Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:12])[C@H:7]([CH3:11])[C@H:8]([NH2:10])[CH3:9])(C)(C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=O.C(N(CC)CC)C>CCO>[C:35]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:21]=2)[C:26]([OH:27])=[C:17]([C:15]([NH:10][C@H:8]([CH3:9])[C@@H:7]([CH3:11])[C:6]([OH:5])=[O:12])=[O:14])[N:18]=1)#[N:36]
Reactant: C[C@@H](N)[C@@H](C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)[C@@H](C)C(=O)O
Temperature: 140 °C
Yield: 29.7 %

Procedure:
A mixture of (2R,3R)-3-amino-2-methyl-butyric acid tert-butyl ester (20 mg, 0.117 mmol), 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (25 mg, 0.078 mmol), and triethylamine (0.050 mL) in EtOH (2 mL) was heated in a microwave reactor at 140° C. for 6 h. The resulting mixture was concentrated to dryness, and the residue was re-dissolved in CH2Cl2 and passed through a plug of silica gel. After evaporating the solvent, the residue was dissolved in CH2Cl2 (3 mL) and treated with trifluoroacetic acid (2 mL) for 2 h. The mixture was concentrated in vacuo, and the resulting residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH ˜2 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 9.4 mg of the title compound as a pale pink solid. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:32]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:34])[CH3:33]>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:39]5[CH:38]=[CH:37][C:36]([NH:35][C:32](=[O:34])[CH3:33])=[CH:41][CH:40]=5)(=[O:44])=[O:43])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)cc1

Procedure:
8-(4-Amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione was condensed with 4-acetamidobenzenesulfonyl chloride under the conditions previously described to give the stated sulfonamide. Recrystallized from acetonitrile to give the pure product as an off-white solid (68%); 1H NMR (DMSO-d6, 300 MHz) δH13.53 (s, 1H), 10.36 (s, 1H), 10.23 (s, 1H), 7.75 (s, 4H), 7.40–7.05 (m, 8H), 5.19 (s, 2H), 4.02 (s, 2H), 3.91 (d, J=7.0 Hz, 2H), 2.13 (s, 3H), 1.35–1.15 (m, 1H) and 0.55–0.35 (m, 4H); EI-HRMS m/e calculated for C31H29FN6O5S (M+) 616.1904, found 616.1922.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[C:10]([Cl:17])=[CH:9][C:4]=1[C:5]([O:7]C)=O.C1(C)C(C)=CC=CC=1.[CH:26]1([CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CO>[CH:26]1([CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:5](=[O:7])[C:4]3[CH:9]=[C:10]([Cl:17])[C:11]([NH:13][C:14](=[O:16])[CH3:15])=[CH:12][C:3]=3[O:2][CH3:1])[CH2:35][CH2:34]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Reactant: NC1CCN(CC2CCCCC2)CC1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1C
Solvent: CO
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Yield: 64 %

Procedure:
A mixture of methyl 2-methoxy-4-acetamido-5-chlorobenzoate (25.7 g; 0.1 moles), xylene (80 ml), 1-cyclohexylmethyl-4-aminopiperidine (21.6 g; 0.11 moles) and aluminium isopropoxide (5 g) was heated to the boiling point whilst methanol was distilled off as it was formed. When the theoretical quantity of methanol was removed, the xylene was distilled off and the residue was dissolved in 2 N hydrochloric acid (200 ml). The aqueous solution was made alkaline with sodium hydroxide solution, extracted with chloroform and the chloroformic layer evaporated to dryness to give N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide (27 g). Its hydrochloride monohydrate was prepared by the procedure described in Example 2, m.p. 219°-221° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[C:18](#[N:22])[CH2:19][CH2:20][CH3:21].[OH-].[Na+]>>[O:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:18](=[NH:22])[CH2:19][CH2:20][CH3:21])[CH2:13][CH2:14]1
Reactant: CCCC#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CCCC(=N)Nc1ccccc1N1CCOCC1

