Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.O1CCOCC1.[F:13][C:14]([F:47])([F:46])[C:15]1[CH:16]=[C:17]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:18][N:19]([CH3:38])[C:20]([C:22]1[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:24][C:25]([CH2:28][C:29](=O)[NH2:30])=[N:26][CH:27]=1)=[O:21]>>[F:47][C:14]([F:13])([F:46])[C:15]1[CH:16]=[C:17]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[CH2:18][N:19]([CH3:38])[C:20]([C:22]1[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:24][C:25]([CH2:28][C:29]#[N:30])=[N:26][CH:27]=1)=[O:21]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(CC(N)=O)nc1-c1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(CC#N)nc1-c1ccccc1
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 0.50 g (1.01 mmol) in 2-carbamoylmethyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide and 0.17 ml pyridine in 10 ml dioxane 0.15 ml (1.06 mmol) trifluoraceticanhydrid were added and the resulting reaction mixture was stirred for 1 hr. at 50°. The reaction mixture was poured on Ice/H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 30:1) to give 0.25 g (51%) 2-cyanomethyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless solid, m.p. 114-116°.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[NH2:25][C@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:27]([NH2:29])=[O:28].C(N(C)C(C)C)(C)C>C(#N)C.CO.C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:25][C@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:27]([NH2:29])=[O:28])[N:3]=1
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: CC(C)N(C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(Cl)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 72 h
Yield: 33.1 %

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (200 mg, 0.539 mmol), (R)-2-amino-4-methylpentanamide (140 mg, 1.078 mmol), and N-isopropyl-N-methylpropan-2-amine (310 mg, 2.69 mmol) in acetonitrile (2 mL) was stirred at 85° C. for 3 d. The resulting crude material was reconstituted in MeOH/DCM/DMF (10.0 mL) and purified via preparative HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound (83 mg, 33%). [M+H] calc'd for C22H26ClFN4O4, 465. found, 465.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[S:31][C:30]([C:32](=[N:34]O)[NH2:33])=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:34]=[C:32]([C:30]4[S:31][C:27]([F:26])=[CH:28][CH:29]=4)[N:33]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1ccc(F)s1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)s4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 35 mg (0.22 mmol, 1.1 eq.) of 5-fluoro-N′-hydroxythiophene-2-carboximidamide were reacted according to the General Method 1. Yield: 51 mg (54% of theory)
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[CH:24]=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[CH:12][C:11]=1[F:34])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:34][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1cn[nH]c1
Yield: 58.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentyl}oxy)benzenesulfonamide (0.12 g, 0.184 mmol) prepared in Example 101c, triethylsilane (0.10 mL), trifluoroacetic acid (0.50 mL), dichloromethane (1.0 mL) and methanol (1.0 mL), to yield the title compound (45 mg, 59%) as a colorless solid.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:22])([C:18]([OH:21])([CH3:20])[CH3:19])[C:15]([OH:17])=[O:16].C(=O)([O-])O.[Na+]>CO>[F:13][C:14]([F:22])([C:18]([OH:21])([CH3:20])[CH3:19])[C:15]([O:17][CH3:2])=[O:16]
Reactant: CC(C)(O)C(F)(F)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(F)(F)C(C)(C)O
Yield: 65 %

Procedure:
A catalytic amount of p-toluenesulfonic acid monohydrate was added to a mixture of 73.3 g of Intermediate 3 in Example 3 and 300 g of methanol. With stirring in a nitrogen atmosphere, the reaction mixture was heated under reflux for 12 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated. The residue was distilled in vacuum, obtaining 52.0 g (yield 65%) of methyl 2,2-difluoro-3-hydroxy-3-methylbutanoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18]C(OCC2C=CC=CC=2)=O)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C1CC=CCC=1.CO>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1)[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(CCN)cc1

