Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[F:32][C:33]([F:42])([F:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40].C([O-])([O-])=O.[K+].[K+]>[I-].[Na+]>[C:23]1([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=2)[NH:16][CH:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][O:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]([F:32])([F:41])[F:42])(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCOc4ccccc4C(F)(F)F)CC3)c[nH]c12
Yield: 44.9 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), 2-(trifluoromethyl)phenol (162 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (22.9 mg, 50%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][CH2:46][C:47]([NH:49][CH2:50][C:51]([NH:53][C@H:54]([C:57]([NH:59][C@H:60]([C:65]([O:67]C(C)(C)C)=[O:66])[CH2:61][C:62](=[O:64])[NH2:63])=[O:58])[CH2:55][OH:56])=[O:52])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])[CH3:11])=[O:8].C([O-])(=O)C.Cl.N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)CC(=O)O.N[C@H](C(O)=O)CCC(=O)O.NCC(O)=O.N[C@H](C(O)=O)C>FC(F)(F)C(O)=O.O.C(O)(=O)C>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@@H:10]([C:12]([NH:14][C@H:15]([C:28]([NH:30][C@H:31]([C:34]([NH:36][C@H:37]([C:43]([NH:45][CH2:46][C:47]([NH:49][CH2:50][C:51]([NH:53][C@H:54]([C:57]([NH:59][C@H:60]([C:65]([OH:67])=[O:66])[CH2:61][C:62](=[O:64])[NH2:63])=[O:58])[CH2:55][OH:56])=[O:52])=[O:48])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[NH2:41])=[O:35])[CH2:32][OH:33])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[O:13])[CH3:11])=[O:8]
Reactant: C[C@@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: C[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reaction time: 1 h
Yield: 68 %

Procedure:
In 2 ml of trifluoroacetic acid is dissolved 240 mg of pGlu-(D)-Ala-Lys(Boc)-Ser-Gln-Gly-Gly-Ser-Asn-OBut and the solution is allowed to stand at room temperature for 60 minutes. The trifluoroacetic acid is distilled off and the residue is precipitated with ether and recovered by filtration. The powders thus obtained are dissolved in 30 ml of water and the solution is passed through a column of Amberlite IRA-410 (acetate-form)(2×4 cm). The effluent is combined with washings and lyophilized. The powdery lyophilizate is dissolved in a small amount of 0.1 N-aqueous acetic acid and put onto a column of Sephadex LH-20 (2.5×125 cm), elution being carried out with 0.1 N-aqueous acetic acid. The fractions from 195 ml through 240 ml are pooled and lyophilized, whereupon 150 mg powders of the indicated compound are obtained. Yield 68%; [α]D25 -16.6°(c=0.5, 50% acetic acid); Rf4 (Avicel)=0.20; amino acid analysis (as hydrolyzed with HCl): Lys, 1.18(1); Asp, 1.00(1); Ser, 1.67(2); Glu, 2.03(2); Gly, 2.09(2); Ala, 0.86(1); average recovery 79%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)(=[O:3])[CH3:2].[H-].[Na+].[I-].[K+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28]Br>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:28][C:27]1[CH:30]=[CH:31][C:32]([Cl:33])=[C:25]([O:24][CH3:23])[CH:26]=1)[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2[nH]1
Reactant: COc1cc(CBr)ccc1Cl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1Cc1ccc(Cl)c(OC)c1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 5-acetoxyindole-2-carboxylate (283 mg) in DMF (6 ml) was added sodium hydride (54 mg, 60% dispersion in oil). The mixture was stirred for 30 minutes, a catalytic amount of potassium iodide and a solution of 3-methoxy-4-chlorobenzyl bromide (345 mg) in DMF (2 ml) was added. The mixture was stirred for 2 hours, quenched with water and extracted with ethyl acetate. The organic extracts were dried, evaporated and the resulting gum was purified by column chromatography elutig with 20% ethyl acetate/isohexane to give the desired product as an oil which solidified on standing (310 mg, 63%). NMR (CDCl3): d 1.4 (t, 3H), 2.3 (s, 3H), 3.8 (s, 3H), 4.35 (q, 2H, 5.8 (s, 2H), 6.5 (dd, 1H), 6.7 (d, 1H), 7.05 (dd, 1H), 7.2-7.4 (m, 4H); m/z 402 (M+H+).
