Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([OH:12])=[O:11])[CH:5]=1)([OH:3])=[O:2].C([O-])(=O)C.[Zn+2:17].C([O-])(=O)C>C(O)C.O>[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O-:12])=[O:11])[CH:5]=1)([OH:3])=[O:2].[Zn+2:17].[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O-:12])=[O:11])[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccnc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccnc(C(=O)[O-])c1
Reaction time: 0.25 h
Yield: 108.1 %

Procedure:
To a solution of 3.34 g (0.02 mol) of 4-carboxypicolinic acid dissolved in 150 ml of ethanol under heating was dropwise added a solution of 2.20 g (0.01 mol) of zinc acetate.dihydrate in 10 ml of water under stirring. After the dropwise addition, the mixture was stirred at the same temperature for 15 minutes. The solid obtained after leaving the mixture to stand for 2 days was collected by filtration, and recrystallized from water to obtain 4.30 g of crystals (yield 99.3%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:20](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][CH:12]=2)[N:7]([CH3:20])[CH:6]=1)=[O:4]
Reactant: O=C(c1c[nH]c2cc(C(F)(F)F)ccc12)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)C(F)(F)F)c2ccc(C(F)(F)F)cc21
Reaction time: 2 h
Yield: 93 %

Procedure:
To a mixture of 2,2,2-trifluoro-1-[6-(trifluoromethyl)-1H-indol-3-yl]ethanone (200 mg, 0.71 mmol) and potassium carbonate (246 mg, 1.8 mmol) in DMF (2 mL) was added iodomethane (0.067 mL, 1.1 mmol) at room temperature. After stirring at the same temperature for 2 hours, the mixture was poured into water, and the aqueous phase was extracted with EtOAc (ethyl acetate)-hexane (2:1, twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4:1 (v/v)) to give 195 mg (93% yield) of the title compound as a pale brown solid:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH2:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:17]=[CH2:18].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[F:22][C:21]([F:24])([F:23])[C:20]([NH:19][CH2:16]/[CH:17]=[CH:18]/[C:2]1[CH:15]=[CH:14][CH:13]=[C:4]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:3]=1)=[O:25]
Reactant: Brc1cccc(OCC2CCOCC2)c1
Reactant: C=CCNC(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC/C=C/c1cccc(OCC2CCOCC2)c1)C(F)(F)F

Procedure:
A mixture of 4-((3-bromophenoxy)methyl)tetrahydro-2H-pyran (1.86 g, 6.86 mmol), N-allyl-2,2,2-trifluoroacetamide (1.14 g, 7.45 mmol), P(o-Tol)3 (0.31 g, 1.02 mmol), Pd(OAc)2 (0.12 g, 0.534 mmol), Et3N (2.0 mL, 14.35 mmol) and anhydrous DMF (10 mL) was degassed by bubbling Ar for at least 5 mins, then applying vacuum/Ar once. The reaction mixture was heated under Ar at +90° C. for 20 hrs then concentrated under reduced pressure. Aqueous NH4Cl was added to the residue and extracted twice with EtOAc. Combined organic layers were washed with brine, treated with activated charcoal and dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (20%-50% EtOAc-hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)allyl)acetamide as a light yellow oil. Yield (2.01 g, 85%); 1H NMR (400 MHz, DMSO-d6) δ 9.70 (m, 1H), 7.21 (t, J=7.63 Hz, 1H), 6.94-7.00 (m, 2H), 6.78-6.83 (m, 1H), 6.48 (d, J=15.85 Hz, 1H), 6.25 (dt, J=15.85, 5.87 Hz, 1H), 3.90-4.00 (m, 2H), 3.75-3.90 (m, 4H), 3.31 (t, J=11.74 Hz, 2H), 1.90-2.04 (m, 1H), 1.60-1.70 (m, 2H), 1.24-1.37 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18](=[O:37])[C@H:19]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:20][C:21]([O:23][CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][CH:27]=[CH2:28])=[O:22])[C@H:15]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:14]2)=[CH:4][C:3]=1[O:43][CH3:44].[CH2:45](C([Sn])=C(CCCC)CCCC)[CH2:46]CC>C1(C)C=CC=CC=1.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>[CH:31]1([C@H:19]([NH:20][C:21]([O:23][CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][CH:27]=[CH2:28])=[O:22])[C:18]([N:16]2[CH2:17][C@H:13]([O:12][C:9]3[C:10]4[C:5](=[CH:4][C:3]([O:43][CH3:44])=[C:2]([CH:45]=[CH2:46])[CH:11]=4)[CH:6]=[CH:7][N:8]=3)[CH2:14][C@H:15]2[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nccc3cc(OC)c(Br)cc23)C[C@H]1C(=O)OCC)C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nccc3cc(OC)c(C=C)cc23)C[C@H]1C(=O)OCC)C1CCCCC1
Temperature: 105 °C
Yield: 87.3 %