Procedure:
Powdered anhydrous aluminium chloride (12 g) was added portion-wise to a stirred slurry of 4-(2-aminophenyl)morpholine (5.34 g) and n-butyronitrile (6 g) at 40°-50° C. The mixture was then heated at 160°-170° C. for 6 hours, allowed to cool and then digested with 40% aqueous sodium hydroxide solution. The solution was extracted with ether and the extract washed with water and brine and dried. Removal of the solvent gave a residue which was crystallised from a 1:1 mixture of ethylacetate and hexane to give N-(2-morpholinophenyl)butyramidine (m.p. 131°) which was converted into its monofumarate salt (m.p. 173° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: O1CCN([CH:7]=[C:8]([C:14](OCC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])CC1.[CH3:19][CH:20]([CH3:33])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH2:32])=[NH:31].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[CH3:19][CH:20]([CH3:33])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]1[NH:32][C:14](=[O:15])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:31]=1
Reactant: CC(C)COc1ccccc1NC(=N)N
Reactant: CCOC(=O)C(=CN1CCOCC1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2OCC(C)C)[nH]c1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
Diethyl morpholinomethylenemalonate (20.0 g) is added to a solution of N-[2-(2-methylpropoxy)phenyl]guanidine (16.1 g) and potassium carbonate (21.5 g) in ethanol (40 ml) and water (40 ml), and the mixture is heated with stirring at 60° C. for 3 hours. After the reaction is completed, water (100 ml) is added to the reaction mixture with stirring under water-cooling, and the mixture is acidified to pH 3 with 10% aqueous HCl. The resulting precipitate is collected by filtration and dissolved in chloroform (300 ml). The chloroform layer is washed with water twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue is recrystallized from DMF to give ethyl 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (16.0 g). M.p. 175°-177° C.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:9])(=[NH:8])[CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C1C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:8][C:5](=[NH:9])[CH2:6][CH3:7])=[O:19])=[CH:13][CH:12]=1
Reactant: CCC(=N)N
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC(=N)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a stirred, cooled mixture of 10.8 g. sodium methoxide in 100 ml. dry benzene was added 21.6 g. propionamidine hydrochloride in one portion and stirring was continued for twenty minutes. To this mixture at room temperature was added a solution of 30.6 g. of 4-chlorophenyl isocyanate in 100 ml. benzene dropwise during 15 minutes and stirring was continued for 18 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. A solution of the resulting residue in either was chilled and treated with ethereal hydrogen chloride until acidic. The solid was collected by filtration to give after recrystallization from acetonitrile 22 g. of the hydrochloride of 1-(4-chlorophenyl)-3-(propanimidoyl)urea; m.p. 191°-192°C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29]C)[CH2:27]C)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])C=C[CH:3]=1.[NH:33]1C=CN=C1C=O.C(CC(NC(C1C=CC(OCCN(C)C)=CC=1)CCC)=O)#N>>[C:31](/[C:9](=[CH:8]\[C:6]1[NH:7][CH:2]=[CH:3][N:33]=1)/[C:10]([NH:12][CH:13]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:29])=[CH:21][CH:22]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: O=Cc1ncc[nH]1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Agent: CCCC(NC(=O)CC#N)c1ccc(OCCN(C)C)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1ncc[nH]1)c1ccc(OCCN(C)C)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 1H-imidazole-2-carbaldehyde was used instead of 6-bromopicolinaldehyde, and 2-cyano-N-(1-(4-(2-(dimethylamino)ethoxy)phenyl)butyl)acetamide (30) was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl) acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 8:92 methanol/dichloromethane, to give 38 (80 mg, 63%) as a light yellow oil: MS (ES+) m/z 453.2 (M+H)+.
Reaction SMILES: [Na].[O-]CC.[Na+].[C:6]([NH:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[CH3:7].Cl[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1>C(O)C.C(OCC)(=O)C.[I-].[K+].CN(C)C=O>[S:26]1[CH:27]=[C:23]([CH2:22][CH2:7][C:6]([NH:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])[N:24]=[CH:25]1
Reactant: ClCc1cscn1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(NC(=O)CCc1cscn1)C(=O)OCC
Temperature: 50 °C
Yield: 98 %

