Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[C:5]([OH:25])[CH:4]=1.N1C=CC=CC=1.[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[S:33]([O:25][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[C:19]2[C:6]=1[C@@:7]1([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]1)(=[O:34])=[O:32]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(O)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(OS(=O)(=O)C(F)(F)F)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 29) (0.61 g, 1.69 mmol) in CH2Cl2 (40 mL), pyridine (0.20 g, 2.54 mmol) was added and the mixture was cooled to 0° C. Tf2O (0.62 g, 2.20 mmol) was added dropwise to the reaction mixture and stirred for 1.5 h. The reaction was diluted with CH2Cl2 and washed with water (2×40 mL). The organic layer was separated, dried (Na2SO4) and concentrated giving (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl trifluoromethanesulfonate (Compound No. 32) (0.825 g, 98%) as a yellow foam. 1H NMR (CDCl3): δ 6.58 (d, 2H), 3.75 (s, 3H), 2.90 (m, 3H), 1.80-1.40 (m, 8H), 1.38 (s, 3H), 1.25-1.00 (m, 2H), 0.95 (s, 3H), 0.90 (m, 1H), 0.85 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:24]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[CH:7][CH:8]=1
Reactant: CO
Reactant: COc1ccc(-c2oncc2CCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(OC)cc1
Yield: 95 %

Procedure:
A mixture of 3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionic acid (2.75 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-methoxyphenyl)-4-isoxazolyl]propionate (2.76 g, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.58–2.70 (2H, m), 2.92–3.04 (2H, m), 3.68 (3H, s), 3.87 (3H, s), 6.96–7.06 (2H, m), 7.59–7.69 (2H, m), 8.18 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:30])[C:12]3[S:19][C:18]([CH2:20]O)=[C:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:46])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:30])[C:12]3[S:19][C:18]([CH2:20][Cl:46])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)c(COCC[Si](C)(C)C)c21
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)c(COCC[Si](C)(C)C)c21
Reaction time: 18 h

Procedure:
To a cold (0° C.), stirred solution of 426 mg of N-(4-chlorobenzyl)-2-(hydroxymethyl)-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 0.46 mL of 2,4,6-collidine in 4 mL of dry DMF is added 0.17 mL of methanesulfonyl chloride. The ice bath is removed and the mixture is allowed to stir for 18 h, then is diluted slowly with water to a volume of 25 mL. The resulting solid is filtered, washed well with water, and dried in vacuo to furnish 429 mg of the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13].[OH2:17]>CN(C=O)C>[S:12](=[O:15])(=[O:17])([OH:14])[NH2:13].[CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NS(=O)(=O)Cl
Reactant: O
Reactant: CC1(CO)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCCCC1
Product: NS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a cold solution (-4° C.) of (1-methylcyclohexyl)methanol (6.2 g, 0.048 mol) in DMF (90 ml) was added 50% oily sodium hydride (2.81 g, 0.059 mol as NaH). After stirring for 1 hr, sulfamoyl chloride (7.82 g, 0.062 mol) was added and the stirring was continued for an additional 30 min at -4° C. The reaction mixture was poured into cold water and extracted with toluene. The organic layer was dried (Na2SO4) and the solvents were removed under vacuum to give a syrup which crystallized upon cooling. Recrystallization from chloroform/hexane gave pure (1-methylcyclohexyl)methane sulfamate, mp 40°-42° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(N(CC)CC)C.Cl.Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH:35]4[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]4)[CH2:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.O>CN(C=O)C>[CH3:1][NH:2][C:3]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C@@H:30]3[CH:35]4[CH2:34][CH2:33][N:32]([CH2:37][CH2:36]4)[CH2:31]3)=[O:29])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:4]
Reactant: CN=C=O
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reaction time: 18 h