Procedure:
The mixture of {1-[4-(2-benzyloxycarbonylamino-ethyl)-phenyl]-ethyl}carbamic acid tert-butyl ester (0.80 g, 2.0 mmol), 1,4-cyclohexadiene (0.96 mL, 10 mmol) and palladium on carbon (100 mg) in ethanol (20 mL)-methanol (5 mL) was heated to reflux for 2 h and brought to room temperature. The mixture was filtered through celite and concentrated to afford a white solid. M+1=265.
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[CH:19][CH:18]=1.Cl.CCOC(C)=O>CCOC(C)=O>[CH3:1][Si:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(Oc2ccc(N)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of tert-butyl {4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}carbamate (14 g) and 4N HCl/AcOEt (30 mL) in EtOAc (30 mL) was stirred at room temperature overnight. The mixture was neutralized with 1N NaOHaq., and extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]aniline (5.4 g) as an orange solid.
Reaction SMILES: [O:1]=[C:2]1[N:13]([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[C:20]([NH2:22])=O)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3]1.ClC1N=C(Cl)N=C(Cl)N=1>CN(C)C=O.O>[O:1]=[C:2]1[N:13]([C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]2[C:20]#[N:22])[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3]1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
To a solution of rel-(1R,2S)-2-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarboxamide (14 mg) in N,N-dimethylformamide (140 μl) was added 2,4,6-trichloro-1,3,5-triazine (8.63 mg) at 0° C. The reaction mixture was stirred at ambient temperature overnight. The solution was diluted with water and extracted with EtOAc/tetrahydrofuran. The organic layer was dried over MgSO4 and concentrated in vacuo. The residual solid was washed with diisopropylethylether to give rel-(1R,2S)-2-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbo-nitrile (3 mg) as a pale brown solid.
Reaction SMILES: OC[C@@H]([NH:10][C@H:11]([C:15]1([CH3:18])[CH2:17][CH2:16]1)[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[ClH:19]>CO.[Pd]>[ClH:19].[NH2:10][C@H:11]([C:15]1([CH3:18])[CH2:17][CH2:16]1)[C:12]([OH:14])=[O:13]
Reactant: CC1([C@@H](N[C@H](CO)c2ccccc2)C(=O)O)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1([C@@H](N)C(=O)O)CC1
Reaction time: 8 h

Procedure:
(R)-2-((S)-2-hydroxy-1-phenylethylamino)-2-(1-methylcyclopropyl)acetic acid (1.0 g, 4.0 mmol) was suspended in MeOH (50 mL). Added 1.0 M HCl in MeOH (4.0 mL, 4.0 mmol) and all solids dissolved to provide a colorless solution. Added 10% Pd/C (100 mg) and stirred under H2 balloon overnight. The reaction mixture was filtered over Celite, rinsing with MeOH. The filtrate was concentrated to a sticky white solid (1.0 g). Trituration with Et2O afforded 700 mg of (R)-2-amino-2-(1-methylcyclopropyl)acetic acid hydrochloride as a white solid.
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[C:14]([NH2:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(Cl)C>C(Cl)Cl>[C:15]1([C:14]2[O:21][C:2]3[CH2:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=3[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccccc1
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CCc2nc(-c3ccccc3)oc2C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
16.0 g (64.23 mmol) ethyl 3-bromo-4-oxo-cyclohexanecarboxylate are combined with 7.8 g (64.39 mmol) benzamide and 50 ml of dichloroethane in a pressure vessel and stirred overnight at 120° C. The reaction mixture is diluted with DCM and washed 2× with 5% potassium carbonate solution as well as 1× with sat. saline solution. The org. phase is dried on magnesium sulphate and the solv. is eliminated completely in vacuo, the residue is purified through silica gel (eluant cyclohexane/EA).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18]([O:20][C:21](=[O:31])[CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:19]>C(#N)C>[CH2:24]([N:23]([CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:31])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCOC(=O)CCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCN(CC(=O)OCC)Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
Under a nitrogen atmosphere, triethylamine (1.73 ml, 0.01243 mol) and ethyl 5-bromovalerate (1.72 ml, 0.0109 mol) were added to a solution of N-benzylglycine ethyl ester (2.0 g, 0.0103 mol) in acetonitrile (40 ml) at room temperature, and the resulting mixture was heated at 60° C. After 1 hour, the mixture was refluxed. After 9 hours, the mixture was concentrated under reduced pressure, and the resulting residue was extracted with water (200 ml) and ethyl acetate (200 ml×2) and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain ethyl 5-[benzyl(2-ethoxy-2-oxoethyl)amino]pentanoate (1.2473 g, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([O:21][CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of trans-N-t-butoxycarbonyl-4-(3-methylphenyl)-3 hydroxy piperidine (117 mg, 0.402 mmol), in DMF (2 ml) at 0° C. was added sodium hydride (24 mg of a 60% dispersion in mineral oil, 0.803 mmol). After 10 min, methyl iodide (0.050 ml, 0.803 mmol) was added and the reaction allowed to warm to room temperature over 16 hrs. The reaction was quenched by the addition of saturated NH4Cl solution (5 ml) and extraction with EtOAc. The organic extracts were washed with brine and dried, (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, 10-15% EtOAc in hexanes) afforded the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.CO.Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 219.4 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (74%) which was obtained as a light yellow solid. To a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (832 mg, 98%) which was obtained as an off white solid. MS: m/e=343.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.O>O1CCCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:16])=[CH:13][CH:12]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Chlorophenylmagnesium bromide (12.97 ml, 1M solution in diethyl ether) was added slowly to a solution of 4-bromobenzaldehyde (2.0 g, 10.81 mmol) in tetrahydrofuran (25 ml) at 0° C., under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and was stirred for 17 hours. Water (3 ml) was then added and the solvent was removed under reduced pressure. The residue was then partitioned between ethyl acetate and 1N HCl solution. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was then purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum ether (1:9), to yield the title compound (2.30 g). LC/MS: (PS-B3) Rt 3.49 [M−H]+ 297.
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].SCC(O)CO.C1(C)C=CC=CC=1>O>[CH2:1]([Sn:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Agent: OCC(O)CS
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC[Sn]CCCC
Yield: 99.5 %