Procedure:
A solution of the product from Step 5 (1.02 g, 1.51 mmol) in PhMe (30 mL) was degassed for 30 minutes by bubbling nitrogen. Tri-n-butylvinyltin (533 μL, 1.81 mmol) and tetrakis(triphenylphosphine)palladium (175 mg, 0.151 mmol) were added, and the reaction mixture was heated to 105° C. for 3 hours, then cooled to RT for 18 hours. The volatiles were evaporated, and the residue was purified by chromatography on silica (20-50% EtOAc/hexane) to afford the title compound (820 mg) as a foam. LRMS ESI+ (M+H)+622.5.
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:50]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])(=[O:53])[CH:51]=O>ClCCCl.O>[CH:17]1[C:16]2[CH:15]([CH2:14][O:13][C:11](=[O:12])[NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:34][C:30]3[S:29][CH:33]=[CH:32][N:31]=3)[CH2:51][C:50](=[O:53])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C=O
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccs1
Temperature: 0 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
A suspension of Fmoc-Lys-OH.HCl (6.07 g, 15 mmol) and thiazole-2-carbaldehyde (1.697 g, 15 mmol) in DCE (100 mL) was refluxed for 30 min under nitrogen. The reaction mixture was cooled to 0° C., and treated sequentially with NaBH(OAc)3 (7.95 g, 37.5 mmol) and crude tert-butyl glyoxalate (3.53 g). The reaction mixture was stirred at room temperature for overnight and decomposed with water. The reaction mixture was extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford (S)-1-(9H-fluoren-9-yl)-14,14-dimethyl-3,12-dioxo-10-(thiazol-2-ylmethyl)-2,13-dioxa-4,10-diazapentadecane-5-carboxylic acid (1.85 g, 21%). MS (ESI), 580 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:3]=1[F:21].C(N(C(C)C)CC)(C)C.C(OCC)C.[S:36](Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:21][C:3]1[C:2]2[C:11](=[N:12][S:36][N:1]=2)[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1C
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nsnc2c(F)c1Nc1ccccc1C

Procedure:
To a stirring solution comprised of methyl 4,5-diamino-3-fluoro-2-(2-methyl-phenylamino)-benzoate (from Step e, Example 1) and diisopropylethylamine (2 equiv.) in an appropriate solvent like diethyl ether or toluene is added a reagent like N-thioaniline or thionyl chloride (1.35 equiv.). The reaction mixture is brought to reflux for one hour. The mixture is quenched with dilute aqueous hydrochloric acid. The organic phase is washed with saturated aqueous sodium bicarbonate and brine, is dried (MgSO4), and is concentrated in vacuo to afford the desired product. The product may be recrystallized with an appropriate solvent like chloroform or ethanol, or may be chromatographed if further purification is necessary.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:21][CH:22]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 4.0 g, 16.4 mmol), and 4-bromofluorobenzene (3.45 g, 19.7 mmol) in THF (80 mL)) were added Palladium catalyst Pd(PPh3)4 (0.57 g, 0.49 mmol) and the freshly prepared sodium hydroxide solution (2.0 g, 49.3 mmol in 25 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.75 g (80%) of the product 4-(4-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15](O)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O.O>C(OCC)(=O)C>[Cl:26][C:15]1[N:14]=[CH:13][N:12]=[C:11]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)CC(c1cc(O)ncn1)C1CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-hydroxypyrimidin-4-yl)propanoate (199 mg) and DMF (13 μL) in ethyl acetate (3.0 ml) was added oxalyl dichloride (220 μL), and the mixture was stirred at room temperature for 1 hr. Water was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (194 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:30][CH:29](O)[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C(N(S(F)(F)[F:38])CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:30][CH:29]([F:38])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: OC1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Fc1cc(CN2CC(F)C2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1

