Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10](N)[CH2:9]1)(OC(C)(C)C)=O.C([N:17](CC)CC)C.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.Cl>[C:22]1([S:28]([N:10]2[CH2:11][CH2:12][CH2:13][C@@H:8]([NH2:17])[CH2:9]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN(N)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N[C@@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 2 h
Yield: 84 %

Procedure:
(R)-3-Boc-aminopiperidine (0.843 g, 4.21 mmol) was dissolved in DCM (10 mL) and then triethylamine (0.88 mL, 6.31 mmol) was added. To this solution at room temperature was added benzenesulfonylchloride (0.818 g, 4.63 mmol). After 2 h, reaction was deemed complete by LCMS and diluted with water and extracted with DCM (30 mL), and the organic layer was separated and dried over magnesium sulfate, filtered and concentrated and taken to the next step as such. The crude product from above was dissolved in DCM (25 mL) and TFA (10 mL) added in one portion. Reaction mixture followed by LCMS. After 3 h, complete Boc-deprotection was observed. At this stage, TFA was stripped in vacuo and then the residue suspended in 3N HCl and washed with ether. The aq. layer was basified and extracted with DCM and the DCM layer separated and dried over magnesium sulfate, filtered and concentrated in vacuo to give 850 mg of (R)-1-(phenylsulfonyl)piperidin-3-amine as the desired product as free base. LCMS (m/z): 241.4 (MH+), 0.43 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(-c2cc(F)cc(F)c2)cc1
Yield: 50.9 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (225 mg, 0.57 mmol, prepared in example 17) and 3,5-difluorophenylboronic acid (108 mg, 0.69 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with methylene chloride to afford 110 mg (51%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([C:8]2[C:9]([C:22]3[CH:32]=[CH:31][C:25]4[O:26][C:27]([F:30])([F:29])[O:28][C:24]=4[CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:8]2[C:9]([C:22]3[CH:32]=[CH:31][C:25]4[O:26][C:27]([F:30])([F:29])[O:28][C:24]=4[CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OC(F)(F)O4)c(N3CCCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc4c(c3)OC(F)(F)O4)c(N3CCCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)quinoxaline-6-carboxylate (110 mg, 0.25 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (40 mg, 1.00 mmol) with stirring overnight at room temperature. The resulting mixture was concentrated in vacuo and dissolved in water (10 mL), adjusted to 6 with HCl (3 N) and collected by filtration to give 3-(azepan-1-yl)-2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (70 mg, 66%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH2:19][N:20]([S:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[CH:27][C:26]=3[CH3:34])(=[O:24])=[O:23])[CH3:21])[O:16][CH:15]=2)=[O:13])[CH3:10])=[CH:5][CH:4]=1)=O.[OH:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1.CC(O)=O.ClCCCl>C(Cl)Cl>[OH:35][CH:36]1[CH2:40][CH2:39][N:38]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([CH:9]([NH:11][C:12]([C:14]3[CH:18]=[C:17]([CH2:19][N:20]([S:22]([C:25]4[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[CH:27][C:26]=4[CH3:34])(=[O:24])=[O:23])[CH3:21])[O:16][CH:15]=3)=[O:13])[CH3:10])=[CH:7][CH:8]=2)[CH2:37]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NC(C)c3ccc(C=O)cc3)co2)c(C)c1
Reactant: OC1CCNC1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NC(C)c3ccc(CN4CCC(O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BF using N-[1-(4-formylphenyl)ethyl]-5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxamide (39 mg, 0.08 mmol), 3-hydroxypyrrolidine (8.7 mg, 0.1 mmol), AcOH (7 mg, 0.12 mmol), STAB (34 mg, 0.16 mmol) and DCE (1 mL). The reaction was diluted with DCM (1 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The organic phase was dried over Na2SO4 and the solvent removed in vacuo. The crude product was purified by FCC eluting with 2-10% MeOH in DCM to afford the title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[CH3:6][OH:7]>OCCC>[CH3:6][O:4][CH2:1][OH:5].[CH3:6][O:7][CH2:1][CH2:2][CH3:3]
Reactant: CO
Reactant: CCC(=O)O
Agent: *CC(*)C
Solvent: CCCO
Product: CCCOC
Product: COCO
Temperature: 60 °C
Reaction time: 0.01 h

Procedure:
NMR Method for hydrocarboxylation product sample analysis. DCl/D2O/propionic acid stock solution preparation: D2O (99.99%, CIL) (74.606 g), 35% DCl in D2O (CIL) (47.755 g) and propionic acid (JT Baker) (2.198 g) were thoroughly mixed in a bottle to give 0.01765 g of propionic acid per g of stock solution. Hydrocarboxylation product sample preparation for 1H NMR analysis: About 50 mg of hydrocarboxylation sample was transferred to a 2 dram screw top vial with a phenolic cap with a polypropylene liner and the exact mass of the sample was recorded. Then 0.8288 g of stock solution was added and the mixture was heated in a heat block for 1 hour at 60° C. The vial was allowed to cool to room temperature and then the solution was transferred to an NMR tube. 1H NMR analysis: 1H NMR was recorded using 30 seconds pulse delay, 90 degree pulse angle, 16 scans and D2O lock solvent. The spectrum was referenced to the CH3 triplet of propionic acid (1.15 ppm). The meq/g concentrations of the following components were obtained from peak integrations (A1 δ 8.36 ppm, F0 δ 4.99, 4.94 ppm, MeOCH2OH δ 4.83 ppm, MGH δ 3.52 ppm, MG δ 3.84 ppm, MGM δ 3.85 ppm, G1 δ 4.35 ppm, MeOH δ 3.47 ppm, MeOPr (methyl propionate) δ 3.76 ppm, HOPr (ISTD) δ 2.50 ppm).