Procedure:
A mixture of 24.99 (0.10 mole) dibutyltin oxide, 21.6g (0.20 mole) 3-mercapto-1,2-propanediol and 300 ml toluene were charged to a round-bottom glass reaction flask fitted with a mechanical stirrer, thermocouple and a reflux condenser with a Dean-Stark water trap. The mixture was heated to reflux temperature, with agitation, and continued at reflux until a clear homogeneous solution formed and all water of reaction was collected in the trap. Removal of the toluene (flash evaporator) yielded 44.5g (99.5% yield) of dibutyltin-bis-(2,3-dihydroxypropylmercaptide), a straw-colored viscous liquid.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]2[C:28]([Cl:29])=[CH:27][C:26]([C:30](=[O:32])[CH3:31])=[C:25]([OH:33])[C:24]=2[CH2:34][CH2:35][CH3:36])[C:8]=1[CH2:37][CH2:38][CH3:39])C.[OH-].[Na+]>CO>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[C:8]([CH2:37][CH2:38][CH3:39])[C:9]=1[O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([C:30](=[O:32])[CH3:31])=[C:25]([OH:33])[C:24]=1[CH2:34][CH2:35][CH3:36])(=[O:15])[CH3:14]
Reactant: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCOCCOc1c(C(C)=O)ccc(OCC(=O)OCC)c1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCOCCOc1c(C(C)=O)ccc(OCC(=O)O)c1CCC
Reaction time: 5 h
Yield: 84.2 %

Procedure:
To a solution of 0.400 g (0.00069 mol) of [4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester in 15 ml of methanol was added 15 ml of 1N sodium hydroxide (0.015 mol). The mixture was stirred at 25° for 5 hours and the methanol was removed in vacuo. The aqueous solution was acidified to pH 4, the gummy precipitate was dissolved in ethyl acetate and washed with sodium chloride solution. The oil obtained on concentration of the ethyl acetate was crystallized from cyclohexane to give 0.32 g, melting point 89°-91° (84% yield) of [4-acetyl-3-[2-[2-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]acetic acid.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH:4]([F:40])[CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=2)=[O:29])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:10][CH:9]=1>C1COCC1.CO>[C:21]1([C:18]2[CH:17]=[CH:16][C:15]([CH:14]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=3)=[O:29])[C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH:4]([F:40])[C:3]([OH:41])=[O:2])=[O:39])=[CH:9][CH:10]=3)=[CH:20][CH:19]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: COC(=O)C(F)CNC(=O)c1ccc(C(NC(=O)Nc2cc(Cl)cc(Cl)c2)c2ccc(C3=CCCCC3)cc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)NC(c1ccc(C(=O)NCC(F)C(=O)O)cc1)c1ccc(C2=CCCCC2)cc1

Procedure:
Hydrolysis of (RS)-3-{4-[1-(4-cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2-fluoropropionic acid methyl ester in a mixture of THF and methanol afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11](C=C)[N:10]2[C:17](=[O:21])[CH2:18][CH:19]=[CH2:20])=[CH:5][CH:4]=1>C(Cl)Cl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]3[N:10]2[C:17](=[O:21])[CH2:18][CH:19]=[CH:20]3)=[CH:7][CH:8]=1
Reactant: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(OC)cc1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: ClCCl
Product: COc1ccc([C@H]2CCC[C@H]3C=CCC(=O)N32)cc1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A solution of 1-[(2R*,6S*)-2-(4-methoxyphenyl)-6-vinylpiperidin-1-yl]-3-buten-1-one (100 mg) and tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) dichloride (30 mg) in methylene chloride (50 mL) was heated under reflux for 1.5 hours. The reaction solution was left to cool to room temperature and then concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=4:1->ethyl acetate) to obtain 28 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[O:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[OH:22][CH2:21][C:18]1[O:17][C:16]([CH2:15][NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(NCc2ccc(CO)o2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: O=C(O)c1cccc(NCc2ccc(CO)o2)c1C(=O)O

Procedure:
3-[(5-Hydroxymethyl-furan-2-ylmethyl)-amino]-phthalic acid dimethyl ester (0.97 g, 3.04 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid. The product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][C:20]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[S:22][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][CH:28]4[CH2:27][CH2:26][N:25]([C:23]5[S:22][N:21]=[C:20]([CH3:19])[N:24]=5)[CH2:30][CH2:29]4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h, starting from 8-(3,4-difluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one. The title compound was obtained as a white solid.