Procedure:
To an oven-dried 2 liter 3-neck round bottom flask equipped with a mechanical stirrer, relux condenser and nitrogen inlet containing 500 mL of absolute ethanol was added sodium (19.8 g, 0.86 mole). This mixture was allowed to reflux until complete dissolution of the sodium metal. The resultant solution of sodium ethoxide was cooled to approximately 40° C. and diethyl acetamidomalonate (186.1 g, 0.86 mole) was added. The resultant mixture was refluxed for 30 minutes, then cooled to about 50° C. and treated with potassium iodide (2.0 g) and dimethylformamide (2 ml). A freshly prepared solution of 4-chloromethylthiazole (0.89 mole) in 200 mL of absolute ethanol was added dropwise over a period of 20 minutes and the mixture was maintained at 50 ° C. for 24 hours. The mixture was then cooled in an ice bath, diluted with ethyl acetate and filtered through a pad of Celite. Concentration and drying gave 265 g of the desired product as light yellow crystals. m.p. 104°-106° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[CH:11]=2)=[CH:4][CH:3]=1.[CH3:24][Mg]I.CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:19]([NH2:20])[CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:11]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]I
Reactant: Cn1nc(-c2cccc(C#N)c2)cc1CCc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(N)c1cccc(-c2cc(CCc3ccc(F)cc3)n(C)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the nitrile from Step 1 (50 mg, 0.16 mmol) in THF (5 mL) was treated with MeMgI in Et2O (3.0 M, 0.32 mL, 0.96 mmol). A milky solution formed, which was stirred at RT for 30 mins, then further MeMgI was added (1.0 mL, 3 mmol) and stirred for 1 hour. A solution of LiAlH4 in THE (1.0 M, 2.5 mL, 2.5 mmol) was added and stirred at RT for 1 hour. The reaction was quenched by addition of H2O and the solvent evaporated under reduced pressure. The residue was partitioned between CH2Cl2 and H2O, the CH2Cl2 layer was separated and the aqueous layer re-extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give crude 1-(3-{5-[2-(4-fluorophenyl)-ethyl]-1-methyl-1H-pyrazol-3-yl}-phenyl)-ethylamine as a yellow gum (50 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].C([CH2:20][C:21](Br)([CH3:25])[C:22](O)=[O:23])C>C(#N)C.C(O)C.C(O)(=O)C.[Fe]>[CH3:20][C:21]1([CH3:25])[C:22](=[O:23])[NH:1][C:4]2[CH:5]=[CH:6][C:7]([CH3:11])=[CH:8][C:9]=2[O:10]1
Reactant: CCCC(C)(Br)C(=O)O
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC#N
Product: Cc1ccc2c(c1)OC(C)(C)C(=O)N2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
6-Nitro-m-cresol (30.6 g) was dissolved in acetonitrile (400 ml), and thereto was added cesium carbonate (163.3 g), and the mixture was warmed to 80° C. To the mixture was added dropwise ethyl 2-bromoisobutyric acid (60 ml), and the mixture was stirred at 80° C. for 6 hours. To the mixture was added dropwise again ethyl 2-bromoisobutyric acid (60 ml), and the mixture was further stirred at 80° C. for 8 hours. The reaction solution was cooled to room temperature, and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water (twice) and saturated aqueous sodium chloride solution (once), and dried over sodium sulfate. The mixture was filtered, and concentrated under reduced pressure to give a crude product. The obtained crude product was dissolved in ethanol (100 ml), and added dropwise in to a solution of iron (90 g) in acetic acid (300 ml), wherein the suspension was previously and separately warmed to 75° C. After the addition was completed, the mixture was stirred at 80° C. for 5 hours, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with water and saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The obtained crude product was washed with hexane, and collected by filtration to give the title compound (32 g) as whited crystal.
Reaction SMILES: C1COCC1.C[Si](Cl)(C)C.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].I[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1>[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CN(P(N(C)C)(N(C)C)=O)C>[C:16]([O:15][C:13]([CH2:12][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
11.4 g (0.170 mol) of powdered zinc and 50 ml of THF are-introduced into a three-necked flask, 2.2 ml of trimethylsilyl chloride are added and the mixture is stirred for 15 minutes, 28 ml (0.174 mol) of tert-butyl 2-bromoacetate are then introduced dropwise and the mixture is stirred for 30 minutes. It is cooled to 0° C. (icebath), 5 g (4.3 mmol) of tetrakis(triphenylphosphine)palladium(0), 10.8 g (43.5 mmol) of 4-iodobenzoic acid and 50 ml of HMPA are introduced and the mixture is heated to 40° C. for one hour. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and ethyl ether (95:5). After evaporation of the solvents, 8.1 g (80% ) of the expected product, melting point 132°-133° C., are collected.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl.[NH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[NH2:15]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:15][NH:14][C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cc(Br)ccc32)cc1

Procedure:
The title compound was prepared from 6-bromo-1H-indole-2,3-dione (Meth-Cohn and Goon, Tetrahedron Letters 1996, 37, 9381-4) and 4-hydrazinobenzenesulfonamide hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ7.05 (s, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 11.2 (s, 1H), 12.7 (s, 1H); APCI−MS m/z 395 (M−H)−.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[N:18]=1.C(N(CC)CC)C.O>O1CCCC1.C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:17]3[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[N:18]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: Brc1ccc(C2CCNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(N2CCOC(c3ccc(Br)cc3)CC2)nc(-c2ccncn2)cc1=O
Yield: 76.7 %

Procedure:
To a suspension of optically active 7-(4-bromo-phenyl)-[1,4]oxazepane hydrochloride (0.10 g, 0.34 mmol) and 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.07 g, 0.30 mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.08 mL), 0.60 mmol) at room temperature. The resulting mixture was stirred over night and poured into water. Extractive workup with chloroform was performed and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by recrystallization from ethyl acetate and diisopropyl ether to yield (+)-2-[7-(4-bromophenyl)-[1,4]-oxazepane-4-yl]-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (A096) (0.10 g, 0.23 mmol, 75%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10](=[O:11])[N:9]([NH2:12])[C:8](SC)=[N:7][N:6]=1)([CH3:4])[CH3:3]>O.C(N)(C)C>[NH2:12][N:9]1[C:10](=[O:11])[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[N:6][N:7]=[C:8]1[NH:6][CH:5]([CH3:10])[CH3:2]
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Solvent: O
Solvent: CC(C)N
Product: CC(C)Nc1nnc(C(C)(C)C)c(=O)n1N
Reaction time: 72 h

