Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.S(Cl)(Cl)=O.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:1][C:2]1[C:3]([C:12]([N:21]([O:22][CH3:23])[CH3:20])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CNOC
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a mixture of 8-hydroxyquinoline-7-carboxylic acid (5.0 g, 26 mmol, TCI America) in methylene chloride (50 mL) was added thionyl chloride (4.24 mL, 58.1 mmol). After stirred at room temperature overnight, the mixture was concentrated to dryness under reduced pressure. The residue was exposed to high vacuum then mixed with tetrahydrofuran (50 mL). To the resultant mixture was added N,O-dimethylhydroxylamine hydrochloride (3.09 g, 31.7 mmol) followed by N,N-diisopropylethylamine (13.8 mL, 79.3 mmol). The reaction was heated at 50° C. overnight, then cooled and quenched with water, and extracted with dichloromethane. The combined organic layers were washed with water, brine and dried over sodium sulfate. After evaporated to dryness, the residue was purified on silica gel, eluting with 0 to 10% methanol in dichloromethane, to give the desired product (4.09 g, 66%). LCMS calculated for C12H13N2O3(M+H)+: m/z=233.1; found: 233.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH2:19](I)[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CC(=O)CC.CCOCC>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:21][CH:20]=[CH2:19])=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Oc2ccc(O)cc2)cc1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CS(C)=O
Solvent: CCOCC
Product: C=CCOc1ccc(Oc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 4-(4-hydroxyphenoxy)benzoic acid methyl ester (5.00 g, 20.5 retool), allyl iodide (3.79 g, 22.5 mmol), potassium carbonate (8.49 g, 61.5 mmol), and dimethylsulfoxide (10 mL) in 2-butanone (40 mL) was refluxed for 24 hours. The mixture was cooled to room temperature and diluted with ether. The resulting mixture was washed once with water and once with saturated sodium bicarbonate solution. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to provide 4.52 g (78%) of the title intermediate as a white solid: mp 75° C.; 1H--NMR (CDCl3) 7.99 (d, J=9 Hz, 2H), 7.03 (d, J=9 Hz, 2H), 6.95 (m, 4H), 6.08 (m, 1H), 5.46 (d, J=14 Hz, 1H), 5.31 (d, J=10 Hz, 1H), 4.55 (d, J=7 Hz, 2H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:11][O:12][C:13](=[O:18])[CH2:14][C:15]([CH3:17])=O.[NH2:19]/[C:20](/[CH3:39])=[CH:21]\[C:22]([O:24][CH2:25][C:26]([CH3:38])([CH3:37])[CH2:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29])=[O:23].N>>[CH3:39][C:20]1[NH:19][C:15]([CH3:17])=[C:14]([C:13]([O:12][CH3:11])=[O:18])[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[C:3]=2[F:10])[C:21]=1[C:22]([O:24][CH2:25][C:26]([CH3:38])([CH3:37])[CH2:27][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:29])=[O:23]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: C/C(N)=C/C(=O)OCC(C)(C)CN(C)Cc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)Cc2ccccc2)C1c1cccc(Cl)c1F

Procedure:
To a solution of 158.5 mg of 3-chloro-2-fluorobenzaldehyde and 116 mg of methylacetoacetate in 1 ml of 2-pranol was added 291 mg of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl 3-aminocrotonate. To the mixture was added 0.1 ml of concentrated aqueous ammonia. The resulting maxture was refluxed for 9 hours. The solvent was distilled off under reduced pressure. The residue was chromatographed over silica gel to give the desired compound (156) with the identical physical properties to those of the compound in the Example 18-(i).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:6]([O:8]CC)=[O:7])C.[OH-].[Na+]>C(O)C>[CH2:15]([O:14][C:12]([NH:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:22])=[O:3])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC(C(=O)O)C(=O)O)OCc1ccccc1
Reaction time: 19 h
Yield: 96.4 %

