Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:35]1([CH2:41][C:42]2[CH:43]=[C:44]([CH:58]=[CH:59][CH:60]=2)[O:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49][NH:50][C:51](=[O:57])[CH2:52][S:53][CH2:54][CH2:55][NH2:56])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[N:35]1([CH2:41][C:42]2[CH:43]=[C:44]([CH:58]=[CH:59][CH:60]=2)[O:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49][NH:50][C:51](=[O:57])[CH2:52][S:53][CH2:54][CH2:55][NH:56][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)c1ccccc1
Reactant: NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CSCCNC(=O)c1ccccc1)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
There was dissolved 0.97 g (0.008 mol) of benzoic acid in 60 ml of dichloromethane and added 1.22 g (0.008 mol) of HOBt and 1.65 g (0.0095 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 3.0 g (0.008 mol) of N-[4-[3-(piperidinomethyl) phenoxy]-cis-2-butenyl]-2-(2-aminoethylthio)acetamide and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give 0.9 g of the titled compound as oily matter.
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[CH:20]=[C:19]3[C:15]([C:16](/[CH:29]=[CH:30]/[C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[N:17][N:18]3COCC[Si](C)(C)C)=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[NH:37][C:38](=[O:40])[CH3:39].B(F)(F)F.CCOCC.Cl>>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[CH:20]=[C:19]3[C:15]([C:16](/[CH:29]=[CH:30]/[C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[NH:37][C:38](=[O:40])[CH3:39]
Reactant: CC(=O)Nc1cccc2c1NC(=O)/C2=C/c1ccc2c(/C=C/c3ccncc3)nn(COCC[Si](C)(C)C)c2c1
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)Nc1cccc2c1NC(=O)/C2=C/c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Yield: 71.2 %

Procedure:
According to the method of A57C, N-((E)-2-oxo-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-7-yl)acetamide (64 mg, 0.11 mmol) was treated with boron trifluoride etherate, followed by 2 N HCl to give the title compound as an orange solid (33 mg, 71%). 1H NMR (400 MHz, d6-DMSO) δ 10.33 (s, 1H), 9.42 (s, 1H), 8.85 (d, J=6.2 Hz, 2H), 8.46-8.30 (m, 4H), 7.98 (s, 1H), 7.87-7.78 (m, 2H), 7.80 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.42-7.35 (m, 2H), 6.81 (t, J=8.1 Hz, 1H), 2.05 (s, 3H); MS ESI 422.1 [M+H]+, calcd for [C25H19N5O2+H]+ 422.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:26][C:27]#[C:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:26][C:27]#[C:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:13]=2)=[N:6][CH:7]=1
Reactant: O=c1ccc(-c2ccc(Cl)cn2)n[nH]1
Reactant: CCCCCOCC#CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOCC#CCn1nc(-c2ccc(Cl)cn2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To a 100 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 2.13 grams (g) of 6-(5-chloropyridin-2-yl)pyridazin-3(2H)-one (10.3 mmol), 2.20 g of potassium carbonate (16 mmol), and 50 mL of dry DMF. The reaction mixture was stirred for about 30 minutes at ambient temperature followed by the dropwise addition of 2.54 g of 4-(pentyloxy)but-2-ynyl methanesulfonate (10.8 mmol) in about 5 mL of dry DMF. The reaction was stirred overnight at ambient temperature, and checked by TLC and GC the next morning. No starting material remained, and one new product was formed. The reaction was poured into about 100 mL of water, and extracted with 3×50 mL of ethyl ether. The combined ether extract was washed with 100 mL of water, 100 mL of saturated aqueous sodium chloride solution, dried, and stripped to the crude product which was purified by silica gel column chromatography. The pure fractions were combined and concentrated under vacuum on a rotary evaporator to afford 1.3 g of a white solid. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 0.90 (m 3H); 1.30 (m, 4H); 1.55 (m, 2H); 3.45 (t, 2H); 4.15 (s, 2H); 5.05 (s, 2H); 7.05 (d, 1H); 7.75 (d, 1H); 8.15 (d, 1H); 8.30 (d, 1H); 8.55 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14]([O:16][C:17](C)=O)=O>>[CH2:14]([O:16][CH:17]=[C:4]([C:3]([C:2]([F:11])([F:12])[F:1])=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Yield: 98 %

