Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:11])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:29])[N:26]([CH3:27])[C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C.O>C(OCC)(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:29])[N:26]([CH3:27])[C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[S:30](=[O:32])(=[O:31])[NH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]([OH:11])=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:7]=1
Reactant: CC(C)c1cc(N)cc(C(C)C)c1O
Reactant: CN1C(=O)CCC1(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(NS(=O)(=O)c2cc(C3(O)CCC(=O)N3C)ccc2Cl)cc(C(C)C)c1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A suspension of 29.1 g of 4-amino-2,6-diisopropylphenol in 450 ml of ethyl acetate is added in portions to a solution of 17.5 g of 5-(4-chloro-3-chlorosulfonylphenyl)-5-hydroxy-1-methyl-2-pyrrolidone and 22.7 g of triethylamine in 200 ml of ethyl acetate. The mixture is stirred at 50° C. for 3 hours, cooled, water is added, the organic phase is separated off, and the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulfate, and the solvent is distilled off. After addition of about 250 ml of methylene chloride to the amorphous red residue it is refluxed and crystallization is induced by scratching. The mixture is stirred at room temperature for 30 min, and the precipitate is filtered off and recrystallized from acetonitrile without prolonged standing. Colorless crystals of melting point 198°-200° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P(O[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)(OCC)(OCC)=O.[CH:37]([C:39]1[S:43][CH:42]=[C:41](B(O)O)[CH:40]=1)=[O:38].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C:41]2[CH:40]=[C:39]([CH:37]=[O:38])[S:43][CH:42]=2)=[CH:35][CH:34]=1
Reactant: CCOP(=O)(OCC)OCc1ccc(Cl)cc1
Reactant: O=Cc1cc(B(O)O)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Temperature: 90 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
A solution mixture of Pd(OAc)2 (144 mg, 0.64 mmol) and triphenylphosphine (TPP) (136 mg, 0.52 mmol) were weighed into a vial, dissolved in acetonitrile and transferred into a 40 mL Wheaton vial containing diethyl 4-chlorobenzyl phosphate (Org. Lett. 2005, 7, 4875-4878; 3.08 g, 11.6 mmol), 5-formylthiophen-3-ylboronic acid (2.0 g, 12.8 mmol), K3PO4 (2.72 g, 12.8 mmol) and a stir-bar. Nitrogen gas was bubbled through the mixture. The vial was closed tightly and heated to 90° C. and vigorously stirred for 16 h. The reaction was diluted with water and extracted with dichloromethane (DCM) (3×100 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (Isco CombiFlash) (0-20% heptane/EtOAc) yielded 4-(4-chlorobenzyl)thiophene-2-carbaldehyde: 835 mg, 28% yield. 1H NMR (400 MHz, CDCl3) δ ppm: 10.10 (d, 1H), 7.80 (d, 1H), 7.63 (m, 1H), 7.55 (m, 2H), 7.40 (m, 2H), 4.23 (s, 2H).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10](/[CH:13]=C/C2C=CC=CC=2)[O:11][CH:12]=1)=[O:7])[CH3:4].[OH2:21]>CC(C)=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:13]=[O:21])[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: O
Reactant: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Agent: N#N
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(C=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of Na104 (3.21 g, 15.00 mmol) in water (26.0) mL was slowly added to a vigorously stirred suspension of silica gel (15.0 g) in acetone (60.0 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (40.0 mL) was added and the reaction mixture was treated at rt with (E)-2-styryl-oxazole-4-carboxylic acid ethyl ester (1.22 g, 5.00 mmol) and RuCl3 hydrate (82 mg, 0.15 mmol). The reaction mixture was stirred at rt in the dark for 30 min, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:9 to 1:2 EA-Hept) gave the title compound as a yellow solid. TLC:rf (3:2 EA-Hept)=0.21. LC-MS-conditions 02: tR=0.51 min; [M+H2O+H]+=188.50.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=O)=O)(C)(C)C.[Cl:18][C:19]1[CH:20]=[C:21]2[C:29](=[C:30]([NH2:32])[CH:31]=1)[NH:28][C:27]1[CH:26]=[N:25][CH:24]=[CH:23][C:22]2=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[C:51]([O-:54])([O-:53])=[O:52].[Na+:55].[Na+]>N1C=CC=CC=1.O.C(Cl)Cl.CO.CCOC(C)=O>[C:51]([O-:54])([O-:53])=[O:52].[Na+:55].[Na+:55].[Cl:18][C:19]1[CH:20]=[C:21]2[C:29](=[C:30]([NH:32][C:15]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]3[NH2:8])=[O:17])[CH:31]=1)[NH:28][C:27]1[CH:26]=[N:25][CH:24]=[CH:23][C:22]2=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)O
