Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][C:7]=1[C:21]([F:24])([F:23])[F:22]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:19])([CH3:20])[O:13]2)=[CH:8][C:7]=1[C:21]([F:22])([F:23])[F:24]
Reactant: COC(=O)C=Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenyl]-acrylic acid methyl ester (preparation 1) in ethyl acetate (200 mL) containing Pd/C (500 mg) was hydrogenated overnight at rt. The catalyst was filtered off through Celite, and the filtrate was concentrated under reduced pressure to afford the title compound as a colorless oil, which was used without further purification. 1H NMR (300 MHz, DMSO) δ 7.92-7.83 (m, 2H), 7.54 (d, 1H), 3.62 (s, 3H), 3.06 (t, 2H), 2.70-2.61 (m, 2H), 1.31 (s, 12H).
Reaction SMILES: Br[C:2]([CH3:20])([CH2:18][Br:19])[C:3](=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[Br:19][CH:18]=[C:2]([CH3:20])[C:3](=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)(CBr)C(=Nc1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(=CBr)C(=Nc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of 1.83 g (4.59 mmol) of phenyl 2,3-dibromo-2-methyl-N-phenylpropanimidate in 10 ml of THF was added 770 mg (5.05 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene and stirred at room temperature for 2 hours. To the mixture was added 1N HCl and extracted with tert-butyl methyl ether. The combined organic layer was washed sequentially with a saturated aqueous NaHCO3 solution and a saturated NaCl solution, dried over anhydrous MgSO4, and then concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 1.26 g of phenyl 3-bromo-2-methyl-N-phenyl-2-propenimidate.
Reaction SMILES: C[C:2]1[C:6]2[N:7]=[C:8](SC)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[S:4][C:3]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[C:39]([NH:41]C(=O)C)[N:38]=[C:37]([NH:45]C(=O)C)[CH:36]=1)CCC>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[S:4][C:3]([CH2:19][N:20]4[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]4)=[CH:2][C:6]=3[N:7]=[C:8]([C:35]3[CH:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:45])[CH:36]=3)[N:9]=2)[CH2:16][CH2:15]1
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)c(C)c2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(NC(C)=O)nc(NC(C)=O)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cc(N)nc(N)c4)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
7-Methyl-2-(methylthio)-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (0.29 mM) was added to 4-tributylstannyl-2,6-diacetylaminopyridine dissolved in 10 mL 1,2-DME followed by the addition of Cu(I)Br-dimethylsulfide and stirred at room temperature for ten minutes. Finally, Pd(PPH3)4 was added and the reaction mixture was heated to reflux under N2 for 2 hours. Complete product formation was confirmed by LCMS. The reaction was diluted with EtOAc, extracted 1× with water and 1× with 1 M HCl. The combined aqueous layers were basified with 10% w/w KOH and extracted the product with EtOAc, dried over MgSO4, and concentrated in vacuo. This crude product was dissolved in 2 N HCl and heated to reflux for 12 hours to remove the acetyl groups and after concentrating in vacuo and HPLC purification gave 279. MS (Q1) 506 (M+)
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1F>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([S:26](=[O:28])(=[O:27])[NH2:29])[CH:22]=[CH:23][C:24]=1[O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(COc2ccc(S(N)(=O)=O)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.478 g) in anhydrous N,N-dimethylformamide (5 mL) was added sodium hydride (0.280 g). The mixture was stirred at room temperature for 30 minutes, followed by addition of 3-chloro-4-fluorobenzenesulfonamide (0.419 g). The mixture was stirred at 40° C. overnight. The reaction was quenched with water (10 mL), and the mixture was adjusted to ˜pH 7 and extracted with ethyl acetate. The crude product was purified on a silica gel column eluting with 60% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:28])[C:18]([C:22]3[N:23]=[C:24]([NH2:27])[S:25][CH:26]=3)=[N:19][O:20][CH3:21])[C:14](=[O:29])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C([O-])(=O)C.[Na+:34].C(O)C>CO>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:28])[C:18]([C:22]3[N:23]=[C:24]([NH2:27])[S:25][CH:26]=3)=[N:19][O:20][CH3:21])[C:14](=[O:29])[N:9]2[C:10]=1[C:11]([O-:13])=[O:12])=[N+:2]=[N-:3].[Na+:34]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CN=[N+]=[N-])CS[C@H]12)c1csc(N)n1

