Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@@H:8]([CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36])[S:32][CH:33]=1)[C:9](N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)=[O:10])(C)(C)C.[OH2:44].OO.O.[OH-].[Li+]>C1COCC1>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35]([NH:34][C:31]1[S:32][CH:33]=[C:29]([CH2:28][C@H:8]([CH2:7][C:6]([OH:5])=[O:43])[C:9]([OH:10])=[O:44])[N:30]=1)=[O:36]
Reactant: O
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1)C(=O)O
Reaction time: 0.08 h

Procedure:
The protected amido acid, 4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}methyl}butanoic acid tert-butyl ester: A solution of the product of section (f) of this example (57.5 mg, 0.10 mmol) in THF (1.5 mL) and H2O (0.5 mL) was cooled to 0°. A 30% aqueous solution of H2O2 (91.3 μL, 0.80 mmol of H2O2) and lithium hydroxide monohydrate (8.5 mg, 0.20 mmol) were added serially to the cooled solution. The mixture was stirred at 0° for 5 min and then at room temperature for 2.5 h. Excess H2O2 was quenched by the addition of a 1.5M aqueous solution of Na2SO3 (as judged by a KI stick indicator). The resulting mixture was diluted with H2O and washed with CH2Cl2 (3×). The aqueous layer was rendered acidic with 1N aqueous HCl and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to dryness to yield the desired monoprotected dicarboxylic acid, i.e. the 4-tert-butyl ester of 2(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}-methyl}butanedioic acid. The monoprotected dicarboxylic acid was used for the following coupling step without purification.
Reaction SMILES: [OH-].[NH4+:2].[O:3]1[CH2:8][CH2:7][N:6]([CH:9]([CH3:15])[C:10](OCC)=[O:11])[CH2:5][CH2:4]1>CO>[O:3]1[CH2:8][CH2:7][N:6]([CH:9]([CH3:15])[C:10]([NH2:2])=[O:11])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C(C)N1CCOCC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C(N)=O)N1CCOCC1

Procedure:
3.5 g (40 mmole) of morpholine were added to a mixture of 3.6 g (20 mmole) of ethyl 2-bromopropionate and 50 ml of dry benzene, and then the mixture was heated under reflux for 7 hours. At the end of this time, the reaction mixture was filtered, the filtrate was concentrated by evaporation under reduced pressure, and the residue was dissolved in chloroform. The resulting solution was washed with water, dried, and concentrated by evaporation under reduced pressure, to give 3.19 g of ethyl 2-morpholinopropionate. 10 ml of methanol and 10 ml of a concentrated aqueous solution of ammonium hydroxide were then added to 3.1 g (16.6 mmole) of this ethyl 2-morpholinopropionate, and the resulting mixture was heated under reflux for 28 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was dried by heating it under reduced pressure, to give 2-morpholinopropionamide as a precipitate.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
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: Cc1ccccc1
Solvent: CCO
Product: NC(=O)c1ccc(-c2ccc(F)cc2)nc1
Temperature: 100 °C
Yield: 90.5 %

Procedure:
A mixture of 6-chloronicotinamide (5.00 g, 31.95 mmol), 4-fluorobenzene boronic acid (4.92 g, 35.14 mmol), and Pd(PPh3)4(1.10 g, 0.96 mmol) in a mixture of toluene (80 ml), ethanol (12 ml) and 2M sodium carbonate (36.74 ml, 73.48 mmol) was degassed (N2) and heated at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and then filtered. The collected solid was washed with water and dried. The dried solid was taken up in methanol (100 ml) and heated to reflux for 20 minutes. The mixture was then cooled to room temperature, filtered and the solid dried to give the title compound (6.25 g, 90%) as a pale grey solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[C:21]([F:22])=[C:20]([CH:23]2[O:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][O:24]2)[CH:19]=[CH:18][C:17]=1[OH:38]>>[F:22][C:21]1[C:16]([F:15])=[C:17]([O:38][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:18]=[CH:19][C:20]=1[CH:23]1[O:24][CH2:25][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:27][O:28]1
Reactant: CCCCCCCCCC1COC(c2ccc(O)c(F)c2F)OC1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCC1COC(c2ccc(OCCCCCCC)c(F)c2F)OC1

