Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH:31]1C1C=CC(B2OC(C)(C)C(C)(C)O2)=CN=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:18]3[CH:19]=[N:20][C:21]([N:33]4[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]4)=[CH:22][CH:23]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: CN1CCNCC1c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (90 mg, 0.202 mmol) and 1-methyl [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (92 mg, 0.303 mmol). The final product was collected as a light brown solid (54 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.65 (d, J=2.27 Hz, 1H) 8.61 (t, J=4.80 Hz, 1H) 8.36 (s, 1H) 8.04-8.08 (m, 2H) 7.83 (s, 1H) 6.96 (d, J=9.09 Hz, 1H) 5.92 (s, 1H) 5.14 (quin, J=6.57 Hz, 1H) 4.42 (d, J=4.80 Hz, 2H) 3.53-3.59 (m, 4H) 2.53-2.61 (m, 2H) 2.40-2.45 (m, 4H) 2.23 (s, 3H) 2.14 (s, 3H) 1.51-1.58 (m, 2H) 1.50 (s, 3H) 1.49 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=542.2 [M+H]+
Reaction SMILES: [CH:1]([NH:4][C:5]([CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C@@H:21]([CH3:28])[CH2:22]OS(C)(=O)=O)[CH:15]=2)[N:10]=[C:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:43]([NH:45][CH2:46][CH3:47])[CH3:44].CCCCCC>C(#N)C>[CH2:43]([N:45]([CH2:46][CH3:47])[CH2:22][C@H:21]([CH3:28])[CH2:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[N:8]([CH2:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:17]2=[O:18])[CH3:44]
Reactant: CCNCC
Reactant: COc1cccc(-c2nc3ccc(OC[C@@H](C)COS(C)(=O)=O)cc3c(=O)n2CC(=O)NC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Product: CCN(CC)C[C@H](C)COc1ccc2nc(-c3cccc(OC)c3)n(CC(=O)NC(C)C)c(=O)c2c1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
To a solution of (R)-(−)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester (1.13 g, 2.18 mmol) in anhydrous acetonitrile (40 mL) was added potassium carbonate (1.51 g, 10.95 mmol) followed by diethyl amine (3.20 g, 4.53 mL, 43.80 mmol) and the reaction mixture was heated at 80° C. in a pressure tube. After 2 days (reaction complete by HPLC), the reaction mixture was concentrated in vacuo to dryness and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (5×150 mL) and with dichloromethane (5×100 mL). The combined organic phase was dried (Na2SO4), solvent evaporated in vacuo, and the resulting residue purified by chromatography on silica gel with a gradient of methanol:dichloromethane (1:19, v/v) to methanol:dichloromethane (1:4, v/v) as eluent. The resultant solid was recrystallised from diethyl ether:hexane to afford (S)-(+)-2-[6-(3-diethylamino-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropy-acetamide (EXAMPLE 4a) (0.69 g, 1.40 mmol, 65% from (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:18])[C@H:14]([CH2:16][OH:17])[NH2:15].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:18])[C@H:14]([CH2:16][OH:17])[NH:15][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CO)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A solution of benzoyl chloride (17 g) in ethyl acetate (40 ml) is added dropwise, with stirring, in an ice-cold mixture of L-serine methyl ester, hydrochloride (15.5 g), water (100 ml), sodium bicarbonate (21.8 g), and ethyl acetate (100 ml). After stirring for 2 hours, the organic phase is separated, dried over sodium sulfate, and evaporated to give crystalline N-benzoyl-L-serine methyl ester (22.0 g).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C@@H:22]([N:29]=[C:30]=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:30]([NH:29][C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:21])=[O:31])[C:3]1=[O:20]
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O)c1ccccc1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and (R)-(+)-α-methylbenzylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product as a mixture of diastereomers: m.p. 146°-150° C.
Reaction SMILES: I.CS[C:4](=NC)[NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[OH:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][NH2:27].C(O)C.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>CO>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[OH:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][NH:27][C:4]1=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[OH:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][NH:27][C:4]1=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CN=C(Nc1cc(C)ccc1N1CCOCC1)SC
Reactant: NCCNCCO
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: Cc1ccc(N2CCOCC2)c(N=C2NCCN2CCO)c1

