Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:16]O[S:18](C1C=CC(C)=CC=1)(=O)=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH2:29]([O:36][C:37]([NH:39][C@@H:40]([CH2:45]OS(C)(=O)=O)[C:41]([O:43][CH3:44])=O)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH:51]1[CH:56]=[CH:55][C:54]([S-:57])=[CH:53][CH:52]=1.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:16][S:57][C:54]1[CH:55]=[CH:56][CH:51]=[CH:52][CH:53]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([CH2:45][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:41]([O:43][CH3:44])=[S:18])=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)[C@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Reactant: [S-]c1ccccc1
Reactant: COC(=O)[C@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Product: COC(=S)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
Recently, Knight and Sibley (D. W. Knight and A. W. Sibley, J. Chem. Soc., Perkin Trans. 1, 1997, 2179-2187) reported that the displacement of N-benzyloxycarbonyl-O-p-toluenesulfonyl serine methyl ester (or methyl (S)-2-benzyloxycarbonylamino-3-methylsulfonyloxypropanoate) with freshly prepared sodium thiophenylate in DMF at about 0° C. afforded the desired N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester (or methyl (R)-2-benzyloxycarbonylamino-3-phenylthiopropanoate) in 98% yield providing a reported optical rotation of [α]20D−17.2 (c, 1.8; MeOH). No enantiomeric ratio of the product was reported. Furthermore, the use of sodium phenolate, prepared from sodium hydride, thiophenol and DMF is not amenable to large scale manufacture.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O.[NH:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCNCC1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-butoxybezenesulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 22 as an off-white solid; 1H NMR (CDCl3) δ 0.98 (t, J=7.38 Hz, 3H), 1.44-1.54 (m, 4H), 1.75-1.84 (m, 4H), 2.54 (t, J=6.24 Hz, 2H), 3.37 (t, J=6.18 Hz, 2H), 4.02 (t, J=6.48 Hz, 2H), 6.99 (dt, J=2.91 Hz, 4.77 Hz, 2H), 7.72(dt, J=2.91 Hz, 4.86 Hz, 2H); MS (ES) m/z 311.9 (MH+); HRMS for C15H21NO4S: 311.1196; Anal. Calcd. for C15H21NO4S: C, 57.86; H, 6.80; N, 4.50. Found: C, 57.69; H, 6.50; N, 4.25.
Reaction SMILES: CO.[CH:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1>[Rh].C(O)(=O)C>[CH:6]1([C@@H:9]([OH:13])[C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)[C@H](O)C1CCCCC1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 200 mL methanol were added 38.0 g of R-(−)-mandelic acid, 2.5 mL acetic acid, and 7.5 g rhodium on carbon (5%, Engelhard 5864). The mixture was sealed in an autoclave, purged with nitrogen, and then filled with hydrogen gas. Hydrogenation was carried out at room temperature for 8 hours at 1400 psi. The reaction mixture was then removed from the autoclave and filtered. The filtrate was concentrated and recrystallized from toluene. The colorless crystals were collected by filtration and dried under vacuum to give 19.8 g of (R)-(−)-2-cyclohexyl-2-hydroxyacetic acid (92.0% yield from 20.7 g R-(−)-mandelic acid). 1H NMR (DMSO-d6): δ (ppm) 3.71 (d, 1H), 1.69-1.52 (m, 6H), 1.16-1.09 (m, 5H). 13C NMR (DMSO-d6): δ (ppm) 175.27, 74.19, 41.15, 28.86, 26.74, 25.84, 25.76, 25.57. IR (KBr): ν (cm−1) 3442, 2935, 2854, 1716, 1452, 1280, 1261, 1232, 1112, 1099. Anal. Calcd. for C8H14O3: C, 60.74; H, 8.92. Found: C, 60.89; H, 8.90. mp 124-126° C. [α]D20=−12.0° (c=1.0, CH3OH).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:14]=[CH:13][N:12]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ncn(Cc3ccccc3)c2-c2ccc(OC)cc2)cc1
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Incremental portions of 1.8 g of sodium hydride (50% strength in white oil) is added to a solution of 10.5 g of 4,5-bis(4-methoxyphenyl)imidazole in 50 ml of absolute dimethylformamide. The mixture is agitated for 30 minutes and then 6.75 g of benzyl bromide in 50 ml of dimethylformamide is added dropwise thereto. After 30 minutes, the mixture is poured on ice water, the product is taken up in ethyl acetate, the organic solution dried over sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from ethanol, thus obtaining 13.89 g of 4,5-bis(4-methoxyphenyl)-1-benzylimidazole, mp 165°-167°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[C:15]1[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[CH:19][CH:20]=1)[C:6]([NH:8][CH2:9][C:10]#[CH:11])=[O:7].[H-].[Na+]>O1CCOCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][C:10]([CH3:11])=[CH:9][N:8]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[N:16]=[N:17][C:18]([N:21]([CH3:32])[CH:22]2[CH2:23][C:24]([CH3:31])([CH3:30])[NH:25][C:26]([CH3:28])([CH3:29])[CH2:27]2)=[CH:19][CH:20]=1
