Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([F:24])=[C:4]2[O:9][CH2:8][C:7]3([CH2:12][CH2:11][CH2:10]3)[N:6]3[CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15](=[O:18])[C:16]([CH:17]=1)=[C:5]23.[N+:25]([O-])([O-:27])=[O:26].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([F:24])=[C:4]2[O:9][CH2:8][C:7]3([CH2:10][CH2:11][CH2:12]3)[N:6]3[CH:13]=[C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15](=[O:18])[C:16]([C:17]=1[N+:25]([O-:27])=[O:26])=[C:5]23
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A solution of ethyl 9′,10′-difluoro-7′-oxospiro[cyclobutane-1,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (580 mg, 1.73 mmol) in concentrated H2SO4 (7 mL) was treated portion wise at 0° C. with solid KNO3 (245 mg, 2.42 mmol). The reaction mixture was stirred for 1 hour at 0° C. and poured into ice-water. The resulting precipitate was collected by filtration, washed with water and dried to yield the title compound (600 mg, 91%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.30 (3H, t, J=7.3 Hz), 1.93-2.09 (2H, m), 2.16-2.25 (2H, m), 2.73-2.80 (2H, m), 4.26 (2H, q, J=7.3 Hz), 4.69 (2H, s), 8.87 (1H, s). ESIMS (+): 381 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.[CH3:15]S(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl.C(Cl)Cl.[Cl-].[Ti+3].[Cl-].[Cl-]>[CH3:15][O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([OH:1])[CH2:3][C:4]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CS(C)=O
Agent: [Ti+3]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CON1C(C)(C)CC(O)CC1(C)C
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
A solution of 7.2 g (5.6 mmol) of 12% titanium(III) chloride in hydrochloric acid is added dropwise under nitrogen over a 15 minute period to a mixture of 1.0 g (5.8 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 1.0 g (8.8 mmol) of hydrogen peroxide, and 15 ml of dimethyl sulfoxide at a temperature of 20° C. The reaction temperature increases to 30° C. during the addition. The mixture is stirred for 45 minutes after the peroxide addition is complete, and is then diluted with methylene chloride (50 ml). The aqueous layer is neutralized by the addition of a saturated aqueous solution of sodium carbonate, then extracted with methylene chloride (50 ml). The combined organic layers are concentrated under reduced pressure, and the crude product is purified by flash chromatography on silica gel (4:1, heptane:ethyl acetate) to afford 100 mg (10% yield) of the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH3:36][NH:37][CH2:38][CH3:39].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][N:37]([CH2:38][CH3:39])[CH3:36])=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: CCNC
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(C)Cc1ccc2c(c1)cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 61.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with N-methylethylamine (0.160 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (211 mg, 0.996 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(N-methylethylaminomethyl)indol-2-yl]isoindolinone (67.0 mg, yield 62%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([CH:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].C=O.O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([CH:27]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28]3)([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: OC(c1cccnc1)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)C1CCCNC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: CN1CCCC(C(O)(c2cccnc2)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)C1
Reaction time: 8 h

Procedure:
To a mixture of (2,4-dichloro-3-phenylquinolin-6-yl)(piperidin-3-yl)pyridin-3-ylmethanol•TFA (15 mg, 0.022 mmol, Example 93), 37% formaldehyde in water (0.010 mL, 0.13 mmol) and MeOH (1 mL) was added NaBH3CN (4.0 mg, 0.064 mmol). The mixture was stirred overnight and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4) δ 8.95 (s, 1H), 8.54-8.68 (m, 2H), 8.41 (d, J=7.58 Hz, 1H), 7.96-8.13 (m, 2H), 7.72 (dd, J=5.14, 7.58 Hz, 1H), 7.53 (d, J=7.09 Hz, 3H), 7.33 (d, J=6.85 Hz, 2H), 3.48-3.64 (m, 1H), 3.10-3.21 (m, 1H), 2.96-3.10 (m, 1H), 2.83-2.97 (m, 1H), 2.80 (s, 3H), 2.66 (s, 1H), 2.01-2.13 (m, 1H), 1.82-2.01 (m, 1H), 1.54-1.82 (m, 2H); MS m/e 478.0 [M+H]+.
Reaction SMILES: NC1C=C(C=CC=1)CNC(=O)OC(C)(C)C.[CH3:17][NH:18][C:19]1[CH:20]=[C:21]([CH:31]=[CH:32][CH:33]=1)[CH2:22][NH:23]C(=O)OC(C)(C)C.C=O.C([BH3-])#N.[Na+]>>[NH2:23][CH2:22][C:21]1[CH:20]=[C:19]([CH:33]=[CH:32][CH:31]=1)[NH:18][CH3:17]
Reactant: CNc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: C=O
Agent: CC(C)(C)OC(=O)NCc1cccc(N)c1
Agent: [BH3-]C#N
Product: CNc1cccc(CN)c1

