Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([CH:45]=2)[C:43]#[N:44])O1>>[C:43]([C:42]1[CH:45]=[C:38]([C:2]2[C:3]([N:24]3[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:23]=2)[CH:39]=[N:40][CH:41]=1)#[N:44]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(C(F)(F)C(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)nicotinamide (Stage 208.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.08 min, m/z=504.4 [M+H]+, m/z=502.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.80-1.92 (m, 1H) 2.86 (d, J=11.25 Hz, 1H) 3.16-3.28 (m, 2H) 3.39 (m, J=9.29 Hz, 1H) 4.21 (br. s, 1H) 4.89 (d, J=3.18 Hz, 1H) 7.67 (d, J=8.80 Hz, 2H) 8.01 (d, J=8.56 Hz, 2H) 8.11 (d, J=2.20 Hz, 1H) 8.38-8.43 (m, 1H) 8.81 (d, J=2.20 Hz, 1H) 8.91 (d, J=1.96 Hz, 1H) 9.03 (d, J=1.96 Hz, 1H) 10.34 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:14])=[CH:6][C:4]1=[O:5])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH2:1]([N:3]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:14])=[C:6]([N+:15]([O-:17])=[O:16])[C:4]1=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCn1c2c(c(O)cc1=O)CCCC2
Solvent: CC(=O)O
Product: CCn1c2c(c(O)c([N+](=O)[O-])c1=O)CCCC2
Temperature: 100 °C

Procedure:
A suspension of 1-ethyl-4-hydroxy-5,6,7,8-tetrahydrocarbostyril (1.74 g; 0.009 mole) in glacial acetic acid (10 ml) was solubilised with concentrated nitric acid (2.5 ml; d 1.42) and the mixture heated for a few minutes at 100° C. After cooling and dilution with water a yellow crystalline solid separated. On recrystallisation from ethanol it had m.p. 152° - 154° C (d).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([N:16]2[CH2:17][CH2:18][CH:13]([C:11]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:19])[F:20])=[O:12])[CH2:14][CH2:15]2)[N:23]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCN(c2ncnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (315 mg, 1.10 mmol, 1.10 equiv) in acetonitrile (5 ml) at room temperature, 2,4-dichloro-1,3,5-triazine (150 mg, 1.00 mmol, 1.00 equiv) and diisopropylethylamine (DIEA, 0.875 ml, 5.00 mmol, 5.00 equiv) were added. The reaction mixture was stirred for 3 h at room temperature. Without workup or purification, the reaction was carried forward to the next step. MS (ES+): m/e 401.8 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:3]1=2>S(Cl)(Cl)=O>[O:1]=[C:2]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([O:20][CH2:8][CH2:2][C:3]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:4]=3)=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(c1)OCC1CCCCC1C2=O
Solvent: O=S(Cl)Cl
Product: CC(C(=O)OCCc1ccccc1)c1ccc2c(c1)OCC1CCCCC1C2=O
Reaction time: 2 h
Yield: 58.8 %

Procedure:
2-(6,6a,7,8,9,10,10a,11-Octahydro-11-oxodibenz[b,e]oxepin-3-yl)propionic acid (1.0 g) was added to thionyl chloride (10 ml) and the mixture was refluxed with stirring for 2 hours. The excess of thionyl chloride was distilled off under reduced pressure. To the oily residue was added a solution of phenethyl alcohol (2 ml) in xylene (20 ml) and the mixture was heated under reflux for 18 hours, cooled and poured into water. The xylene layers were separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel, using toluene as an eluent, to give the title compound (0.4 g) as an oil. IR νmaxfilm cm-1 : 1720, 1670 (C=O). HRMS m/e: 392.2007 (M+) (Molecular weight calculated for C25H28O4 : 392.1987).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:28]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
A solution of 1-(t-butyloxycarbonyl)-1,4-diazepane (92.0 g, 0.46 mol) and triethylamine (96.0 ml, 69.7 g, 0.69 mol) in dichloromethane (500 ml) at 0° C. was treated dropwise with a solution of 4-morpholinecarbonyl chloride (64.0 ml, 82.0 g, 0.55 mol) in dichloromethane (100 ml) and the reaction was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was then diluted with dichloromethane (400 ml) and washed with 2N citric acid (3×400 ml), saturated brine (1×500 ml), dried over MgSO4 and evaporated to give the subtitle compound as an off-white solid (141.7 g, 98%). Rf 0.80 (0.880 aqueous ammonia:methanol:dichloromethane 1:10:90, v/v). MS m/z 314 (MH)+. Found: C,57.50; H,8.69; N,13.41; C15H27N3O4 requires C, 57.50; H, 8.69; N,13.41%.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]1[C@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23](OC(C)(C)C)=O)[CH2:7]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].BrC1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1>>[CH2:1]([NH:5][C@H:6]1[C@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:38][C:39]3[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76 %