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC1CCCCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of cis-2-(tert-butoxycarbonylamino)-cyclohexane carboxylic acid (255 mg, 1.05 mmol) in pyridine (10 ml) was stirred at RT. 6-chloro-9H-β-carbolin-8-ylamine (218 mg, 1.00 mmol) was added, followed by EDCI (315 mg, 1.64 mmol) and the slightly turbid pale orange solution was stirred at RT for 16 hr. The solution was diluted with H2O (20 ml) and poured into a separatory funnel containing H2O (50 ml) and EtOAc (50 ml). The mixture was shaken and the layers were separated. The aqueous layer was extracted with EtOAc (50 ml) and the combined organic layers were washed with brine. The organic layer was dried, filtered and concentrated to yield a yellow oil which was placed under high vacuum for 4 hr. The resulting yellow-brown glass was slurried in CH2Cl2 (10 ml) at RT. Trifluoroacetic acid (5 ml) was added and the slurry instantly dissolved to form a clear orange solution. The solution was stirred at RT for 45 min, then concentrated to a brown residue. The residue was azeotroped from toluene (3×10 ml) to yield a yellow solid. A solution of dilute aqueous Na2CO3 was prepared by adding a small volume of 10% aqueous Na2CO3 to H2O (50 ml) until the aqueous solution reached a pH of 10. The yellow solid was dissolved in minimal MeOH and was added drop-wise to the aqueous solution with stirring. The precipitate which formed was filtered, washed with H2O and placed under high vacuum to yield 2-amino-cyclohexanecarboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide as pale yellow solid (147 mg).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][C:12]=3[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])[C:7](=[O:31])[C:6]=2[C:5]([OH:32])=[CH:4][CH:3]=1.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O>C1C=CC=CC=1>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]1[N:27]([CH2:26][CH2:25][NH:24][C:9]2[C:8]3[C:7](=[O:31])[C:6]4[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=4[OH:32])[C:14](=[O:16])[C:13]=3[C:12]([NH:17][CH2:18][CH2:19][N:20]3[CH2:3][CH2:2][O:1][CH:21]3[C:22]3[O:23][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[CH2:28][CH2:29][O:30]1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Reactant: O=Cc1ccco1
Solvent: c1ccccc1
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN3CCOC3c3ccco3)ccc(NCCN3CCOC3c3ccco3)c21

Procedure:
A suspension of 3.11 g. of 1,4-dihydroxy-5,8-bis[[2-(2-hydroxyethylamino)ethyl]amino]anthraquinone [prepared as described in Example 1(A)] in 55.0 ml. of benzene containing 2.02 g. of 2-furaldehyde is stirred and heated under reflux using a Dean-Stark trap. A total of 0.2 ml. of water is collected as distillate over a 3 hour period, with no additional water after a total of 7 hours of refluxing. The hot solution is filtered, removing a small amount of blue-black solid. The filtrate is concentrated and petroleum ether is added to give a gum which slowly solidifies. The solid is collected and washed with benzene to give 2.05 g. of a blue-black solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:15][Si:16]([CH3:43])([CH3:42])[CH2:17][CH2:18][O:19][CH2:20][N:21]1[C:25]2[N:26]=[CH:27][N:28]=[C:29]([C:30]3[CH:31]=[N:32][N:33]([C:35]4([CH2:39][C:40]#[N:41])[CH2:38][NH:37][CH2:36]4)[CH:34]=3)[C:24]=2[CH:23]=[CH:22]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:40]([CH2:39][C:35]1([N:33]2[CH:34]=[C:30]([C:29]3[C:24]4[CH:23]=[CH:22][N:21]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:15])([CH3:43])[CH3:42])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:31]=[N:32]2)[CH2:36][N:37]([C:2]2[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:38]1)#[N:41]