Procedure:
17.4 mg (0.30 mmol) of methyl isocyanate and 84.8 μl (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. 47 mg (73.5% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Br)[CH:3]=1.CCCCCC.C([Li])CCC.[S:21](=[O:23])=[O:22].CC[O:26]CC>>[Br:1][C:2]1[CH:3]=[C:4]([S:21]([OH:26])(=[O:23])=[O:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOCC
Reactant: O=S=O
Reactant: Clc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=S(=O)(O)c1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1,3-Dibromo-5-chlorobenzene (WAKO, 5.98 g) was dissolved in ether (200 mL), and added with 1.6M n-butyl lithium n-hexane solution (KANTO, 15.2 mL) and liquefied sulfur dioxide (9.7 mL) at −70° C. After being allowed to warm to room temperature, the mixture was stirred for 5 hours. The solvent was distilled off under reduced pressure to obtain the target compound as a crude product. LCMS Method B, retention time 0.83 minutes, (ES−) 254.9
Reaction SMILES: [O:1]=[C:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1.O>O.NN>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C:2]3=[O:1])[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)C(=O)c4ccccc43)ccc21
Agent: NN
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)Cc4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
7-[3-(2,3-Dioxo-2,3-dihydroindol-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.3 g) was suspended in hydrazine hydrate (3 ml), and the liquid was stirred for two hours while heated under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=85:15). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether/hexane, thereby obtaining the title compound (0.18 g) as a pale brownish white powder.
Reaction SMILES: F[C:2]1[C:9](C#N)=[C:8](F)[C:7](F)=[C:6](F)[C:3]=1[C:4]#N.FC1C(F)=C(F)C(F)=C([C:19]#[N:20])C=1C#N.F[C:30]1C(F)=C(F)C=C(F)C=1C#N>>[CH3:30][CH:4]([C:19]#[N:20])[C:3]1[CH:2]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: N#Cc1c(F)cc(F)c(F)c1F
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Product: CC(C#N)c1ccccc1
Reaction time: 5 h

Procedure:
By a method similar to Example 11, a reaction was carried out using 2,4,5,6-tetrafluoroisophthalonitrile, instead of 3,4,5,6-tetrafluorophthalonitrile. After 5 hours, the reaction solution was analyzed by gas chromatography, whereupon the conversion of 2,4,5,6-tetrafluoroisophthalonitrile was found to be 36% and the yield of 2,3,4,6-tetrafluorobenzonitrile (based on 2,4,5,6-tetrafluoroisophthalonitrile) was 20%. At the same time, 1.1 mmol of α-methylbenzylcyanide was produced. This corresponded to 0.35 times molar amount relative to the production of 2,3,4,6-tetrafluorobenzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.Cl.[NH:30]1[CH2:33][CH:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:31]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:26]([N:30]2[CH2:33][CH:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:31]2)[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: COC(=O)C1CNC1
Reactant: CC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C1CN(C(C)c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanone (1.76 g, 4.53 mmol) and methyl azetidine-3-carboxylate hydrochloride (1.03 g, 6.80 mmol) according to reference R and the general procedure for reductive amination gave racemic methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)azetidine-3-carboxylate. Separation of enantiomers was accomplished by SFC chromatography (Column: Chiralcel OJ-H (21×250 mm, 5 um)×2; A: Liquid CO2; B: Ethanol (0.2% IPA); Isocratic: 80:20 (A:B); Flow Rate: 70 mL/min; Outlet Pressure: 100 bar) to give (R)-methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)azetidine-3-carboxylate and (S)-methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated: 487.2; Observed: 488.1 (M++1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:18][C@H:17]([NH2:19])[CH2:16][C@H:11]2[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:15][O:14][C:12](=[O:13])[C@@H:11]1[CH2:16][C@@H:17]([NH:19][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][N:10]1[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9]
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)CCCCCNC(=O)OC(C)(C)C)CN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a mixture of 300 mg of 18 (1.06 mmol), 244 mg (1.06 mmol) of 6-(Boc-amino)-caproic acid (Bachem), and 485 mg (1.27 mmol, 1.2 equiv.) of HATU in 4 mL of DMF was added 525 μL (3.0 mmol, ˜3 equiv.) of diisopropylethylamine. The resulting mixture was stirred at room temperature overnight, then diluted with ˜100 mL EtOAc and washed with 1 N HCl (three times), 1 N NaOH (twice), then brine, and dried (MgSO4), filtered, and concentrated to an orange oil. This was dissolved in CH2Cl2, loaded onto silica, and eluted with 3:2 CH2Cl2/CH3CN to give 308 mg (0.62 mmol, 58%) of 19 as a foamy white solid. 1H-NMR (400 MHz, CDCl3, 6 ppm) 7.90 (dd, J=1 Hz, 8 Hz, 2H), 7.60 (tt, J=1 Hz, 8 Hz, 1H), 7.53 (tt, J=1 Hz, 8 Hz, 2H), 5.71 (d, J=6 Hz, 1H), 4.58 (br s, 1H), 4.53 (t, J=8Hz, 1H), 4.47 (m, 1H), 3.66 (s, 3H), 3.54 (q, J=5 Hz, 1H), 3.39 (dd, J=3 Hz, 11 Hz, 1H), 3.08 (m, 2H), 2.24 (m, 2H), 2.02 (t, J=8 Hz, 2H), 1.56 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H), 1.28 (m, 2H); 13C-NMR (400 MHz, CDCl3, 8 ppm) 173.21, 172.19, 164.53, 138.83, 133.62, 129.58, 128.04, 123.12, 59.13, 53.70, 52.97, 49.68, 40.68, 37.47, 36.59, 30.08, 28.82, 26.64, 25.38; m/z: 498 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.CC([N:27]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:41]=[C:40]([CH:42]=O)[NH:39][N:38]=2)=[CH:33][CH:32]=1)C(=O)[O-])(C)C>CN(C=O)C>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]3[N:21]=[C:42]([C:40]4[NH:39][N:38]=[C:37]([C:34]5[CH:35]=[CH:36][C:31]([NH2:27])=[CH:32][CH:33]=5)[CH:41]=4)[NH:22][C:17]=3[CH:16]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2cc(C=O)[nH]n2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc3nc(-c4cc(-c5ccc(N)cc5)n[nH]4)[nH]c3c2)CC1
Temperature: 65 °C
Yield: 70 %

