Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([O:19]C)=[O:18])=[CH:11][CH:12]=2)[N:7]=1.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([OH:19])=[O:18])=[CH:11][CH:12]=2)[N:7]=1
Reactant: COC(=O)c1ccc2c(=O)[nH]c(Cc3cccc(Cl)c3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(=O)[nH]c(Cc3cccc(Cl)c3)nc2c1
Yield: 93.3 %

Procedure:
A mixture of 336 mg of methyl 2-(3-chlorobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate which was synthesized in Production Example 1, 3.0 mL of aqueous 1N sodium hydroxide solution and 6 mL of ethanol was heated for 2.5 hours under reflux. The reaction solution was allowed to cool off, and to which 3.0 mL of 1N hydrochloric acid and 5 mL of water were added. Whereupon precipitated crystals were recovered by filtration, washed with water and through-flow dried under heating, to provide 300 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C@@H:36]([C:49](O)=[O:50])[CH2:37][C:38]3[CH:47]=[C:46]([CH3:48])[C:41]4[NH:42][C:43](=[O:45])[O:44][C:40]=4[CH:39]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:52]=[CH:53][CH:54]=[CH:55][C:22]=2[NH:21]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:19]=[C:20]1[N:26]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C@H:36]([CH2:37][C:38]3[CH:47]=[C:46]([CH3:48])[C:41]4[NH:42][C:43](=[O:45])[O:44][C:40]=4[CH:39]=3)[C:49]([N:1]3[CH2:6][CH2:5][CH:4]([N:7]4[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]4)[CH2:3][CH2:2]3)=[O:50])=[O:34])[CH2:31][CH2:32]2)[CH2:25][CH2:24][C:23]2[CH:52]=[CH:53][CH:54]=[CH:55][C:22]=2[NH:21]1
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(=O)oc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
56 mg (0.22 mmol) ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate were added to a solution of 100 mg (0.20 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 71 mg (0.22 mmol) TBTU and 31 μL (0.22 mmol) triethylamine in 1 mL DMF and the reaction mixture was shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were concentrated by evaporation and lyophilised.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)#[N:2].C(O)(C(F)(F)F)=[O:44]>C(Cl)Cl>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[NH:26][S:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=1[C:1]([NH2:2])=[O:44])=[N:14][CH:15]=[CH:16]2)(=[O:25])=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C#N)nccc3c2)c(OC)c1
Solvent: ClCCl
Product: NC(=O)c1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO; 0.085 g, 0.179 mmol), (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (0.058 g, 0.268 mmol), Pd(PPh3)4 (0.021 g, 0.018 mmol), and potassium carbonate (0.123 g, 0.893 mmol). Dioxane (0.893 ml) and water (0.298 ml) were added, the vial was flushed with argon and sealed, and microwaved at 90° C. for 30 minutes. A small amount of 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide was observed; however the predominant product was observed as the coupling product with hydrolysis of the nitrile. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and 2-(6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)benzamide. The protected nitrile was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford 2-(6-(N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)benzamide (0.049 g, 0.102 mmol, 57.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.61 (d, J=5.7 Hz, 1H), 8.54 (s, 1H), 8.10-8.03 (m, 3H), 7.98 (d, J=8.4 Hz, 1H), 7.87-7.81 (m, 1H), 7.79-7.68 (m, 2H), 7.34 (br. s., 1H), 7.27 (d, J=4.5 Hz, 1H), 6.86 (d, J=4.5 Hz, 1H). m/z (ESI) 479.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][C:3]=1[OH:13].[Br:14]Br>C(O)(=O)C>[Br:14][C:4]1[C:3]([OH:13])=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2
Reactant: Cc1ccc2cc(O)c(Cl)cc2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1ccc2c(Br)c(O)c(Cl)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.1 %

