Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([O:14]CC)=[O:13])=[N:9]2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[OH-].[K+]>C(O)C>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([OH:14])=[O:13])=[N:9]2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: CCOC(=O)c1nc2cc(N)c(C(F)(F)F)cc2[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc2nc(C(=O)O)c(=O)[nH]c2cc1C(F)(F)F
Yield: 47.6 %

Procedure:
To a solution of ethyl 7-amino-3,4-dihydro-3-oxo-6-trifluoromethylquinoxaline-2-carboxylate (55.9 mg, 186 μmol) in ethanol (2 ml) was added 1N aqueous solution of potassium hydroxide (446 μl, 446 μmol), and the mixture was refluxed for 1.5 hours. After cooling, solvent was distilled off, water was added and the pH value was brought to 2 with 4N hydrochloric acid. Solvent was distilled off again and small quantity of water was added. The crystals were collected by filtration, washed with water and then air-dried to obtain 24.2 mg of the title compound as dark red powder. Yield 45%.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][O:29][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[O:11][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[N:19]=[CH:18][N:17]=[C:16]2[O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCCCC1
Temperature: 110 °C
Yield: 84.8 %

Procedure:
1-(2-Chloroethyl)piperidine hydrochloride (0.83 g, 4.5 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.73 mmol), (prepared as described for the starting material in Example 1), and potassium carbonate (2.6 g, 18.8 mmol) in DMF (30 ml), and the mixture heated at 110° C. for 2.5 hours and allowed to cool. The insolubles were removed by filtration, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 6-methoxy-4-phenoxy-7-(2-piperidinoethoxy)quinazoline (1.2 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:18]([OH:20])=O)[CH:4]=1.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>S(Cl)(Cl)=O>[NH:23]1[C:22]([NH:21][C:18]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[N:6]=2)=[O:20])=[N:26][N:25]=[N:24]1
Reactant: COc1cc(C(=O)O)nc(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 65.8 %

Procedure:
In the same manner as described in Example 13-(1), 4-methoxy-6-(4-nitrophenyl)-2-pyridinecarboxylic acid (2.54 g), thionyl chloride (30 ml) and 5-aminotetrazole (1.2 g) are treated to give N-(5-tetrazolyl)-4-methoxy-6-(4-nitrophenyl)-2-pyridinecarboxamide (2.08 g). M.P. 279°-281° C. (decomp.) (recrystallized from dimethylformamide)
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([OH:21])=O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:24])=O>>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([Cl:24])=[O:21])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCC1CCC(C2CCC(CC(=O)O)CC2)CC1
Product: CCCCCC1CCC(C2CCC(CC(=O)Cl)CC2)CC1

