Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2](=[O:35])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]2[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1.[OH-].[Na+].C([OH:40])C.Cl>O>[C:23]([O:22][C:21]([NH:20][CH2:19][C:9]1[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:11][C:12]2[C:7]([C:8]=1[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[CH:6][C:5]([CH2:4][CH2:3][C:2]([OH:40])=[O:35])=[CH:14][CH:13]=2)=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: CCO
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCC(N)=O)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCC(=O)O)cc23)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of tert-butyl [6-(3-amino-3-oxopropyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (2.38 g, 5.0 mmol), 4N aqueous sodium hydroxide solution (12.5 ml, 50 mmol) and ethanol (20 ml) was stirred at 80° C. for 2 hrs. The reaction mixture was poured into water, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]propanoic acid (2.01 g, yield 84%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Product: COc1ccc(NC(=O)c2ccc(Cl)cc2[N+](=O)[O-])cc1
Yield: 92.4 %

Procedure:
The title compound was prepared from 4-chloro-2-nitro-benzoic acid (6.0 g, 30 mmol) and p-anisidine (4.0 g, 33 mmol) using the procedure of step 1 of the Example 1 to provide the title compound (8.5 g, 90%).
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](Cl)=[O:16])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47].C(N(CC)CC)C>C(Cl)Cl>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][CH2:44][NH:43][C:15](=[O:16])[C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C@@H:12]([C:10]([O:9][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Reactant: NCCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pivaloyloxymethoxycarbonyl)-2,4-(R*,R*)-dibenzylbutyryl chloride (1.2 g) in 10 ml of methylene chloride is added slowly to a solution of 1.15 g of benzyl 3-aminopropionate p-toluenesulfonic acid salt and 0.46 ml of triethylamine in 20 ml of methylene chloride. The reaction is stirred overnight at room temperature. The solution is washed with 2N hydrochloric acid, then with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to give N-[4-pivaloyloxymethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid benzyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCN(C(=O)Nc2noc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added isopropyl chloroformate (0.102 ml, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 90.0 mg (48.9%) of the desired product as a solid.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Cl[C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1>CO>[CH:1]1([CH2:4][NH:5][C:7]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1CC1
Solvent: CO
Product: O=C(O)c1cnc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Cyclopropanemethylamine (1.70 g, 23.90 mmol) was added to a solution of 6-chloro-5-nitronicotinic acid (1.12 g, 5.53 mmol) in MeOH (25 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was dissolved in H2O (20 mL), and the solution was acidified by adding 3N HCl until pH=3. The mixture was extracted with EtOAc and CH2Cl2 (2×100 mL) and the combined extracts were washed with brine, dried over Na2SO4, concentrated in vacuo to give a bright yellow solid (1.30 g) which was used in the following reaction without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:23][O:24][CH3:25])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH:13]2[CH2:14][N:11]([CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:23][O:24][CH3:25])[CH2:12]2)=[CH:21][CH:20]=1
Reactant: COC[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](N)CCN1CC(Oc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-carbamic acid tert-butyl ester (0.87 g, 2.26 mmol) in dichloromethane (7 ml) is treated with trifluoroacetic acid (2 ml), and stirred at ambient temperature for 18 hours. The solvent is evaporated and the residue taken up in water, made alkali with 4.0 M aqueous sodium hydroxide solution and extracted into dichloromethane. The organic phase is dried over MgSO4 and evaporated to afford (S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propylamine. [MH]+ 285.20
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.[N+:9]([C:12]1[CH:22]=[CH:21][C:15]([CH2:16][O:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10].[OH-].[Na+].Cl>O.O1CCCC1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]([N:3]2[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]2)=[O:19])=[CH:21][CH:22]=1)([O-:11])=[O:10]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@@H]1CSCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 116.2 %