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CO[CH:14]=[CH:15][C:16]#[N:17].Cl>CCCCCC.C(OCC)(=O)C.O>[F:8][C:7]([F:10])([F:9])[C:6](=[O:11])[CH:5]=[CH:4][NH:3][CH:14]=[CH:15][C:16]#[N:17]
Reactant: NC=CC(=O)C(F)(F)F
Reactant: COC=CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: N#CC=CNC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.6 g, 15 mmol) was charged and washed with hexane twice. Into this flask, 1,3-dimethyl-2-imidazolydinone (20 ml) was added and a solution prepared by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (2.1 g, 15 mmol) and 3-methoxyacrylonitrile (1.2 g, 15 mmol) in 1,3-dimethyl-2-imidazolydinone (5 ml) was added dropwise under ice-cooling. After stirring the mixture at room temperature for 3 hours, the reaction mixture was poured into water (200 ml). This mixture was acidified with concentrated hydrochloric acid under ice-cooling and then extracted with ethyl acetate. The obtained organic layers were washed with saturated brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/ethyl acetate=3/1 to 2/1) to obtain 2.60 g (yield 92.0%) of a mixture of title compounds (IIa) and (IIb).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:21])=[C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[Br:21][C:13]1[C:10]2[CH2:11][CH2:12][NH:6][CH2:7][CH2:8][C:9]=2[S:15][C:14]=1[CH2:16][C:17]([F:19])([F:18])[F:20]
Reactant: CCOC(=O)N1CCc2sc(CC(F)(F)F)c(Br)c2CC1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Cc1sc2c(c1Br)CCNCC2
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
The product of step (b) (0.18 mmol) was dissolved in CHCl3 (3 mL) and treated with TMSI (1 mmol, 200 uL). After heating for ½ hour at 70° C., another 200 uL of TMSI was added and heating was continued for ½ hour. The reaction was cooled and carefully quenched with 0.5 mL each of EtOH and water. The reaction was diluted with 1M NaOH (3 mL) and the product was extracted into DCM (2×5 mL). The organic extracts were concentrated and the residue was purified by preparative HPLC-MS. 1H NMR (CD3OD) δ 3.75 (q, J=10.5 Hz, 2H), 3.43-3.34 (m, 4H), 3.26 (t, J=5.4 Hz, 2H), 3.16 (t, J=5.4 Hz, 2H), 3.16 (t, J=5.4 Hz, 2H); MS: ESI (positive): 316, 314 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[Cl:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[CH2:38][OH:39].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[N:9][N:10]=3)[N:7]=2)[CH:26]=[CH:25][C:24]=1[CH2:38][OH:39]
Reactant: CC1(C)OB(c2ccc(CO)c(Cl)c2)OC1(C)C
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A suspension of 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (170 mg, 575 μmol), (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (309 mg, 1150 μmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii) dichloromethane adduct (126 mg, 172 μmol), cesium carbonate (749 mg, 2299 μmol) in Dioxane (0.3 mL) and water (0.3 mL) was sparged with argon for 5 min then heated to 100° C. with stirring. 1:30 am. After 90 min, LCMS suggests 95% conversion. Reaction then partitioned between 9:1 CHCl3/IPA (25 mL) and 5% NaHCO3 (15 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). Combined organics dried with MgSO4, concentrated onto dry silica (10 g), and then purified on silica (12 g) eluting with 0>10% 2M NH3 in MeOH/DCM. Resulting solid triturated with methanol (2 mL) and collected by filtration. MS (ESI pos. ion) m/z: 402 (MH+). Calc'd exact mass for C22H16ClN5O: 401.