Reactant: C#CCNC(=O)c1ccc(-c2ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ncc(C)o2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-(prop-2-yn-1-yl)benzamide (190 mg, 0.44 mmol) in dioxane (8 mL) was added 60% wt NaH (52 mg, 1.31 mmol). The reaction was refluxed for 5 h, then cooled to RT and diluted in EtOAc and water. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified via HPLC to give 6-(2-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (106 mg). LCMS Rt=0.97 min (condition B); MS (M+1)=436.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.08 (d, J=8.1 Hz, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.72 (dd, J=8.1, 1.5 Hz, 1H), 7.65 (d, J=1.3 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J=9.6 Hz, 1H), 5.20-5.39 (m, 1H), 3.96 (s, 3H), 2.99 (s, 3H), 2.43 (s, 3H), 1.74 (dd, J=12.4, 3.3 Hz, 2H), 1.47-1.59 (m, 2H), 1.43 (s, 6H), 1.31 (s, 6H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC
Temperature: 70 °C
Reaction time: 1 h

Procedure:
9.07 g (51.0 mmol) of N-bromosuccinimide and 120 mg of azobis(isobutyronitrile) were added to a solution of 7.64 g (42.4 mmol) of methyl 4-methyl-2-methoxybenzoate in 140 ml of carbon tetrachloride under a stream of nitrogen, and the resulting mixture was stirred at 70° C. for 1 hour. A further 200 mg of azobis(isobutyronitrile) were then added, making a total addition of 320 mg (1.95 mmol). The reaction mixture was then stirred for 1 hour, after which an aqueous solution of sodium sulfite was added to the mixture to decompose any excess of the reagent. The organic phase was concentrated by evaporation under reduced pressure to one-fourth of its original volume. The concentrate was diluted with ethyl acetate, and the diluted solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, giving 11.26 of crude methyl 4-bromomethyl-2-methoxybenzoate as a residue.
Reaction SMILES: C(OC([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37]C1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Product: CN[C@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Br)c23)C1
Product: Cl

Procedure:
Intermediate 24a was used in the method of Example 39 instead of Intermediate 26 to obtain the title compound as hydrochloride.
Reaction SMILES: CN(C)[CH:3]=[O:4].C1([C@@H](N)C)C=CC=CC=1.[CH2:15]([O:22][C@@H:23]([CH3:27])[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(Cl)(Cl)=O>CO>[CH2:15]([O:22][C@@H:23]([CH3:27])[C:24]([O:4][CH3:3])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](OCc1ccccc1)C(=O)O
Reactant: CN(C)C=O
Agent: C[C@H](N)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](C)OCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Dimethyl formamide (0.5 ml) was added to a mixture of (S)-1-phenylethanamine salt of (S)-2-(benzyloxy)propanoic acid compound of formula-13a obtained in step-c) of above examples-9 &. 10 (200 g) and methanol (600 ml) and the reaction mixture was cooled to 0-5° C. Thionyl chloride (58.4 ml) was slowly added to the reaction mixture at 0-5° C. over a period of 1 hour and stirred for 1 hour at 0-10° C. After completion of the reaction, the reaction mixture was quenched with water and extracted with dichloro methane. Both aqueous and dichloro methane layers were separated, dichloro methane layer was washed with 10% sodium chloride and water. Distilled off the solvent completely from dichloro methane layer to get title compound. Yield: 129 g; Chiral purity: 99.5%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])[CH:4]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:3]=1.[CH3:22]C(C)([O-])C.[K+].CCOC(C)=O>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]1[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)=[O:9])([CH3:12])([CH3:16])[CH3:22]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Oc1ccccc1)N1C=CC(Cl)=CC1C1CCCC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C=CC(Cl)=CC1C1CCCC1