Procedure:
A solution of ethyl 4,4,4-trifluoroacetoacetate (46 g, 0.25 mol) triethyl orthoformate (74 g, 0.50 mol) and Ac2O (77 g, 0.75 mol) was heated at 120-140° C. for 7 h. The mixture was concentrated and distilled to give the title compound in a 98% yield (58.6 g); b.p. 80-90° C., 1.5 mm/Hg.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[C:32]([O:44][CH3:45])=[N:33][N:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:35]=3[NH2:36])=[CH:30][C:25]=2[O:24][CH2:23]1>N1C=CC=CC=1>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[C:32]([O:44][CH3:45])=[N:33][N:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:35]=3[NH:36][S:9](/[CH:8]=[CH:7]/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:11])=[O:10])=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: COc1nn(Cc2ccccc2)c(N)c1-c1ccc2c(c1)OCO2
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1nn(Cc2ccccc2)c(NS(=O)(=O)/C=C/c2ccccc2)c1-c1ccc2c(c1)OCO2
Reaction time: 24 h
Yield: 72 %

Procedure:
(E)-2-phenylethensulfonyl chloride (138 mg) and dimethylaminopyridine (40 mg) were added at room temperature under an atmosphere of nitrogen to a solution of 4-(1,3-benzodioxol-5-yl)-1-benzyl-3-methoxy-1H-pyrazol-5-amine (Preparation 58) (100 mg) in anhydrous pyridine (3 ml). After 24 h, another portion of (E)-2-phenylethensulfonyl chloride (32 mg) was added and the reaction was stirred for 48 h before the mixture was concentrated under reduced pressure. To the beige solid was added an aqueous solution of HCl (1N, 10 ml) and the mixture was extracted with dichloromethane (3×10 ml). The organic fractions were combined, dried on sodium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (5 ml) and an aqueous solution of sodium hydroxyde (2N, 2.25 ml) was added. The reaction was stirred overnight. The reaction mixture was then diluted with water (20 ml), acidified with an aqueous solution of HCl (2N) and the solution was extracted with ethyl acetate (3×15 ml). The combined organic fractions were washed with brine (15 ml), dried on sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with hexane:ethyl acetate (2:1) to yield the title compound as colourless oil (109 mg) which crystallises in a mixture of ether and ethyl acetate.
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7]1=[O:13])(=O)=O.[C:14]([O-])(=[S:16])[CH3:15].[K+]>CC(C)=O>[C:14]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7]1=[O:13])(=[S:16])[CH3:15]
Reactant: CN1CCCC(OS(C)(=O)=O)C1=O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=S)OC1CCCN(C)C1=O
Yield: 40.1 %

Procedure:
A mixture of 1-methyl-2-oxo-3-piperidinyl methanesulfonate (1.7 g., 0.008 mole) and potassium thioacetate (1.39 g., 0.012 mole) in 80 ml. acetone was refluxed under nitrogen for 20 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in 50 ml. ethyl acetate and 50 ml. water. The ethyl acetate layer was washed with 50 ml. water and 50 ml saturated aqueous sodium chloride solution, dried over anhydrous sodium acetate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to yield 600 mg (40% yield) of the title compound. NMR (CDCl3): 1.7-2.5 (c) and 2.38 (s) (total 7H); 3.0 (s, 3H); 3.36 (m, 2H); and 4.2 (m, 1H)ppm.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH3:17])=[C:4]([C:14]#[N:15])[C:5](=[O:13])[N:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)[CH3:9])[CH:7]=1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH:10]1([CH:8]([N:6]2[CH:7]=[C:2]([C:21]3[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=3)[C:3]([O:16][CH3:17])=[C:4]([C:14]#[N:15])[C:5]2=[O:13])[CH3:9])[CH2:12][CH2:11]1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: COc1c(Br)cn(C(C)C2CC2)c(=O)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1c(-c2ccn(C)n2)cn(C(C)C2CC2)c(=O)c1C#N
Temperature: 100 °C
Yield: 39.2 %

