Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:25]([O-:27])=[O:26])=[C:6]([CH2:9][N+:10]3[N:11]([CH2:19][CH2:20][O:21]C(=O)C)[C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.Cl.[NH2:39][C:40]1[S:44][N:43]=[C:42](/[C:45](=[N:49]/[O:50][CH2:51][CH:52]=[CH2:53])/[C:46](Cl)=[O:47])[N:41]=1.CCOCC>ClCCl>[NH2:39][C:40]1[S:44][N:43]=[C:42]([C:45](=[N:49][O:50][CH2:51][CH:52]=[CH2:53])[C:46]([NH:1][C@@H:2]2[C:28](=[O:29])[N:4]3[C:5]([C:25]([O-:27])=[O:26])=[C:6]([CH2:9][N+:10]4[N:11]([CH2:19][CH2:20][OH:21])[C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=4)[CH2:7][S:8][C@H:3]23)=[O:47])[N:41]=1
Reactant: CC(=O)Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCOC(C)=O
Reactant: C=CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC(C)=O)n3CCO)CS[C@H]12)c1nsc(N)n1
Yield: 20.4 %

Procedure:
To a solution of di(trifluoroacetic acid) salt of 7β-amino-3-[3-acetamido-2-(2-acetoxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (1 g) and N-(trimethylsilyl)acetamide (2.01 g) in dichloromethane (20 ml) was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetyl chloride hydrochloride (0.520 g) under stirring and ice-cooling. The mixture was stirred for one hour at room temperature. The reaction mixture was added to ether under stirring and ice-cooling. The produced amorphous solid was dried in vacuo and dissolved in water. The aqueous solution was adjusted to pH 13 with 1N aqueous sodium hydroxide under stirring at -3°~0° C. and stirred for 2 hours at the same temperature. The aqueous solution was adjusted to pH 2 with 1N hydrochloric acid and subjected to column chromatography on Diaion HP-20 and the elution was carried out with 10% aqueous isopropyl alcohol. The fractions containing the object compound were combined, concentrated to remove isopropyl alcohol and lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[3-acetamido-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (222 mg).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Br:9][C:10]1[C:23]([F:24])=[C:22]([F:25])[C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[C:12]([F:26])[C:11]=1[F:27]>O1CCCC1>[Br:9][C:10]1[C:23]([F:24])=[C:22]([F:25])[C:13]([C:14]([C:16](=[CH:3][N:4]([CH3:5])[CH3:6])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[C:12]([F:26])[C:11]=1[F:27]
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(Br)c(F)c1F
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1c(F)c(F)c(Br)c(F)c1F

Procedure:
Dimethylformamide dimethylacetal (11.85 g) was added to a solution of 33.63 g ethyl 4-bromo-2,3,5,6-tetrafluorobenzoylacetate in 100 ml tetrahydrofuran cooled in an ice-bath. The reaction mixture was then immersed in a warm water bath in order to drive it to completion. The resulting solution was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)[N:3]=1.[CH2:22]([N:24](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+]>ClCCl.C(OCC)(=O)C.C1(C)C=CC=CC=1.O.CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][C:22]#[N:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1nn(-c2ccc(CO)cn2)c(C)c1-c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(-c2ccc(CC#N)cn2)c(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
To a stirred solution of [6-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)pyridin-3-yl]methanol (step 2, 1.51 g, 5.41 mmol), triethylamine (0.90 mL, 6.49 mmol), and dichloromethane (30 mL) was added methanesulfonyl chloride (0.46 mL, 5.95 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was treated with potassium cyanide (1.76 g, 27.0 mmol), N,N-dimethylformamide (25 mL) and water (5 mL) at 65° C. for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and toluene (2:1) and washed with water. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with hexane/ethyl acetate (6:1) to afford 0.63 g (41%) of the title compound: MS (ESI) m/z 289 [M+H]+, 287 [M−H]−, 1H-NMR (CDCl3) δ 8.39-8.38 (1H, m), 7.94 (1H, d, J=8.6 Hz), 7.79-7.76 (1H, m), 7.46-7.29 (5H, m), 3.77 (2H, s), 2.61 (3H, s), 2.31 (3H, s).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[N+:1]([CH2:3][C:4]([N:18]1[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:20][CH2:19]1)=[O:6])#[C-:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: [C-]#[N+]CC(=O)OC
Product: [C-]#[N+]CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared in accordance with Method B with methyl isocyanoacetate (2.51 g, 25.29 mmol) and piperazine-1-carboxylic acid tert-butyl ester (6.28 g, 33.85 mmol. The reaction mixture was stirred 1 h at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10% aqueous citric acid (2×25 mL), dried over MgSO4, filtered and evaporated. tert-Butyl 4-(2-isocyanoacetyl)piperazine-1-carboxylate SLA 07116C was obtained as a colorless oil (0.41 g, 6.5% yield).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:33]=[C:32]([F:34])[C:21]2[N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=[N:24][C:20]=2[C:19]=1[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:28]([O:27][C:25]([N:22]1[C:21]2[C:32]([F:34])=[CH:33][C:18]([N:17]=[C:8]=[S:9])=[C:19]([CH3:35])[C:20]=2[N:24]=[CH:23]1)=[O:26])([CH3:30])([CH3:31])[CH3:29]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (0.393 mg) and 4-dimethylaminopyridine (0.01 g) in methylene chloride (100 mL) is added dropwise over 30 minutes a solution of 5-amino-1-tert-butoxycarbonyl-7-fluoro-4-methylbenzimidazole (0.409 g) in methylene chloride (70 mL). The mixture is stirred at room temperature for 3 hours then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[C:10]([O:15][CH3:16])=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:21]([Cl:36])=[CH:20][N:19]=1.Cl.O1CCOCC1>C(O)(C)C>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[C:10]=2[O:15][CH3:16])=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)c(OC)c2CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)c2CC1