Temperature: -42 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a stirred solution of 4-Chloro-1-(phenoxycarbonyl)-2-cyclopentyl-1,2-dihydropyridine (5.52 g, 17.3 mmol) in 200 ml of THF at −42° C. was added dropwise over 15 minutes a 1.0M solution of potassium t-butoxide (50 mL, 50 mmol). The resulting orange solution was stirred for 1 h at −42° C. The cooling bath was removed, and the reaction mixture was allowed to stir for 20 min while being slowly warmed to room temperature. Water (50 ml) and ether (70 ml) were added and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with cold 1.0 N NaOH (2×35 ml), and brine. The organic phase was dried over MgSO4, filtered through Celite, and concentrated in vacuo to give the crude product. Column chromatography with 5% EtOAc in hexanes afforded 3.71 g (75.7%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ 6.89-6.67 (dd, 1H), 5.58 (br s, 1H), 5.27-5.23 (m, 1H), 4.92-4.62 (m, 1H), 2.21 (m, 1H), 1.892-1.25 (m, 17H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:51]([NH2:59])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:59][CH2:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (75 mg, 0.20 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) at ambient temperature was added phenethylamine (28 μL, 0.22 mmol) and N,N-diisopropylethylamine (105 μL, 0.60 mmol). The resulting yellow solution was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine (5 mL), then dried over sodium sulfate and concentrated to afford ethyl 6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as an off-white solid (89 mg, 93% yield).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]3[C:20]4[CH:26]=[C:25]([C:27]5[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=5)[CH:24]=[N:23][C:21]=4[NH:22][C:18]=3[CH:17]=[N:16][C:15]=2[C:33]#[N:34])[CH2:9]1)=O)(C)(C)C.C([Cl:38])(=O)C>CO>[ClH:38].[CH3:32][N:30]1[CH:31]=[C:27]([C:25]2[CH:24]=[N:23][C:21]3[NH:22][C:18]4[CH:17]=[N:16][C:15]([C:33]#[N:34])=[C:14]([O:13][CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[C:19]=4[C:20]=3[CH:26]=2)[CH:28]=[N:29]1
Reactant: Cn1cc(-c2cnc3[nH]c4cnc(C#N)c(OC5CCN(C(=O)OC(C)(C)C)C5)c4c3c2)cn1
Reactant: CC(=O)Cl
Solvent: CO
Product: Cl
Product: Cn1cc(-c2cnc3[nH]c4cnc(C#N)c(OC5CCNC5)c4c3c2)cn1
Yield: 100 %

Procedure:
3-[6-Cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (28 mg, 0.06 mmol) was treated with a mixture of acetyl chloride and methanol (2:5, 1 mL). After 1 h the mixture was concentrated in vacuo and the resultant residue was triturated with acetonitrile, the solid collected by filtration and dried in vacuo to afford the compound as a yellow solid (25 mg, 100%). 1H NMR (DMSO-D6, 400 MHz): 13.07 (s, 1H), 9.83 (s, 1H), 9.63 (s, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.82 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.45 (s, 1H), 8.11 (d, J=0.8 Hz, 1H), 5.68-5.61 (m, 1H), 3.98-3.88 (m, 5H), 3.62-3.43 (m, 2H), 2.43-2.34 (m, 1H), 2.29-2.17 (m, 1H). LCMS (Method A): RT=4.97 min, M+H+=360.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].[N:34]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:28](=[O:32])[C:29]([NH2:34])=[O:30])=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1
Reactant: c1ccncc1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
To a solution of 150 mg (0.371 mmol) of [[2-(methylthio)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 5 mL of chloroform was added 0.10 mL of oxalyl chloride followed by 0.04 mL of pyridine. The reaction stirred at ambient temperature and was monitored by nmr for conversion to product. Additional oxalyl chloride (0.030 mL) was added after 24 hours. After 48 hours, the reaction was quenched into 4.0 mL of dilute ammonium hydroxide and the product was extracted into 5.0 mL of methylene chloride. The organic phase was washed with water, dried with sodium sulfate and concentrated to 400 mg of yellow solid. The residue was purified by flash chromatography (38 g of silica, ethyl acetate) to provide 109 mg (62%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (300 MHz, dmso-d6) δ1.00 (t, 3H), 2.45 (s, 3H), 2.90 (q, 2H), 3.65 (s, 3H), 4.97 (s, 2H), 5.52 (s, 2H), 7.01 (m, 1H), 7.31 .(m, 3H), 7.60 (s, 1H), 8.02 (s, 1H)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)(=[O:7])=[O:6].CC(C)([O-])C.[K+]>CC(O)(C)C.O>[CH:4]1([S:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCCCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 79 %

Procedure:
To a solution of methyl 4-(3-chloropropylsulfonyl)benzoate (1.89 g, 6.83 mmol) in 2-methylpropan-2-ol (20 mL) was added potassium tert-butoxide (1.53 g, 13.7 mmol) and the slurry heated at 80° C. for 10 min. Additional 2-methylpropan-2-ol (20 mL) was added to facilitate stirring and the heating continued for 25 min. The reaction mixture was diluted with water (100 mL) and washed with ethyl acetate (3×100 mL). The aqueous layer was acidified with 1N HCl and extracted with ethyl acetate (3×100 mL). The combined organics were dried over Na2SO4, filtered and the solvent removed in vacuo to provide 4-cyclopropylsulfonylbenzoic acid (1.22 g, 79%) as a beige solid. ESI-MS m/z calc. 226.0. Found 227.3 (M+1)+; Retention time: 0.86 minutes (3 min run).
