Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[Si:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([N-]C(C)C)(C)C.[Li+].[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>C(OCC)(=O)C>[Si:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[C:16]=1[Cl:30])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(F)c1Cl
Temperature: 0 °C
Yield: 29.5 %

Procedure:
A tetrahydrofuran solution (10 mL) of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluoropyridine (469.1 mg, 1.94 mmol) was mixed with lithium diisopropylamide (1.08 M in tetrahydrofuran, 2.16 mL, 2.33 mmol) under cooling with ice. The reaction mixture was stirred at 0° C. for an hour, then added to hexachloroethane (840.0 mg, 3.50 mmol) and warmed slowly to room temperature for 12 hours with stirring. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 5/1) to give the desired product (157.7 mg, 30% yield).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:7]([O:19][CH3:20])[CH2:6]1)=[O:4].O.[OH-].[Li+]>CO.O>[C:15]([O:14][C:12]([NH:11][C@@H:8]1[CH2:9][CH2:10][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6][C@H:7]1[O:19][CH3:20])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CO[C@@H]1C[C@H](C(=O)O)CC[C@H]1NC(=O)OC(C)(C)C
Yield: 96.3 %

Procedure:
The ester (e) (5.47 g, 19 mmol) and lithium hydroxide monohydrate (0.96 g, 23 mmol) in methanol/water (50 ml/50 ml) were stirred at room temperature for 18 hours then evaporated to dryness. The residue was partitioned between ethyl acetate and water (30 ml) containing sodium dihydrogen phosphate (7 g). The aqueous phase was further extracted with ethyl acetate and the combined extracts washed with brine, dried and evaporated to give a solid (5.0 g, 96%).
Reaction SMILES: [OH:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>>[OH:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[Br:11])=[O:20]
Reactant: Nc1ccc(F)c(F)c1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccccc1Br)Nc1ccc(F)c(F)c1O

Procedure:
The urea was prepared from 2-hydroxy 3,4-difluoro aniline(0.290 g, 2 mmol) and 2-bromophenylisocyanate(0.4 g) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane(0.254 g, 37%). EI-MS m/z 343(M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([SH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[CH:20]1([S:26][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Reactant: SC1CCCCC1
Solvent: C1CCOC1
Product: O=C(Nc1nc2cccc(SC3CCCCC3)n2n1)c1cccnc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.1 %

Procedure:
To a solution of N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 136 mg; 0.5 mmol; 1.0 eq.) in dry THF (10 mL) was added in one pot cyclohexyl mercaptan (58 mg; 0.5 mmol; 1.0 eq.). The reaction mixture was stirred at rt for 14 h. The product precipitated upon addition of water after which filtration and washing with MeOH and Et2O gave the title compound as a white solid (78 mg, 44%). HPLC, Rt: 2.94 min. (purity 94.6%). LC/MS, M+(ESI): 354.1, M−(ESI): 352.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](I)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:13])[CH:3]=1.[C:14]([Cu])#[N:15].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([C:14]#[N:15])[CH:11]=1
Reactant: COC(=O)c1c(F)cc(Cl)cc1I
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)cc(Cl)cc1C#N
Temperature: 110 °C
Yield: 22.3 %