Procedure:
The same operation as in Example (1h) was performed using tert-butyl trans(±)-3-(butylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (77d) (16.3 mg, 0.038 mmol), sodium carbonate (40 mg, 0.38 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (1f) (13.2 mg, 0.046 mmol), to obtain 15.5 mg of the title compound (76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[C:10](Cl)[N:11]=1)=[O:5])[CH3:2].[CH3:30][Sn](C)(C)C>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[C:10]([CH3:30])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)c2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O
Temperature: 135 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of 7-chloro-1-(4-fluoro-phenyl)-4-hydroxy-3-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (60 mg, 0.146 mmol), tetramethyltin (104 mg, 0.584 mmol) and Pd(PPh3)2Cl2 in DMF (1 mL) was stirred at 135° C. for 2 h; then the reaction was cooled, diluted with EtOAc, washed with water and saturated sodium chloride aqueous solution respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified on column to give the desired title product (30 mg); ESI MS (m/z): 391 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[CH:21][C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[C:24]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[CH:21][C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7-[(S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.045 mmol), phenylboronic acid (11.1 mg, 0.091 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (18.8 mg, 0.136 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.10 (d, J=6.8 Hz, 3H), 6.55 (q, J=6.6 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 7.48-7.56 (m, 3H), 7.59 (d, J=2.3 Hz, 1H), 7.76 (d, J=9.6 Hz, 1H), 7.80-7.85 (m, 2H), 8.05 (s, 1H), 8.21 (d, J=9.6 Hz, 1H). MS (ES+): m/z 373.09 (100) [MH+]. HPLC: tR=2.28 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3][NH:2]1.CN(C)CCCN=C=NCC.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](O)=[O:37])=[CH:30][CH:29]=1.Cl>ClCCl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]([N:2]2[CH2:3][CH2:4][CH:5]3[CH:10]([CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][CH2:6]3)[CH2:1]2)=[O:37])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C1CCCC2CCNCC21
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1CCCC2CCN(C(=O)CCc3ccc(F)cc3)CC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A solution of ethyl (4aSR,8SR,8aSR)-decahydroisoquinoline-8-carboxylate (273 mg, 1.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (309 mg, 1.61 mmol) in dichloromethane (10 mL) was treated with 3-(4-fluorophenyl)propanoic acid (271 m, 1.61 mmol). The mixture was stirred at room temperature for 4 hours, and then treated with 1.0 N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (3×5 mL), and the combined organic phases were washed with 1.0 N aqueous sodium hydroxide, dried over magnesium sulfate and concentrated to provide a residue. The residue was purified by radial thin layer chromatography, eluting with 33% ethyl acetate/hexane, to provide a colorless oil (385 mg, 82%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[C:13]2=[O:30])=[CH:8][CH:7]=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:19][CH:18]=3)[C:13]2=[O:30])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: CN(C)CCOc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCOc1ccc(N2CCN(c3ccc(Oc4ccccc4)cc3)C2=O)cc1
Reaction time: 8 h

