Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:17]([N:19]([CH3:36])[C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([N:19]([CH3:36])[C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:30])([CH3:32])[CH3:31])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O

Procedure:
To a solution of 183 mg (0.290 mmol) of Z-Phe-Val-N-Me-Tyr(3-tBu)-NH2 in 3 ml of methanol, 100 mg of 10% palladium carbon was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 5 hours. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:methanol=10:1) to yield Phe-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 108 mg (75%). NMR(method g,CDCl3): δ 0.69(3H,dd,J=6.9,17.8 Hz), 0.89(3H,dd,J=6.9,14.5 Hz), 1.36(9/2H,s), 1.39(9/2H,s), 2.67(1H,dd,J=9.6,13.5 Hz), 2.78-2.94(1H,m), 2.97(3/2H,s), 3.09(3/2H,s), 3.12-3.40(2H,m), 3.59(1H,ddd,J=3.6,9.3,10.2 Hz), 4.34-4.42(1/2H,m), 4.68(1/2H,dd,J=6.6,11.1 Hz), 4.79(1/2H,dd,J=7.9,8.9 Hz), 5.18-5.26(1/2H,m), 5.35(1/2H,brs), 5.49(1/2H,brs), 6.60(1H,dd,J=7.9,12.2 Hz), 6.86(1H,ddd,J=1.6,6.3,6.3 Hz), 7.06(1H,s), 7.16-7.34(5H,m), 7.76(1/2H,brs), 7.85(1/2H,d,J=8.9 Hz), 7.95(1/2H,d,J=7.9 Hz).
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][C@:5]([NH2:17])([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[F:16])[CH3:6].[CH3:19][NH:20][C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=S>>[C:26]([O:25][C:24](=[O:30])[NH:23][C:21]1[N:20]([CH3:19])[C:3](=[O:18])[CH2:4][C@:5]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[F:16])([CH3:6])[N:17]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)C[C@](C)(N)c1cc([N+](=O)[O-])ccc1F
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CN1C(=O)C[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(2-fluoro-5-nitro-phenyl)-butyric acid methyl ester (14.8 mmole) and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-(2-fluoro-5-nitro-phenyl)-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (3.13 g) was obtained as pale yellow foam. MS (ESI): m/z=381.2 [ M+H]+.
Reaction SMILES: [N:1]1([C:7]([O:9][C@H:10](/[CH:12]=[CH:13]\[C:14]([NH:16][C@@H:17]2[CH2:22][C@H:21]([CH3:23])[C@H:20]([CH2:24]/[CH:25]=[C:26](\[CH3:29])/[CH:27]=[CH2:28])[O:19][C@@H:18]2[CH3:30])=[O:15])[CH3:11])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([C@H:33]1[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][C@:35]2([O:37][CH2:36]2)[C@@H:34]1[OH:43])=C.C1(=O)C=CC(=O)C=C1>C(Cl)CCl>[N:1]1([C:7]([O:9][C@@H:10]([CH3:11])/[CH:12]=[CH:13]\[C:14]([NH:16][C@@H:17]2[CH2:22][C@H:21]([CH3:23])[C@H:20]([CH2:24]/[CH:25]=[C:26](\[CH3:29])/[CH:27]=[CH:28]/[C@H:33]3[O:40][C:39]([CH3:41])([CH3:42])[CH2:38][C@:35]4([O:37][CH2:36]4)[C@@H:34]3[OH:43])[O:19][C@@H:18]2[CH3:30])=[O:15])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C=C[C@H]1OC(C)(C)C[C@@]2(CO2)[C@@H]1O
Reactant: C=C/C(C)=C/C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(=O)N2CCOCC2)C[C@@H]1C
Agent: O=C1C=CC(=O)C=C1
Solvent: ClCCCl
Product: CC(/C=C/[C@H]1OC(C)(C)C[C@@]2(CO2)[C@@H]1O)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(=O)N2CCOCC2)C[C@@H]1C
Temperature: 42 °C
Reaction time: 14 h

Procedure:
To a stirred solution of recovered (S,Z)-5-((2R,3R,5S,6S)-2,5-dimethyl-6-((E)-3-methylpenta-2,4-dienyl)-tetrahydro-2H-pyran-3-ylamino)-5-oxopent-3-en-2-yl morpholine-4-carboxylate and (3R,4R,5R)-5-ethenyl-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-4-ol (22.1 mg) in ClCH2CH2Cl (200 μL) was added benzoquinone (1.0 mg, 0.010 mmol) and Grela Catalyst (2.0 mg, 3.0 μmol) at 23° C. under an open atmosphere. The reaction mixture was then heated to 42° C. After an additional 14 h at the same temperature, the reaction was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10→80% EtOAc in hexanes) on silica gel (8 mL) to give (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[(2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-pentenamide as a pale tan solid. The combined yield of (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[(2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-pentenamide after one cycle is 15.7 mg (44%). Some of the tan (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[(2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-pentenamide was purified by semi-preparative HPLC (Conditions: flow rate=2.5 mL, from 30% to 100% MeCN in H2O over 30 min; Column=Varian Pursuit XRs C18 column (5 μm packing, 250×10 mm); Retention time 16.70 min; Detection=237 nm) to afford (2Z,4S)-4-[(morpholinylcarbonyl)oxy]-N-[(2R,3R,5S,6S)-tetrahydro-6-[(2E,4E)-5-[(3R,4R,5R)-4-hydroxy-7,7-dimethyl-1,6-dioxaspiro[2.5]oct-5-yl]-3-methyl-2,4-pentadien-1-yl]-2,5-dimethyl-2H-pyran-3-yl]-2-pentenamide as a colorless oil that was subsequently used for biological experiments.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:26])(=[O:25])=[O:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].CS(C)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:26])(=[O:24])=[O:25])(=[O:15])=[O:16])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Reaction time: 0.75 h

Procedure:
A solution of 3-[5-methyl-3-[2-(methylsulfonyl)phenylsulfonyloxy]-phenoxy]propanol (1.16 g, 2.9 mmol), as prepared in the preceding step, anhydrous dimethyl sulfoxide (0.62 mL, 8.7 mmol), and N,N-diisopropylethylamine (1.0 mL, 6.1 mmol) in anhydrous dichloromethane (30 mL) was treated with sulfur trioxide pyridine complex (0.97 g 6.1 mmol) at 0° C. The reaction mixture was stirred for 0.75 h before quenching with 10% aqueous citric acid (40 mL). The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (4×40 mL). The dichloromethane layers were combined and washed with brine, dried, and evaporated to dryness. The material was used without purification in the next step.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[NH2:15])[CH2:4]CC.[CH2:16]([N:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=O)=[CH:24][CH:23]=1)[CH2:19][CH2:20][OH:21])[CH3:17]>[OH-].[Na+].O>[ClH:1].[NH2:14][C:11]1[C:12](=[N:28][C:25]2[CH:24]=[CH:23][C:22]([N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][OH:21])=[CH:27][CH:26]=2)[CH:13]=[C:8]([O:7][CH2:3][CH3:4])[C:9](=[NH:15])[CH:10]=1
Reactant: CCCCOc1ccc(N)cc1N
Reactant: CCN(CCO)c1ccc(N=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC1=CC(=Nc2ccc(N(CC)CCO)cc2)C(N)=CC1=N
Reaction time: 3 h

Procedure:
A solution of 4-butoxybenzene-1,3-diamine dihydrochloride in 4.2 ml of 0.25N sodium hydroxide is added to a solution of 2-[ethyl(4-nitrosophenyl)amino]ethanol in 4.2 ml of water at 50° C. After 3 hours at 50° C., the supernatant is removed and the residual gum is washed with water and then taken up in isopropyl ether. The solid formed is filtered off and dried. 360 mg of 2-{[4-(2-amino-5-ethoxy-4-imino cyclohexa-2,5-dienylideneamino)phenyl]-ethylamino}ethanol hydrochloride 65 are thus obtained in the form of a black powder.