Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:2]1.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.[CH3:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][C:55]=1[N+:61]([O-:63])=[O:62]>CN(C)C=O.C(OCC)(=O)C>[CH3:53][C:54]1[CH:60]=[CH:59][C:57]([NH:58][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[CH:56][C:55]=1[N+:61]([O-:63])=[O:62]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(N2CCOCC2)c(C(F)(F)F)c1
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
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
4-Morpholino-3-(trifluoromethyl)benzoic acid (694 mg, 2.523 mmol) was dissolved in dimethylformamide (5.6 mL), HATU (1.92 g, 5.047 mmol) and N,N-diisopropylethylamine (1.37 mL, 7.851 mmol) were added thereto and stirred at room temperature for 30 minutes. 4-Methyl-3-nitroaniline (256 mg, 1.682 mmol) was added to the reaction mixture and subjected to a reaction at 45° C. for 19 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (10 mL) and washed with an aqueous sodium hydrogen carbonate solution (10 mL). The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated mixture was crystallized using ethyl acetate (3 mL) n-hexane (30 mL) to obtain the title compound (673 mg) as a brown solid.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[NH:17][C:18](=[O:41])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[CH:23][CH:22]=1)(C)(C)C>C(O)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][C:6]([OH:42])=[O:5])=[C:10]([NH:17][C:18](=[O:41])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH:11]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)CNc1ccc(C#N)cc1NC(=O)COc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CC(=O)O
Product: N#Cc1ccc(NCC(=O)O)c(NC(=O)COc2ccc(OC3CCNCC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A solution of N-[4-cyano-2-[4-(1-tert-butoxycarbonylpiperidin-4-yloxy)phenoxyacetamido]phenyl]glycine tert-butyl ester (16.91 g) in acetic acid (500 ml) was stirred at 75° C. for 12 hours. The solvent was evaporated and to the obtained residue was added trifluoroacetic acid (100 ml), and the mixture was stirred at room temperature for 30 min. After completion of the reaction, the solvent was evaporated. To the obtained residue was added ice and then aqueous sodium hydroxide solution and the resultant solid was collected by filtration and washed successively with water and ethyl acetate to give N-[4-cyano-2-[4-(piperidin-4-yloxy)phenoxyacetamido]phenyl]glycine (8.642 g). In the same manner as in Example 1, Step 1, the title compound (9.506 g) was obtained from this compound, di-tert-butyl dicarbonate (6.96 g) and 1N aqueous sodium hydroxide solution (23.4 ml).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:49]([O:56][C:57]([NH:59][CH2:60][CH2:61][CH:62]([NH2:73])[C:63]1[NH:67][C:66]2[CH:68]=[CH:69][C:70]([Cl:72])=[CH:71][C:65]=2[N:64]=1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[CH2:49]([O:56][C:57]([NH:59][CH2:60][CH2:61][C@H:62]([NH:73][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:63]1[NH:67][C:66]2[CH:68]=[CH:69][C:70]([Cl:72])=[CH:71][C:65]=2[N:64]=1)=[O:58])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NC(CCNC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCNC(=O)OCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 87 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-[3-(benzyloxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)propylamine in tetrahydrofuran. Yield: 87%; Rf value: 0.50 (silica gel; dichloromethane/methanol=9:1); C31H32ClN5O4 (574.08); mass spectrum: (M+H)+=574/576 (chlorine isotope) and (M−H)−=572/574 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[N:18]1([CH2:27][CH2:28][C:29](O)=[O:30])[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20].C(Cl)Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:29](=[O:30])[CH2:28][CH2:27][N:18]1[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20])[CH3:2]
Reactant: Cc1cn(CCC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCn1cc(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
N-(N′-Boc-aminoethyl)glycine ethyl ester (1.0 g, 0.0041 mol) was dissolved in DMF (12 ml). DhbtOH (0.73 g, 0.0045 mol) and 3-(1-thyminyl)-propanoic acid (0.89 g, 0.0045 Mol) were added. Methylene chloride (12 ml) then was added and the mixture was cooled to 0° C. on an ice bath. After addition of DCC (1.01 g, 0.0049 mol), the mixture was stirred at 0° C. for 2 h, followed by 1 h at room temperature. The precipitated DCU was removed by filtration, washed with methylene chloride (25 ml), and a further amount of methylene chloride (50 ml) was added to the filtrate. The organic phase was extracted with sodium hydrogen carbonate (1 volume saturated diluted with 1 volume water, 6×100 ml), potassium sulfate (1 volume saturated diluted with 4 volumes water, 3×100 ml), and saturated aqueous sodium chloride (1×100 ml), dried over magnesium sulfate, and evaporated to dryness, in vacuo. The solid residue was suspended in methylene chloride (15 ml), and stirred for 1 h. The precipitated DCU was removed by filtration and washed with methylene chloride. The filtrate was evaporated to dryness, in vacuo, and the residue purified by column chromatography on silica gel, eluting with a mixture of methanol and methylene chloride (gradient from 1 to 6% methanol in methylene chloride). This afforded the title compound as a white solid (1.02 g, 59%). Anal. for C19H30N4O7, found (calc.) C, 53.15 (53.51); H, 6.90 (7.09); N, 12.76 (13.13). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:14][C:15](=[O:18])[CH2:16]Cl)([CH2:12][OH:13])[CH:9]([F:11])[F:10])[C:5]([F:19])=[C:4]([Si](CC)(CC)CC)[CH:3]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]2([CH:9]([F:11])[F:10])[NH:14][C:15](=[O:18])[CH2:16][O:13][CH2:12]2)[C:5]([F:19])=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@](CO)(NC(=O)CCl)C(F)F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: O=C1COC[C@](c2nc(Br)ccc2F)(C(F)F)N1
Temperature: 100 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of N—[(R)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamide (2.32 g, 4.88 mmol) in t-butanol (50 ml) was added potassium tert-butoxide (7.31 ml, 7.31 mmol, 1M in THF) and the solution was stirred in a closed vial for 18 h at 100° C. The reaction mixture was diluted with ethyl acetate, washed with water, sat. NaHSO4 solution and brine, dried over sodium sulfate, filtered and evaporated. The crude product (2.36 g) was chromatographed over silica gel (24 g redisep column, cyclohexane/ethyl acetate 10-80%) to give the title compound. 1.13 g (71% yield). Triethylsilylated lactam (640 mg) was recovered.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(O)=[O:11]>>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)CCc1ccccc1C(=O)O
Product: COC(=O)CCc1ccccc1C(=O)NCCc1ccccc1

