Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([CH3:23])=[N:7][CH:8]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]([CH3:23])=[N:7][CH:8]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9](=[O:11])[N:10]([CH3:26])[C:4]=2[CH:3]=1
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)N(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.2 %

Procedure:
162b (2.0 g, 4.98 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 ml), to this was added potassium carbonate (1.72 g, 12.44 mmol) and iodomethane (0.847 g, 5.97 mmol) and the reaction was sealed in a pressure flask and stirred for 12 hours at room temperature. The reaction was diluted with water and ethyl acetate (20/70 ml). The aqueous solution was then extracted with ethyl acetate (3×20 ml). The organic layers combined, washed with water (1×100 ml), dried over magnesium sulfate, filtered and the filtrate concentrated to give the title compound 162c (1.58 g, 77.5%). 1H NMR (CDCl3, 300 MHz): δ 7.43–7.28 (m, 7H), 6.68 (d, 1H, J=8.1 Hz), 5.15–5.05 (m, 3H), 3.38 (s, 3H), 2.45 (d, 3H, 1.5 Hz) ppm.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH3:21][O:22][C:23](=[O:33])[C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)=[O:32])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: COC(=O)c1ccc(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-benzoic acid methyl ester was prepared starting from intermediate D and 4-isocyanato-benzoic acid methyl ester. MS calcd. for C25H21ClN3O4 [(M+H)+] 462.1, obsd. 462.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CO)cc1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
240 g of manganese dioxide were added to a solution of 30 g (0.14 mol) of 2-t-butyl-5-hydroxymethyl-l-nitrobenzene (prepared as described in Preparation 10) in 450 ml of chloroform, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was filtered to remove manganese dioxide, and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane as the eluent, to give 27.4 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[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][CH3:34]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (309 mg, 1.21 mmol) and 1-bromotetradecane (1.34 g, 4.84 mmol), alcohol 36 was obtained as a colorless oil (270 mg, 49% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([S:8]([N:11]([CH3:29])[N:12]=[CH:13][C:14]2[N:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)(=[O:10])=[O:9])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([S:8]([N:11]([CH3:29])[N:12]=[CH:13][C:14]2[N:18]3[CH:19]=[C:20]([C:23]4[CH:24]=[N+:25]([O-:36])[CH:26]=[CH:27][CH:28]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)N(C)N=Cc1cnc2ccc(-c3cccnc3)cn12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)N=Cc1cnc2ccc(-c3ccc[n+]([O-])c3)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To an ice-cooled solution of 5-fluoro-N, 2-dimethyl-N′-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methylene) benzenesulfonohydrazide (step 1, 18 mg, 0.043 mmol) in CH2Cl2 was added 3-chloroperoxybenzoic acid (14.46 mg, 0.065 mmol). The reaction mixture was stirred for 3 h at RT. The reaction mixture was then poured on to water. Organic layer was separated, washed with saturated solution of NaHCO3 and dried over Na2SO4. Crude compound was purified by column chromatography (silica gel, 5% EtOAc in petroleum ether) to obtain the title compound. Yield: 64%; 1H NMR (DMSO-d6; 300 MHz,): δ 9.45 (s, 1H), 8.57 (s, 1H), 8.32-8.31 (m, 2H), 8.03 (s, 1H), 7.83-7.79 (m, 2H), 7.67-7.64 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.56 (m, 1H), 7.43-7.36 (m, 3H), 3.40 (s, 3H), 2.54 (s, 3H); MS: m/z 440 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][NH:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][N:36]([CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(CC(F)(F)F)C1
Yield: 47.3 %

