Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH2:26][OH:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH2:26][O:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.16 ml of methanesulphonyl chloride followed by 3.86 ml of triethylamine are added to a solution of 5 g of (R)-3-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester in 80 ml of DCM cooled to 0° C. The medium is stirred at 0° C. for 1 h 30 min and 0.7 ml of triethylamine and 0.54 ml of methanesulphonyl chloride are again added. After 30 min at 0° C., the medium is hydrolysed, and the organic phase is washed twice in water and then with a saturated NaCl solution, and then dried over MgSO4. The medium is evaporated, to give 6.8 g of a pale yellow oil.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)=[O:32])[CH2:27][CH2:26]1>>[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([N:11]3[C@@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[CH:35][CH:34]=2)=[O:32])[CH2:29][CH2:30]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@@H](CO)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 76.9 %

Procedure:
Using (R)-3-benzyloxymethylisothiazolidine 1,1-dioxide (370 mg) described in Preparation Example 10 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (643 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 32, the title compound (522 mg) was obtained.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[CH:30]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:27][C:25]([CH3:28])([CH3:26])[CH2:24][O:23][C:5]1[C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:10]=[CH:11]/[C:12]1[N:13]=[C:14]2[N:18]([C:19]=1[C:20]([NH:38][C:35]1[S:36][CH:37]=[C:33]([CH:30]([CH3:32])[CH3:31])[N:34]=1)=[O:21])[CH:17]=[CH:16][S:15]2
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: CC(C)c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)c1csc(NC(=O)c2c(/C=C/c3cccc(OC(F)F)c3OCC(C)(C)C)nc3sccn23)n1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 4-(isopropyl)-1,3-thiazol-2-amine (41 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (26 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 60 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 1.26 (d, J=6.9 Hz, 6H), 2.92-2.98 (m, 1H), 3.57 (s, 2H), 6.64 (s, 1H), 7.18 (t, J=74.7 Hz, 1H), 7.20-7.30 (m, 2H), 7.42 (s, 1H), 7.64-7.70 (m, 1H), 7.83 (d, J=15.6 Hz, 1H), 8.12-8.18 (m, 1H), 8.60-8.70 (m, 1H), 12.86 (br s, 1H); APCI-MS (m/z) 547.26 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[CH:17]=[C:6]3[C:7]4[C:12]([CH2:13][CH2:14][N:5]3[C:4](=[O:18])[N:3]=2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=4)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(N)c1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1cccc(Nc2cc3n(c(=O)n2)CCc2cc(OC)ccc2-3)c1

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-methoxyaniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.59 (s, 1H), 7.68 (d, 1H), 7.52 (br, 1H), 7.30 (d, 1H), 7.23 (t, 1H), 7.05-6.95 (2H), 6.63 (dd, 1H), 6.35 (s, 1H), 3.98 (t, 2H), 3.84 (s, 3H), 3.75 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 350.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2].CO.Cl.C(=O)(O)[O-].[Na+]>O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 2 h
Yield: 81.3 %