Procedure:
To a solution of (R)-thiazolidine-4-carboxylic acid (20.0 g) in a mixture of water (100 ml) and tetrahydrofuran (100 ml) was added a solution of 4-nitrobenzyloxycarbonyl chloride (32.4 g) in tetrahydrofuran (60 ml) under ice-cooling with stirring, keeping the pH between 8.5 and 9.0 with 4N aqueous sodium hydroxide. After stirring for 30 minutes, the mixture was adjusted to pH 1 with concentrated hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, and evaporated under reduced pressure to give (R)-3-(4-nitrobenzyloxycarbonyl)thiazolidine-4-carboxylic acid (54.5 g) as a crude syrup.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][CH2:8][N:9]1[CH2:29][CH2:28][C:12]2([O:17][CH2:16][CH2:15][N:14]([C:18]([C:20]3[N:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[S:23][CH:24]=3)=[O:19])[CH2:13]2)[CH2:11][CH2:10]1.[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[CH:34]=[CH2:35].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(#N)C>[CH:25]([C:22]1[S:23][CH:24]=[C:20]([C:18]([N:14]2[CH2:13][C:12]3([CH2:28][CH2:29][N:9]([CH2:8][CH2:7][C:6]4[CH:5]=[C:4]([CH:32]=[CH:31][CH:30]=4)[CH2:3][CH2:2][O:1][CH2:35][CH2:34][C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH2:11]3)[O:17][CH2:16][CH2:15]2)=[O:19])[N:21]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCO)c4)CC3)C2)cs1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC#N
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4cccc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (9-(3-(2-hydroxyethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (limiting reagent) in acetonitrile (5 volumes) was added tert-butyl acrylate (5 molar equivalents) followed by benzyltrimethylammonium hydroxide solution (40% by weight in water, 0.3 molar equivalents). The mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[O:5][C:6]1[S:27][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[N:12]([CH2:15][CH2:16][CH2:17]OC3CCCCO3)[C:13](=[O:14])[C:8]=2[C:7]=1[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)O.[SiH](CC)(CC)CC.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>CC(=O)OCC.O>[F:50][C:49]([F:52])([F:51])[C:47]([O:53][CH2:17][CH2:16][CH2:15][N:12]1[C:13](=[O:14])[C:8]2[C:7]([CH2:28][C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[C:6]([O:5][C:4]3[CH:37]=[CH:38][CH:39]=[C:2]([Cl:1])[CH:3]=3)[S:27][C:9]=2[N:10]([CH3:26])[C:11]1=[O:25])=[O:48]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of 6-(3-chlorophenoxy)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (45 mg, 0.076 mmol) in TFA (0.9 mL) was added Et3SiH (0.3 mL). The reaction was stirred at RT for 15 min then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (40 mg, 89.5% yield) as an oil. LCMS: MH+ 587 and TR=2.308 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].[Cl:35][C:36]1[CH:41]=[CH:40][C:39](I)=[CH:38][CH:37]=1>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:39]3[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)NCc1cc(-c2ccn(-c3ccc(Cl)cc3)n2)ccc1Cl

Procedure:
To a mixture of methyl N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]carbamate (i.e. the product of Step B, Example 4) (0.2 g, 0.75 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.043 g, 0.3 mmol), copper(I) iodide (0.03 g, 0.15 mmol) and potassium carbonate (−325 mesh) (0.622 g, 4.5 mmol) in dioxane (4 mL) was added 1-chloro-4-iodobenzene (0.27 g, 1.13 mmol). The reaction mixture heated at reflux overnight and then concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.156 g) melting at 151-153° C.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6].[Cr](O)(O)(=O)=[O:25].O>CC(C)=O>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:25])=[O:23])[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[Cr](=O)(O)O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(CO)c1
Solvent: O
Solvent: CC(C)=O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(C(=O)O)c1
Yield: 98.3 %

