Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[F:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[O:25][CH2:26][C:27]([NH2:29])=O.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]2[C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[N:29]=[C:27]2[CH2:26][O:25][C:24]2[CH:30]=[CH:31][CH:32]=[C:22]([F:21])[CH:23]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NC(=O)COc1cccc(F)c1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(Cl)c2)c(COc2cccc(F)c2)n1
Temperature: 165 °C
Reaction time: 24 h
Yield: 22.5 %

Procedure:
A mixture of N-(3-chloro-4-morpholinophenyl)-3-oxobutanamide (0.89 g, 3.00 mmol), 2-(3-fluorophenoxy)acetamide (1.01 g, 5.97 mmol) and titanium tetraisopropanolate (7.2 mL) in xylene (20 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 45 mL of toluene and 60 mL of saturated NH4Cl aqueous solution were added. The resulting mixture stirred at rt overnight and filtered and the filtrate was extracted with DCM (60 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.29 g, 23%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([O:11][C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)=[O:13])[CH3:10]>C1COCC1.CO>[CH2:9]([O:11][C:12]([C:14]1[NH:15][C:16]([Br:8])=[CH:17][CH:18]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc(Br)[nH]1
Reaction time: 2 h
Yield: 55.3 %

Procedure:
NBS (0.15 mg, 0.83 mmol) was added to a stirred cold (0-5° C.) solution of 1H-pyrrole-2-carboxylic acid ethyl ester (200 mg, 1.44 mmol) in THF: MeOH (2:1, 24 mL). Stirring was continued at same temperature for 2 hrs. Solvent was removed under vacuum to get the residue. The residue obtained was purified by column chromatography (using silica gel of 200-430 mesh and 10% Ether in Hexane as eluent) to afford 100 mg (31.95% yield) of 5-bromo-1H-pyrrole-2-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 9.4 (bs, 1H), 6.8 (s, 1H), 6.2 (s, 1H), 4.4-4.2 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11])[CH:2]=[CH2:3].[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1>CN(C)C=O>[CH2:1]([O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[O:11][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:24])([F:26])[F:25])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C=CCO[C@@H]1CCCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@H]1CCCC[C@@H]1Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
To 15 mL anhydrous DMF (dimethylformamide) was added trans 2-allyloxy-cyclohexanol (1.144 g, 7.323 mmol), then NaH (60% in oil, 0.4261 g, 10.65 mmol) was added and stirred at room temperature 15 min. Then 4-fluoro-2-trifluoromethyl benzonitrile (1.435 g, 7.59 mmol) was added, and the solution was stirred at room temperature overnight. The DMF solution was extracted twice with hexane. Then the reaction mixture was poured into 100 mL of water and extracted three times with ether. The combined ether layers were extracted three times with water, then once with brine, and dried over magnesium sulfate, filtered, and the solvent removed. The crude product was chromatographed with a hexane/methylene chloride mixture (100% hexane to 1:1 hexane/methylene chloride). The desired fractions were combined, and the solvent removed to give 0.6245 g product. HNMR (CDCl3, ppm) 7.70-7.68 (1H, d, J=8.8 Hz), 7.32 (1H, s), 7.19-7.16 (1H, d, J=8.8 Hz), 5.80-5.71 (1H, m), 5.20-5.0 (2H, m), 4.30-4.20 (1H, m), 4.10-4.00 (1H, m) 4.00-3.90 (1H, m), 3.50-3.39 (1H, m), 2.20-2.00 (2H, m), 1.80-1.70 (2H, m), 1.65-1.20 (5H, m). FNMR (CDCl3)-62.67 ppm. MS+326.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[N:5][CH:6]=[CH:7][CH:8]=1>FC(F)(F)C(O)=O.C(OCC)(OCC)(OCC)C>[CH2:4]([O:9][C:10]1([CH3:11])[O:13][CH2:12][CH:11]([CH2:10][O:9][C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=2)[O:14]1)[CH3:3]
Reactant: COc1cccnc1OCC(O)CO
Agent: CCOC(C)(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC1(C)OCC(COc2ncccc2OC)O1
Reaction time: 3 h

