Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[C:12]([I:13])[C:5]=12.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.O>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:11]=[C:12]([I:13])[C:5]=12
Reactant: Clc1ccnc2[nH]cc(I)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(I)c2c(Cl)ccnc21
Reaction time: 2.5 h
Yield: 83 %

Procedure:
To a mixture of 95% sodium hydride (28 mg, 1.1 mmol) and 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (278 mg, 1.0 mmol) in 10 mL DMF was added benzenesulfonyl chloride (194 mg, 1.1 mmol) and the reaction mixture stirred for 2.5 hours then diluted with water and the resulting precipitate collected by filtration to give the title compound in 83% yield. MS (ESI+) m/z 418.9 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][N:16]([CH3:19])[C:10]=3[N:11]=[C:12]([C:14]#[N:15])[N:13]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][N:46]([CH:49]3[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O.O.CCOC(C)=O>[CH:49]1([N:46]2[CH2:47][CH2:48][CH:43]([CH2:42][CH2:41][O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[C:9]5[CH:18]=[CH:17][N:16]([CH3:19])[C:10]=5[N:11]=[C:12]([C:14]#[N:15])[N:13]=4)=[CH:4][C:3]=3[C:20]([F:23])([F:22])[F:21])[CH2:44][CH2:45]2)[CH2:50][CH2:51]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C3CC3)CC2)cc1
Reactant: Cn1ccc2c(-c3ccc(O)c(C(F)(F)F)c3)nc(C#N)nc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccc2c(-c3ccc(OCCC4CCN(C5CC5)CC4)c(C(F)(F)F)c3)nc(C#N)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
4-[4-Hydroxy-3-(trifluoromethyl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (100 mg) and potassium carbonate (87 mg) were added to a solution of 2-(1-cyclopropylpiperidin-4-yl)ethyl 4-methylbenzenesulfonate (152 mg) in DMAc (2 mL) at room temperature, and the mixture was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, EtOAc, water, and a saturated aqueous NaHCO3 solution were added thereto, and the mixture was stirred. Extraction was performed on the mixture using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (Hex:CHCl3=50:50 to 0:100), whereby 4-{4-[2-(1-cyclopropylpiperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (54 mg) was obtained as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 4-fluoro-3-nitroaniline (0.5 g, 0.023 mol) in DCM (10 ml) and pyridine (0.98 g, 0.012 mol) was added methanesulfonyl chloride (0.54 g, 0.0048 mol) portion wise at 0° C. with constant stirring. The reaction mixture was allowed to stir at 0° C. for 4 h. The reaction mixture was concentrated and diluted with water (20 ml) and extracted with DCM (3×15 ml). The combined organic layers were washed with 1 N HCl and NaHCO3 solution dried over Na2SO4 and concentrated in vacuo to afford the desired product N-(4-fluoro-3-nitrophenyl)methane sulfonamide as off a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.23 (s, 1H), 7.93-7.91 (d, J=8.4 Hz, 1H), 7.62-7.54 (m, 2H), 3.59 (s, 3H). LCMS (ES) m/e MS (M−1=233). Purity: 80%.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1COCC1.C([Li])CCC.[CH:24]([Si:27](Cl)([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])([CH3:26])[CH3:25]>CCOCC>[CH:24]([Si:27]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH3:26])[CH3:25]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of 3.0 g (18.07 mmol) of fluorene in 50 mL of dry ether and 25 mL of freshly distilled THF was added dropwise 13 mL of 1.4M n-butyllithium. The mixture was refluxed for 3 hours, cooled to room temperature, and treated with 3 mL (14.02 mmol) of triisopropylsilyl chloride in one portion. The mixture was refluxed for 3 days, cooled to room temperature, and washed with sat'd NH4Cl (2×50 mL) and water (50 mL). The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo to give an oil which was triturated with methanol to afford 3.34 g (73.8%) of the crude silane as a yellowish solid. Recrystallization from EtOH gave 2.98 g (65.9%) of 9-triisopropylsilylfluorene as white needles, m.p. 122°-123° C.; 1H NMR (CDCl3): δ 0.91 (d, 18H, Si-C-Me2), 1.09-1.42 (hept, 3H, Si-CH-Me2 , 4.26 s, 1H, ArCHAr), 7.05-8.00 (m, 8H, aryl).
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.[O:11]=[C:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:33])[C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=2)[CH2:19][CH2:18]1)[CH2:13][C:14](O)=[O:15].CCN=C=NCCCN(C)C.Cl.O1C=NC(C2C=CC(N)=CC=2)=N1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[O:11]=[C:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:33])[C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=2)[CH2:19][CH2:18]1)[CH2:13][C:14]([NH2:7])=[O:15]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
HOBt (49 mg, 0.36 mmol) and DMAP (55 mg, 0.45 mmol) were added to a stirred solution of 3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionic acid (100 mg, 0.3 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (69 mg, 0.36 mmol) followed by 4-[1,2,4]-oxadiazol-3-yl-phenylamine (53 mg, 0.33 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using silica 60-120 mesh (30% ethyl acetate in hexane) to afford 15 mg (11%) of N-(4-[1,2, and 4]oxadiazol-3-yl-phenyl)-3-oxo-3-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 474.13 (M+1)+, 98.2%, 1H NMR: (DMSO-d6): δ 10.5 (s, 1H), 9.7 (s, 1H), 8.0 (d, 2H), 7.8 (d, 2H), 7.5 (t, 2H), 3.6 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[C:25]1([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2CC2CCOCC2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Temperature: 125 °C
Yield: 70.4 %