Procedure:
Palladium(II) hydroxide (20 mg) was added to a solution of 1-(4-(2-dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in ethanol (5 mL) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was shaken for 8 hours. The catalyst was filtered off and the filtrate was concentrated. The product with the molecular weight of 417.51 (C25H27N3O3); MS (ESI): 418 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12]O.[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Ni].C1(C)C(C)=CC=CC=1>[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCCc1ccc2ccccc2c1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: [Ni]
Solvent: Cc1ccccc1C
Product: O=C(NC1CCN(CCc2ccc3ccccc3c2)CC1)c1ccccc1

Procedure:
2-(2-Naphthyl)ethanol (3.44 g., 0.02 mole), 4-benzamidopiperidine (4.08 g., 0.02 mole) and Raney Nickel (W7 ca. 5 g.) were suspended in xylene (200 ml.) and the stirred mixture boiled under reflux for 16 hours. Liberated water was removed by means of a Dean and Stark apparatus. The mixture was filtered hot and evaporated to ca. 100 ml. The resulting yellow solution was stored until crystallisation was complete. The title compound was obtained as off-white needles (3.30 g.), m.p. 189°-191° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>[Cl-].[Ca+2].[Cl-]>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 33 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and calcium chloride (1 g, 9 mmol) were added to (S)-epichlorohydrin (185 g, 2 mol). The mixture was stirred at room temperature (33° C.) for 8 hours. Filtered, and the solvent was evaporated to provide 57 g of colorless oil in 97% yield.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:1][C:2]1[C:3]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:4][S:5][CH:6]=1
Reactant: CC1CSCC1CN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1cscc1CBr
Temperature: 85 °C
Yield: 53.3 %

Procedure:
2-(4-Methyl-tetrahydro-thiophen-3-ylmethyl)-isoindole-1,3-dione (410.0 mg, 1.59 mmol) and NBS (312.0 mg, 1.75 mmol) were dissolved in CCl4 (8.0 mL). AIBN (100 mg) was added in one portion. The mixture was heated at 85° C. under N2 for 90 min. After cooling down, the mixture was passed through a short silica gel column (4×10 cm), eluted with CH2Cl2. The solution obtained was concentrated and the residue was recrystallized from EtOAc/Hexanes (5/1) to give 2-(4-Bromomethyl-thiophen-3-ylmethyl)-isoindole-1,3-dione (285 mg, 50%) as a white solid. 1H NMR (CDCl3) δ 4.74 (s, 2H), 4.91 (s, 2H), 7.29-7.30 (d, 1H, J=3.3 Hz), 7.70-7.71 (d, 1H, J=3.3 Hz), 7.70-7.73 (m, 2H), 7.82-7.87 (m, 2H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:13])/[CH2:4][S:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])=[O:6].[O:14]1[C:18](=O)[CH2:17][CH2:16][C:15]1=[O:20]>CN(C)C=O>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[S:5]([CH2:4][C:3]1[N:13]=[C:18]([CH2:17][CH2:16][C:15]([OH:20])=[O:14])[O:1][N:2]=1)(=[O:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: N/C(CS(=O)(=O)c1cccs1)=N\O
Solvent: CN(C)C=O
Product: O=C(O)CCc1nc(CS(=O)(=O)c2cccs2)no1
Yield: 96.8 %