Procedure:
The sub-title compound was prepared from benzeneethanamine and the product of step (a) using the method of Example 6(a) as a white solid mp 68°-70°.
Reaction SMILES: [CH3:1][C@:2]12[CH2:20][CH2:19][C@H:18]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH2:16][OH:17])[CH2:14][CH2:13][C@H:12]([OH:21])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:22].C[Si:24]([CH2:27]C(N)=O)([CH3:26])[CH3:25]>N1C=CC=CC=1>[CH3:25][Si:24]([CH3:27])([CH3:26])[O:21][C@H:12]1[CH2:13][CH2:14][C@@:15]2([CH2:16][O:17][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:18]2[CH2:19][CH2:20][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C@@H:3]2[O:22][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:11]1
Reactant: C[Si](C)(C)CC(N)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O[Si](C)(C)C)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O[Si](C)(C)C

Procedure:
Androst-5-ene-3β,17β,19-triol is dissolved in dry pyridine and trimethylsilylacetamide added thereto. The reaction is completed at room temperature within a few minutes. The pyridine is removed under reduced pressure and the residue purified from an acetone-hexane solution to yield the desired 3β,17β,19-tri(trimethylsiloxy)androst-5-ene.
Reaction SMILES: [OH-].[NH4+:2].[N+:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11](Cl)(=[O:13])=[O:12])([O-:5])=[O:4]>O1CCCC1>[N+:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH2:2])(=[O:13])=[O:12])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccsc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sccc1[N+](=O)[O-]
Yield: 111.6 %

