Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:24]([Mg]Br)[CH3:25].[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[CH2:1]([C@H:8]1[O:12][C:11]([CH3:13])([CH3:14])[O:10][C@@H:9]1[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[CH2:24][CH3:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC[Mg]Br
Reactant: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C(O)CC)cc1
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 4-(((4R,5R)-5-heptyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)benzaldehyde (N) (16 mg, 0.05 mmol) in THF (0.2 mL) at 0° C. was added ethylmagnesium bromide (20 μL, 3M in THF) dropwise. After one hour, the reaction mixture was heated to refluxing temperature for an additional hour until TLC indicated completion of the reaction. Upon completion, saturated aqueous NH4Cl was added, and the mixture extracted with ether. The collected organic layers were washed with brine, dried with MgSO4, filtered and concentrated. Preparative thin layer chromatography (25% EtOAc/Hex, 250 μm, silica) yielded the title compound (6 mg, 0.017 mmol, 35%). 1H NMR (CDCl3, 300 MHz) δ 7.27 (2H, d, J=7.2 Hz), 7.21 (2H, d, J=8.1 Hz), 4.58 (1H, t, J=6.6 Hz), 3.88-3.81 (1H, m), 3.71-3.65 (1H, m), 2.92 (1H, dd, J=0.02, 18.6 Hz), 2.82 (1H, dd, J=0.02, 18.6 Hz), 1.86-1.68 (2H, m), 1.51-1.29 (12H, m), 1.37 (3H, s), 1.35 (3H, s), 0.92-0.85 (6H, m); HRMS (FAB+) calcd for C22H35O3 [M−H]: 347.2586; found 347.2575, C22H35O3.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:35][C:36]([CH2:38]Cl)=[CH2:37]>CN(C=O)C.C(Cl)Cl>[Cl:35][C:36](=[CH2:37])[CH2:38][O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:16](=[O:25])[C:17]4=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]4[C:19]3=[O:20])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)c(=O)oc2c(C)c(O)ccc12
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=C(Cl)COc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 25 °C

Procedure:
A slurry of 7-hydroxy-4,8-dimethyl-3-phthalimidomethylcoumarin (649 mg, 1.86 mmol), potassium carbonate (320 mg, 2.60 mmol), potassium iodide (15 mg, 0.093 mmol), and 2,3-dichloro-1-propene (0.20 mL, 2.23 mmol) in DMF (15 mL) was stirred at 55-65° C. for 8 hours, allowed to cool to room temperature, then chilled in an ice water bath. The solid was filtered off to obtain the first crop of crude product (1.09 g). Half of the solvent was removed from the filtrate and after chilling, a second crop of crystals was obtained (33 mg). The solids were combined, dissolved in CH2Cl2, and washed with water several times. The organic layer was dried and evaporated to give 7-(beta-chloroallyloxy)-4,8-dimethyl-3-phthalimidomethylcoumarin, a white solid (690 mg, 87%). 1H NMR (CDCl3): δ 7.66-7.83 (m, 4H), 7.49 (d, J=9.1 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 5.56 (s, 1H), 5.47 (s, 1H), 4.91 (s, 2H), 4.67 (s, 2H), 2.59 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[I-].[K+].[CH3:12][CH:13]([CH3:16])[CH2:14]O.ClCCl>O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][CH2:12][CH:13]([CH3:16])[CH3:14]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)CO
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)CNc1c(F)cccc1F
Temperature: 190 °C
Yield: 14.4 %