Reactant: CC(C)NC(=O)c1ccc(Br)cc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Temperature: 105 °C
Yield: 61 %

Procedure:
A mixture of 4-bromo-N-isopropylbenzamide (1.82 g, 7.52 mmol), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrogen chloride (2.23 g, 5.00 mmol), palladium acetate (78 mg, 0.35 mmol, Aldrich [3375-31-3]), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (405 mg, 0.700 mmol, Aldrich [161265-03-8]), and cesium carbonate (3.03 g, 9.30 mmol) in toluene (22 mL) was de-gassed and purged several times with N2 (g) prior to heating at 105° C. in a sealed vial for 2 days. Upon cooling to room temperature the reaction mixture was filtered through a pad of celite, concentrated in-vacuo and purified by flash chromatography on a silica gel column eluting with MeOH in methylene chloride (0-5%) to afford the desired product (1.74 g, 61% yield). LCMS (M+H)+: m/z=571.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018, 10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (NIS, 12.03 g, 53.45 mmol, 1.05 equiv) at 25° C., and the resulting reaction mixture was stirred at 25° C. for 2 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc-hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled down to 0-5° C. for 2 b. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc-hexane (2×25 mL), and dried in vacuo to afford the crude, (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 15.1 g, 17.15 g theoretical, 88%) as off-white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1019: 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07 (t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 1H, J=7.8, 8.7 Hz); C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][NH:19][CH3:20])=[CH:13][CH:14]=2)[C:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:8]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(C(C)C)CC)(C)C.Cl[C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[N:19]([CH3:20])[CH2:18][CH2:17][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:34]=[CH:35][CH:36]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:8]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:9]2[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cc(OCCNC)ccc2n1Cc1cccc(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cc(OCCN(C)c3nc4ccccc4o3)ccc2n1Cc1cccc(OC)c1
Temperature: 120 °C
Yield: 97 %

Procedure:
To a solution of Ethyl 1-(3-methoxybenzyl)-3-(4-methoxyphenyl)-5-[2-(methylamino)ethoxy]-1H-indole-2-carboxylate (Example 156, 100 mg, 0.2028 mmol) in N,N-dimethylformamide (1.5 ml) was added diisopropylethylamine (0.09 ml, 0.5167 mmol, 2.5 eq.) and 2-chlorobenzoxazole (0.03 ml, 0.2636 mmol, 1.3 eq.). The reaction mixture was heated at 120° C. for 4 hr. After cooling the reaction was diluted with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash column (silica gel, dichloromethane to dichloromethane:methanol 95:5). The desired product was obtained as a light yellow oil in 97% yield (119 mg), MS (M+H)=606.3, Rf=0.69 (dichloromethane/methanol 95:5).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[ClH:14]>CO.[Pt](=O)=O>[ClH:14].[CH3:7][C:2]([CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)([CH3:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)c1ccncc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)C1CCNCC1
Reaction time: 46 h

Procedure:
0.115 g of methyl 2-methyl-2-pyridin-4-ylpropionate [79757-27-0] are dissolved in 5 ml of methanol in an autoclave. The solution is admixed with 0.35 ml of 1.2M HCl in methanol and 0.012 g of platinum(IV) oxide and the reaction mixture is hydrogenated at 4 bar and 23° C. over 46 hours. The catalyst is filtered off through Hyflo and the filtrate is concentrated by evaporation. The title compound is obtained as a light brown residue. Rf=0.05 (200:20:1 dichloromethane-methanol-25% conc. ammonia).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11](#[N:15])[CH:12]([CH3:14])[CH3:13].[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:18]=1[CH2:19]Br.O>C1COCC1>[CH3:13][C:12]([CH3:14])([CH2:19][C:18]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([F:25])[C:17]=1[F:16])[C:11]#[N:15]
