Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1Br)(C)(C)C.[OH:21][C:22]1[CH:23]=[C:24]([C:28]#[CH:29])[CH:25]=[CH:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1.Cl>O.CC(C)=O.C(Cl)Cl.O1CCOCC1.[Pd](Cl)Cl>[OH:21][C:22]1[CH:23]=[C:24]([C:28]#[C:29][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[CH:18][C:9]=2[O:8][CH2:7][C:6]([OH:5])=[O:20])[CH:25]=[CH:26][CH:27]=1
Reactant: C#Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)COc1ccc2ccccc2c1Br
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(O)COc1ccc2ccccc2c1C#Cc1cccc(O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (1-bromo-naphthalen-2-yloxy)-acetic acid tert-butyl ester (Intermediate 217, 125 mg; 0.37 mmol), 3-hydroxyphenylacetylene (53 mg; 0.44 mmol), palladium(II) chloride (3.3 mg; 0.02 mmol), triphenylphosphine (10 mg; 0.04 mmol) and piperidine (73 μl; 0.74 mmol) in distilled water (1.1 ml) and Acetone (1.4 ml) was stirred overnight at 60° C. The reaction mixture was extracted by EtOAc and the organic phases was dried over MgSO4, concentrated to dryness and purified by preparative HPLC. The intermediate obtained was diluted in DCM (1 ml) and treated with a 4 M solution of HCl in dioxane (930 μl). After stirring overnight, the reaction mixture was concentrated to dryness and purified by preparative HPLC to afford the title compound as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:33]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH:30][S:40]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)(=[O:42])=[O:41])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=S(=O)(Cl)N1CCCCCC1
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CC(NS(=O)(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-(2-amino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (220 mg, 0.50 mmol), homopiperidinesulfonyl chloride (110 mg, 0.55 mmol, prepared by the method of Von Geldem, et al., J. Med. Chem., 1996;39:968-981), N,N-diisopropylethylamine (129 mg, 1.00 mmol), and DMAP (20 mg) in DMF (1 mL) is stirred at room temperature for 72 hours, diluted with ethyl acetate, and washed with water, 1N HCl, saturated NaHCO3 solution and brine, dried over anhydrous sodium sulfate, and concentrated. The oily residue thus obtained was purified via flash chromatography (30% EtOAc/hexane) followed by preparative TLC (2 elutions, 30% EtOAc/Hexane) to afford 39 mg of a clear colorless oil which is dissolved in 0.5 mL CHCl3, diluted with 4 mL hexane, and maintained at 3° C. until crystallization occurred. The crystals are collected and weigh 10.1 mg (3%), mp=123-124° C.
Reaction SMILES: [CH:1]([C:4]1[N:8]([CH3:9])[C:7]2[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:6]=2[N:5]=1)([CH3:3])[CH3:2].C(C1N(CCCC)C2C=C(C(F)(F)F)C=CC=2N=1)(=O)CC(C)C.C1(C2N(C)C3C=C(C(F)F)C=CC=3N=2)CCC1.C1(C2N(CC)C3C=C(F)C=CC=3N=2)CC1.C(C1N(C)C2C=C(Br)C=CC=2N=1)C(C)C.C(C1N(CCCC)C2C=C(C(F)(F)F)C([N+:107]([O-:109])=[O:108])=CC=2N=1)(=O)CC(C)C.C1(C2N(C)C3C=C(C(F)F)C([N+]([O-])=O)=CC=3N=2)CCC1.C1(C2N(CC)C3C=C(C(F)(F)C(F)(F)F)C([N+]([O-])=O)=CC=3N=2)CC1.C(C1N(CCCCCC)C2C=C(C(F)(F)F)C([N+]([O-])=O)=CC=2N=1)(C)C.C(C1N(C)C2C=C(Br)C([N+]([O-])=O)=CC=2N=1)C(C)C>>[CH:1]([C:4]1[N:8]([CH3:9])[C:7]2[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[C:12]([N+:107]([O-:109])=[O:108])=[CH:13][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccc(C(F)(F)F)cc2n1C
Reactant: CCCCn1c(C(=O)CC(C)C)nc2cc([N+](=O)[O-])c(C(F)(F)F)cc21
Agent: CC(C)Cc1nc2cc([N+](=O)[O-])c(Br)cc2n1C
Agent: CC(C)Cc1nc2ccc(Br)cc2n1C
Agent: CCCCCCn1c(C(C)C)nc2cc([N+](=O)[O-])c(C(F)(F)F)cc21
Product: CC(C)c1nc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1C

Procedure:
In a similar manner by substituting for the 2-isopropyl-1-methyl-6-trifluoromethylbenzimidazole reactant of this example an equivalent quantity of: 2-isovaleryl-1-butyl-6-trifluoromethylbenzimidazole, 2-cyclobutyl-1-methyl-6-difluoromethylbenzimidazole, 2-cyclopropyl-1-ethyl-6-pentafluorothylbenzimidazole, 2-isopropyl-1-hexyl-4,6-ditrifluoromethylbenzimidazole, 2-cyclopropyl-1-ethyl-6-fluorobenzimidazole, 2-isobutyl-1-methyl-6-bromobenzimidazole, there is produced: 2-isovaleryl-1-butyl-5-nitro-6-trifluoromethylbenzimidazole, 2-cyclobutyl-1-methyl-5-nitro-6-difluoromethylbenzimidazole, 2-cyclopropyl-1-ethyl-5-nitro-6-pentafluoroethylbenzimidazole, 2-isopropyl-1-hexyl-5-nitro-6-trifluoromethylbenzimidazole, and 2-isobutyl-1-methyl-5-nitro-6-bromobenzimidazole, respectively.
Reaction SMILES: Br[CH:2]([C:14]([C:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[S:19][CH:20]=1)=[O:15])[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].C(#N)C.C[O-].[Na+].[C:31]([OH:39])(=[S:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)(=O)C>[C:31]([S:38][CH:2]([C:14]([C:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[S:19][CH:20]=1)=[O:15])[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(c1csc2ccccc12)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reactant: OC(=S)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C(SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1csc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
As for Example 21, 1-[3-bromo-3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline (0.01 mole) in 25 ml. of acetonitrile is added to a mixture of 0.01 mole of sodium methoxide and 0.015 mole of thiobenzoic acid in 25 ml. of acetonitrile. The mixture is stirred at room temperature for 16 hours, one ml. of acetic acid is added and the solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and water containing acetic acid. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is removed in vacuo to give the product of the Example as a yellow glass.
Reaction SMILES: C(O[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[CH:9]=1)=O)(=O)C.[F:21][C:22]([F:33])([F:32])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26].B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH3:20][O:19][C:10]1[CH:9]=[C:8]([C:6]2[N:27]=[C:25]([C:24]3[C:23]([C:22]([F:32])([F:21])[F:33])=[N:31][CH:30]=[CH:29][CH:28]=3)[O:26][CH:5]=2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]=1[O:17][CH3:18]
Reactant: NC(=O)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)COC(C)=O)cc([N+](=O)[O-])c1OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COc1cc(-c2coc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a solution of 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoethyl acetate (4.24 g, 15 mmol) in xylene (30 mL) were added 2-(trifluoromethyl)nicotinamide (3.135 g, 16.5 mmol) and boron trifluoride etherate (0.18 mL, 15 mmol). The resulting yellow solution was heated to reflux for 18 hours and then cooled to room temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated, washed with brine and the dried over anhydrous magnesium sulphate, filtered and evaporated. The pure 4-(3,4-dimethoxy-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)oxazole was obtained by column chromatography over silica gel (petroleum ether/ethylacetate 2:1) as a pale yellow solid, 2.488 g (42%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([N:20]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)[CH:21]2[CH2:26][CH2:25][N:24]([C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:23][CH2:22]2)=[O:19])[C:15]2[N:51]=[CH:52][CH:53]=[CH:54][C:14]=2[C:13](=[O:55])[N:12]=1.[C:56]([OH:65])(=[O:64])[C@@H:57]([C@H:59]([C:61]([OH:63])=[O:62])[OH:60])[OH:58]>CO>[OH:60][CH:59]([CH:57]([OH:58])[C:56]([OH:65])=[O:64])[C:61]([OH:63])=[O:62].