Procedure:
The title compound was prepared as described in Example 103C using (S)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}urea (0.198 g, 0.38 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.139 g, 0.6 mmol), and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) at 40° C. for 3 hours, which was purified by silica gel chromatography with 70-85% EtOAc/hexane as eluants to afford (5)-1-(5-tert-butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yloxy]quinazolin-4-yloxy}phenyl)urea as solid (0.108 g, 47%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.62 (s, 1H), 7.93 (s, 1H), 7.65 (t, 1H), 7.54 (s, 1H), 7.39 (t, 1H), 7.32 (m, 1H), 7.20 (s, 1H), 7.01 (d, 1H), 5.89 (s, 1H), 5.06 (m, 1H), 4.03 (s, 3H), 3.41 (m, 1H), 3.18 (q, 2H), 2.9-3.08 (m, 3H), 2.44 (m, 1H), 2.2 (m, 1H), 1.33 (s, 9H); LC-MS (ESI) m/z 601 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:9]([CH3:10])=[CH:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].ClC1C=CC=CC=1.[C:19]1([CH3:26])[CH:24]=[CH:23][CH:22]=[C:21](Cl)[CH:20]=1>[Cl-].[Zn+2].[Cl-].O>[C:19]1([CH3:26])[CH:24]=[CH:23][CH:22]=[C:21]([C:8]2[C:6](=[O:7])[N:5]([CH3:11])[C:3](=[O:4])[N:2]([CH3:1])[C:9]=2[CH3:10])[CH:20]=1
Reactant: Cc1cccc(Cl)c1
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1cccc(-c2c(C)n(C)c(=O)n(C)c2=O)c1
Reaction time: 3 h
Yield: 14 %

Procedure:
In a 100 mL round bottom flask equipped with a condenser and an air lock was placed compound 2 (see FIG. 3) (5.00 g, 32.4 mmol), anhydrous zinc chloride 3 (4.45 g, 32.6 mmol), dry chlorobenzene (20 mL) and m-tolyl chloride (4.6 mL, 5.38 g, 34.8 mmol). The reaction was brought to reflux in an oil bath and vigorously stirred for 3 h. After cooling, water (40 mL) was added through the condenser, dropwise at first and then with increasing speed. The condenser was then rearranged for distillation and the chlorobenzene was removed by azeotropic distillation. The solution was then cooled in an ice bath, and diethyl ether (30 mL) was added while stirring to give a precipitate. The precipitate was filtered and recrystallized from 2-propanol to yield 3d (1.11 g, 26.3%); m.p. 136.8-139° C. 1H NMR (600 MHz, CD2Cl2) δ 7.68-7.66 (m, 1H), 7.65-7.62 (m, 1H), 7.44-7.40 (m, 1H), 7.35 (t, J=7.6, 1H), 3.46 (s, 3H), 3.30 (s, 3H), 2.40 (s, 3H), 2.18 (s, 3H). 13C NMR (151 MHz, CD2Cl2) δ 194.00, 161.07, 152.22, 151.98, 139.22, 138.16, 134.94, 130.03, 129.01, 126.93, 113.36, 32.36, 28.32, 21.54, 17.99. MS (ES+) (m/z): [M+1]+ calculated for C15H17N2O3, 273.12. found 237.10.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:42])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][O:32]C(=O)C)(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:42])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][OH:32])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2CCOC(C)=O)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2c(Cc3cc4c(cc3CCO)OCO4)sc3ncccc23)c1Cl
Yield: 83.3 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-{2-[2-(acetoxy)ethyl]-4,5-(methylenedioxy)benzyl}thieno[2,3-b]pyridine-3-sulfonamide (83 mg, 0.13 mmoles), methanol (3 ml) and 4N HCl (1 ml). Recrystallization from CH2Cl2/hexanes provided 55 mg (84%) of the title compound as a white solid, m.p. 104-106° C.
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24]>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:4][CH2:3][C:2]([F:11])([F:1])[CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])=[O:24]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Reactant: O=C(O)CCCCCCCCCCBr
Product: O=C(CCCCCCCCCCBr)OCC(F)(F)C(F)C(F)(F)F