Procedure:
To a stirred solution of 7-chloro-2-methylquinolin-6-ol (1C) (450 mg, 2.3 mmol) in acetic acid (15 mL) was added Br2 (0.13 mL, 2.4 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 2 hours. The solid that formed was filtered and collected to give 1D as an off-white solid as the HBr salt (847 mg, 100%). LCMS-ESI+ (m/z): 281.1, 283.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C(=O)N([Br:16])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:16])[N:3]=1
Reactant: Cc1cncc(Br)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: BrCc1cncc(Br)n1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
To a solution of 2-bromo-6-methyl-pyrazine (3.0 g, 17.31 mmol) in CCl4 (25 mL) was added NBS (4.60 g, 26.01 mmol) and AIBN (0.248 g, 1.734 mmol) at RT. The mixture was stirred at 55° C. for 48 h. H2O was added followed by extraction with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified over silica eluting with 5% EtOAc:Hexane to obtain i (1.40 g, 32%). 1H NMR (CDCl3, 400 MHz): δ 8.64 (s, 1H), 8.62 (s, 1H) and 4.50 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([OH:15])=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:14])[CH:7]=1.[CH3:17][C@@H:18](O)[CH2:19][CH:20]=[CH2:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([O:15][C@H:20]([CH2:19][CH:18]=[CH2:17])[CH3:21])=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:14])[CH:7]=1
Reactant: Oc1cccc(Cl)c1-c1cc(Br)ccc1F
Reactant: C=CC[C@@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cccc(Cl)c1-c1cc(Br)ccc1F
Reaction time: 8 h
Yield: 41.8 %

Procedure:
5′-Bromo-6-chloro-2′-fluoro-[1,1′-biphenyl]-2-ol (750 mg, 2.49 mmol, 1.0 equiv) were mixed with (R)-pent-4-en-2-ol (428 mg, 4.97 mmol, 2.0 equiv) and PPh3 (1305 mg, 4.97 mmol, 2.0 equiv) in tetrahydrofuran (8 mL). To this solution was added DEAD (2266 μl, 4.97 mmol, 2.0 equiv) dropwise and stirred overnight. The solution was mixed with silica gel and concentrated and purified by 40 g ISCO column with 0-10% EtOAc/hexane to afford 5-bromo-2′-chloro-2-fluoro-6′-((S)-pent-4-en-2-yloxy)-1,1′-biphenyl (385 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 7.49-7.44 (m, 1H), 7.41-7.36 (m, 1H), 7.29 (s, 1H), 7.11-6.99 (m, 2H), 6.87 (dd, J=8.3, 2.0 Hz, 1H), 5.73-5.56 (m, 1H), 5.07-4.93 (m, 2H), 4.36 (dq, J=8.8, 6.0 Hz, 1H), 2.37-2.16 (m, 2H), 1.20 (dd, J=6.0, 3.0 Hz, 3H). LCMS (M+1)=369.0.
Reaction SMILES: [CH3:1][C:2](=C)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.I([O-])(=O)(=O)=[O:16].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[O:16]=[C:2]([CH3:1])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(C)Cc1ccc2c(c1)COC2=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Cc1ccc2c(c1)COC2=O
Reaction time: 0.17 h