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24]Cl)[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[C:34]([O:33][C:32](=[O:38])[NH:31][C@@H:28]1[CH2:29][CH2:30][N:26]([CH2:24][C:22]2[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:13](=[O:14])[NH:12][CH2:11][C:1]45[CH2:10][CH:5]6[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]6)[CH2:2]4)[CH2:8]5)[N:20]3[CH:21]=2)[CH2:27]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc2nc(CCl)cn12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cn3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccc3n2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-(adamantanylmethyl)-2-(chloromethyl)imidazo[1,2-a]pyridine-5-carboxamide (HCl salt, 700 mg, 1.78 mmol), tert-butyl (3R)-pyrrolidin-3-ylcarbamate (496 mmol, 2.66 mmol) and potassium carbonate (615 mg, 4.45 mmol) in DMF (25 mL) is stirred at RT for 20 h. The reaction mixture is diluted with EtOAc and water. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. Purification of the residue by silica gel chromatography (10% MeOH, 1% NH4OH in DCM) affords the title compound. 1H-NMR (δ, ppm, CDCl3 as internal standard): 8.35 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.15 (dd, J=7.2 and 9.0 Hz, 1H), 7.08 (d, J=6.9 Hz, 1H), 6.33 (t, J=5.7 Hz, 1H), 4.16 (m, 1H), 3.85 (d, J=13.5 Hz, 1H), 3.78 (d, J=13.2 Hz, 1H), 3.2 (d, J=6.6 Hz, 2H), 2.91-2.64 (m, 2H), 2.44-2.21 (m, 2H), 2.02 (m, 3H), 1.77-1.58 (m, 15H), 1.41 (s, 9H).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH3:9])(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[C:14]([O:13][C:11](=[O:12])[NH:10][C@@H:7]([CH2:8][CH3:9])[CH2:6][N:18]=[N+:19]=[N-:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)butyl methanesulfonate (13.4 g, 50 mmol) in DMF (100 mL) was added sodium azide (6.5 g, 100 mmol). The reaction mixture was heated at 70° C. for 18 h. After cooling to rt, water was added, and the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (SiO2; 0-50% EtOAc/hexanes) provided the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.87 (d, J=8.6 Hz, 1H), 3.54-3.37 (m, 1H), 3.27-3.20 (m, 2H), 1.45-1.25 (m, 2H), 1.39 (s, 9H), 0.82 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]([S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])=[O:4])=[CH2:2].[N+:13]([CH:16]([CH3:18])[CH3:17])([O-:15])=[O:14].C(N(C(C)C)C(C)C)C.Cl>CC(=O)OCC>[CH3:17][C:16]([N+:13]([O-:15])=[O:14])([CH3:18])[CH2:2][CH2:1][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=CS(=O)(=O)Oc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(CCS(=O)(=O)Oc1ccccc1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.43 g of phenyl ethenesulfonate and 4.60 ml of 2-nitro-propane was heated to 80° C. and, at 80° C., 0.89 ml of ethyidiisopropylamine was added dropwise. The mixture was stirred at 80° C. for 4 hours and 30 minutes, left to stand at RT for 16 hours and then stirred at 80° C. for a further 2 hours. Cooling to RT was followed by addition of 250 ml of a 2N aqueous HCl solution and extraction 3 times with 150 ml of EA each time. Drying over Na2SO4 and removal of the solvent in vacuo were followed by coevaporation 3 times with 100 ml of toluene each time. 13.47 g of a pale yellow oil were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[N:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:41]4[CH2:42][CH2:43][CH:38]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:39][CH2:40]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: C1CC(N2CCOCC2)CCN1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(N2CCOCC2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(4-morpholinyl)piperidine as in General Procedure 10 to give the title compound. LCMS: m/z=598.99 (M+H+); retention time=0.52 minutes.