Procedure:
Triethylamine (2.32 g, 23 mmol) was added to a solution of 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine as the tetra-hydrochloride salt in anhydrous DMF (11 mL) after five minutes, a solution of 1,1-dimethylethyl[4-(5-formyl-1H-pyrazol-3-yl)phenyl]carbamate in anhydrous DMF (2 mL) was added to the diamine. The reaction flask was left open to the air and heated to 65° C. After twelve hours the reaction was concentrated in vacuo and the residue purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the product (0.60 g, 70% yield). (Note that the BOC group was removed under the purification conditions.)
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1.[N:15]([O:17]CCC(C)C)=O.[ClH:23]>>[Cl:23][C:9]([CH3:11])([CH3:10])[CH:8]([N:15]=[O:17])[CH2:7][N:6]1[C:2]([CH3:1])=[CH:3][N:4]=[C:5]1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)CCON=O
Reactant: CC(C)=CCn1c(C)cnc1[N+](=O)[O-]
Reactant: Cl
Product: Cc1cnc([N+](=O)[O-])n1CC(N=O)C(C)(C)Cl
Yield: 60 %

Procedure:
3-Chloro-3-methyl-2-nitroso-1-(5-methyl-2-nitro-1H-imidazol-1-yl)butane was prepared in 60% yield from 1-(5-methyl-2-nitro-1H-imidazol-1-yl)-3-methyl-2-butene (1.0 g, 5.12 mmol, Example 27), isoamyl nitrite (5.0 mL) and concentrated HCl (5.0 mL) following the procedure described for the preparation of its positional isomer (Example 27B) as a light blue solid; mp. 102°-105° C. (decomp); 1H NMR (DMSO-d6) δ 1.73 [s, 6H, C(CH3)2 ], 2.32 (s, 3H, imi-CH3), 5.53 (s, 2H, NCH2), 6.97 (s, 1H, imi-CH) and 11.58 (s, 1H, NOH). MS m/e 261 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10]P(=O)(OCC)OCC)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[C:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=O)C.O1CCC[CH2:37]1>O1CCOCCOCCOCCOCC1.ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([CH3:37])=[CH:23][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:19][CH:20]=1)=[O:5])[CH3:2]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Reactant: C1CCOC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1ccc(C(C)=Cc2ccc3ccccc3c2)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
31 g of diethyl 4-ethoxycarbonyl-benzylphosphonate and a few drops of 1,4,7,10,13-pentaoxa-cyclopentadecane are added to a suspension of 5.5 g of sodium hydride in 100 cm3 of tetrahydrofuran. The mixture is stirred at 45° C. for one hour and 17 g of 2-acetyl-naphthalene are then added. It is kept at 45° C. for three hours, allowed to cool, then diluted with dichloroethane. The insoluble matter is filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallised twice from ethanol. 14 g of the expected product are obtained. Melting point: 96° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2cccc(Cl)c2)c1

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 3-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxycarbonyl-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b) of Example 1, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=S)[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1.O.[NH2:20]N.C[N:23]([CH3:26])C=O>>[CH2:6]1[C:7]2[C:8]3[N:9]([CH:26]=[N:23][N:20]=3)[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[N:12]3[CH:1]=[CH:2][C:3]([C:13]=23)=[CH:4][CH2:5]1
Reactant: CN(C)C=O
Reactant: NN
Reactant: S=C1Nc2ccccc2N2CCc3cccc1c32
Solvent: O
Product: C1=c2ccn3c2=C(CC1)c1nncn1-c1ccccc1-3
Yield: 68.2 %