Procedure:
A mixture of 50 g (0.17 mol) of 4-(4-pentylcyclohexyl) cyclohexyl acetic acid and 135 Ml of thionyl chloride was heated for 4 hours to reflux. Excess amount of thionyl chloride was separated under a reduced pressure to obtain 4-(4-pentylcyclohexyl)cyclohexyl acetic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[Cl:14][C:15]1[C:22]([F:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O)(=O)C.[F-].[NH4+]>C1(C)C=CC=CC=1.O1CCOCC1.CCCCO.CCCCO.CCCCO.CCCCO.[Ti].C(OCC)(=O)C>[Cl:14][C:15]1[C:22]([F:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:16]=1[CH:17]=[N:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2
Reactant: COc1ccc(C=O)c(Cl)c1F
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Agent: [Ti]
Agent: [F-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COc1ccc(C=Nc2cc(F)cc3[nH]c(=O)ccc23)c(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To 1.6 g (9 mmol) 5-amino-7-fluoro-1H-quinolin-2-one and 1.69 g (9 mmol) 2-chloro-3-fluoro-4-methoxybenzaldehyde in 27 ml toluene and 8 ml 1,4-dioxane are added 1.96 ml acetic acid and 7 ml tetrabutyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 1 hour. Phases are separated and addition of ethylacetate is repeated two times while stirring is done under reflux and phases are separated while they are still hot. The combined organic phases are concentrated and the residue is purified by flash chromatography on silica gel (ethyl acetate, then methanol in dichloromethane 15% to 20%) to yield 2.17 g of 5-{[1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]-amino}-7-fluoro-1H-quinolin-2-one. 465 mg NaH (55% in mineraloil, 9.7 mmol) were washed with dry THF and suspended together with 2.6 g (7.5 mmol) of 5-{[1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]amino}-7-fluoro-1H-quinolin-2-one in 90 ml THF. t-Butyldimethylsilyl chloride is added as solid and the mixture is stirred for 3.5 hours while it becomes a clear solution. In parallel 0.96 ml 1,1,1-trifluoro-2,3-epoxypropane in 24 ml THF and 7 ml hexane are cooled to −100° C. and 4.5 ml of a 2.5 M n-butyl lithium solution in hexane are added over 10 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition the previously prepared 1-{t-butyldimethylsilyl}-5-{[1-(2-chloro-3-fluoro-4-methoxyphenyl)methylidene]amino}-7-fluoroquinolin-2-one solution in THF is added over 30 minutes while the temperature does not exceed −95° C. After 3 hours at −100° C. 7.5 ml diethyl ether are added and the reaction mixture is warmed to room temperature over one hour. The reaction is quenched by addition of saturated ammonium chloride solution. After stirring for 30 minutes the phases are separated and the aqueous layer is extracted with dichloromethan, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (ethyl acetate in hexane 50 to 100%) yields 2.14 g of 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyloxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-one which is used for some of the following examples for opening of the oxirane ring with different nucleophiles.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(N)c1
Product: COc1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-methoxy-phenyl)-carbamic acid tert-butyl ester (Example J9) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a light yellow solid (258 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CC(=O)Nc1ccc(CCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of 4.5 g (0.022 mole) 4-(acetylamino)benzenebutanol in 25 ml pyridine, add 8.3 g (0.044 mole) tosyl chloride and chill in the refrigerator overnight. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonium hydroxide, 90:10). At the completion of the reaction, pour the reaction mixture onto 500 ml ice water and stir for 15 minutes. Extract the aqueous mixture with 3×300 ml ether. Wash the combined organic layers with 1N hydrochloric acid, then with water, dry over potassium carbonate, filter and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH3:15][S:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([CH2:26][NH2:27])[CH:23]=[CH:22][C:20]=2[N:21]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:15][S:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([CH2:26][NH:27][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CSc1nc2ccc(CN)cc2s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc2ccc(CNc3ncc(C(F)(F)F)cc3[N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A mixture of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (500 mg, 2.21 mmol), (2-(methylthio)benzo[d]thiazol-6-yl)methanamine from Step 4 of Example 23 (583 mg, 2.76 mmol), and triethylamine (837 mg, 8.29 mmol) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:0 to 10:1 petroleum ether/EtOAc to give N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitro-5-(trifluoromethyl)pyridin-2-amine as a yellow solid (150 mg, 84.7%). 