Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.CCCCCC.CO[C:17]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[N:24]=[CH:25]N(C)C)=[O:18]>O1CCCC1.C(O)(=O)C>[O:18]=[C:17]1[C:2]([C:1]#[N:3])=[CH:25][NH:24][C:23]2[CH:22]=[CH:21][S:20][C:19]1=2
Reactant: COC(=O)c1sccc1N=CN(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1c[nH]c2ccsc2c1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A solution of 1.04 ml (20 mmol) of acetonitrile in 7 ml of tetrahydrofuran was added to a solution of 12.5 ml of 1.6 M n-butyl lithium in hexane (20 mmol) in 25 ml of tetrahydrofuran at −78° C. After 15 minutes, a solution of 2.019 g (9.5 mmol) of 3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester in 25 ml of tetrahydrofuran was added dropwise over 1 h. The reaction mixture was stirred at −78° C. for 30 minutes, and then allowed to warm to room temperature. After stirring at room temperature for 1 h, the reaction mixture was cooled to −50° C. and 1.4 ml of acetic acid was added. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from acetone and hexanes to give 0.668 g (40%) of red-brown solid. 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.94 (d, J=5.4 Hz, 1H), 7.25 (d, J=6 Hz, 1H); LC-MS (ESI) m/z 177.0 (M+1).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1)=[O:13].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:9]([NH:8][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[C:30]([O:29][CH3:28])[CH:31]=3)[CH:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1N
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2C)c1
Yield: 77.1 %

Procedure:
Triethylamine (0.101 g) was added to a stirred mixture of 3-amino-N-(3-dimethylaminophenyl)-4-methylbenzamide (0.135 g), 3-methoxybenzoyl chloride (0.13 g) and methylene chloride (5 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue was triturated under a mixture of ethyl acetate and isohexane. There was thus obtained the title compound as a solid (0.156 g); Mass Spectrum: M+H+ 404.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Br:23]Br>CO>[NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Br:23]
Reactant: COC(=O)c1cccc(-c2ccc(N)nn2)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-c2cc(Br)c(N)nn2)c1
Reaction time: 16 h
Yield: 38.9 %

Procedure:
In a 150 mL round bottom flask was placed methyl 3-(6-aminopyridazin-3-yl)benzoate (2.29 g, 10 mmol), NaHCO3 (1.68 g, 20 mmol) and methanol (40 mL). To this suspension was added Br2 (1.6 g, 10 mmol) drop wise over about 30 minutes at room temperature. The mixture was stirred for 16 h, then filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=2:1) to give methyl 3-(6-amino-5-bromopyridazin-3-yl)benzoate (1.2 g, 39%) as a light orange solid. LC-MS: [M+H]+, 308.0, tR=1.377 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH:32]=O)[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH2:32][NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=4[N:10]=[C:9]3[C:18]([OH:21])([CH3:19])[CH3:20])[CH2:6][CH2:7]1)[CH2:26]2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCC(N)CC1
Reactant: O=CC1Cc2ccc(F)cc2C1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@@H](NCC2Cc3ccc(F)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of 2-[1-(4-amino-cyclohexyl)-5-methyl-1H-benzoimidazol-2-yl]-propan-2-ol (prepared as cis/trans-isomer mixture) and 5-fluoro-indan-2-carbaldehyde. The less polar of the two substances isolated by chromatography gave cis-2-(1-{4-[(5-fluoro-indan-2-ylmethyl)-amino]-cyclohexyl}-5-methyl-1H-benzoimidazol-2-yl)-propan-2-ol. The analysis of the 1H-NMR confirmed the cis-conformation of the cyclohexane. LC-MS showed a single peak, C27H34FN3O (m/e) calcd 435.2686, obsd 436.3 (M+H).
Reaction SMILES: O[C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][C@@H:2]([CH3:21])[CH2:3][C@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
1.8 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile obtained in the above Example 1 was dissolved in 36 ml of carbon tetrachloride. 3.0 g of triphenylphosphine was added thereto and the obtained mixture was stirred under reflux for five hours. After distilling off the solvent, the residue was extracted with n-hexane and desolvated. The obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and diethyl ether (9:1) as a developing solvent. Thus, 1.50 g of (S ,S) -4-[4'-(3"-chloro-1"-methylbutoxy)phenyl]benzonitrile was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7](=[O:20])[CH:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[C:7](=[O:20])[CH:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1NC(Cc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)NC(=O)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
7-Chloro-3-(2-chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (0.8 g, 2.39 mmol), powdered potassium carbonate (0.495 g, 3.58 mmol) and 4-methoxybenzyl chloride (0.39 mL, 2.86 mmol) were suspended in N,N-dimethylformamide (20 mL) and stirred at ambient temperature overnight. The solution was poured into water (100 mL) and ethyl acetate (150 mL). The layers were separated and the organic layer was washed with water (2×100 mL) then brine, and dried with sodium sulfate, decanted and concentrated in the presence of silica gel. The product was purified by column chromatography eluting with a gradient of 0-50% ethyl acetate in hexanes to yield 7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (0.65 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ 3.06 (m, 1H), 3.30 (m, 2H), 3.66 (s, 3H), 4.13 (m, 1H), 4.82 (d, 1H), 5.34 (d, 1H), 6.76 (d, 2H, J=8.79 Hz), 6.96 (d, 2H, J=8.79 Hz), 7.21-29 (m, 2H), 7.36-45 (m, 2H), 7.54-7.61 (m, 3H), 8.97 (d, 1H, J=5.86 Hz); ESI m/z 455.1.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].CS(O[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=O)=O>CN(C)C=O.O>[NH2:1][C@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Temperature: 25 °C