Procedure:
Tert-butyl 3-aminobenzylcarbamate was converted to tert-butyl 3-(methylamino)benzylcarbamate following standard reductive amination conditions using formaldehyde and sodium cyanoborohydride. 3-(aminomethyl)-N-methylaniline was then generated by removal of the Boc protecting group by treatment with HCl (in methanol or dioxane) or trifluoroacetic acid in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(O)(=O)C.CCOCC>C(O)C.Cl.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(N)ccc1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Chloro-5-nitroanisol (10 g, 0.053 mol), iron powder (15 g, 0.26 mol) and glacial acetic acid (20 ml, 0.355 mol) were combined in 125 ml ethanol. Concentrated HCl (2 drops) was added and the mixture refluxed 2 hours. Additional iron powder (5 g) and concentrated HCl (1 drop) were added and reflux continued for an additional 16 hours. The reaction mixture was cooled, poured into equal volumes each of ice/water and ether, filtered and the layers separated. The aqueous layer was extracted with fresh ether and the combined ether layers extracted with 1N HCl. The original aqueous and 1N HCl extract were combined, the pH adjusted to 6 with saturated Na2CO3 and extracted with fresh ether. The last ether extract was dried over MgSO4 and stripped to yield title product, 82 g, m.p. 77°-79° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[O-:10][C:11]#[N:12].[Na+].Cl>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:11]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)NCc1ccc(Cl)cc1

Procedure:
100 ml of 95% 4-chlorobenzylamine and 51.53 g of sodium cyanate in 1 liter of water were treated below 25° C. with 194 ml of 4N HCl. Further sodium cyanate (5.15 g) was added and the pH adjusted to 7.3. After 3 days the solid was collected, washed with water and dried to give the title compound (131.1 g) as a white solid mp 186-9° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CN1C(=O)CCC1.[OH-].[K+].[CH:25]([C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][N:36]2C(=O)C3C(=CC=CC=3)C2=O)=[N:31][CH:32]=1)=[CH2:26]>O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][CH2:25][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][NH2:36])=[N:31][CH:32]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(CCCN2C(=O)c3ccccc3C2=O)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(CCCN)nc2)CCN(C)C1
Temperature: 120 °C
Reaction time: 12 h
Yield: 44.1 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.005 mol) was taken into NMP (3 mL), and to it was added finely crushed KOH (280 mg, 0.005 mol) and 2-(3-(5-vinylpyridin-2-yl)propyl)isoindoline-1,3-dione (146 mg, 0.005 mol). The reaction was heated at 120° C. for 12 h. The reaction was monitored by LCMS. After 12 h, 2 mL of water was added to the reaction mixture and heated at 120° C. for 12 h. The reaction was monitored by LCMS. After completion of reaction the mixture was cooled and water was added, followed by extraction with EtOAc. The organic extract was dried over sodium sulfate and concentrated under vacuum to yield 800 mg of crude product. 1HNMR (CDCl3, Oxalate salt) d (ppm): 8.17 (s, 1H), 7.22 (s, 1H), 1.18 (d, 1H), 7.15 (d, 1H), 6.95 (m, 2H), 4.20 (t, 2H), 3.70 (s, 2H), 3.0 (t, 2H), 2.90 (t, 2H), 2.80 (t, 2H), 2.70 (t, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 2.37 (m, 2H), 1.80 (t, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH:18]([CH3:20])[CH3:19].C(O)(=O)C.C(O)(=O)C.C(N)CN>C(O)C.C(OCC)(=O)C>[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH:32]=[C:6]3[S:5][C:4](=[S:7])[N:3]([CH:8]4[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]4)[C:2]3=[O:1])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Reactant: CC(C)Cc1ccc(-c2ccc(C=O)o2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: NCCN
Product: CC(C)Cc1ccc(-c2ccc(C=C3SC(=S)N(C4CCCC(C(=O)O)C4)C3=O)o2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 72 %