1H NMR (300 MHz, DMSO-d6) δ 9.46 (t, J=1.8 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H), 7.97 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.49-7.45 (m, 1H), 4.95 (d, J=6.6 Hz, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 401 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:12]([CH2:41][OH:42])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C([C@@H](NC(N2CCOCC2)=O)CC2C3C(=CC=CC=3)C=CC=2)=O)(=[O:10])=[O:9])=[CH:4][C:3]=1Cl.[C:48]1([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:53]=[CH:52][C:51]([CH2:54][C@H:55]([NH:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:56]([OH:58])=O)=[CH:50][CH:49]=1>>[C:63]([O:62][C:60](=[O:61])[NH:59][C@H:55]([C:56](=[O:58])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:43][CH:44]([CH3:45])[CH3:46])[CH2:41][OH:42])[CH2:54][C:51]1[CH:50]=[CH:49][C:48]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[CH:53][CH:52]=1)([CH3:66])([CH3:64])[CH3:65]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)c(Cl)c1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from the amine, (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (XII) (example 28, step D), and the acid, (2S)-3-biphenyl-4-yl-2-tert-butoxycarbonylamino-propionic acid, as described in general procedure E. The final product was obtained in 67% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:11]=1)[CH2:7]O)[CH3:2].S(Cl)([Cl:28])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:28][CH2:7][C:6]1[CH:9]=[C:10]([CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19]
Reactant: O=S(Cl)Cl
Reactant: CCOc1cc(CO)cc(OCc2nc(-c3ccccc3)oc2C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1cc(CCl)cc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of 3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (4.38 g) in toluene (80 ml) was added dropwise thionyl chloride (1.69 g) at room temperature. After stirring for 90 min, ethyl acetate (100 ml) was added to the reaction mixture and the mixture was washed with aqueous sodium bicarbonate and then with water. The organic layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio) were recrystallized from ethyl acetate-hexane to give 4-(3-chloromethyl-5-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (4.25 g, 92%) as colorless prism crystals. melting point: 86–87° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([Cl:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[ClH:44]>C1COCC1>[ClH:41].[ClH:44].[Cl:41][C:39]1[CH:40]=[C:35]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH:36]=[C:37]([Cl:43])[C:38]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCNCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl 4-((trans-4-((3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-yl)amino)cyclohexyl)methyl)piperazine-1-carboxylate (50 mg, 0.80 mmol) in THF (5 mL) was added aqueous 1 N HCl (4 mL) and the reaction mixture was heated at 65° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The residue was dissolved in methanol (5 mL) and HCl (1 M in water, 2.0 mL, 2 mmol) was added. The resultant solution was concentrated to give the desired product (19.9 mg, 41%) as an off-white solid. 1H NMR (500 MHz, MeOD) δ 9.10 (s, 1H), 8.48 (s, 1H), 8.28 (dd, J=8.7, 1.8 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.73 (s, 2H), 4.57-4.53 (m, 1H), 3.67-3.63 (br s, 4H), 3.63-3.31 (br s, 2H), 3.14-3.10 (br s, 2H), 2.74 (s, 3H), 2.46 (d, J=12.2 Hz, 2H), 2.18 (d, J=12.8 Hz, 2H), 2.08 (br s, 1H), 1.80 (q, J=12.4 Hz, 2H), 1.41-1.34 (m, 2H). ESI MS m/z 527 [C28H32Cl2N4O2+H]+; HPLC>99% (AUC), tR=9.49 min.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:28]([OH:30])=[O:29])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN1C(=O)CCC1>[NH2:1][C@H:2]([C:28]([OH:30])=[O:29])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C(NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(NCCCC[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2.5 gr Fmoc-Lys(Mtt)-OH was dissolved in 150 ml NMP.620 mg of HOBt was added following the addition of 1.3 gr of TBTU. Then, 3.5 gr of Rink amide resin (0.58 mmole/gr) was added and the reaction was stirred at room temperature for 3.5 hr. Then, the loaded resin was washed with NMP, MeOH, DCM and then dried in vacuum. 4.4 gr. of loaded resin was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:34])[N:9]([CH3:33])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:20][N:19]=[C:18]([CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)[N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.CN>C(O)C>[NH2:22][CH2:21][C:18]1[N:17]=[C:16]([C:15]2[N:14]=[CH:13][N:12]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=4[C:8](=[O:34])[N:9]([CH3:33])[CH2:10][C:11]=23)[O:20][N:19]=1
Reactant: CN1Cc2c(-c3nc(CN4C(=O)c5ccccc5C4=O)no3)ncn2-c2cccc(Cl)c2C1=O
Agent: CN
Solvent: CCO
Product: CN1Cc2c(-c3nc(CN)no3)ncn2-c2cccc(Cl)c2C1=O
Yield: 71.1 %

