Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH:12]([S:16][CH3:17])[C:13](O)=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].O.[NH2:20][NH2:21]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH:12]([S:16][CH3:17])[C:13](=[O:14])[NH:20][N:21]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CSC(CC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSC1CC(c2cc(Cl)c(C)c(Cl)c2)=NNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
1.54 g (0.005 mole) of 4-(3,5-dichloro-4-methylphenyl)-2-methylthio-4-oxobutyric acid, prepared as described in step (c) above, were suspended in 5 ml of ethanol and then 0.25 g of hydrazine monohydrate was added, at room temperature, to the suspension, after which the mixture was stirred for 1 hour at room temperature. The mixture was then heated under reflux for 6 hours, after which it was cooled and the resulting crystals were collected by filtration and washed with a small amount of ethanol, to give 1.32 g (yield 87.1%) of the desired Compound No. 22, melting at 163°-165° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=2[O:25]C)=[N:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.C1CCCCC=1>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[OH:25])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: C=CCn1nc(-c2ccc(O)cc2O)c2cccc(C(F)(F)F)c21
Yield: 109.7 %

Procedure:
Prepared according to Method D step C from 1-allyl-3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.065 g, 0.18 mmol), boron tribromide (0.136 mL, 1.4 mmol) and 1.0 mL of cyclohexene to give the product (0.066 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH:26]=[CH:27][CH:28]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH2:43]>C(O)C.CS(C)=O.[OH-].[Na+].OO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])[CH:26]=[CH:27][CH:28]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)(=[O:43])[NH2:2]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl (1-((3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C8, 173 mg) in ethanol (4 mL) and dimethyl sulfoxide (2 mL), 2.0 mol/L aqueous sodium hydroxide (0.45 mL) and 35% aqueous hydrogen peroxide (87 μL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, water (15 mL) was added. The solid matter was taken by filtration, washed successively with water and ethyl acetate, and then dried under reduced pressure to obtain (S)-tert-butyl (1-((3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C7, 102 mg) as white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]([F:47])([F:46])[C:6]1[CH:7]=[C:8]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27]([OH:29])=O)[CH2:13][C@H:12]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:10].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O1CCCC1>[F:43][C:42]([F:44])([F:45])[C:40]1[CH:39]=[C:8]([CH:7]=[C:6]([C:5]([F:4])([F:47])[F:46])[CH:41]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:29])[N:2]([CH3:3])[CH3:1])[CH2:13][C@H:12]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:10]
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOC[C@H]3C(=O)O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOC[C@H]3C(=O)N(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A tetrahydrofuran solution of dimethylamine (2 M, 0.32 ml) was added to a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-carboxymorpholino)-2-butynyl]piperazine (0.13 g), 1-hydroxybenzotriazole (85 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) in N,N-dimethylformamide (5 ml), and the whole was stirred at room temperature for 5 hours. After the solvent was removed by evaporation, dichloromethane and sodium hydrogen carbonate solution were added to the residue. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with 3% of methanol in dichloromethane as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-dimethylcarbamoylmorpholino)-2-butynyl]piperazine. It was dissolved in ethyl acetate (10 ml) and the solution was added 4N hydrogen chloride in ethyl acetate (0.26 ml). The mixture was evaporated in vacuo and the residue was triturated with a mixture of ethyl acetate and isopropyl ether to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-dimethylcarbamoylmorpholino)-2-butynyl]piperazine dihydrochloride (0.12 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][C:20]4=[O:25])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22](=[O:38])[CH2:21][C:20]4=[O:25])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCSCC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCS(=O)CC1=O
Temperature: -12.5 °C
Reaction time: 1 h

