Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:29][OH:30])[N:4]=1.C(N(C(C)C)CC)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][N:12]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[N:4]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOCCOCCN(CCOc1cc(CO)nc(CO)c1)CCC(=O)OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCN(CCOc1cc(COS(C)(=O)=O)nc(COS(C)(=O)=O)c1)CCC(=O)OC
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution of 80 mg of methyl 3-([2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-propanoate in 8 ml of DCM, precooled to −25° C., was added 183 μl of diisopropylethylamine and 57 μl of methanesulfonyl chloride. The mixture was stirred for 1 hour at −15° C. and then washed with 5 ml of water. The aqueous phase was extracted with 5 ml of DCM. The organic phases were combined, dried over MgSO4 and concentrated under reduced pressure. 110 mg of methyl 3-([2-(2,6-bis-methanesulfonyloxymethyl-pyridin-4-yloxy)-ethyl]-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-amino)-propanoate were obtained. LC/MS (B): tr=2.67 min; [M+H]+: m/z 587
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([C@@H:36]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[N:37]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:33]([OH:35])=O)=[C:28]([F:50])[CH:27]=1.Cl.Cl.[CH3:53][C@H:54]1[C:62]2[C:61]([N:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)=[N:60][CH:59]=[N:58][C:57]=2[C@H:56]([OH:69])[CH2:55]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([C@H:36]2[N:37]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[C:38]([CH3:41])([CH3:42])[CH2:39][CH2:40]2)[C:33]([N:66]2[CH2:67][CH2:68][N:63]([C:61]3[C:62]4[C@H:54]([CH3:53])[CH2:55][C@@H:56]([OH:69])[C:57]=4[N:58]=[CH:59][N:60]=3)[CH2:64][CH2:65]2)=[O:35])=[C:28]([F:50])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@H](C(=O)O)c2ccc(Br)cc2F)CCC1(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
HATU (0.149 g, 0.391 mmol) was added to a solution of (R)-2-(4-bromo-2-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.168 g, 0.391 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.1 g, 0.326 mmol; see Example 3, Step 12), and N-ethyl-N-isopropylpropan-2-amine (0.171 mL, 0.977 mmol) in DCM (8 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was then quenched with H2O. The reaction was washed with H2O (3×30 mL). The organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography yielded (S)-tert-butyl 5-((S)-1-(4-bromo-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.0334 g, 0.0517 mmol, 15.9% yield). LCMS (APCI+) 646.4, 648.5 m/z [M+H]+; Retention time=4.25 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.CC1C=CN=C(N)C=1C.C(N(CC)CC)C.C1(=O)[O:50][C:48](=[O:49])[CH2:47]CC1>O1CCCC1>[C:48]([OH:50])(=[O:49])[CH3:47].[CH3:26][O:25][C:24]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19](/[CH:18]=[CH:17]/[C:15]([CH2:14][C:12](/[CH:11]=[CH:10]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)=[O:13])=[O:16])[CH:27]=1
Reactant: O=C1CCCC(=O)O1
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: Cc1ccnc(N)c1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)O

