Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18][C:19](=[N:27][OH:28])[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl>COCCOC.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18]/[C:19](=[N:27]\[OH:28])/[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1cc(C(CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C)=NO)ccn1
Agent: Cl
Solvent: COCCOC
Solvent: C1COCCO1
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)c(F)c3)cc2)c2ccccc2C)=N/O)ccn1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a suspension of 3-fluoro-4′-[3-[hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid (example 112; 151 mg) in DME (2.5 mL) was added HCl in dioxane (4M, 0.8 mL) at rt. The reaction mixture was stirred at 50° C. for 4 hours, was concentrated and dissolved in ethyl acetate (5 mL) and a saturated aqueous solution of NaHCO3 (0.1 mL). A saturated aqueous solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 3-fluoro-4′-[3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid as a yellow solid, MS (ESI+): m/z=469.3 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:29])([F:28])[F:27])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16].[H-].[Na+].O>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:27])([F:29])[F:28])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C(F)(F)F)c21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C(F)(F)F)c21
Temperature: 100 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (81 mg) and 1-ethyl-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (103 mg) in DMF (dry) (1.5 ml) was added NaH (19.12 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound as white crystals (62.2 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.O.O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)nc1Br
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 2-bromo-3-methoxy-6-nitropyridine (2.0 g, 8.6 mmol) in ethanol (20 mL) was added SnCl2.2H2O (3.9 g, 17 mmol) at room temperature. The reaction was heated at reflux for 2H. After cooling to room temperature, the reaction mixture was poured into water (50 mL), basified to pH to 8 with saturated NaHCO3 and extracted with ethyl acetate (50×3 mL). The combined organic layers were dried over Na2SO4, evaporated in vacuo and purified by chromatography on silica gel (20% ethyl acetate in petroleum ether) to afford 6-bromo-5-methoxypyridin-2-amine (1.1 g, 65%). 1H-NMR (300 MHz, CDCl3) δ 7.09 (d, J=8.4, 1H), 6.43 (d, J=8.4, 1H), 4.27 (br s, 2H), 3.82 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH2:3].[CH3:4][C:5]([O:8][C:9]([NH:11][CH:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[N:18]=[CH:17][S:16][CH:15]=1)=[O:10])([CH3:7])[CH3:6]>>[C:5]([O:8][C:9]([NH:11][C@@H:12]([CH2:13][C:14]1[N:18]=[CH:17][S:16][CH:15]=1)[C:19]([NH:3][CH3:2])=[O:21])=[O:10])([CH3:4])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC(Cc1cscn1)C(=O)O
Reactant: CN
Agent: Cl
Product: CNC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C

Procedure:
Methylamine hydrochloride (1.2 mmol) and Boc-L-3-(4-thiazolyl)alanine (1.0 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, acid wash omitted) and the product used without further purification. Yield, 250 mg, 88%.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=1)[C:40]([O:42][CH3:43])=[O:41]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[CH:45][CH:44]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COC(=O)c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Method D, 2.08 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 1.13 g of methyl 3-(bromomethyl)benzoate are used to obtain the title compound as a slightly yellowish oil. Rf=0.31 (1:2 EtOAc-heptane); Rt=6.06.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:5]=[C:11]=[O:13]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C=NCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 232.7 %