Procedure:
204 mg (0.48 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide are dissolved in a mixture of 12 ml dichloromethane and 1.2 ml acetic acid at −15° C. and combined with 110 mg (0.48 mmol) 3-chloroperbenzoic acid. The mixture is then stirred for one hour at −15 to −10° C., heated to ambient temperature and stirred for a further 3 hours. Then the reaction mixture is combined with semi-concentrated sodium hydrogen carbonate solution and extracted with a solvent mixture dichloromethane/methanol 19:1. The combined organic phases are washed with water, dried over magnesium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluting gradient: ethyl acetate/(ethanol/conc. ammonia solution 19:1)=1:0->4:1).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([C:11]([CH3:13])=O)=[CH2:10]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:13][C:11]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:8]=2)[N:6]=[CH:10][CH:9]=1
Reactant: Cc1ccc(N)cc1
Reactant: C=CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccc2nccc(C)c2c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirred solution of 4-methylaniline (1 g. 9.3 mmol.) in acetic acid (10 ml), activated silferc (1.5 g. ferric chloride 9.3 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.72 g, 10 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.27 g. 9.3 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 60%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:42](O)=[O:43]>>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:42]([C:34]1[NH:33][C:41]2[C:36]([CH:35]=1)=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:43])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc2ccccc2[nH]1
Yield: 42.1 %

Procedure:
In a manner analogous to that described in Example 27, from 27 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester and 11.3 mg of 2-indolecarboxylic acid there were obtained 15 mg of N-[3(S)-[[N-(2-indolylcarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester: MS: m/e 592 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].Br[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:13][CH2:12][CH2:11][N:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1COCCN1
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COCCN1CCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
Add NaH (0.47 g, 11.8 mmol) to a solution of morpholin-3-one (Vieles, P.; Seguin, J., Bulletin de la Societe Chimique de France, 1953, 287-9) (1.0 g, 9.9 mmol) in DMF (10 ml) at room temperature. Stir for 30 min, add (2-bromo-ethoxymethyl)-benzene (2.2 g, 10.2 mmol), and stir at room temperature for 18 h. Dilute with water and extract with EtOAc (2×). Combine the organics, dry, and concentrate. Purify by flash chromatography using 0-5% MeOH in CH2Cl2, to give the product as an oil. (1.7 g, 74%). 1H NMR (400 MHz, CDCl3): δ 7.28 (m, 5H), 4.48 (s, 2H), 4.13 (s, 2H), 3.80 (t, 2H, J=5.1 Hz), 3.65 (m, 2H), 3.59 (dd, 2H, J=7.5, 2.6 Hz), 3.48 (t, 2H, J=5.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[N:9]2)=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=1.[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:18])[N:10]=[N:9]2)=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1cc(F)ccc1-n1nn[nH]c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(F)ccc1-n1nnn(C)c1=O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of 1-(4-fluoro-2-isopropoxyphenyl)-1H-tetrazol-5(4H)-one (4.10 g, 17.2 mmol, 1 equiv), K2CO3 (7.15 g, 52.0 mmol, 3 equiv), and iodomethane (3.25 mL, 52.0 mmol, 3 equiv) in DMF (40 mL) was stirred at RT ON. The reaction mixture was partitioned between water and EtOAc, then the layers were separated. The aqueous layer was extracted with EtOAc 2×, and the combined organic layer was washed with brine 1×. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 1-(4-fluoro-2-isopropoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (3.50 g, 81%) as a brown oil that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 7.46-7.51 (dd, 1H, J=6.3 Hz, 8.4 Hz), 7.20-7.25 (dd, 1H, J=2.7 Hz, 11 Hz), 6.87-6.94 (td, 1H, J=2.7 Hz, 8.1 Hz), 4.63-4.75 (hept, 1H, J=6.0 Hz), 3.59 (s, 3H), 1.16-1.18 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −107.0 (sextet); m/z=253 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[OH:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][OH:33]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:30]([CH2:31][CH2:32][OH:33])[CH2:29][CH2:28][OH:27])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: OCCNCCO
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN(CCO)CCO)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with bis-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at 50° C. for 3 hours to yield trans-(4-{4-[bis-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 471 (MH+, 1Cl).
Reaction SMILES: C(=O)([O-])O.[K+].Cl[CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:9].[C-:19]#[N:20].[K+].Cl>O>[C:19]([CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:9])#[N:20]
Reactant: O=C(O)CCCCCNC(=O)CCl
Reactant: [C-]#N
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: N#CCC(=O)NCCCCCC(=O)O
Reaction time: 17 h

