Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](SC)=[N:13][C:12]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25][NH2:26]>C(O)C>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14]([NH:26][CH2:25][CH:24]([O:27][CH3:28])[O:23][CH3:22])=[N:13][C:12]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: CSC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2CCC1
Solvent: CCO
Product: COC(CNC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2CCC1)OC
Yield: 61.1 %

Procedure:
A solution of (2-methylsulfanyl-4,5-dihydro-3H-benzo[b]azepin-8-yl)-carbamic acid tert-butyl ester (2.2 g, 7.2 mmol) and 2,2-dimethoxyethanamine (1.0 g, 9.5 mmol) in ethanol (200 mL) was heated in an oil bath at 100° C. for 14 hours. The mixture was concentrated and purified by silica gel chromatography with DCM/MeOH (9:1) to give [2-(2,2-dimethoxy-ethylamino)-4,5-dihydro-3H-benzo[b]azepin-8-yl]-carbamic acid tert-butyl ester (1.6 g, 4.4 mmol, 61%): 1H NMR (300 MHz, CDCl3) δ 7.1 (m, 2H), 6.93 (s, 1H), 6.48 (s, 1H), 4.69 (t, 1H), 3.66 (d, 2H), 3.54 (s, 6H), 2.61 (t, 2H), 2.2 (br, 4H), 1.61 (s, 9H); MS (m/e) 364 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([OH:19])[CH3:18].O>CN(C=O)C>[OH:19][CH2:17][CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(O)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCO)cc1
Yield: 80.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (366 mg, 3 mmol) in anhydrous DMF (7 ml), under nitrogen atmosphere, K2CO3 (829 mg, 6 mmol), and, after 10 minutes, bromoethanol (450 mg, 3.6 mmol) were added. The mixture was heated to reflux for 3 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution, dried with Na2SO4. After evaporation of the solvent, the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 2/1); 400 mg (yield 80%) of pure product of the title were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.CN(C)[CH2:17][CH2:18]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[C:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:17][CH3:18])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
5-Acetylsalicylic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (382 mg), 1-hydroxybenzotriazole hydrate (306 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-acetylsalicylate (211 mg, yield 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:50].[K+].Cl>O1CCOCC1.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:50])[C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Reactant: [OH-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2cc(OCc3ccccc3)cc(O)c2s1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
5-(benzyloxy)-7-bromo-2-methylbenzo[d]thiazole 4.03D (560 mg, 1.7 mmol) Pd2(dba)3 (77 mg, 0.084 mmol), and 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (142 mg, 0.335 mmol) were taken up in 1,4-dioxane (6 mL) under Ar. Aqueous 2 M KOH (2.5 mL, 5 mmol) was added and the mixture was heated to 90° C. After 1 h, the mixture was cooled to r.t. and was diluted with EtOAc (50 mL), and water (30 mL). The aqueous phase was and acidified with 3 M aqueous HCl (1.8 mL, 5.4 mmol). The phases were separated, and the organic phase was washed with saturated aqueous NaHCO3 (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (10-55% EtOAc in hexanes) to provide 5-(benzyloxy)-2-methylbenzo[d]thiazol-7-ol 4.03E. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H14NO2S: 272.1; found 272.1.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([N:13]1[CH2:14][CH2:15][C:10]2([CH2:9][C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]2=[O:1])[CH2:11][CH2:12]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1c2ccccc2CC12CCNCC2
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)Cc1ccccc1C2=O
Reaction time: 1 h