Procedure:
Curcumin (1.00 g) was dissolved in tetrahydrofuran (50 ml) in a 250 mL round bottom flask under a flow of nitrogen gas. Dimethyl amino pyridine (56 mg) and triethyl amine (1.33 ml) were added. The color changed from yellow to light red. Glutaric anhydride (50 ml) was dissolved in 5 mL of tetrahydrofuran and added in drops using a pressure equalizing addition funnel. The mixture was refluxed and stirred over night. The mixture was cooled and concentrated. 50 mL of ethyl acetate was added, cooled with ice, 20 mL of 0.5 N HCl was added. The organic layer was separated and washed with brine. The brine was combined with the HCl wash, and the combined solution was extracted with 25 mL of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered, concentrated under vacuum to get 1.30 g. TLC indicated no curcumin, NMR consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH2:17]1[O:21][C:20]2[CH:22]=[C:23]([CH2:26][C:27](O)=[O:28])[CH:24]=[CH:25][C:19]=2[O:18]1>>[O:18]1[C:19]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:28])=[CH:22][C:20]=2[O:21][CH2:17]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(Cc1ccc2c(c1)OCO2)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 55 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3,4-(methylenedioxy) phenylacetic acid in 55% yield. The product was purified by crystallization from acetonitrile. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=371, 1H NMR (MeOH-d4): 3.61 s (2H), 5.82 s (2H), 6.20 s (1H), 6.66 d, 8 Hz (1H), 6.74 dd, 8.1 Hz (1H), 6.76 d, 1 Hz (1H), 7.03 t, 8 Hz (1H), 7.12 t, 8 Hz (1H), 7.25 t, 8 Hz (1H), 7.33–7.36 m (2H), 7.48 d, 8 Hz (1H), 7.52 d, 8 Hz (1H), 7.99 d, 8 Hz (1H).
Reaction SMILES: O[CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])O)O)=[O:4].[CH2:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>OS(O)(=O)=O>[C:9]([O:18][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:10])[CH2:7][CH2:5][C:3]([CH3:2])=[O:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)CCO
Agent: O=S(=O)(O)O
Product: CC(=O)CCC(=O)OCCC(C)C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
In the third experiment, a mixture of crystalline fructose (10 g) in isoamyl alcohol (40 mL) and concentrated H2SO4 (0.10 mL) was placed in a sealed Teflon-lined reaction vessel inside a high-density rotor for treatment via microwaves in a MicroSYNTH Microwave Labstation. The sample was heated from room temperature to 160° C. in 3.5 min., and kept there for 10 min. using an irradiation power of 1000 Watts. The vessel was cooled. Analysis indicates a 55% molar yield of isoamyl HMF and 16% yield of isoamyl levulinate from fructose.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[OH:17][C@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([N:20]2[CH2:21][CH2:22][C@H:18]([OH:17])[CH2:19]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O[C@H]1CCNC1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O[C@H]1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)phenyl bromide (44.0 g), (S)-3-hydroxypyrrolidine hydrochloride (17.8 g), tris(dibenzylideneacetone)dipalladium(0) (5.88 g), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (8.00 g) and sodium tert-butoxide (36.0 g) in toluene (280 ml) was refluxed with stirring under an argon gas atmosphere for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 20:1-2:1) to give the title compound (12.0 g, yield 28%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:16])[CH2:12]1.C(N(CC)CC)C>O1CCOCC1>[F:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH:11]2[CH2:12][N:13]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([N:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:27]4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)=[O:16])[CH2:14]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: NCC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(CNc2cccc(F)n2)C1
Temperature: 80 °C

Procedure:
Add 2,6-difluoropyridine (55 μL, 70 mg, 0.61 mmol, 2.0 equiv) to a solution of (3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone (134 mg, 0.301 mmol, 1 equiv) and triethylamine (120 μL, 87 mg, 0.86 mmol, 2.9 equiv) in 1,4-dioxane (3 mL) and heat at 80° C. for 16 h. Mass spec shows no desired product. Add more triethylamine (120 μL) and 2,6-difluoropyridine (110 μL). After 32 h at 80° C., LC/MS shows a small amount of desired product. Add more triethylamine (200 μL) and 2,6-difluoropyridine (110 μL). After 38 h, add more triethylamine (200 μL) and 2,6-difluoropyridine (110 μL). After 100 h, transfer the reaction solution to a column of silica gel (80 mm×20 mm dia.) and elute (50-65% EtOAc/hex) to yield 65 mg (40%) of [3-[(6-fluoro-pyridin-2-ylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a white foam. MS (m/e): 541.02 (M+1); 539.17 (M−1).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([OH:13])CO)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>O>[C:1]([NH:8][CH2:9][CH:10]=[O:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(O)CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC=O

Procedure:
3-(Boc-amino)-1,2-propanediol (21g, 110 mmol) was dissolved in water (200 ml) and stirred with potassium m-periodate (25.3g, 110 mmol) at room temperature under argon for 2h. The reaction mixture was filtered and washed with methylene chloride (100 ml). The aqueous layer was extracted with methylene chloride (3×150 ml). The organic extract was washed with brine (SOmI), dried and evaporated to dryness to give a light pink oil. This oil was purified by flash column chromatography using silica gel and CH2Cl2/ethyl acetate as the eluent. Yield was 14g (80%). 1HNMR (CDCl3) d 1.45 (s, 9H, t-Butyl), 4.08 (d, 2H, CH2), 5.24 (bs, 1H, NH) and 9.67 (s, 1H, CHO).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][O:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.CN(C=O)C>CCOC(C)=O>[CH3:17][O:18][CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=2)[CH2:20]1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: COC1CCNC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1CCN(c2nc(C(F)(F)F)ccc2C=CC(=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.2 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0.198 mmol) in 3-methoxy-pyrrolidine (40 mg, 0.396 mmol) was added DMF (1.0 ml). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographed to yield the 3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (59 mg, 98%).
Reaction SMILES: C([O:8][CH2:9][C:10]1([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12][CH2:11]1)C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>CCOCC>[CH:18]1([C:10]2([CH2:9][OH:8])[CH2:15][O:14][C:13]([CH3:16])([CH3:17])[O:12][CH2:11]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC1(C)OCC(COCc2ccccc2)(C2CCCCC2)CO1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)OCC(CO)(C2CCCCC2)CO1

