Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24].O>C(Cl)Cl>[C:22]([N:9]=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:12]=[CH:11]1)(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N=c1ccn(-c2ccccc2)nc1
Reaction time: 4 h
Yield: 47.2 %

Procedure:
11.5 g (114 millimoles) of triethylamine were added dropwise to 9.3 g (44.8 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride and 5.3 g (49.7 millimoles) of isobutyryl chloride in 50 ml of methylene chloride at room temperature, while stirring. After the addition was complete, stirring was continued for 4 hours at room temperature, after which water was added to the reaction mixture. The organic phase was separated off and mixed thoroughly with dilute hydrochloric acid (100 ml of water and 20 ml of concentrated hydrochloric acid). The methylene chloride phase was discarded, and the aqueous layer was brought to pH 10 with sodium hydroxide solution. The resulting solid substance was filtered off under suction, washed with water, dried and recrystallized from toluene/hexane. 5.1 g (47% of theory) of 1,4-dihydro-4-isobutyrylimino-1-phenylpyridazine were isolated as yellowish beige crystals of melting point 138° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](I)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(CC)CC)C.[CH3:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:41]#[C:40][C:39]([CH3:43])([CH3:42])[CH3:38])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a 25 mL RBF under nitrogen, 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (1 eq.), copper iodide (0.025 eq.) and tris(dibenzylideneacetone)dipalladium (0) (0.01 eq.) are taken. DMF, triethylamine (2.5 eq.) and 3,3-dimethyl-but-1-yne (2 eq.) are added and the reaction mixture is stirred at 40° C. for 2 h under a N2 atmosphere. The reaction mixture is filtered on celite and washed with ethyl acetate. The solution is diluted with water and extracted 2 times with ethyl acetate. The organic phases are combined and washed 3 times with water. The organic layer is separated, dried (Na2SO4), evaporated to about 2 mL and then 8 mL of heptane is added. It is evaporated to 2-4 mL and cooled in an ice bath. The formed white solid is filtered, washed with heptane and dried in oven to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: C(N(CC)CC)C.S(Cl)(C)(=O)=O.[CH3:13][O:14][C:15]([CH:17]1[CH:21]([C@@H:22]([CH3:25])[CH2:23]O)[CH2:20][N:19]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:18]1)=[O:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[I-:49].[Na+]>ClCCl.C(OCC)(=O)C.CO>[CH3:13][O:14][C:15]([CH:17]1[CH:21]([C@@H:22]([CH3:25])[CH2:23][I:49])[CH2:20][N:19]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:18]1)=[O:16]
Reactant: [I-]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@@H](C)CO
Agent: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@@H](C)CI
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Triethylamine (2.7 mL, 19.1 mmol) and mesyl chloride (1.2 mL, 15.3 mmol) were added to a solution of 4-[(R)-2-hydroxy-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (4.1 g, 12.8 mmol) in dichloromethane (100 mL) under ice-cooling, and then the mixture was stirred at room temperature for 30 minutes. After adding methanol to the reaction mixture, the mixture was blended with a mixture of ethyl acetate and a 10% citric acid solution. The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in acetone (100 mL). Sodium iodide (4.1 g, 27.4 mmol) was added, and the mixture was heated to reflux for 20 hours. The reaction mixture was cooled and then the solvent was evaporated under reduced pressure. The resulting residue was blended with a mixture of ethyl acetate and water. The organic layer was washed with a saturated sodium thiosulfate solution and brine, dried over magnesium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to give 5.0 g (84%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2 g of 3-bromo-4-methylbenzoic acid were suspended in 9.4 g of thionyl chloride and stirred at 60° C. for 2 h. The cooled reaction mixture was concentrated under reduced pressure, taken up in 20 ml of acetonitrile, admixed with 887 mg of lithium tert-butoxide and stirred at room temperature for 20 h. For workup, the reaction mixture was admixed with ethyl acetate and water. The organic phase was removed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; n-heptane) and afforded tert-butyl 3-bromo-4-methylbenzoate. 