Procedure:
2.8 g (20 mMol) potassium hydrogen carbonate was added to 8.3 g (40 mMol) 6-(chloracetamido) hexanoic acid dissolved in 25 ml water. 3.2 g (48 mMol) potassium cyanide was then added to the clear solution which was cooled on ice. The reaction mixture was stirred for 17 hours and was then acidified with HCl (2 N). The residue after extraction was purified by chromatography (silica gel, solvent: ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]2=[O:36])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]2=[O:36])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(C1CCN(C(=O)OCc2ccccc2)CC1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CC(C1CCN(C(=O)OCc2ccccc2)CC1)N1CCNCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a solution of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)-3-[4-(tert-butoxycarbonyl)-2-oxopiperazine-1-yl]propionate (4.78 g) in ethyl acetate (15 ml) was added 4N hydrochloric acid in ethyl acetate (15 ml) and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was diluted with water, made basic with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was washed with saturated brine, dried and concentrated to give pale yellow amorphous of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)-3-(2-oxopiperazine-1-yl)propionate (2.34 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].[CH3:11][O:12][C:13](=[O:27])[C:14]1[C:15](=[CH:20][C:21]([N+]([O-])=O)=[CH:22][CH:23]=1)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[CH3:19][O:18][C:16](=[O:17])[C:15]1[C:14](=[CH:23][C:22]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:3])=[CH:21][CH:20]=1)[C:13]([O:12][CH3:11])=[O:27]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OC
Reactant: Nc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Sc2ccccc2N)cc1C(=O)OC
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
Sodium hydride, 60% dispersion in mineral oil, (0.18 g, 4.5 mmol) was added to a solution of 2-aminothiophenol (0.59 ml, 4.0 mmol) in dry DMF (5 ml) at −20° C. The mixture was stirred at −20 to −30° C. for 10 minutes. A solution of 4-nitrophthalic acid dimethyl ester (0.83 g, 3.5 mmol) in dry DMF (5 ml) was added dropwise. The reaction mixture was stirred at −30° C.±5° C. for 1 hour and then at room temperature for 20 hours, poured into icewater (20 ml) and finally extracted with ethyl acetate (3×25 ml). The combined organic phase was washed with water (25 ml), dried over magnesium sulphate, and evaporated to dryness in vacuo. The crude product was purified on silica gel (eluent: methylene chloride) to give 4-(2-aminophenylsulfenyl)phthalic acid dimethyl ester (yield: 0.56 g (51%)) as a golden oil. 1H—NMR (CDCl3) in ppm: δ 3.85 (3H,s); 3.87 (3H,s); 4.29 (2H,broad s); 6.72-685 (2H,m); 7.07 (1H,d.d.); 7.23-7.34 (2H,m); 7.43 (1H,d.d.): 7.63 (1H,d).
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH2:7][CH2:8][CH2:9][N:10]=1)[N+]([O-])=O.N[CH2:12][CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C(C)=CC=CC=1>O>[NH:6]1[CH2:7][CH2:8][CH2:9][N:10]=[C:5]1[NH:1][CH2:12][CH:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCCN1
Solvent: Cc1ccccc1C
Solvent: O
Product: OC(CNC1=NCCCN1)c1ccccc1

Procedure:
A mixture of 7.2 parts of 1,4,5,6-tetrahydro-2-nitraminopyrimidine, 7.55 parts of α-(aminomethyl)benzyl alcohol and 12 parts of xylene is stirred and refluxed for 4 hours on a water-tap. The xylene is evaporated and the residue is dissolved in 20 parts of acetone. The product is crystallized at room temperature. It is filtered off and dried, yielding α-(1,4,5,6-tetrahydro-2-pyrimidinylaminomethyl)benzyl alcohol.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][NH:17]1>>[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][N:17]1[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]2[C:6]=1[CH2:7][C:8](=[O:15])[NH:9]2
Reactant: O=C1Cc2c(OCCCl)ccc(F)c2N1
Reactant: c1ccc2c(c1)CNC2
Product: O=C1Cc2c(OCCN3Cc4ccccc4C3)ccc(F)c2N1
Yield: 75 %