Procedure:
Add 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17-one (12.9 g.) with stirring under nitrogen to methanol (300 cc.) containing 11N hydrochloric acid (20 cc) and water (13 cc.). Stir two hours and add sodium bicarbonate (21 g.) portionwise. Filter the mixture and evaporate the filtrate to dryness. Recrystallize the residue from ethyl acetate (75 cc.) to obtain the title compound (10 g.), m.p. 158-161° C; ultraviolet absorption peak at 240 mμ (ε17,800); infrared absorption peaks at 5.78, 6.00, 6.17 μ.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(-n2cc([N+](=O)[O-])cc2C#N)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-methylphenyl)pyrrole-2-carbonitrile (1.0 g) in acetic anhydride (4 ml) was added nitric acid (231 μl, 94%) dropwise at 5° C. The mixture was stirred at the same temperature for 3 hours and then poured into ice water. The pH was adjusted to 5-7 by the addition of saturated aqueous sodium bicarbonate solution. The separated oil was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to yield 1-(4-methylphenyl)-4-nitropyrrole-2-carbonitrile (471 mg) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)CNS(=O)(=O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
To a solution of 4-bromo-N-isobutyl-benzenesulfonamide (0.25 g, 856 μmol) in anhydrous dimethylacetamide (5 mL) was added NaH (60% dispersion in mineral oil, 37.7 mg, 942 μmol) and the mixture was stirred at room temperature for 15 minutes. 4-Fluorobenzyl bromide (117 μL, 942 μmol) was added and reaction heated at 90° C. for 2 hours. The reaction was left to cool to room temperature, water added and then extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-25% DCM in cyclohexane) to give 4-bromo-N-(4-fluoro-benzyl)-N-isobutyl-benzenesulfonamide (267 mg, 78%) 1H NMR (300 MHz, CDCl3): δ 7.65-7.66 (m, 4H), 7.23 (m, 2H), 6.99 (t, 2H), 4.27 (s, 2H), 2.89 (d, 2H), 1.64 (dt, 1H), 0.74 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][CH:17]=[CH:18][C:11]=23)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[CH:8][C:2]=2[F:1])[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)cc2F)cc(-c2ccncc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
11 mg (50 μmol) of 2-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (from example XX) are suspended in 5 ml of water. 9.3 mg (50 μmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) and 0.01 ml of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline with saturated sodium bicarbonate solution and extracted 3× with ethyl acetate, and the extracts are dried over sodium sulfate and concentrated using a rotary evaporator.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[OH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[CH:24][CH:25]=2)=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CCOc1cc(CC(=O)OC)c(CC)c(OCC=C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1cc(OCC=C)c(C(=O)c2ccc(O)cc2)c(CC(=O)OC)c1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
Methyl 3,5-diallyloxy-2-ethylphenylacetate (1.0 g, 3.3 mmol) obtained in Example 5, Step 3 was dissolved in trifluoroacetic acid (9.0 mL), and 4-hydroxybenzoic acid (1.4 g, 10 mmol) and trifluoroacetic anhydride (1.2 mL) were added thereto, followed by stirring at room temperature for 20 hours. To the mixture were further added 4-hydroxybenzoic acid (0.92 g, 6.6 mmol) and trifluoroacetic anhydride (1.4 mL), followed by stirring for 6 hours. The reaction mixture was added dropwise to a saturated aqueous solution of sodium hydrogencarbonate (0.10 L), and the resulting mixture was extracted with ethyl acetate (50 mL×4). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in a 7 mol/L solution of ammonia in methanol (100 mL), followed by stirring at room temperature for 1 day. After the reaction mixture was concentrated under reduced pressure, 3 mol/L hydrochloric acid (40 mL) was added thereto, followed by extraction with ethyl acetate (50 mL×3). The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/10-1/2) to obtain methyl 3,5-diallyloxy-2-ethyl-6-(4-hydroxybenzoyl)phenylacetate (0.84 g, 57%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:11]=[N:10][N:9]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17]C)=O)[N:8]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:15](=[O:17])[C:14]1[CH:19]=[CH:20][CH:21]=[C:12]([N:9]2[N:8]=[C:7]([NH:6][C:5]([NH2:22])=[N:4][CH2:3][C:2]([F:1])([F:24])[F:23])[CH:11]=[N:10]2)[CH:13]=1
Reactant: COC(=O)c1cccc(-n2ncc(NC(N)=NCC(F)(F)F)n2)c1
Reactant: NCCO
Product: NC(=NCC(F)(F)F)Nc1cnn(-c2cccc(C(=O)NCCO)c2)n1

Procedure:
A mixture of methyl 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoate (0.2 g.) and ethanolamine (5 ml.) was heated at 80° overnight. The mixure was evaporated and the thick oily residue was purified by chromatography on silica gel using EtOAc and isopropanol (6:1 v/v) as eluant. The product was recrystallised from isopropanol to give N-(2-hydroxyethyl)-3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzamide, m.p. 171°-173°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)[CH3:2].O[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(COc2cccc(C=O)c2)cc1

Procedure:
Mix 4-ethoxybenzyl alcohol (3.35 g. 22 mmol), 3-hydroxy-benzaldehyde (2.69 g, 22 mmol), triphenylphosphine (5.8 g, 22 mmol) and diethylazadicarboxylate (3.83 g, 22 mmol) in tetrahydrofuran (25 mL). Stirat room temperature under anhydrous atmosphere until the reaction is done. Concentrate the solution in vacuo and dilute with a small quantity of ethyl ether. Filter any precipitate and concentrate the filtrat in vacuo. Purify by silica gel chromatography to give 3-(4-ethoxybenzyloxy)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C[N:30]([C:32](ON1N=NC2C=CC=NC1=2)=[N+:33](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:33][C:32]#[N:30])=[O:27])=[CH:23][CH:24]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A 8-mL vial was charged with 2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetic acid (95 mg, 0.23 mmol, 1 eq.), cyamide (15 mg, 0.36 mmol, 1.5 eq.), HATU (130 mg, 0.36 mmol, 1.5 eq.), diisopropylethylamine (90 mg, 0.69 mmol, 3 eq.) and DMF (1 ml). The resulting mixture was stirred at rt overnight until the starting acid was consumed. The mixture was added to NaHCO3 aq. (5 ml) and extracted with ethyl acetate (3×5 ml). The organic layers were combined and dried over Na2SO4. Removal of solvent gave a residue, which was purified by chromatography on silica gel using a preparation TLC plate and 2% of MeOH in DCM as mobile phase to give the title compound as a white solid (20 mg, 20% yield). MW=435.93. 1H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.43 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 3.69 (s, 2H), 3.18 (t, J=5.6 Hz, 2H), 2.94 (d, J=6.4 Hz, 2H), 2.27 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].O=[CH:10][CH2:11][CH2:12][C:13]([O:15]CC(C)C)=O>>[O:8]=[C:5]1[CH2:6][N:7]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[N:4]1[CH2:2][CH3:3]
Reactant: CCNC(=O)CN
Reactant: CC(C)COC(=O)CCC=O
Agent: Cl
Product: CCN1C(=O)CN2C(=O)CCC12

