Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[CH2:9]1[C:14](=[O:15])[N:13]([O:16][C:17](ON2C(=O)CCC2=O)=[O:18])[C:11](=[O:12])[CH2:10]1.N1C=CC=CC=1>C(#N)C>[OH:16][N:13]1[C:14](=[O:15])[CH2:9][CH2:10][C:11]1=[O:12].[C:17](=[O:16])([O-:18])[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: OCc1cccnc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C([O-])OCc1cccnc1
Product: O=C1CCC(=O)N1O
Reaction time: 1 h
Yield: 115.3 %

Procedure:
To a solution of 2.5 g (22.9 mmol) of 3-pyridylcarbinol in 100 mL of anhydrous acetonitrile was added 8.8 g (34.4 mmol) of N,N′-disuccinimidyl carbonate and 5.55 mL (68.7 mmol) of pyridine. The solution was stirred for 1 hour and then concentrated in vacuo. The residue was dissolved in ethyl acetate, then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to afford 5.3 g of N-Hydroxysuccinimide-3-pyridylmethyl carbonate, mass spectrum m/e=251 (M+H), which was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14]([CH2:22][C:23]#C)[CH2:15]2)=[N:6][CH:7]=1.C(Cl)(=[O:38])C>>[C:22]([N:14]1[CH2:13][CH:12]2[CH2:21][CH2:20][CH:16]([C:17]3[C:11]2=[CH:10][C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:25][C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([NH:30][CH3:31])=[O:29])[C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:19][CH:18]=3)[CH2:15]1)(=[O:38])[CH3:23]
Reactant: CC(=O)Cl
Reactant: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(C)=O)C2)ncc1Cl

Procedure:
2-[2-(10-Acetyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide and acetyl chloride in an analogous manner to Example 282. Product isolated as a yellow foam (30 mg, 91%). LCMS (m/e) 491 (M+1); 1H-NMR (CDCl3, 400 MHz,) major rotomer δ 11.08 (s, 1H), 8.61 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.56-7.38 (m, 3H), 7.32-7.21 (m, 1H), 7.13-7.01 (m, 2H), 6.95 (s, 1H), 6.26 (bs, 1H), 4.34-4.20 (m, 1H), 3.80-3.69 (m, 1H), 3.43-3.30 (m, 1H), 3.28-3.18 (m, 1H), 3.15-2.99 (m, 2H), 3.03 (d, 3H, J=1.9 Hz), 2.07 (s, 3H), 2.02-1.92 (m, 2H), 1.84-1.67 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]2([CH2:20][C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)SCCCS2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].IC.C[OH:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:36])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CO
Reactant: COc1cc(CC2(Cc3cc(OC)c(OC)c(OC)c3)SCCCS2)cc(OC)c1OC
Solvent: CI
Product: COc1cc(CC(=O)Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 72 g of the compound prepared in (b) above in 96% aqueous methanol was heated to 40° C., after which time 50 ml of iodomethane was added. The reaction mixture was then stirred for 24 hours, while the temperature was maintained at 40° C. The solvent was then evaporated to give an oily residue which was crystallized from a mixture of ethyl acetate and petroleum ether to yield a solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].Br[CH2:24][C:25]#[N:26].[H-].[Na+]>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:24][C:25]#[N:26])[C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=C2SCN(CC#N)C2=O)cc(C(C)(C)C)c1O
Yield: 40.7 %

