Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[CH:7]=[O:8].CC(=CC)C.C1C[O:17]CC1.Cl([O-])=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:17])=[O:8]
Reactant: O=Cc1[nH]ccc1Br
Reactant: C1CCOC1
Agent: CC=C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1[nH]ccc1Br
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a solution of 3-bromo-1H-pyrrole-2-carbaldehyde (0.44 g, 2.53 mmol) in tert-butanol (5.0 ml) was added 2-methyl-2-butene/2M in THF (5.09 ml, 48.0 mmol). To the reaction mixture was added sodium phosphate mono-H2O (2.461 g, 17.70 mmol) and sodium chlorite (2.058 g, 22.76 mmol) dissolved in water (5.00 ml) at RT over a period of 15 min. The solution was stirred overnight. The reaction mixture was acidified to pH˜4 with 10% aqueous citric acid and extracted with EtOAc (5×30 mL). The organic layers were combined, dried over sodium sulfate filtered and evaporated. The crude material was triturated with minimal amount of EtOAc to afford 3-bromo-1H-pyrrole-2-carboxylic acid (0.35 g, 73% yield) as a tan solid. The filtrate solution was evaporated to afford an impure mixture of the product as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.55 (br. s., 1H) 12.00 (br. s., 1H) 6.96 (t, 1H) 6.26 (t, 1H). MS: m/z 188.0 (M−1).
Reaction SMILES: [CH2:1]([O:9][P:10]([CH2:13][CH2:14][O:15]C(=O)C)([CH3:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl>CO>[CH2:1]([O:9][P:10]([CH2:13][CH2:14][OH:15])([CH3:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOP(C)(=O)CCOC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCOP(C)(=O)CCO
Yield: 82.5 %

Procedure:
100 g of 2-acetoxyethyl-methyl phosphinic acid n-octyl ester are heated to 65°-70°C in 200 ml of methanol containing 0.5 wt.% of HCl, while simultaneously removing by distillation a mixture of methyl acetate/methanol. After distillation under reduced pressure 70 g of 2-hydroxyethyl-methyl-phosphinic acid-n-octyl ester (b.p. 139°C/0.2 torr) are obtained, corresponding to a yield of 82.5% of the theoretical.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:12]2[C:13]3[C:14](=[O:22])[C:15]([F:21])([F:20])[CH2:16][C:17]=3[CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Mg]Br>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:12]2[C:13]3[C:14]([OH:22])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])[C:15]([F:21])([F:20])[CH2:16][C:17]=3[CH:18]=[CH:19][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCc2ccc3c(c2CC1)C(=O)C(F)(F)C3
Solvent: CCOCC
Product: COc1ccccc1C1(O)c2c(ccc3c2CCN(C(=O)OC(C)(C)C)CC3)CC1(F)F
Temperature: 25 °C
Yield: 84.5 %