Procedure:
5-Benzyloxymethyl-5-cyclohexyl-2,2-dimethyl-1,3-dioxane (3.0 g.) in dry ether (10 ml.) was added to liquid ammonia (100 ml.) at -70°. Sodium (0.5 g.) was added to the stirred solution. Stirring was maintained at -70°, for one hour. The mixture was then allowed to warm up to -30° and solid ammonium chloride (2.0 g.) was added. The ammonia was removed from the reaction mixture under a current of nitrogen. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. 5-Cyclohexyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane was obtained as a cream solid (2.15 g.) and was used without further purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][CH:10]([CH3:40])[C:11]([O:13][C@@H:14]1[C@@H:18]([CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[O:17][C@@H:16]([N:26]2[C:30]3[N:31]=[C:32]([NH:37][CH:38]=[O:39])[N:33]=[C:34]([O:35][CH3:36])[C:29]=3[CH:28]=[CH:27]2)[CH2:15]1)=[O:12]>C(Cl)Cl>[Cl:1][C:28]1[C:29]2[C:34]([O:35][CH3:36])=[N:33][C:32]([NH:37][CH:38]=[O:39])=[N:31][C:30]=2[N:26]([C@@H:16]2[O:17][C@H:18]([CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[C@@H:14]([O:13][C:11](=[O:12])[CH:10]([CH3:40])[CH3:9])[CH2:15]2)[CH:27]=1
Reactant: COc1nc(NC=O)nc2c1ccn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
N-chlorosuccinimide (87 mg, 0.67 mmol) is added to a solution of compound (18) (300 mg, 0.67 mmol in 5 ml of DMF). After it has been stirred (at room temperature for 20 h), the solution is added to a mixture of CH2Cl2 /5% aq. NaHCO3 (50 ml, 9:1). The organic layer is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2 /acetone, 95:5). The main zone is concentrated, and n-hexane is added to the residue. The precipitated colorless crystals (230 mg, 71%) are isolated. Melting point: 119-120° C. 1H-NMR ([D6 ] DMSO): δ=1.09 (d, J=7.0, CH3), 1.15 (d, J=6.9, CH3), 2.45, 2.60, 2.63, 2.89 (4m, CH and Hα,β --C(2')), 4.06 (s, OCH3), 4.18 (m, H--C(5')), 4.28 (m, H--C(4')), 5.35 (m, H--C(3')), 6.47 (m, H--C(1')), 7.58 (s, H--C(6)), 9.45 (d, J=8.9, NH), 10.84 (d, J=9.6, HCO). Anal. calculated for C21H27CIN4O7 (482.9): C, 52.23, H, 5.64, N, 11.60; found: C, 52.51, H, 5.69, N, 11.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH3:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C.CO.C(OCC)(=O)C>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@:10]([CH2:13][CH2:14][N:49]2[CH2:50][CH2:51][CH:46]([NH:45][C:37]3[N:36]([CH3:35])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:47][CH2:48]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: Cn1c(NC2CCNCC2)nc2ccccc21
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(Nc4nc5ccccc5n4C)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 48 h