Procedure:
(1Z)-N′-hydroxy-2-(2-thienylsulfonyl)ethanimidamide (0.250 g) with dihydro-2,5-furandione (0.114 g) in dimethylformamide (0.2 ml) was heated at 120° C. for 2 hours. The reaction was allowed to cool and triturated with diethyl ether and filtered to leave 3-{3-[(2-thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propanoic acid (0.332 g).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]([CH2:24][OH:25])[C@H:11]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Cl[S:47]([NH2:50])(=[O:49])=[O:48]>C(#N)C>[C:1]([O:9][C@H:10]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:13][C@H:12]([CH2:24][O:25][S:47]([NH2:50])(=[O:49])=[O:48])[C@H:11]1[O:26][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccncc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: NS(=O)(=O)OC[C@H]1C[C@@H](NC(=O)c2ccncc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
To a solution of (1S,2R,3R,5R)-3-(hydroxymethyl)-5-(isonicotinoylamino)cyclopentane-1,2-diyl dibenzoate (160. mg, 0.350 mmol) in ACN (10.0 mL) at 0° C. was added DBU (0.0600 mL, 0.401 mmol) and the mixture was stirred for 15 min. A freshly prepared 1.40 M solution of chlorosulfonamide (0.500 mL, 0.700 mmol, as prepared in Example 1d) was then added dropwise via syringe and the mixture was stirred for 2.5 h at 0° C. before being allowed to warm to rt. The mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (50.0 mg, 27%). LC/MS: Rt=1.57 min, ES+ 540. (FA standard).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([CH2:8][C:9](=O)[CH3:10])=O)=[CH:4][CH:3]=1.[NH2:14][C:15]([NH2:17])=[O:16].Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.C(O)C>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]2[CH:8]=[C:9]([CH3:10])[N:17]=[C:15]([OH:16])[N:14]=2)=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: CC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2ccc(F)cc2)nc(O)n1
Yield: 46.9 %

Procedure:
A mixture of 5 g of 4-fluorobenzoylacetone, 1.66 g of urea, 25 ml of ethanol, and 3.8 ml of concentrated hydrochloric acid was refluxed for 20 hours. This reaction mixture was cooled, poured into iced water, made basic with aqueous solution of potassium carbonate, and neutralized with acetic acid. The crystals that separated out were collected by filtration, washed with isopropyl ether, and dried to provide 2.65 g of pale yellow crystals.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[C:3]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:2]=1.[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:22]([N:21]([CH3:20])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:10]([OH:19])([C:11]([F:13])([F:14])[F:12])[C:15]([F:16])([F:18])[F:17])=[CH:2][CH:1]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNCCc1ccccc1
Reactant: O=C(O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CN(CCc1ccccc1)C(=O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
CDl (194.4 mg, 1.2 mmol) is added to the solution of 4-(2-hydroxyhexafluoroisopropyl) benzoic acid (288 mg, 1 mmol) in THF (10 mL) at room temperature. The reaction mixture is stirred for 10 minutes and N-methylphenethylamine (0.174 mL, 1.2 mmol) is introduced. The reaction mixture is then stirred for 14 hours. The solvent is removed and the residue is dissolved in EtOAc. The organic phase is washed with 1N HCl, saturated NaHCO3 and brine and dried over MgSO4. The product is obtained in pure form after removal of solvents (278.8 mg). 1H NMR (CD3OD, every peak appears as a pair) δ2.76 (t, 2H), 3.12 (s, 3H), 3.44 (t, 2H), 7.01 (d, 2H), 7.20 (d, 2H), 7.30 (m, 3H), 7.62 (d, 2H); ESIMS: m/z 406 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[C:10]([O:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[CH:26][CH:27]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:10]([O:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[O:33][C:34]=3[CH3:35])=[CH:26][CH:27]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CCC(=O)O)cn1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A mixture of ethyl 3-[1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]propionate (746 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]propionic acid (639 mg, yield 90%), which was then recrystallized from acetone-hexane. melting point: 130–131° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O>>[Cl:13][C:14]1[CH:15]=[C:16](/[CH:17]=[CH:11]/[C:10](=[O:12])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: COc1cccc(CC(C)=O)c1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: COc1cccc(CC(=O)/C=C/c2ccc(Cl)c(Cl)c2)c1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 1-(3-methoxyphenyl)propan-2-one and 3,4-dichlorobenzaldehyde following the procedure outlined in Example 9.1 above. 1H NMR (CDCl3, δ): 7.56 (d, J=2.0 Hz, 1H) 7.48 (d, J=16.0 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.3 (m, 2H), 6.8(m, 3H), 6.73 (d, J=16.0 Hz, 1H), 3.88 (s, 2H), 3.79 (s, 3H). 13C NMR (CDCl3, δ): 196.5, 159.8, 140.4, 135.3, 134.4, 134.3, 133.1, 130.8, 129.8, 129.7, 127.3, 126.2, 121.7, 115.1, 112.5, 55.1, 48.7.