Procedure:
A mixture of 20 g of technical metribuzin in 75 ml water and 28 ml isopropylamine was refluxed with stirring for 72 hours. The reactants were cooled and the solid product was isolated by filtration and drying. The m.p. was 158° and the structure was confirmed by elemental analysis and NMR analysis.
Reaction SMILES: [CH2:1]([C@@:5]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:9][C@H:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[C@H:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=2)[NH:6]1)[CH:2]([CH3:4])[CH3:3].[C:35]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([C:43]([N:6]2[C@@H:7]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:17]=3)[C@@H:8]([C:10]3[CH:15]=[N:14][CH:13]=[CH:12][N:11]=3)[CH2:9][C@@:5]2([CH2:1][CH:2]([CH3:4])[CH3:3])[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[O:44])=[CH:46][CH:47]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cnccn2)[C@H](c2cccc(-c3ccccc3)c2)N1
Product: CC(C)C[C@@]1(C(=O)OC(C)(C)C)C[C@H](c2cnccn2)[C@H](c2cccc(-c3ccccc3)c2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The ester from stage A was acylated with 4-tert-butylbenzoyl chloride in a similar manner to that described in Intermediate 3, to afford rel-(2S,4S,5R)-1-(4-tert-butylbenzoyl)-2-isobutyl-4-pyrazin-2-yl-5-(3-phenyl-phenyl)-pyrrolidine-2-carboxylic acid, tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.[O-:17][C:18]#[N:19].[K+]>C(O)(=O)C.O>[N:15]1[C:9]2[NH:8][C:7]3[CH:16]=[C:3]([CH2:2][NH:1][C:18]([NH2:19])=[O:17])[CH:4]=[CH:5][C:6]=3[S:11][C:10]=2[N:12]=[CH:13][CH:14]=1
Reactant: N#C[O-]
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NCc1ccc2c(c1)Nc1nccnc1S2
Reaction time: 2 h
Yield: 14 %

Procedure:
A solution of 420 mg of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in acetic acid (2 ml)/water (4 ml) was heated to 70° C. and potassium cyanate (1 g in total) was added thereto over 2 hours. Then the reaction mixture was brought back to room temperature and diluted with water. The solid thus precipitated was filtered, washed well with water and recrystallized from dimethyl sulfoxide/ethyl acetate to thereby give 70 mg of the title compound as yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1)[C:4]([OH:6])=[O:5].Cl.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[CH:3]([NH2:2])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1
Reactant: CO
Reactant: NC(Cc1ccc2oc(=O)[nH]c2c1)C(=O)O
Agent: Cl
Product: COC(=O)C(N)Cc1ccc2oc(=O)[nH]c2c1

Procedure:
The product from Example 1 (0.1 mole) is held at reflux in 1500 ml of methanol saturated with HCl gas for 6 hours. The alcoholic solution is evaporated to yield a product which is recrystallized from water or methanol:ether to yield the title compound.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH3:31][O:32][C:33](=[O:36])[CH:34]=[CH2:35].CO.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:31][O:32][C:33](=[O:36])/[CH:34]=[CH:35]/[C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC#N
Product: COC(=O)/C=C/c1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 1 h
Yield: 37 %

Procedure:
Mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50 mg, 0.10 mmol) and methylacrylate (0.5 mL, excess) in a mixture of acetonitrile: TEA; 1 mL:0.5 mL was degassed with nitrogen and palladium acetate (10 mg) was added to it. Reaction mixture was stirred for one hour under nitrogen at reflux, more palladium acetate (15 mg) was added and the refluxing was continued for 7 hours (monitored by tlc). Methanol (1 mL) was added followed by the addition of potassium carbonate (70 mg, 0.51 mmol) and stirring was continued for 1 hour. Solvent was distilled and the crude material was purified over silica gel column (eluent Hexane:diethylether; 1:1) to afford the title compound as yellow crystalline solid (17 mg, 37%); 1H NMR (300 MHz, CDCl3) δ 7.61 (d, 1H, J=15.76 Hz), 7.14 (s, 2H, benzoyl Hs), 6.98 (d, 1H, J=8.64 Hz), 6.89 (d, 1H, J=8.69 Hz), 6.81 (d, 1H, J=15.78 Hz), 3.96 (s, 3H, OMe), 3.95 (s, 3H, OMe), 3.81 (s, 6H, 2×OMe), 3.77 (bs, 3H, OMe).