Reaction SMILES: CON(C)[C:4](=[O:38])[CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][C@@H:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([O:28][Si](C(C)(C)C)(C)C)[C:17]4([CH3:37])[CH3:36])=[CH:11][CH2:10]1)[CH3:8].[CH3:40][CH2:41][CH:42]([Mg]Br)[CH2:43][CH3:44].C(O)C.Cl>>[OH:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][C:4]([CH:42]([CH2:43][CH3:44])[CH2:41][CH3:40])=[O:38])[CH2:10][CH:11]=4)[C:17]1([CH3:37])[CH3:36]
Reactant: CON(C)C(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: CCC(CC)[Mg]Br
Agent: Cl
Solvent: CCO
Product: CCC(CC)C(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid-N-methoxy-N-methyl amide (0.57 g) is reacted with 3-pentylmagnesiumbromide and hydrolysed with ethanol/HCl following the procedure outlined in example 6 to give the title compound (13 mg). 1H-NMR (CDCl3, 300 MHz): δ=5.35 (1H, s); 3.23 (1H, m). MS: Calculated: 454.7. Found: 454.3.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[C:2]1[C:9]([OH:11])=[O:10].[C:12](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH3:12][O:7][C:6]([C:5]1[S:1][C:2]([C:9]([OH:11])=[O:10])=[CH:3][CH:4]=1)=[O:8]
Reactant: O=C(O)c1ccc(C(=O)O)s1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)O)s1
Yield: 26.3 %

Procedure:
1.72 g (10 mmol) of thiophene-2,5-dicarboxylic acid and 3.18 g (30 mmol) of sodium carbonate suspended in 25 mL of DMF were stirred with 623 μL of methyl iodide at room temperature overnight. The sodium salt of the desired product was extracted with water, and 12M of hydrochloric acid was added to the combined aqueous layer. The desired product was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous ammonium chloride and dried over anhydrous magnesium sulfate. The desired product was purified by silica gel column chromatography to give 0.49 g of a colorless solid (yield 28%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:39]4[CH2:40][CH2:41][C@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CC[C@H](N(C)C)C4)n3)sc2c1-c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40 mg, 0.08 mmol) in dioxane (1 mL) was added (S)—N,N-dimethylpyrrolidin-3-amine (89 mg, 0.78 mmol) at room temperature. The reaction mixture was allowed to stir for an additional 30 minutes and then concentrated in vacuo to provide the desired product. LCMS-ESI+: calc'd for C31H37ClN5O3S: 594.2 (M+H+); Found: 594.4 (M+H+).