Procedure:
Sodium azide (7.65 g, 118 mmol) was added to a solution of 1,1-dimethylethyl (3R)-3-[(methylsulfonyl)oxy]-piperidine-1-carboxylate (21.9 g, 78.5 mmol) in dry dimethylformamide (120 mL) and the resultant suspension heated at 70° C. for 48 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted into ethyl acetate. The organic phase was washed two further times with water, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (10:90 to 50:50), to give the title compound as an oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C[N:20]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21]1.[CH3:28]NCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu](I)I.C(Cl)(Cl)Cl>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:20]4[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CNCCNC
Reactant: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: Cn1ccc(C(=O)O)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccn(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A suspension of 1-cyclobutyl-4-(4-iodophenoxy)piperidine (3 g; can be synthesized in accordance with the method described in WO2008072703), methyl 1H-pyrrole-3-carboxylic acid (1.75 g), N,N′-dimethylethylenediamine (0.592 g), copper iodide (0.32 g) and cesium carbonate (2.32 g) in toluene (8.4 mL) was stirred at 110° C. for 4 hours. The reaction mixture was left to cool to room temperature and, after adding chloroform, filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (NH form silica gel; eluent: n-hexane/ethyl acetate=88/12-0/100) to give the titled compound as a colorless solid (1.42 g).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([C:25]2[N:30]=[CH:29][C:28](Br)=[CH:27][N:26]=2)[CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[CH:15]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[N:34]1.C(=O)([O-])O.[Na+].O>COCCOC.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>[CH:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[CH:15]=2)[C:25]2[N:30]=[CH:29][C:28]([C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)=[CH:27][N:26]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CC[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(Br)cn2)C1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)OC(=O)N1CC[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)C1
Temperature: 95 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
To a mixture of (S)-3-{(5-bromo-pyrimidin-2-yl)-[3-chloro-5-(trifluoromethyl)benzyl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester (0.19 mmol, 100 mg), 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.23 mmol, 48 mg), tetrakis(triphenylphosphine)palladium(0) (0.02 mmol, 22 mg) and 2M aqueous sodium hydrogen carbonate (0.19 mL) in 1,2-dimethoxy-ethane (0.6 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: CH2Cl2/EtOAc). To the obtained mixture in CH2Cl2 (1 mL) is added saturated aqueous sodium carbonate (0.04 mL) and NaIO4 (82 mg). The mixture is stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (S)-3-{(3-Chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester (67 mg, 67%); ESI-MS m/z: 523 [M+1]+, Retention time 2.16 min (condition A).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22](=[O:24])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 99.1 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid (300 mg, 0.84 mmol), aniline (0.15 mL, 1.70 mmol), DMAP (60 mg, 0.50 mmol) and EDC.HCl (320 mg, 1.70 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated under vacuum and the residue was subjected to flash silica gel column chromatography eluting with methanol/CH2Cl2 (1:99, v/v) to give the desired amide 18 as a white solid (360 mg, 99% yield). 1H NMR (300 MHz, CDCl3) δ 1.55 (m, 4H), 2.60 (m, 2H), 3.20 (m, 2H), 4.58 (s, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.88 (d, 2H), 7.15 (m, 31), 7.35 (m, 7H), 7.58 (d, 2H), 8.25 (s, 1H). m/7/z (ESI): 433 [C26H28N2O4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[F:12][C:13]1[C:14]([C:20](=[NH:22])[NH2:21])=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1.[N:23]1([CH2:29][C:30](=O)[CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])(=O)C.[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([CH2:29][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[NH:21][C:20]([C:14]2[C:13]([F:12])=[CH:18][C:17]([F:19])=[CH:16][N:15]=2)=[N:22]1
Reactant: N=C(N)c1ncc(F)cc1F
Reactant: COC(=O)CC(=O)CN1CCOCC1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C1=C(CN2CCOCC2)NC(c2ncc(F)cc2F)=NC1c1ccc(F)cc1Cl