Procedure:
To a slurry of 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methyl)azetidin-3-ol (0.100 g, 0.2 mmol) in 1 mL DCM under nitrogen at 0° C. was added (diethylamino)sulfur trifluoride (0.05 ml, 0.3 mmol). Upon consumption of starting material, the reaction was quenched with ice and 1 N NaOH. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM 3, and the combined cloudy organics were treated with a small amount of MeOH to give a solution, were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by RPHPLC, gradient, TFA/ACN in TFA/H2O provided material that was taken up in DCM and washed with saturated aq. NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-(2-fluoro-4-((3-fluoroazetidin-1-yl)methyl)-phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a solid. MS (ESI) m/z: Calculated: 433.1; Observed: 434.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[C:17]([O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:16][C:2]1([CH3:1])[O:6][C:5](=[O:7])[CH:4]([CH:8]([C:9]([N:24]2[CH2:25][CH2:26][CH2:27][C@H:23]2[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:28])=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[O:3]1
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C1OC(C)(C)OC1=O
Reaction time: 8 h

Procedure:
To 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid G-1 (10 mmol; prepared as described in Method F, above) in DMF (50 mL) was added proline O-t-butyl ester (10 mmol), DIEA (25 mmol) and PyBOP (10 mmol) and the solution stirred for 8 h. The reaction was diluted with ethyl acetate and washed with water, sodium bicarbonate, brine, and then dried (Na2SO4). The filtrate was concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)pentane G-2 (5 mmol, 50%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:29][CH:30]3[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[CH2:33][CH:30]([NH:29][C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:28])=[CH:17][CH:18]=3)[N:10]=2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4ccccc4)cc3)nc(N3CCOCC3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)Nc1ccc(-c2nc(NC3CNC3)nc(N3CCOCC3)n2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 30 mg (0.055 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 20 (83%); (M+H) 447.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:11][C@@H:10]1[NH:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=2)=[O:24])=O)(C)(C)C.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][C:40]2[N:43]=[C:44](C([O-])=O)[S:45][C:39]=2[CH2:38]1.[Li+]>O1CCOCC1>[ClH:34].[C:17]([NH:16][C:15]([C@H:13]1[CH2:12][CH2:11][C@H:10]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([Cl:34])=[CH:29][CH:28]=3)=[O:24])[C@H:9]([NH:8][C:6]([C:44]2[S:45][C:39]3[CH2:38][N:37]([CH3:36])[CH2:42][CH2:41][C:40]=3[N:43]=2)=[O:5])[CH2:14]1)=[O:21])([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)NC(C)(C)C)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1