Procedure:
Compound 2 (3.49 mmol, 1.08 g) was dissolved in 3 mL 95% ethanol and treated with 3.49 mL 2N NaOH. The clear, colorless solution was left at room temperature for 19 hours until no starting material could be detected by tlc on silica gel (benzene:ethyl acetate, 4:1). Ethanol was evaporated under reduced pressure at room temperature. The aqueous solution was washed once with ether and then acidified with concentrated HCl to pH 2.5. The milky solution was extracted with ethyl acetate (3x). The pooled extract was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness. The product was crystallized from ether to yield 0.852 g of compound 3; mp 144°-145° C.; homogeneous by the tlc on silic gel (CHCl3 :methanol:acetate acid, 5:13:1); 250 MHz nmr (acetone-d6, ppm) 5.00 (1H, d, J=8 Hz, α--H), 5.10 (2H, s, ArCH2 --), 6.84 (1H, d, J=8 Hz, amide H), 7.36 (5H, m, ArH5). In a 60 MHz spectrum run in low water content acetone, a 9.7 ppm (2H, broad s, exchangeable with D2O) was also observed.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]Cl)=[C:13]([C:19]([Cl:22])([Cl:21])[Cl:20])[CH:12]=1)([O-:10])=[O:9]>CCOCC>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[S:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][C:13]=1[C:19]([Cl:20])([Cl:21])[Cl:22])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)N(Sc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl)C(C)C
Yield: 94.2 %

Procedure:
A solution of 40 g of diisopropylamine in 400 ml of ether is placed in a stirred apparatus; at 10° C., 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 200 ml of ether is dripped in. After the mixture has been reacted for 4 hours at 25° C., it is filtered and concentrated. There is obtained 70 g (95% of theory) of N,N-diisopropyl-4-nitro-2-trichloromethylphenylsulfenamide; m.p.: 104° C.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O-:12][Mn](=O)(=O)=O.[K+].[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:1]([N:8]1[C:9](=[O:12])[S:10][N:20]([CH2:18][CH3:19])[C:21]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=O
Reactant: S=C=NCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CCn1sc(=O)n(Cc2ccccc2)c1=O

Procedure:
Reagents: Benzyl isothiocyanate (0.86 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), ethyl isocyanate (0.51 ml, 6.5 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:18]2[C:17](=[O:19])[C:16]([C:20]([OH:22])=[O:21])=[CH:15][N:7]3[C:8]4([CH2:14][CH2:13][O:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:24].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][CH2:33][NH2:34].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O.O>[NH2:1][C:2]1[C:18]2[C:17](=[O:19])[C:16]([C:20]([OH:22])=[O:21])=[CH:15][N:7]3[C:8]4([CH2:14][CH2:13][O:12][CH2:11]4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:34][CH2:33][CH2:32][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[C:3]=1[F:24]
Reactant: NCCCc1ccccn1
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCOC1)CO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1c(F)c(NCCCc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3C1(CCOC1)CO2
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A solution of 8′-amino-9′,10′-difluoro-7′-oxospiro[oxolane-3,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (300 mg, 0.887 mmol), 3-(2-pyridyl)propylamine (181 mg, 1.33 mmol) and triethylamine (0.185 mL, 1.33 mmol) in DMSO (4 mL) was stirred at 100° C. for 6 h. To the reaction mixture, water and saturated NH4Cl solution were added to pH <4 and stirred for 30 min. The resulting precipitate was collected by filtration, washed with water and EtOH, and dried to yield 8′-amino-9′-fluoro-7′-oxo-10′-[3-(2-pyridyl)propylamino]spiro[oxolane-3,3′(2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (373 mg, 93%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ1.90-1.98 (2H, m), 2.26-2.39 (2H, m), 2.77 (2H, t, J=7.3 Hz), 3.42-3.51 (2H, m), 3.73 (1H, d, J=10.4 Hz), 3.91-3.97 (1H, m), 4.07-4.13 (1H, m), 4.16 (1H, d, J=10.4 Hz), 4.24 (1H, d, J=11.0 Hz), 4.35 (1H, d, J=11.0 Hz), 6.01-6.10 (1H, m), 6.92 (2H, brs), 7.18 (1H, dd, J=6.7, 5.5 Hz), 7.24 (1H, d, J=7.9 Hz), 7.67 (1H, td, J=7.3, 1.8 Hz), 8.42 (1H, s), 8.45 (1H, d, J=4.3 Hz), 15.27 (1H, s). HRESIMS (+) 455.17350 (Calcd for C23H23FN4O5, 455.17307).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31][C:32]1[N:37]=[C:36]([CH:38](O)[CH2:39][C:40]2[CH:48]=[C:47]([CH3:49])[C:46]3[C:42](=[CH:43][N:44]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:45]=3)[CH:41]=2)[CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.CCCCCC>[Br:31][C:32]1[N:37]=[C:36]([CH:38]([N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:39][C:40]2[CH:48]=[C:47]([CH3:49])[C:46]3[C:42](=[CH:43][N:44]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:45]=3)[CH:41]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CC(O)c2cccc(Br)n2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc(CC(c2cccc(Br)n2)N2C(=O)c3ccccc3C2=O)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 118.3 %

