Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8](F)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]([O:17]C(=O)C)([CH3:16])[CH3:15].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O.[OH-].[Li+].CCOC(C)=O>CN(C)C1C=CN=CC=1.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C:14]([OH:17])([CH3:15])[CH3:16]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(S(=O)(=O)F)cc1Cl
Reactant: C1CCNCC1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(O)C(=O)Nc1ccc(S(=O)(=O)N2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of N-[2-chloro-4-(fluorosulphonyl)phenyl]-2-acetoxy-2-methylpropanamide (Method B) (340 mg, 1 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and piperidine (0.1 ml, 1 mmol) in acetonitrile (5 ml) was heated under reflux for 18 h. After evaporation to dryness, the residue was dissolved in 1% aqueous ethanol (10 ml) and lithium hydroxide monohydrate (84 mg, 2 mmol) was added. The mixture was stirred for 2 h at ambient temperature, then EtOAc (25 ml) was added. The resulting solution was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography using 50% EtOAc/isohexane to yield the title compound as an oil (226 mg, 0.6 mmol). NMR: 1.4 (s, 6H), 1.5 (m, 6H), 2.9 (m, 4H), 6.2 (d, 1H), 7.7 (d, 1H), 7.8 (m, 1H), 8.6 (d, 1H), 9.8 (s, 1H); MS: 361 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[ClH:11]>C1(C)C=CC=CC=1>[Cl:11][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(CO)cc1
Reactant: Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CCl)cc1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
20 g (0.132 moles) of 90 percent pure 4-hydroxymethylbenzaldehyde were stirred for 2 hours at 80° C. under an argon atmosphere with 50 ml of 37 percent HCl (0.58 moles) and 200 ml of toluene. After cooling to room temperature, the aqueous phase was separated off and the toluene phase was evaporated in vacuo. This gave 16.2 g of crude product which, according to NMR, contained 78.8% by weight of 4-chloromethylbenzaldehyde, 10% by weight of 1,4-bis-chloromethylbenzene and 11.2% by weight of an unknown substance. A 4-chloromethylbenzaldehyde yield of 12.8 g, corresponding to 62.5% of the theoretical yield was calculated from the NMR result.
Reaction SMILES: [CH2:1]=C1CN(C(OC(C)(C)C)=O)C1.[CH2:13]1[C:18]2([O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16][C:15](=O)[CH2:14]1>>[CH2:1]=[C:15]1[CH2:16][CH2:17][C:18]2([O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:13][CH2:14]1
Reactant: O=C1CCC2(CC1)OCCCO2
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Product: C=C1CCC2(CC1)OCCCO2

Procedure:
The title compound was prepared following the methodology described for Compound 28a replacing 1-Boc-3-azetidinone with 7,11-dioxaspiro[5.5]undecan-3-one. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; Et2O) to give the title compound as a pale-yellow oil. Yield: 96.3%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:10]([CH2:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1
Reactant: ClCc1cnccn1
Reactant: CN1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Nc2nc3ccccc3n2Cc2cnccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a stirred mixture of 11.5 parts of N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine and 144 parts of N,N-dimethylformamide was added 5 parts of a sodium hydride dispersion 50%. AFter stirring for 1 hour at room temperature, a solution of 12.8 parts of 2-(chloromethyl)pyrazine in N,N-dimethylformamide was added dropwise to the thus obtained mixture. Upon complete addition, stirring was continued for 2 hours at 50° C. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.5 parts (9.3%) of N-(1-methyl-4-piperidinyl)-1-(2-pyrazinylmethyl)-1H-benzimidazol-2-amine; mp. 169.3° C. (compound 69).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]=O.O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH:13]([CH3:15])[CH3:14])[C:16](=[O:18])[O:17][CH2:19]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Yield: 95 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-valine (25.1 g, 0.1 mol) in toluene (500 ml) are added paraformaldehyde (4.0 g) and p-toluene-sulfonic acid monohydrate (1.0 g), and the mixture is refluxed for 30 minutes, during which the generated water is removed with a Dean-Stark apparatus. The reaction solution is washed successively with a 5% aqueous sodium hydrogen carbonate solution and a saturated brine, dried over magnesium sulfate, and the solvent is removed by evaporation under reduced pressure. The residue is recrystallized from toluene to give (4S)-4-isopropyl-5-oxo-1,3-oxazolidine-3-carboxylic acid benzyl ester (25.0 g, yield: 95%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[C:9]([I:15])[CH:8]=2)=[C:5]([CH3:16])[O:4][N:3]=1.[C:17](C1NC=CN=1)(C1NC=CN=1)=[O:18]>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([I:15])[C:10]3[NH:14][C:17](=[O:18])[NH:13][C:11]=3[CH:12]=2)=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(I)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Yield: 72 %