Reaction SMILES: C(#N)C.C(N(CC)C(C)C)(C)C.[CH3:13][C:14]1[C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:22])[O:16][N:15]=1.Cl[CH2:24][N:25]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][C:31]([O:40][CH3:41])=[CH:32][C:33]=2[CH:37]([CH3:39])[CH3:38])[S:26]1(=[O:28])=[O:27]>C(OCC)(=O)C>[CH3:13][C:14]1[C:18]([C:19]([O:21][CH2:24][N:25]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][C:31]([O:40][CH3:41])=[CH:32][C:33]=3[CH:37]([CH3:39])[CH3:38])[S:26]2(=[O:27])=[O:28])=[O:20])=[C:17]([CH3:22])[O:16][N:15]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1c(C)noc1C)C2=O
Reaction time: 0.08 h
Yield: 10 %

Procedure:
Acetonitrile (3 ml), followed by N,N-diisopropylethylamine (0.26 ml, 1.5 mmol) were added to 3,5-dimethylisoxazole-4-carboxylic acid (0.21 g, 1.5 mmol). The mixture was stirred for 5 minutes, then 2-chloromethyl-4-isopropyl-6-methoxysaccharin (0.30 g, 1 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate (75 ml) and washed with saturated NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative layer chromatography eluting with CH2Cl2 (100%) to afford 0.041 g (10%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl 3,5-dimethylisoxazole-4-carboxylate as a white solid, m.p. 136.8°-139.1° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:5][C:4]([CH:12]=O)=[N:3]1.[Cl-].[CH3:15][C:16]1[N:21]2[N:22]=[C:23]([CH2:25][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:24]=[C:20]2[C:19]([CH3:45])=[N:18][CH:17]=1>>[CH3:15][C:16]1[N:21]2[N:22]=[C:23]([CH:25]=[CH:12][C:4]3[N:5]=[C:6]([N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)[N:2]([CH3:1])[N:3]=3)[N:24]=[C:20]2[C:19]([CH3:45])=[N:18][CH:17]=1
Reactant: Cn1nc(C=O)nc1N1CCCC1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Product: Cc1ncc(C)n2nc(C=Cc3nc(N4CCCC4)n(C)n3)nc12
Yield: 39.5 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using 1-methyl-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole-3-carbaldehyde (45 mg, 250 μmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (115 mg, 250 μmol, Eq: 1.00) as starting materials. Chromatography afforded 5,8-Dimethyl-2-[2-(1-methyl-5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-yl)-vinyl]-[1,2,4]triazolo[1,5-a]pyrazine (32 mg, 39.5%) as white solid. MS: m/z=325.5 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[OH:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([C@@H:34]([CH3:38])[C:35](O)=[O:36])[CH:28]=[CH:27]2.C(Cl)CCl.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([CH:34]([CH3:38])[C:35]([O:10][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:21])=[O:36])[CH:28]=[CH:27]2
Reactant: COc1ccc2cc([C@@H](C)C(=O)O)ccc2c1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(C)C(=O)O[C@H](Cc3c(Cl)cncc3Cl)c3ccc(OC)c(OC)c3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (50 g, 152 mmol), (R)-2-(6-methoxynaphthalen-2-yl)propanoic acid (38.6 g, 168 mmol), DMAP (20.5 g, 168 mmol), and EDC (43.8 g, 229 mmol) were dissolved in DMF (300 ml), and the reaction mixture was stirred at RT for 2 hours. Thereafter, water (500 ml) was added, and the solution stirred till complete precipitation occurs. The solid was filtered and dissolved in DCM (500 ml). The organic solution was washed with aqueous HCl 1N (2×500 ml), saturated aqueous NaHCO3 solution (500 ml) and dried over Na2SO4. The solvent was evaporated under vacuum and the solid residue sonicated in EtOH (300 ml) and triturated for 1 hour. The resulting precipitate was collected by filtration and dried under vacuum at 40° C. for 4 h to give 79 g (99% yield) of the title compound, as diastereoisomeric mixture.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2cc(OCCCCCC(=O)O)nc(-c3ccccc3)c2)cc1

Procedure:
The procedure in Example 4 is followed but using ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]-oxy}hexanoate (3.9 g), potassium hydroxide pellets (0.81 g) dissolved in distilled water (10 cc), and ethanol (150 cc). The reaction mixture is refluxed for 2 hours. The product is purified by recrystallization in toluene (70 cc) to obtain 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoic acid as yellowish crystals; (m.p.=131°-133° C.)