Procedure:
2 drops of trifluoroacetic acid are added to a solution of 62 g of 3-(3-methoxy-2-pyridyloxy)-1,2-propanediol in 350 ml of triethyl orthoacetate and the mixture is left to stand for 3 hours at 20°-30°. On evaporation, crude 2-ethoxy-5-(3-methoxy-2-pyridyloxymethyl)-2-methyl-1,3-dioxolane is obtained in the form of an oil, which is used without purification.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:27])=[O:26])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C2CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), benzenesulfonyl chloride (10 μL, 0.0784 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:47]=[CH:46][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:45])([C:41]([F:44])([F:43])[F:42])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[CH:20][C:19]=1[F:48].O.ClCCl>O1CCOCC1>[F:48][C:19]1[CH:20]=[C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:45])([C:37]([F:38])([F:39])[F:40])[C:41]([F:43])([F:44])[F:42])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)[CH:46]=[CH:47][C:18]=1[NH:17][C:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16]
Reactant: Nc1ccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 130 °C
Yield: 14.1 %

Procedure:
Phenyl pyridin-4-ylcarbamate (0.461 mmol, 0.099 g) was added to a stirred solution of 2-(4-((4-(4-amino-3-fluorobenzyl)piperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.279 mmol, 0.139) in dioxane (7 mL) and mixture heated in a microwave reactor for 10 minutes at 130° C. Water (10 mL) was added to the reaction followed by dichloromethane (10 ml). The organic layer was separated, washed with water (3×10 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by preparative HPLC giving the title compound (0.023 g). MS (ESI) m/z 586.3 [M+H]+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.CI.[C:14](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:14][N:1]1[CH2:2][CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CCNCC1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding 1N hydrochloric acid (20 mL) and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. This step was repeated and ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4-carboxylic acid (1.79 g) as a colorless solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]([C:8]1[N:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[C:27]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:43][N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]([C:8]1[N:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[C:27]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[N:11]([CH2:13][C:14]([NH:44][CH3:43])=[O:16])[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCCN(CCCC)C(=O)c1cn(CC(=O)O)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cn(CC(=O)NC)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-(dibutylcarbamoyl)-2-(4-(methoxycarbonyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-imidazol-1-yl)acetic acid (180 mg, 0.31 mmol) in dry DMF (5 mL) was added HATU (595 mg, 1.56 mmol), methylamine (Aldrich, 78 μL, 1.56 mmol, 2.0 M in THF) and diisopropylethyl amine (544 μL, 3.13 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature over 30 min and stirring was continued for 16 h. The reaction mixture was diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give crude product. The crude material was purified by flash chromatography (gradient from 20 to 50% EtOAc/hexanes) to provide (85 mg, 46%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.22-8.19 (m, 1H), 8.10 (dd, J=6.0, 1.6 Hz, 1H), 7.58 (s, 0.5H), 7.56-7.52 (m, 1H), 7.50 (s, 0.5H), 7.36-7.10 (m, 3.5H), 6.94 (d, J=7.6 Hz, 0.5H), 4.76 (br s, 1H), 4.65 (br s, 3H), 3.98 (s, 3H), 3.97-3.95 (m, 1.5H), 3.73 (t, J=5.6 Hz, 1.5H), 3.60-3.30 (m, 3H), 3.00-2.85 (m, 2H), 2.65 (s, 1.5H), 2.64 (s, 1.5H), 1.47-1.24 (m, 6H), 0.96-0.84 (m, 5H), 0.80 (t, J=7.4 Hz, 1.5H), 0.60 (t, J=7.4 Hz, 1.5H); MS(ESI+) m/z 588.4 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].OS(O)(=O)=O.[CH3:19]O>>[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:12]=1)[C:9]([O:11][CH3:19])=[O:10]
Reactant: NCc1ccc(Cl)c(C(=O)O)c1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(CN)ccc1Cl

Procedure:
To a solution of 5-(aminomethyl)-2-chlorobenzoic acid hydrochloride (17.0 g, 76.5 mmol) in methanol (200 mL) was added conc.H2SO4 (15 mL). The reaction mixture was refluxed for 15 h. The reaction mixture was concentrated and water was added. The aq. solution was basified with sodium bicarbonate. The reaction mixture was extracted with 10% MeOH:DCM and concentrated to afford 15.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.1 (br s, 2H), 3.73 (s, 2H), 3.85 (s, 3H), 7.50 (s, 2H), 7.77 (s, 1H); MS (m/z): 200.05 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH2:10][C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[O:12])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH:1]1([C:7]([NH:9][CH:10]([C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=C(CNC(=O)C1CCCCC1)c1ccco1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)C1CCCCC1)C(=O)c1ccco1
Yield: 56.3 %