Procedure:
2,6-difluoroaniline (387 mg, 3 mmol), potassium iodide (996 mg, 6.00 mmol) and [Cp*IrCl2]2 (33.1 mg, 0.030 mmol) were dissolved in 2-methyl-1-propanol (3 mL, 32.4 mmol). The resulting mixture was heated by microwaves to 190° C. for 8 hours. To the reaction mixture was added dichloromethane (10 mL) and water (10 mL) and the organic phase separated (hydrophobic frit). Diethyl ether was added and the solution filtered through a silica cartridge (10 g) eluting with further diethyl ether. The filtrate was evaporated in vacuo, then purified by flash silica (Si) chromatography (using a 0-100% dichloromethane-cyclohexane gradient). The appropriate fractions were combined and concentrated to give the title product (80 mg) as a colourless oil. LCMS (M+1) 186, RT 1.26 mins.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][OH:7])[CH3:2].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH3:2]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCOCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-ethoxy-1-propanol (940 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1([C:11]([OH:13])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]1.[CH3:14]O>>[CH3:5][C:6]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]1
Reactant: CO
Reactant: CC1(C(=O)O)CCCO1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(C)CCCO1
Yield: 93 %

Procedure:
Thionyl chloride (0.15 mL, 2.1 mmol) is added dropwise at 0° C. to a solution of 2-methyltetrahydro-2-furancarboxylic acid (250 mg, 1.9 mmol) in methanol (2.0 mL). After bringing the reaction mixture to room temperature, it is heated under reflux for 1 h. The solvent is removed under reduced pressure, the crude is dissolved in DCM and filtered through a pad of silica. Removal of the solvent under reduced pressure affords 276.0 mg of methyl 2-methyltetrahydro-2-furancarboxylate that is used in the next step without further purification. Yield: 93%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (3H, s), 1.78-1.85 (1H, m), 1.91-1.99 (2H, m), 2.30-2.37 (1H, m), 3.75 (3H, s), 3.92-4.02 (2H, m).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[CH:55]=3)[OH:53])[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([O:66][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:74])[CH3:2].N1C=CC=CC=1.F>O1CCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[CH:55]=3)[OH:53])[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([OH:66])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4cccc(OC)c4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: *CC(*)C
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4cccc(OC)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-(3""-methyoxyphenyl)-2'"-hydroxyethyloxy-)3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetrone (29 mg in 0.6 mL tetrahydrofuran contained in a polypropylene vial) was added 80 μL of a solution of hydrogen fluoride-pyridine complex (40% in (2:1) tetrahydrofuran:pyridine) and the mixture stirred at room temperature. After 48 hours, the reaction was quenched by the careful addition of saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics were dried by passage through a magnesium sulfate plug, concentrated in vacuo and purified by flash chromatography (ethyl acetate:hexane (1:1)+1% methanol) to give the title compound (9.5 mg).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>>[CH2:21]([N:28]1[CH2:2][CH:3]2[CH:5]([C:4]2([CH3:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:6]1=[O:8])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CN(Cc3ccccc3)C(=O)C21
Yield: 55.4 %

Procedure:
A solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 10 g, 33.6 mmol) in benzylamine (21.6 g, 201.6 mmol) was heated to 160° C. for 16 h. The mixture was cooled, 2N hydrochloric acid was added (200 ml), and the mixture was extracted with dichloromethane (3×250 ml). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (600 g) column chromatography eluting with dichloromethane, then a gradient of dichloromethane:ethyl acetate ending with pure ethyl acetate. Appropriate fractions were combined and concentrated in vacuo to give the title compound as an amber oil (6 g, 55%).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C[N+]1C=CN([S:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])C=1.[CH:25]1([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([C:43](=[O:45])[CH3:44])[CH2:39][CH2:38]3)=[CH:33][C:32]=2[F:46])[CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:43]([N:40]1[CH2:39][CH2:38][N:37]([C:34]2[CH:35]=[CH:36][C:31]([CH2:30][N:29]([CH:25]3[CH2:26][CH2:27][CH2:28]3)[S:15](=[O:17])(=[O:16])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:32]([F:46])[CH:33]=2)[CH2:42][CH2:41]1)(=[O:45])[CH3:44]
Reactant: C[n+]1ccn(S(=O)(=O)Oc2ccccc2)c1
Reactant: CC(=O)N1CCN(c2ccc(CNC3CCC3)c(F)c2)CC1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(CN(C3CCC3)S(=O)(=O)Oc3ccccc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
To a solution of 3-methyl-1-(phenoxysulfonyl)-1H-imidazol-3-ium triflate (143 mg, 0.6 mmol) and 1-(4-(4-((cyclobutylamino)methyl)-3-fluorophenyl)piperazin-1-yl)ethanone (150 mg, 0.49 mmol) in DCM (20 mL) was added diisopropylethylamine (1 mL). The mixture was stirred at ambient temperature for 16 h. After the solvent was removed, the residue was purified by prep-HPLC to provide the title compound (67.3 mg, 29.6%). 1H NMR (400 MHz, DMSO-d6) δ 7.44-7.40 (m, 2 H), 7.34-7.24 (m, 4 H), 6.79-6.67 (m, 2 H), 4.46 (s, 2 H), 4.20-4.17 (m, 1 H), 3.73-3.66 (m, 4 H), 3.26-3.17 (m, 4 H), 2.19-2.15 (m, 2 H), 2.14 (s, 3 H), 2.03-1.98 (m, 2 H), 1.62-1.52 (m, 2 H). LCMS (ESI): m/z 483.9 [M+Na+].
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C@H:16]2[C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H][H]>CO.C1COCC1.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:5])=[C:8]([C@H:16]2[C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C1CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)C1CC1
Yield: 102.8 %