Procedure:
Into a glass vial containing the product from step (b) (130 mg, 0.385 mmol) in diethyl ether (5 ml), 2-methoxyphenyl magnesium bromide (3.85 ml, 1.92 mmol) was added. The reaction mixture was stirred at reflux for 30 minutes. The reaction was cooled to room temperature, quenched with of 10% aqueous NH4Cl (50 ml), and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and the solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexanes) gave the sub-title compound as a yellow oil (145 mg). MS: ESI (positive): 446 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH:13](OC)=[O:14]>COCCOC>[F:3][C:4]([F:12])([F:11])[CH2:5]/[C:6](=[CH:13]/[OH:14])/[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC=O
Reactant: COC(=O)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)/C(=C\O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a suspension of NaH (0.512 g, 12.81 mmol) in DME (15 mL) was added a solution of methyl 4,4,4-trifluorobutanoate (1 g, 6.41 mmol) and methyl formate (0.594 mL, 9.61 mmol) in DME (10 mL) dropwise at 0° C. The mixture was stirred at room temperature overnight. After removing the solvent, the residue was diluted with water (50 mL), extracted with ether once, and neutralized to pH<7 by AcOH. The aqueous layer was separated and extracted with EA twice. The combined organic phase was dried over sodium sulfate, filtered, and concentrated to afford the title compound (0.875 g, 4.75 mmol, 74.2% yield). LCMS: rt=2.23 min, [M+H+]=185
Reaction SMILES: C([O:3][C:4](=[O:31])[C@@H:5]([NH:7][C@H:8]([C:23](=[O:30])[NH:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:6])C.[OH-].[Na+].Cl>CCO>[Cl:22][C:18]1[CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]([NH:7][C@@H:5]([CH3:6])[C:4]([OH:31])=[O:3])[C:23](=[O:30])[NH:24][C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
(S)-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester (100 mg, 0.226 mmol) was treated with 2M aqueous NaOH (2 mL) and EtOH (0.5 mL). After stirred at room temperature for 1 hour, the reaction mixture was acidified with 2M HCl to adjust pH 1. The resulted precipitate was collected by filtration. The obtained material was crystallized from EtOH to give (S)-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid (94 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7](N)=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.Cl.N([O-])=O.[Na+].[I-:15].[K+]>O>[Cl:1][C:2]1[C:7]([I:15])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)c1N
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccnc(Cl)c1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A mixture of 2-chloro-4-methylpyridin-3-amine (1.0 g, 7.0 mmol) and concentrated hydrochloric acid (4.4 mL) was cooled to 0° C. and a solution of sodium nitrite (0.5 g, 7.5 mmol) in water (8 mL) was added dropwise. The mixture was stirred for 1 hour at 0° C. and then was added dropwise to a stirred solution of potassium iodide (1.6 g, 9.6 mmol) in water (9 mL). The mixture was warmed to ambient temperature and stirred overnight. The mixture was extracted with diethyl ether and the organic phase was washed with aqueous sodium thiosulphate, brine, dried (MgSO4) and evaporated in vacuo. The crude product was recrystallized from hexane to give the title compound (0.88 g, 47%) as a white solid.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][C:2]1=[C:6]([C:13](C(OOCC)=O)=[O:14])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1>>[S:3]1[CH2:4][CH2:5][S:1][C:2]1=[C:6]([C:13](=[O:14])[NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: Cc1csc(N)n1
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCCS1
Product: Cc1csc(NC(=O)C(C(=O)OC(C)C)=C2SCCS2)n1

Procedure:
Following the procedure of Example 22, the titled compound was prepared as a white solid (41%) from isopropyl 2-(1,3-dithiolan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate and 2-amino-4-methylthiazole.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](I)=[C:11]([CH:24]=1)[CH2:12][O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].C(O[CH:30]1[NH:33][C:32](=[O:34])[CH2:31]1)(=O)C.[Cl-].[NH4+].[OH-].[NH4+]>CCOCC.CSC.C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:30]2[NH:33][C:32](=[O:34])[CH2:31]2)=[C:11]([CH2:12][O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:24]=1
Reactant: CC(=O)OC1CC(=O)N1
Reactant: CC(C)[Si](OCc1cc(Cl)ccc1I)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)[Si](OCc1cc(Cl)ccc1C1CC(=O)N1)(C(C)C)C(C)C
Temperature: -50 °C
Yield: 86 %

Procedure:
n-Butyl-lithium (2.5 M solution in hexanes, 3.6 mL) was added to stirred solution of [(5-chloro-2-iodobenzyl)oxy](triisopropyl)silane (3.82 g, 9.0 mmol) in ether (18 mL) at −78° C. under nitrogen. After 10 min a solution of copper(I) bromide-dimethylsulfide complex (0.925 g, 4.5 mmol) in dimethylsulfide (36 mL) was added and the solution was warmed to −50° C. A solution of 4-acetoxy-2-azetidinone (0.291 g, 2.25 mmol) in THF (2 mL) was added and the solution was warmed to −30° C. After a further 1 h the reaction was poured into 10% ammonium chloride solution basicified with ammonium hydroxide and extracted into ether. The organic layer was dried (Na2SO4) and evaporated in vacuo to an oil which was purified by flash column chromatography on silica (eluting with 5% methylene chloride/0-50% ethyl acetate/hexanes gradient) to give 4-(4-chloro-2-{[(triisopropylsilyl)oxy]methyl}phenyl)azetidin-2-one (0.712 g) as a heavy oil: 1H NMR (CDCl3, 400 MHz) δ 1.08 (d, J=6.4 Hz, 18H), 1.16 (septet, J=6.4 Hz, 3H), 2.78 (dd, J=2.6, 14.8 Hz, 1H), 3.45 (dq, J=14.8, 2.6 Hz, 1H), 4.72 (d, J=13.1 Hz, 1H), 4.78 (d, J=13.1 Hz, 1H), 4.94 (q, J=2.6 Hz, 1H), 6.06 (br s, 1H), 7.30 (dd, J=2.1, 8.4 Hz, 1H), 7.43 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:30]([O:32]CC)=O)=O)[CH2:13][CH2:12]1.O.[NH2:36][NH2:37]>C(O)C>[NH2:36][N:37]1[C:30](=[O:32])[C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=2[N:23]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)C1=C(NC(=O)CCCCN2CCN(c3ccc4ccccc4n3)CC2)CCCC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nn1c(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CCCC2
Reaction time: 4 h
Yield: 51 %