Procedure:
6.5 g of N-cyclohexylcarbonyl-(2-furylcarbonyl)methylamine, 1.3 g of 61% sodium hydride and 5.1 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 5.0 g ethyl 3-cyclohexylcarbonylamino-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 56.2%
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[CH2:36][CH2:35][CH2:34][CH2:33][N:32]4[CH:37]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:40][N:39]=[N:38][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[CH2:36][CH2:35][CH2:34][CH2:33][N:32]4[CH:37]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [H-].[Na+].C([N:7]1[C:11]([NH:12]C(=O)C(F)(F)F)=[C:10]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[OH:26])[CH:9]=[N:8]1)(C)(C)C.[Cl:27][C:28]1[C:29](F)=[CH:30][C:31]([F:50])=[C:32]([S:34]([N:37]([C:45]2[N:46]=[CH:47][S:48][CH:49]=2)C(=O)OC(C)(C)C)(=[O:36])=[O:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.CO.O>[NH2:12][C:11]1[NH:7][N:8]=[CH:9][C:10]=1[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][C:29]1[C:28]([Cl:27])=[CH:33][C:32]([S:34]([NH:37][C:45]2[N:46]=[CH:47][S:48][CH:49]=2)(=[O:36])=[O:35])=[C:31]([F:50])[CH:30]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)n1ncc(-c2cc(Cl)ccc2O)c1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Nc1[nH]ncc1-c1cc(Cl)ccc1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a suspension of sodium hydride (29 mg, 1.2 mmol) in dimethylformamide (1 mL) was added N-(1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-5-yl)-2,2,2-trifluoroacetamide (Preparation 209, 239 mg, 0.661 mmol) and stirred for 30 minutes. To this was added tert-butyl 5-chloro-2,4-difluorophenylsulfonyl(thiazol-4-yl)carbamate (Preparation 453, 206 mg, 0.501 mmol) and stirred for 24 hours. After this time only a small amount of product was observed, so potassium carbonate (40 mg, 0.3 mmol) was added and the reaction heated at 55° C. for 3 days. The reaction was cooled, diluted with ethyl acetate and the organic extract washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by automated flash column chromatography eluting with ethyl acetate:hexanes (gradient 0:1 to 1:0, by volume) afforded fully protected product. This residue was dissolved in methanol (1 mL) and sodium carbonate solution (2 M aqueous, 0.08 mL, 0.2 mmol) and water (0.2 mL) added. The reaction was stirred at room temperature for 6 hours and then heated at 55° C. for 16 hours before concentrating in vacuo and passing through a short silica gel column eluting with methanol:dichloromethane (gradient 0:1 to 1:9, by volume). All product related fractions were combined, concentrated in vacuo, dissolved in methanol (saturated in gaseous hydrogen chloride) and heated at 50° C. for 16 hours. Purification by preparative HPLC afforded the title compound as a white solid, 31 mg, 12% yield.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[N:15][C:14]=3[C:24]([OH:26])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC(C=O)=CC=1.[CH2:35]([O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH2:50])[CH:45]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:24]([C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:26])[CH:45]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: O=C(O)c1nc(-c2ccncc2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Agent: O=Cc1ccncc1
Product: O=C(OCc1ccccc1)c1cccc(NC(=O)c2nc(-c3ccncc3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-pyridine-4-yl-1H-imidazole-4-carboxylic acid (prepared according to the procedure of Example 70, steps a and b, with the modification that pyridine-4-carboxaldehyde was used instead of 2-dimethylamino-benzaldehyde in step a) was reacted with 3-amino-benzoic acid benzyl ester according to the procedure of Example 177, step a to afford 3-{[5-(2-adamantan-1-yl-ethyl)-2-pyridine-4-yl-1H-imidazole-4-carbonyl]-amino}-benzoic acid benzyl ester. The benzyl group was removed following the procedure of Example 1, step e, to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 13.20 (1H, br s), 9.88 (1H, s), 8.67 (2H, dd), 8.47 (1H, s), 8.00 (3H, m), 7.64 (1H, d), 7.41 (1H, t), 3.01 (2H, m), 1.95 (3H, br s), 1.65 (6H, m), 1.55 (6H, s), 1.44 (2H, m). The product was converted to the maleic acid salt and lyophilised from water/dioxan. Found: C, 60.81; H, 6.48; N, 8.95%. C32H34N4O7.2.5 mols H2O requires: C, 60.85; H, 6.22; N, 8.87%.
Reaction SMILES: C([O:3][C:4](=[O:57])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([NH:20][C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[CH:17]=[C:16]([CH3:30])[C:15]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([C:40]2[CH:44]=[C:43]([C:45]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[NH:46])[S:42][C:41]=2[S:55][CH3:56])(=[O:39])=[O:38])[CH:32]=1)=[O:12])C.[Li+].[OH-]>C1COCC1.O>[C:51]([O:50][C:48]([NH:47][C:45](=[NH:46])[C:43]1[S:42][C:41]([S:55][CH3:56])=[C:40]([S:37]([C:33]2[CH:32]=[C:31]([C:15]3[C:16]([CH3:30])=[CH:17][C:18]([NH:20][C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])=[O:22])=[CH:19][C:14]=3[NH:13][C:11](=[O:12])[NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:57])=[O:3])[CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:44]=1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(NC(=O)OCC[Si](C)(C)C)cc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2NC(=O)NCCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 99 %

