Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][OH:27].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][O:27][S:29]([CH3:28])(=[O:31])=[O:30]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(CO)cc(OC)c21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COS(C)(=O)=O)cc(OC)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
A mixture of 100 mg (0.23 mmol) [4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-methanol, 26 μl (0.33 mmol) methanesulfonyl chloride and 60 μl (0.35 mmol) diisopropylethylamine in 4 ml dichloromethane is stirred at 0° C. for 2 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo to afford 120 mg of the title compound as an oil that is used directly in the next reaction.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:48])[N:32]([C:40]1[S:41][C:42]([CH:46]=[O:47])=[C:43]([Cl:45])[N:44]=1)[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:26]([O:30][C:31](=[O:48])[N:32]([C:40]1[S:41][C:42]([CH:46]([OH:47])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[C:43]([Cl:45])[N:44]=1)[CH2:33][C:34]1[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N(Cc1ccncc1)c1nc(Cl)c(C=O)s1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(Cc3ccncc3)C(=O)OC(C)(C)C)nc2Cl)c2cccnc21
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.44 g, 1.1 mmol) in tetrahydrofuran (20 mL) at −20° C., isopropylmagnesium chloride (2 M in tetrahydrofuran, 0.6 mL, 1.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C. in 10 minutes. The reaction mixture was then cooled to −40° C. A solution of (4-chloro-5-formyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (518, 0.26 g, 0.73 mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to −10° C. over 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (519, 397 mg, 86%). MS (ESI) [M+H+]+=628.3.
Reaction SMILES: C(OC([NH:8][CH:9]([C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C(#N)C.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]>C(N(CC)CC)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH:9]([NH2:8])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:17]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)NC(c1ccccn1)[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3ccccn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
3-(R)-[1-Tert-butoxycarbonylamino-1-(2-pyridyl)methyl]pyrrolidine [F2] (0.535 mmol) was added to an acetonitrile suspension (5 ml) of 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (169 mg, 0.534 mmol), and the mixture was heated under reflux for 19 hours in the presence of triethylamine (0.5 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue was dissolved in chloroform (50 ml), this was washed with 10% citric acid (40 ml) and saturated brine (40 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (5 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at roam temperature and then washed with chloroform (50 ml×5). This hydrochloric acid aqueous solution was adjusted to an alkaline liquid property by adding 10 mol/l sodium hydroxide aqueous solution and then stirred at room temperature for 1 hour. This suspension was adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×3). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol to obtain 136 mg (54%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]([OH:14])[CH3:13].[CH3:15][Si:16]([CH3:19])([CH3:18])Cl.C[Si](C)(C)N[Si](C)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:15])[CH3:13]
Reactant: CC(O)Cc1c[nH]c2ccc(F)cc12
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ccc(F)cc12)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The alcohol 49 (10 mmol) was dissolved in absolute THF (15 ml) with exclusion of moisture. Trimethylchlorosilane (2.1 ml, 15.3 mmol) and hexamethyldisilazane (4.9 ml, 23.3 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The course of the reaction was monitored by thin layer chromatography. When the reaction had ended, the solvent was removed under vacuo. The remaining residue was a viscous oil which was taken up in diethyl ether (30 ml), and saturated NaHCO3 (30 ml) was added. The phases were separated, and the aqueous phase was extracted twice with 15 ml portions of Et2O. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. The resulting product was initially in the form of an oil and crystallized spontaneously. The crude product was further purified by recrystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Br:12][C:13]1[CH:14]=[C:15](/[CH:16]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=Cc1cccc(Br)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Br)c1)c1ccc(Cl)cc1F
Yield: 62.1 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (1.9 g, 11 mmol) was reacted with 3-bromobenzaldehyde (Aldrich) (1.57 mL, 13.4 mmol), methanolic solution (25 wt %) of sodium methoxide (2.8 mL, 12 mmol) in methanol (50 mL) at 50° C. for 3 h to give (Z)-3-(3-bromo-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (2.3 g, 60%).
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:12](=[O:16])[C@@H:13]([OH:15])[CH3:14])[C:8](=[O:17])[N:7]([CH3:18])[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]1=2)(=[O:3])[CH3:2].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>N1C=CC=CC=1>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][C:24](=[O:25])[O:15][C@H:13]([C:12](=[O:16])[NH:11][C@@H:9]2[C:8](=[O:17])[N:7]([CH3:18])[C:6]3[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=3[N:4]([C:1](=[O:3])[CH3:2])[CH2:10]2)[CH3:14])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)N1C[C@H](NC(=O)[C@H](C)O)C(=O)N(C)c2ccccc21
Solvent: c1ccncc1
Product: CC(=O)N1C[C@H](NC(=O)[C@H](C)OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
A solution of 50 mg (0.16 mmol) of (S)—N—((S)-5-acetyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-hydroxy-propionamide in 1.5 ml of pyridine was treated with 39 mg (0.18 mmol) of 4-nitrophenyl chloroformate, and the mixture was stirred at room temperature for 18 h. For the working-up, the solvent was evaporated and the residue chromatographed on silica gel using a 3:1-mixture of heptane and ethyl acetate as the eluent. There were obtained 31 mg (40% of theory) of carbonic acid (S)-1-((S)-5-acetyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl)-ethyl ester 4-nitro-phenyl ester; MS: m/e=488 (M+NH4)+. The ester was treated with 0.7 ml of 2,2,3,3,3-pentafluoro-propylamine and the mixture was stirred at room temperature for 36 h. For the working-up, 3 ml of ethyl acetate were added and the solution was washed with a saturated solution of sodium carbonate and a saturated solution of sodium chloride. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a gradient of a 98:2- to 95:5-mixture of dichloromethane and methanol as the eluent. There were obtained 12 mg (38% of theory) of the title compound as a white solid; MS: m/e=498 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.[O:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: OC1CCOCC1
Reactant: O=C1c2ccc(Cl)cc2CCc2c(O)cccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccc(Cl)cc2CCc2c(OC3CCOCC3)cccc21
Yield: 45 %