Procedure:
A mixture of 3-bromo-5-hydroxy-2-oxo-1-(tetrahydro-pyran-4-ylmethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.18 mmol), PhSnBu3 (0.070 mL, 0.21 mmol), and PdCl2(PPh3)2 (25 mg, 0.035 mmol) in DMF (3 mL) was heated at 125° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (20 mL) were added. 1 M HCl was added with stirring until pH was about 2. The aqueous layer was extracted with EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified twice by silica gel chromatography (0-4% MeOH/CH2Cl2, then 15-100% EtOAc/hexanes+1% AcOH) to give 50 mg of the title compound as a light yellow solid. MS: (+) m/z 395.26 (M+1).
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][CH2:7][C@@H:8]([C:17]2[O:18][CH:19]=[C:20]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:21]=2)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:5][CH2:6][CH2:7][C@@H:8]([C:17]2[O:18][CH:19]=[C:20]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:21]=2)[CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1coc([C@H](CCCC2CCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1coc([C@H](CCCC2CCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
A solution of tert-butyl (3R)-6-cyclobutyl-3-{4-[(dimethylamino)carbonyl]-1,3-oxazol-2-yl}hexanoate (Preparation 120) (240 mg, 0.66 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1.2 ml) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene and dichloromethane. The oil was purified by column chromatography on silica gel eluting with 97:3:0.3 (dichloromethane:methanol:acetic acid) to afford the title compound as a white solid (161 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:12]2[C:7](=[C:8]([N+:18]([O-])=O)[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[NH:6][CH:5]=1)[CH3:3]>CO.O.[Pd]>[NH2:18][C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[C:12]2[C:7]=1[NH:6][CH:5]=[C:4]2[CH:2]([CH3:3])[CH3:1]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]cc(C(C)C)c2c1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cc(N)c2[nH]cc(C(C)C)c2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
To a solution of crude ethyl 3-(1-methylethyl)-7-nitro-1H-indole-5-carboxylate (D218) (10.1 g, 28.5 mmol, 1 equiv) in MeOH (250 ml) and H2O (25 ml) was added 10% palladium on charcoal (50% wet, 1.5 g, 8% w/w) and NH4COOH (17 g, 280 mmol, 10 equiv) and the resulting mixture was stirred at 70° C. for 3 h then cooled to room temperature. The catalyst was filtered off through a pad of celite and most of the MeOH was removed in vacuo. The residue was diluted with AcOEt and the organic layer was washed with a saturated NaHCO3 aqueous solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 3/1 to 1/1) gave methyl 7-amino-3-(1-methylethyl)-1H-indole-5-carboxylate (D221) (1.47 g, 21%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([N:15]=[CH:16]N(C)C)=[S:14])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](=[O:27])[CH2:25]Br>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[S:14][C:25]([C:24](=[O:27])[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[CH3:21])=[CH:16][N:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=NC(=S)NCCCCNC(=O)OC(C)(C)C
Reactant: Cc1ccccc1C(=O)CBr
Product: Cc1ccccc1C(=O)c1cnc(NCCCCNC(=O)OC(C)(C)C)s1
Yield: 69 %