Procedure:
A solution of 6-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid ethyl ester ((Example 259: step a) 0.437 g, 0.507 mmol) in THF:water (2:1, 15 mL) was treated with solid LiOH (0.097 g, 4.06 mmol) and stirred at room temperature 18.5 h. The THF was removed in vacuo, and the remaining aqueous solution was acidified to pH 5 with glacial acetic acid. The solution was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.4222 g, 99%) as an off-white solid. ESI-MS (m/z): Calcd. for C37H51N5O9S3Si (M+H): 834.3; 834.2.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.[Na].[NH:17]1C2[C:22](=CC(S(O)(=O)=O)=CC=2)[C:20](=O)[C:18]1=O.O=P(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.C(N)CC>C1COCC1.C(OCC)(=O)C>[CH2:18]([NH:17][S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:10]2=[O:11])(=[O:14])=[O:13])[CH2:20][CH3:22]
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: O=C1Nc2ccc(S(=O)(=O)O)cc2C1=O
Agent: [Na]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reaction time: 0.67 h
Yield: 60 %

Procedure:
2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonyl chloride (0.10 g, 0.41 mmol), prepared by the reaction of the sodium salt of 5-isatinsulfonic acid with POCl3, was dissolved in 5 mL THF. This solution was cooled in an ice bath and DIEA (0.14 mL, 2.0 eq) was added slowly, followed by n-propylamine (35 uL, 1.0 eq). Stirring was continued for 40 min and the solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and the solvent was removed by evaporation. The residue was purified by SiO2 chromatography to give the title compound (65 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1>O1CCOCC1>[Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[N:13]1[CH:14]=[CH:15][N:16]=[C:12]1[CH3:11]
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: Cc1ncc[nH]1
Solvent: C1COCCO1
Product: Cc1nccn1-c1cnn(C)c(=O)c1Cl
Yield: 27.3 %

Procedure:
A solution of 10.0 g (54.2 mmol) of 4,5-Dichloro-2-methyl-2H-pyridazin-3-one (CAS: [933-76-6]) and 8.90 g (108.4 mmol) of 2-methylimidazole in 50 ml of dioxane was stirred for 16 h at 100° C. The solution was concentrated in vaccuo and the residue was purified by flash chromatography over silicagel using a 95:5 mixture of methylene chloride and methanol as eluant to yield 3.33 g (14.82 mmol, 27%) of the title compound as a white crystalline solid, MS: m/e=225.1, 227.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6](=[O:11])[C:5]=1[OH:12])([OH:3])=[O:2].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([O:12][C:5]1[C:6](=[O:11])[N:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[C:1]([O:3][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cn1ccc(C(=O)O)c(O)c1=O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1=O

Procedure:
4-Carboxy-1-methyl-3-hydroxy-2(1H)-pyridinone (6.8 g, 0.04 mol) is mixed with benzyl chloride (12.1 g, 0.088 mol), anhydrous potassium carbonate (13.8 g, 0.1 mol) in anhydrous dimethylformamide (DMF) (120 mL). The mixture is heated at 75°-80° C. under N2 in darkness for 16 hours. The reaction mixture is filtered and rotary evaporated to yield a dark oil, which is purified by a silica gel plug as mentioned in the synthesis of 1-methyl-3-hydroxy-2(1H)pyridinone above, to give the 3-benzyloxy-4-benzyloxycarbonyl-1-methyl-2(1H)-pyridinone as a pale yellow, thick oil. It is mixed with methanol (50 mL) and a 6M NaOH solution (10 mL). The mixture is stirred at room temperature for 4 hours, then evaporated to dryness. The residue is dissolved in water (100 mL), and acidified with 6M HCl solution to pH 2 to give the title compound (9.3 g 88.7%), as a white crystalline product, m.p. 152°-153° C. 1H NMR (250 MHz, CDCl3): δ 3.616 (s, 3H), 5.611 (s, 2H), 6.695 (d, 1H, J=7.13), 7.152 (d, 1H, J=7.16), 7.35-7.48 (m, 5H). Anal. for C14H13NO4. 0.2 H2O (262.87), Calcd. (found): C, 63.97 (64.05); H, 5.14 (5.14); N, 5.33 (5.18).