Procedure:
A solution of phthalimide (294 mg, 2 mmol) and triphenylphosphine (525 mg, 2 mmol) in anhydrous methylene chloride (10 mL) was added via syringe to (±)-1-(6-bromopyridin-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethanol (460 mg, 1 mmol). To the resulting suspension was then added diisopropylazidodicarboxylate (0.3 mL, 1.5 mmol) under nitrogen at room temperature via syringe. The resulting mixture was stirred at room temperature overnight (17 h). The mixture was diluted with hexane and purified by flash column chromatography to give a light yellow oil (700 mg, 100%). MS (ESI) [M+H]+=592. HPLC tR=2.05 min.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[F:20][C:2]([F:19])([F:1])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCNC(c2cccc(C(F)(F)F)c2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.1 %

Procedure:
Methyl 2-(3-(trifluoromethyl)phenyl)piperidine-4-carboxylate (1.4 g, 4.87 mmol) was dissolved in DCM (50 mL), then DIPEA (2.128 mL, 12.18 mmol) was added. Methyl chloroformate (0.537 mL, 6.82 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 4 h, washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), dried through a phase separator and evaporated yielding dimethyl 2-(3-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (1.7 g, quant.) as an orange oil. MS m/z 346 (M+H)+
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]2[C:8]=1[CH:9]=[CH:10][CH2:11]2.Br[CH2:18][CH:19](Br)[CH2:20][CH3:21].Cl>CCCCCC.O1CCCC1>[CH3:4][C:3]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:1]2[C:2]=1[CH:21]=[CH:20][CH:19]2[CH2:18][CH:10]([CH:11]1[C:12]2[C:8](=[C:7]([CH3:6])[CH:15]=[CH:14][C:13]=2[CH3:16])[CH:9]=[CH:10]1)[CH2:11][CH3:12]
Reactant: CCC(Br)CBr
Reactant: Cc1ccc(C)c2c1C=CC2
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC1C=Cc2c(C)ccc(C)c21)C1C=Cc2c(C)ccc(C)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
52 ml (83.2 mmol) of a 1.6 M solution of butyllithium in hexane were added dropwise to 11.8 g (92 mmol) of 4,7-dimethylindene in 200 ml of tetrahydrofuran at room temperature under an Ar atmosphere, and the mixture was stirred at 60° C. for 1 hour. It was cooled to -78° C., 5 ml (40 mmol) of 1,2-dibromobutane were added, and stirring was continued overnight at room temperature. The reaction mixture was poured onto 2 N aqueous HCl and the organic phase was separated off, washed with saturated aqueous NaHCO3 solution and NaCl solution in succession and dried (MgSO4). The oil which remained after the solvent had been stripped off under reduced pressure was chromatographed on 350 g of silica gel (hexane). After drying under an oilpump vacuum, 1.4 g (10%) of product were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH:39]([C:40]2[NH:44][C:43]3[CH:45]=[C:46]([C:49]4[CH:54]=[CH:53][C:52](B5OC(C)(C)C(C)(C)O5)=[CH:51][CH:50]=4)[CH:47]=[CH:48][C:42]=3[N:41]=2)[CH:38]2[CH2:64][CH:35]1[CH2:36][CH2:37]2)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.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>[C:27]([O:31][C:32]([N:34]1[CH:39]([C:40]2[NH:44][C:43]3[CH:45]=[C:46]([C:49]4[CH:54]=[CH:53][C:52]([C:23]5[CH:22]=[CH:21][C:20]([C:17]6[NH:16][C:15]([CH:14]7[CH2:13][C:10]8([CH2:11][CH2:12]8)[CH2:9][N:8]7[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[N:19][CH:18]=6)=[CH:25][CH:24]=5)=[CH:51][CH:50]=4)[CH:47]=[CH:48][C:42]=3[N:41]=2)[CH:38]2[CH2:64][CH:35]1[CH2:36][CH2:37]2)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2[nH]1
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: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]c5c4)cc3)cc2)[nH]1
Temperature: 90 °C
Yield: 30 %