Procedure:
Combine (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.34 g, 0.63 mmol) and (1-methyl-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.24 g, 1.0 mmol), and N,N-diisopropylethylamine (0.26 mL, 2.4 mmol) in acetonitrile (25 mL). Heat to reflux. After 2 days, cool and dilute the reaction mixture with ethyl acetate. Extract twice with 1/1 brine/water, saturated aqueous sodium bicarbonate, and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting sequentially with ethyl acetate and then 50% methanol/ethyl acetate to give a residue. Partition the residue between ethyl acetate and water. Separate the layers and extract the organic layer with water. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.24 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[CH:11][C:10]=1[CH:25]=[O:26]
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(-n2cnnn2)ccc1O
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 4-tetrazol-1-yl-phenol (0.01 mol) in trifluoroacetic acid (20 ml) and hexamethylenetetramine (0.04 mol) was heated at 70° for 18 h, cooled to room temperature and quenched with 2N solution of sulfuric acid (50 ml). The mixture was extracted with ethyl acetate (3×100 ml), dried (MgSO4), filtered and concentrated to give a residue which was purified by FCC (dichloromethane/methanol (9:1)) to afford the title compound in 30% yield.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]=1[F:1])=[O:16]
Reactant: Nc1ccc(S(N)(=O)=O)cc1F
Reactant: O=C(Cl)CCl
Product: NS(=O)(=O)c1ccc(NC(=O)CCl)c(F)c1
Temperature: 0 °C

Procedure:
2-Fluoro-4-sulphamoyl-aniline (7.6g) and α-chloroacetyl chloride (12.0g) were refluxed together for 60 min. The reaction product was ground in a mortar with ice/water and filtered (8.3g). Recrystallisation from ethyl acetate to give beige needles m.p. 185°-187°
Reaction SMILES: [O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][CH2:15][CH2:14][NH:13][C:12]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([O:23]CC)=[O:22].Cl>>[O:1]=[C:2]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][CH2:15][CH2:14][NH:13][C:12]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)CN1CCCC(CCc2ccc3c(n2)NCCC3)C1=O
Agent: Cl
Product: O=C(O)CN1CCCC(CCc2ccc3c(n2)NCCC3)C1=O

Procedure:
A solution of 1-7 (71 mg, 0.21 mmol) and 6N HCl (15 mL) was stirred at 55° C. for 2 h, followed by concentration to give 1-8 as a pale yellow gum. TLC Rf =0.09 (silica, 20% CH3OH/EtOAc)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)=[CH:22][C:21]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)C>O1CCCC1>[Cl:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10][OH:9])[CH2:17][CH2:16]2)=[N:19][CH:20]=[C:21]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:22]=1)=[O:33]
Reactant: CCOC(=O)CC1CCN(c2ncc(S(C)(=O)=O)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cnc(N2CCC(CCO)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred mixture of 0.202 g (5.32 mmol) of lithium aluminum hydride in dry tetrahydrofuran (2 mL), cooled to 0° C., is added 1.70 g (3.54 mmol) of [3′-(3-chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a solution in tetrahydrofuran (6 mL). The mixture is warmed to room temperature and stirred for 1 hour then cooled in an ice bath. Excess reactants are consumed by the dropwise addition of water (0.2 mL) followed by a 15% NaOH solution (0.2 mL) and additional water (0.4 mL). The mixture is stirred at room temperature for 30 minutes then filtered through a pad of diatomaceous earth. The filter pad is washed with tetrahydrofuran and the combined filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on neutral alumina to yield 1.3 g (86%) of 3-chloro-N-[4-(2-hydroxy-ethyl)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8](=[C:16]2[CH2:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]([CH3:24])([CH3:25])[CH2:17]2)[C:5]2[CH:6]=[CH:7][C:2]([C:31]3[C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccccc1B(O)O
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccccc1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 160 °C
Yield: 67.5 %

Procedure:
A sealed tube containing 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.30 g, 0.75 mmol), (2-methoxycarbonylphenyl)boronic acid (0.29 g, 1.50 mmol), Pd(PPh3)4 (87 mg, 0.08 mmol), 2 M Na2CO3 (4 mL) and DME (4 mL) was heated at 160° C. for 25 minutes. Cooled to room temperature, the mixture was extracted with EtOAc. The EtOAc extracts were combined and washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc in hexanes to give 0.23 g (68%) of the title compound (248) as off-white solid. mp 177-178° C. 1H NMR (400 MHz, CDCl3): δ 0.96 (s, 6H), 0.97 (s, 6H), 1.32 (s, 2H), 2.03 (s, 4H), 3.57 (s, 3H), 4.60 (s, 1H), 6.78 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 7.15-7.25 (m, 4H), 7.36-7.44 (m, 2H), 7.48-7.56 (m, 1H), 7.76-7.82 (m, 1H). LCMS (ESI): m/z 455 (M+H)+, 453 (M−H)−.