Procedure:
3-Ethyl-6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (50.0 mg, (0.23 mmol) was dissolved in isopropanol (3 mL) and the mixture was treated with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (58 mg, 0.17 mmol) and 4N HCl/Dioxane (0.056 mL, 0.20 mmol). The reaction was then irradiated at 140° C. for 20 minutes. The solution was reduced en vacuo and the product was isolated and purified by flash column chromatography (0% MeOH/DCM-15% MeOH/DCM) to afford 3.83 mg of N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a white foam, LC/MS (ESI)=523.39 (M+H). 1H NMR (400 MHz, DMSO, d6) δ 7.93 (s, 1H), 7.82 (m, 2H), 7.07 (d, 1H, J=8.59), 6.86 (m, 1H), 6.77 (m, 1H), 3.71 (m, 2H), 3.62 (s, 3H), 2.89 (s, 3H), 2.67 (m, 4H), 2.59 (m, 1H), 2.53 (m, 2H), 2.42 (m, 2H), 2.34 (m, 1H), 2.04 (m, 2H), 1.70 (m, 2H), 1.35 (m, 2H), 1.23 (m, 2H), 1.03 (m, 3H).
Reaction SMILES: O.Cl.Cl.[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:8]=2[CH2:7]1.CN(C)C1CC[C:26]2[O:27]C3C=CC(N)=CC=3[C:25]=2C1.Cl.Cl.C(Cl)(=O)C>>[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:26](=[O:27])[CH3:25])=[CH:13][C:12]=3[C:8]=2[CH2:7]1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: O
Product: CC(=O)Nc1ccc2oc3c(c2c1)CC(N(C)C)CC3
Yield: 76.6 %

Procedure:
Beginning with 9.0 mg (0.029 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine dihydrochloride hemihydrate and 2.8 mg (0.036 mMol) of acetyl chloride, 6.05 mg (77%) of the title compound were recovered by the procedure described in Example 2.
Reaction SMILES: F[C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH-:18].[Na+]>S([O-])([O-])(=O)=O.[Cu+2]>[OH:18][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CCCCCCOc1cccc(C(N)=O)c1F
Reactant: [OH-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCCCCCOc1cccc(C(N)=O)c1O
Temperature: 100 °C
Reaction time: 14 h

Procedure:
A mixture of 2-fluoro-3-Hexoxy-benzamide (0.30 g, 1.2 mmol), copper sulfate (0.10 g, 0.4 mol) copper (0.015 g, 0.2 mmol) and NaOH (2.5 ml) was stirred at 100° C. for 14 hrs. After completion of reaction the reaction mixture was acidified and extracted with EtOAc. The obtained crude compound was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as yellow (0.15 g, 50%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 3.9 (s, 3H), 7.11-7.18 (m, 2H), 7.53-7.58 (m, 1H). MS ES+ (229.0 M+2H adduct). HPLC (Method 7) Rt=11.16 min.
Reaction SMILES: C(OCC)C.[CH2:6]([C:13]1[C:14]2[CH2:21][CH2:20][CH:19]([C:22](OCC)=[O:23])[CH2:18][C:15]=2[S:16][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:6]([C:13]1[C:14]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][C:15]=2[S:16][CH:17]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1CCc2c(Cc3ccccc3)csc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCC1CCc2c(Cc3ccccc3)csc2C1
Reaction time: 0.5 h