Procedure:
To a solution of 1.13 g (5.6 mmoles) 1,3-dihydro-1-oxospiro[2H-indene-2,4'-piperidine] in 15 ml methylene chloride cooled to 0° C. was added 1.23 g (12.0 mmoles) acetic anhydride. The solution was stirred at 0° for 1 hour and the solvent was removed in vacuo to give crude 1'-acetylspiro[2H-indene-2,4'-piperidine]-1(3H)-one.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[C:13]([O:17][C:18]([NH:20][C@@H:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CN1CCOCC1.C(Cl)CCl>CCOC(C)=O>[F:1][C:2]1[C:7]([O:8][C:22](=[O:23])[C@@H:21]([NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Pentafluorophenol (8.75 g, 47.5 mmol) dissolved in EtOAc (5 mL) was added to a solution of 2(S)-tert-butoxycarbonylamino-3,3-dimethyl-butyric acid (10 g, 43 mmol) in EtOAC (35 mL) and the mixture cooled to 0° C. NMM (4.75 mL, 43 mmol) followed by EDC (9.12 g, 47.6 mmol) were added to this cooled solution and the reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with EtOAc (200 mL) and washed with 1M HCl (2×200 mL), 1M Na2CO3 (3×200 mL) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 10% EtOAc in hexanes) to give the title compound as a white solid (12.03 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O-:13])=[O:12])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH:15]([OH:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:22][C:23](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:22][CH3:23])=[O:12])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(O)c1c(C)nc2cc(C(=O)[O-])nn2c1Cl
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)nc2cc(C(=O)OCC)nn2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a mixture of 7-chloro-6-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (5.9 g 13.81 mmol) in CH2Cl2 (100 mL) was added Dess-Martin (5.86 g, 13.81 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with sat. aq. NaHCO3 solution (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford the desired ethyl 7-chloro-6-(2-ethoxy-2-oxoacetyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (3.5 g, 9.27 mmol, 67.1% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 4.56-4.43 (m, 4H), 2.63 (s, 3H), 1.50-1.41 (m, 6H). LCMS (M+1)=340.13.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]([C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1)([CH3:38])[CH3:37]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:43]3[CH:42]=[CH:41][CH:40]=[C:39]([CH:36]([CH3:38])[CH3:37])[CH:44]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CC(C)c1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)c1

Procedure:
5-{4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (100 mg, 0.17 mmol) was treated as described in general procedure G using 3-isopropylphenyl boronic acid to provide 5-{4-[4-(2,4-dichloro-phenyl)-2-(3′-isopropyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.OS(O)(=O)=O.O>C(O)(=O)C>[Cl:10][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[C:4]2\[CH2:3][NH:2][CH2:8][CH2:7]/[C:6](=[CH:15]\[C:14]3[CH:17]=[CH:18][C:11]([Cl:1])=[CH:12][CH:13]=3)/[C:5]\2=[O:9])=[CH:13][CH:12]=1
Reactant: Cl
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1CCCNCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1/C(=C/c2ccc(Cl)cc2)CCNC/C1=C\c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Azepan-4-one hydrochloride (0.45 g, 3.0 mmol) and 4-chlorobenzaldehyde (0.92 g, 6.6 mmol) were dissolved in acetic acid (10 mL), conc. H2SO4 (1 mL) was added drop-wise and the reaction stirred at rt for 24 h. After addition of water (30 mL) a precipitate was formed, filtered off, and dried in vacuum to give the product in 91% purity as a yellow solid. LCMS A: Rt 2.04 m/z [M]+ 358.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cn1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2ccc(Br)cn2)cc1