Procedure:
Quantities: 1-bromoheptane (0.31 g, 1.46 mmol), potassium carbonate (0.4 g, 3 mmol) and compound from Example 126 (0.Sg, 1.46 mmol). The experimental procedure was as described in Example 38.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][OH:7])(=[O:4])=[O:3].C(N(CC)CC)C.[S:15](Cl)([CH3:18])(=[O:17])=[O:16]>C(Cl)Cl>[CH3:18][S:15]([O:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 7606.8 %

Procedure:
To a round-bottom flask containing 2-(methylsulfonyl)ethanol (400 mg, 3.22 mmol) at 0° C. was added DCM (10 ml) and triethylamine (4.91 μl, 0.035 mmol), followed by dropwise addition of mesyl chloride (2.96 mg, 0.026 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 2 hr. The reaction mixture was diluted with DCM and washed with sat NaHCO3 and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified via ISCO (0-60% EtOAc/Hexane) to yield 2-(methylsulfonyl)ethyl methanesulfonate (400 mg, 61%). LCMS (m/z): 203.0 (MH+), retention time=0.37 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.Cl[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[O:19].CN1CCOCC1>O1CCCC1>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:18](=[O:19])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: COCCOC(=O)Cl
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCOC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
107 mg of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylamine (0.48 mmol) were dissolved in tetrahydrofuran. 96 mg of 2-methoxyethyl chloroformate (0.68 mmol) and 79 mg of N-methylmorpholine (0.78 mmol) were added at room temperature. The mixture was left to stir at room temperature for 1 day, precipitated solid was filtered off and the solvent was removed under reduced pressure. This gave a yellowish oil which was used without further purification in the next reaction.
Reaction SMILES: C([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.[C:15]([C:23]([OH:25])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:8]([N:6]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:5][C:23]([C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])([CH3:13])([CH3:9])[CH3:7]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)C(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
N'-t-butyl-N-benzoylhydrazine (1 g), benzoyl formic acid (1 g), and methanesulfonyl chloride (0.7 g) were stirred in toluene (35 ml) and saturated sodium bicarbonate (15 ml) at approximately 5° C. Triethylamine was added slowly, dropwise to the reaction mixture, and slowly warmed to room temperature. After stirring for 1 hour, the reaction mixture was diluted with toluene (20 ml) and the organic layer was washed several times with water. The organic layers were dried over magnesium sulfate, filtered and the toluene rotavapped off to afford a white gum. The crude product was chromatographed on silica gel (G:230-400 mesh) using a methylene chloride ether solvent system as eluent to afford a 65% yield of a white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f25) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4Br)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Br
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1-c1ccccn1
Yield: 46.6 %

Procedure:
A mixture of 1.94 g of N-[4-(5H-pyrrolo-[2, 1-c][1,4]benzodiazepin-10(11H) -ylcarbonyl)phenyl]-2-bromobenzamide, 2.95 g of 2-pyridyl tri-n-butyl tin and 400 mg of tetrakis (triphenylphosphine)palladium(O) is refluxed for 24 hours in degassed toluene for 24 hours. The reaction mixture is concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 70% ethyl acetate:hexane to give 900 mg of the desired product as a pale yellow solid:M+ 1=485.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[C:6](Cl)(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[C:6]([O:3][CH2:2][C:1]([OH:5])=[O:4])(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CO
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(O)COC(=O)C=Cc1ccccc1
Yield: 25.2 %