Procedure:
A mixture of the product of Example 3 and 5 ml of a molar solution of sodium acetate in methanol was stirred and was vacuum filtered to recover a brown solid. The fltrate was added to 1 ml of ethanol and was vacuum filtered to remove a second insoluble. The solid phases were added to 5 ml of ethanol and the mixture was vacuum filtered. The filtrate was evaporated to dryness and the residue was taken up in a little ethanol to obtain a second crop which was added to 2 ml of methanol. 5 ml of ethanol were added thereto and the mixture was vacuum filtered. The filtrate was evaporated to dryness and the residue was triturated with a little absolute ethanol to obtain 0.4 g of the syn isomer of sodium 3-azidomethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: CN(C)C=O.OC1C=CC(S([N:16]2[CH2:22][CH2:21][CH:20]3[CH2:23][CH:17]2[C:18](=[O:24])[O:19]3)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[CH:17]12[CH2:23][CH:20]([O:19][C:18]1=[O:24])[CH2:21][CH2:22][NH:16]2
Reactant: O=C1OC2CCN(S(=O)(=O)c3ccc(O)cc3)C1C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1OC2CCNC1C2
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a dimethylformamide (0.6 mL) solution of 2-(4-Hydroxy-benzenesulfonyl)-6-oxa-2-aza-bicyclo[3.2.1]octan-7-one (101.1 mg) and cesium carbonate (331.3 mg) is added the aryl halide (2.5 equiv). The reaction is heated to 50° C. with shaking for 12-24 hours. The sample is cooled, diluted with water and ethyl acetate, and extracted two times with ethyl acetate. The organic layers are combined, dried over sodium sulfate and concentrated. The product is precipitated from diethyl ether to give the Aryloxy-benzenesulfonyl)-6-oxa-2-aza-bicyclo[3.2.1]octan-7-one.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]1(N)[CH2:16]C[CH2:14]1>>[CH2:8]([O:7][C:5]([C:4]1[N:10]=[CH:11][N:2]([CH:12]2[CH2:16][CH2:13][CH2:14]2)[CH:3]=1)=[O:6])[CH3:9]
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Reactant: NC1CCC1
Product: CCOC(=O)c1cn(C2CCC2)cn1

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (WO 2007042545) (45 g, 0.27 mol) was added to cyclobutylamine (50 g, 0.70 mol) and heated to reflux for 2 hours. The solution was then cooled and concentrated. The residue was purified by column chromatography over silica gel (3:1 EtOAc:Heptane). The oily residue was triturated with TBME:heptane (1:1) and the resulting solid was collected and dried, giving 1-cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester (35 g, 67%, second crop not harvested). 1-Cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester (35 g, 0.21 mol) was dissolved in 6 N HCl (300 mL) and refluxed for 1 day. The solution was concentrated to dryness in vacuo. The solid was azeotroped with toluene, triturated with toluene and then dried under vacuum, giving the title compound 88% yield, 37.2 g, m/z 167 [M+H]+.
Reaction SMILES: [CH:1]12[CH:7]([C:8]([OH:10])=O)[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13]1>>[C:19]1([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:8]([CH:7]3[CH:4]4[CH2:3][CH2:2][CH:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)C1C2CCC1CC2
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1C2CCC1CC2

Procedure:
7-Norbornanecarboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-7-norbornanecarboxamide.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:18]=[CH:17][C:11](OCC(O)=O)=[CH:10][CH:9]=1>CN(C)C=O.ClCCl>[CH3:7][C:8]1[CH:18]=[CH:17][C:11]([O:3][CH2:2][C:1]([Cl:6])=[O:5])=[CH:10][CH:9]=1
Reactant: Cc1ccc(OCC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(=O)Cl)cc1
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (8.83 ml) and N,N-dimethylformamide (3 drops) were added at room temperature to a solution of 4-methylphenoxyacetic acid (6.73 g) in dichloromethane (70 ml), and the reaction mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, then the resulting acidic gas was removed as the toluene azeotrope, and the product was dried under reduced pressure to give 4-methylphenoxyacetyl chloride. A 1.61N solution of n-butyl lithium in hexane (25.2 ml) was added dropwise at −78° C. to a solution of (S)-4-benzyl-2-oxazolidinone (7.08 g) in tetrahydrofuran (70-ml), and after the completion of the dropwise addition, the reaction mixture was stirred at −78° C. for 30 minutes. To this resulting solution was added at −78° C. a solution of 4-methylphenoxyacetyl chloride obtained above in tetrahydrofuran (70 ml) followed by stirring at 0° C. for 1 hour. The resulting reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed successively with a 1N aqueous solution of hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate =3/1˜1/1) to afford the target compound (9.00 g) as a colorless oil.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[OH-].[K+].[CH2:10](I)[CH3:11]>CCO>[C:1]([O:7][CH2:10][CH3:11])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: CCI
Reactant: C=CCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCC(=O)OCC
Temperature: 25 °C
Yield: 65 %

