Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].CO[C:16](=O)[CH:17]([CH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[C:46]([CH3:48])[CH:47]=1)[NH:44][N:43]=[CH:42]2)[CH2:18][C:19](=[O:37])[N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1>O1CCCC1>[CH2:4]([C:3]1[N:11]=[C:16]([CH:17]([CH2:38][C:39]2[CH:40]=[C:41]3[C:45](=[C:46]([CH3:48])[CH:47]=2)[NH:44][N:43]=[CH:42]3)[CH2:18][C:19]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH2:22][CH2:21]2)=[O:37])[O:1][N:2]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1cc(C)c2[nH]ncc2c1
Reactant: N=C(Cc1ccccc1)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nc(Cc3ccccc3)no2)cc2cn[nH]c12
Temperature: 65 °C
Yield: 27 %

Procedure:
To a solution of N-hydroxy-2-phenyl-acetamidine (0.27 mmol, 3 equiv, this and the other amidine intermediates of the present invention were prepared as described in J. Med. Chem. 1993, 1529-1538) in anhydrous tetrahydrofuran (4 mL) was added sodium hydride (0.27 mmol, 3 equiv) under nitrogen. The mixture was heated at 65° C. for 30 min before addition of a solution of (±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyric acid methyl ester (0.09 mmol, 1 equiv) in tetrahydrofuran (3 mL). The reaction mixture was heated at 65° C. overnight. Tetrahydrofuran was removed in vacuo and the reaction mixture was taken up in methylene chloride, washed with water (3×4 mL), dried over sodium sulfate and concentrated. Flash chromatography on silica gel using methanol/methylene chloride from 0 to 10% gave an impure product. The final product was obtained by preparative HPLC in 27% yield. LC/MS: tR=1.60 min, 590 (MH)+. 1H-NMR (400 MHz, CD3OD) δ 7.92 (1H, s), 6.90-7.25 (10H, m), 6.74 (1H, d, J=8.00 Hz), 4.32-4.57 (2H, m), 4.24-4.29 (2H, m), 3.79-4.06 (5H, m), 2.79-3.31 (5H, m), 2.57 (1H, m), 2.44 (3H, s), 1.50-1.82 (4H, m).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:31][CH3:32])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:21]>C(#N)C>[CH2:31]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:26]1)[CH3:32]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: CCN(CC)CCC1CCCNC1
Solvent: CC#N
Product: CCN(CC)CCC1CCCN(C(=O)N2c3ccccc3NC(=O)c3cccnc32)C1
Yield: 54 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[2-(diethylamino)ethyl]piperidine in a yield of 54% of theory. Colourless crystals, m.p. 110°-113° C. (acetonitrile).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[N:16][CH:17]=1>>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:22])([F:10])[F:21])=[CH:17][N:16]=2)=[CH:3][CH:4]=1)[CH3:9]
Reactant: CCc1ccc(Br)cc1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: CCc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-ethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 295.2 [M+H]+) was prepared from 1-bromo-4-ethyl-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[C:6]([OH:14])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNOC
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
N,O-dimethyl hydroxyl amine hydrochloride (4.393 g, 45.037 mmol) was added to a stirred solution of benzoic acid (5.0 g, 40.943), EDC.HCl (9.418 g, 49.132) and N-methyl morpholine (4.141 g, 40.943 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at rt for 4 h. After completion of the reaction, the reaction mixture was concentrated. Diethyl ether was added and the mixture was extracted with water and brine. The organic layer was dried over Na2SO4 and filtrated. Concentration of the organic layer furnished the title compound as a colorless liquid (4.933 g, 73%). [1H-NMR (CDCl3, 300 MHz) δ 7.72-7.64 (m, 2H), 7.52-7.36 (m, 3H), 3.58 (s, 3H), 3.38 (s, 3H); HPLC RtA=6.281 min. (98%); LCMS RtA=0.38 min; [M+H]+=166.1]
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:46]2[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=2)O1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)aniline were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene as pale yellow powder. APCI-Mass m/Z 630/632 (M+H). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene was treated in a manner similar to Example 106-(3) to give the desired 1-(β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene as pale yellow foam. APCI-Mass m/Z 479/481 (M+NH4).
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]([CH3:24])([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1)([OH:3])=O.OC1C2N=NNC=2C=CC=1.[CH3:41][C:42]1[CH:48]=[C:47]([O:49][CH3:50])[C:46]([CH3:51])=[CH:45][C:43]=1[NH2:44].Cl.CN(C)CCCN=C=NCC>ClCCl.C(N(CC)CC)C>[CH3:41][C:42]1[CH:48]=[C:47]([O:49][CH3:50])[C:46]([CH3:51])=[CH:45][C:43]=1[NH:44][C:1](=[O:3])[CH2:4][N:5]([CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]([CH3:23])([CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1
Reactant: COc1cc(C)c(N)cc1C
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCN(CC(=O)O)Cc2ccco2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(NC(=O)CN(CCc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
98 mg of 1,1-dimethylethyl 2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]-ethyl]phenyl]thio]-2-methyl-propanoate, 33 mg of hydroxybenzotriazole, 0.09 ml of triethylamine, 34 mg of 2,5-dimethyl-4-methoxyaniline and 49 mg of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are dissolved in 5 ml of dichloromethane. The mixture is stirred at room temperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water and sat. NaCl solution. The combined organic phases are dried (MgSO4) and purified chromatographically (dichloromethane/ethyl acetate 5+1). This gives 48 mg of a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7](Br)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[C:1]([O:5][C:6](=[O:10])[CH:7]([P:11]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: CCOP(=O)(OCC)C(C)C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
2-Bromo-propanoic acid tert-butyl ester (17.4 g, 83 mmol) and triethyl phosphite (14.5 g, 87 mmol) were mixed, and the mixture was stirred at 110° C. overnight. The reaction mixture was dried under reduced pressure to give the title compound (23.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].C(N(CC)CC)C.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1.Cl>O1CCCC1>[F:34][C:35]([F:45])([F:46])[C:36]1[CH:44]=[CH:43][C:39]([C:40]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=2[Cl:26])[CH3:13])=[O:41])=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran were placed in a reaction vessel, to which 0.25 g of 4-trifluoromethylbenzoyl chloride was slowly added dropwise with stirring at room temperature. After completion of the addition, the reaction mixture was further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.59 g (yield, 96%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-(4-trifluoromethylbenzoyl)oxime, nD25.6 1.5300.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21]>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:18]([F:17])[CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Reactant: COc1ccc(N)cc1F
Product: CCn1c(=O)ccc2cnc(Nc3ccc(OC)c(F)c3)nc21
Temperature: 175 °C
Yield: 41 %