Procedure:
To 76F (1.6 g) in methanol (40 mL) and THF (20 mL) was added 10% Pd/C (500 mg). The mixture was hydrogenated with a hydrogen balloon for 2.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 76H (1.54 g, 95% yield). 1H NMR (400 MHz, DMSO-d6, 100° C.) δ ppm 0.86-0.97 (m, 2H) 0.98-1.06 (m, 3H) 1.13-1.24 (m, 4H) 1.30 (s, 9H) 1.98 (dd, J=12.09, 8.24 Hz, 1H) 2.16 (d, J=11.54 Hz, 1H) 2.68 (s, 1H) 2.83 (d, J=7.15 Hz, 1H) 3.42 (d, J=7.15 Hz, 1H) 3.61-3.71 (m, 1H) 4.11 (q, J=7.15 Hz, 2H) 5.74 (s, 1H) 6.50-6.57 (m, 2H) 7.47 (d, J=9.34 Hz, 1H), LC-MS 439 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:17]2[CH:16]=[N:15][C:10]3[NH:11][CH2:12][C:13](=[O:14])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]=3[CH:18]=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Product: CC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 20 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (35 mg)was reacted with 4-acetylphenyl boronic acid as in General Procedure 4B to give the title compound as a yellow solid (20% yield). M.p.=200° C., LCMS: m/z=358.24 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.61 (3H, s), 4.36 (2H, s), 5.22 (2H, s), 7.21 (1H, d, J=2.0 Hz), 7.28 (4H, m), 7.37 (4H, m), 7.96 (2H, d, J=8.3 Hz), 8.01 (1H, d, J=1.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH:25]3[CH2:27]O3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:10][C:9]=1[O:28][CH2:29][O:30][CH3:31])([CH3:4])([CH3:3])[CH3:2].NC(N)=[S:35]>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH2:24][CH:25]3[CH2:27][S:35]3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:10][C:9]=1[O:28][CH2:29][O:30][CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1cc(Oc2ccc(S(=O)(=O)CC3CO3)cc2)ccc1NC(=O)OC(C)(C)C
Reactant: NC(N)=S
Solvent: CO
Solvent: ClCCl
Product: COCOc1cc(Oc2ccc(S(=O)(=O)CC3CS3)cc2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
To a solution of 20 (0.40 g, 0.86 mmol) in CH2Cl2 (5 mL) was added a mixture of thiourea (0.10 g, 1.3 mmol, 99%) in methanol (5 mL). The resulting mixture was stirred for 24 h at room temperature, after which the solvent was removed under reduced pressure. The residue was partitioned between CH2Cl2 and water. The organic layer was dried over anhydrous Na2SO4 and was filtered. Evaporation of solvent and purification by silica gel chromatography (hexanes/EtOAc=4/1) gave 0.34 g of 21 (83%). 1H NMR (500 MHz, CDCl3) δ 1.53 (s, 9H), 2.14 (dd, J=1.8, 5.0 Hz, 1H), 2.52 (dd, J=1.5, 5.9 Hz, 1H), 3.04 (dq, J=5.6, 7.8 Hz, 1H), 3.15 (dd, J=8.0, 14.2 Hz, 1H), 3.47 (s, 3H), 3.51 (dd, J=5.6, 14.4 Hz, 1H), 5.19 (s, 2H), 6.72 (dd, J=2.6, 8.8 Hz, 1H), 6.91 (d, J=2.6 Hz, 1H), 7.08-7.01 (m, 3H), 7.85-7.80 (m, 2H), 8.16-8.08 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 24.4, 26.2, 28.5, 56.6, 62.7, 80.8, 95.3, 107.3, 114.1, 117.3, 119.4, 126.2, 130.8, 131.6, 146.6, 149.3, 152.8, 163.5. HRMS (FAB) calcd for C22H28NO7S2 (M+H+) 482.1302. found 482.1301.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH:15]=[N:16][C:12]([CH3:11])=[N:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ncn(-c2ccc(Cl)cc2C=O)n1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
In a 25 ml RBF, a mixture of 5-chloro-2-fluorobenzaldehyde (505 mg, 3.09 mmol), 3-methyl-1H-1,2,4-triazole (270 mg, 3.09 mmol), Cs2CO3 (1007 mg, 3.09 mmol) in DMSO (6179 μl) was heated at 45° C. for 4 hrs and stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water. The combined organic phase was washed with brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography to yield 74A as white solid product (140 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.95 (s, 1H), 9.02 (s, 1H), 7.96-7.88 (m, 2H), 7.80 (d, J=8.4 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:18])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9]1.Cl[CH2:20][C:21]([CH2:23]Cl)=[CH2:22]>O1CCOCC1>[CH3:7][CH:8]1[C:16]2[CH:15]=[C:14]3[O:17][CH2:22][C:21](=[CH2:20])[CH2:23][O:18][C:13]3=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: C=C(CCl)CCl
Reactant: CC1CCc2cc(O)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C1COc2cc3c(cc2OC1)C(C)CC3
Yield: 36.4 %