Reaction SMILES: [OH:1][C@H:2]1[CH2:42][N:5]2[C:6](=[O:41])[C@@H:7]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@H:8]([CH3:32])[CH2:9][CH:10]([CH3:31])[CH2:11][CH2:12][CH:13]=[CH:14][C@@H:15]3[CH2:20][C@@:16]3([C:21](=[O:30])[NH:22][S:23]([C:26]3([CH3:29])[CH2:28][CH2:27]3)(=[O:25])=[O:24])[NH:17][C:18](=[O:19])[C@@H:4]2[CH2:3]1.Cl[C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[CH:47]=[C:46]([N:56]([CH3:58])[CH3:57])[N:45]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH3:57][N:56]([CH3:58])[C:46]1[N:45]=[C:44]([O:1][C@H:2]2[CH2:42][N:5]3[C:6](=[O:41])[C@@H:7]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@H:8]([CH3:32])[CH2:9][CH:10]([CH3:31])[CH2:11][CH2:12][CH:13]=[CH:14][C@@H:15]4[CH2:20][C@@:16]4([C:21](=[O:30])[NH:22][S:23]([C:26]4([CH3:29])[CH2:28][CH2:27]4)(=[O:24])=[O:25])[NH:17][C:18](=[O:19])[C@@H:4]3[CH2:3]2)[C:53]2[C:48]([CH:47]=1)=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2
Reactant: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Reactant: COc1ccc2c(Cl)nc(N(C)C)cc2c1
Agent: CC(C)(C)[O-]
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nc(N(C)C)cc2c1
Solvent: CS(C)=O
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)NS(=O)(=O)C6(C)CC6)C[C@H]5C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)nc(N(C)C)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-hydroxy-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (150 mg, 0.246 mmol),1-chloro-6-methoxy-N,N-dimethylisoquinolin-3-amine (69.8 mg, 0.295 mmol), and potassium tert-butoxide (138 mg, 1.228 mmol) was added DMSO (5 mL) and then the mixture was sonicated for 15 min. The resulting solution was stirred for 4 h at room temperature. The reaction was quenched with water, acidified with 6 N HCl to pH=4, and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4, filtered, and concentrated to give the crude tert-butyl ((2R,6S,7R,13aS,14aR,16aS,Z)-2-((3-(dimethylamino)-6-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate that was used in the next step as is. MS: MS m/z 811.6 (M++1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=1.[CH2:20]([O:22][C:23]([N:25]=[C:26]=S)=[O:24])[CH3:21].C(N=C=NC(C)C)(C)C>C(#N)C.C(N(CC)CC)C>[NH2:19][C:13]1[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=[C:15]2[C:14]=1[N:18]=[C:26]([NH:25][C:23](=[O:24])[O:22][CH2:20][CH3:21])[NH:17]2
Reactant: CCOC(=O)N=C=S
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of the product of example 5, step (c) (10.5 g) in acetonitrile (50 ml) and triethylamine (17 ml) was added to an ice cold stirred solution of ethoxycarbonylisothiocyanate (3 ml) in acetonitrile (50 ml). This mixture was then stirred at room temperature for 20 min. Diisopropylcarbodiimide (4.5 ml) was then added and the reaction mixture was stirred at reflux for 2 hr and allowed to cool. The reaction mixture was evaporated to dryness and purified by flash chromatography on silica gel (ethyl acetate:dichloromethane, 1:1) to yield the sub-titled compound as a yellow solid (3.0 g).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9](Br)[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:7][C:6]=1[C:18]([F:21])([F:20])[F:19])C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.O.[OH-].[Li+]>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:9]2[C:8]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[N:7][C:6]([C:18]([F:19])([F:20])[F:21])=[C:5]([CH:10]=2)[C:4]([OH:22])=[O:3])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid ethyl ester (2 g, 5.05 mmol) was dissolved in ethanol (30 ml). To this solution was added with stirring [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) CH2Cl2 (41.2 mg, 0.05 mmol), 4-chlorophenylboronic acid (828.8 mg, 5.3 mmol), water (4.8 ml) and lithium hydroxide (246.7 mg, 10.1 mmol). This mixture was heated to 70° C. for 2.5 h and cooled to room temperature. Water (12 mL) and lithium hydroxide (370.0 mg, 15.1 mmol) was added and stirred at 70° C. for 0.5 h. The reaction mixture was cooled to room temperature, treated with water (40 ml) and toluene (40 ml) and extracted. The phases were separated, the organic phase extracted with water (30 ml). The combined water phase was acidified with HCl 2N and extracted with ethylacetate. Organic phases were pooled, dried with Na2SO4 and the volatiles removed in vacuo. The residue was dissolved in ethanol (6 ml) and treated with water (12 ml) to give after crystallization the title compound (1.82 g) as light brown crystals; MS (ISN) 398.0 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[C:5]([CH3:13])=[CH:4][C:3]=1[CH:14]([CH3:17])[CH:15]=[CH2:16].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:9]=[CH:10][CH:11]=[CH:12]2)[C:5]([CH3:13])=[CH:4][C:3]=1[CH:14]([CH3:17])[CH:15]=[CH2:16])(=[O:20])[CH3:19]