Procedure:
A mixture of 8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (124 mg, 0.52 mmol) and 148 mg (1.05 mmol) of 3-fluoro-4-methoxyaniline was heated at 175° C. for 10 minutes. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate. Recrystallization from ethyl acetate and hexane provided 67 mg (41 %) of 8-ethyl-2-(3-fluoro-4-methoxyphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 196-198° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:38])[N:8]([C:27]2[N:32]=[CH:31][C:30]([O:33][CH2:34][C:35](O)=[O:36])=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl.C([N:42]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.N>O.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:38])[N:8]([C:27]2[N:28]=[CH:29][C:30]([O:33][CH2:34][C:35]([NH2:42])=[O:36])=[CH:31][N:32]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCc1nc(C)n(-c2ncc(OCC(=O)O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCCc1nc(C)n(-c2ncc(OCC(N)=O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
Process 2: The dichloromethane (3 mL) solution of 2-{2-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]pyrimidin-5-yl oxy}acetic acid (51 mg, 0.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (29 mg, 0.15 mmol) and 1-hydroxybenzotriazol-hydrate (21 mg, 0.15 mmol) was stirred at room temperature for 1 hr. Ammonia (28% aqueous solution, 0.5 mL) was added thereto and stirred at room temperature for 4 hrs. The reaction mixture was added water and extracted with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (chloroform/methanol) to obtain 2-{2-{4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl}pyrimidin-5-yl oxy}acetamide (35 mg, 69%) as a colorless and transparent oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([CH3:32])[CH:8](N)[O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:6]=1.[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:40]CC(OC)CSCCCCCCCCCCCCCCCC)(=[O:39])=[O:38]>>[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([NH:40][CH2:32][CH:7]([N:5]1[N:4]=[N:3][C:2]([CH3:1])=[N:6]1)[CH2:8][O:9][C:10](=[O:30])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:39])=[O:38]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OC(N)C(C)n1nnc(C)n1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)n1nnc(C)n1