Procedure:
4-Pentenoic acid (12.0 g, 0.120 mol) was dissolved in 200 ml of dry EtOH and KOH pellets (7.1 g, 0.126 mol) were added. The mixture was stirred at room temperature until homogeneous. Ethyl iodide (24.3 g, 0.156 mol) was added and the solution was refluxed for 48 hrs. The cooled solution was poured onto H2O (600 ml) and extracted with pentane (200 ml). The organic extract was washed with H2O (2×500 ml) and dried (MgSO4). Solvent removal afforded 10.0 g (65%) of ethyl 4-pentenoate. From the ethyl 4-pentenoate the corresponding epoxy ester, ethyl 4,5-epoxy-pentanoate, is prepared as follows: ethyl 4-pentenoate (9.90 g, 77.3 mmol), and m-chloroperbenzoic acid (18.5 g, 92.8 mmol, 85% assay) were dissolved in 300 ml of CH2Cl2 and stirred for 18 hr in an oil bath at 50° C. The mixture was then filtered, washed with 10% NaHSO3, saturated aqueous NaHCO3 (2X), and H2O (2X) before drying (MgSO4). Concentration under slight vacuum at room temperature followed by distillation (32° C., 0.07 mm) afforded 6.1 g (55%) of the ethyl 4,5-epoxy-pentanoate.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]2[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[C:19](=[O:26])[C:18]([C:27](O)=[O:28])=[CH:17]2)=[CH:13][CH:12]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[CH3:59][C@H:60]1[O:65][C@@H:64]([CH3:66])[CH2:63][NH:62][CH2:61]1.Cl>CN(C=O)C>[CH3:66][C@H:64]1[O:65][C@@H:60]([CH3:59])[CH2:61][N:62]([C:27]([C:18]2[C:19](=[O:26])[C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][N:16]([CH2:15][C:14]3[CH:30]=[CH:31][C:11]([F:10])=[CH:12][CH:13]=3)[CH:17]=2)=[O:28])[CH2:63]1
Reactant: COC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)O)c1=O
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccc(F)cc2)cc(C(=O)N2C[C@@H](C)O[C@@H](C)C2)c1=O
Reaction time: 0.25 h

Procedure:
DIPEA (228 μl) was added to a solution of the compound obtained in Step 2 of Example 26 (200 mg) and COMU (365 mg) in DMF (2.5 ml) at room temperature, and the mixture was stirred for 15 minutes. cis-2,6-Dimethylmorpholine (162 μl) was added and the mixture was stirred for four hours. A 1 N hydrochloric acid solution was added at room temperature, and the organic layer was extracted with ethyl acetate, washed with brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->30:1 (v/v)] to give 30 mg of the title compound as an oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]([F:14])[F:13])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9])#[N:2].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:12]([F:14])[F:13])=[C:7]([CH:11]=1)[C:8]([N:10]=[C:16]=[O:17])=[O:9])#[N:2]
Reactant: N#Cc1cnc(C(F)F)c(C(N)=O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: N#Cc1cnc(C(F)F)c(C(=O)N=C=O)c1
Yield: 88.4 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 5-cyano-2-(difluoromethyl)nicotinamide (1.0 g), oxalyl chloride (3.2 g, 25.3 mmol) and DCM (20 mL) to afford 1.0 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:12]Br)=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1COCC1.C(=O)(O)[O-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:12][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:20]
Reactant: C1COCCN1
Reactant: O=c1c(-c2ccccc2)c(CBr)oc2ccc(Br)cc12
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2)c(CN2CCOCC2)oc2ccc(Br)cc12
Yield: 131.3 %

Procedure:
To a solution of Intermediate 3 (0.30 g, 0.761 mmoles) in THF (2 ml), was added morpholine (0.066 g, 0.761 mmoles) at RT and refluxed for 12 h. The reaction mixture was cooled, diluted with aqueous bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.40 g, 79% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.12 (d, J=2.2 Hz, 1H), 7.98 (dd, J=8.8, 2.3 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.45-7.39 (m, 3H), 7.29 (d, J=7.0 Hz, 2H), 3.50 (t, J=4.2 Hz, 4H), 3.40 (s, 2H), 2.32 (br S, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[O:13][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cc(C=O)cc(O)c1OC
Product: CCOC(=O)CCCOc1cc(C=O)cc(OC)c1OC