Procedure:
A suspension of 25.7 g (186 mmol) of potassium carbonate were heated to reflux with stirring. At this temperature, over the course of 5 h, a mixture of 15.3 g (93.2 mmol) of 1-methylindane-5,6-diol and 11.6 g (92.8 mmol) of 3-chloro-2-chloromethylprop-1-ene dissolved in 50 ml of dioxane was added dropwise. When addition was complete, the mixture was stirred for a further 1 h under reflux and the inorganic solids precipitated out were filtered off with suction after cooling the reaction mixture. The solids were washed with acetone and the combined organic phases freed from solvent on a rotary evaporator. After flash chromatography (pentane/ether, 19:1, Rf=0.66) on silica gel, 7.3 g (36%) of 1-methyl-7-methylene-2,3,7,8-tetrahydro-1H,6H-5,9-dioxacyclohepta[f]indene were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29]>CO>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][CH:10]=[CH:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:14][CH:15]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Cc1ccc(-c2ncco2)cc1-c1ccc(N)cc1
Solvent: CO
Product: Cc1ccc(-c2ncco2)cc1-c1ccc(NS(=O)(=O)c2c(F)cccc2F)cc1
Temperature: 80 °C
Yield: 54.7 %

Procedure:
To a solution of 2′-Methyl-5′-oxazol-2-yl-biphenyl-4-ylamine (c) (30 mg, 0.12 mmol) in MeOH (2 mL) was added 2,6-difluorobenzene sulfonyl chloride (30 μL, 0.22 mmol). The reaction was heated to 80° C. for 2 hr before the solvent was removed. Column chromatography afforded Compound 1 (28 mg, 55%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[C:26]1([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([S:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]([N:4]4[CH2:5][CH:2]([O:1][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])[CH2:3]4)=[O:7])=[CH:13][CH:12]=3)(=[O:16])=[O:15])[CH:18]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)OC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Reaction time: 15 h
Yield: 74 %

