Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO.[CH2:4]1[C@H:8]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[N:11]=[CH:10]2)[O:7][C@H:6]([CH2:19][OH:20])[C@H:5]1[OH:21]>O>[CH2:4]1[C@@H:8]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[N:11]=[CH:10]2)[O:7][C@@H:6]([CH2:19][OH:20])[C@@H:5]1[OH:21]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CCO
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@@H](O)[C@H](CO)O1

Procedure:
mp 189-190° C. (EtOH 95) (identical to commercial 2′-deoxy-D-adenosine) 1H NMR (200 MHz, DMSO-D6):δ 8.35 and 8.14 (2s, 2H, H2 and H8), 7.34 (s1, 2H, NH2), 6.35 (dd, 1H, H1′, J 6.1 Hz, J 7.85 Hz), 5.33 (d, 1H, OH2′, J 4.0 Hz), 5.28 (dd, 1H, H3′, J 4.95 Hz; J 6.6 Hz), 4.42 (m, 1H, OH5′), 3.88 (m, 1H, H4′), 3.63-3.52 (m, 2H, H5′a and H5′b), 2,71 (m, 1H, H2′a), 2.28 (m, 1H, H2′b). (identical to commercial 2′-deoxy-D-adenosine) αD+26° (c 0.5 water) (commercial 2′-deoxy-D-adenosine −25° (c 0.5 water)). UV λmax 260 nm (ε 14100) (H2O). Mass analysis (FAB+, GT) m/z 252 (M+H)+, 136 (BH2)+
Reaction SMILES: C([O:4][C:5](=[O:7])[O-:6])(C)C.[CH3:8][N+:9]([CH3:12])([CH3:11])[CH3:10]>O>[C:5](=[O:4])([O-:7])[OH:6].[CH3:8][N+:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)OC(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: O
Product: O=C([O-])O
Reaction time: 3 h

Procedure:
88.5 g of tetramethylammonium isopropylcarbonate and 45.0 g of water were introduced in the same reactor as used in Preparation Example 1 and heated with stirring. After the temperature reached 120° C., the reaction was continued for 3 hours at 120° C. Tetramethylammonium hydrogencarbonate was obtained in a yield of 95.0 mol %.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Reactant: NC1CCOCC1
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NC2CCOCC2)cn1
Yield: 46 %

Procedure:
As described in example 9, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (100 mg, 0.28 mmol), and 4-aminotetrahydropyran instead of tetrahydrofuran-3-amine, was converted to the title compound (56 mg, 46%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 96.5:3.5) and trituration with isopropyl ether. MS: m/e=328.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[C:31]2[O:30][C:29]([C:32]#[N:33])=[CH:28][C:27](=[O:34])[C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[C:32]([C:29]1[O:30][C:31]2[C:22]([CH2:21][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)=[CH:18][CH:19]=3)=[CH:23][CH:24]=[CH:25][C:26]=2[C:27](=[O:34])[CH:28]=1)#[N:33]
Reactant: N#Cc1cc(=O)c2cccc(CBr)c2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Yield: 27.4 %

Procedure:
1.0 g of 2-(4-hydroxyphenoxy)methylquinoline, 1.0 g of 8-bromomethyl-2-cyano-4-oxo-4H-1-benzopyran and 0.5 g of potassium carbonate are stirred at room temperature in 5 ml of dimethylformamide for 2 days. The reaction mixture is diluted with ethylacetate, filtered and concentrated. The residue is chromatographed on silica gel to give 0.45 g of 2-cyano-8-(4-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran.
Reaction SMILES: FC1C=CC(C2C3C(=CC([S:18][C:19]4[S:20][C:21]([C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])=[CH:22][N:23]=4)=CC=3)OC(=O)C=2)=CC=1>CCO.CCCCCC>[F:30][C:27]([F:28])([F:29])[C:24]([C:21]1[S:20][C:19]([SH:18])=[N:23][CH:22]=1)([OH:31])[CH2:25][CH3:26]
Reactant: CCC(O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F
Solvent: CCCCCC
Solvent: CCO
Product: CCC(O)(c1cnc(S)s1)C(F)(F)F

Procedure:
A solution of (±)-1,1,1-trifluoro-2-(2-mercapto-1,3-thiazol-5-yl)butan-2-ol (1.2 g) from step 2 of example 1 in EtOH/hexane (20 ml, 1:4) was injected (1×1.2 g) onto a CHIRALPAK AD preparative (5 cm×50 cm) HPLC column (eluting with hexane/EtOH, 4:1; at 75 ml/min with UV detection at 280 nm). The enantiomers were separated with the faster eluting enantiomer having a retention time of ˜19 min (enantiomer #1, (2S)-1,1,1-trifluoro-2-(2-mercapto-1,3-thiazol-5-yl)butan-2-ol) and the slower eluting enantiomer having a retention time of ˜34 min (enantiomer #2, (2R)-1,1,1-trifluoro-2-2-mercapto-1,3-thiazol-5-yl)butan-2-ol). The eluants were concentrated to provide enantiomer #1 (0.468 g, 99% ee) and enantiomer #2 (0.426 g, 98% ee).
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](C=O)[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH3:44])[CH:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]>Cl.C1COCC1>[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[NH:24][CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([CH2:36][N:37]([CH3:44])[CH:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[CH:34][CH:35]=4)=[O:28])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3)cc1
Yield: 74.9 %

Procedure:
In 1N hydrochloric acid (50 ml) and THF (50 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.4 g). The solution was refluxed for 4.5 hours, concentrated, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 28) (1.0 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[ClH:28].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3c(F)cccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3c(F)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 106 %