Procedure:
A mixture of 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (101 mg, 0.243 mmol, 1 eq.), 3-{6-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-benzoimidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (150 mg, 0.291 mmol, 1.2 eq.), tetrakis(triphenylphosphine)palladium (5%, 17 mg) and 2M potassium carbonate aqueous solution (5 eq., 0.73 mL) in 1.5 mL DME was heated to 90° C. under Are overnight. The reaction mixture was cooled and dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexane) to give 3-(6-{4′-[2-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (53 mg, yield 26%). LCMS-ESI−: calc'd for C44H50N6O4: 726.91. Found: 727.2 (M+H+).
Reaction SMILES: CC1C=C[C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O-:19])(=[O:18])[C:12]1C=CC=[CH:14][CH:13]=1>>[C:8]1(=[O:10])[O:9][CH2:3][CH2:4][CH2:5]1.[CH:13]([CH2:12][C:11]([OH:19])=[O:18])=[CH2:14]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C([O-])c1ccccc1
Product: C=CCC(=O)O
Product: O=C1CCCO1

Procedure:
The reaction was carried out as described in Example 15, with the exception that 170 grams of the allyl ester of p-toluylic acid were used instead of the benzoate. 21.2 grams of γ-butyrolactone and 8.8 grams of vinyl acetic acid were obtained.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[CH:9][CH:8]=1.S(Cl)(Cl)=O.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:24]=[C:25]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:26][NH:27][CH:28]1[CH2:30][CH2:29]1>ClCCl.CN(C)C=O>[F:21][C:22]([F:38])([F:39])[C:23]1[CH:24]=[C:25]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:26][N:27]([CH:28]1[CH2:29][CH2:30]1)[C:13](=[O:15])[C:12]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:16])=[CH:8][CH:9]=[N:10][CH:11]=1
Reactant: FC(F)(F)c1cc(CNC2CC2)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A solution of 106 mg (0.5 mmol) 4-o-tolyl-nicotinic acid in 5 ml dichloromethane and 2 drops N,N-dimethylformamide was stirred with 0.1 ml (1.4 mmol) thionyl chloride for 1.5 h at room temperature. The solvent was removed and the residue was taken up in 5 ml dichloromethane and 0.3 ml triethylamine. After the addition of 155 mg (0.55 mmol) (3,5-bis-trifluoromethyl-benzyl)-cyclopropyl-amine the mixture was stirred at room temperature for 1 h and washed twice with water. The organic layer was dried (magnesium sulfate) and evaporated. The crude oil was subjected to column chromatography to give 140 mg (58%) of the title compound as an oil.
Reaction SMILES: N1CCCN2CCCCCC=12.[C:12]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]3[N:24]=[C:25](S(C)(=O)=O)[N:26](COCC[Si](C)(C)C)[C:21]3=[CH:20][C:19]=2[Cl:39])=[CH:14][CH:13]=1.[Si]([O:53][C@H:54]1[C@H:58]2[O:59][CH2:60][CH:61]([CH2:62][CH2:63][OH:64])[C@H:57]2[O:56][CH2:55]1)(C(C)(C)C)(C)C.O>CN(C=O)C>[C:12]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]3[N:24]=[C:25]([O:64][CH2:63][CH2:62][CH:61]4[C@H:57]5[O:56][CH2:55][C@@H:54]([OH:53])[C@H:58]5[O:59][CH2:60]4)[NH:26][C:21]3=[CH:20][C:19]=2[Cl:39])=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(CCO)CO[C@@H]21