Procedure:
To 2-Amino-5-bromopyridine (15, 6.10 g, 0.0352 mol) in toluene (90.0 mL) were added 4-chlorobenzaldehyde (40, 5.00 g, 0.0356 mol), trifluoroacetic acid (8.0 mL, 0.10 mol) and triethylsilane (16.5 mL, 0.103 mol). The reaction was heated to reflux for 48 hours. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude residue was crystallized with ethyl acetate to give compound (41, 6.8 g, 65.4%).
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:16]=1[NH2:17])([CH3:14])[CH3:13].C(N(CC)CC)C>C(OCC)(=O)C.ClCCl>[CH3:24][CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:15]([CH:12]([CH3:14])[CH3:13])[C:16]=1[NH:17][C:3](=[O:4])[CH:2]([Br:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:23]
Reactant: O=C(Cl)C(Br)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
The α-bromophenylacetylchloride (21.0 g, 89.7 mmol) was added slowly via pipet to a cooled (0° C.) solution of 2,6-diisopropylaniline (15.9 g, 89.7 mmol) and triethylamine (12.5 mL, 89.7 mmol) in ethyl acetate (1600 mL). The resulting slurry was warmed (25° C.) then stirred (1 hour). The resulting mixture was diluted with ethyl acetate (1000 mL) and dichloro methane (500 mL), then washed with water (1000 mL), with 0.5N aqueous HCl (2×1000 mL), with saturated aqueous sodium bicarbonate (1×600 mL), with brine (1×600 mL), then dried (MgSO4) and concentrated to a solid. The solid was recrystallized from ethyl acetate to yield 27.2 g (81.0%) of (±)-N-[2,6-bis(1-Methylethyl)phenyl]-α-bromobenzeneacetamide as a white solid, mp 207°-209.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=O)[C:6]([CH:8]1[CH2:10][CH2:9]1)=O)[CH3:2].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([NH:28][NH2:29])[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4]([C:5]1[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:29][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:30])[CH:23]=2)[C:6]=1[CH:8]1[CH2:10][CH2:9]1)=[O:19])[CH3:2]
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C(=O)c1ccncc1)C(=O)C1CC1
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Yield: 12 %

Procedure:
In analogy to the procedure described in Example 164B], 3-cyclopropyl-3-oxo-2-(pyridine-4-carbonyl)-propionic acid ethyl ester (Example 162 A]) and 3-(trifluoromethyl)phenylhydrazine gave the title compound as a white solid (12%). MS: 402.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: Cc1ccccc1-n1ccc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxypyrrolo[3,2-c]quinoline(377 mg, 1.0 mmol) was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 6 to obtain 303 mg of desired compound as solid in 73% of yield.
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[CH2:9]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25]([OH:27])=[O:26])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25]([O:27][CH3:3])=[O:26])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodomethane (2.0 mL), K2CO3 (5.60 g), (S)-6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoic acid (1) (NovaBiochem, A29340), and anhydrous DMF (20 mL) were combined and stirred at ambient temperature for 2 hours. The reaction mixture was subjected to an aqueous work-up, affording (S)-methyl 6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoate (TU3000-090) as clear oil. MS (ESI+): calcd. 417.20. found 417.20 (MNa+), calcd. 295.16. found 295.209((M-Boc)H+). H-NMR (400 MHz, CDCl3):1.372 (2H, m), 1.425 (9H, s), 1.515 (2H, m), 1.623 (1H, m), 1.785 (1H, br.s), 3.175(2H, m), 3.723 (3H, s), 4.284 (1H, m), 4.848 (1H, br.s), 5.084 (3H, overlapping br.s and s), 7.344 (5H, m). C-NMR (100 MHz, CDCl3): 22.340, 28.268, 29.307, 32.313, 40.569, 52.272, 53.099, 66.597, 79.897, 128.061, 128.100, 128.471, 136.519, 155.435, 156.426, 173.230.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Reactant: O=C(CCl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reaction time: 15 h
Yield: 62.1 %

Procedure:
In 150 ml of N,N-dimethylformamide is dissolved 12.3 g of 3(S)-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one, and 8.7 g of benzyl chloroacetate, 8.7 g of anhydrous potassium carbonate and 1 g of potassium iodide are added to the solution. After stirring for 15 hours, the mixture is poured in ice-cooled water. The deposited material is collected by filtration, washed with water and recrystallized from ethyl acetate-hexane to give 11.7 g of benzyl 3(S)-tert-butoxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as colorless prisms, melting at 122°-124° C.
Reaction SMILES: [C:1](/[C:3](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)/[C:4]([O:6][CH2:7][CH:8]1[CH2:12][O:11]C(C)(C)[O:9]1)=[O:5])#[N:2].C(N(CC)CC)C>C1COCC1.CO>[C:1](/[C:3](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)/[C:4]([O:6][CH2:7][CH:8]([OH:9])[CH2:12][OH:11])=[O:5])#[N:2]
Reactant: CN(C)c1ccc(/C=C(\C#N)C(=O)OCC2COC(C)(C)O2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(/C=C(\C#N)C(=O)OCC(O)CO)cc1
Reaction time: 20 h
Yield: 75 %