Procedure:
For the synthesis of the title compound, 0.45 g (1.7 mmol) of 8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.28 g (0.0027 mol) of tetrahydropyran-4-ol, 0.77 g (2.9 mmol) of P(Ph)3 and 0.41 g (2.0 mmol) of diisopropyl azodicarboxylate in 2 ml of THF are reacted by method P. C20H19ClO3 (Mr=342.83); yield: 45%
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:19]=[C:18]([C:20]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:22])[N:17]([CH3:23])[N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cn2)c1CNc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 80 %

Procedure:
As described for example 163c, 3-((3-(5-fluoropyridin-2-yl)-5-methylisoxazol-4-yl)methylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (76 mg, 0.23 mol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (95 mg, 80%) which was obtained as a white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[Cl:18][C:19]1[CH:20]=[C:21]([F:37])[C:22]2[O:26][CH2:25][CH2:24][C:23]=2[C:27]=1[CH2:28][CH2:29][CH2:30][NH:31][C:32]([CH:34]1[CH2:36][CH2:35]1)=[O:33]>C(O)(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([F:37])[C:22]2[O:26][CH:25]=[CH:24][C:23]=2[C:27]=1[CH2:28][CH2:29][CH2:30][NH:31][C:32]([CH:34]1[CH2:36][CH2:35]1)=[O:33]
Reactant: O=C(NCCCc1c(Cl)cc(F)c2c1CCO2)C1CC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: O=C(NCCCc1c(Cl)cc(F)c2occc12)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.1 %

Procedure:
Lead tetraacetate (313 mg) was added to a solution of cyclopropanecarboxylic acid [3-(5-chloro-7-fluoro-2,3-dihydro-benzofuran-4-yl)-propyl]-amide (0.2 g) in glacial acetic acid (5 ml) and the mixture stirred at room temperature for 18 h. The solvent was evaporated and the resdue purified by preparitive HPLC to give the title compound as a colourless solid (20 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:21][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(I)cc1)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 110.7 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-(4-iodophenyl)-propanoic acid (5.0 g, 12.8 mmol) in DMF (50 mL) was treated with K2CO3 (2.2 g, 15.4 mmol). After stirring for 15 min, the solution was cooled to 0° C. and treated with iodomethane (1.0 mL, 15.4 mmol) After the addition was complete, the reaction mixture was stirred at room temperature for another 16 h, filtered and the resulting solid was washed with ethyl acetate (200 mL). The filtrate was washed successively with 5% aq HCl, sat. aq NaCl, dried over MgSO4 and concented. Purification by flash column chromatography (5% ethyl acetate in heptane) provided the desired product (5.74 g, 98%) as an oil. 1H NMR (CDCl3), δ 7.61 (d, J=9 Hz, 2 H), 7.74 (d, J=9, 2H), 4.97 (d, J=7 Hz, 1 H), 4.56 (m, 1 H), 3.73 (s, 3 H), 3.02 (ddd, J=7, 7, 12 Hz, 2 H), 1.47 (s, 9 H)
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][C:13]([O:15]CC)=[O:14])[N:11]=2)[CH2:6][CH2:5]1>C1COCC1.O>[CH:4]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[N:11]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1coc(C2CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1coc(C2CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
Lithium hydroxide monohydrate (7.83 g, 186.7 mmol) was added to ethyl (2-cyclopropyl-1,3-oxazol-4-yl)acetate (Preparation 91, 7.00 g, 35.9 mmol) in THF (200 mL) and water (100 mL). The mixture was stirred at room temperature for 2 hours then the reaction mixture volume was reduced to one third by evaporation in vacuo. The aqueous residue was acidified using aqueous 1M HCl then extracted with EtOAc (200 mL). The organic phase was evaporated in vacuo and the crude material was triturated with diethyl ether (100 mL) to afford the title compound as a white solid (66%, 4.00 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.FC1C=C([C:36]2([OH:41])[CH2:40][CH2:39][O:38][CH2:37]2)C=C(F)C=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:4]1[CH:5]=[C:6]([C:36]2([OH:41])[CH2:40][CH2:39][O:38][CH2:37]2)[CH:7]=[C:2]([F:1])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCOC3)cc2F)OC1(C)C
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2c(F)cc(C3(O)CCOC3)cc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydrofuran-3-ol (Intermediate 143) gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[O:29]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccccc1F
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccccc2F)cc1