Procedure:
In 120 ml of ethanol, 8.0 g of ethyl 2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]cyclohex-1-enecarboxylate as synthesized in above Step 4-1-C was dissolved, and to the solution 60 ml of hydrazine monohydrate was added, followed by 4 hours' heating under reflux. Distilling the solvent off under reduced pressure, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1) to provide 3.8 g (51%) of 3-amino-2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-5,6,7,8-tetrahydro-3H-quinazolin-4-one.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1.[H][H]>C(O)C.Cl.[Pt]=O>[ClH:1].[NH2:10][CH:7]1[CH2:6][NH:5][C:4](=[NH:3])[CH2:9][CH2:8]1
Reactant: Nc1ccc(N)nc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: N=C1CCC(N)CN1

Procedure:
2,5-diaminopyridine dihydrochloride (1.2 g) and platinum oxide (500 mg) in ethanol (20 mL) and conc HCl (2 mL) were shaken on a Parr hydrogenation apparatus at 55 psi of hydrogen overnight. Product was obtained as a dark solid which was purified by C-18-reverse phase chromatography, eluting with H2O/CH3CN. Fractions containing the product were lyophilized, redissolved in 1N HCl and lyophilized to give the product as a yellow solid. The analysis of the product was found to be consistent with the proposed structure. MH+=114; 1H NMR (D2O): δ3.8-3.6 (m, 2H); 3.4-3.25 (m, 1H); 2.75-2.65 (m, 2H); 2.25-2.15 (m, 1H); 2.15-1.85 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[N:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)Cn1nc(C(N)=O)c2ccncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nn(CC(=O)O)c2cnccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (663 mg, 2.40 mmol) in CH2Cl2 (20 mL) was added TFA (10 mL, 130 mmol), and the resulting mixture was stirred at RT for 6 h. The reaction mixture was concentrated in vacuo, the residual solid was suspended in methanol and volatiles were removed again in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=1)=[O:16]
Reactant: COC[C@@H]1CCCN1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Product: COC[C@@H]1CCCN1C(=O)c1cnoc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and (S)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (12.8 mg). Calcd for C17H17F3N2O3: 354.1191, found 354.1189.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:15](=O)([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)[O:16]N1C(=O)CCC1=O.CCN(C(C)C)C(C)C>C1COCC1>[CH3:12][C:11]([CH3:14])([CH3:13])[C@H:3]([NH:2][C:15]([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:16])[C:4]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)O[C@H]1CCOC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
A mixture of (S)-tert-butyl 2-amino-3,3-dimethylbutanoate hydrochloride (0.05 g, 0.223 mmol), (S)-2,5-dioxopyrrolidin-1-yl tetrahydrofuran-3-yl carbonate (0.056 g, 0.246 mmol) and Hunig's base (0.078 mL, 0.447 mmol) in THF (2.25 mL) was stirred at room temperature for 12 hours. The solvent was evaporated and the product was purified by chromatography on silica gel eluting with 0-15% ethyl acetate in dichloromethane to give the title compound (0.037 g, 55% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27](O)=[O:28])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:11])[F:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O[N:64]=[C:65]([O:67][CH2:68][CH3:69])[NH2:66]>CN(C)C=O>[CH2:68]([O:67][C:65]1[N:66]=[C:27]([CH:15]2[CH2:14][CH:13]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][C:9]([F:12])([F:10])[F:11])=[C:2]([F:1])[CH:3]=3)[CH2:18][N:17]([C:19]([N:21]3[CH2:22][CH2:23][S:24][CH2:25][CH2:26]3)=[O:20])[CH2:16]2)[O:28][N:64]=1)[CH3:69]
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Reactant: CCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)c(F)c3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 400 mg (0.783 mmol, purity 85%) of the carboxylic acid from Example 79A in 10.6 ml of N,N-dimethylformamide were added, at room temperature, 357 mg (0.939 mmol) of HATU and 0.30 ml (1.72 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 118 mg (1.02 mmol, purity 90%) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and stirred at room temperature overnight. The reaction solution was diluted with 11 ml of N,N-dimethylformamide and then stirred at 140° C. for 3 h. The reaction solution was purified directly by means of preparative HPLC. Yield: 111 mg (28% of theory)
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2[CH:21]=O)[CH2:3]1.[CH2:23]([S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2)(=[O:27])=[O:26])[CH3:24]>>[CH3:8][CH:6]1[NH:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:9][CH2:10][CH2:11][C:12]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]=2/[CH:21]=[C:31]2\[C:32](=[O:37])[NH:33][C:34]3[C:30]\2=[CH:29][C:28]([S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])=[CH:36][CH:35]=3)[CH2:5]1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC1CN(CCCc2c(C=O)[nH]c3c2CCCC3)CC(C)N1
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CC(C)NC(C)C1)CCCC3)C(=O)N2
Yield: 53.4 %