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:24]([C:25]2[N:30]=[CH:29][N:28]=[C:27]([O:31][C:32]3[C:37]4[N:38]=[C:39]([NH2:41])[S:40][C:36]=4[CH:35]=[CH:34][CH:33]=3)[CH:26]=2)=[CH:23][CH:22]=[C:21]([C:42]([F:45])([F:44])[F:43])[N:20]=1.C(=O)([O-])[O-].[K+].[K+].[C:52](OC(=O)C)(=[O:54])[CH3:53]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:24]([C:25]2[N:30]=[CH:29][N:28]=[C:27]([O:31][C:32]3[C:37]4[N:38]=[C:39]([NH:41][C:52](=[O:54])[CH3:53])[S:40][C:36]=4[CH:35]=[CH:34][CH:33]=3)[CH:26]=2)=[CH:23][CH:22]=[C:21]([C:42]([F:45])([F:43])[F:44])[N:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCCCN1CCCNc1nc(C(F)(F)F)ccc1-c1cc(Oc2cccc3sc(N)nc23)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NCCCN4CCCCC4C)ncn3)cccc2s1
Temperature: 90 °C

Procedure:
A mixture of 4-(6-(2-(3-(2-methylpiperidin-1-yl)propylamino)-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)benzo [d]thiazol-2-amine trifluoroacetic acid salt, Example 80, (29 mg, 0.052 mmol), potassium carbonate (35 mg, 0.253 mmol) and acetic anhydride (2 mL) was heated at 90° C. in a microwave synthesizer for 10 min. to give MS (ESI, pos. ion.) m/z: 658 (M+1). The reaction mixture was dissolved in DCM (10 mL), filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Prodigy 5μ ODS-3 100 Å column, gradient: 20-100% CH3CN (0.1% TFA)/H2O (0.1% TFA) over 15 min) to give the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 700 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([N+:29]([O-:31])=[O:30])[C:13]([NH:19]CC4C=CC(OC)=CC=4)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:32]([CH3:34])[CH3:33])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[NH2:19][C:13]1[C:12]([N+:29]([O-:31])=[O:30])=[C:11]2[C:16]([C:17](=[O:18])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([CH:32]([CH3:33])[CH3:34])[O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CNc2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c2[N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1oc2c([N+](=O)[O-])c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Chlorophenyl)-2-isopropyl-7-(4-methoxybenzylamino)-8-nitro-chromen-4-one (80 mg, 0.167 mmol) is dissolved in trifluoroacetic acid (2 ml), and the solution is stirred at room temperature for 2 h. The mixture is then poured onto crushed ice and warmed to room temperature, and the yellow precipitate formed is collected by filtration. The solid is washed with water and then dissolved in ethyl acetate (10 ml). The solution is washed sequentially with 50% aqueous sodium bicarbonate solution (10 ml) and saturated brine (10 ml), dried (MgSO4), filtered and evaporated to give a pale yellow solid. This is triturated with n-pentane/diethyl ether and filtered to give a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:30])([F:18])[F:31])=[CH:25][CH:24]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 16.3 %

Procedure:
Example 14 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and [4-(trifluoromethyl)phenyl]acetic acid (0.041 g) to give thetitle compound (0.015 g).