Procedure:
The title compound was synthesised from [4-(3-Dimethylaminomethylene-thioureido)-butyl]-carbamic acid tert-butyl ester and 2-methyl phenacylbromide (Literature: WO9907666) according to the procedure described for Example 25 in 69% yield. MS (m/e): 390.2 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([NH:6]C(=O)C)=[CH:4][CH:3]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH3:39])[CH:33]=1>O.[Cu]Cl.CN1CCCC1=O>[F:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:2]2[CH:3]=[CH:4][C:5]([NH2:6])=[CH:10][CH:11]=2)=[C:34]([CH3:39])[CH:33]=1
Reactant: Cc1cc(F)ccc1O
Reactant: CC(=O)Nc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(F)ccc1Oc1ccc(N)cc1
Temperature: 200 °C
Yield: 27 %

Procedure:
A microwave vessel was charged with 4′-bromoacetoanilide (1.19 g, 5.56 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.23 mL, 1.1 mmol), copper(I) chloride (0.22 g, 2.2 mmol), cesium carbonate (5.42 g, 16.7 mmol), 4-fluoro-2-methylphenol (0.70 g, 5.6 mmol), and N-methyl-2-pyrrolidone (5 mL). The reaction mixture was heated at 200° C. in a microwave oven for 20 minutes. The reaction mixture then was cooled to ambient temperature and diluted with deionized water (20 mL). The dilution was extracted with ethyl acetate (20 mL) and the extract combined with saturated sodium bicarbonate (aq., 100 mL). The mixture was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was diluted with concentrated hydrochloric acid (15 mL) and the dilution was heated at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with 4N sodium hydroxide until basic. The dilution was extracted with methylene chloride (30 mL) and the extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give 4-(4-fluoro-2-methylphenoxy)aniline (0.33 g, 1.5 mmol, 27% yield) as off-white solid. MS (EI) for C13H12FNO. found 218.1 (MH+).
Reaction SMILES: [CH2:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2].[Na].O>CC(CC(C)C)O.C1(C)C=CC=CC=1>[CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(=Cc1ccc(C)cc1)C(=O)O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(C)CC(C)O
Solvent: O
Product: CCC(Cc1ccc(C)cc1)C(=O)O

Procedure:
A suspension of 91 g of α-ethyl-4-methyl-cinnamic acid in 1.5 liters of methyl-isobutyl-carbinol is added dropwise within one hour to 100 g of sodium in 250 cc of toluene at 130° while stirring well. After a further hour, sodium is no longer present and the mixture is cooled and 500 cc of water are carefully added thereto. The aqueous phase is separated and the methyl-isobutyl-carbinol phase is again extracted twice with water. The entire aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The ether extract is washed with water, dried over sodium sulphate and evaporated. The crude α-ethyl-4-methyl-dihydrocinnamic acid is obtained as an oil and may be purified by chromatography.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.O>CN(C)C=O>[O:9]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCCOc1ccccc1
Yield: 100 %

Procedure:
60% Sodium hydride (1.16 g) was suspended in dimethylformamide (40 ml), and phenol (3 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and a solution of 1,6-dibromohexane (7.78 g) in dimethylformamide (10 ml) was dropwise added, which was followed by stirring at room temperature for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 8.2 g of 6-phenoxyhexyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][C@@H:18]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[C@H:17]([O:37][CH2:38][C:39]([O:41]CC4C=CC=CC=4)=[O:40])[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:19][C@H:18]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[C@@H:17]([O:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:16]3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCC(N3C[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)[C@H](OCC(=O)OCc4ccccc4)C3)CC2)cn1
Solvent: CO
Product: COc1ccc(N2CCC(N3C[C@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)[C@@H](OCC(=O)O)C3)CC2)cn1
Reaction time: 2 h