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: O[C@@H]1CO[C@@H]2C(CCOc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.019 ml, 0.128 mmol) was added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (52.6 mg, 0.102 mmol) and 2-((3aR,6R,6aS)-6-((tert-butyldimethylsilyl)-oxy)hexahydro-furo[3,2-b]furan-3-yl)ethanol (38.4 mg, 0.133 mmol) in DMF (1 ml) and the mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative TLC, eluting with EtOAc/isohexane (1:1) to give the title compound. LC-MS: calculated for C38H52ClN3O5Si2 721.31 observed m/e: 722.39 (M+H)+ (Rt 1.58/2 min)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]6[CH:45]=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][C:41]=5[CH3:49])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]6[CH:45]=[CH:46][CH:47]=[CH:48][C:43]6=[N:42][C:41]=5[CH3:49])=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)nc5ccccn45)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)nc5ccccn45)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazol[1,2-a]pyridin-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.43 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetatehexane 3:1→ethyl acetate), and was recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazol[1,2-a]pyridin-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 163) (456.5 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[NH2:10].N[C:12](N)=O.[OH2:15]>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:10]=[C:9]([OH:15])[N:8]2[CH3:12]
Reactant: O
Reactant: CNc1ncnc(Cl)c1N
Reactant: NC(N)=O
Product: Cn1c(O)nc2c(Cl)ncnc21
Temperature: 180 °C
Yield: 60 %

Procedure:
A mixture of 4.76 parts of 6-chloro-N4 methyl-4,5-pyrimidinediamine and 7.2 parts of urea was stirred and heated for 1 hour at 180° C. After cooling, the residue was suspended in water. The product was filtered off and dried, yielding 3.3 parts (60%) of 6-chloro-9-methyl-9H-purin-8-ol (intermediate 174).
Reaction SMILES: Cl.C(O)(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(Cl)Cl.[C:14](Cl)(=[O:18])C(Cl)=O.[N-:20]=[N+]=[N-].[Na+]>C1(C)C=CC=CC=1>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:20]=[C:14]=[O:18])[CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=Nc1cccnc1
Reaction time: 3 h

Procedure:
Nicotinic acid hydrochloride (296 mg, 2.40 mmol) was suspended with 2 ml of methylene chloride and 2 ml of oxalic chloride was added and refluxed with stirring for 3 hours, then concentrated in reduced pressure. Residue was suspended with 10 ml of toluene and sodiumazide (468 mg, 7.2 mmol) was added and refluxed with stirring for 1 night to form 3-pyridylisocyanate. Methyl (1S,8S,12S)-2-aminomethyl-4,4-dimethyl-3,5,11-trioxa-12-benzyloxy-tricyclo[6.4.0.0<2,6>] dodec-9-en-9-carboxylate was added to above obtaind solution, and 2 ml of pyridine was added drop by drop and stirred for 2 hours at room temperature. Ethylacetate was added to reaction mixture and washed with saturated sodium bicarbonate and saturated saline solution. After drying and concentrating with anhydrous magnesium sulfate, residue was purified by using silica gel column chromatography (hexane/ethylacetate=2/1, v/v), and 550 mg of captioned compound was obtained (yield: 90%).