Procedure:
A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (8.4 g prepared as described in Example 227), N-(2-hydroxyethyl)ethylenediamine (6.8 ml) and ethanol (80 ml) was heated under reflux for 30 hours to give an oil which was treated with fumaric acid in methanol to give 4-(2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]-4-methylphenyl)morpholine sesquifumarate (m.p. 135°-136° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][NH:8][C:7]=2[CH:14]=1)#[N:2].[H-].[Na+].[CH:17]12[O:22][CH:18]1[CH2:19][CH2:20][CH2:21]2>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][N:8]([CH:17]3[CH2:21][CH2:20][CH2:19][CH:18]3[OH:22])[C:7]=2[CH:14]=1)#[N:2]
Reactant: CC1(C)CNc2cc(C#N)ccc2O1
Reactant: C1CC2OC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(C2CCCC2O)c2cc(C#N)ccc2O1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 1.0 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine followed by addition of 0.24 g of sodium hydride. The mixture was stirred at 70° C. for 1 hour and after cooling to room temperature, 0.5 ml of cyclopentene oxide was added. The mixture was stirred at 70° C. for 3 hours. The reaction mixture was then allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water and aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and the resulting crude crystals were recrystallized from ethyl acetate-hexane to give 0.53 g of 6-cyano-3,4-dihydro-4-(2-hydroxycyclopentan-1-yl)-2,2-dimethyl-2H-1,4-benzoxazine.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](OC)=[O:31]>CCCCCC.C1COCC1>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[CH:30]=[O:31]
Reactant: COC(=O)c1cccc(Cc2cccc(OCc3ccc4ccccc4n3)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Cc2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisobutyl aluminum hydride (0.01 mol) in hexane is added dropwise to a solution of methyl 3-(3-(2-quinolinylmethyloxy)benzyl)benzoate (0.01 mol) in 100 ml of THF at 0° C. The reaction mixture is stirred at 0° C. for 30 minutes and then quenched with methanol and Rochelle salt. Extraction with ethyl acetate and purified by column chromatography gives 3-(3-(2-quinolinylmethyloxy)benzyl)benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][N:5]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=2)[C:4](=[O:18])[CH2:3]1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:5]4[CH2:6][C:2]([CH3:1])([CH3:19])[CH2:3][C:4]4=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(N2CC(C)(C)CC2=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)CC4=O)cc3)CC2)c(C)c1
Yield: 65.8 %

Procedure:
Using ethyl 4-(4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (131 mg) described in Preparation Example 49 and 1-(3,5-dimethylpyridin-2-yl)piperazine (96 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (134 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:30](Cl)(Cl)=[S:31]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:30]=[S:31])[C:14]([N:15]3[CH2:16][CH2:17][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:20]3)=[CH:13][C:5]=2[N:6]=1)([CH3:11])([CH3:12])[CH3:10]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)c1nc2cc(N3CCN(S(C)(=O)=O)CC3)c(N)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1nc2cc(N3CCN(S(C)(=O)=O)CC3)c(N=C=S)cc2s1

Procedure:
A mixture of 1 g of 6-amino-2-tert-butyl-5-[4-methanesulphonylpiperazin-1-yl]benzothiazole and 500 g of sodium bicarbonate in 100 ml of chloroform is cooled in an ice-bath and 2 ml of thiophosgene in 10 ml of chloroform is added to it under stirring. The mixture is stirred over-night at ambient temperature. After filtering off the solid the filtrate is evaporated and the residue is subjected to silica gel column chromatography. Elution with 1% methanol in chloroform gives 2-tert-butyl-6-isothiocyanato-5-[4-methanesulphonylpiperazin-1-yl]benzothiazole melting at 128°-130°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][CH2:11][C@H:12]2[C@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=3)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@@H:18]2[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][C@H:12]2[CH2:11][NH:10][C:8]([C:3]2[C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:9])=[CH:20][C:21]=1[F:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ncccc2N)C1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ncccc2NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (6R,7R)-6-({[(3-aminopyridin-2-yl)carbonyl]amino}methyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (110 mg) in DMF (3 ml) was added 60% sodium hydride at 0° C., and the mixture was stirred for 30 min. Methanesulfonyl chloride (53 μL) was added, and the mixture was warmed to room temperature, and stirred overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (44.4 mg).
Reaction SMILES: CN(C)CCCN=C=NCC.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:26]3[C@H:22]([CH2:23][NH:24][CH2:25]3)[C@@H:21]([OH:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:34][N:35]([CH3:50])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:50][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([N:24]1[CH2:23][C@H:22]2[C@H:26]([C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:19][CH2:20][C@@H:21]2[OH:27])[CH2:25]1)=[O:48]
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: CN(C)CCCOc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)CCCOc1ccccc1CC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
0,766 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is added to a solution, cooled to 10° C., of 1 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol, 0.97 g of 2-(3-dimethylaminopropoxy)phenylacetic acid and 0.05 g of 1-hydroxybenzotriazole in 50 cm3 of dichloromethane. The reaction mixture is stirred for 90 minutes 20° C. and then washed twice with 50 cm3 of water and with 50 cm3 of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 2.9 cm, height 23 cm), eluting under a nitrogen pressure of 0.7 bar with 1,2-dichloroethane and methanol mixtures (1 liter at 90/10 by volume and 1.5 liters at 70/30 by volume) and collecting fractions of 25 cm3. Fractions 10 to 84 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.1 g of (3aR,4S,7aR)-2-{[2-(3-dimethylaminopropoxy)phenyl]-acetyl}-7,7-diphenyl-4-perhydroisoindolol in the form of a cream-colored meringue.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][N:6]=1)=[NH:4].[CH2:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:37])[C:26]=1[O:27][CH2:28][C@@H:29]([OH:36])[CH2:30][NH:31][C:32](=[O:35])[CH2:33][OH:34])[C:21](O)=O)[CH3:17]>>[CH2:16]([C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][N:6]=3)[N:4]=2)[CH:24]=[C:25]([CH3:37])[C:26]=1[O:27][CH2:28][C@@H:29]([OH:36])[CH2:30][NH:31][C:32](=[O:35])[CH2:33][OH:34])[CH3:17]
Reactant: Cc1cc(C(=N)NO)ncc1CC(C)C
Reactant: CCc1cc(C(=O)O)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: CCc1cc(-c2nc(-c3cc(C)c(CC(C)C)cn3)no2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 34.4 %