[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([N:20]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([F:50])([F:48])[F:49])=[CH:45][CH:46]=3)=[CH:37][CH:36]=2)[CH:21]2[CH2:22][CH2:23][N:24]([C:27]([CH3:32])([CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:26]2)=[O:19])[C:15]2[N:51]=[CH:52][CH:53]=[CH:54][C:14]=2[C:13](=[O:55])[N:12]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]-acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate (8.5 g, 1 equiv) was suspended in methanol (100 ml) and warmed to 50° C. until the solid dissolved. L-Tartaric acid (1.675 g, 1.0 equiv) was added in one portion and stirred for 30 minutes at room temperature. The solution was concentrated in vacuo to an off-white powder that was dried in a vacuum oven at room temperature.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N:20]=[N:21][NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]#[N:34])#[N:9].N1C=CC=CC=1>O>[C:5]([N:20]([C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[C:8]#[N:9])[N:21]=[N:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]#[N:34])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N

Procedure:
Alternatively, 3-acetyl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene is prepared by addition of 25 ml. of acetic anhydride to a solution of 5.0 g. (0.013 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in 65 ml. of pyridine. The reaction mixture is stirred at 25° for twelve hours, then it is poured into water. The aqueous mixture is extracted with ether, the layers are separated and the ether phase is washed with water, 5% aqueous sodium bicarbonate and water, dried (MgSO4) and concentrated to give 3-acetyl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C.[Br:32][C:33]1[N:38]=[C:37]([CH:39]=O)[CH:36]=[CH:35][CH:34]=1.O>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37](/[CH:39]=[CH:2]/[O:3][CH3:4])[N:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CO/C=C/c1cccc(Br)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (7.37 g, 21.5 mmol) in THF (100 mL) at −10° C. was added LDA (1.8M in THF/hexane/ethylbenzene, 11.94 mL, 21.5 mmol). The resulting red suspension was stirred at −10° C. for 1 h. To this was added a solution of 6-bromopyridine-2-carboxaldehyde (2.0 g, 10.8 mmol) in THF (60 mL). The resulting colourless suspension was slowly warmed to r.t. over 2.5 h. The reaction mixture was poured into water and extracted with Et2O (3×75 mL). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo to give a pale yellow oil. Purification by column chromatography (SiO2, 20:1 heptane:EtOAc) gave the title compound (506 mg, 22%) as a yellow oil. δH (CDCl3) 7.61 (1H, d, J 12.6 Hz), 7.37 (1H, t, J 7.7 Hz), 7.16 (1H, dd, J 7.9 and 0.8 Hz), 6.98 (1H, dd, J 7.5 and 0.6 Hz), 5.78 (1H, d, J 12.6 Hz), 3.73 (3H, s). LCMS (ES+) 215.97 (M+H)+, RT 3.50 minutes (Method 1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].I[CH3:22]>CC(C)=O.[Ag]=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][CH3:22])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CI
Agent: O=[Ag]
Solvent: CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1
Temperature: 57 °C
Reaction time: 28 h
Yield: 95.2 %

Procedure:
To 2.00 g (7.16 mmol) of (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester in 20 mL of acetone was added 5.64 g of silver oxide (24.3 mmol) and 1.56 mL of iodomethane (25.0 mmol) and the mixture was stirred at 57° C. for 28 h. The solution was cooled to 25° C., filtered through celite and concentrated. Purification was through 50 mL of silica by eluting with EtOAc:Hexane (8:1) and the purified fractions were concentrated to give a 2.0 g (96%) of (2S,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester as a clear oil. HPLC: Rt 3.79 min. (100% area). 1H NMR (CDCl3, 400 MHz) δ: 7.31-7.23 (5H, m), 5.22-5.00 (2H, m), 4.44-4.40 (1H, m), 4.10-4.02 (1H, m), 3.76 (3H, s), 3.69-3.60 (1H, m), 3.54 (2H, s), 3.29 (3H, bs), 2.42-2.30 (1H, m). LCMS (ESI) (M+Na+) m/z: 316.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[C:39](=[O:41])=[O:40].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([C@@:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:39]([OH:41])=[O:40])([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:17]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COCCCC[C@@](O)(c1cccc(Br)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C=O