Procedure:
Ammonium hydroxide (28% aqueous, 2.4 mL, 17.57 mmol) was added to a stirred solution of 3-nitro-thiophene-2-sulfonyl chloride (1.00 g, 4.39 mmol) in tetrahydrofuran (50 mL) at room temperature. After 15 min the reaction mixture was concentrated under reduced pressure. The residue was triturated in methanol and dichloromethane. The solid was collected by filtration and dried to give 1.02 g (quantitative yield) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4cccs4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 60. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, 1H, J=3.52 Hz), 7.46 (d, 1H, J=4.69 Hz), 7.17 (d, 2H, J=8.21 Hz), 7.16-7.10 (m, 2H), 6.87-6.86 (m, 1H), 6.81 (d, 2H, J=8.60 Hz), 6.72-6.69 (m, 2H), 4.21 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.12 (d, 1H, J=14.08 Hz), 3.01 (t, 2H, J=6.26 Hz), 2.38 (s, 3H), 2.30 (s, 3H), 1.41 (s, 3H); HRMS (ES+) m/z exact mass calcd for C27H28NO5S 478.1688, found 478.1692.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]([NH:24][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])=[O:23])[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22](=[O:23])[NH:24][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: CC(NC(=O)CC(N)C(=O)O)c1ccccc1
Product: CC(NC(=O)CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O)c1ccccc1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-N-(1-phenyl-ethyl)-succinamic acid to provide the title compound in good yield.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[C:5]1=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[O:18]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=2)[CH:12]=[CH:13][N:4]1[CH2:3][CH2:2][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc2ccn(CCBr)c(=O)c2c1
Reactant: C1CCNCC1
Product: COC(=O)c1ccc2ccn(CCN3CCCCC3)c(=O)c2c1

Procedure:
The title compound was prepared from methyl 2-(2-bromoethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (96 mg, 0.31 mmol) and piperidine (0.31 mL, 3.1 mmol) following the procedure outlined in Example 44, step 2 (80 mg, 82%). LC-MS: (FA) ES+ 315.
Reaction SMILES: C=O.[C:3](O)(=O)C.[Cl:7][C:8]1[C:9]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:36][CH2:35]2)=[N:10][CH:11]=[C:12]([C:14](=[O:33])[NH:15][C:16]2[S:17][C:18]([CH2:27][NH:28][CH:29]3[CH2:32][CH2:31][CH2:30]3)=[C:19]([C:21]3[S:22][CH:23]=[C:24]([Cl:26])[CH:25]=3)[N:20]=2)[CH:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.ClCCCl>[Cl:7][C:8]1[C:9]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:36][CH2:35]2)=[N:10][CH:11]=[C:12]([C:14](=[O:33])[NH:15][C:16]2[S:17][C:18]([CH2:27][N:28]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[CH3:3])=[C:19]([C:21]3[S:22][CH:23]=[C:24]([Cl:26])[CH:25]=3)[N:20]=2)[CH:13]=1
Reactant: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CNC4CCC4)s3)cc2Cl)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CN(C)C4CCC4)s3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
110 μl of a formaldehyde aqueous solution (35%) and 76 μl of acetic acid were added to 2 ml of 1.2-dichloroethane solution of 79 mg of ethyl 1-[3-chloro-5-({4-(4-chlorothiophen-2-yl)-5-[(cyclobutylamino)methyl]thiazol-2-yl}carbamoyl)-2-pyridyl]piperidine-4-carboxylate, and the mixture was stirred at room temperature for 1 hour. Subsequently, 45 mg of NaBH(OAc)3 was added, and the solution was stirred at room temperature for 1 hour. Chloroform was added to the reaction solution, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, with water and with brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane:EtOAc=4:1 to 2:1) to obtain 58 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[cyclobutyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:22])=[CH:4][N:3]=1.Cl.[OH-].[Na+]>[Fe]>[NH2:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([NH:13][CH3:14])=[O:12])=[C:9]([NH:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:18]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1Nc1nc(Cl)ncc1Cl
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Product: CNC(=O)c1ccc(N)cc1Nc1nc(Cl)ncc1Cl
Yield: 60.1 %

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-4-nitro-benzamide (0.248 g, 0.72 mmol), Iron (0.202 g, 3.62 mmol), and HCl (3 mL, 0.1 mol) were heated at 50° C. for 1 h. The reaction mixture was neutralized with NaOH and extracted with CH2Cl2. The suspension was filtered, and the resulting solids were washed with CH2Cl2 and EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 135 mg (60%) title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:13])[CH:5]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[N:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN1CCOCC1.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:3]=1
Reactant: COC(=O)Nc1cc(=O)[nH]c(N)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1