Procedure:
The title compound (32 mg) is prepared by coupling and cyclizing N-hydroxy-5-isobutyl-4-methyl-pyridine-2-carboxamidine (40 mg, 193 μmol) with 3-ethyl-4-[(S)-2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid (60 mg, 193 μmol) as described in Example 1; LC-MS: tR=0.95 min, [M+H]+=482.86.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]([O:40]CC)=[O:39])[CH2:34][CH2:33]3)=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:33][CH2:34][CH:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37]3)=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CCOC(=O)C1CCN(C(=O)c2ccc(Cn3c(C(=O)OC)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)N2CCC(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
To a mixture of 6-bromo-2-[4-(4-ethoxycarbonylpiperidine-1-carbonyl)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (290 mg), methanol (5 ml) and tetrahydrofuran (5 ml) was added a solution (0.1 ml) of 8N aqueous sodium hydroxide and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by preparative liquid chromatography to give the title compound (72 mg, 26%).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I>C1COCC1>[CH3:19][S:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:14])[CH3:15])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)n1nc(Br)c2ccc(S)cc2c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a solution of 7-mercap-to-2-isopropyl-4-bromo-2H-phthalazin-1-one (0.77 g, 2.6 mmol) in THF (8 ml), was added NaH (60%, 0.13 g, 3.1 mmol) portion-wise. After stirring for 5 min, methyl iodide (0.44 g, 3.1 mmol) was added dropwise and stirring was continued for four hours. The mixture was concentrated under vacuum and the residue was subjected to flash column chromatography (elution: 90% heptane, 10% EtOAc) to give the title compound (0.44 g, 54% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO), 8.02 (1H, d), 7.88 (1H, d), 7.75 (1 H, d), 5.26-5.15 (1H, m), 2.59 (3H, s), 1.35 (6H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1.[CH3:28]O.S(=O)(=O)(O)O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:28])=[O:24])=[CH:26][CH:27]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1

Procedure:
Material from Example 3 was heated at reflux in a solution of methanol/sulfuric acid for 18 h. The solution was concentrated to remove the methanol and the resulting aqueous solution was extracted with chloroform to yield the title compound. ESMS (M+H)+=374.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([O:14][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:5]=2)=[CH:13][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)Nc1cc(O)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(OCc2ccccc2)ccc1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 17 h
Yield: 178.5 %

Procedure:
A suspension of 1.1 g (5.64 mmol) of 2-acetylamino-4-hydroxy-benzoic acid (preparation: Recl. Trav. Chim. Pays-Bas, 72, p195, 1953), 1.6 ml (13.53 mmol) of benzyl chloride, 3.9 g (28.18 mmol) of potassium carbonate in DMF (15 ml) was stirred at 80° C. for 17 h under argon. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 and water. The layers were separated, the aqueous layer once extracted with CH2Cl2, the organic layers combined, washed with brine, dried over MgSO4 and concentrated in vacuo, to give 1.89 g (85.75%) of the desired 2-acetylamino-4-benzyloxy-benzoic acid benzyl ester as an off-white solid. ISP mass spectrum, m/e: 376.5 (M+1 calculated for C23H21NO4: 375.42).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11]C)=[O:10])=[C:4]([CH3:13])[N:3]=1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=[O:10])=[C:4]([CH3:13])[N:3]=1
Reactant: COC(=O)c1c(C)nc(C)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(C)c(C(=O)O)c(C)n1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Methyl 2,4,6-trimethylpyrimidine-5-carboxylate (27 g), methanol (27 ml) and water (27 ml) were charged. 25% sodium hydroxide solution (25 ml) was charged and the batch warmed to 50° C. for 90 minutes. The batch was cooled to between −5 and 0° C. and concentrated hydrochloric acid was charged slowly, keeping the temperature within the range of −5 to +5° C. until a pH of 1.5 was reached (22.5 ml conc. HCl used). The batch was agitated for-about 1.5 hours at about 2.7° C. The solid product was recovered by filtration. The batch was dried under vacuum at 40–45° C. The 2,4,6-trimethylpyrimidine-5-carboxylic acid was recrystallized from ethyl acetate. m. p. 163–164° C., 1H NMR (CD3OD): δ2.43 (6H, s, CH3), δ2.52 (3H, s, CH3). 13H CMR (CD3OD): δ170.42, δ168.30, δ166.09, δ126.63, δ25.64, δ22.97. HR-MS; Calculated for C8H11N2O2, m/z=167.0821. Found 167.0816.