Procedure:
A solution of 0.38 g (2.4 mmol) of 2-chloro-4-fluorobenzaldehyde in 10 ml of isopropanol is heated together with 0.46 g (2.4 mmol) of the compound from Example VI, 0.48 g (2.4 mmol) of the compound from Example VIII and 0.24 g (2.88 mmol) of sodium acetate under reflux for 2 hours. The reaction mixture is concentrated, and the residue is taken up in dichloromethane and extracted with 2N hydrochloric acid. The aqueous phase is made alkaline with dilute ammonia solution and extracted with dichloromethane. The organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (20:1→10:1) as mobile phase, and the product is crystallized from diethyl ether.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)[CH3:21].C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].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>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1)[CH3:21]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CCc1ccccc1B(O)O
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: [Na+]
Solvent: CC#N
Product: CCc1ccccc1-c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Yield: 14.6 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 2-ethylphenylboronic acid (60 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 297 (11 mg). ESI-MS: 349.1 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:12][CH2:13]Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH3:15][P:16](OCC)(=[O:20])[O:17][CH2:18][CH3:19]>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:12][CH2:13][P:16]([O:17][CH2:18][CH3:19])([CH3:15])=[O:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CCOC(=O)[C@H](CCCl)NC(=O)OC
Reactant: CCOP(C)(=O)OCC
Product: CCOC(=O)[C@H](CCP(C)(=O)OCC)NC(=O)OC

Procedure:
2.6 g (11.6 mmol) of ethyl (S)-2-(methoxycarbonylamino)-4-chlorobutanoate and 6.3 g (46.4 mmol) of diethyl methanephosphonate are stirred for 15 h at 140° C. The excess diethyl methanephosphonate is then removed at 90° C. under a high vacuum. The crude product thus obtained is produced as a colorless oil and shows no further impurities in 1H-NMR; yield: 2.8 g (82%),
Reaction SMILES: Br[CH:2]([CH2:7]Br)[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:22]1[CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C(Br)CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a solution of methyl 2,3-dibromopropionate (92.50 g, 10.0 mmol) and K2CO3 (4.10 g 30.0 mmol) in acetonitrile (30 mL) was added dropwise benzylamine (1.20 mL, 11 mmol). After being stirred at rt for 4 h, and the reaction mixture was quenched with a saturated aqueous NH4Cl solution. The organic material was extracted with EtOAc, the extracts dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex 2/1) to give the title compound (1.62 g, 85%).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][OH:21])[CH3:17].[H-].[Na+]>CN(C=O)C>[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][O:21][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:17]
Reactant: CCN(CC)CCO
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1OCCN(CC)CC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.06 g (5.00 mmol) of ethyl 2-fluoro-5-nitrobenzoate and 0.58 mL (5.00 mmol) of 2-diethylaminoethanol are dissolved in 20 mL of DMF and at 0° C. 0.36 g (7.45 mmol) of sodium hydride (50%) is added. The mixture is stirred for 45 minutes at 0° C., poured onto ice water, and finally extracted three times with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is eliminated and the residue is purified through a silica gel column with petroleum ether/ethyl acetate (4:1) as eluant. Yield: 0.30 g (19% of theory); C15H22N2O5 (M=310.35); calc.: molecular ion peak (M+H)+: 311; found: molecular ion peak (M+H)+: 311; Rf value: 0.1 (silica gel, petroleum ether/ethyl acetate (4:1)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) and pyrrolidine in DMSO at 23° C. according to the general procedure C. Obtained as a yellow solid (6.65 g).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16]1.C(OCC)(=O)C>CO.[Pd]>[ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16]1
Reactant: Cc1ccccc1C(=CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccccc1C(CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Yield: 79.8 %

Procedure:
The acid prepared in Example 26 (1.0 g, 2.4 mmol) was dissolved in methanol (20 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (50% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a residue which was treated with ethyl acetate to give 0.8 g (80%) of the title compound as a solid.
Reaction SMILES: [N:1]([C:4]1([CH3:11])[CH:9]([OH:10])[CH2:8][CH:7]=[CH:6][CH2:5]1)=[N+:2]=[N-:3].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH3-]C#N.[Na+]>CO.C(Cl)Cl.CO>[N:1]([C:4]1([CH3:11])[CH2:5][CH2:6][N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:8][CH:9]1[OH:10])=[N+:2]=[N-:3]
Reactant: CC1(N=[N+]=[N-])CC=CCC1O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1(N=[N+]=[N-])CCN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A solution of 6-azido-6-methylcyclohex-3-enol (3.9 g, 25 mmol) in MeOH/DCM (100 mL/20 mL) cooled to −78° C. was degassed by bubbling nitrogen through it for 5 min. Ozone was then bubbled through the reaction mixture until a greyish-blue colour persisted. Nitrogen was again bubbled through the cold reaction mixture until only a pale colour persisted. A solution of benzylamine (2.7 g, 25 mmol) dissolved in MeOH (5 mL) was added followed by NaCNBH3 (6.4 g, 101.5 mmol) in MeOH (10 mL). The mixture was allowed to warm to room temperature and stirred for 16 hr. The solvents were removed under reduced pressure and the residue partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was further extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (40 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (1-10% 7 M NH3 in MeOH/DCM) gave 5-azido-1-benzyl-5-methylazepan-4-ol as a viscous yellow oil (4.8 g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.25-7.34 (m, 5H), 3.69-3.62 (m, 2H), 3.51-3.47 (m, 2H), 2.96-2.89 (m, 1H), 2.69-2.62 (m, 3H), 2.19-2.11 (m, 1H), 1.99-1.85 (m, 1H), 1.78-1.68 (m, 1H), 1.61-1.57 (m, 1H), 1.43 (s, 3H).