Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[CH2:7][C@H:8]([N:31](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].CC(O)=O>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:47])[CH2:7][C@H:8]([NH2:31])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2ccc(CC[C@H](CC(=O)OC(C)(C)C)N(Cc3ccccc3)[C@H](C)c3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2ccc(CC[C@@H](N)CC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 15 h
Yield: 160.5 %

Procedure:
To a stirred solution of (R)-3-[benzyl-((R)-1-phenylethyl)amino]-5-(4′-heptyloxy-biphenyl-4-yl)pentanoic acid tert-butyl ester (2.82 g, 4.45 mmol) in EtOAc (50 ml) were added AcOH (2.5 ml) and Pd(OH)2 on carbon (Pd(OH)2 ca. 20 wt %, 1.07 g), and then the mixture was set under H2 atmosphere. After being stirred for 15 h, the mixture was filtered through a pad of Celite and washed with MeOH. The filtrate and washings were combined, and concentrated in vacuo to give (R)-3-amino-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.14 g) which was used for the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Reaction time: 16 h
Yield: 89.4 %

Procedure:
To ethyl 1H-pyrazole-4-carboxylate (5.01 g, 35.7 mmol) in DMF (60 mL) was added 1-(chloromethyl)-4-methoxybenzene (6.16 g, 39.3 mmol) and K2CO3 (7.41 g, 53.6 mmol). The reaction mixture was stirred for 16 hours and concentrated under reduced pressure to remove DMF. The residue was diluted with EtOAc (100 mL), washed with H2O (30 mL) and brine (20 mL), dried (Na2SO4) and concentrated. Silica gel chromatography (EtOAc/hexanes 1:5) provided the desired product (8.31 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([OH:9])=[O:8])[CH:4]([CH3:6])[CH3:5].Cl[CH2:11]Cl>>[CH3:11][O:8][C:7](=[O:9])[C@H:3]([CH:4]([CH3:6])[CH3:5])[NH2:2]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: ClCCl
Agent: Cl
Product: COC(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg of methyl ester of L-(+)-valine hydrochloride are placed in a round-bottom flask. 45 mL of buffer solution (K2HPO4/K3PO4 (pH=12.4)), then 22.5 mL of anhydrous dichloromethane are successively added. The mixture is agitated at room temperature for 30 min. The organic phase is separated, washed with brine, dried on magnesium sulfate, filtered and concentrated under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:4][C:3]=1[Br:29].[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37](O)=[O:38])[N:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[NH2:30][C:31]1[S:32][CH:33]=[C:34]([CH2:36][C:37]([NH:1][C:2]2[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]3[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:8]3[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:4][C:3]=2[Br:29])=[O:38])[N:35]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(NC(=O)Cc3csc(N)n3)c(Br)c2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of 115 mg (0.25 mmol) of tert-butyl (2S,5R)-2-(4-amino-3-bromobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (i-80a) and (2-amino-1,3-thiazol-4-yl)acetic acid (77 mg, 0.30 mmol) in 3.0 mL anhydrous DMF was added HOBt (44 mg, 0.32 mmol) followed by EDC (66 mg) and DIEA (0.22 mL, 1.25 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. The mixture was washed with water and extracted with dichloromethane (2×2 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by Gilson reverse phase HPLC eluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA buffer to afforded the product (105 mg, 81%). m/z (ES) 601(M)+ and 603 (M+2)+, also 623 (MNa)+ and 625 (MNa+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][C:27]1[N:32]=[N:31][CH:30]=[C:29]([C:33](O)=[O:34])[CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:33]([C:29]3[CH:28]=[C:27]([CH3:26])[N:32]=[N:31][CH:30]=3)=[O:34])[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(C(=O)O)cnn1
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Product: Cc1cc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)Cc3ccc(F)cc3)C2)cnn1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(6-methyl-pyridazine-4-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 6-methyl-pyridazine-4-carboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 501.1 [M]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:13])[CH3:12])[N:6]=[CH:5]2.[NH2:14][C@@H:15]([CH3:24])[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([O:17][C@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:15]([NH2:14])[CH3:24])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)([CH3:13])[CH3:12]
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: CC(C)n1ncc2cc(I)ccc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: CC(C)n1ncc2cc(O[C@H](c3ccccc3)[C@H](C)N)ccc21
Temperature: 125 °C
Reaction time: 2 h

Procedure:
A mixture of 5-iodo-1-isopropyl-1H-indazole (129c, 461 mg, 1.26 mmol), (1R,2S)-2-amino-1-phenylpropan-1-ol (286 mg, 1.89 mmol), copper (I) iodide (25 mg, 130 μmol), and cesium carbonate (1.45 g, 3.8 mmol) in butyronitrile (5 ml) was stirred at 125° C. for 2 h. Then the mixture was cooled to r.t., the inorganic material was removed by filtration and washed with ethyl acetate. The combined organic solutions were concentrated in vacuo, and the product purified by flash chromatography on silica gel (ethyl acetate/methanol). Yield 200 mg (51%) of a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@:12]3([CH2:20][C@@H:19]3[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:11]2=[O:28])[CH:5]=1.COC(=O)C1C=CC=C(N2C3C(=CC=CC=3)[C@]3(C[C@H]3C3C=CC(Cl)=CC=3)C2=O)C=1.O.[OH-].[Li+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:19]2[C@@:12]3([C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:29])=[O:2])[C:11]3=[O:28])[CH2:20]2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1cccc(N2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Agent: COC(=O)c1cccc(N2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(N2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of methyl-3-((1S,2R)-2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)benzoate and methyl-3-((1R,2S)-2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)benzoate (50 mg) in 1 mL of methanol was added 0.1 mL of water, followed by lithium hydroxide (10 mg), The mixture was stirred for 14 hours at room temperature. HPLC monitored the reaction finished. The solvent was removed under reduced pressure. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as a white powder. (11 mg) LC/MS m/e calcd. for C23H16ClNO3 389, observed (M+H)+: 390.1. 1H NMR (400 MHz, DMSO-d6) δppm 2.14 (dd, J=9.09, 5.05 Hz, 1 H) 2.41 (dd, J=8.08, 5.05 Hz, 1 H) 3.25 (t, J=8.59 Hz, 1 H) 6.19 (d, J=7.33 Hz, 1 H) 6.77-6.86 (m, 2 H) 7.12 (t, J=7.71 Hz, 1 H) 7.36-7.46 (m, 4 H) 7.72 (t, J=7.83 Hz, 1 H) 7.76-7.85 (m, 1 H) 8.01-8.09 (m, 2 H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8].Cl>ClCCl>[C:1]([NH:5][S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 1.4 ml (13.3 mmol) of tert-butylamine are added dropwise to a solution of 1.00 g (3.58 mmol) of methyl 2-(chlorosulfonyl)-6-nitrobenzoate in 8 ml of dichloromethane, and the reaction mixture is then allowed to warm to room temperature. After 2 h, the reaction mixture is poured into ice-water, adjusted to pH 3 using 2 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase is then dried over sodium sulfate, filtered off and concentrated to dryness under reduced pressure. The residue that remains is digested with diethyl ether and filtered off with suction. This gives 1.06 g (91% of theory) of methyl 2-[(tert-butylamino)sulfonyl]-6-nitrobenzoate of m.p. 89-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([F:21])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-fluoro-3-trifluoromethyl-aniline (69 mg, 0.39 mmol). The title compound was obtained as a solid (95 mg, 57% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.82 (1H, s), 9.01 (2H, s), 8.68 (1H, s), 8.09 (1H, m), 7.97 (1H, m), 7.54 (1H, m). MS m/z: 510.03, 512.02 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(F)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(F)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3,4-difluoro-phenyl)-ethanol (1.00 g, 6.33 mmol) in tetrahydrofuran (63.0 mL) at 0° C. was added triethylamine (1.95 mL, 13.9 mmol) followed by methanesulfonyl chloride (0.538 mL, 6.96 mmol). The solution was allowed to warm to room temperature overnight, quenched with water (20 mL), and diluted with ethyl acetate (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with saturated NaHCO3 (1×20 mL), brine (1×20 mL), dried over MgSO4, filtered, and concentrated to give the title compound. 1H NMR (CDCl3) δ 2.92 (s, 3H), 3.01 (t, J=6.59 Hz, 2H), 4.37–4.40 (m, 2H), 6.94–6.97 (m, 1H), 7.03–7.06 (m, 1H), 7.07–7.15 (m, 1H) ppm. 19F NMR (CDCl3) 8–140.48–, 137.71 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)o2)cc1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)cc1
Yield: 70.51 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-06) (1.6 g, 70.51%) was synthesized as a white solid from 3-benzyloxy-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-06) (2.2 g, 5.13 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])(=[O:8])[O:5]CC)C.C[Si](I)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:32]([O:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:18])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3CP(=O)(OCC)OCC)cc2)cc1
Agent: C[Si](C)(C)I
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3CP(=O)(O)O)cc2)cc1

Procedure:
{2-[(4′-Octyloxy-biphenyl-4-carbonyl)-amino]-benzyl}-phosphonic acid diethylester is dissolved in CH2Cl2 and and the mixture obtained is treated with trimethylsilyl iodide at 0°. The mixture obtained is stirred at 0° for several hours and diluted with toluene. From the mixture obtained solvent is evaporated. The evaporation residue obtained is dissolved in 1N NaOH solution, washed with EtOAc, HCl is added, precipitation occurs and the precipitate obtained is collected. {2-[(4′-Octyloxy-biphenyl-4-carbonyl)-amino]-benzyl}-phosphonic acid is obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[C:20]2[C@@H:21]3[C@H:26]([CH2:27][CH2:28][C:19]=2[CH:18]=[CH:17][CH:16]=1)[NH:25][CH2:24][CH2:23][CH2:22]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:25]3[C@@H:26]4[C@@H:21]([C:20]5[C:15]([O:14][CH3:13])=[CH:16][CH:17]=[CH:18][C:19]=5[CH2:28][CH2:27]4)[CH2:22][CH2:23][CH2:24]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: COc1cccc2c1[C@H]1CCCN[C@H]1CC2
Product: COc1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 55 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-10-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 55% of theory; LC (method 1): tR=2.67 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: NCCC[Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C(O)(=O)C>O>[CH2:7]([O:6][SiH:5]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH3:8]
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCO[SiH](OCC)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Aminopropyltriethoxysilane (1 ml) and 1.8 ml of 0.1% acetic acid were made up to 10 ml with water and added to 0.4 g sedimented yeast cells, which had been produced as described in Example 1. The mixture was stirred at room temperature for 24 hours and the cells were then separated and washed thoroughly with water. A 1% suspension of the treated cells in PBS, containing 5% glutaraldehyde was added to 2.5 mg of horseradish peroxidase in 2.5 ml PBS and kept at 21° C. for one hour. The cells were then separated and washed with PBS by centrifugation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[CH:30]1([NH2:33])[CH2:32][CH2:31]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:33][CH:30]2[CH2:32][CH2:31]2)=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3CC3)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with cyclopropylamine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=453.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(C(c3ccccc3)c3ccccc3)C2)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a stirred solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (330 mg) in dimethylformamide (6 mL) was added potassium carbonate (158 mg) and 1,1′-(bromomethylene)dibenzene (225 mg), and the mixture was stirred at 60° C. for 2 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (hexane:ethyl acetate=4:1 then chloroform:methanol=20:1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (210 mg) as an oil.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=O)[CH:35]=[CH:36][CH:37]=2)[CH:25]=1.[CH2:44]([S:46]([NH2:49])(=[O:48])=[O:47])[CH3:45]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]([CH3:43])([CH3:42])[C:39]([NH:49][S:46]([CH2:44][CH3:45])(=[O:48])=[O:47])=[O:41])[CH:35]=[CH:36][CH:37]=2)[CH:25]=1
Reactant: CCS(N)(=O)=O
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC(=O)C(C)(C)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) is added to a stirred ice cold solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (100 mg, 0.22 mmol), ethanesulfonamide (25 mg, 0.23 mmol) and 4-Dimethylaminopyridine (27 mg, 0.22 mmol) in dry DCM under nitrogen atmosphere. The ice bath is removed and the reaction mixture is stirred overnight at 60° C. The volatiles are removed under reduced pressure, the residue is dissolved in ethyl acetate, washed with 0.1 N HCl, brine and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by chromatography (SiO2 packed column), eluting with EtOAc/DCM to afford ethanesulfonic acid [2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionyl]-amide [67 mg, Example 95(a)]. LCMS: RT=2.49 minutes, MS: 551, 553 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:33]#[C:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:8][C:9]=1[N:10]([C:24]([CH:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1)=[O:4].C1COCC1.CO.O.[OH-].[Li+]>O>[CH3:36][C:35]([CH3:37])([CH3:38])[C:34]#[C:33][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:24]([CH:26]2[CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:16]=2)[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)c1ccc(Oc2ccccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCC(C(=O)N(c2ccc(Oc3ccccn3)cc2)c2cc(C#CC(C)(C)C)sc2C(=O)O)CC1
Temperature: 60 °C
Yield: 70 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-phenyl]-amino}-thiophene-2-carboxylic acid methyl ester (174 mg, 0.33 mmol) in a 3:2:1 mixture of THF:MeOH:water (5 mL) was treated with lithium hydroxide monohydrate (0.69 g, 1.65 mmol) and heated to 60° C. for 1 hour. The organic volatiles were evaporated under reduced pressure and the crude material was purified by reverse-phase HPLC to afford the title compound in 70% yield. MS (m/z): 517.0 [M+H]−; HPLC retention time: 4.90 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).