Procedure:
7.03 g of 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-thiazolidinone and 2.64 g of bromoacetonitrile were reacted in the presence of 0.97 g of 60% sodium hydride in mineral oil and 330 ml of tetrahydrofuran. Work-up of the reaction mixture provided 3.21 g of the desired title product, m.p. 186°-188° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH:8]([CH3:15])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10].[Cl:16][C:17]1[C:22]([OH:23])=[CH:21][C:20]([N:24]2[C:29](=[O:30])[N:28]([CH3:31])[C:27](=S)[N:26]([CH3:33])[C:25]2=[O:34])=[C:19]([F:35])[CH:18]=1>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([F:35])[C:20]([N:24]2[C:25](=[O:34])[N:26]([CH3:33])[CH2:27][N:28]([CH3:31])[C:29]2=[O:30])=[CH:21][C:22]=1[O:23][CH:8]([CH3:15])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10]
Reactant: Cn1c(=S)n(C)c(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C=CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(C)Oc1cc(N2C(=O)N(C)CN(C)C2=O)c(F)cc1Cl
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.37 g (2.65 mmol) of K2CO3 and 0.51 g (2.65 mmol) of rac. allyl 2-bromopropionate were added approximately at 20° C. to a solution of 0.80 g (2.52 mmol) of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,5-dimethyl-6-thioxo-[1,3,5]triazinane-2,4-dione in 15 ml of dimethylformamide. After the reaction mixture had been stirred for two hours at approximately 20° C., it was stirred into ice-water. The product was extracted three times with methyl tert-butyl ether. The combined organic phases were dried over magnesium sulfate and then concentrated. The crude product (1.18 g) was purified by column chromatography (mobile phase: cyclohexane/ethyl acetate=15:1). Yield: 0.88 g (81%); 1H NMR (270 MHz, in CDCl3): δ[ppm]=1.7 (d, 3H), 3.8 (s, 6H), 4.6 (m, 2H), 4.7 (q, 1H), 5.2 (d, 1H), 5.3 (d, 1H), 5.9 (m, 1H), 6.9 (d, 1H), 7.3 (d, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14].C>O1CCCC1>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1nccs1
Agent: C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1nccs1
Temperature: -90 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (-98° C.) of n-butyllithium (2.5M in hexane, 5.39 mL, 13.4 mmol, 1.1 eq) in tetrahydrofuran (100 mL) under nitrogen was added a solution of 2-bromothiazole (2.00 g, 12.2 mmol) in tetrahydrofuran (30 mL). A suspension formed as the substrate was added. After stirring at -90° C. for 30 min, freshly distilled trimethylsilyl chloride (1.55 mL, 12.2 mmol, 1.0 eq) was added. The reaction was warmed to -30° C. over 1 h and quenched with saturated aqueous sodium bicarbonate (50 mL). The aqueous phase was extracted with diethyl ether (2×40 mL). Combined organic extracts were washed with aqueous bicarbonate (2×40 mL), saturated brine (1×40 mL) and dried with anhydrous sodium sulfate. The solvents were removed and the product purified by Kugelrohr distillation at reduced pressure (2400 pascal, 110° C.). By NMR the title compound was contaminated with small amounts of starting material but no further purification was considered necessary. No accurate yield was established. MS (CI, CH4) m/z 158 (M+1,100), 186 (M+29,17).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: FC(F)(F)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccccc1CC1c2ccccc2CCc2ccccc21
Reaction time: 17 h

Procedure:
Add 5-(2-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.16 g, 0.45 mmol) to a mixture of 10% Pd/C (0.075 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (2.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrated the filtrate to give the title product. MS (m/e): 352 (M+). Analysis for C23H19F3: Calcd: C, 78.39 H, 5.43. Found: C, 78.84 H, 5.11.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:15][CH2:14]1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:14][CH2:15][CH:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH2:17][CH2:18]1)[CH2:10][O:11][S:35]([CH3:34])(=[O:37])=[O:36])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCC(O[Si](C)(C)C(C)(C)C)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 109.2 %