Procedure:
Methyl 4-chloro-2-fluoro-6-iodobenzoate (1.99 g, 10.6 mmol) was dissolved in DMF (12 mL). CuCN (2.84 g, 31.7 mmol) was added and the suspension was heated under microwave at 110° C. for 18 min. EtOAc was added and the suspension was filtered through a piece of filter paper. The filtrate was washed three times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (heptane:EtOAc 1:0 to 9:1) to give the product as a colorless solid (505 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.56 (s, 1H), 7.40 (d, 1H, J=8 Hz), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 161.78 (d, J=58 Hz), 159.44, 139.16 (d, J=11 Hz), 129.96, 121.99, 121.74, 115.48, 114.72, 53.04.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[OH-].[Na+].Cl.Cl[CH:11]([CH3:14])[CH2:12][NH2:13].O>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:14][CH2:11][CH2:12][NH2:13])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CC(Cl)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1CCCN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
A solution of 2-methylimidazole (0.820 g, 10.0 mmol) in DMF (10 mL) was cooled in an ice/water bath and sodium hydroxide (1.00 g, 25.0 mmol) added. The resulting mixture was stirred for 30 min, then 2-chloropropylamine hydrochloride (1.30 g, 10.0 mmol) added in one portion. The resulting suspension was then stirred for 16 h during which time the reaction slowly warmed to room temperature. After this time the mixture was poured into water (500 mL) and the mixture extracted with ether (3×100 mL). The combined ether extracts were dried over sodium bicarbonate, filtered and concentrated under reduced pressure to afford 0.726 g (52% yield) of 3-(2-methylimidazol-1-yl)propylamine as a yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.00 (d, J=1.4 Hz, 1H), 6.79 (d, J=1.4 Hz, 1H), 3.97 (t, J=7.3 Hz, 2H), 2.63 (t, J=7.1 Hz, 2H), 2.35 (s, 3H), 1.87 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]=[C:21]([CH3:24])[NH:22][CH:23]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[N:20]=[C:21]([CH3:24])[N:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: Cc1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)nc1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-[(2-methyl-1H-imidazol-4-yl)carbonyl]piperazine (0.50 g, 1.53 mmol), methyl bromoacetate (0.28 g, 1.84 mmol) and potassium carbonate (0.63 g, 4.6 mmol) in N,N-dimethylformamide (5 mL) was stirred at 50° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate 50:50). The residue was washed with hexane-ethyl acetate and purified by silica gel column chromatography (hexane/ethyl acetate 50:50 to 0/100 then ethyl acetate/methanol 100/0 to 90/10) to give the title compound (0.25 g, 40%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[C:9]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[CH:20][N:21]([CH3:23])[CH3:22]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To 13.2 g of 1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone in 100 mL of DMF was added 23.8 g of N,N-dimethyformamide dimethyl acetal. The mixture was stirred at 75° C. for 16 hours. The solution was then concentrated and used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1nc([C@H](C)N)n2-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2c1nc([C@H](C)Nc1ncnc3[nH]cnc13)n2-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(4-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 3 (100 mg, 0.398 mmol), 6-chloro-9H-purine (68 mg, 0.438 mmol) and DIPEA (83 μL, 0.478 mmol) in n-butanol (1 mL) was stirred in a sealed vial at 100° C. for 20 h. After cooling to RT, the mixture was partitioned between DCM and water. The organic layer was then separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then sonicated in cyclohexane affording 108 as an off-white solid (56 mg, 38%) LCMS: RT 3.17 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.13 (1H, bs), 8.08 (1H, s), 7.96-7.85 (1H, m), 7.67-7.44 (5H, m), 7.12-6.99 (2H, m), 6.86 (1H, d, J=7.80 Hz), 5.49 (1H, br), 2.56 (3H, s), 1.57 (3H, d, J=6.86 Hz)
Reaction SMILES: [F:1][C:2]1([F:12])[C:5]([F:7])([F:6])[CH2:4][C:3]1([CH3:11])[C:8](Cl)=[O:9].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C([Mg]Br)C>ClCCl.[Cl-].[Zn+2].[Cl-]>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:8]([C:3]2([CH3:11])[CH2:4][C:5]([F:7])([F:6])[C:2]2([F:12])[F:1])=[O:9])=[CH:14]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC1(C(=O)Cl)CC(F)(F)C1(F)F
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ccccc23)CC(F)(F)C1(F)F
Yield: 28.6 %

Procedure:
A mixture of 2,2,3,3-tetrafluoro-1-(methyl)-cyclobutanecarbonyl chloride (ABCR, 1.0 g, 4.9 mmol), indole (0.57 g, 4.9 mmol), ethylmagnesium bromide (1.0 M solution in THF, 5.4 ml, 5.4 mmol) and zinc chloride (1.0 M solution in Et2O, 5.4 mL, 5.4 mmol) in 50 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.40 g, 1.4 mmol, 29% yield). MS (DCI/NH3) m/z 286 (M+H)+.
Reaction SMILES: [CH3:1][OH:2].[Cl:3][S:4]([N:7]=[C:8]=[O:9])(=[O:6])=[O:5]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:8](=[O:9])[NH:7][S:4]([Cl:3])(=[O:6])=[O:5]
Reactant: CO
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A solution of methanol (10.2 mL, 252 mmoles) in 15 mL toluene was added dropwise to a solution of chlorosulfonyl isocyanate (22.0 mL, 252 mmoles) in 75 mL toluene at 0° C. The mixture was removed from the cooling bath and stirred for one-half hour at room temperature, then cooled to 0° C. and 65 mL ice cold hexanes was added. The white precipitate was collected by filtration and washed two times with a small amount of cold hexanes and dried in vacuo to give 33.0 g of a white solid, mp 72°-74° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:45][CH2:46][CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:65])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH3:64])[CH:58]=2)=[CH:51][C:50]=1[C:66]1[N:70]([CH3:71])[N:69]=[CH:68][CH:67]=1>ClCCl>[C:1]([NH:4][C@@H:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([NH:45][CH2:46][CH2:47][O:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:65])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH3:64])[CH:58]=2)=[CH:51][C:50]=1[C:66]1[N:70]([CH3:71])[N:69]=[CH:68][CH:67]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CSCC[C@H](NC(C)=O)C(=O)O
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)[C@H](CCSC)NC(C)=O)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
(S)-2-acetamido-4-(methylthio)butanoic acid (17.8 mg, 1.25 eq), triethylamine (20.8 mL, 2.0 eq) and HATU (35.4 mg, 1.25 eq) were dissolved in 3 mL of dichloromethane and stirred at room temperature for 10 minutes. At this time N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30 mg, 74.5 μmol) dissolved in 2.0 mL of dichloromethane was added and the reaction was stirred at room temperature for 3 hr. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 57.3% yield. LCMS m/z (%)=540 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 2.01 (s, 4 H), 2.07 (s, 3 H), 2.38-2.44 (m, 2 H), 3.46-3.65 (m, 2 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 4.03-4.12 (m, 2 H), 4.45-4.53 (m, 1 H), 6.39 (d, J=2.02 Hz, 1 H), 7.02 (d, J=9.60 Hz, 1 H), 7.11 (dt, J=4.80, 2.53 Hz, 1 H), 7.38-7.42 (m, 2 H), 7.43-7.46 (m, 1 H), 7.63-7.71 (m, 2 H), 7.86 (s, 1H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=1[NH:8][NH2:9])#[N:2].Cl>CO.C(OCC)(=O)C>[NH2:2][C:1]1[C:3]2[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=2[NH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)c1cc(C#N)c(NN)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc2c(N)n[nH]c2s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.5 %