1H NMR: 8.0, s, 1H; 7.8, d, 1H, 7.5, d, 1H, 2.4, s, 3H, 1.55, s, 9H.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH3:28][NH:29][CH3:30]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25][N:29]([CH3:30])[CH3:28])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1nnc(CNC(=O)CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CNC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nnc(CNC(=O)CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
To a solution of 5-chloro-2-[3-(2-chloroacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (0.4 g) in methanol (4 ml) and chloroform (8 ml), 40% aqueous dimethylamine (0.5 g) is added, and the resultant mixture is stirred at room temperature for 24 hours. The reaction mixture is evaporated under reduced pressure, and the residue is shaken with methylene chloride (20 ml). The methylene chloride layer is washed with aqueous sodium bicarbonate and water in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, whereby 5-chloro-2-[3-(2-dimethylaminoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone is obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:33])[C:26]1[C:31](Br)=[CH:30][CH:29]=[N:28][CH:27]=1.C([O-])(O)=O.[Na+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[C:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH:12]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1cnccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 72 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
A solution of PdCl2(PPh3)2 (1.3 g, 1.9 mmol, 0.05 eq.) in THF (250 mL) was stirred for 10 minutes under nitrogen. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (11.7 g, 37.8 mmol, 1.0 eq.) was added and the resulting solution was stirred for another 10 minutes. 4-Bromonicotinic acid methyl ester (8.2 g, 38.0 mmol, 1.0 eq.) in THF (100 mL) and NaHCO3 (16.1 g, 151.9 mmol, 4.0 eq.) in H2O (76 mL) were added, and the resulting solution was stirred for 6 hours while the temperature was maintained at 72° C. in an oil bath. The mixture was cooled to room temperature and the reaction was then quenched with water (50 mL). The resulting solution was extracted with EtOAc (150 mL). The organic layer was washed with saturated aqueous NaCl (3×200 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:5) to yield 3,6-dihydro-2H-[4,4]bipyridinyl-1,3′-dicarboxylic acid 1-t-butyl ester 3′-methyl ester (8.7 g) as a white solid. ES m/z: [M+H]+319.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CS(C)=O.C1COCC1.CCOC(C)=O>[CH:27]1([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]3[C:4]4=[N:3][S:2](=[O:1])(=[O:19])[CH2:7][CH2:6][N:5]4[CH:8]=[CH:9][CH:10]=3)=[CH:13][CH:14]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: BrC1CCCCCC1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCCCCC4)cc3)C2=N1
Temperature: 130 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a mixture of 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg), potassium carbonate (390 mg) in DMSO (5 mL) was added bromocycloheptane (250 mg). The mixture was stirred at 130° C. for 1 hr. Another bromocycloheptane (100 uL) was added and the mixture was stirred at room temperature overnight. 0.5 N NaOH aq., EtOAc and THF were added and the extracted organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from MeCN/IPE to give the title compound (144 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1)[NH:9][CH2:10][CH2:11][C:12]2=[O:14]
Reactant: COc1ccc(NCCC(=O)O)c([N+](=O)[O-])c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: COc1cc2c(c([N+](=O)[O-])c1)NCCC2=O
Yield: 43.2 %