Procedure:
A mixture of 3-(4-oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (0.075 g, 0.29 mmol), 5-(4-isobutyl-phenyl)-furan-2-carbaldehyde (0.069 g, 0.30 mmol) and ethylenediamine diacetate (0.057 g, 0.32 mmol) in anhydrous ethanol (12 mL) was stirred 30 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (250 mL) and extracted with 0.6 N aq. sodium hydrogensulfite (2×50 mL). The organic layer was separated, dried over sodium sulfate and concentrated. The residue was triturated with hot acetonitrile (5 mL) and allowed to cool to room temperature. The product was filtered off, washed on the funnel with acetonitrile (0.5 mL) and dried in a vacuum oven at 60° C. for 17 h to afford 3-{5-[1-[5-(4-isobutyl-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-cyclohexanecarboxylic acid (98 mg, 72%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (6H, d, J=6.4 Hz), 1.16-1.45 (2H, m), 1.68 (1H, m), 1.84-1.92 (4H, m), 2.25-2.54 (3H, m), 4.98 (1H, m), 7.27 (1H, d, J=3.6 Hz), 7.36 (2H, m), 7.36 (1H, d, J=3.6 Hz), 7.58 (1H, s), 7.77 (2H, m), 12.22 (1H, s). LC/MS: APCI 469.51, HPLC 100%.
Reaction SMILES: [C:1](O)(=O)CCCCCCCCCCCCCCC.[C:19]([OH:38])(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.CC/C=C\C/C=C\C/C=C\CCCCCCCC(O)=O>>[CH3:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]/[CH:28]=[CH:27]\[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]([O:38][CH3:1])=[O:37]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC

Procedure:
Fatty acid methyl ester mixture based on a fatty acid mixture with the following composition: 5% palmitic acid, 1% stearic acid, 67% oleic acid, 11% linolenic acid (a product of Henkel KGaA).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([O:17]CC)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:20]([OH:22])[CH3:21].[OH-].[K+]>O>[C:20]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:22])[CH3:21]
Reactant: CCOC(=O)c1cnc(-c2cccc(N)c2)nc1O
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cccc(-c2ncc(C(=O)O)c(O)n2)c1

Procedure:
The crude residual 2-(m-aminophenyl)-4-hydroxy-5-carbethoxypyrimidine is heated for 4.5 hrs. in 150 ml. of ethanol containing 1.12 g. (0.02 mole) of potassium hydroxide and 25 ml. of water. The mixture is concentrated under reduced pressure to a small volume and sufficient 6N hydrochloric acid added such that the aqueous phase is just acid to Congo red paper. The resulting solid, 2-(m-aminophenyl-4-hydroxy-5-carboxypyrimidine, is filtered and dried.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:30])=[C:6]([P:23]2(=[O:29])[O:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:2].[B-].[Na+].[Cl-].[Na+]>CO>[OH:2][CH2:1][C:3]1[NH:4][C:5]([CH3:30])=[C:6]([P:23]2(=[O:29])[O:24][CH2:25][CH2:26][CH2:27][O:28]2)[CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])[C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1=C(C=O)NC(C)=C(P2(=O)OCCCO2)C1c1ccccc1C(F)(F)F
Agent: [B-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=C(CO)NC(C)=C(P2(=O)OCCCO2)C1c1ccccc1C(F)(F)F
Yield: 60.1 %

Procedure:
The 2-formyl compound (1.06 g) obtained in Example 5 was dissolved in 7 ml of methanol and, with ice cooling and stirring, 90 mg of sodium borohydrate was added thereto. After stirring for 1 hour, 20 ml of sodium chloride solution was added to the reaction solution, extracted with chloroform, the chloroform layer was washed with water, dried, concentrated, and the residue was purified by a flash chromatography to give 0.64 g of pale yellow powder.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[CH3:20][O:21]C1C=CC(OC)=CC=1C=O>>[CH3:19][O:18][C:5]1[CH:4]=[CH:3][C:2]([O:21][CH3:20])=[CH:7][C:6]=1[CH:8]([OH:17])[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1ccc(OC)c(C(O)C#Cc2ccccc2)c1
Yield: 93 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,5-dimethoxybenzaldehyde (1.00 g, 6.02 mmol) was reacted to give the title compound (1.50 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 7.42-7.34 (m, 5H), 7.18-7.15 (d, 1H), 6.97-6.94 (d, 1H), 6.87-6.83 (m, 1H), 6.03-6.01 (d, 1H), 5.77-5.74 (d, 1H), 3.78 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][NH:9]P(=O)(OCC)OCC)=[CH:4][CH:3]=1.C(OC(C)C)(C)C.[ClH:25].P(N)(=O)([O-])[O-]>>[ClH:25].[Br:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1
Reactant: CCOP(=O)(NCCc1ccc(Br)s1)OCC
Agent: Cl
Agent: NP(=O)([O-])[O-]
Solvent: CC(C)OC(C)C
Product: NCCc1ccc(Br)s1
Yield: 60 %