Procedure:
To a solution of (2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethylsilyloxy)-cyclohexyl)propan-1-ol (23 g, 59 mmol) in CH2Cl2 (250 mL) was added Et3N (15 g, 148 mmol). The reaction mixture was cooled to −20° C. and a solution of MsCl (14.9 g, 131 mmol) in CH2Cl2 (40 mL) added dropwise. After returning to rt then stirring for an additional 1 h, at which point TLC showed no starting material, water (100 mL) was added and the mixture was extracted with CH2Cl2 (2×150 mL). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give crude (2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethyl-silyloxy)cyclohexyl)-1-methanesulfonyloxypropane (30 g) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.[CH2:16]([S:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Br)=[CH:29][CH:30]=[N:31]2)=[CH:26][N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH2:16]([S:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([C:4]3[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=3[O:2][CH3:1])=[CH:29][CH:30]=[N:31]2)=[CH:26][N:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Brc1ccnc2cc(SCc3ccccc3)ncc12
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(SCc3ccccc3)ncc12
Temperature: 110 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A screw capped vial was charged with 2-methoxy-4-(trifluoromethyl)phenyl boronic acid (0.096 g, 0.438 mmol), 7-(benzylthio)-4-bromo-1,6-naphthyridine (0.145 g, 0.438 mmol), and potassium phosphate tribasic (0.279 ml, 1.313 mmol). Dioxane (1.756 ml) and water (0.585 ml) were added and the vial was purged with argon, followed by addition of Pd(AmPhos)2Cl2 (0.019 g, 0.026 mmol). The vial was capped and heated to 110° C. After 3 hours, the reaction was cooled to room temperature, diluted with water (30 mL), and washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel MPLC chromatography (40 g), eluting with 0 to 100% ethyl acetate in heptanes. The fractions were collected and the solvent was removed under reduced pressure to provide 0.129 g of 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-1,6-naphthyridine as an off white solid. m/z (ESI) 427.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OB(O)c1cc(F)ccc1O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(F)ccc2O)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a degassed mixture of 1,4-dioxane:water (4:1, 15 mls) was added (5-fluoro-2-hydroxyphenyl)boronic acid (0.781 g, 5.0 mmol), methyl 6-chloronicotinate (0.86 g, 5.0 mmol), potassium carbonate (2.08 g, 15.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) and the resulting mixture stirred at 80° C. for 2 h. After this time additional tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) was added and then heating continued at 80° C. for 3 h. The mixture was then stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue suspended in ethyl acetate (50 ml). The suspension was filtered through a plug of arbocel and the filtrate concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium carbonate (3×100 ml). The aqueous washings were combined and extracted with ethyl acetate (3×50 ml). The ethyl acetate layers were combined, dried with anhydrous MgSO4 and concentrated in vacuo to afford a solid which was recrystallised from dichloromethane/heptane to afford the title compound as a yellow solid (0.71 g) (57%). 1H NMR (400 MHz, CDCl3) □ ppm 9.14 (1H, s), 8.46-8.40 (1H, m), 7.91-7.86 (1H, m) 7.53-7.46 (1H, m), 7.11-7.03 (1H, m), 7.02-6.96 (1H, m), 3.99 (3H, s). LRMS: AP m/z 248 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:10]2[CH2:12][CH2:11]2)[CH:3]=1.Cl.[NH2:14][C:15]([CH3:24])([CH3:23])[C:16](OC(C)(C)C)=[O:17].[C:25](Cl)(Cl)=[O:26]>>[CH:10]1([C:4]2[CH:3]=[C:2]([N:1]3[C:16](=[O:17])[C:15]([CH3:23])([CH3:24])[NH:14][C:25]3=[O:26])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:11][CH2:12]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: N#Cc1ccc(N)cc1C1CC1
Agent: Cl
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C3CC3)c2)C1=O

Procedure:
Compound 158.1 was prepared by the process as described for 1.1 by reaction of 158.3 with tert-butyl 2-amino-2-methylpropionate hydrochloride and phosgene (solution in toluene). Molecular weight 269.11 (C15H15N3O2); retention time Rt=1.43 min. [B]; MS (ESI): 270.18 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:2]1=2.[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][CH2:8][CH:9]([N:10]=[C:11]=[O:12])[C:2]1=2
Reactant: O=C(Cl)Cl
Reactant: NC1CCCc2ccsc21
Solvent: Cc1ccccc1
Product: O=C=NC1CCCc2ccsc21