Procedure:
Starting from 3-(4-methoxy-2-nitrophenylamino)propionic acid (50.0 g), phosphorus pentoxide (80.0 g) and toluene (350 ml), 2,3-dihydro-6-methoxy-8-nitro-4(1H)-quinolinone (yield 20.0 g) was obtained in a manner similar to Step 1 of Example 1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]2[NH:15][C:16](=[O:24])[C:17]([CH:19]3[CH2:22][C:21](=[O:23])[CH2:20]3)=[CH:18][C:13]2=[N:12][N:11]=1.Cl.Cl[CH2:27][C:28]1[N:32]([CH3:33])[N:31]=[CH:30][N:29]=1>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]2[N:15]=[C:16]([O:24][CH2:27][C:28]3[N:32]([CH3:33])[N:31]=[CH:30][N:29]=3)[C:17]([CH:19]3[CH2:20][C:21](=[O:23])[CH2:22]3)=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: O=C1CC(c2cc3nnc(-c4ccccc4F)n3[nH]c2=O)C1
Reactant: Cn1ncnc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C1CC(=O)C1
Temperature: 80 °C

Procedure:
Sodium hydride (60% dispersion in oil, 62 mg, 1.54 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-7-(3-oxocyclobutyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0.23 g, 0.7 mmol) in anhydrous N,N-dimethylformamide (5 ml), and heated to 80° C. under an atmosphere of nitrogen for 0.5 hours. The solution was allowed to cool before addition of 5-chloromethyl-1-methyl-1H-1,2,4-triazole monohydrochloride (prepared using the conditions described in EP-A-170073) (0.14 g, 0.85 mmol). The reaction was then heated to 80° C., under an atmosphere of nitrogen, for 18 hours. The solution was allowed to cool, concentrated and the residue was purified by chromatography on silica using 0-5% methanol/dichloromethane as eluent to give the required product as a white solid. Data for the title compound: 1H NMR (360 MHz, CDCl3) δ3.29-3.38 (2H, m), 3.45-3.56 (2H, m), 3.73-3.82 (4H, m), 5.52 (2H, s), 7.26-7.31 (1H, m), 7.35-7.39 (1H, m), 7.56-7.60 (1H, m), 7.81-7.85 (1H, m), 7.88 (1H, s), 7.98 (1H, s); MS (ES+) m/e 394 [MH]+.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:11][CH2:12][CH2:13][OH:14]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: OCCCCl
Reactant: Oc1cccc(Cl)c1
Agent: [Na]
Product: OCCCOc1cccc(Cl)c1
Yield: 84 %

Procedure:
To a solution of 37.3 g. (0.2 mol) 3-(3-chlorophenoxy)-1-propanol (obtained by the reaction of 3-chlorophenol sodium salt with 3-chloro-1-propanol in boiling ethanol; b.p.0.4 =112°-116°; yield 84%) and 42 ml. (0.3 mol) triethylamine in 150 ml. chloroform, one adds dropwise, with stirring, exclusion of moisture and cooling to -15°, a solution of 20 ml. (0.26 mol) methanesulphonic acid chloride in 50 ml. chloroform within 2 hrs., stirs for a further 2 hrs. at -10°, leaves to come to room temperature overnight and pours the reaction mixture, with stirring, into a mixture of 300 ml. ice water and 5 ml. 36% hydrochloric acid. After separating off the chloroform phase, one washes it twice with 100 ml. amounts of water and subsequently with aqueous sodium hydrogen carbonate solution to remove acid, dries over anhydrous sodium sulphate and evaporates under reduced pressure. One obtains, in practically quantitative yield (58.7 g.) 3-(3-chlorophenoxy)-propyl 1-methanesulphonate, still containing about 10% chloroform, as a slowly crystallising oil. The crystallisate has, after washing with petroleum ether and drying in a vacuum desiccator, the m.p. 36°-37°.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2].Br[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17])[CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2]
Reactant: C=CCCCBr
Reactant: CCn1c(=O)c2[nH]cnc2n(CC)c1=O
Product: C=CCCCn1cnc2c1c(=O)n(CC)c(=O)n2CC

Procedure:
is prepared analogously to Example 12 from 1,3-diethyl-xanthine and 5-bromopent-1-ene; the yield relative to the starting material used is 84%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:36](=[O:38])[CH3:37])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32](O)([CH3:34])[CH3:33])=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:36]([OH:38])[CH3:37])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32]([CH3:34])=[CH2:33])=[CH:31][C:18]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=C(C)c1ccc2c(c1)C(=CCCN1CCC(c3ccc(Cl)cc3)(C(C)O)CC1)c1cccnc1CO2
Temperature: 0 °C