Procedure:
A solution containing 3.42 g. (0.01 mol) diethyl N-[2-(5-bromothien-2-yl)-ethyl]-phosphoramidate in 50 ml. diisopropyl ether saturated with hydrogen chloride is stirred overnight at ambient temperature. The crystals formed are filtered off and washed with diisopropyl ether. After drying, there is obtained 1.45 g. (yield: 60%, referred to the phosphoramidate used) of the desired product in the form of silverygrey flakes; m.p. 220° C. (decomposition)
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:17])[CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[N:12][C:13]=2[C:14]=1[O:15]C)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:22][NH2:23].[Cl-].[Al+3].[Cl-].[Cl-].C([O-])(O)=O.[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:22][NH:23][C:3]([C:5]1[N:6]([CH3:17])[CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[N:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)C1=C(OC)c2ncccc2CN1C
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CN1Cc2cccnc2C(O)=C1C(=O)NCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 124G (150 mg, 0.64 mmol), 3,5-dichlorobenzylamine (153 mg, 0.87 mmol) and aluminum chloride (27 mg, 0.20 mmol) in toluene (8 mL) was refluxed for 4 h under nitrogen. After cooling to room temperature, the reaction mixture was treated with aqueous saturated NaHCO3 solution and ethylenediaminetetraacetic acid (1 g, 3.4 mmol) to pH 7. The mixture was extracted with chloroform four times. The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by preparative reverse-phase HPLC to give 124H.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: c1ccc(CN2CCN(c3ccc(-c4ccccc4)cc3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 12.45 g (0.037 mol) of 1-benzyl-4-biphenyl-4-yl-piperazine and 4 g of palladium hydroxide in 360 ml of methanol is stirred for 6 hours at ambient temperature in a Parr apparatus under a hydrogen pressure of 50 psi. The catalyst is separated off and the filtrate is evaporated down.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>O=S(Cl)Cl.CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[C:4]=3[N+:16]([O-:18])=[O:17])[N:9]=[CH:8][N:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Reactant: Nc1cccc(Br)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (1.0 g, 3.98 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) was added a few drops of DMF (0.05 mL). The reaction mixture was then heated with stirring at 90° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then 3-bromoaniline (0.69 g, 3.98 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The solvents were removed and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.05) as eluent to give the desired (3-bromo-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine as a yellow solid. (Yield 1.2 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[N:9]1[C:20](=[O:41])[CH2:21][NH:22][C:23](=[O:40])[NH:24][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([O:30]CC[Si](C)(C)C)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[N:9]1[C:20](=[O:41])[CH2:21][NH:22][C:23](=[O:40])[NH:24][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[C:28]([OH:30])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2Cl)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2Cl)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 38.8 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 41, but starting from 2.0 g of 2-trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-chlorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate and 6.5 cm3 of 1M tetrabutylammonium fluoride solution. The crude product is purified by chromatography on silica [eluent: ethyl 0.65 g of acetate/methanol (90/10 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in diisopropyl ether, 0.65 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-chlorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoic acid is thus obtained in the form of an amorphous solid ([α]D20 =+88°±2° (C=0.39%; CHCl3)) [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 7.3 to 7.6 (m, 7H, aromatic); 7.95 (bs, 1H, N--C6H4 -- in position 2). Infrared spectrum (KBr), characteristic bands in cm-1 : 3390, 2985, 2940, 2600, 1735, 1660, 1610, 1560, 1375, 1240, 1155, 755, 685].
Reaction SMILES: [CH3:1][NH:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(C)[C:4]#[N:5].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH3:1][NH:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][NH2:5]
Reactant: CNC(C)(C#N)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CNC(CN)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 106.7 %

Procedure:
A solution of 2-methylamino-2-phenyl-propionitrile (7.8 g) in toluene (60 mL) was cooled to −78° C. and DIBAL-H solution (104 mL of a 20% solution in toluene) was added drop wise under nitrogen. The reaction mixture was slowly warmed to room temperature and then left at stirring for 17 h. After completion, the reaction mixture was quenched with 30 mL methanol and then 100 mL water. All solvents were evaporated and crude material was taken into 50 mL of water and acidified to pH=1 with 1N HCl. The mixture was extracted with ethyl acetate and separated, and the aqueous layer was basified to pH=14 with 30% NaOH solution. The free diamine was extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated to obtain the desired known N1-methyl-1-phenylethane-1,2-diamine (CAS 66308-14-3) (7.8 g) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[CH:10]=[C:11]([Cl:16])[C:12](Cl)=[N:13][CH:14]=1>CN(C=O)C.C(OCC)(=O)C.O>[Br:8][C:9]1[CH:10]=[C:11]([Cl:16])[C:12]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:13][CH:14]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(Br)cnc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of cyclopropylmethanol (4.64 mL) in DMF (100 mL) was added sodium hydride (60% oil, 2.29 g), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 5-bromo-2,3-dichloropyridine (10.0 g), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (8.11 g).