Procedure:
59 mg of pale yellow solid 3-{4-[3-(2-fluorophenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2-fluorophenyl isocyanate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:12][Mg]Br>>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH3:12]
Reactant: O=C(CCCl)c1ccccc1
Reactant: C[Mg]Br
Product: CC(O)(CCCl)c1ccccc1

Procedure:
4-chloro-2-phenylbutan-2-ol was prepared from 3-chloro-1-phenylpropan-1-one and methylmagnesium bromide following a procedure analogous to that described in Preparation 1 Method 1 Step 2.
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([CH2:10][N:11]([C:23](=[O:36])[CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[C:71]([N:88]1[CH2:93][CH2:92][NH:91][CH2:90][CH2:89]1)([O:73][CH2:74][CH:75]1[C:87]2[C:82](=[CH:83][CH:84]=[CH:85][CH:86]=2)[C:81]2[C:76]1=[CH:77][CH:78]=[CH:79][CH:80]=2)=[O:72]>C(#N)C>[CH:86]1[C:87]2[CH:75]([CH2:74][O:73][C:71]([N:88]3[CH2:89][CH2:90][N:91]([C:13](=[O:14])[C@@H:12]([N:11]([CH2:10][C:9]4[CH:37]=[CH:38][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=4)[C:23](=[O:36])[CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:92][CH2:93]3)=[O:72])[C:76]3[C:81](=[CH:80][CH:79]=[CH:78][CH:77]=3)[C:82]=2[CH:83]=[CH:84][CH:85]=1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCNCC1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid (1.5 g, 2.86 mmol) and TBTU (1.1 g, 3.43 mmol) was dissolved in acetonitrile (30 mL) and DIPEA (1.5 mL, 8.6 mmol) and stirred at rt for 5 min, followed by the addition of Fmoc-piperazine hydrobromide (1.22 g, 3.15 mmol). The reaction mixture was stirred at rt for 16 h and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 ml) and washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silicagel, EtOAc/heptane=3/7) to give 1.75 g (75%) of 4-(2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionyl)-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester. LC-MS: tR=1.25 min; [M+H]+=814.5.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][N:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO.[Cl-].[Na+].O>[CH3:37][O:36][C:34]([C:33]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:21][N:22]=1)[N:7]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:35]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1CCc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2CCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
5-Bromo-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1-phenethyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (371 mg, 0.628 mmol) was dissolved in 10 mL of MeOH and placed in ice bath. NaOMe solution (0.43 mL, 1.88 mmol, 25 wt % in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, followed by addition of 50 mL of brine. The resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified twice by silica gel chromatography (first eluted with 5-60% EtOAc/hexanes+2% AcOH, then with 0-20% EtOAc/CH2Cl2) to give 166 mg of the title compound. MS: (+) m/z 403.13, 405.14 (M+1, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:55][C:56]1([F:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:32][C:6]1[CH:5]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:59]3[CH2:60][CH2:61][C:56]([F:62])([F:55])[CH2:57][CH2:58]3)=[O:41])=[CH:37][CH:38]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:24])[CH3:23])[CH:28]([CH3:29])[CH3:30])[CH2:18][CH2:19]2)[C:10]1=[O:31]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(F)(F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (4.0 g, 6.45 mmol) in CH2Cl2 (40 mL) with 1,1′-carbonyldiimidazole (2.09 g, 12.91 mmol) and stir for 1 hour at room temperature. Treat the reaction with 4,4-difluoropiperidine hydrochloride (1.53 g, 9.68 mmol) and diisopropylethylamine (1.69 g, 9.68 mmol) and stir for 12 hours at room temperature. Load the mixture on silica gel column and flash with 25% to 35% ethyl acetate in hexanes to afford 3.8 g (81%) of the title compound. MS (m/z): 722 (M+).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[Br:16][C:13]1[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[C:14]=1[Br:15]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(OC)cc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2c(Br)c(Br)c3c(O)c(C(=O)NCC(=O)O)ncc32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dibromo-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 512 (M+H)+.