Procedure:
The product of Example 457 (64 mg, 0.12 mmol) was dissolved in anhydrous methanol (2.5 mL) and the resulting solution cooled to 0° C. Sodium borohydride (37 mg, 1 mmol,) was added portionwise over 5 h. The reaction was quenched with water and concentrated. The crude product residue was purified by reverse phase HPLC (water, acetonitrile, formic acid gradient) to afford the titled compound (note elimination of tertiary benzylic alcohol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:28][CH3:29].[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:28][CH3:29])[C:16]2=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21

Procedure:
The mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.50 g), sodium hydride (380 mg) and iodoethane (1.60 mL) in DMF (40 mL) was stirred at 20° C. under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) as a colorless solid.
Reaction SMILES: C([N:4]1[C:17]2[C:16]([C:18](=[O:20])[NH2:19])=[CH:15][C:14]([CH2:21][CH3:22])=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([CH2:23][CH3:24])[CH:9]=2)(=O)C.Cl>CO.CC(C)=O>[CH2:21]([C:14]1[CH:15]=[C:16]([C:18](=[O:20])[NH2:19])[C:17]2[NH:4][C:5]3[C:10]([O:11][C:12]=2[CH:13]=1)=[CH:9][C:8]([CH2:23][CH3:24])=[CH:7][CH:6]=3)[CH3:22]
Reactant: CCc1ccc2c(c1)Oc1cc(CC)cc(C(N)=O)c1N2C(C)=O
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: CCc1ccc2c(c1)Oc1cc(CC)cc(C(N)=O)c1N2
Temperature: 0 °C

Procedure:
A solution containing 1.4 g of the just-mentioned phenoxazine compound in 10 ml of methanol and 8 ml of acetone was treated with 10 ml of concentrated hydrochloric acid and heated to reflux for 30 minutes. The mixture was cooled to 0° C. and the solids filtered. The solid was slurried in 10 percent sodium carbonate. To this was then added 50 ml of 1:1 acetone:ethylacetate. The mixture was filtered and the layers split. The organic phase was dried over sodium sulfate and the solvent removed to give crude 3,7-diethylcarbamoyl(10H)phenoxazine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:25])=[C:4]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:5](=[O:15])[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH3:37])=[O:35]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:25][C:34]([O:36][CH3:37])=[O:35])=[C:4]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:5](=[O:15])[O:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: Cc1cc(C)c(-c2c(O)c(Cl)c(-c3ccc(Cl)cc3)oc2=O)c(C)c1
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Oc1c(Cl)c(-c2ccc(Cl)cc2)oc(=O)c1-c1c(C)cc(C)cc1C
Temperature: 20 °C
Reaction time: 20 h
Yield: 92.3 %

Procedure:
3.8 g (10 mmol) of 5-chloro-6-(4-chlorophenyl)-4-hydroxy-3-(2,4,6-trimethylphenyl)-2-pyrone (Example I-a-1) are initially charged in 25 ml of ethyl acetate. At 20° C., 1.0 g (10 mmol) of triethylamine are added and a solution of 0.95 g (10 mmol) of methyl chloroformate in 10 ml of ethyl acetate is added dropwise at 0° C. The mixture is subsequently stirred at 20° C. for 20 h. Precipitated triethylamine hydrochloride is filtered off with suction and washed with ethyl acetate. The combined mother liquors are washed twice with 50 ml of half-concentrated sodium chloride solution each time, dried over magnesium sulphate and concentrated under reduced pressure. 4.0 g (92.4% of theory) of crude 5-chloro-6-(4-chlorophenyl)-4-methoxycarbonyloxy-(2,4,6-trimethylphenyl)-2-pyrone are obtained. Recrystallization from 50 ml of cyclohexane affords 3.1 g (72% of theory) of pure product which melts at 136-138° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][S:11]([C:14]3[CH:19]=[C:18](Cl)[CH:17]=[CH:16][C:15]=3[C:21]([F:24])([F:23])[F:22])(=[O:13])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=[C:28]([NH2:41])[N:27]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:41][C:28]1[N:27]=[C:26]([CH3:25])[C:31]([C:18]2[CH:17]=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[C:14]([S:11]([NH:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)(=[O:13])=[O:12])[CH:19]=2)=[CH:30][N:29]=1
Reactant: O=S(=O)(Nc1ccc2c(c1)OCO2)c1cc(Cl)ccc1C(F)(F)F
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Cc1nc(N)ncc1-c1ccc(C(F)(F)F)c(S(=O)(=O)Nc2ccc3c(c2)OCO3)c1