Procedure:
To (E)-methyl 3-methoxy-2-(2-[3-hydroxymethylphenoxy]phenyl)propenoate (2.43 g, prepared as described in Example 17) stirred in acetone (100 ml) at 5°-10° C., was added chromic acid [made by dissolving chromium trioxide (6.5 g) in 18.5 ml water containing 5.5 ml of concentrated sulphuric acid]until a reddish brown colour persisted, and GC indicated the disappearance of all the starting alcohol. The mixture was then poured into water and extracted with ether. The ether extracts were washed with water, dried and evaporated to give (E)-methyl 3-methoxy-2-(2-[3-carboxyphenoxy]phenyl)propenoate as a pale yellow oil (2.495 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C[C:31]([N:33](C)C)=O>[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14]([C:31]#[N:33])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1ncc2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 3-bromo-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (200 mg), Zn(CN)2 (31 mg), Zn dust (3.5 mg), Pd2(dba)3 (20 mg), dppf (24.4 mg) in DMA (1 mL) was heated to 120° C. for 145 min; then the mixture was partitioned between EtOAc and water, the organic phase was then washed with sat. NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated sequentially to give a residue, which was purified with column to give desired title compound (83 mg). The title compound, ESI MS (m/z): 402 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:29]2[CH2:30][CH2:31][N:32]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:33][CH2:34]2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-[(4-chloro-phenyl)-phenyl-methyl]-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C29H31ClN2O5 [M+H]+: 524.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].Cl>ClCCl.N1C=CC=CC=1>[CH2:25]([N:27]([CH2:28][CH3:29])[S:16]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH:6]=1)(=[O:18])=[O:17])[CH3:26]
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Reactant: CCNCC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(Cl)cc2Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.08 g, 2.50 mmol) was dissolved in dichloromethane (5 ml) and at 0° C. added dropwise to a solution of diethylamine (0.30 ml, 2.51 mmol) in pyridine (20 ml). The mixture was stirred for 1 hour at 0° C., acidified with 1N HCl and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent was evaporated off. The residue was purified by chromatography (silica gel, CH2Cl2). Yield: 0.22 g=19% 13C (100 MHz, DMSO-d6) δ 149.98, 147.50, 136.21, 132.37, 130.43, 129.63, 129.21, 126.15, 123.56, 122.86, 122.72, 114.90, 41.77, 41.02, 14.02
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]=[C:31]=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: COc1cc(N=C=O)cc(OC)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: COc1cc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)cc(OC)c1

Procedure:
87 mg of solid yellow 3-{4-[3-(3,5-dimethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3,5-dimethoxyphenyl isocyanate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[S:10][C:9]=1[NH:17][C:18]([NH2:20])=[NH:19].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C)C=O>[CH2:2]([N:13]1[CH2:14][CH2:15][C:16]2[N:8]=[C:9]([NH:17][C:18]([NH2:20])=[NH:19])[S:10][C:11]=2[CH2:12]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCc2nc(NC(=N)N)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-bromohexane (0.11 mmol) is added to a suspension of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)-guanidine (0.1 mmol) and caesium carbonate (0.22 mmol) in dimethylformamide (0.3 ml) and the reaction mixture is stirred overnight at room temperature. After adding 2M caustic soda solution (1 ml) the mixture is extracted with ethyl acetate, the combined organic phases are dried over sodium sulphate and then concentrated by evaporation, the title compound being obtained in pure form.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].Br[Mg][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(OCC)C.Cl.O>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]([CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[OH:8]
Reactant: Cc1oc(-c2ccccc2)cc1C=O
Reactant: Br[Mg]C1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)cc1C(O)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-methyl-5-phenylfuran-3-carbaldehyde (1.9 g) in tetrahydrofuran (30 mL) was added dropwise bromo(tetrahydro-2H-pyran-4-yl)magnesium-diethyl ether solution (30 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (10% ethyl acetate/hexane to 40% ethyl acetate/hexane) to give the title compound (2.3 g, 86%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13]O)[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1.[C:29](O)(=O)[CH3:30].C(=O)C.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:29]([CH3:30])=[N:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1
Reactant: ON=C(C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1)N1CCOCC1
Reactant: CC(=O)O
Agent: CC=O
Solvent: ClCCl
Solvent: CCO
Product: Cc1nc(N2CCOCC2)c2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A mixture of 0.4 g of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine, 5 ml of glacial acetic acid and 0.4 ml of acetaldehyde was heated to reflux for 5 minutes. The usual workup and chromatography of the crude reaction mixture on 5 g of silica gel using 5% (v/v) of ethanol in methylene chloride gave yellow crystalline product identical with that described above.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:21])[C@@H:11]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[BH4-].[Na+]>CO.C(Cl)Cl>[O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:10]2)[CH2:7][CH2:6]3
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](N3CCCC3)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reaction time: 12 h

Procedure:
After dissolving 39.2 g of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17-one in a mixture of 392 ml of methanol and 56 ml of methylene chloride. 14.7 g Sodium borohydride are portionwise added while stirring and introducing nitrogen at such a rate that the temperature reaches room temperature as a maximum. The solution containing a precipitate is left to stand for 12 hours, then methylene chloride is evaporated, and the residue is diluted with water. The precipitate is filtered, thoroughly washed with water, dried and recrystallized from methanol to obtain the title product in a yield of 33.3 g (89.5%), m.p.: 167°-169° C.