Procedure:
(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-4-[N-(tert-butyl)carbamoyl]-N1-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]1([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][O:18][CH2:17]1.[S:28]1(=[O:39])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:21]([NH:20][C:16]1([CH2:15][NH:14][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=[C:2]([N:31]3[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[S:28](=[O:39])[CH2:29][CH2:30]3)[N:11]=2)[CH2:19][O:18][CH2:17]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCC1(NCc2ccccc2)COC1
Reactant: O=S1CCNCc2ccccc21
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC3(NCc4ccccc4)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 55-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 3-(aminomethyl)-N-benzyloxetan-3-amine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 514, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (s, 1 H), 7.81-7.77 (m, 2 H), 7.66-7.56 (m, 4 H), 7.47-7.45 (m, 2 H), 7.31-7.29 (m, 3 H), 5.45-5.35 (d, 1 H), 5.10 (brs, 1 H), 4.82-4.80 (m, 6 H), 4.71-4.69 (m, 2 H), 4.16 (s, 2 H), 3.51 (m, 2 H), 2.46 (s, 3 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:9].O>CN(C)C=O>[N:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)c1ccc(CCc2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)c1ccc(CCc2ccccc2)cc1
Yield: 77.4 %

Procedure:
To a solution containing 3.4 g of imidazole in 5 ml of dimethylformamide, stirred at 0/+5° C., 2.58 g of 4-chloroacetyl-bibenzyl were slowly added. The reaction mixture was stirred for few minutes, then allowed to stand and then poured into water. The product thus formed was filtered off, purified by silica gel column chromatography (eluant: benzene/acetone) and then crystallized from ethyl acetate to give 2.24 g of the title compound melting at 134°-6° C. Yield 77%.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([OH:21])=O)=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:8]=1)=[N+:2]=[N-:3].C[N:23](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[N:1]([C:4]1[S:5][C:6]([C:19]([NH2:23])=[O:21])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:8]=1)=[N+:2]=[N-:3]
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Reactant: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(=O)O)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(N)=O)s1
Reaction time: 0.3 h
Yield: 78.9 %

Procedure:
To a solution of 1.76 g (5.60 mmole) of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid and 30 mL of dimethylformamide was added 2.75 g (7.01 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) and 3.0 mL (17.2 mmole) of ethyldiisopropylamine. The mixture was stirred for 18 minutes, then 0.4541 g (8.49 mmole) of ammonium chloride was added. The mixture was concentrated under reduced pressure and diluted with 350 mL of ethyl acetate and 75 mL of water. The ethyl acetate layer was washed with 50 mL of water, 50 mL of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 10:90-100:0) to give 1.384 g of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][NH:12][C:13](=[O:22])[C:14]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)=[C:8]3[NH:7][C:6]=2[CH:23]=1.[OH-:24].[Na+].[CH2:26]=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][N:12]([CH2:26][OH:24])[C:13](=[O:22])[C:14]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)=[C:8]3[NH:7][C:6]=2[CH:23]=1
Reactant: [OH-]
Reactant: O=c1[nH]cc2c(c1-c1ccc(Cl)cc1)Nc1cc(Br)ccc1S2
Reactant: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Br)cc1N2
Yield: 51 %

Procedure:
To 2.0 g. of 7-bromo 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (4.9 mmol.) in 20 ml. dimethylformamide was added 12 ml. of a 5% sodium hydroxide solution (15.0 mmol.) and the resulting suspension was heated on a steam bath until a solution formed. To the solution was then added 20 ml. of a 36% formaldehyde solution (24.0 mmol.), and the resulting reaction mixture was heated until a yellow precipitate formed. The hot reaction mixture was filtered, and the precipitate was washed well with water and dried under high vacuum at room temperature to yield 7-bromo-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a yellow powder (1.1 g,; 51% yield) having the structural formula, ##STR23## a melting point of 182° C. (with decomposition) and the following elemental analysis:
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol.) in 50 ml dry methylene chloride. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight. The reaction mixture was then washed with 20 ml of a 10% solution of ammonium chloride, then with 20 ml of distilled water. The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid. Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90% after recrystallization). m.p. 214° C.; 1H NMR (200 MHz, CDCl3) δ 7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3×C6H5), 7.1-7.2 (m, 6H, 3×C6H5), 7.0 (m, 1H, Ph3CNCH═CH), 6.81 (m, 1H, Ph3CNCH═CH); 13C NMR (50 MHz, CDCl3) δ 142.3, 139.0, 129.6, 128.2, 128.3, 121.6.