Reactant: CC(C)C#N
Reactant: Fc1ccc(F)c(CBr)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)Cc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1M in THF, 26.6 mL, 26.6 mmol) was added to a solution of isobutyronitrile (2.4 mL, 26.6 mmol) in THF at −78° C. and stirred for 25 minutes. 2,3,6-trifluorobenzyl bromide (2.3 mL, 17.8 mmol) was added and the reaction was warmed to room temperature and stirred for 1.5 h. Water was added to quench the reaction and it was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield 2,2-dimethyl-3-(2,3,6-trifluorophenyl)propanenitrile (34) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[Na+].Cl[CH2:13][CH2:14][OH:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:13][CH2:14][OH:15]
Reactant: COc1ccccc1O
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1OCCO
Yield: 41.6 %

Procedure:
A solution of 43.2 g (0.35 mole) of 2-methoxyphenol (guaiacol, Aldrich) in 200 ml of ethanol was stirred and treated with 29 ml (0.36 mole) of 50% sodium hydroxide solution. To this solution was added a solution of 28.2 g (0.35 mole) of 2-chloroethanol (Aldrich) in 50 ml of ethanol and the reaction mixture was heated at reflux for 2 hr. The solids were removed by filtration. The filtrate was evaporated under reduced pressure and the viscous residue was partitioned between 300 ml of 15% sodium hydroxide solution and 500 ml of ethyl ether. The organic layer was washed with 200 ml of 15% sodium hydroxide solution, 300 ml of water, dried (magnesium sulfate) and the solvent evaporated under reduced pressure to give 24.5 g (42%) of the title compound as a lightly colored viscous oil.
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH2:8]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]1[C:24]([OH:26])=[O:25])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:27](N(CC)CC)C>C1(C)C=CC=CC=1.O1CCCC1>[CH2:8]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]1[C:24]([O:26][CH3:27])=[O:25])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
To methanol (500 ml) was added conc. sulfuric acid (10 ml) below 30° C. To this solution was added (2S,4R)-1-benzyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine (100 g) and the resulting mixture was heated under reflux for 4 hours. To the mixture was added triethylamine (63 ml) below 10° C. and the mixture was evaporated in vacuo keeping a bath temperature of rotary evaporator below 40° C. to give a syrup. To this syrup were added tetrahydrofuran (100 ml) and toluene (200 ml) successively, and then evaporated in vacuo keeping the bath temperature below 40° C. This procedure was performed once more to give (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine. The compound obtained above was dissolved in a mixture of ethyl acetate (1000 ml) and triethylamine (63 ml). To this solution was added dropwise a solution of methanesulfonyl chloride (35 ml) in ethyl acetate (100 ml) at 0°-5° C. over a period of 1.5 hours. This mixture was stirred at the same temprature for additional 30 minutes. This mixture was poured into ice-cold water (1000 ml) with stirring. The organic layer was separated, and washed with 1N hydrochloric acid (1000 ml), saturated aqueous sodium hydrogen carbonate (1000 ml) and brine (1000 ml) successively. This organic layer was evaporated in vacuo keeping the bath temperature below 40° C. to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine. The compound obtained above was dissolved in a of tetrahydrofuran (200 ml) and ethanol (300 ml). To this solution was added sodium borohydride(28.5 g) by three portions below 10° C. and then this mixture was stirred at 25°-30° C. for 2 hours. This mixture was poured into ice-cold water (5000 ml) containing conc. sulfuric acid (92 ml) with vigorous stirring, and the stirring was continued for additional 1 hour to give a white crystal. This crystal was collected by filtration and washed with ice-cold water (500 ml) to give (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (95.2 g).