Procedure:
3-[3-(3,5-Dimethyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (62 mg, 0.22 mmol), prepared as described in Example 24, was condensed with 50 mg (0.22 mmol) of 5-ethylsulfonyloxindole to provide (60 mg, 53% yield) of the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([OH:27])=O)=[N:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Br:24])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:28]([O:35][CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].N1C=CC=CC=1.O=P(Cl)(Cl)Cl>O1CCCC1.CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Si:28]([O:35][CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C:25]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Br:24])[N:11]=1)=[O:27])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (377) (4.0 g, 8.9 mmol) in tetrahydrofuran (150 mL) was added [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) (5.8 g, 26.73 mmol). To the reaction mixture, pyridine (2.159 mL, 26.726 mmol) was added, followed very slow addition of POCl3 (2.454 mL, 26.726 mmol) at −15° C. the resulting reaction mixture was stirred for 2 h at same temperature. 2 drops of dimethylformamide were added to the reaction mixture which was thereafter allowed to stir at room temperature for 16 h while silica thin layer chromatography was performed (50% ethyl acetate in hexane; Rf=0.5). After completion of the reaction, the reaction mixture was quenched with ice cold water (150 mL) and extracted with ethyl acetate (2×250 mL). The combined organic parts were dried and concentrated and the resulting crude residue was purified on a column (normal silica 100-200 mesh) to get 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (378) (2.9 g, 50.15%) as a colorless gummy liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCN3CCOCC3)c2)c2ccc(F)cc21
Yield: 70.2 %

Procedure:
Following the general method as outlined in Example 41 Step 1, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 250 mg; 0.73 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (272 mg; 1.46 mmol), 233 mg (70%) of the title compound was obtained as a brown solid after purification by a silica gel chromatography (petroleum ether/EtOAc=1/1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:17])=[N-]>CCOCC>[CH3:17][O:13][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Yield: 90 %

Procedure:
A solution of the acid (23) in ether (200 ml) at room temperature was treated with ethereal diazomethane until the yellow colour just persisted and tlc showed there to be no starting material present. The volatiles were then removed in vacuo leaving the product (24) as a light orange oil (17.89 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, piperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.65 minutes; C21H20Cl2N4O2 (431.32); mass spectrum: (M+H)+=431.2.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH:9]=[CH:10][N+:11](=[N:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])[O-:12])=[CH:7][CH:6]=1)[C:2]#[CH:3].[BH4-].[Na+].O.C(OCC)(=O)C>CN(C)C=O.CO>[CH2:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH:9]=[CH:10][N+:11](=[N:13][CH:14]([CH3:18])[CH:15]([OH:17])[CH3:16])[O-:12])=[CH:7][CH:6]=1)[C:2]#[CH:3]
Reactant: C#CCOc1ccc(C=C[N+]([O-])=NC(C)C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C=C[N+]([O-])=NC(C)C(C)O)cc1
Reaction time: 1 h
Yield: 83 %

Procedure:
44.39 g (134.4 mmol) of 3-(4-(2-propynyloxy)-styryl-ONN-azoxy)-2,2-propylenedioxybutane, a compound disclosed in EP-A-443,513 was subjected to deketalization reaction with iron chloride-silica gel according to the process disclosed in EP-A-443,513 to give 38.94 g of a crude product of 3-(4-(2-propynyloxy)styryl-ONN-azoxy)-2-butanone as a colorless paste. This was dissolved in a mixed solvent of 80 ml of dimethylformamide and 240 ml of methanol, 5 g (134.4 mmol) of sodium borohydride was added, and the mixture was stirred under ice cooling for 1 hour. After the reaction, 300 ml of water and 200 ml of ethyl acetate were added to the reaction solution to carry out extraction. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (diethyl ether-hexane =2:1) to give 30.75 g of the desired compound as a colorless paste (yield 83%).