Procedure:
A solution of 10 ml of diethyl ether containing 2.8 g of 3-benzyl-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene was slowly added dropwise into a suspension of 100 ml of diethyl ether containing 421 mg of lithium aluminum hydride under ice-cooling. After stirring as it was for 30 minutes, 0.4 ml of water, 0.4 ml of an aqueous 1N sodium hydroxide solution and 0.4 ml of water were successively added to the reaction solution and the mixture was dried over anhydrous magnesium sulfate. After filtering, the solvent was removed, to give 2.5 g of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.CN(C)CCN(C)C.[Li]CCCC.CN([CH:29]=[O:30])C.[NH4+].[Cl-]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[CH:29]=[O:30]
Reactant: COc1ccc2c(c1)OCCO2
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1C=O)OCCO2
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A cooled (−20° C.) mixture of 6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine (2.119 g; 12.80 mmol), and N1,N1,N2,N2-tetramethylethane-1,2-diamine (2.28 ml; 15.30 mmol) in anh. THF (100 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (8.00 ml; 12.80 mmol). The resulting mixture was further stirred at −20° C. for 1 h. Anh. DMF (5.0 ml; 64.57 mmol) was then added, and the mixture was stirred at rt for 20 min. Aq. sat. NH4Cl and Et2O were successively added, and the aq. layer was further extracted with Et2O. The mixed organic layers were washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded 6-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-5-carbaldehyde as a yellow oil. LC-MS (conditions A): tR=0.52 min.; [M+H]+: 195.19 g/mol.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.[Cl-].[NH4+]>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1[nH]nc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Br)c1=O
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 4-bromo-6-chloropyridazin-3(2H)-one (1.0 equiv.) and Cs2CO3 (1.2 equiv.) in DMF (0.07 M) was added iodomethane (1.5 equiv.) drop-wise over 20 min. The resulting mixture was stirred for 3 h. The reaction mixture was then diluted with ammonium chloride, then extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo to yield as a brown solid. The oil was further purified via silica gel column chromatography eluting with 100% heptanes to 80% ethyl acetate:heptanes to yield 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one as an off-white solid in 79% yield. LCMS (m/z) (M+H)=222.9/224.9, Rt=0.54 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.77-3.86 (m, 3H) 7.56-7.69 (m, 1H).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH3:7][CH2:8][S:9]([O:11][C:12]([CH:15]1[CH:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=2)[O:18][C:17](=[O:35])[CH2:16]1)([CH3:14])[CH3:13])=[O:10].S([O-])([O-])(=[O:38])=S.[Na+].[Na+]>CC(C)=O.O.C(O)(=O)C>[CH3:7][CH2:8][S:9]([O:11][C:12]([CH:15]1[CH:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=2)[O:18][C:17](=[O:35])[CH2:16]1)([CH3:13])[CH3:14])(=[O:38])=[O:10]
Reactant: O=S([O-])([O-])=S
Reactant: CCS(=O)OC(C)(C)C1CC(=O)OC1OCc1cccc(Oc2ccccc2)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)OC(C)(C)C1CC(=O)OC1OCc1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.084 g of potassium permanganate was added at 0° C. to a mixture of 0.214 g of trans dl 4-(2-ethylsulfinyloxy-isopropyl)-5-[(3-phenoxyphenyl)-methoxy]-tetrahydrofuran-2-one, 4 ml of acetone, 0.3 ml of acetic acid and 2 ml of water and the mixture was stirred at 0° C. for 2 hours. A solution of 0.050 g of potassium permanganate, 1 ml of water and 1 ml of acetone was added to the mixture which was then stirred at 0° C. for 17 hours and was poured into a sodium thiosulfate solution. The mixture was extracted with methylene chloride and the organic phase was washed with sodium bicarbonate solution and then with water, dried and evaporated to dryness without heating. The residue was chromatographed over silica gel and eluted with an 8-2 benzene-ethyl acetate mixture to obtain 0.090 g of trans dl 4-(2-ethyl-sulfonyloxy-isopropyl)-5-[(3-phenoxyphenyl)-methoxy]-tetrahydrofuran-2-one whose IR and NMR spectrum were identical to the compound of Example 1.
Reaction SMILES: [NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:19]3[CH2:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:31])(=[O:30])[CH2:21][CH2:20]3)[CH:9]=2)[CH2:5][O:4][CH2:3]1.[CH:32](=O)[CH3:33].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[O:30]=[S:22]1(=[O:31])[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH2:25][N:19]([C:10]2[CH:9]=[C:8]([NH:7][CH2:6][C:2]3([NH:1][CH2:32][CH3:33])[CH2:5][O:4][CH2:3]3)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=2)[CH2:20][CH2:21]1
Reactant: CC=O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N)COC3)c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCNC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C)cc23)COC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.6 %