Reaction SMILES: [C:1]([O:12][CH2:13][C:14](=[O:16])[CH3:15])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[BH4-].[Na+].C(O)(=O)C.C(OCC)C>O1CCCC1.C1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]([O:12][CH2:13][CH:14]([OH:16])[CH3:15])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)OCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCCCC(=O)OCC(C)O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 98.5 %

Procedure:
1-Decanoyloxypropan-2-one (44.3 g, 0.194 mole) was dissolved in a solution of tetrahydrofuran (1100 cm3) and benzene (200 cm3). After cooling to 5°, ice water (80 cm3) was added. Sodium borohydride (11 g, 0.291 mole) was added to the stirred solution in small proportions to maintain the temperature at 5°. After addition the reaction was stirred at 5° for 45 minutes and glacial acetic acid (14 cm3) was added dropwise. Stirring at 5° was continued for a further 30 minutes. Diethyl ether and chloroform (200 cm3 each) were added and the mixture washed with water (2×200 cm3), a 1% sodium bicarbonate solution (200 cm3) and brine (200 cm3). The organic phase was dried over sodium sulphate and evaporated to yield 1-decanoyloxypropan-2-ol as a colorless liquid (44.0 g, 0.191 mole, 98%), ir (neat) 3600-3100, 2920, 2860, 1730, 1460, 1375, 1240, 1175, 1110, 1055 cm-1 ; pmr (CDCI3) δ 4.0 (m, 2 H), 3.6 (m, 1 H), (D2) m 1 H), 2.3 (t, 2 H), 2.0-1.0 (bm, 17 H) and 0.85 (t, 3 H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9].F[C:16]1C=CC=CC=1S(Cl)(=O)=O.C([Li])CCC.IC.FC1C=CC=C(C)C=1S(OC(C)C)(=O)=O>>[F:1][C:2]1[C:7]([CH3:16])=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][CH:12]([CH3:14])[CH3:13])(=[O:9])=[O:10]
Reactant: CC(C)OS(=O)(=O)c1ccccc1F
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cc1cccc(F)c1S(=O)(=O)OC(C)C
Agent: [Li]CCCC
Solvent: CI
Product: Cc1cccc(S(=O)(=O)OC(C)C)c1F

Procedure:
Isopropyl 2-fluorobenzenesulfonate was made from 2-fluorobenzenesulfonyl chloride and treated first with butyl lithium and then with iodomethane in a manner analogous to that set forth above in Example to yield isopropyl 2-fluoro-6-methylbenzenesulfonate (formed as a 2:1 mixture with isopropyl 2-fluoro-3-methylbenzenesulfonate as the minor isomer).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:18])[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[CH:19]1([C:22]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:25]([CH2:35][NH2:36])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCOCC1.C(OC(=O)C)C>[CH:19]1([C:22]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:25]([CH2:35][NH:36][C:15](=[O:17])[CH:14]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12])=[C:2]([F:1])[CH:3]=3)[CH3:18])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1
Reactant: Cc1cccc(-c2nc(C3CC3)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(C3CC3)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.8 %

Procedure:
To a stirred solution of 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (41 mg, 0.148 mmol) and (6-cyclopropyl-2-m-tolylpyridin-3-yl)methanamine (35 mg, 0.148 mmol) in dioxane were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (43 mg, 0.222 mmol), 1-hydroxybenzotriazole (30 mg, 0.222 mmol) and triethylamine (0.05 mL, 0.37 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-((6-cyclopropyl-2-m-tolylpyridin-3-yl)methyl)-2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanamide (example 20) (38 mg) was obtained as 52% yield.