Procedure:
A six gram sample of 4,5,6,7-tetrahydrobenzo[b]thiophen-7-amine is stirred in 20 ml. of toluene at 100° C. and phosgene is slowly introduced into the mixture through a gas tube. The flow of phosgene is terminated after most of the solid amine hydrochloride disappears. The mixture is then filtered and the filtrate is evaporated to dryness to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.[CH2:28]([N:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][C:38]2([OH:41])[CH2:39][CH2:40][N:35]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
30 ml of tetrahydrofuran was added to 2.00 g of N-t-butoxycarbonyl-4-acetylaniline, and 8.8 ml of a 1.7M t-butyl lithium·pentane solution was added thereto under an argon stream at -78° C. Then, 1.41 g of 1-benzyl-4-piperidone was dissolved in 20 ml of tetrahydrofuran, and the solution was added dropwise. After stirring for 2 hours, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 2.07 g of the title compound as white powder.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:27].CC(O)=O>CN(C=O)C>[NH2:1][C@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].[ClH:27]
Reactant: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NCSC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
BocCys(Acm)ONp is prepared from BocCys(Acm)OH (Novabiochem, Laufelingen, CH) and p-nitrophenol by reaction with N,N'-dicyclohexylcarbodiimide (DCC) in ethyl acetate and used without purification for the preparation of Boc-Cys(Acm)-Pro-OH (XII) by reacting it with H-Pro-OH in DMF/etyl acetate/HCl at 0° C. while keeping pH neutral by addition of Et3N. Yield 81%. Purity >95% (TLC). Boc-Asn-Cys(Acm)-Pro-OH (XIII) is obtained by deblocking XII in HCl/HOAc att room temperature, dissolving the thus obtained raw H-Cys(Acm)-Pro-OH·HCl in DMF and neutralizing it with Et3N, and adding Boc-Asn-ONp (Novabiochem, Laufelingen, CH) at -5° C. while keeping pH neutral. XIII is isolated in 81% yield. [α]D20 =-77.1° (1 g/100 ml DMF). The tetrapeptide derivative X is prepared from XIII and Boc-Gln-ONp (Novabiochem, Laufelingen, CH) in a way corresponding to the preparation of XIII from XII and Boc-Asn-ONp. Yield 78.5%; [α]D20 =-89.7° (1 g/100 ml H2O).
Reaction SMILES: [C:1]([O:4][CH:5]([O:18][C:19](=[O:21])[CH3:20])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])[CH2:9]Cl)(=[O:3])[CH3:2].[I-:22].[Na+]>CC(C)=O>[C:1]([O:4][CH:5]([O:18][C:19](=[O:21])[CH3:20])[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:17])[CH3:16])[CH2:9][I:22])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)Oc1ccc(CCl)cc1C(OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(CI)cc1C(OC(C)=O)OC(C)=O
Yield: 91.1 %

Procedure:
3-(Diacetoxymethyl)-4-acetoxybenzyl chloride (987 g., 3.14 mole) and sodium iodide (494 g., 3.29 moles) in 3.5 liters acetone are refluxed for 6 hours. The reaction mixture is filtered, the filtrate is evaporated to dryness, triturated in ether and filtered to yield 1,162 g (91%) of 3-(diacetoxymethyl)-4-acetoxybenzyl iodide, m.p. 117°-120° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH:12]([C:21]([O:23]CC)=[O:22])[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[CH:1]1([C:7]2[C:8]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH:12]([C:21]([OH:23])=[O:22])[CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1Cn2c(c(C3CCCCC3)c3ccc(C(=O)OC)cc32)-c2ccccc2O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Oc1ccccc1-3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 6-ethyl 9-methyl 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-6,9-dicarboxylate (270 mg, 0.60 mmol) in tetrahydrofuran (1 ml), methanol (1 ml) and water (1 ml) was added lithium hydroxide monohydrate (30 mg, 0.71 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 hr. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 12-cyclohexyl-9-methoxycarbonyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-6-carboxylic acid as a crude product. The obtained crude product was used in Example 3-3 without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C(C(O)=O)[NH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14].CN(C=O)C>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:1]([C:2]([Cl:4])=[O:3])[NH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1[nH]c(C(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c(C(=O)Cl)cc1Cl
Reaction time: 8 h

Procedure:
Oxalyl chloride (0.430 mL, 4.91 mmol) was added to a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-2-carboxylic acid (0.500 g, 2.45 mmol) in DCM (50 mL). DMF (9.51 μl, 0.123 mmol) was added to the reaction mixture and the resulting suspension was stirred overnight. The solvent was evaporated to afford the title compound as a crude product (0.804 g) which was used with no further purification. 1H NMR (400 MHz, CDCl3) δ ppm 11.02 (s, 1H), 7.11 (d, 1H), 3.97 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[CH:19]=[C:18]([CH3:21])[N:17]=[C:16]([NH2:22])[C:15]=2[N:14]=[C:13]1[CH2:23][O:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:22][C:16]1[C:15]2[N:14]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:20]=2[CH:19]=[C:18]([CH3:21])[N:17]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
Isobutyryl chloride (181 μL, 1.73 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (0.435 g, 1.57 mmol), triethylamine (280 μL, 2.04 mmol) and chloroform (8 mL). The reaction mixture was allowed to stir at ambient temperature for 4 hours then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution (10 mL). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (30 g of silica gel eluting with 1 L of 2% methanol in chloroform containing 0.5% triethylamine) to provide 0.225 g of N-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}-2-methylpropanamide as a white powder, m.p. 170.5-172.5° C.