-methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione using the procedures described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][C@H:9]1[C:32](O)=[O:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:68][NH:69][CH2:70][CH2:71][CH2:72][CH2:73][CH:74]=[CH2:75].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Si:15]([O:14][C@H:12]1[CH2:13][C@@H:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C@H:9]([C:32](=[O:33])[N:69]([CH2:70][CH2:71][CH2:72][CH2:73][CH:74]=[CH2:75])[CH3:68])[CH2:10][CH2:11]1)([C:28]([CH3:29])([CH3:31])[CH3:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCCCCNC
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a cold solution of compound 38 (1.80 mmol), TBTU (2.17 mmol), and N-methylhex-5-en-1-amine tosylate salt 31a (2.17 mmol) in DMF (100 mL) was added diisopropyl ethyl amine (5.4 mmol) dropwise under nitrogen at 0° C. The reaction mixture was stirred overnight at room temperature, then quenched with water and extracted with diethyl ether. The organic layer was washed with brine, then dried on magnesium sulphate, concentrated under reduced pressure, and purified by chromatography on silica gel to yield compound 39 as a beige solid in 85% yield. MS (ESI, EI+): m/z=578 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[NH2:8].[C:13]1(=O)OC(=O)CCC1>>[N:5]1([C:6](=[O:9])[C:7]2[NH:8][CH:13]=[N:1][C:2]=2[N:3]([CH3:12])[C:4]1=[O:11])[CH3:10]
Reactant: O=C1CCCC(=O)O1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O

Procedure:
Following the method of Cook et al, Res. Comm. Chem. Path. Pharm. 13:497(1976), 4,5-diamino-1,3-dimethylpyrimidine-2,6-dione is heated with glutaric anhydride to yield the following: ##STR15##
Reaction SMILES: [CH:1]1([N:7]([CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]2[C:35]3[S:34][C:33](=[O:36])[NH:32][C:31]=3[C:30]([OH:37])=[CH:29][CH:28]=2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:39][C:40]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:41]=1[CH2:42][CH2:43][NH2:44].C(N(CC)CC)C>C(O)C>[CH:1]1([N:7]([C:8](=[O:11])[CH2:9][CH2:10][NH:44][CH2:43][CH2:42][C:41]2[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:40]=2[F:39])[CH2:12][CH2:13][N:14]([CH2:25][CH2:26][C:27]2[C:35]3[S:34][C:33](=[O:36])[NH:32][C:31]=3[C:30]([OH:37])=[CH:29][CH:28]=2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCCc1cccc(F)c1F
Reactant: C=CC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cccc(F)c1F)C1CCCCC1
Temperature: 60 °C

Procedure:
Benzyl 2-(N-cyclohexylacrylamido)ethyl(2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)carbamate prepared as in Example 12 step i) (0.33 g), 2,3-difluorophenethylamine hydrochloride (0.244 g) and triethylamine (0.176 mL) were dissolved in ethanol (3 mL) and heated at 60° C. for 48 h. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the sub-title product (0.420 g) as a light brown gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[CH:6][CH:7]=[N:8]2.[CH2:23]([N:25]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28](=[O:34])[N:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:26]1=[O:42])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([C:29]3[C:28](=[O:34])[N:27]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[C:26](=[O:42])[N:25]([CH2:23][CH3:24])[CH:30]=3)=[O:32])=[CH:20][CH:21]=1)=[CH:6][CH:7]=[N:8]2
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc2nccc(Oc3ccc(N)cc3)c2c1OC
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4ccc(OC)c(OC)c34)cc2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(5,6-dimethoxy-quinolin-4-yloxy)-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp>250° C.; LCMS m/z=557 (M+1); 1H NMR (DMSO) δ: 10.92 (s, 1H), 8.86 (s, 1H), 8.48 (m, 1H), 7.79 (m, 2H), 7.49 (s, 1H), 7.35-7.42 (m, 5H), 7.24-7.27 (m, 2H), 6.49 (m, 1H), 4.00 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.29 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[NH2:28][C:29]1[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:28][C:29]2[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: COc1ncccc1N
Product: COc1ncccc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 3-amino-2-methoxypyridine (commercially available, CAS RN 20265-38-7). The compound was purified by preparative HPLC (Phenomenex Gemini column) using a gradient of acetonitrile:water (10:90 to 95:5). Light brown solid (28%). MS (ESI): m/z=390.040 [M+H]+.