Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1ccc(OC)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1ccc(OC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
To a solution of 2-allyl-5-methoxyphenol (20.30 g, 0.124 mol) in DMF (500 mL) was added potassium carbonate (68.35 g, 0.495 mol) followed by benzyl bromide (23.26 g, 0.136 mol) and tetrabutylammonium iodide (4.57 g, 0.012 mol). The reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (1000 mL) to dissolve any solids and extracted with diethyl ether (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:19) provided 28.44 g (90%) of 1-allyl-2-(benzyloxy)-4-methoxybenzene as a colorless oil. Rf=0.88 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C17H18O2: C, 80.28; H, 7.13. Found: C, 82.43; H, 7.09.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][P:5]([O-:12])[O:6][CH2:7][C:8]([F:11])([F:10])[F:9].C1CCN2C(=NCCC2)CC1.[C:26]1([C:32]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:33]2[CH:37]=[C:36]([CH2:38]Cl)[N:35]=[CH:34]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[F:14][C:2]([F:1])([F:13])[CH2:3][O:4][P:5]([CH2:38][C:36]1[N:35]=[CH:34][N:33]([C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:37]=1)(=[O:12])[O:6][CH2:7][C:8]([F:11])([F:9])[F:10]
Reactant: [O-]P(OCC(F)(F)F)OCC(F)(F)F
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=P(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(OCC(F)(F)F)OCC(F)(F)F
Yield: 29.9 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)phosphite (0.11 ml, 0.6 mmol) in THF (1.5 ml) were added 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) (0.09 ml, 0.6 mmol) and (1-triphenylmethylimidazol-4-yl)methyl chloride (71.8 mg, 0.2 mmol). The reaction mixture was refluxed under argon flow for 22 hours. The solvent was removed under reduced pressure, and water (10 ml) was added to the residue, which was then extracted 3 times with ethyl acetate (10 ml). The resultant organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained white solid was purified through chromatography on silica gel column using ethyl acetate-hexane (3:2) to give bis(2,2,2-trifluoroethyl)(1-triphenylmethylimidazol-4-yl)methylphosphonate (34 mg, 30%) as a white powder. This powder was recrystallized from a mixture of ethyl acetate and hexane to provide a white small needle crystal (m.p. 145-148° C.).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([CH:25]=3)[C:21]([O:23]C)=[O:22])=[CH:11][CH:10]=2)[N:5]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:14]=[CH:13][C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([CH:25]=3)[C:21]([OH:23])=[O:22])=[CH:11][CH:10]=2)[N:5]=1
Reactant: COC(=O)c1cc(Oc2ccc(-c3noc(C)n3)nc2)ccc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(Oc3ccc([N+](=O)[O-])c(C(=O)O)c3)cn2)no1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.3 %

Procedure:
1.96 ml of aqueous 5 N sodium hydroxide solution was added to a solution of 700 mg of methyl 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-nitrobenzoate in 5 ml of methanol and 5 ml of tetrahydrofuran, and stirred at room temperature for 2.5 hours. Aqueous 10% citric acid solution was added to neutralize it, then extracted with ethyl acetate, and the organic layer was dried, and the solvent was evaporated away under reduced pressure to obtain 399 mg of 5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-nitrobenzoic acid as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.O1CCCC1.C([Li])CCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>CCCCCC>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[C:6]=1[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cnn(C2CCCCO2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)cnn1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 73.8 %

Procedure:
To a solution of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0.258 g, 1.55 mmol) in tetrahydrofuran (6 mL, 70 mmol) at −78° C. was added 2.5 M of n-butyllithium in hexane (0.80 mL). The reaction was stirred at −78° C. for 50 minutes, and then tributyltin chloride (0.60 mL, 2.2 mmol) was added. The reaction was kept at −78° C. for 2 hours and then quenched with saturated aqueous NH4Cl and warmed to room temperature. The reaction mixture was diluted with more water and extracted with ethyl acetate. The organic portion was dried with MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptanes) to yield 520.6 mg (74%) of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(tributylstannyl)-1H-pyrazole. LCMS (ESI): M+H=457.2; 1H NMR (400 MHz, DMSO-d6) δ 7.31 (s, 1H), 5.11 (d, J=8.3 Hz, 1H), 3.81 (d, J=11.4 Hz, 1H), 3.59-3.48 (m, 1H), 2.23 (dd, J=20.7, 9.4 Hz, 1H), 2.04 (s, 3H), 1.97 (d, J=12.8 Hz, 1H), 1.90 (d, J=13.3 Hz, 1H), 1.48 (m, 9H), 1.30 (dd, J=14.5, 7.3 Hz, 6H), 1.20-0.97 (m, 6H), 0.86 (t, J=7.3 Hz, 9H).
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.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]#[N:36])=[CH:30][CH:29]=2)O1>>[C:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([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:29][CH:30]=1)#[N:36]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CC#N)cc2)cc1
Yield: 68.1 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (356 mg, 0.91 mmol, prepared in example 2) and [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile (275 mg, 1.13 mmol) were treated as described in example 6. The product was chromatographed on Chromatotron® eluting with 99.5:0.5 methylene chloride:ethyl acetate to afford 237 mg (68%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.B([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+].N#N>CC#N.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)O)cc4)cnc3N)[nH]c2c1
Temperature: 90 °C
Yield: 61.7 %