Procedure:
To a solution of 5-(2-methylprop-2-en-1-yl)-2-benzofuran-1(3H)-one (175 mg, 0.930 mmol) in THF was added osmium tetroxide (295 mg, 0.0460 mmol) and the mixture was stirred for 10 minutes. Then a solution of sodium periodate (497 mg, 2.32 mmol) in water was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with DCM, and washed with Na2S2O3 solution. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (30% ether/hexanes) to afford the title compound. LC-MS (IE, m/z): 191.3 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([OH:24])=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([O:24][CH3:25])=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: COC(=O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alanine (100 g, 0.29 mol), potassium carbonate (82 g, 0.59 mol) and methyl iodide (42 g, 0.29 mol) in DMSO (1200 mL) was stirred at room temperature. After 12 hours, the reaction mixture was extracted with ethyl acetate, and the organics were separated and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to give methyl 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alaninate. MS ESI calc'd. for C17H25N2O6 [M+H]+ 353. found 353. 1H NMR (400 MHz, CDCl3) δ 7.36-7.33 (m, 5H), 5.09 (s, 2H), 4.34-4.30 (m, 1H), 3.74 (s, 2H), 3.59 (t, J=6.0 Hz, 2H), 2.62 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([O:36][C:37]([F:40])([F:39])[F:38])[CH:27]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][S:32]([C:29]2[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][C:28]=2[O:36][C:37]([F:40])([F:38])[F:39])(=[O:34])=[O:33])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1 g, 0.0047 mol) in CH2Cl2 were added diisopropylethylamine (1.63 mL, 0.0093 mol) and 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (1.03 mL, 0.0051 mol). The reaction mixture was stirred at ambient temperature for 1 hr and then washed with water. The aqueous layer was extracted with CH2Cl2 (twice), the organic layers were combined, dried over MgSO4, and concentrated. The resulting precipitate was recrystallized with CH2Cl2 and hexanes to give trans-[4-(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-cyclohexyl]-carbamic acid tert-butyl ester (2.39 g, 0.0046 mol, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:11])[CH:3]=1.[CH2:12](O)[CH3:13]>S(Cl)(Cl)=O>[CH2:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[I:11])[CH3:13]
Reactant: CCO
Reactant: O=C(O)c1ccc(Br)cc1I
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-iodo-benzoic acid (4.0 g; 12.24 mmol) is stirred in thionyl chloride (8.0 ml) under reflux for 1 hour. The reaction mixture is evaporated under reduced pressure and taken up immediately in 20 ml methylene dichloride and cooled down to 0° C. Ethanol (20.0 ml; 342.96 mmol) is added and stirred for 1 hour at ambient temperature. The ethanol is evaporated and the residue taken up in methylene dichloride and extracted with saturated NaHCO3 solution. The organic layer is separated, dried over MgSO4 and evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][S:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:14](=[O:19])[NH:15][CH:16]=[CH:17][N:18]=2)[CH2:8][CH2:7]1.ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][S:5]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[C:14](=[O:19])[NH:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:11]1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1[nH]ccnc1CN1CCC(SCc2ccccc2F)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]ccnc1CN1CCC(S(=O)Cc2ccccc2F)CC1
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
After dissolving 57 mg of 3-[4-(2-fluorobenzylthio)piperidino]methyl-1H-pyrazin-2-one in 3 ml of dichloromethane, 31 mg of 3-chloroperbenzoic acid was added at below −70° C., the mixture was stirred for 30 minutes, and then an additional 5 mg of 3-chloroperbenzoic acid was added and the stirring was continued for 20 minutes. Aqueous sodium thiosulfate solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform/methanol/ammonia water) to obtain the title compound (16 mg, 27% yield).
Reaction SMILES: CN1CCOCC1.[C:8]([NH:12][C:13]([C:15]1[N:16]=[C:17]([O:23][CH3:24])[S:18][C:19]=1[C:20](O)=[O:21])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([N:12]1[C:20](=[O:21])[C:19]2[S:18][C:17]([O:23][CH3:24])=[N:16][C:15]=2[C:13]1=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1nc(C(=O)NC(C)(C)C)c(C(=O)O)s1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1nc2c(s1)C(=O)N(C(C)(C)C)C2=O

Procedure:
3.75 g (37.1 mmol) of N-methylmorpholine, 1.20 g (10 mmol) of 4-N,N-dimethylaminopyridine and 8.70 g of a 50% strength solution (13.7 mmol) of propanephosphonic anhydride in CH2Cl2 were added in succession to a solution of 2.6 g (10 mmol) of 4-tert-butylaminocarbonyl-2-methoxythiazole-5-carboxylic acid in 100 ml of CH2Cl2 at -5° C. The mixture was refluxed for 6 hours, after which the solvent was removed and the residue was taken up with ethyl acetate. The solution was extracted twice with saturated sodium bicarbonate solution and once with 5% strength citric acid solution, washed with water and dried over MgSO4. After removal of the solvent, the crude product was purified by chromatography over silica gel (eluant: 1:1 cyclohexane/ethyl acetate) and 1.20 g (50%) of product of melting point 63°-66° C. were obtained in this manner (Active ingredient Example No. 4.014).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:4]2[CH2:5][CH:6]([CH3:8])[CH2:7][CH:2]([CH3:1])[CH2:3]2)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]
Reactant: CC1CNCC(C)C1
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CC(C)CC(C)C2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 20.7 %