Procedure:
The process of claim 2 comprising (a) reacting at reflux about 1 mole of 2,2,3,4,4,4-hexafluorobutanol and about 1 mole of 11-bromoundecanoic acid to obtain 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate and then (b) reacting about 1 mole of 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate with about 1 mole pyridine to obtain 2,2,3,4,4,4-hexafluorobutyl 11-pyridylundecylate bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[S:43](Cl)(=[O:45])=[O:44].O>ClCCl>[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[S:43]([O:30][C:27]1[CH:26]=[CH:25][C:24]([N:10]2[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:13]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:29][CH:28]=1)(=[O:45])=[O:44]
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)c2cccs2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (100 mg, 0.22 mmol) and triethylamine (0.31 ml, 2.25 mmol) in dichloromethane (2.5 ml) were cooled to −78° C. 2-Thiophenesulfonyl chloride (287 mg, 1.57 mmol) dissolved in dichloromethane (2.5 ml) was carefully added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h, and at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase washed with water and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (110 mg, 83%) as a solid.
Reaction SMILES: CCCCCC.C(ON[C:16](=[O:39])[C@H:17]([N:22]([P@:30]([CH3:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][CH:19]([CH3:21])[CH3:20])C1C=CC=CC=1.C(OCC)(=[O:42])C>>[CH3:38][P:30]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@@H:17]([C:16]([OH:39])=[O:42])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:31]
Reactant: CCOC(C)=O
Reactant: CC(C)C[C@H](C(=O)NOCc1ccccc1)N(Cc1ccccc1)[P@@](C)(=O)c1ccccc1
Solvent: CCCCCC
Product: CC(C)C[C@H](C(=O)O)N(Cc1ccccc1)P(C)(=O)c1ccccc1

Procedure:
N-Benzyloxy-2(R)-[[(R)-methylphenylphosphinyl]benzylamino]-4-methylpenta-namide and N-benzyloxy-2(R)-[[(S)-methylphenylphosphinyl]benzylamino]-4-methyl-pentanamide: N-(R/S-Methylphenylphosphinyl)-N-benzyl-D-leucine (1.5 g, 4.17 mmol) is dissolved in N-dimethylformamide and cooled to 0° C. To this is added sequentially hydroxybenzotriazole hydrate (1.69 g, 12.5 mmol), N-methylmorpholine (1.37 mL, 12.5 mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC, 959 mg, 5 mmol)). After stirring 10 minutes, O-benzylhydroxylamine hydrochloride (666 mg, 4.17 mmol) is added and the reaction is allowed to stir for 3 hours, warming to room temperature. Two diastereomers are observed by TLC. To the mixture is added water, and the mixture is extracted with ethyl acetate. The organics are combined, washed with water and brine, dried over sodium sulfate, and concentrated to give an oil. The diastereomers are then isolated by silica gel flash chromatography (1:1 hexane:ethyl acetate) to give N-benzyloxy-2(R)-[[(R)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide: Rf =0.25 (1:1 hexane:ethyl acetate; 31P NMR (CD3OD) d 43.89; and N-benzyloxy-2(R)-[[(S)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide Rf =0.15 (1:1 hexane:ethyl acetate).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)C[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:54])CC2)CC1>>[OH:54][CH:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:2][CH2:3]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Oc3ccc(F)cc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(4-fluoro-phenoxy)-1H-indole-2-carboxylic acid 145 (see example 120) and amine 21.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[O:28])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:32]2[CH2:31][CH2:30][N:29]([C:27]([N:24]3[CH2:25][CH2:26][N:21]([C:18]4[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=4)[CH2:22][CH2:23]3)=[O:28])[CH2:34][CH2:33]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C(N1CCNCC1)N1CCN(c2ccncc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of 4-trifluoromethylphenylsulphonyl chloride (6.62 g) in dichloromethane (5 mL) was added dropwise over 10 minutes to a stirred solution of 1-[1-(4-pyridyl)piperazin-4-ylcarbonyl]piperazine (5.7 g) (prepared as in Example 1) in dichloromethane (50 mL) containing triethylamine (6 mL) at 20° C. The reaction mixture was stirred for 2 hours at 20° C. The organic phase was washed with water (3×100 mL) and saturated brine solution (2×100 mL) dried and evaporated. The residue was purified by chromatography on silica gel, eluting with a mixture of dichloromethane: methanol (95:5) to give, as a sandy-coloured solid, 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(4-pyridyl)piperazin-4-ylcarbonyl]piperazine (6.0 g): NMR (CDCl3): 3.08(t, 4H), 3.30-3.40 (m, 8H), 3.40-3.45(t, 4H), 6.63(d, 2H), 7.82(d, 2H), 7.90(d, 2H), 8.30(d, 2H); EI-MS m/z 484(M+H).
Reaction SMILES: C([O:8][N:9]([CH2:12][C:13]1([C:21]([NH:23][NH:24][C:25]2[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:16][CH:15]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14]1)[CH:10]=[O:11])C1C=CC=CC=1>CO.[Pd]>[CH2:17]([CH:15]1[CH2:16][C:13]([CH2:12][N:9]([OH:8])[CH:10]=[O:11])([C:21]([NH:23][NH:24][C:25]2[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:14]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CC(CN(C=O)OCc2ccccc2)(C(=O)NNc2nccc(C(F)(F)F)n2)C1
Agent: [Pd]
Solvent: CO
Product: CCCCC1CC(CN(O)C=O)(C(=O)NNc2nccc(C(F)(F)F)n2)C1
Reaction time: 4 h
Yield: 71.9 %