Procedure:
A mixture of tert-butyl 4-cyano-5-hydrazinothiophene-2-carboxylate (1.0 g, 4.2 mmol) and hydrochloric acid (0.7 mL of 37% solution) in methyl alcohol (15 mL) was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with an aqueous solution of sodium bicarbonate. Organic layer was separated, dried over anhydrous sodium sulfate, and evaporated to give 0.9 g of the title compound.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[CH:17]=[O:18].[Mn]([O-])(=O)(=O)=[O:20]>O.CC(C)=O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[C:17]([OH:20])=[O:18]
Reactant: O=Cc1c(Br)ccc2c1OCO2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1c(Br)ccc2c1OCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
Potassium permanganate (1.03 g, 6.55 mmol) was dissolved in water (25 mL). 5-Bromo-1,3-benzodioxole-4-carboxaldehyde (0.60 g, 2.62 mmol) was dissolved in acetone (25 mL) and slowly added to the permanganate solution and the reaction mixture was stirred at ambient temperature for 24 h at which time TLC analysis indicated the reaction complete. The reaction mixture was quenched with 5% sodium sulfite (100 mL). Concentrated HCl (10 mL) was added and the mixture turned a pale yellow color. The solution was extracted with ethyl acetate and the organic layers were dried with magnesium sulfate and concentrated by rotary evaporation to afford 0.34 g of product (1.39 mmol, 53% yield) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[CH:4]=[C:3]1[C:14]([OH:16])=O.CCN(CC)CC.[NH2:24][C:25]1[C:26]([O:40][CH3:41])=[C:27]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:28]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:30]=1>>[C:31]([C:29]1[CH:28]=[C:27]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:26]([O:40][CH3:41])=[C:25]([NH:24][C:14]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][C:9]=3[N+:11]([O-:13])=[O:12])=[O:16])[CH:30]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cn1c(C(=O)O)cc2cccc([N+](=O)[O-])c21
Solvent: CCN(CC)CC
Product: COc1c(NC(=O)c2cc3cccc([N+](=O)[O-])c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 12 h
Yield: 86.4 %

Procedure:
A suspension of 1-methyl-7-nitroindole-2-carboxylic acid (220 mg, 1 mmol) in 5 mL of SO2Cl was heated at reflux for 3 h to give a yellow solution. The excess SO2Cl was removed by distillation and the resulting yellow solid was dissolved in 5 mL of dry THF. Et3N (0.21 mL, 1.5 mmol) and N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (327 mg, 1.2 mmol) were added successively and the mixture was stirred 12 h. The reaction mixture was extracted with EtOAc to give 410 mg (87%) of 1-methyl-7-nitroindole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:11]=[N:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:18]3)[CH:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:28])([F:27])[F:29])[CH2:11][NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2ccc(C(N)=O)nc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2ccc(C(N)=O)nc12)C(F)(F)F
Reaction time: 16 h