Procedure:
To a solution of 2-chlorobenzylamine (1.0 g, 7.06 mmol) in a mixture of CH2Cl2 and H2O (10 mL/10 mL), triphosgene (838 mg, 2.82 mmol) and NaHCO3 (1.78 g, 21.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was partitioned between CH2Cl2 and water. The combined organic layers are dried over MgSO4 and filtered. The solvent was evaporated to give the desired product (1.1 g, 93%). EI-MS m/z 168.7 (M+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO.CCCCCC>[Cl:12][C:4]1[N:3]=[C:2]([O:14][CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (20.0 g, 96.1 mmol) in MeOH (100 mL) was added 0.5 M NaOMe in MeOH (423 mL, 211 mmol) dropwise. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was then concentrated to ca. ⅓ of the volume and slowly poured into saturated NH4Cl solution (200 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined EtOAc extracts were dried (Na2SO4), and concentrated in vacuo to yield a tan solid which was suspended in hexane (500 mL) and sonicated for 10 min. The resulting solid was collected by suction filtration and dried under suction to yield 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine as a powder. 1H-NMR (400 MHz, CDCl3) δ: 6.39 (s, 1H), 6.28 (br s, 2H), 4.05 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH:7]=1.[Se](=O)=[O:13]>O1CCOCC1.O>[CH3:9][C:4]1([CH3:10])[C:3](=[O:11])[C:2]([CH3:1])=[CH:7][C:6](=[O:8])[C:5]1=[O:13]
Reactant: O=[Se]=O
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Solvent: C1COCCO1
Solvent: O
Product: CC1=CC(=O)C(=O)C(C)(C)C1=O

Procedure:
129.4 g of 2,6,6-trimethylcyclohex-2-ene-1,4-dione (from Example 1) were added to a solution of 100 g of selenium dioxide in a mixture of 800 ml of dioxane and 50 ml of water, and the mixture was refluxed for 9 hours with stirring. The precipitate of elemental selenium was then filtered off with suction, and then all the low boilers were removed in a rotary evaporator. The residue was distilled at 125° C./20 mbar. The distillate was melted, mortared with n-hexane and then extracted with 600 ml of n-hexane. The target product crystallized out in the form of yellow needles.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:35][C@H:36]1[CH2:41][C:40]2[C:42]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)=[CH:43][CH:44]=[CH:45][C:39]=2[O:38][CH2:37]1>CN(C)C=O>[CH3:52][N:49]1[CH2:50][CH2:51][N:46]([C:42]2[C:40]3[CH2:41][C@H:36]([NH:35][C:18](=[O:19])[C:17]4[CH:21]=[CH:22][C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH2:1][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[CH2:13][CH2:12]5)=[CH:15][CH:16]=4)[CH2:37][O:38][C:39]=3[CH:45]=[CH:44][CH:43]=2)[CH2:47][CH2:48]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCN(Cc5ccccc5)CC4)cc2)CO3)CC1
Temperature: 75 °C
Reaction time: 20 h
Yield: 80.8 %

Procedure:
A suspension of 4-(4-benzylpiperazin-1-yl)benzoic acid (1.3 g, 4.2 mmol) and 1,1′-carbonyldiimidazole (740 mg, 4.2 mmol) in N,N-dimethylformamide (30 mL) was heated to 75° C. for 1.5 h. The reaction mixture was cooled to 50° C. and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran (1.0 g, 4.0 mmol) was added. The solution was stirred at 50° C. for 20 h and the solvent was evaporated in vacuo giving 3.5 g of a crude product. Purification by chromatography on a silica gel column using chloroform/methanol/concentrated ammonia 95:5:0.5 as the eluent gave 1.7 g (80% yield) of the title compound as a pale yellow solid: mp sinters>85° C.; TSPMS m/z (relative intensity) 526 (100, M+1); [α]22D−130° (c 1.0, chloroform).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[CH:13]=[C:14]([C:16](=[O:18])[CH3:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[CH:13]=[C:14]([CH:16]([OH:18])[CH3:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 1-[6-(benzyloxy)-1-benzofuran-2-yl]ethanone (25.7 g, 96.6 mmol) in methanol (300 mL) was added sodium borohydride (3.67 g, 96.6 mmol) by small portions, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the solvent was evaporated. Ethyl acetate was added thereto, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give the title compound (18.3 g, yield 71%).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:34][NH2:35])=[N:23][C:24]=2[NH:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)(=O)C.[S:36]([C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)([OH:39])(=[O:38])=[O:37].CN(C)CCCN=C=NCC>CN(C)C=O.O>[OH:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:34][NH:35][C:44]([C:43]1[CH:42]=[CH:41][C:40]([S:36]([OH:39])(=[O:38])=[O:37])=[CH:48][CH:47]=1)=[O:45])=[N:23][C:24]=2[NH:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(CN)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccc(S(=O)(=O)O)cc1
Reaction time: 4 h
Yield: 47.4 %