Procedure:
To a solution of 3,5-dimethylpiperidine (1.1 g, 9.86 mmol) and DIEA (3.1 mL, 18 mmol) in anhydrous CH3CN (40 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.0 g, 8.87 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, concentrated, and charged (DCM) to a 120 g ISCO silica gel cartridge and gradient eluted (5-15% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(3,5-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 756 mg (20%) as a mixture of diastereomers. A sample of the product subjected to prep HPLC on Waters-Atlantis column (30×100 mm S5) running 15 min gradient from 10-100% B (MeOH/water/TFA), yielding two bands. The major isomer. 1H NMR (500 MHz, CDCl3) δ 5.21-5.14 (m, 1H), 2.87 (br. s, 4H), 2.70 (s, 3H), 2.41 (s, 3H), 1.77-1.71 (m, 3H), 1.29 (d, J=6.2 Hz, 6H), 0.85 (d, J=6.6 Hz, 6H), 0.68 (q, J=11.9 Hz, 1H). UPLC (M+H)=413.15.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: NCCN1CCOCC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)NCCN1CCOCC1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with 4-(2-aminoethyl)morpholine similar to as described in Example 2 to afford 13.3 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(2-morpholinoethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 486 (M)+. 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.02 (d, J=10.5 Hz, 1H), 5.47 (s, 1H), 5.08-4.77 (m, 2H), 4.61-4.48 (m, 2H), 3.70-3.51 (m, 3H), 3.51-3.35 (m, 1H), 2.49-2.30 (m, 3H), 1.49 (s, 6H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH:24](I)([CH3:26])[CH3:25]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:25][CH2:24][CH3:26])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(C)I
Product: CCCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 49.6 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and isopropyl iodide (10.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2-methylethyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (11.2 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[CH:6]1([Mg]Cl)[CH:10]=[CH:9][CH:8]=[CH:7]1>>[CH2:2]=[CH:3][CH:4]([C:7]1[CH2:6][CH:10]=[CH:9][CH:8]=1)[CH3:5]
Reactant: Cl[Mg]C1C=CC=C1
Reactant: C=CCCBr
Product: C=CC(C)C1=CC=CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 4-bromo-1-butene (100 g of 97 wt %, 0.719 mol) was added cyclopentadienyl magnesium chloride (800 mL of 1 M solution in THF, 0.8 mol) at 0° C. in 50 minutes. After stifling for an additional 15 minutes at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a brown liquid (94.2 g, crude buten-3-ylcyclopentadiene). To the crude buten-3-ylcyclopentadiene (94.2 g) dissolved in THF (500 mL) was added n-BuLi (70 mL of 10 M in hexanes, 0.7 mol) at −78° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (133.8 g, 0.735 mol) dissolved in THF (400 mL) at 0° C. in 35 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (152 g, 74.4% yield based on 4-bromo-1-butene) as a dark red viscous oil.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.Cl[C:11]1[C:12](Cl)=[C:13](Cl)[C:14](Cl)=[C:15]2[C:20](=[O:21])[O:19][C:17](=O)[C:16]=12.N[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[N:34]=[C:33]([CH3:36])[CH:32]=[CH:31]2.[OH-].[Na+]>O>[CH:28]1[CH:29]=[C:30]2[CH:31]=[CH:32][C:33]([CH:36]3[C:17](=[O:19])[C:16]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:20]3=[O:21])=[N:34][C:35]2=[CH:26][CH:27]=1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Cc1ccc2cccc(N)c2n1
Agent: O=C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 249.8 %

Procedure:
270 g of benzoic acid were placed in a stirred reaction vessel and melted. At from 125° to 130° C., there were added to the melt 82 g of tetrachlorophthalic anhydride followed by 19 g of 8-aminoquinaldine. The mixture was heated to 140° C. and stirred at that temperature for 2 hours and then heated to 160° C. and stirred for a further 2 hours. The reaction mixture was then cooled to 130° C. and there was added thereto a mixture of 400 ml of water and 160 g of 50% w/w caustic soda solution. The pigment suspension was filtered in vacuo, washed to neutrality with water and dried. There were obtained 82 g (98%) of quinophthalone of the formula ##STR5##