Procedure:
N-Benzo[1,3]dioxol-5-yl-5-chloro-2-trifluoromethyl-benzenesulfonamide (0.088 g, 0.23 mmol), 4-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Intermediate G, prepared according to WO 2007/084786, p. 92) (0.082 g, 0.34 mmol) and PdCl2(dppf).DCM (0.0185 g, 0.023 mmol) are placed in a microwave vial containing degassed DME (2 ml) and 2M Na2CO3 (0.23 ml). The resulting mixture is heated using microwave radiation at 120° C. for 60 minutes. After evaporation of the solvent, the reaction mixture is purified by flash chromatography on silica eluting with cyclohexane/EtOAc (1:2) to afford the title compound.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3[C:21](=[O:22])[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.ClN1C(=O)CCC1=O.C(OC(=O)N[C@H](C1NC(C2C=CC=CC=2F)=CN=1)[C@H](C1C=CC=CC=1)C)(C)(C)C.C(OC(N[C@H](C1C=CC(OCC(=O)N(C)C)=CC=1)C(O)=O)=O)(C)(C)C.[NH2:91][C@H:92]([C:118]1[CH:123]=[CH:122][C:121]([O:124][CH2:125][C@H:126]([OH:129])[CH2:127][OH:128])=[CH:120][CH:119]=1)[C:93]([NH:95][C@H:96]([C:105]1[NH:106][C:107]([C:110]2[CH:115]=[CH:114][C:113]([I:116])=[CH:112][C:111]=2[F:117])=[CH:108][N:109]=1)[C@H:97]([C:99]1[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=1)[CH3:98])=[O:94]>>[OH:129][C@H:126]([CH2:127][OH:128])[CH2:125][O:124][C:121]1[CH:122]=[CH:123][C:118]([C@H:92]2[NH:91][C:21](=[O:22])[N:95]([C@H:96]([C:105]3[NH:106][C:107]([C:110]4[CH:115]=[CH:114][C:113]([I:116])=[CH:112][C:111]=4[F:117])=[CH:108][N:109]=3)[C@H:97]([C:99]3[CH:100]=[CH:101][CH:102]=[CH:103][CH:104]=3)[CH3:98])[C:93]2=[O:94])=[CH:119][CH:120]=1
Reactant: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@H](O)CO)cc1)c1ncc(-c2ccc(I)cc2F)[nH]1
Agent: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccccc2F)[nH]1
Agent: O=C1CCC(=O)N1Cl
Product: C[C@@H](c1ccccc1)[C@@H](c1ncc(-c2ccc(I)cc2F)[nH]1)N1C(=O)N[C@H](c2ccc(OC[C@H](O)CO)cc2)C1=O

Procedure:
Prepared by the same method as described in example 1 except that (i) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step F was omitted; (ii) (R)-tert-butoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid (prepared as described in example 33) was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 36-G, and (iii) cyclization of (R)-2-amino-2-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-N-{(1S,2S)-1-[5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-acetamide in step 36-H was performed as described in example 34. HR-MS: calcd for C30H28FlN4O5 [M+H+] 671.1161. Found 671.1156.