Procedure:
4-(2-Chloroethoxy)-7-fluoro-1,3-dihydro-indol-2-one was reacted with isoindoline in the same manner described for intermediate 16 to afford the title compound in 75% yield as a thick oil. The fumarate salt was prepared in ethanol: mp 210°-212° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]1([Si](C)(C)C)[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3].[B:14](Cl)([Cl:16])[Cl:15]>>[CH3:1][Si:2]([C:5]1([B:14]([Cl:16])[Cl:15])[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C1([Si](C)(C)C)C=CC=C1
Reactant: ClB(Cl)Cl
Product: C[Si](C)(C)C1(B(Cl)Cl)C=CC=C1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
16 g (0.076 mole) of compound 1 were placed in a round bottom flask which was equipped with a dry ice cooling bath. 8.9 g (0.076 mole) BCl3 were condensed at −78° C. in a Schlenk tube and thereafter were added drop-wise to the round bottom flask over a period of 5 minutes. The reaction mixture was slowly heated to room temperature over 1 hour and was then maintained at 55 to 60° C. for a further 2 hours. All the volatile compounds were removed under vacuum (3 mm Hg=4 mbar). Subsequent distillation at 39° C. and 0.012 mbar gave 14.1 g of compound 2 (85% of the theoretical yield). The 1H NMR results agreed with the literature data and showed that a series of isomers had been produced (see J. Organometallic Chem. 169 (1979), 327). 11B NMR (64.2 MHz, C6D6): δ+31.5.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:32]1[N:36]2[C:37]3[C:42]([NH:43][CH2:44][C:35]2=[CH:34][CH:33]=1)=[CH:41][CH:40]=[CH:39][CH:38]=3>O1CCCC1>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:43]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]3[CH:32]=[CH:33][CH:34]=[C:35]3[CH2:44]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: c1ccc2c(c1)NCc1cccn1-2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.51 g of, 4-[(2-methylbenzoyl)-amino]benzoyl chloride and 0.36 g of 1,1'-carbonyldiimidazole in 6 ml of tetrahydrofuran is stirred at room temperature for 1 hour. To the reaction mixture is added 0.17 g of 4,5-dihydropyrrolo-[1,2-a]-quinoxaline followed by heating at reflux for 60 hours. The volatiles are concentrated in vacuo to a residue which is dissolved in ethyl acetate. The organic layer is washed with 1N HCl, 1M NaHCO3, brine, dried with Na2SO4 and filtered through hydrous magnesium silicate. The volatiles are concentrated in vacuo to a residue which is chromatographed by elution with 1:2 ethyl acetate-hexanes to give 0.14 g of the desired product as a white solid, m.p. 206°-2070° C.;
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C@H](CCCCCCCCCCC)CC(O)=O)C1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:23]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dicyclohexylcarbodiimide (963 mg, 4.67 mmol), 4-dimethylaminopyridine (574 mg, 4.70 mmol) and (R)-3-benzyloxytetradecanoic acid (1.50 g, 4.48 mmol) were added to a solution of the compound of Reference Example 5 (1.96 g, 3.71 mmol) in methylene chloride (30 ml) and the mixture was stirred at room temperature for 18 hours. Dicyclohexylurea produced during the reaction was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate. The ethyl acetate layer was successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using cyclohexane:ethyl acetate 4:1 as the eluant to give the desired product (2.79 g, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)nc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(Cl)nc2)cc1
Temperature: 25 °C

Procedure:
A solution of Example 252F (1.56 g, 6.4 mmol) in THF (30 mL) at room temperature was treated with a solution of LiOH.H2O (0.537 g, 12.8 mmol) in water (5 mL), heated to reflux for 4 hours, cooled to room temperature and concentrated. The mixture was neutralized with 1N HCl and extracted ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (APCI) m/e 234 (M+H)+.