Procedure:
To a stirred solution of N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (200 mg, 0.46 mmol, prepared in analogy to Example 2-2), acetaldehyde (25.6 μL, 0.46 mmol) and acetic acid (270 μL) in methanol (8 mL) was added dropwize a solution of sodium cyanoborohydride (34 mg, 0.54 mmol) in tetrahydrofuran (0.5 mL). After being stirred for 12 hours at room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 42 mg of the desired product as a white solid (yield was 20%). MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, J=1.9 Hz, 1 H), 7.89-7.87 (t, J=2.2 Hz, 1 H), 7.64-7.58 (m, J=6.0 Hz, 2 H), 7.49-7.45 (m, J=4.0 Hz, 1 H), 7.35 (d, J=2.1 Hz, 1 H), 7.27-7.24 (m, J=2.5 Hz, 1 H), 6.17 (s, 1 H), 5.11 (s, 2 H), 4.52 (d, 2 H), 4.37 (d, 4 H), 3.62-3.45 (t, J=2.4 Hz, 2 H), 3.58 (d, 2 H), 2.53 (m, 2 H), 2.37 (s, 3 H), 1.07-1.03 (t, J=3.6 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26])(=[O:19])=[O:18]>>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:25](=[O:26])[C:24]3[CH:28]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=[CH:22][C:23]=3[C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Reactant: N#Cc1ccc(N2CCNCC2)cc1F
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)N2CCN(c3ccc(C#N)c(F)c3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 2-Fluoro-4-piperazin-1-yl-benzonitrile [204192-45-0] and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 471.0 MH+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([S:34](C2C=CC(C3C=C4N=C(CCC5NC(=S)CCCC5)NC4=NC=3)=CC=2)(=[O:36])=[O:35])[CH2:30][CH2:29]1)[CH3:27].N>CO>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([S:34]([C:4]2[CH:3]=[CH:2][C:1]([C:7]3[CH:8]=[C:9]4[N:15]=[C:14]([CH2:16][CH2:17][CH:18]5[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]5)[NH:13][C:10]4=[N:11][CH:12]=3)=[CH:6][CH:5]=2)(=[O:35])=[O:36])[CH2:30][CH2:29]1)[CH3:27]
Reactant: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=S)N5)nc4c3)cc2)CC1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Agent: N
Solvent: CO
Product: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(N)=N5)nc4c3)cc2)CC1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 157 mg of 7-(2-{6-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepane-2-thione (compound A7) and 6.90 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 90 hours. Purification by flash chromatography on LiChroprep-NH2® (eluent gradient: ethyl acetate/0-100 vol. % 2-propanol) affords 28 mg of the title compound as an amorphous solid of m.p. 199° C. ESI-MS: 528.2 (MNH4+), 510.4 (MH+), TLC: Rf=0.30 (LiChroprep-NH2® HPTLC, neat methanol).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[N:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])=[N:8]2)#[N:2].C1C[O:33]CC1.O>>[C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[N:6]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:7]([C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH3:14])=[N:8]2)(=[O:33])[NH2:2]
Reactant: C1CCOC1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(C#N)c2c(=O)n1-c1ccccc1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(C(N)=O)c2c(=O)n1-c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of (S)-tert-butyl (1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate (105 mg, 0.269 mmol) in THF/H2O (1 mL each) was added Ghaffar's catalyst. The mixture was heated to 80° C. overnight. Purification by flash chromatography (25 g silica, 0-100% EtOAc/DCM) provided (S)-tert-butyl (1-(5-carbamoyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate as a white solid. ES/MS 409.1 (M+H+).
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1N1CCOCC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
Ammonium chloride (2 g) and iron powder (18.9 g) were added to a mixed solvent of water (65 ml) and ethanol (197 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-morpholinobenzonitrile (19.7 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (12.9 g), melting point: 147–148° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)([O-:33])=[O:32]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 138 %

Procedure:
{4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (300 mg, 0.94 mmol), 2-fluoronitrobenzene (100 μl, 0.95 mmol) and potassium carbonate (150 mg, 1.08 mmol) were stirred together at room temperature in N,N-dimethylformamide (1 ml) for 2 days. The reaction mixture was concentrated in vacuo and the residue partitioned between water (30 ml) and ethyl acetate (100 ml). The layers were separated and the organic phase washed with water (2×20 ml), dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow gum (570 mg, 100%). HRMS ESI+ m/z 440.2537 [MH]+.