Procedure:
Combine (3-Hydroxy-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone (95 mg, 0.219 mmol), triethylamine (0.200 mL, 1.43 mmol, excess) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in dichloromethane (1.0 mL) and treat with N,N-dimethylcarbamoyl chloride (0.050 mL) at room temperature. Stir for 15 h, load directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to yield 82 mg of Dimethyl-carbamic acid 1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl ester as a white foam (74%). LRMS: MH+ 503.97.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:9]([CH2:12][S:13]([N:16]2[CH2:21]C[CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Na+].BrC1C=CC(CS([O-])(=O)=[O:34])=C(C(OC)=O)C=1OC.N1CCC(O)C1>>[Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:9]([CH2:12][S:13]([N:16]2[CH2:17][CH2:18][CH:19]([OH:34])[CH2:21]2)(=[O:14])=[O:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCCCC2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)[O-])ccc(Br)c1OC
Agent: OC1CCNC1
Agent: [Na+]
Product: COC(=O)c1c(CS(=O)(=O)N2CCC(O)C2)ccc(Br)c1OC

Procedure:
Prepared as a colourless oil by proceeding in a similar manner to Intermediate 147, starting from methyl (4-bromo-3-methoxy-2-methoxycarbonylphenyl)methanesulphonic acid sodium salt (Intermediate 148, 0.134 g) and 3-pyrrolidinol (0.12 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:12]([NH:22][CH2:23][CH2:24][C:25](O)=[O:26])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N=C=NCCCN(C)C)C.CCN(CC)CC>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:25](=[O:26])[CH2:24][CH2:23][NH:22][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: COC(=O)CCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)CCNC(=O)OCc1ccccc1
Yield: 91.3 %

Procedure:
The compound 35 was prepared using General Procedure B with 6-aminohexanoic acid methyl ester hydrochloride salt (3.0 g, 16.5 mmol), N-Cbz-β-alanine (3.68 g, 16.5 mmol), 1-hydrobenzotriazole (HOBt) (2.68 g, 19.8 mmol), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDC) (3.80 g, 19.8 mmol) and Et3N (5.52 mL, 39.6 mmol) in CH2Cl2, (100 mL). Recrystallization of the crude product from a mixture of MeOH and H2O (10:1 ratio) afforded 5.28 g (91%) of the desired product (35) as a white solid. 1H NMR (CDCl3): 7.32 (m, 5H, ArH), 5.82 (s, 1H, NH), 5.54 (s, 1H, NH), 5.07 (s, 2H, OCH2Ar), 3.64 (s, 3H, OCH3), 3.45 (dt, J=6.1, 12.0 Hz, 2H, CH2NHCO), 3.21 (dt, J=6.4, 12.8 Hz, 2H, CH2NHCO), 2.38 (dt, J=6.1, 6.8 Hz, 2H, CH2CO), 2.29 (t, J=7.2 Hz, 2H, CH2CO), 1.61 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.33 (m, 2H, CH2).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].O.O.[F-].[K+].[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:8][C:7]1[NH:6][C:5](=[O:9])[NH:4][C:3](=[O:10])[C:2]=1[N:25]1[CH2:26][CH2:27][N:22]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:23][CH2:24]1
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Product: Cc1[nH]c(=O)[nH]c(=O)c1N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
A mixture of 20.5 g (0.10 mole) of 5-bromo-6-methyl-2,4(1H,3H)pyrimidinedione and 10.3 g (0.11 mole) of potassium fluoride dihydrate in 130 ml of 1-benzylpiperazine was heated under reflux for 72 hours. The reaction mixture was then cooled and poured into 800 ml of ice water. The solid which formed was collected and washed with water to give 8.10 g of the product as an off-white solid. A 1.0 g portion of the crude product was recrystallized from methanol to give an off-white solid, mp 263° C.