Procedure:
5-(3,5-dimethylisoxazol-4-yl)-3-iodobenzene-1,2-diamine (253 g, 0.77 mol, 1.0 eq) was treated with carbonyl diimidazole (187 g, 1.15 mol, 1.5 eq) and DMAP (47 g, 384 mmol, 0.5 eq) in THF (2.5 L) at 80° C. for 16 h. The precipitate was obtained by filtration. The solid was triturated with EA/PE (1/1) to give 197 g of 6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:23][Si:24]([CH3:27])([CH3:26])[O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CCC2=O

Procedure:
A mixture of 19-hydroxy-4-androstene-3,17-dione, trimethylchlorosilane and pyridine is refluxed in benzene for a period of 18 hours. The resulting suspension is filtered, the volatiles removed in vacuo and concentrated to a yellow oil. The oil is placed upon a silica gel chromatographic column packed in chloroform and eluted with chloroform. The chloroform eluate is evaporated to dryness in vacuo and the residue is recrystallized twice from hexane to yield the desired 19-(trimethylsiloxy)-4-androstene-3,17-dione.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl:13][C:14]1[C:15]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:29][C@H:30]4[CH2:34][CH2:33][O:32][C:31]4=[O:35])=[C:23]3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:13][C:14]1[C:15]([N:20]2[C:24]3[N:25]=[CH:26][N:27]=[C:28]([O:29][C@@H:30]([CH2:34][CH2:33][OH:32])[C:31]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=4)=[O:35])[C:23]=3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1OCC[C@@H]1Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)[C@H](CCO)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
Trimethylaluminium (0.347 mL, 0.69 mmol) was added to 5-methylpyridin-2-amine (71.7 mg, 0.66 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (3S)-3-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)dihydrofuran-2(3H)-one (Intermediate T1) (200 mg, 0.60 mmol) in toluene (2 mL) and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was then heated at 50° C. for 2 hours. The reaction mixture was allowed to cool and was neutralised with citric acid (1M, aq.) and then diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 10% MeOH in DCM to afford the product (185 mg, 69.8%). 1H NMR (400 MHz, CDCl3) 2.30 (3H, s) 2.33-2.40 (1H, m), 2.44-2.52 (1H, m), 2.55 (1h, s), 3.83-3.92 (2H, m), 6.07-6.10 (1H, m), 7.46-7.49 (1H, m), 7.52-7.55 (1H, m), 8.00-8.02 (1H, m), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.47 (1H, s), 8.61-8.62 (1H, m), 8.64 (1H, s), 8.68 (1H, s); m/z (ESI+) (M+H)+=440; HPLC tR=1.68 min.
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15]([OH:17])=[O:16].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:2]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:15]([OH:17])=[O:16])(=[O:1])[CH3:3]
Reactant: C1CCOC1
Reactant: Nc1cc(C(=O)O)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(=O)O)ccc1Cl
Temperature: 0 °C

Procedure:
Tetrahydrofuran (THF) room temperature (RT), NaHCO3 solution 101.9 g (582 mmol) of 3-amino-4-chlorobenzoic acid were suspended in 700 ml of acetic acid and then admixed with 64.8 ml (687 mmol) of acetic anhydride. The mixture was heated under reflux for 15 h and, after cooling, was added to 1.5 l of ice-water. The precipitated crystals were isolated by filtration with suction, washed with water, and dried in a vacuum cabinet at 70° C. for 17 h.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:44][CH2:45][CH3:46])[N:18]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[C:19](=[O:28])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:44][CH2:45][CH3:46])[N:18]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[NH:3][C:4](=[O:7])[O:5][N:43]=3)=[CH:32][CH:31]=2)[C:19](=[O:28])[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[CH3:14]
Reactant: CCCc1nc(CC)c(-c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)c(-c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A mixture of hydroxylammonium chloride (2.46 g), sodium hydrogen carbonate (3.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(4-fluorophenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.94 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.51 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.77 g, 72%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][C:16]=3[Cl:27])[C:9]([O:11][CH2:12][CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1.[C:28]([OH:32])(C)(C)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=[O:63]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[Cl:27][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:20][C:15]=1[CH2:14][N:8]1[C:6]2=[N:7][C:2]([C:28]([OH:32])=[O:63])=[CH:3][CH:4]=[C:5]2[N:10]=[C:9]1[O:11][CH2:12][CH3:13]
Reactant: [C]=O
Reactant: CCOc1nc2ccc(Br)nc2n1Cc1ccc(-c2ccccc2)cc1Cl
Reactant: CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1nc2ccc(C(=O)O)nc2n1Cc1ccc(-c2ccccc2)cc1Cl