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C([O-])C.[Na+].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:17]=[C:18]([NH:22][N:23]=[C:24](Br)[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1>C(O)C>[CH2:8]([O:7][C:1]([C:2]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:23][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:33])([F:14])[F:32])[CH:17]=2)[C:3]=1[CH3:5])=[O:6])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: FC(F)(F)c1cccc(NN=C(Br)c2ccncc2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
An ice cooled solution of ethyl acetoacetate (0.21 ml, 1.63 mmol) in 10 ml ethanol was treated with a solution of sodium ethanolate 21% (in ethanol, 0.6 ml, 1.63 mmol). The reaction mixture was stirred 1 h at 0° C., then N-[3-(trifluoromethyl)phenyl]pyridine-4-carbohydrazonoyl bromide (562 mg, 1.63 mmol) in 5 ml ethanol was added drop wise. The yellow suspension was stirred 1 h at room temperature and 2 days at 50° C. The reaction mixture was concentrated in vacuo and the residual product partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The organic phases were dried over magnesium sulfate and evaporated. Column chromatography (EtOAc:n-heptane 1:1) gave the title compound as a light brown oil (130 mg, 21%). MS: 376.5 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][CH:6]=[N:5][C:4]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[O:7][CH:6]=[N:5][C:4]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)=[O:1]
Reactant: N#Cc1ccc(-c2ncoc2CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1ccc(-c2ncoc2C=O)cc1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
A mixture of 4-(5-(hydroxymethyl)oxazol-4-yl)benzonitrile (190 mg, 0.95 mmol, 1.00 equiv) and MnO2 (1.9 g, 21.85 mmol, 23.03 equiv) in dichloromethane (5 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with 0-6% of ethyl acetate in petroleum ether to yield 20 mg (11%) of 4-(5-formyloxazol-4-yl)benzonitrile as a white solid. 1H-NMR (300 MHz, CDCl3): δ 10.02 (s, 1H), 8.90 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.08-8.02 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH:10]([C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[NH2:11]>CO.C(O)(=O)C>[NH:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[NH:10][N:11]=[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1ccncn1
Reactant: NNc1nc2ccccc2[nH]1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NNc1nc2ccccc2[nH]1)c1ccncn1

Procedure:
A mixture of 4-acetyl pyrimidine (0.412 g, 3.37 mmol) and 2-hydrazinobenzimidazole (0.50 g, 3.37 mmol) in 15 ml of methanol is refluxed after the addition of 5 drops of glacial acetic acid, until monitoring of the reaction by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (10:1)) did not reveal any further reaction. The reaction mixture is stored over night in the refrigerator at approximately 5° C. The precipitate is filtered and recrystallized from a mixture of ethyl acetate and diisopropyl ether. Yield: 0.65 g (76% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[C:4]([F:19])[CH:3]=1.[Cl-].[NH4+]>CO.[Zn]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[C:4]([F:19])[CH:3]=1
Reactant: N#Cc1ccc(-c2cc([N+](=O)[O-])c(N)cc2F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: N#Cc1ccc(-c2cc(N)c(N)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a mixture of 4′-amino-2′-fluoro-5′-nitrobiphenyl-4-carbonitrile (Preparation 90, 0.5 g, 2 mmol) and zinc dust (0.78 g, 12 mmol) in methanol (10 mL) was added ammonium chloride (0.41 g, 8 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was filtered through celite washing through with methanol (40 mL). The filtrate was concentrated to afford a solid that was purified using silica gel column chromatography eluting with EtOAc:heptanes 1:1 to afford the title compound as a brown solid (0.45 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([N:14]=[C:15]=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl.O1CCCC1.C(OCC)(=O)C>[CH2:7]([NH:14][C:15](=[O:16])[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCC(=O)O
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CCNC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a solution of β-alanine 5.0 g (56 mmol) in dichloromethane 56 ml and tetrahydrofuran 56 ml was added benzyl isocyanate 6.6 ml (53 mmol) at 0° C. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate 200 ml and washed with water 200 ml and brine 200 ml. The residual solution was concentrated to about 100 ml in vacuo. To the mixture was added 1N sodium hydroxide solution 60 ml at 0° C. The aqueous phase was acidified with 3N HCl aq. 20 ml and then extracted with ethyl acetate 100 ml twice. The extract was washed with brine 50 ml and dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. To the residue was added ether:n-hexane=1:1 30 ml and the precipitate was corrected by filtration to obtain the title compound 7.05 g (59%).
Reaction SMILES: Cl[C:2](OCC)=[O:3].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][OH:30])=[NH:28])=[CH:23][N:22]=1)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH2:35]([O:34][C:32]1[CH:31]=[C:17]([CH:16]=[C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][C:2](=[O:3])[O:30][N:29]=2)=[CH:23][N:22]=1)=[O:19])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)Cl
Reactant: N=C(NO)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2noc(=O)[nH]2)cn1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
Ethyl chloroformate (32 μL, 0.33 mmol) was added to a solution of 3,5-bis(benzyloxy)-N-{5-[(hydroxyamino)(imino)methyl]pyridin-2-yl}benzamide (140 mg, 0.30 mmol) in pyridine (5 mL). This solution was heated at reflux overnight. The mixture was cooled and concentrated under reduced pressure. DCM and methanol were used to dissolve the remaining material and the solution was washed with water. The organic solution was concentrated under reduced pressure and the residue was purified on silica by MPLC (eluting firstly with 5% methanol/DCM then 10% methanol/DCM). The title compound was obtained as a colourless solid (103 mg, 70%). 1H NMR δ (d6-DMSO): 5.19 (4H, s); 6.87 (1H, s); 7.28-7.46 (12H, m); 8.21 (1H, dd); 8.38 (1H, d); 8.79 (1H, s); 11.14 (1H, br s); m/z (LCMS; ESI+) 495 (MH+).