Procedure:
2-(5-Methyl-2H-tetrazol-2-yl)-1-octadecylcarbamoyloxypropylamine IVh2 is allowed to react and worked up by the same procedure as described in (4). m.p. 70°-70.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:27])[C:25]=1[OH:26])[CH:21]=O>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:16])[CH:15]=[CH:21][C:20]2[CH:23]=[C:24]([CH3:27])[C:25]([OH:26])=[C:18]([CH3:17])[CH:19]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(C=CC(=O)c2ccc(Oc3ccccc3)cc2)cc(C)c1O

Procedure:
This compound was synthesized from 4′-phenoxyacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([CH2:17][OH:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1cccc(I)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1cccc(I)c1
Reaction time: 1.5 h

Procedure:
A solution of [(R)-1-hydroxymethyl-2-(3-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester K-9 (5.32 g, 14.1 mmol) in DCM (100 mL) was added dropwise to a RT suspension of DMP (6.78 g, 15.5 mmol) in DCM (40 mL) and the resulting mixture was stirred for 1.5 h. The reaction was quenched with 20% aq. NaHCO3 and 10% aq. Na2S2O3 and stirred for 1 h. The layers were separated and the aqueous layer was extracted with DCM (2×). The combined organic extracts were washed with 1M aq. HCl, brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was subsequently triturated with a little DCM to give the title compound as an orange solid. LC-MS A: tR=0.87 min; [M+H]+=No ionisation.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH2:28][CH3:29])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Pb+3:17])=[C:21]([CH2:28][CH3:29])[CH:20]=1
Reactant: [Pb+4]
Reactant: CCc1cc(Br)ccc1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1[Pb+3]
Temperature: 40 °C

Procedure:
Dry chloroform (30 ml) is added to a mixture of lead tetraacetate (8.52 g, 19.3 mmol) and mercuric diacetate (0.28 g, 0.875 mmol) under an atmosphere of nitrogen, and the reaction mixture is stirred and heated to 40° C. 4-Bromo-2-ethylphenylboronic acid (4.0 g, 17.5 mmol) is added in one portion and the mixture is stirred at 40° C. for 4 hours. The reaction mixture is cooled to 0° C., and potassium carbonate (2.66 g, 19.3 mmol) is added portionwise. The mixture is stirred for 5 minutes, then filtered through a small plug of diatomaceous earth, washing with chloroform. The filtrate concentrated under reduced pressure to give 4-bromo-2-ethylphenyllead triacetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (460 mg, 1.23 mmol) from Step 2 of this Example in DCM (25 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (333 mg, 1.35 mmol), and the mixture was allowed to warm to rt and stirred for a further 30 min. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was re-extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (481 mg, 100%) as a cream solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.40-8.50 (m, 2H), 7.84-7.95 (m, 2H), 7.50 (d, J=8.3 Hz, 1H), 5.68 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 391 and 393 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[C:29]1([P:35](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:29]1([P:35]([O:1][N:2]=[C:3]2[CH:4]=[CH:5][C:6](=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[C:10]#[N:11])[CH:7]=[CH:8]2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)=C2C=CC(=NOP(=O)(c3ccccc3)c3ccccc3)C=C2)cc1OC
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 119.2 %