Procedure:
To a solution of N-benzyloxy-N-{3-butyl-1-[N′-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazinocarbonyl]-cyclobutylmethyl}-formamide (0.07 g, 0.15 mmol) in methanol (10 mL) was added 10% Pd/C (0.02 g). The reaction mixture was subjected to hydrogenation for 4 h at room temperature. The reaction mixture was then filtered through a pad of Celite@, and washed with methanol (20 mL). Removal of the solvent provided the title compound as a beige solid (0.042 g, 73%). MH+390.
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:22]([C:24]1[N:25]=[CH:26][O:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:23])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:21]=[C:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[O:13][CH:14]=[C:10]([NH:9][C:22]([C:24]2[N:25]=[CH:26][O:27][C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:23])[N:11]=1
Reactant: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncoc2-c2ccc(F)cc2)co1
Agent: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CCCCc1nc(NC(=O)c2ncoc2-c2ccc(F)cc2)co1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(4-fluoro-phenyl)-oxazole-4-carbonyl]-[2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (41 mg, 0.09 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.07 mL, 0.90 mmol). After stirring at rt for 4 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a white solid. LC-MS-conditions 01: tR=1.00 min, [M+H]+=372.04.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[N:10]1([C:8]([C:5]2[N:6]=[CH:7][C:2]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:3][CH:4]=2)=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(c1ccc(I)cn1)N1CCCCC1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(N2CCOCC2)cn1)N1CCCCC1
Reaction time: 2 h
Yield: 34.7 %

Procedure:
A mixture of 5-iodo-2-(piperidin-1-ylcarbonyl)pyridine (71 g, 0.23 mol), palladium (II) acetate (1.03 g, 46 mmol), 2-(di-tert-butylphosphino)biphenyl (2.76 g, 92 mmol), morpholine (23.7 g, 0.28 mol), and sodium tert-butoxide (27.8 g, 0.28 mol) in toluene (400 mL) was stirred under argon at 95 C for 2 hours. The product was isolated by chromatography (silica gel, ethyl acetate) and recrystallized from ethanol to give 4-[6-(piperidin-1-ylcarbonyl)pyridin-3-yl]morpholine (yield 37%, 22 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]2)=[C:20](Br)[CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]2)=[CH:22][CH:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2-c2ccccc2)S(=O)(=O)N1
Temperature: 100 °C
Yield: 35.8 %

Procedure:
To a solution of methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoate (52.0 mg, 0.0990 mmol) in toluene (1.0 mL) and 1,4-dioxane (1.0 mL) was added phenylboronic acid (14.5 mg, 0.119 mmol), 2 M sodium carbonate in water (0.30 mL) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) under an atmosphere of nitrogen. The resulting mixture was heated at 100° C. overnight. The reaction solution was filtered, and purified by preparative LCMS to afford product as a white solid (18 mg, 38%). 1H NMR (400 MHz, CD3OD): δ 7.28 (m, 13H), 5.03 (m, 1H), 4.47 (m, 1H), 3.26 (m, 3H), 3.00 (m, 1H). LCMS found for C26H25N2O7S (M+H)+: m/z=509.