Procedure:
Compound 13 (0.5 g, 1.5 mmol) was dissolved in a mixture of THF/MeOH (1:1) and DOWEX-H+ resin (0.10 g) was added and the heterogeneous mixture was stirred for 20 hours. The DOWEX-H+ resin was removed by filtration and triethylamine (50 mg, 0.5 mmol) was added and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (100% ether) to give compound 14. 14: 75% yield; bright yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.94 (d, 2H, J=9.1 Hz), 6.69 (d, 2H, J=9.2 Hz), 4.42-4.32 (m, 2H), 4.05 (m, 1H), 3.80-3.70 (m, 2H), 3.12 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 199.0, 164.8, 155.5, 154.0, 134.6, 119.4, 117.9, 111.8, 111.7, 92.8, 70.3, 70.2, 66.9, 66.8, 63.6, 63.5, 40.3, 40.2; HRMS Calc for C15H18N2O4 (M+H)+ 291.1345 Found 291.1361.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:15])[CH:10]=[C:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+].O.CCOC(C)=O>O=S(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:15])[CH:10]=[C:11]([CH2:13][N:16]=[N+:17]=[N-:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cn1cc(CO)nc1-c1ccc(I)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cn1cc(CN=[N+]=[N-])nc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methanol prepared above (46 mg, 0.15 mmol) in SOCl2 (2 mL) was stirred at room temperature for 15 min. It was concentrated in vacuo to give a residue, which was then partitioned between EtOAc and 5% aq. NaHCO3. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in DMF (2 mL). To the solution, NaN3 (70 mg, 1.1 mmol) was added. After the mixture was stirred at room temperature for 2 days, water and EtOAc were added. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl azide (46 mg). MS 340.0 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O[CH:40]2[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][CH:40]([O:21][C:19]2[CH:18]=[CH:17][C:15]3[C:16]4[N:10]([CH2:11][CH2:12][O:13][C:14]=3[CH:20]=2)[C:9]2[CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:25][C:8]=2[C:7]=4[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:41]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(O)ccc1-3
Reactant: Cc1ccc(S(=O)(=O)OC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1cc(OC2CCCN(C(=O)OC(C)(C)C)C2)ccc1-3
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of methyl 12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.80 g, 2.04 mmol) in N,N-dimethylformamide (8 ml) were successively added tert-butyl 3-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (1.09 g, 3.07 mmol) and potassium carbonate (0.57 g, 4.08 mmol) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure to give methyl 3-(1-tert-butoxycarbonylpiperidin-3-yloxy)-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (0.68 g). The obtained compound was used for Step 3 without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:23](=O)[CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:14]([CH2:23][CH3:24])[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(Cc1ccc(Cl)cc1)C1CCNCC1
Reaction time: 10 h
Yield: 40 %

Procedure:
4-(4-Chloro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in CH2Cl2 and acetaldehyde (0.678 g, 3.2 mmol), Na(OAc)3BH (0.163 g, 3.7 mmol) and 1 drop of AcOH was added. The solution was stirred in a sealed vessel for 10 h. The reaction mixture was washed with 1N NaOH, brine and dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (15% ethyl acetate/85% hexane) to yield the title compound (0.350 g, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH2:18]=O.[CH:20]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])(=[O:24])=[O:23])=[CH2:21]>>[CH2:1]([O:3][C:4]([CH:5]1[CH2:18][CH:20]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:32])([F:34])[F:33])(=[O:23])=[O:24])[CH2:21][N:6]1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)CNc1cccc2ccccc12
Reactant: C=O
Reactant: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc2ccccc12

Procedure:
In analogy to the procedure described in example 343d, (naphthalen-1-ylamino)-acetic acid ethyl ester (CAS Reg. No. 107456-67-7) was reacted with paraformaldehyde and 1-ethenesulfonyl-2-trifluoromethyl-benzene (example 243c) to give the title compound as brown oil. MS (ESI): m/z=478.2 [M+H]+.