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-[2-(aminomethyl)-6-(cyclopentylamino)purin-9-yl]oxolan-3-yl acetate (55 mg, 0.15 mmol) in a mixture of N,N-dimethylformamide (5 ml) and water (10 ml) was added 4-sulfobenzoic acid (37 mg, 0.153 mmol) and 1(3-dimethylaminopropyl)-3-ethylcarbodiimide (28 mg, 0.147 mmol), and the mixture was stirred for 4 hours. Solvent was removed under reduced pressure, and the residue was purified by HPLC, to provide 4-[N-({9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}methyl)carbamoyl]benzenesulfonic acid (39 mg). MS MH+548.57.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:11]=2[CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:25]=3)[C:11]=2[CH2:12][S:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:39])=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CSc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CS(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 25.3 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(phenylthio)methyl]-1H-1,2,3-triazole-4-carboxamide (145 mg, 0.344 mmol) obtained in Example 130 was dissolved in THF (3.0 ml), m-chloroperbenzoic acid (purity 65%, 110 mg, 0.412 mmol, 1.2 eq.) was added with stirring at 0° C., and the mixture was stirred for additional 1.5 hr. The reaction mixture was diluted with ethyl acetate (20 ml), washed with 5% aqueous sodium sulfite solution, 2% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:1-5:1) on silica gel (manufactured by E. Merck, Art.7734, 10 g). The fraction obtained by elution with ethyl acetate-hexane (5:1) was concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (38 mg, 0.087 mmol, 25.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[OH:12].Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[O:12][CH2:17][CH2:16][N:15]([CH3:19])[CH3:14]
Reactant: CC(=O)Nc1ccc(Cl)c(O)c1
Reactant: CN(C)CCCl
Agent: Cl
Product: CC(=O)Nc1ccc(Cl)c(OCCN(C)C)c1
Yield: 80 %

Procedure:
The compound 24a was prepared starting from 17a and 2-dimethylamino ethyl chloride hydrochloride, following the general procedure H, as given in Example 9, in 80% yield.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[Na].CO.Cl.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])[CH3:18]>O>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:18][C:17]([O:20][CH2:21][CH3:22])=[O:19])[CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(=O)C(OCC)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 40 g of ethyl diethoxyacetate (227 mmol) in 67 mL of ethyl acetate there are added under argon, in portions, 6 g of sodium (261 mmol). The reaction mixture is then stirred at ambient temperature for 48 hours. There are added 10 mL of methanol, and then the mixture is hydrolysed with 65 mL of water. The pH of the reaction mixture is adjusted to pH 6 by adding 1N aqueous HCl solution. The mixture is separated and then extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over MgSO4, filtered and concentrated to dryness. The title product is obtained in the form of an oil which is used in the next Step without being otherwise purified.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([CH3:13])[NH:8]2.ClCCl.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>N1C=CC=CC=1>[CH:17]1([C:20]([N:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:13])=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc2c1CC[C@H](C)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc2c1CC[C@H](C)N2C(=O)C1CC1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A 1000-mL 3-necked round-bottom flask was charged with (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (47.41 g, 267.5 mmol), dichloromethane (500 mL), and pyridine (38 mL). Cyclopropanecarbonyl chloride (28.4 g, 271.7 mmol) was added dropwise with stirring at 0° C., and the resulting solution stirred for 3 h at 0° C. The reaction mixture was poured into 400 mL of water/ice, and then washed with 2 N hydrochloric acid (1×100 mL) and brine (3×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 0-15% ethyl acetate/petroleum ether) to afford (2S)-1-cyclopropanecarbonyl-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (64.6 g, 98%) as a yellow solid. MS (ES, m/z): 246 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13](=O)[NH:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2].CN(C)C=O.O=P(Cl)(Cl)[Cl:38].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([Cl:38])=[N:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1=C(C)Nc2c(c(=O)[nH]c(=O)n2-c2ccccc2)C1c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(C)Nc2c(c(Cl)nc(=O)n2-c2ccccc2)C1c1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
The compound from step 5 (11 g, 27.3 mmol) was taken in 100 ml dry chloroform and then charged with DMF (dimethylformamide) (2 ml, 27 mmol). POCl3 (14 ml) was dissolved in advance in 26 ml chloroform and was added under stirring in an argon atmosphere. The reaction mixture was then stirred at 70 C for 6 h. The reaction was monitored by LC-MS. The reaction mixture was cooled down to room temperature and poured into 25% ice cold solution of potassium acetate (150 ml) under vigorous stirring, organic phase was separated, aqueous phase was extracted with DCM (dichloromethane) (2×100 ml) and the combined organic solution was dried over magnesium sulfate and then the solvent was evaporated under vacuum yielding yellow solids (8.3 g, 19.7 mmol, 72%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:4]1[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2ccsc2c(=O)[nH]1
Product: Cc1nc(Cl)c2sccc2n1
Yield: 88 %