Procedure:
1,2-Dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-thione (5 g), hydrazine monohydrate (5 ml) and dimethylformamide (150 ml) were combined and refluxed overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by high performance liquid chromatography (2% methanol/dichloromethane) to yield 3.5 g (68.2%) of product. Recrystallization from tetrahydrofuran gave the analytical sample, mp 177°-178° C.
Reaction SMILES: CN(CCN(C)C)C.C([Li])CCC.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN([CH:24]=[O:25])C>C1COCC1>[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Fc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccncc1F
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a solution of TMEDA (389 uL, 2.58 mmol) in THF (10 mL) at −78° C. was added a solution of n-butyl lithium in THF (2.5M, 1.03 mL, 2.58 mmol). After 30 minutes at −78° C., 3-fluoropyridine (221 uL, 2.57 mmol) was added. After another 2 hours at −78° C., DMF (219 uL, 2.83 mmol) was added. After a further 2 hours at −78° C., the reaction was quenched with saturated aqueous NaHCO3 (20 mL), extracted with ether (4×15 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the crude oil. Purification by column chromatography on silica gel (Hexanes: EtOAc 4:1) afforded the title compound as a pale yellow oil (120 mg, 37%). 1H NMR (CDCl3) 7.68 (t, 1H, J=5.2 Hz), 8.62 (d, 1H, J=4.7 Hz), 8.70 (s, 1H), 10.42 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15]C)=[O:14])=[C:5]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:4][C@H:3]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33].O1CCCC1.O.[Li+].[OH-].Cl>CCOCC>[NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[C:5]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:4][C@H:3]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33]
Reactant: COC(=O)c1cccc(OCC2=C(c3cccnc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1CC(COc2cccc(C(=O)O)c2)=C(c2cccnc2)C[C@H]1c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of Example 9B (18 mg, 0.037 mmol) in mixture of tetrahydrofuran/H2O (0.5 mL/0.25 mL), LiOH (9.4 mg, 0.22 mmol) was added at room temperature. The reaction mixture was stirred overnight. It was acidified with 2N HCl in ether until the pH=3 and purified by reverse-phase high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (14 mg, 80%). 1H NMR (500 MHz, methanol-d4) δ ppm 8.65-8.76 (m, 2H), 8.25-8.33 (m, 1H), 7.81-7.91 (m, 1H), 7.48-7.65 (m, 3H), 7.30-7.44 (m, 3H), 7.01-7.10 (m, 1H), 4.48-4.59 (m, 2H), 4.00-4.12 (m, 1H), 3.74-3.87 (m, 1H), 2.60-3.02 (m, 4H). MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH2:22]O.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH2:22][S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)c1ccc2c(Sc3ccccc3Cl)c(CO)[nH]c2c1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Cc1[nH]c2cc(S(C)(=O)=O)ccc2c1Sc1ccccc1Cl
Reaction time: 0.17 h

Procedure:
[3-(2-chloro-phenylsulfanyl)-6-methanesulfonyl-1H-indol-2-yl]-methanol (1 mmole) (as prepared in Example 5) was dissolved in 2 mL CH2Cl2 and treated with 0.3 mL NEt3 followed by 0.08 ml MsCl. After stirring 10 min. 3 mL DMF was added followed by 0.5 g NaSO2Me. The mixture was stirred overnight. The reaction mixture was evaporated to dryness and applied to a PTLC plate. Elution with 1:1 EtOAc/hexane gave 80 mg 3-(2-chloro-phenylsulfanyl)-6-methanesulfonyl-2-methanesulfonylmethyl-1H-indole 601, MS: 343 ([M+H]+).
Reaction SMILES: [SH:1][NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl.C(OC(=O)CN[C:32](=O)[C@H:33]([CH2:35]C1C=CC=CC=1)N)C.Cl.C(OC(=O)CNC(=O)[C@H](CC(C)C)N)C>>[SH:1][NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH2:12][C:13]1[CH:15]=[CH:35][CH:33]=[CH:32][CH:14]=1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NS
Reactant: CCOC(=O)CNC(=O)[C@@H](N)Cc1ccccc1
Agent: CCOC(=O)CNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NS

Procedure:
This mercaptopeptidyl ester was prepared substantially similarly as HS-Leu-Leu-Gly-OC2H5, above, except that an equivalent amount of L-phenylalanylglycine ethyl ester hydrochloride was used in the coupling reaction instead of L-leucylglycine ethyl ester hydrochloride.