Procedure:
703 mg (1.47 mmol) of 8-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]quinoline-2-carboxylic acid amide in 10 ml of methanol and 5.0 ml of tetrahydrofuran are mixed with 449 mg (11.8 mmol) of sodium borohydride. After 16 hours, the solvent is concentrated by evaporation, the residue is taken up in water and ethyl acetate, extracted with ethyl acetate, and the combined organic phases are dried on sodium sulfate. After removal of the solvent and purification on silica gel with hexane-ethyl acetate (0–50%) as well as dichloromethane-methanol (0–7%), 358 mg (51% of theory) of the product is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][CH2:11][C:12]([NH:14][CH2:15][C:16](=[O:19])[CH2:17][CH3:18])=O)=[CH:8][N:9]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH2:17]([C:16]1[O:19][C:12]([CH2:11][S:10][C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:8]=2)=[N:14][CH:15]=1)[CH3:18]
Reactant: CCC(=O)CNC(=O)CSc1cnc(NC(C)=O)s1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCc1cnc(CSc2cnc(NC(C)=O)s2)o1
Temperature: 57.5 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of [[2-(acetylamino)-5-thiazolyl]thio]-N-(2-oxobutyl)acetamide (10.5 g, 34.8 mmol) in acetic anhydride (100 mL) was added conc. sulfuric acid (10 mL). The mixture was stirred at 55-60° C. for 2 h and sodium acetate (15 g, 0.18 mol) was added to the mixture. The mixture was concentrated in vacuo. To the residue was added cold water (100 mL). The precipitated solid was collected, washed with water and dried. It was purified by a flash column chromatography (SiO2 ; methylene chloride: MeOH/100:5) to afford N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (4.2 g, 43%) as a solid, mp 147-148° C. 1H NMR (CDCl3) δ12.47 (s, 1 H), 7.29 (s, 1 H), 6.61 (s, 1 H), 3.91 (s, 2 H), 2.64 (q, J=7.6 Hz, 2 H), 2.25 (s, 3 H), 1.21 (t, J=7.6 Hz, 3 H) ppm; MS m/e 284 (M+H)+ ;
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:24])[C@H:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:12][C@@H:13]([C:15]([O:17]CC)=[O:16])[CH3:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(O)=O>CO.[OH-].[Na+]>[CH2:1]([NH:9][C:10](=[O:24])[C@H:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:12][C@@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)NCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@H](N[C@H](C)C(=O)O)C(=O)NCCc1ccccc1
Reaction time: 12 h
Yield: 61.5 %

Procedure:
N[1-(R)-Ethoxycarbonylethyl]-L-Leucine N-phenethylamide (710 mg, 2.1 mM) was dissolved in MeOH (50 ml) and treated with IN NaOH (3 ml, 3 mM) at room temperature. After 12 h, the reaction mixture was acidified with AcOH and evaporated in vacuo to a solid which was washed with H2O and dried to yield the title compound (400 mg); m.p. 201°-205°; (Found: C, 66.44; H, 8.55; N,9.11; C17H26N2O3 requires C,66.64; H,8.55; N,9.14%); νmax (Nujol) 3330, 1660 and 1530 cm-1 ; δ (d6DMSO) 0.825 (6H,t,J=6.2 Hz, (CH3)2CH), 1.15 (3H,d, J=6.8 Hz, CH3CH), 1.29 (2H,m,CH2CH), 1.55 (1H, heptet,J=7 Hz, CH(CH3)2), 2.71 (2H,t,J= 7 Hz, CH2C6H5), 3.0 (1H,q,J=7 Hz, CHCH3), 3.14 (1H,t,J=7 Hz, α-CH), 3.32 (2H,q,J=6 Hz, NHCH2CH2), 7.12 (5H,m,C6H5), 7.5 (2H,br S,OH and CHNHCH) and 8.15 (2H,t,J=5 Hz, NHCH2).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=1[CH3:22])[OH:11])[CH2:2]2.[CH3:23][C:24]1[C:32]2[CH2:31][O:30][C:29](=[O:33])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]1[CH2:36][O:35]1>CS(C)=O.O>[CH:1]12[N:8]([CH2:36][CH:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:29](=[O:33])[O:30][CH2:31][C:32]=4[C:24]=3[CH3:23])[OH:35])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=1[CH3:22])[OH:11])[CH2:2]2
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: Cc1c(C(O)CN2CC3CCC(C2)N3)ccc2c1COC2=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(O)CN2CC3CCC(C2)N3CC(O)c2ccc3c(c2C)COC3=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of isomer (37A) of 5-[2-(3,8-diazabicyclo[3.2.1]oct-3-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one (53 mg, 0.175 mmol) and 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (57 mg, 0.210 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by prep-TLC (MeOH/DCM=1:15) and then separated by SFC chiral chromatography to obtain two separated isomers A and B of 5,5′-[3,8-diazabicyclo[3.2.1]octane-3,8-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one).