Procedure:
10.16 g (0.036 mol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-3,4-dimethoxyphenylacetonitrile (prepared as described in Example 13.1) and 3.64 g (0.036 mol) of triethylamine are dissolved in 180 ml of tetrahydrofuran and cooled to 0-5° C. 8.52 g (0.036 mol) of diphenylphosphoryl chloride, dissolved in 70 ml of tetrahydrofuran, are added dropwise. When the addition is completed, the ice bath is removed and the solution stirred overnight at room temperature. Water and ethyl acetate are subsequently added, the organic layer is washed several times with saturated sodium chloride solution and water and dried over magnesium sulfate. Evaporation of the solvent gives 20.7 g of a viscous red oil, which is further purified by filtration over silica gel (eluent: hexane/ethyl acetate 9:1). Yield: 11.5 g (62%) (4-diphenylphosphoryloxyimino-cyclohexa-2,5-dienylidene)-3,4-dimethoxyphenyl-acetonitrile, reddish viscous oil which solidifies upon standing. 31P-NMR (CDCl3; δ relative to H3PO4 as external reference): 37.102 and 2.9.092 ppm (P(V) of the (E) and (Z)-isomers). 1H-NM R (CDCl3, δ [ppm]): 7.9-7.75 (m, 4H); 7.55-7.35 (m, 6H), 7.4-6.65 (m, 7H); 3.91/3.90 (s, 3H, (E)/(Z) isomers); 3.89/3,88 (s, 3H, (E)/(Z) isomers).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:11]1([O:16][C:17](=[O:24])[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[NH2:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:19][C:18]1([C:17]([O:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:24])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: NC1(C(=O)OC2CCCC2)CCCC1
Reactant: O=Cc1cccc(CBr)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=C(OC1CCCC1)C1(NCc2cccc(CBr)c2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 3-(bromomethyl)-benzaldehyde (0.467 g, 2.44 mmol) in dichloroethane (20 mL) was added cycloleucine cyclopentyl ester (0.802 g, 4.06 mmol) and sodium triacetoxyborohydride (1.18 g, 5.56 mmol). The mixture was stirred at room temperature for 3 hours, then poured into ethyl acetate (200 mL) and washed with saturated ammonium chloride solution (3 times 50 mL). The organic fraction was dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, 7:3 heptane:ethyl acetate) to yield the desired product (0.568 g, 61% yield). LC/MS: m/z 380/382 [M+H]+
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[N:17]=1)C(OC(C)(C)C)=O)(C)(C)C.[ClH:47].O1CCOCC1>C(Cl)Cl>[ClH:47].[C:37]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:35][C:34]([CH2:33][CH:22]([NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:25])=[O:26])[C:18]2[N:17]=[C:16]([NH:8][CH2:7][C:6]([OH:46])=[O:5])[CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccc3)cc2)NS(=O)(=O)c2cccnc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CNc1cccc(C(Cc2ccc(-c3ccccc3)cc2)NS(=O)(=O)c2cccnc2)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a solution of tert-butyl({6-[(biphenyl-4-ylmethyl)(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}tert-butoxycarbonylamino)acetate (931 mg, 1.44 mmol) obtained in Example 6-(a) in methylene chloride (14.4 ml) was added a 4N hydrogen chloride/1,4-dioxane solution (7.2 ml), and the mixture was left at room temperature for 16 hours. Further, it was stirred at 50° C. for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, followed by addition of methylene chloride to the residue, and a precipitated solid was collected by filtration. The resulting solid was dried under reduced pressure at room temperature to afford the title compound (760 mg) as a white solid. (Yield: 94%)