Procedure:
A mixture of 5-bromo-1-(1-cyclopropylethyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step B of Example 163 (66 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (69 mg), tetrakis(triphenylphosphine)palladium(0) (26 mg), aqueous sodium carbonate solution (2 M, 0.666 mL) and 1,2-dimethoxyethane (3.0 mL) was heated with microwave irradiation at 100° C. for 1 hr under argon atmosphere. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and then silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (26 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH:10](O)[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:25][N:26]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=S(=O)(CC(O)CCCc1ncccn1)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(/C=C/CCCc1ncccn1)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred solution of the 5-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]piperazin-1-yl}sulfonyl)pentan-2-ol (9.10 g, 18.6 mmol), triethylamine (13 mL, 93.0 mmol) in DCM (200 mL) at 0° C. was added methanesulfonyl chloride (2.16 mL, 27.9 mmol). The reaction was stirred at 0° C. for 15 minutes, warmed to room temperature and stirred for 16 hours. The reaction mixture was then washed with water (200 mL) and the aqueous back extracted with DCM (200 mL). The combined DCM extracts were washed with brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-{[(1E)-5-pyrimidin-2-ylpent-1-en-1-yl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine as an orange solid (8.79 g, 18.6 mmol, 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][C:19]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[NH:23][C:21](=[O:22])[CH:20]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:30][C:28]1[CH:29]=[C:24]2[C:25]([C:19]([CH3:18])=[CH:20][C:21](=[O:22])[NH:23]2)=[CH:26][CH:27]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1cc(=O)[nH]c2cc(N)ccc12
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc4c(C)cc(=O)[nH]c4c3)c2cc1OC
Yield: 92.2 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.174 g of carbostyril 124, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.356 g of 6,7-dimethoxy-4-(4-methyl-2-oxo-1,2-dihydro-quinolin-7-ylamino)-quinoline-3-carbonitrile as a solid, mp>300° C.; mass spectrum (electrospray, m/e): M+H 387.1446.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[O-]CC.[Na+].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:5]=[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1cc2ccoc2cn1
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1cc2ccoc2cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
5-Ethoxycarbonylfuro[2,3-c]pyridine(956 mg, 5.0 mmol) was dissolved in 10 mL of toluene, 510 mg (7.5 mmol) of sodium ethoxide was added at room temperature to the solution, and 661 mg (7.5 mmol) of ethyl acetate was then added dropwise at room temperature with stirring. After all the ethyl acetate had been added, the reaction mixture was heated to 80° C., and a reaction was carried out for 4 hours. The reaction solution was then cooled to 5° C. and was neutralized with 450 mg (7.5 mmol) of acetic acid as the temperature was held 5-10° C., the solution was stirred for 30 minutes as the temperature was maintained, 1 mL water was then added, and the solution was returned to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator, and the resulting solids were recrystallized from a mixed solvent of toluene-hexane, giving 840 mg (72% yield) of ethyl β-oxo-5-furo[2,3-c]pyridinepropionate in a purity of 99% by HPLC.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([O-:22])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:26]([O:32][CH2:33]I)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([O:22][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: Cc1c(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a solution of 29.4 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 0.8 ml of dry DMF was added 0.017 ml of iodomethyl pivalate under the atmosphere of argon at −30° C., and the mixture was stirred for 4 hours during which the temperature was raised up to 10° C. The reaction mixture was diluted with 10 ml of ethyl acetate, separated, and the aqueous layer was extracted twice with ethyl acetate, while the organic layer was washed with 10 ml of semi-saturated aqueous saline. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 1 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=20:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give 7.9 mg of the title compound.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[N:11]1([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2o1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc2oc(N3CCNCC3)nc2c1
Reaction time: 1 h

Procedure:
A solution of 1.5 g (0.01 mol) of chlorobenzoxazole in 20 ml of dichloromethane is added dropwise at 0° C. to a solution of 1 g (0.012 mol) of piperazine and 7 ml (0.05 mol) of triethylamine in 10 ml of dichloromethane and the mixture is stirred for one hour at this temperature. Then it is extracted with water. The organic phase is dried over sodium sulphate, the drying agent is filtered off and the filtrate is concentrated by evaporation. The residue is washed with acetone.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH3:5][O:6][C:7]1[C:8]([O:25][CH3:26])=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][NH:14][C:13](=[O:23])[CH2:12][C:11]=2[CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:5][O:6][C:7]1[C:8]([O:25][CH3:26])=[CH:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]([CH2:2][CH2:3][CH3:4])[C:13](=[O:23])[CH2:12][C:11]=2[CH:24]=1
Reactant: CCCI
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NNC(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1N=C(c2ccccc2)c2cc(OC)c(OC)cc2CC1=O
Reaction time: 72 h
Yield: 72 %