Procedure:
Glycine ethylamide hydrochloride (2.1 g, 15.1 mmol) and isobutyl 4-oxobutanoate (2 g, 12.6 mmol) were reacted together according the procedure of Example 2 to give the title compound, 0.5 g (23.5%) as a viscous oil. Rf=0.51 (silica gel plates, eluent dichloromethane-methanol 9:1). NMR (CDCl3): deltaH =5.27 (t, J=6 Hz, 1H, N--CH--N); 4.20 and 3.45 (ABq, J=17 Hz, 2H, N--CH2 --CO); 3.25 (q, J=7 Hz, 2H, NCH2CH3); 2.70-1.75 (c.a., 4H, COCH2CH2CH); 1.12 (t, J=7 Hz, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=168 (M+), 112 (M-C3H4O)+, 97 (M-C4H7O)+.
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[C:11]([C:29](O)=[O:30])=[C:10]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)(=O)C(Cl)=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1)[C:11]([CH2:29][OH:30])=[C:10]2[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cn2c(CO)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
DMF (0.1 ml) was added to a suspension of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (5.5 g) in THF (55 ml), and oxalyl chloride (1.9 ml) was added dropwise under ice-cooling. The reaction mixture was allowed to warm to room temperature, stirred for 30 min., and concentrated under reduced pressure. The residue was suspended in a mixture of THF (90 ml) and 1,2-dimethoxyethane (90 ml), and under ice-cooling sodium borohydride (1.62 g) and methanol (3 ml) were added. The mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was poured into water under ice-cooling. 10% Hydrochloric acid was added to acidify the aqueous layer, and THF and methanol were evaporated under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the title compound (5.3 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(=[N:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.[C:27]([NH:35][CH:36]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37][CH2:38][CH:39]=[O:40])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[NH2:20][CH:21]([CH:39]([OH:40])[CH2:38][CH2:37][CH:36]([NH:35][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CN=Cc1ccccc1
Reactant: CCOC(=O)C(CCC=O)NC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(CCC(O)C(N)C(=O)OCC)NC(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
Diisopropylamine (2.34 ml, 16.7 mmoles) is added to anhydrous THF (75 ml) and cooled to -10° C. At this point 2.24M n-BuLi (6.8 ml, 15.2 mmoles) is added slowly. After complete addition the reaction mixture is stirred for 10 minutes before being cooled to -78° C. At that temperature ethyl N-benzylideneglycinate (4) (2.9 g, 15.2 mmoles) is added and stirring is allowed to proceed for 15 minutes before aldehyde (8) (4.0 g, 15.2 mmoles), dissolved in anhydrous THF (25 ml), is added dropwise to the yellow anion. After complete addition the reaction is stirred another 11/2 hours before being poured into cold 5% aqueous NH4Cl. This mixture is extracted with CHCl3 (3×100 ml). The combined extracts are washed with saturated aqueous NaCl, dried over MgSO4, filtered and evaporated to dryness. The oily residue is taken up in THF (300 ml) and shaken with 5% aqueous HCl (200 ml) in a separatory funnel. This mixture is washed with Et2O (3×100 ml), basified with solid NaHCO3 and extracted with CHCl3 (3×150 ml). The combined extracts are washed with saturated aqueous NaCl (1×150 ml), dried over MgSO4, filtered and evaporated to dryness in vacuo to yield 4.0 g (72% yield) of the desired compound as a yellow glass. 'H-N.M.R. (CHCl3 /TMS): δ=1.20 (t, 3H, --CH2CH3); 1.28 (t, 3H, --CH2CH3 ); 1.45-2.20 (m, 4H, --CH2CH2 --); 2.46 (broad s, 2H, --NH2); 3.18-4.00 (m, 2H, >CH--NH2, CHOH); 4.19 (q, 2H, --CH2CH3); 4.25 (q, 2H, --CH2CH3); 4.53-5.08 (m, 1H, >CH--NH--); 7.05-7.97 ppm (m, 5H, Ph).