Procedure:
2-Methylthieno[3,2-d]pyrimidin-4(3H)-one (compound 32b, 0.18 g, 1.13 mmol) was heated to 110° C. in POCl3 overnight. The solvent was removed under reduced pressure, and the residue was neutralized with saturated NaHCO3 solution. The product was extracted into CH2Cl2, and the organic phase separated, washed with brine, and dried (MgSO4). After removal of the solvent compound 32c was obtained as a yellow-orange solid (0.21 g, 88%). Compound 32c was used without further purification. Rf=0.16 (10% EtOAc/hexane). 1H NMR (400 MHz, DMSO-d6): δ 2.71 (s, 3H), 7.66 (d, J=5.6 Hz, 1H), 8.54 (d, J=5.6 Hz, 1H). LCMS 185 (M+H). Anal. (C23H29N8OF.0.35H2O.0.35 hexane) C, H, N. HPLC>98% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O.N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:18][C:14]1[NH:13][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc[nH]1
Agent: COc1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)C(=Cc1ccc[nH]1)C(=O)N2
Temperature: 85 °C

Procedure:
5-Methoxyindolin-2-one was prepared by the method of Crestini, C.; Saladino, R. Synth. Commun. (1994), Vol. 24, NO. 20, p. 2835. A solution of 5-methoxyindolin-2-one (0.41 g, 2.5 mmol) and 2-pyrrolecarboxaldehyde (0.25 g, 2.6 mmol) in ethanol (5 mL) was treated with piperidine (0.05 g, 0.65 mmol). The reaction mixture was then heated to 85° C. for 3 hours. The reaction was then cooled to ambient temperature and the reaction mixture was chromatographed on SiO2 (12 g) using 3:1 hexane/ethyl acetate to afford 5-methoxy-3-[(pyrrol-2-yl)methylene]indolin-2-one; (0.48 g); 1H NMR (400 MHz, DMSO-d6) δ 3.74 (s, 3H), 6.30 (m, 1H), 6.60–6.80 (m, 3H), 7.30 (m, 1H), 7.35 (m, 1H), 7.76 (m, 1H), 10.80 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]2[O:30][C:31]([C:37]([F:40])([F:39])[F:38])=[C:32]([C:34](O)=[O:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:34]([C:32]3[N:33]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:30][C:31]=3[C:37]([F:39])([F:40])[F:38])=[O:35])=[CH:15][N:14]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COC1CN(c2ccc([N+](=O)[O-])cn2)C1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COC1CN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1
Yield: 48 %

Procedure:
[1-(5-Nitro-pyridin-2-yl)-azetidin-3-yloxy]-acetic acid tert-butyl ester (210 mg, 0.679 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (183 mg, 0.71 mmol), DIPEA (355 uL, 2.03 mmol) and BOP (315 mg. 0.74 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy)-acetic acid tert-butyl ester as a light brown solid (169 mg). ES-MS calcd for C25H25F3N4O5 (m/e) 518.50, obsd 519.1 (M+H).