Procedure:
Add dropwise under an inert atmosphere 400 μl of iodopropane to a solution of 200 mg (0.675 mmol) of 7,8-dimethoxy-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIaa and 121 mg (0.878 mmol) of K2CO3 in solution in 5 ml of DMF. After 72 hours at room temperature, add 30 ml of H2O and extract three times with 30 ml of Et2O. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt 1/hexane 1). Yield: 72%. M: 48–52° C. 1H-NMR (300 MHz, CDCl3): d 0.83 (t, J=7.34, 3H, CH3), 1.65–1.72 (m, 2H, CH2CH3), 2.85–3.62 (m, 4H, CH2CH2CH3+5-CH2), 3.74 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.67 (s, 1H Ar), 6.89 (s, 1H Ar), 7.43–7.47 (m, 3H Ar), 7.65–7.68 (m, 2H Ar).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:28])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])=[C:14]([F:27])[CH:13]=3)[O:11][C:6]=2[C:5]([F:29])=[CH:4][C:3]=1[F:30].[H-].[Na+].Br[CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38].[Cl-].[NH4+]>CN(C)C=O>[C:23]([O:22][C:20]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:6]3[C:5]([F:29])=[CH:4][C:3]([F:30])=[C:2]([NH:1][CH2:38][CH2:37][CH2:36][CH:35]=[CH2:34])[C:7]=3[C:8](=[O:28])[CH:9]=2)=[CH:13][C:14]=1[F:27])[CH3:19])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: C=CCCCBr
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCCCNc1c(F)cc(F)c2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
852 mg (2.03mmol) of the resulting 5-amino-2-[4-[N-(tert-butoxycarbonyl)-N-methylamino]-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 30 ml of dimethylformamide under argon atmosphere, 165 mg of sodium hydride (60% oil dispersion) and 0.48 ml of 5-bromo-1-pentene were added under ice-cooling and the mixture was stirred at room temperature for 2 hours. 85 mg of sodium hydride (60% oil dispersion) and 0.24 ml of 5-bromo-1-pentene were added and the mixture was stirred for additional 1 hour. An aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:1) to give 239 mg (24%) of 2-[4-[N-(tert-butoxycarbonyl)-N-methylamino]-3-fluorophenyl]-6,8-difluoro-5-(4-pentenylamino)-4H-benzopyran-4-one.
Reaction SMILES: [CH3:1][C:2]1([CH2:5][C@@:6]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:11][C:10](=[O:12])[N:9]([C@H:13]3[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)[CH2:8][CH2:7]2)[CH2:4][O:3]1>C1COCC1>[OH:3][C:2]([CH3:4])([CH3:1])[CH2:5][C@@:6]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N2CC[C@](CC3(C)CO3)(c3ccccc3)OC2=O)C1
Solvent: C1CCOC1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.1 %

Procedure:
A solution of (3S)-tert-butyl 3-((6S)-6-((2-methyloxiran-2-yl)methyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)piperidine-1-carboxylate (2.87 g, 6.67 mmol) in dry THF (50 mL) was cooled to 0° C. After 20 min, the mixture was allowed to warm up to rt slowly. The mixture was stirred 2 h at rt, before being cooled to 0° C. again. The mixture was quenched with water (10 mL), 1% aq HCl (25 mL), diluted with EtOAc (120 mL). After separation, the organic layer was washed with brine (20 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120 g silica gel column, eluted with a 50-100% EtOAc in hexanes gradient, to afford (S)-tert-butyl 3-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)piperidine-1-carboxylate (0.55 g, 19% yield). LC-MS Method 1 tR=1.64 min., m/z 455 (M+Na).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[C:15]([F:16])=[CH:14][C:13]([NH:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:12][C:11]=1[F:24])=[O:5])=[N-]>C1(C)C=CC=CC=1.ClCCl.C1(C)C=CC=CC=1.[Cu+2]>[F:24][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:19])[O:20][CH:21]([CH3:23])[CH3:22])[CH:14]=[C:15]([F:16])[C:10]=1[C@H:9]1[C@H:3]2[C@@H:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: CC(C)OC(=O)Nc1cc(F)c(/C=C/COC(=O)C=[N+]=[N-])c(F)c1
Agent: [Cu+2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1cc(F)c([C@@H]2[C@H]3COC(=O)[C@H]32)c(F)c1

Procedure:
A solution of (2E)-3-{2,6-difluoro-4-[(isopropoxycarbonyl)amino]phenyl}prop-2-enyl diazoacetate (2.4 g, 7.07 mmol) in 170 mL of toluene/dichloromethane (1:2) was added dropwise over 14 h to a refluxing solution of bis-(N-t-butylsalicylaldiminato) copper(II) (0.147 g, 0.35 mmol) in 120 mL of toluene. After the addition was complete, the reaction mixture was heated another hour at reflux, then cooled, filtered and concentrated. The crude oil was purified by column chromatography (15-40% EtOAc-hexanes) to provide the title compound (a racemic mixture) as a yellow solid.