Procedure:
5-Bromo-3-(2-chloro-4-phenylbenzyl)-2-ethoxy-3H-imidazo[4,5-b]pyridine (57 mg) was dissolved in N,N-dimethylformamide (1.3 ml) and tert-butyl alcohol (1.0 ml) and triethylamine (30.4 mg), 1,3-bis(diphenylphosphino)propane (17 mg) and palladium (II) acetate (9.3 mg) were successively added. The mixture was stirred under a 10 atm. carbon monoxide atmosphere at 85° C. for 48 hr. The insoluble matter was filtered off and washed with chloroform. The filtrate and washing were combined and concentrated to dryness under reduced pressure. The residue was purified by thin layer chromatography (chlorofozm:methanol=19:1) to give 3-(2-chloro-4-phenylbenzyl)-2-ethoxy-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (43 mg) as a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([NH:16][C:17](=[O:19])[CH3:18])=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[OH-].[Na+].Cl.C>O.CO>[C:17]([NH:16][C:4](=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[C:3]([OH:20])=[O:2])(=[O:19])[CH3:18]
Reactant: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NC(=Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A 2-l. three-necked flask, equipped with thermometer mechanical stirrer and reflux condenser was charged with 90.4 g (0.31 moles) of alpha-acetamido-6-chloro-3-indoleacrylic acid methylester, 200 ml (0.40 moles) of 2 N aqueous sodium hydroxide and 400 ml of methylalcohol. The mixture was stirred and heated at an internal temperature of 55°-58° for 90 minutes. 800 ml of distilled water was added and the brown slightly turbid solution filtered through a Buchner funnel. The clear filtrate was acidified with 90 ml (0.54 moles) of 6 N aqueous hydrochloric acid. The precipitate was collected on a Buchner funnel and washed with distilled water. The wet cake was transferred into flask and suspended in 180 ml of dimethylformamide and 600 ml of methyl alcohol. The mixture was heated on a steam bath to reflux until a brown, slightly turbid solution was formed. 6 g of charcoal was added and reflux was continued for 10 minutes. The hot mixture was quickly filtered through a bed of Celite. The deep yellow, clear filtrate was transferred into a 2-l. flask, equipped with reflux-condenser and dropping funnel and brought again to reflux under an atmosphere of nitrogen. 240 ml of distilled water was added over a 5 minute period while reflux was maintained. The mixture was allowed to stand overnight under an atmosphere of nitrogen at room temperature. The product was collected by suction filtration, washed with methylalcohol-water 1:1 and dried at 85°/0.5 mmHg, to constant weight to give 78.6 g (86%) of product, as yellow crystals, m.p. 225°.
Reaction SMILES: Cl[CH2:2][Cl:3].[CH3:4][OH:5].N.[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:12]=[CH:11]2>ClC1C=C(Cl)C=CC=1C#CC(O)=O.C1COCC1>[N:19]1([CH2:18][CH2:17][N:13]2[C:14]3[C:10](=[CH:9][C:8]([NH:7][C:4](=[O:5])[C:15]#[C:14][C:10]4[CH:11]=[CH:12][C:2]([Cl:3])=[CH:8][CH:9]=4)=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc2c(ccn2CCN2CCCC2)c1
Reactant: ClCCl
Reactant: CO
Agent: N
Agent: O=C(O)C#Cc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: O=C(C#Cc1ccc(Cl)cc1)Nc1ccc2c(ccn2CCN2CCCC2)c1

Procedure:
Prepared analogously to Example 3.1.e. from 5-amino-1-(2-pyrrolidin-1-ylethyl)-1H-indole and (2,4-dichlorophenyl)propynoic acid in THF as solvent. Yield: 133 mg (31.2% of theory); C23H21Cl2N3O (M=426.34); melting point: 127° C.-129° C.; calc.: molecular ion peak (M+H)+: 426/428/430; found: molecular ion peak (M+H)+: 426/428/430; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [CH2:1]([N:4](CC=C)[CH2:5][C:6]1[S:7][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:2]=[CH2:3].CN1C(=O)CC(=O)N(C)C1=[O:33].CCN(C(C)C)C(C)C.[C:50](Cl)(=O)[C:51]1C=CC=[C:53]([O:57][CH3:58])[CH:52]=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH2:21]([O:20][CH:17]1[CH2:18][CH2:19][N:14]([S:11]([C:8]2[S:7][C:6]([CH2:5][NH:4][C:1](=[O:33])[C:2]3[CH:3]=[CH:50][CH:51]=[CH:52][C:53]=3[O:57][CH3:58])=[CH:10][CH:9]=2)(=[O:12])=[O:13])[CH2:15][CH2:16]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(OCCCCCC)CC2)s1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: COc1cccc(C(=O)Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCCCOC1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccccc3OC)s2)CC1
Reaction time: 3 h
Yield: 36.4 %