Agent: O=C([O-])[O-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(C(=O)O)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxy-pentyl)piperidine-1-carboxylate (279.1 mg, 0.61 mmol) in THF (5 mL) at −70° C. was added t-butyllithium in pentane (1.7 M, 0.71 mL, 1.22 mmol) dropwise. When the addition was complete dried carbon dioxide was bubbled through the reaction system for 10 min, and completion of reaction was confirmed by LC-MS. The solution was warmed to rt, and sat'd aq Na2CO3 solution (5 mL) was added. The organic layer was separated, and washed once with 1 N NaOH (2 mL). The combined aqueous solutions were acidified with 1 N aq HCl and extracted with EtOAc (5×5 mL). The organic layer was dried over Na2SO4, and concentrated under vacuum to give 3-((S)-1-((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)-1-hydroxy-5-methoxy-pentyl)benzoic acid (152.4 mg, 59%) as a white solid. MS m/z 422 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].[F:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:22]([CH:10]3[CH2:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:25]([F:27])([F:28])[F:26])[CH:4]=4)[CH2:13][N:12]([C:14]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[O:15])[CH2:11]3)[O:23][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C(F)(F)F
Reactant: NC(=NO)c1cccc(F)c1
Product: Cc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1C(F)(F)F

Procedure:
100 mg (about 0.24 mmol) of the compound from Example 160A and 55 mg (0.36 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 67 mg (54% of theory).
Reaction SMILES: CO.[OH:3][CH:4]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8](=O)[C:7]([CH3:14])=[CH:6][CH:5]1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.[CH3:22][O:23][NH2:24].[OH-].[Na+]>O.N1C=CC=CC=1>[CH3:22][O:23][N:24]=[C:8]1[CH2:9][C:10]([CH3:12])([CH3:11])[CH:4]([OH:3])[CH:5]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[C:7]1[CH3:14]
Reactant: CON
Reactant: CC1=CC(N2CCCCC2)C(O)C(C)(C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CON=C1CC(C)(C)C(O)C(N2CCCCC2)C=C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a methanol solution (30 ml) containing the 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 16 (3 g, 12.5 millimoles) were added methoxyamine hydrochloride (1.57 g, 18.8 millimoles) and pyridine (3.0 g), and the mixture was stirred first at room temperature and then while slowly heating to 55° C., and after 5 hours of stirring at that temperature, it was allowed to stand at room temperature overnight. The reaction solution was then poured into water and alkalified with a 10% aqueous sodium hydroxide solution (20 ml). The aqueous solution was subjected to extraction with benzene and dried over anhydrous magnesium sulfate. The benzene solution was concentrated under reduced pressure, to obtain 3.49 g of 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime as crude crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](O)=O)=[CH:2]1.[NH2:9][C:10]1[C:11](=[O:24])[N:12]([CH2:21][CH2:22][CH3:23])[C:13](=[O:20])[N:14]([CH2:17][CH2:18][CH3:19])[C:15]=1[NH2:16]>>[CH2:21]([N:12]1[C:11](=[O:24])[C:10]2[NH:9][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[N:16][C:15]=2[N:14]([CH2:17][CH2:18][CH3:19])[C:13]1=[O:20])[CH2:22][CH3:23]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccsc1
Product: CCCn1c(=O)c2[nH]c(-c3ccsc3)nc2n(CCC)c1=O

Procedure:
The starting 1,3-dipropyl-8-(3-thienyl)xanthine is prepared in a manner analogous to that described in Example 2 hereinafter using 3-thiophenecarboxylic acid and 5,6-diamino-1,3-dipropyluracil, mp>250° C.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[C:8]([CH3:21])=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=1.CON(C)[C:25](=[O:27])[CH3:26].Cl>O1CCCC1.C(OCC)C.C1CCCCC1.CCCCCC>[F:6][C:7]1[C:8]([CH2:21][C:25](=[O:27])[CH3:26])=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1c(F)cccc1NC(=O)OC(C)(C)C
Reactant: CON(C)C(C)=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(=O)Cc1c(F)cccc1NC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
4.3 ml of a 1.3M solution of sec-butyllithium in 98/2 v/v cyclohexane/hexane are added, dropwise, while maintaining the temperature between −40° C. and −30° C., to a solution of 0.5 g of tert-butyl (3-fluoro-2-methylphenyl)carbamate in 10 ml of tetrahydrofuran under argon and cooled to −40° C. The reaction mixture is then cooled to −50° C., and then a solution of 0.27 ml of N-methoxy-N-methylacetamide in 4 ml of tetrahydrofuran is added dropwise while maintaining the temperature between −50° C. and −40° C. The mixture is then allowed to warm up to approximately −10° C., and then stirred at this temperature for 0.5 hour. It is then treated with 5.6 ml of a 1N hydrochloric acid solution and then diluted with 20 ml of diethyl ether and allowed to warm up to ambient temperature with stirring for 1 hour. After settling out, the organic phase is separated and the aqueous phase is extracted with 40 ml of diethyl ether. The organic phases are combined, washed with 3×40 ml of water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 30 g cartridge of 15-40 μm silica, elution being carried out with a 90/10 v/v cyclohexane/ethyl acetate mixture, at a flow rate of 30 ml/min, and then on a 30 g cartridge of 15-40 μm silica, elution being carried out with pure dichloromethane, at a flow rate of 30 ml/min. 0.38 g of tert-butyl [3-fluoro-2-(2-oxopropyl)phenyl]carbamate is thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)/C=C(/C)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CC(C)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A mixture of ethyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)crotonate (11.4 g, Reference Example 7) and ammonium formate (about 30 g) in ethanol (about 200 ml) was warmed in an oil-bath to 60° C. Palladium on charcoal (10%, about 1 g) was added in one portion under a blanket of nitrogen—effervescence began almost immediately. The mixture was stirred at about 60° C. for about one hour, then cooled to room temperature and filtered through Celite. The filtrate was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water, then dried and then evaporated to give the title compound (11.1 g) as a colourless, mobile oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[C:13]([F:27])[C:12]=2[F:28])=[O:9])[C:4](=[O:29])[N:3]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CC#[N:53]>CCOC(C)=O.O>[NH2:53][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:29])[N:3]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[C:12]([F:28])[C:13]=2[F:27])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2F)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Ic1ccccc1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2F)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To a suspension of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2,3-difluorophenoxy)picolinamide (108 mg, 0.22 mmol) in EtOAc (2.5 mL), CH3CN (2.5 mL) and H2O (1.5 mL) was added iodobenzene diacetate (96 mg, 0.30 mmol) at 0° C. The reaction was stirred at 0° C. for 30 minutes, then warmed up to rt and continued to stir for 4 hours. The mixture was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (EtOAc/CH3OH (v/v)=10/1) to give the title compound as a pale yellow solid (32 mg, 32.3%).