Procedure:
Employing the method of Preparation 3, 3.30 g (18.41 mmol) of 3,4-dimethoxy-5-hydroxybenzaldehyde is alkylated with ethyl 4-bromobutyrate. 4-(2,3-Dimethoxy-5-formylphenoxy)butanoic acid, ethyl ester is obtained as a yellow-orange oil after drying under high vacuum at 60° C. (5.45 g, 100%): IR (neat) 1735, 1690 cm-1 ; 1 H-NMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 297 (M+ +H). Analysis calculated. for C15H20O6 : C, 60.80; H, 6.80; O, 32.40. Found: C, 60.51; H, 6.86; O, 32.63.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[N:23][N:24]([C:26]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=2[CH:28]=O)[CH:25]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:28]1[C:27]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:26]=1[N:24]1[CH:25]=[C:21]([Cl:20])[CH:22]=[N:23]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: COc1ccc(-n2cc(Cl)cn2)c(C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-n2cc(Cl)cn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Yield: 27.1 %

Procedure:
A solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (180 mg, 0.70 mmol) and 2-(4-chloro-pyrazol-1-yl)-5-methoxy-benzaldehyde (270 mg, 1.14 mmol) in acetic acid (5 mL) is warmed to 100° C. for 16 hours, then cooled to room temperature and neutralized with NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) follows by reverse phase HPLC (20-100% CH3CN/H2O, each solvent containing 0.1% TFA) affords the title compound (90 mg, 27%). LCMS (ESMS): m/z 474.20 (M++1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)C(Cl)=O)([O-])=O.[CH2:13]([O:20][C:21](=[O:25])[C@@H:22]([CH3:24])N)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Sn](Cl)(Cl)(Cl)Cl>>[CH2:13]([O:20][C:21](=[O:25])[C@@H:22]([C:11]1[CH:10]=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=1)[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: C[C@@H](C(=O)OCc1ccccc1)c1cccc(N)c1

Procedure:
3-Nitrobenzoyl chloride was reacted with D-alanine benzyl ester, then reduced with tin chloride to produce (R)-2-(3-amino-phenyl)-propionic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 11.96 (1H, br s), 9.46 (1H, br s), 8.57 (1H, br d), 8.16 (1H, s), 7.96 (1H, d), 7.54 (1H, d), 7.40-7.35 (1H, m), 4.41 (1H, m), 2.87 (2H, m), 2.63 (1H, m), 1.94-1.32 (30H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.15; H, 8.33; N, 9.04%. C39H59N5O9.2.0 mols H2O requires: C, 60.21; H, 8.16; N, 9.00%.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)=[O:34]>O1CCOCC1>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:33]([O:35][C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)=[O:34])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a suspension of 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine (63 mg, 0.2 mmol) in dioxane (10 ml) was added diisopropylethylamine (33 μl, 0.2 mmol) and p-tolyl chloroformate (0.2 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/30), yielding the pure title compound as yellowish solid (60 mg, 67%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[Cl:9].[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>C(O)(C)C>[Cl:9][C:3]1[N:4]=[N:5][C:6]([Cl:8])=[CH:7][C:2]=1[N:11]([CH2:12][CH2:13][OH:14])[CH3:10]
Reactant: Clc1cc(Br)c(Cl)nn1
Reactant: CNCCO
Solvent: CC(C)O
Product: CN(CCO)c1cc(Cl)nnc1Cl
Yield: 90.1 %

Procedure:
A solution of 4-bromo-3,6-dichloro-pyridazine (1.11 g, 5 mmol), (J.Chem. Soc., Perkin Trans I, 1974, 696), and 2-(methylamino)ethanol (0.75 g, 10 mmol) in isopropanol (10 ml) was heated at reflux for 30 minutes. The solvent was removed by evaporation, the residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH9 with solid potassium carbonate. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give 2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol (1 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH:20]=O)[CH3:2].[NH2:22][C:23]1[C:24]([CH2:32][CH2:33][CH3:34])=[N:25][N:26]([CH3:31])[C:27]=1[C:28]([NH2:30])=[O:29]>[Pd].C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:20]1[NH:30][C:28](=[O:29])[C:27]2[N:26]([CH3:31])[N:25]=[C:24]([CH2:32][CH2:33][CH3:34])[C:23]=2[N:22]=1)[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C=O
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Temperature: 200 °C
Reaction time: 46 h

Procedure:
A solution of xylene (60 mL) containing 1-(4-ethoxy-3-formylphenylsulfonyl)-4-methylpiperazine (4.0 g, 0.013 mol, prepared analogously to the methods described in DE 24 44 720) and 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (Example 37 of EP 0463756) (2.6 g, 0.014 mol) was submitted to 46 hours at 200° C. and 34.5 kPa (5 psi). The reaction was allowed to cool and the catalyst (10% Pd/C, 3.1 g, 50% w/w) was added. The reaction was heated at 200° C. under 34.5 kPa (5 psi) of pressure for a further 12 hours. The catalyst was recovered by filtration and the organic solvent removed in vacuo to give 4.2 g of crude product, which was purified by trituration in methyl ethyl ketone (MEK). This yielded 3.3 g (53%) of the title compound as an off-white solid.