Procedure:
5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (1.855 g, 6.099 mmol), 4-boronobenzoic acid (1.012 g, 6.099 mmol) and Na2CO3 (1.293 g, 12.20 mmol) suspended in MeCN (30 mL)/water (30 mL). The mixture was degassed (5×N2 vacuum cycles) and Pd(PPh3)4 (704.8 mg, 0.6099 mmol) added. The mixture was degassed again and heated to 90° C. No sign of product was observed therefore 25 mL aliquots were heated in the microwave for 1 hour at 140° C. which led to product formation. The mixture was allowed to cool and washed with DCM (×2). The aqueous layer was acidified to pH4 (1M HCl) and the resulting precipitate collected, washed with water and dried overnight under vacuum to give the product as a bright yellow solid, (1.30 g, 62% Yield); MS (ES+) 346
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)([O:10][CH2:11][CH2:12]O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:15]2)([O:10][CH2:11][CH2:12][N:31]2[C:27](=[O:37])[C:28]3[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30]2=[O:32])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCO)c2cccc(Cl)c2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCN2C(=O)c3ccccc3C2=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 50.9 %

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-hydroxyethoxy)ethyl)piperidine-1-carboxylate (1.000 g, 2.6 mmol), phthalimide (1.490 g, 10.1 mmol), triphenylphosphine (4.130 g, 15.7 mmol), and DIAD (3.430 g, 17.0 mmol) in THF was stirred at rt for 40 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford 0.6792 g (51%) of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl)piperidine-1-carboxylate. MS ESI +ve m/z 537 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10](=O)[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([NH2:24])=[NH:23].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:24]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[N:23]=2)[CH:5]=[N:6][CH:7]=1
Reactant: N=C(N)c1ccccn1
Reactant: CC(C)(C)C(=O)C#Cc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2cncc(Br)c2)nc(-c2ccccn2)n1

Procedure:
To a solution of 1-(5-bromo-pyridin-3-yl)-4,4-dimethyl-pent-1-yn-3-one (1 eq, 770 mg, 2.89 mmol) in THF (12 ml) is added pyridine-2-carboxamidine (1.5 eq, 684 mg, 4.34 mmol) and Na2CO3 (2.4 eq, 736 mg, 6.94 mmol). The resulting mixture is heated using microwave radiation for 1 h at 150° C. The solvent is removed in vacuo and the residue is partitioned between sat. aqueous NaHCO3 solution and DCM. The organic portion is dried (MgSO4) and concentrated in vacuo. The resulting residue is purified using column chromatography (DCM/MeOH) to give the title compound; [M+H]+=369/371.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[OH:27][C:7]1[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[N:11][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:9]2[S:18][N:19]=[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:8]=12
Reactant: CCOC(=O)c1nc(-c2cccnc2)c2snc(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1nc(-c2cccnc2)c2snc(-c3ccccc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-hydroxy-3-phenyl-7-pyridin-3-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 407.1 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:24]([NH2:26])=[O:25])[C:16]2[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CC(C)=O.[O-2].[O-2].[Mn+4]>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:24]([NH2:26])=[O:25])[C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=2)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=O)cc1