Procedure:
To a solution of benzyl rel-({(3R,4R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-3-yl}oxy)acetate in methanol (400 μL) was added and Palladium (10%) on Carbon (50 mg) the was purged with hydrogen gas for two minutes; the reaction was then subjected to 1 atmosphere of hydrogen gas for two hours. The flask was purged with argon; the mixture was filtered, then purified by preparative HPLC to afford rel-({(3S,4S)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]-4-[({[3-trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-3-yl}oxy)acetic acid. 1H-NMR (CDCl3) δ: 1.10-1.25 (m, 2H), 1.80-2.40 (m, 4H), 2.50-2.70 (m, 2H), 2.95-3.15 (m, 1H), 3.20-3.35 (m, 1H), 3.40-3.80 (m, 4H), 3.85 (s, 3H), 3.90-4.40 (m, 5H), 4.40-60 (m, 2H), 6.62 (t, J=7.8 Hz, 1H), 7.10-7.15 (m, 1H), 7.38-7.58 (m, 1H), 7.60 (m, 2H), 8.00-8.25 (m, 2H), 9.45 (bs, 1H). MS m/z: 581 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=1[C:11]([OH:13])=O>CS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[S:8][C:9]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=1[C:11]2=[O:13]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Sc1ccccc1Br
Agent: CS(=O)(=O)O
Product: O=c1c2cc([N+](=O)[O-])ccc2sc2c(Br)cccc12
Temperature: 150 °C

Procedure:
2-(2-Bromo-phenylsulfanyl)-5-nitro-benzoic acid (34 g, 96 mmol) was suspended in methanesulphonic acid (400 ml) and heated at 150° C. The crude mixture was slowly poured onto ice with vigorous stirring and the precipitate formed was filtered. The solid was suspended into water (50 ml) quenched to pH 7-8 with conc. ammonia solution and filtered. The yellow/lime colored solid was dried under vacuum at 50° C. to give the crude title compound, which was used without any further purification (23.09 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[C:33]2=[O:41])=[C:28]([CH3:42])[CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:34]5[C:33](=[O:41])[N:32]([C:29]6[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=6[CH3:42])[CH:37]=[CH:36][CH:35]=5)=[O:39])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1cc(F)ccc1-n1cccc(C(=O)O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-n1cccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol) and 1-(4-fluoro-2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (98 mg, 0.398 mmol) in N,N-dimethylformamide (2 mL) were added N,N-diisopropylethylamine (105 μL, 0.612 mmol) and HATU (151 mg, 0.398 mmol), and the mixture was stirred at room temperature for 4 hr. Ethyl acetate, tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (140 mg, 82%) as a slightly yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH:9]([OH:21])[CH2:10][NH:11][CH:12]([C:14](=[O:20])[NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:13])(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[ClH:32].[NH2:7][C@@H:8]([CH2:22][C:23]1[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=1)[C@H:9]([OH:21])[CH2:10][NH:11][C@H:12]([C:14]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:20])[CH3:13]
Reactant: CC(C)CNC(=O)C(C)NCC(O)C(Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CNC(=O)[C@H](C)NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-(1-isobutylcarbamoyl-ethylamino)-propyl]-carbamic acid tert-butyl ester (2.7 g, 6 mmol) is dissolved in excess 4N hydrochloric acid in dioxane, and the reaction is stirred 2 h at room temperature. The solution is concentrated under reduced pressure to give the title compound. ESI MS m/z 344.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:57]([O:59][C:60](=[O:70])[CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][N:64]=1)[CH3:58]>CN(C)C=O>[CH2:57]([O:59][C:60](=[O:70])[CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:65][N:64]=1)[CH3:58]
Reactant: CCOC(=O)CCc1ccc(N)cn1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCc1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
A solution of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (0.7 g, Reference Example 31) in anhydrous dimethylformamide (25 ml) was treated sequentially with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.85 g), diisopropylethylamine (0.54 g) and a solution of 3-(5-amino-pyrid-2-yl)propanoic acid ethyl ester [0.42 g, Reference Example 4(a)] in dimethylformamide (5 ml). After stirring at room temperature for 5 hours and standing over night the reaction mixture was evaporated. The residue was treated with ethyl acetate and the resulting solution was washed three times with water, then with brine and then evaporated. The residue was subjected to flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (97:3, v/v) to give the title compound (0.68 g) as a white foam.