Reactant: C=CC(C)c1cc(C)c(-n2cccc2)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CC(C)c1cc(C)c(-n2cccc2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A few drops of pyridine are added to a solution of 26.7 g (0.12 mole) of 3-[2-hydroxy-5-methyl-4-(pyrrol-1-yl)-phenyl]-1-butene in 370 ml of acetic anhydride and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto ice and extracted three times with methylene chloride. The methylene chloride phases are washed with dilute sodium bicarbonate solution, then with water, until neutral, are combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Filtration over a little silica gel with methylene chloride yields 3-[2-acetoxy-5-methyl-4-(pyrrol-1-yl)-phenyl]-1-butene, Rf (toluene/ethyl acetate=10:1):0.55.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].O>O1CCCC1.CCCCCC>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Brc1cccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reaction time: 0.5 h

Procedure:
A solution (10 mL) of 2-bromothiophene (1.0 g) in tetrahydrofuran was cooled to −70° C., and a 1.6 mol/L solution (4.2 mL) of n-butyllithium in hexane was added dropwise. After stirring at the same temperature for 30 min, tributyltin chloride (2.1 g) was added dropwise. After further stirring for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual oil (2.4 g) containing the title compound was used for the next step without purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH3:16][C:17]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19]>CCOCC>[OH:19][C:18]1[C:17]([CH3:16])=[C:23]([OH:24])[CH:22]=[CH:21][C:20]=1[CH:14]=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: Cc1c(O)cccc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1c(O)ccc(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Phosphorus oxychloride (80 mL, 0.86 mol) was added to a stirred mixture of N-methylformanilide (102 mL, 0.82 mol) in ether (250 mL). The mixture was stirred for 1 hour at room temperature and then cooled in ice. 2-Methyl resorcinol (Aldrich, 100 g, 0.81 mol) was added and the mixture was allowed to warm to room temperature while stirring overnight. The precipitated intermediate product was collected by filtration and rinsed with ether (3x). The intermediate was hydrolyzed by dissolving in a mixture of acetone (250 mL) and water (250 mL) and stirring for 30 minutes. Water (2 L) was added, the mixture was brought to a boil, and then allowed to cool and deposit crystalline product. This was recrystallized a second time from water (4 L) to afford pure product (70 g, 57%). M.p. 150° C. (Lit. 152-3° C. [W. Baker et al., J. Chem. Soc., 2834-5 (1949)⟧ NMR (DMSO-d6): w 1.973 (s, 3H), 6.551 (d, J=8.5 hz, 1H), 7.428 (d, J-8.5 hz, 1H), 9.703 (s, 1H), 10.745 (s, 1H), and 11.592 (s, 1H).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH2:23]([C:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:36][S:33]([C:30]2([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)(=[O:34])=[O:35])=[O:21])=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)C1(Cc2ccccc2)CC1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)C1(Cc2ccccc2)CC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 1-benzyl-cyclopropanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. MS (M−H) calcd for C22H22FN2O6S: 461.1. Found: 461.2. HRMS (M+H) calcd for C22H24FN2O6S: 463.1339. Found: 463.1331. 1H NMR (500 MHz, CDCl3) 0.95 (m, 2), 1.26 (m, 2), 3.25 (s, 2), 3.85 (s, 3), 4.79 (s, 2), 6.43 (s, 1), 7.06-7.32 (overlapping m, 9). Anal calcd for C22H23FN2O6S: C, 57.13; H, 5.01; N, 6.05. Found: C, 56.06; H, 5.42; N, 6.25.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].N1C=CN=C1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CCOCC>[C:28]([Si:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cccc(I)c1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cccc(I)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 3-iodo-benzyl alcohol (4.68 g, 20 mmol) in CH2Cl2 (40 mL) is added imidazole (1.49 g, 22 mmol) and t-butyldiphenylsilyl chloride (5.74 g, 22 mmol). The resulting mixture is stirred for 1 h diluted with ether washed with water and brine, dried over MgSO4 and concentrated to give the title compound as an oil (9.41 g). MS (EI) 472 (M)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.CC(C)([O-])C.[K+].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@:28]1([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[C@@H:30]([CH3:31])[O:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@:28]([OH:29])([C@H:30]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)[CH3:31])[CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1
Reactant: OC1CCN(c2ncccn2)CC1
Reactant: C[C@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](OC1CCN(c2ncccn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 1-(pyrimidin-2-yl)piperidin-4-ol (19.4 mg, 0.08 mmol) in N,N-dimethylformamide (0.5 mL) was added potassium tert-butoxide (10.7 mg, 0.01 mmol), followed by stirring at room temperature for 2 hrs. The resulting solution was mixed with 1-(((2R,3R)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (20.0 mg, 0.08 mmol) and anhydrous potassium carbonate (13.2 mg, 0.01 mmol) and stirred at room temperature for one hr. The resulting reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous ammonium chloride solution and then with saline to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and concentrated by evaporation at reduced pressure. The concentrate was purified using silica gel chromatography to afford the title compound (yield 21%).