Procedure:
35.1 g (74 mmol) of 7-chloro-5,6-dihydro-5-methyl-3-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-4H-imidazo[1,5-a]-[1,4]benzodiazepin-6-one were stirred with 190 ml of methylamine in ethanol) and 100 ml of ethanol at 80° for 3 hours. The solution was concentrated, the residue was taken up in methylene chloride and 100 ml of 4N hydrochloric acid and the solution was washed three times with methylene chloride. The aqueous phase was made alkaline with 105 ml of 4N sodium hydroxide solution and extracted six times with methylene chloride. After drying the combined organic solutions and evaporating the solvent there were obtained 18.14 g (71%) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was used without further purification as the starting material for the Example described hereinafter.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].CC[Mg+].[Br-].[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37]>O1CCCC1>[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]([OH:37])[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: O=Cc1ccccc1F
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(O)c3ccccc3F)c(Cc3ccccc3C(F)(F)F)sc21

Procedure:
5-Bromo-1-isobutyl-3-methyl-6-[2-(trifluoromethyl)benzyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 1 part c)) (100 mg) was dissolved in tetrahydrofuran (2 ml) and EtMgBr (210 ul of a 1M solution in tetrahydrofuran) was added. After 10 min 2-fluorobenzaldehyde (210 μl of a 1M solution in tetrahydrofuran) was added. After 1 hr the reaction was quenched via addition of water. The reaction was concentrated in vacuo and extracted into dichloromethane, concentrated in vacuo and purified by chromatography eluting with 0-75% diethyl ether in isohexane to yield 5-[(2-fluorophenyl)hydroxymethyl]-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione. This was redissolved in dichloromethane (1 ml) and added to a mixture of oxalyl chloride (50 ul) and dimethyl sulphoxide (100 μl) in dichloromethane (1 ml) at −78° C. After 30 mins triethylamine (260 ul) was added and the reaction allowed to warm to room temperature. The reaction was then washed with water and evaporated to dryness before the residue was purified by chromatography eluting with 0-75% diethyl ether in hexane to yield the title compound (11 mg).
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]1([NH:27][C:28]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)OCCCCC/C=C(\c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (4 g, 15 mmoles) and phenyl isocyanate (1.6 ml, 15 mmoles) were dissolved in methylene chloride (20 ml), and triethylamine (0.5 ml) was added to the solution. The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (2:1) as the developing solvent and recrystallization of the product from a mixture of ethyl acetate and isopropyl ether gave 1-phenylaminocarbonyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (3.2 g, 55%)
Reaction SMILES: C([O:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])C.[CH2:11]([N+:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:23])[CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C.O>[CH2:11]([CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([O-:3])=[O:10])[CH3:12].[CH2:24]([N+:21]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH3:23])[CH3:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCC(=O)OCC
Agent: CCCCCCCCCC[N+](C)(C)CCCCCCCCCC
Solvent: CCO
Solvent: O
Product: CCCCC(CC)C(=O)[O-]

Procedure:
End grain pine wafers were weighed and then soaked with didecyldimethylammonium ethylhexanoate in ethanol/water until a weight gain of 35% was observed.
Reaction SMILES: [C:1]([S:4][C:5]([CH3:45])([CH3:44])[CH:6]([NH:36]C(OC(C)(C)C)=O)[C:7]([O:9][C@H:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:22]=1)[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][N+:15]([O-:19])=[CH:14][C:13]=1[Cl:20])=[O:8])(=[O:3])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[C:1]([S:4][C:5]([CH3:45])([CH3:44])[CH:6]([NH2:36])[C:7]([O:9][C@H:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:22]=1)[CH2:11][C:12]1[C:13]([Cl:20])=[CH:14][N+:15]([O-:19])=[CH:16][C:17]=1[Cl:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)SC(C)(C)C(N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
4-((2S)-2-(3-(acetylthio)-2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (118 mg, 0.170 mmol) was dissolved in DCM (1 ml). HCl 4N in dioxane (425 μl, 1.70 mmol) was added and the mixture stirred for 30 minutes at RT. The reaction mixture was diluted with DCM. The organic layer was washed with NaHCO3 sat. sol. (2×) and brine, dried over Na2SO4 and evaporated under vacuum. The crude product was purified by preparative reverse-phase HPLC to give 101 mg of the desired compound (quantitative yield).