Procedure:
The above compound was prepared from 4-[(1-(2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzyl alcohol by oxidation with active manganese dioxide in absolute acetone and subsequent purification by column chromatography on silica gel (chloroform/acetone=20:1).
Reaction SMILES: [CH:1]1([N:7]([CH3:16])[C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1.C(OCC)C>CN(C=O)C>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH:33]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)[N:34]2[CH2:35][CH2:36][N:37]([C:9](=[O:11])[C@@H:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH3:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:38][CH2:39]2)=[CH:45][CH:44]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCCCC1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)N(C)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid (0.200 g, 0.880 mmol, Example 21, Step A) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.389 mL, 1.76 mmol) and solid O-benzotriazol-1-yl-N,N,N,′,N′-tetramethyluronium hexafluorophosphate (0.334 g, 0.880 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.254 g, 0.880 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 90 minutes at ambient temperature, reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (30% EtOAC in hexanes). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.39 g (78%) of the pure titled compound as a white solid; mp 171-182° C. APCI-MS m/z 498.3 (MH+).
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][C:57]=1[CH2:66][NH2:67]>CN(C)C=O>[F:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]([F:63])([F:64])[F:65])=[CH:58][C:57]=1[CH2:66][NH:67][C:8](=[O:10])[C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:11][CH3:12]
Reactant: NCc1cc(C(F)(F)F)ccc1F
Reactant: CC[C@H](C(=O)O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C(=O)NCc1cc(C(F)(F)F)ccc1F)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of (S)-2-phenylbutanoic acid (1-d, 50 mg, 0.30 mmol, Sigma-Aldrich, Milwaukee, Wis.) and diisopropylethylamine (98 uL, 0.60 mmol) in N,N-dimethylformamide (1 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 158 mg, 0.30 mmol). After 15 min, (2-fluoro-5-(trifluoromethyl)phenyl)methanamine (1-g, 60 mg, 0.30 mmol, Synthesis, Inc., Wyndham, N.H.) was added. The reaction mixture was stirred for 3 h, partitioned between dichloromethane and 0.5N—NaOH. The aqueous layer was removed and the organic layer washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was concentrated in vacuo to give the desired product (1-1); HRMS (M+1)=340.129; 1H NMR (500 MHz, CDCl3) δ7.49 (bs, 1 H), 7.41 (d, 1 H, J=6.5 Hz), 7.34-7.26 (m, 5 H), 7.10 (t, 1 H, J=9.0 Hz), 5.77 (bs, 1 H), 4.47 (d, 1 H, J=3.0 Hz), 3.30 (t, 2 H, J=7.5 Hz), 2.22 (m, 1 H), 1.82 (m, 1 H), 0.89 (t, 3 H, J=7.5 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(F)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(F)cc3)CC2)cc1
Yield: 9 %

Procedure:
1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (4.77 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5 g (79%); off white solid; mp 114° C.; MS: 450 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C@H:3]1[C:13]([OH:15])=[O:14].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([N:4]1[C@@H:3]([C:13]([OH:15])=[O:14])[C:2]([CH3:16])([CH3:1])[S:6][C@H:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CC1(C)S[C@@H](c2ccccc2)N[C@H]1C(=O)O
Solvent: c1ccncc1
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccccc1
Temperature: 0 °C

Procedure:
0.47 g (2 mmoles) of 5,5-dimethyl-2(S)-phenylthiazolidine-4(S)-carboxylic acid is suspended in 5 ml of pyridine while stirring. The temperature of the suspension is adjusted to 5° C. by cooling with ice-water and 0.17 g of acetyl chloride is dropped in. The mixture is stirred for 1 additional hour, then poured in 60 ml of ice-cold 2N sulphuric acid. After several hours, the precipitated product is filtered out, washed with water and dried. The product is dissolved in ethanol and water is added to precipitate the title compound in a yield of 0.38 g (70.3%), m.p.: 216°-217° C., [α]D20 =-109° (c=0.686, methanol).
Reaction SMILES: CS([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=O)=O.BrC1C=C[C:23]([S:26](C)(=[O:28])=[O:27])=CC=1>>[CH3:23][S:26]([C:10]1[CH:5]=[CH:6][C:7]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[CH:15][CH:16]=2)=[CH:8][CH:9]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CO)cc2)c1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1

Procedure:
This compound was prepared in a manner analogous to the preparation of (3′-methanesulfonyl-biphenyl-4-yl)-methanol (WO 01/70753, Example 27) using 1-bromo-4-methanesulfonyl-benzene as the starting material. LCMS found for C14H15O3S (M+H)+: m/z=263.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.Br[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[C:22]([O:24][CH3:25])=[O:23].Cl>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:20]2[CH:21]=[CH:12][C:13]([C:22]([O:24][CH3:25])=[O:23])=[CH:14][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2ccc(F)cc2)c(C(=O)OC)c1
Reaction time: 3 h

Procedure:
A 2.0M solution of 4-fluorobenzyl zinc bromide in tetrahydrofuran (95 ml, 190 mmol; Negishi, E-i. and King, A. O., J.O.C.1977,42,1821) was added dropwise over 20 minutes to a stirred solution of dimethyl 4-bromoisophthalate (20.0 g, 73.2 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.67 g, 0.73 mmol) in tetrahydrofuran (270 ml) at ambient temperature under an inert atmosphere. During the addition the internal temperature rose to 40° C. The reaction mixture was stirred for 3 hours and then poured into 2M. HCl (1500 ml) cooled in an ice bath and the product extracted into ethyl acetate (3×700 ml). The extracts were washed with water (500 ml), brine (500 ml), dried, and the solvent evaporated under reduced pressure. The residue was taken up in a small quantity of dichloromethane, isohexane added, and the solid, which crystallised from the solution, filtered and dried to give methyl 4-(4-fluorobenzyl)-3-methoxycarbonylbenzoate (10.5 g)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. EI-MS m/e (%): 303 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[O:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]=[CH:19]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnco3)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.63 (s, 3H), 7.33 (m, 2H), 7.37 (s, 1H), 7.56 (m, 3H), 7.67-7.3 (m, 3H), 7.94 (m, 1H), 7.97 (s, 1H), 8.52 (b, 1H), 9.45 (s, 1H). MS: m/z 454.1 (M++1).