Procedure:
A solution of 326a (134 mg, 0.3 mmol), 1,3 Dimethylbarbituric acid (94 mg, 0.6 mmol) and Tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) were stirred under Argon in 3 mL CH2Cl2. The reaction was followed by HPLC until all starting material disappeared. The crude was evaporated to dryness and taken up in dry THF. To this solution was added DIEA (230 ul, 1.5 mmol) and 3-anisoylchloride 0.3 mmol). The reaction was stirred for 3 h, EtOAc was added and the organic layer was extracted with NaHCO3 sat, HCl (0.1N) and brine. The dry solution was evaporated and purified by flash chromatography on silica gel using cyclohexane/EtOAc 7:3 as eluent. 326 was obtained as an oil (54 mg, 37%): H1 NMR (CDCl3) δ 7.43-7.25 (m, 4H), 7.15-7.05 (m, 2H), 6.60 (m, 1H), 4.83 (d, J=6.0 Hz, 2H), 3.86 (s, 3H), 3.35 (d, J=6.6, 2H), 335-3.23 (m, 3H), 2.95 (m, 2H), 1.94 (m, 2H), 1.86 (m, 2H), 1.70-1.50 (m, 5H), 1.30-1.20 (m, 8H), 0.87 (t, J=6.8, 3H), M/Z APCI: 495.2 (M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C1CCN2C(=NCCC2)CC1.BrC[CH:40]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[N:52]=[C:51]([C:53]3[C:57]([CH2:58][CH2:59][CH3:60])=[C:56]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[O:55][N:54]=3)[O:50][N:49]=2)=[CH:44][CH:43]=1)[OH:41]>>[OH:41][CH:40]([C:42]1[CH:43]=[CH:44][C:45]([C:48]2[N:52]=[C:51]([C:53]3[C:57]([CH2:58][CH2:59][CH3:60])=[C:56]([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[O:55][N:54]=3)[O:50][N:49]=2)=[CH:46][CH:47]=1)[CH2:6][N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC[C@@H](C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (45.4 mg, 0.198 mmol) was added TFA/DCM (1:1). The mixture was stirred for 1 hour and solvent was removed solvent in vacuo, followed by chasing once with DCM. The resulting mixture was dried in vacuo. This crude residue was dissolved in DMSO (2 mL) and DBU (0.060 mL, 0.396 mmol) was added. After 5 minutes, 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) was added. The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 20-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 6 mg of (3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.21 (2H, d, J=7.91 Hz), 7.71 (2H, dd, J=8.02, 1.65 Hz), 7.47-7.56 (5H, m), 4.46 (1H, br. s.), 4.10 (2H, d, J=6.37 Hz), 3.25-3.61 (2H, m), 2.92-3.03 (3H, m), 2.91 (2H, br. s.), 2.01-2.27 (1H, m), 1.81-2.00 (3H, m), 1.60-1.76 (2H, m, J=7.61, 7.61, 7.61, 7.61, 7.36 Hz), 1.20-1.59 (1H, m), 0.95 (3H, t, J=7.36 Hz). MS (m+1)=503. HPLC Peak RT=3.32 minutes (Analytical Method A). Purity=96%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:41]([F:46])([F:45])[CH2:42][CH2:43][CH3:44])[CH2:13][CH2:14][CH2:15][C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C@H:18]([OH:28])[C@@H:17]1[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH:38](C)C)=[O:36].C(N(CC)CC)C>C(Cl)Cl>[F:46][C:41]([F:45])([CH2:42][CH2:43][CH3:44])[C:12](=[O:11])[CH2:13][CH2:14][CH2:15][C@H:16]1[C@H:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:19][C:18](=[O:28])[C@@H:17]1[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: CCCC(F)(F)C(O)CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1OC1CCCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Reaction time: 0.33 h

Procedure:
A solution of oxalyl chloride in methylene chloride (2M, 3.5 ml) was cooled to -78° C., followed by addition of DMSO (1.1 ml). A solution of the compound (18) (0.906 g) in methylene chloride (11 ml) was added dropwise. The resultant mixture was stirred at the range of -35 to -25° C. for 1.5 hours, and triethylamine (2.lml) was added dropwise. After 20 minutes, 1Nhydrochloric acid was added. The crude product obtained after the usual work-up was subjected to silicagel column chromatography to give the titled compound (19).