Reaction SMILES: C[Li].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)[C:14](O)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCC[CH2:29]1.[OH2:33]>CCOCC>[CH3:29][C:14]([C:13]1[CH:12]=[C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=1)=[O:33]
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: C1CCOC1
Reactant: O
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reaction time: 1.5 h

Procedure:
Over a period of 1.5 hours, methyl lithium (531 ml. of a 2 molar solution, 1.06 M) is added over a nitrogen atmosphere to a rapidly stirring solution of 3,5-dibenzyloxybenzoic acid (175 g., 0.532 M) in ether (250 ml.) tetrahydrofuran (1400 ml.) maintained at 15°-20° C. After stirring an additional 0.75 hour at 10°-15° C., water (600 ml.) is slowly added keeping the reaction temperature below 20° C. The aqueous layer is separated and extracted with ether (3×250 ml.). The organic phases are combined, washed with saturated sodium chloride solution (4×300 ml.), dried over sodium sulfate, and concentrated under vacuum to give an oil which slowly crystallized from isopropyl ether. The crude product is recrystallized from ether-hexane to yield 104.7 g. (59%) of product; m.p. 59°-61° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>CC(C)=O>[CH2:17]([O:16][C:8]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C@H:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)=[O:15])[CH3:18]
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)[C@H]1CCCC(=O)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
Under an atmosphere of argon, 24.0 mg (0.04 mmol, S/C=50) of RuH[(R,R)-Tsdpen] (1,3,5-trimethylbenzene), 194 μL (2.0 mmol) of 2-cyclohexenone, 304 μL (2.0 mmol) of diethyl malonate, and 2 mL of acetone were placed in a 20 mL Schlenk tube and stirred at 30° C. for 48 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 330 mg (64% yield) of the title compound. After this was converted into an ethylene ketal derivative as shown below, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane: 2-propanol=97:3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 77% ee.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].C[O-].[Na+].[Cl:13][CH2:14][C:15]#[N:16]>CO>[Cl:13][CH:14]([S:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[CH:2]=1)[C:15]#[N:16]
Reactant: Sc1cccc(Cl)c1Cl
Reactant: N#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC(Cl)Sc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
15.0 g (83.8 mmol) of 2,3-dichloro-thiophenol are introduced into 50 ml of absolute methanol, 4.5 g (83.8 mmol) of sodium methanolate are added in portions, with cooling, and the mixture is stirred for 15 minutes at room temperature. 6.3 g (83.8 mmol) of chloroacetonitrile are subsequently added dropwise, and the mixture is stirred for 2 hours at room temperature and for a further 5 hours at reflux temperature. The entire batch is then filtered while hot and concentrated in vacuo. 10.8 g (59.1% of theory) of 2,3-dichloro-phenylthioacetonitrile are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[N:29]1([CH2:28][CH2:27][CH2:26][NH:25][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:13]3[C:12]([CH3:24])=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[O:7])[CH:14]=3)=[CH:16][CH:17]=2)=[O:23])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCCn2ccnc2)cc1

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 1-(3-aminopropyl)imidazole (19.5 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum N-(4′-{[(3-imidazol-1-ylpropyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide (44.1 mg, 66%). NMR; δH [2H6]-DMSO 9.92,(1H, s), 8.58,(1H, t), 8.35,(1H, s), 7.92,(2H, d), 7.78,(1H, t), 7.67-7.65,(2H, m), 7.60,(1H, d), 7.44,(2H, d), 7.27,(1H, d), 7.22,(1H, m), 6.98,(1H, m), 6.89,(1H, m), 4.03,(2H, t), 3.26,(2H, q), 2.19,(3H, s), 1.97,(2H, m). LCMS: retention time 2.31 min, MH+429.