Reaction SMILES: Cl.[C:2]1([NH:8][C:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1([C:26]#[N:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(OCC)(=O)C>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(O)(C)C>[C:2]1([NH:8][C:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:20]=[CH:19][C:17]([NH:18][C:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[NH:27])=[CH:16][CH:15]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCC(=O)Nc2ccccc2)cc1
Reactant: N#CN1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Solvent: CC(C)O
Product: N=C(Nc1ccc(CCCC(=O)Nc2ccccc2)cc1)N1CCCC1

Procedure:
To a stirred suspension of the product of step (a) (1.7 g; 0.0052 moles) in 30 ml of chlorobenzene was added a catalytic amount of 4-dimethylaminopyridine. To this was added 1-pyrrolidinecarbonitrile (1.2 ml; 0.016 moles) and the reaction then heated to reflux for 6 hours. The reaction was then cooled and the solvent decanted. To the residue was added 100 ml of 2N sodium hydroxide. The aqueous phase was then extracted 3×75 ml of chloroform and the organic extract was dried over magnesium sulphate. Evaporation of the solvent gave a white solid which was the dissolved in hot isopropanol 5 ml, and 100 ml ethyl acetate. Upon cooling a white solid crystallized and was collected by filtration. The above compound was dried at 70° C. for 72 hours to give N-(4(3-((phenylamino)carbonyl)propyl)phenyl)-1-pyrrolidinecarboximidamide, M.P.164°-165° C.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[N:21]=[N:22][NH:23][CH:24]=3)=[C:9]([OH:25])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=S)C=CC=CC=1>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[N:21]=[N:22][NH:23][CH:24]=3)=[C:9]([OH:25])[C:8]2=[S:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c(O)c(CCCCCCCc2c[nH]nn2)ccn1-c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Oc1c(CCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Product: Oc1c(CCCCCCCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 86.2 %

Procedure:
Reaction of 159f (0.12 g, 0.532 mmol) and P4S10 (0.076 g, 0.17 mmol) under neat conditions as described for synthesis of 162b gave compound 162f (0.054 g, 43%) as a olive green semi-solid. 1H NMR (400 MHz, DMSO) δ 8.55 (m, 1H), 7.81 (d, J=8.2 Hz, 2H), 7.65 (d, J=6.2 Hz, 1H), 7.42 (m, 2H), 7.30 (m, 1H), 7.02 (m, 1H), 6.85 (m, 1H), 4.50 (m, 2H), 4.36 (t, J=7.1 Hz, 2H), 1.85 (d, J=7.0 Hz, 4H), 1.33 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 147.76, 130.66, 128.76, 130.39, 128.98, 128.80, 128.06, 125.97, 125.67, 119.46, 60.10, 50.25, 30.11, 29.67, 28.33, 26.13, 26.10. HRMS (FAB) calcd for C20H25N4OS [M+H]+ 369.174. found 369.1762.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[CH:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:5]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1C(=O)c2c(c(OC)c(F)c(F)c2[N+](=O)[O-])N(C2CC2)C1c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccccc2)n(C2CC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A suspension of ethyl 1-cyclopropyl-6,7-difluoro-1,2,3,4-tetrahydro-8-methoxy-5-nitro-4-oxo-2-phenylquinoline-3-carboxylate (2.60 g, 5.82 mmol) and manganese dioxide (39.0 g, 449 mmol) in CH2Cl2 (60 mL) was stirred at room temperature for 16 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 5:1→1:1) to yield ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxo-2-phenylquinoline-3-carboxylate (1.05 g, 41%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:15]=1)[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C([Li])(C)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[S:32]([NH2:35])(=[O:34])=[O:33]>O1CCCC1>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][C:6]1[CH:15]=[C:2]([CH:30]([OH:31])[C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:26]=2)[CH:3]=[CH:4][C:5]=1[O:16][CH3:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(Br)cc1O[Si](C)(C)C(C)(C)C
Reactant: NS(=O)(=O)c1cc(C=O)ccc1Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of (5-bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane (2 g, 6.32 mmol) dissolved in tetrahydrofuran (25 mL) at −78° C. under nitrogen is dropwisely added 1.7 M of tert-butyllithium (8.06 mL, 12.6 mmol). The reaction mixture is stirred at −78° C. for 5 minutes. Then, the solution of 2-chloro-5-formyl-benzenesulfonamide (0.462 g, 2.11 mmol) in tetrahydrofuran (5 mL) is added slowly. The reaction mixture is warmed up to room temperature and stirred for 24 h. The reaction is quenched with 1 N of HCl, and extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) provides 0.57 g (59%) of the title compound as a brown oil. 1H NMR (CDCl3): δ 8.00 (m, 1H), 7.40 (m, 2H), 6.70 (d, 3H), 5.70 (s, 1H), 5.00 (m, 2H), 3.70 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H).