Procedure:
To a solution of glycolic acid (15.2 g.) in pyridine (100ml.) was added cinnamoyl chloride (33.4 g.) with stirring under cooling. The reaction mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure at 50° to 60° C. The residue was adjusted to pH 1 with concentrated hydrocloric acid and extracted with ether. The extract was washed with water and a sodium chloride aqueous solution, in turn and concentrated under reduced pressure to give colorless crystals (45 g.). These crystals were dissolved in a sodium bicarbonate aqueous solution and adjusted to pH 3 to 3.5 with aqueous hydrochloric acid and extracted with ether. The extract was treated with a conventional manner to give crude product (16.5 g.). The product was recrystallized from benzene to give a product of 2-cinnamoyloxyacetic acid (10.4 g.), m.p. 116° to 121° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])=[C:7]([CH3:18])[C:6]=2[CH:19]=1.[BH4-].[Na+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[OH:11])=[C:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(Br)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
(5-Bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methanone (7.5 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (100 mL) and methanol (15 mL), and sodium borohydride (90%, 1.9 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (10 mL) and 1N hydrochloric acid (50 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (7.4 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:13][CH:14]=1.I[CH2:27][C:28]([NH2:30])=[O:29]>O>[F:8][C:9]1[CH:10]=[CH:11][C:12](=[N:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:13]([CH2:27][C:28]([NH2:30])=[O:29])[CH:14]=1
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(F)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.43 g, 0.018 mol) was mixed with N,N-Dimethylformamide (67.4 mL) and N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide 1 (4.0 g, 0.015 mol) was added. The reaction was stirred at room temperature for 10 minutes. Iodoacetamide (3.3 g, 0.018 mol) was added and the mixture was stirred at room temperature for 24 hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (4×75 mL). Organic layers were combined then dried with magnesium sulfate and the solvent removed. The crude product was chromatographed on silica using 5% methanol in dichloromethane to give 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide 2 Rf 0.26, 5% methanol.dichloromethane; MS m/z 324 (M+H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]([CH2:17][CH3:18])[C:7]2=[O:19].[CH3:20][C@@H:21]1[C:25]2[NH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:24]=2[C:23](=[O:38])[NH:22]1>>[C:13]([NH:12][C:9]1[N:8]([CH2:17][CH3:18])[C:7](=[O:19])[C:6]2[C:11](=[C:2]([C:27]3[NH:26][C:25]4[C@@H:21]([CH3:20])[NH:22][C:23](=[O:38])[C:24]=4[CH:28]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCn1c(NC(C)(C)C)nc2c(Br)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: CCn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](C)NC4=O)cccc2c1=O
Yield: 14.5 %

Procedure:
This compound (8.8 mg, 11% yield) as an off-white solid was prepared according to the procedure given in 405, using 8-bromo-3-ethylquinazoline-2,4(1H,3H)-dione (52 mg, 0.160 mmol, 481d) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (84 mg, 0.321 mmol, 705) as the starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 12.41 (1H, br. s.) 8.02 (1H, d, J=8.41 Hz) 8.06 (1H, d, J=8.61 Hz) 7.23 (1H, br. s.) 6.84 (1H, s) 5.61 (1H, br. s.) 4.66 (1H, br. s.) 4.16 (1H, d, J=7.04 Hz) 3.50 (2H, s) 1.67 (9H, s) 1.54 (3H, d, J=6.46 Hz) 1.40 (3H, t, J=6.85 Hz). m/z (ESI, +ve) 380.0 (M+H)+.
Reaction SMILES: CN(C)S([N:6]1[C:10]([CH2:11][NH:12][CH2:13][CH3:14])=[CH:9][N:8]=[CH:7]1)(=O)=O.[Cl:16][C:17]1[CH:22]=[C:21](F)[CH:20]=[CH:19][N:18]=1.Cl.N>C(O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N:12]([CH2:13][CH3:14])[CH2:11][C:10]2[NH:6][CH:7]=[N:8][CH:9]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CCNCc1cncn1S(=O)(=O)N(C)C
Reactant: Fc1ccnc(Cl)c1
Agent: Cl
Agent: N
Solvent: CCO
Product: CCN(Cc1cnc[nH]1)c1ccnc(Cl)c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 5-ethylaminomethyl-imidazole-1-sulfonic acid dimethylamide (0.2 g, 0.86 mmol) and 2-chloro-4-fluoropyridine (0.12 g; 0.91 mmol) was heated in a sealed vessel in a microwave oven for 30 min at 140° C. Then after cooling a solution of hydrochloric acid in ethanol (5 N, 1 ml) was added and the mixture was stirred at 90° C. overnight. For workup aqueous ammonia solution was added to basic pH and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (SiO2; ethyl acetate/methanol 8:2) to yield a white solid, (0.13 g, 64%); MS (ISP): 239.0 ((M+H)+.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[Br:15])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1Br
Temperature: 0 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
To a solution of 20.80 g (108.7 mmol) of N-acetyl-4-tert-butyl aniline and 0.33 g (2 mmol) of ferric chloride in 70 ml of acetic acid is added dropwise 17.9 g (112 mmol) of bromine while the temperature is kept between 30° C. and 40° C. Then the reaction mixture is stirred 4 hours and poured into 500 ml of ice water. The precipitate is filtered off, washed with water and recrystallized from 70% ethanol. Thus is obtained 24.33 g (83%) of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-])=O)[CH2:15][CH2:14][CH:13]([O:20][C:21](=[O:23])[CH3:22])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(=O)C>C(O)C.[Zn]>[NH2:17][CH:16]1[CH2:15][CH2:14][CH:13]([O:20][C:21](=[O:23])[CH3:22])[CH2:12][CH:11]1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2[N+](=O)[O-])cc1OC
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC

Procedure:
2.1 g of (±)-acetic acid (1SR,3RS,4RS)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexyl ester (compound C5) are dissolved in 50 ml of ethanol and treated with 2 g of zinc powder. 5 ml of acetic acid are added dropwise at boiling heat. After 1 h the reaction mixture is filtered and the filtrate is concentrated. The residue is used without further purification for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (84 mg) was prepared from (3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (100 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure A.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][CH:11]1[CH2:14][CH:13]([C:15]2[C:20](Cl)=[N:19][N:18]3[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])=[N:23][N:24]=[C:17]3[CH:16]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.O>[CH2:3]([O:10][CH:11]1[CH2:14][CH:13]([C:15]2[C:20](=[O:1])[NH:19][N:18]3[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])=[N:23][N:24]=[C:17]3[CH:16]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1ccccc1-c1nnc2cc(C3CC(OCc4ccccc4)C3)c(Cl)nn12
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(OCc2ccccc2)C1

Procedure:
4N Sodium hydroxide (3 ml, 12 mmol) was added to a solution of 7-(3-benzyloxycyclobutyl)-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (0.98 g, 2.4 mmol) in 1,4-dioxane (30 ml) and water (8 ml), heated to reflux for 18 hours. The solvent was evaporated and the residue dissolved in diethyl ether (50 ml) and water (50 ml) and separated. The aqueous layer was acidified to pH 2 with 2N hydrochloric acid and the resultant solid collected by filtration, washed with water (50 ml), followed by diethyl ether (50 ml) and dried under vacuum at 100° C. for 18 hours. Data for the title compound: 1H NMR (400 MHz, CDCl3), cis and trans isomers present in 4:1 ratio, δ 1.95-2.03 (1.6H, m), 2.31-2.38 (0.4H, m), 2.50-2.56 (0.4H, m), 2.68-2.76 (1.6, m), 3.05-3.13 (1H, m), 3.65-3.73 (0.2H, m), 4.06-4.15 (0.8H, m), 4.46 (2H, s), 6.80-6.87 (2H, m), 7.22-7.37 (6H, m), 7.55-7.61 (1H, m), 7.63 (0.8H, m), 7.68 (0.2H, s); MS (ES+) m/e 391 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:15]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ncc(Cl)cn1
Product: COC(=O)C(=O)Nc1ncc(Cl)cn1

Procedure:
The method described in Referential Example 242 was performed by use of 2-amino-5-chloropyrimidine and methyl chlorooxoacetate, whereby the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[C:17](OCC)(OCC)(OCC)[CH3:18]>C(OC(=O)C)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=[C:17]2[CH3:18])=[CH:10][CH:11]=1)#[N:16]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#Cc1ccc(Nc2ccncc2N)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cnccc2n1-c1ccc(C#N)cc1

Procedure:
A mixture of 3-amino-4-[N-(4-cyanophenyl)amino]pyridine (see part (b)) (9.31 g, 44.3 mmol), triethyl orthoacetate (40 ml) and acetic anhydride (30 ml) was heated under reflux for 2 hours under nitrogen, cooled, then concentrated under reduced pressure The brown residue was dissolved in 1M hydrochloric acid and washed with ethyl acetate (200 ml). The aqueous layer was rendered basic with saturated aqueous ammonia and extracted with dichloromethane (3×200 ml). The combined extracts were washed with water, dried (MgSO4) and concentrated to give the title compound (6.5 g), as a brown solid.