Procedure:
A stirred suspension of 500 g of methyl 2-amino-1,6-dihydro-6-oxo-4-pyrimidinecarbamate in 1.45 l of N-methylmorpholine and 9 l of methylene chloride is heated to reflux temperature. Subsequently, 815 g of toluene-4-sulfonyl chloride are added thereto and the mixture is stirred at reflux for 16 hours. The mixture is evaporated at 40° in a water-jet vacuum and the residue is treated with 9 l of water. The insoluble material is filtered off under suction and washed firstly with 5 l of water and thereafter with 5 l of ether. After drying at 40° in vacuo, there is obtained light brown methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate of melting point 188°-190°. A sample recrystallized from acetonitrile has a melting point of 190°-192°.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[O:17]=[C:18]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:19][NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Br:63][C:64]1[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][C:65]=1[C:66](O)=[O:67]>CN(C=O)C.O>[Br:63][C:64]1[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][C:65]=1[C:66]([N:38]1[CH2:39][CH2:40][N:35]([C:18](=[O:17])[CH2:19][NH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[O:22])[CH2:36][CH2:37]1)=[O:67]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(-c4ccccc4)cc3)CC2)c1
Reaction time: 8 h
Yield: 34 %

Procedure:
DIPEA (66 mg, 0.51 mmol) was added to a stirred solution of biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide TFA salt (90 mg, 0.21 mmol) in DMF (2 mL). HOBT (28 mg, 0.21 mmol) and EDCI.HCl (40 mg, 0.21 mmol) were then added. After 2 minutes 2-bromo-5-methoxy benzoic acid (40 mg, 0.17 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was diluted with cold water. The product was extracted with ethyl acetate and the ethyl acetate layer was washed with NaHCO3 solution, saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford crude product, which was purified by column chromatography (using silica gel of 160-120 mesh and 2.5% MeOH in chloroform as eluent) to afford 31 mg (34% yield) of biphenyl-4-carboxylic acid {2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a white solid. LC-MS purity: 98.31%, HPLC Purity: 97.73%. 1H NMR: (DMSO) δ 8.7-8.6 (b s, 1H), 8.0 (m, 2H), 7.8 (m, 4H), 7.6-7.4 (m, 4H), 7.0 (m, 2H), 4.2 (m, 2H), 3.8 (s, 3H), 3.4-3.7 (m, 6H), 3.2-3.1 (m, 2H).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([Cl:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][N:7]=1)=[O:5])C.C(O[C:20]([C:22]1[N:23](CCNC(OC(C)(C)C)=O)N=C(COC2C=CC=CC=2)C=1)=O)C.C(OC(C1C=C2C(=O)NCCN2N=1)=O)C>>[CH2:15]([O:14][C:12]([C:9]1[C:10]([Cl:11])=[C:6]2[C:4](=[O:5])[NH:23][CH2:22][CH2:20][N:7]2[N:8]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1Cl
Agent: CCOC(=O)c1cc2n(n1)CCNC2=O
Product: CCOC(=O)c1nn2c(c1Cl)C(=O)NCC2

Procedure:
The compound was prepared from 4-chloro-1H-pyrazole-3,5-dicarboxylic acid diethyl ester and 2-(2-tert-butoxycarbonylamino)ethyl bromide using the methods described in the preceding examples 5 (2-(2-tert-butoxycarbonylamino-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 48 (4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[H-].[Na+].[F:12][C:13]1[C:28]([F:29])=[C:27]([F:30])[CH:26]=[C:25](F)[C:14]=1[C:15]([O:17]CC1C=CC=CC=1)=[O:16]>C1C=CC=CC=1.CCCCCC.C(O)(=O)C>[CH2:1]([O:8][C:25]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([F:12])[C:28]([F:29])=[C:27]([F:30])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1c(F)cc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1c(OCc2ccccc2)cc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
6.5 g of benzyl alcohol was dissolved in 150 ml of benzene. While the resultant solution was cooled with water, 2.4 g of sodium hydride (60%) was added and reacted. To the reaction mixture was added 15 g of benzyl 2,3,4,6-tetrafluorobenzoate, and stirred at room temperature for 1 hour. 3.6 g of acetic acid was added, followed by the removal of the solvent by distillation. To the residue, 6.5 g of potassium hydroxide and 50 ml of water and 100 ml of methanol were added. They were reacted at 50° C. for 30 minutes. 6 g of acetic acid was added, followed by the removal of the solvent by distillation. To the residue were added 50 ml of benzene and 7% aq. potassium hydroxide solution. The resultant mixture was shaken, followed by separation into two layers. Concentrated hydrochloric acid was added to the water layer so that the water layer was rendered acidic. The thus-acidified water layer was extracted twice with 100 ml portions of chloroform. The extract was treated with anhydrous magnesium sulfate and the solvent was distilled out. A solid thus formed was dispersed in n-hexane and then collected by filtration, whereby 4.7 g of 6-benzyloxy-2,3,4-trifluorobenzoic acid was obtained as colorless powder.