Procedure:
A mixture of 1.2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-9-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.65 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.3 g of potassium carbonate and 50 ml of acetone is treated in the same manner as described in Example 56. The crude product thus obtained is converted to its hydrochloride and recrystallized from isopropanol. 1.7 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl-]-9-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are obtained.
Reaction SMILES: Br[C:2]1[C:3]([NH2:15])=[N:4][CH:5]=[C:6]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[F:16][C:17]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][OH:24])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:15][C:3]1[C:2]([C:33]2[CH:32]=[CH:31][C:18]([C:19]([NH:21][C@@H:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][OH:24])=[O:20])=[C:17]([F:16])[CH:34]=2)=[CH:7][C:6]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][N:4]=1
Reactant: CC1(c2cnc(N)c(Br)c2)CCOCC1
Reactant: CC1(C)OB(c2ccc(C(=O)N[C@H](CO)c3ccccc3)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4ccccc4)c(F)c3)c2)CCOCC1
Temperature: 120 °C
Yield: 34.2 %

Procedure:
To a solution of 3-bromo-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (70 mg, 0.26 mmol) in DME (4 mL) was added (S)-2-fluoro-N-(2-hydroxy-1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (298 mg, 0.77 mmol) and sodium carbonate (0.64 mL, 1.29 mmol). The mixture was purged with nitrogen for 10 min, then PdCl2(dppf)-CH2Cl2 (31.6 mg, 0.039 mmol) was added. The reaction mixture was heated to 120° C. in an oil bath for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography on silicagel (ISCO) eluting with 0-100% ethyl acetate in heptane to give 70 mg crude product, which was purified by HPLC to give (S)-4-(2-amino-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-(2-hydroxy-1-phenylethyl)benzamide (40.8 mg, 0.089 mmol, 34.5% yield) as TFA salt. LCMS (m/z): 450 (MH+), 0.61 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (t, J=7.83 Hz, 1H) 7.77-7.65 (m, 2H) 7.50 (dd, J=11.74, 7.43 Hz, 1H) 7.42-7.36 (m, 4H) 7.33 (d, J=7.43 Hz, 2H) 7.21 (d, J=11.74 Hz, 1H) 5.33 (d, J=4.70 Hz, 1H) 4.08-3.94 (m, 2H) 3.83-3.65 (m, 4H) 1.97 (ddd, J=13.40, 8.12, 5.09 Hz, 2H) 1.72 (d, J=13.69 Hz, 2H) 1.35 (s, 3H)
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:13].Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[OH:70][CH2:71][CH2:72][N:73]([CH2:77][C:78](O)=[O:79])[CH2:74][CH2:75][OH:76]>>[ClH:13].[ClH:13].[OH:76][CH2:75][CH2:74][N:73]([CH2:72][C:71]([N:35]1[CH2:36][CH2:37][N:32]([C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][N:16]=3)=[CH:39][CH:38]=2)[CH2:33][CH2:34]1)=[O:70])[CH2:77][CH2:78][OH:79]
Reactant: O=C(O)CN(CCO)CCO
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(CN(CCO)CCO)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 21 %

Procedure:
The crude product obtained using dihydrochloride of Compound 18 (150 mg, 0.370 mmol) N-methylmorpholine (0.0812 mL, 0.740 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99.3 mg, 0.370 mmol), 1-hydroxybenzotriazole monohydrate (64.9 mg, 0.481 mmol) and di(hydroxyethyl)aminoacetic acid (60.4 mg, 0.370 mmol) in a similar manner to Example 5, was purified by C-18 column chromatography (water/methanol=67/33), followed by treating with 10% hydrogen chloride-methanol solution (0.775 mL) and triturating in ethyl acetate to obtain Compound 144 (43.5 mg, 21%).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)=[O:4].[NH2:15][CH2:16][C:17]([N:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]2[C:38]3[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[C:34]=3[CH:33]=[CH:32][CH:31]=2)[C:22]=1[Cl:48])[CH3:20])=[O:18].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:48][C:22]1[C:23]([CH2:28][O:29][C:30]2[C:38]3[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[C:34]=3[CH:33]=[CH:32][CH:31]=2)=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:19]([CH3:20])[C:17](=[O:18])[CH2:16][NH:15][C:12](=[O:14])[CH2:11][N:8]1[CH2:7][CH2:6][CH:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: CNC(=O)C1CCN(CC(=O)O)CC1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: CNC(=O)C1CCN(CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)CC1

Procedure:
2-(4-(methylcarbamoyl)piperidin-1-yl)acetic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide were combined as described for compound 1 to give 13. LCMS (+ESI) 682 (M+). 1H-NMR (CDCl3, δ): 8.58 (m, 1H), 7.88 (bt, 1H), 7.58 (t, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 5.67 (s, 2H), 5.28 (s, 2H), 4.20 (d, J=2.8 Hz, 3H), 3.82 (dd, 1H), 3.56 (dd, 1H), 3.24 (s, 3H), 2.94 (m, 4H), 2.81 (d, J=4.8 Hz, 3H), 2.18 (m, 3H), 1.85 (m, 5H). Calcd. for C33H37Cl2N7O5+3.1H2O: C, 53.67; H, 5.90; N, 13.28. Found: C, 53.29; H, 5.52; N, 12.92.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1.[Li+].[OH-].Cl>C1COCC1>[CH:17]1([CH2:16][CH:15]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[O:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:9][CH:10]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)CCNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a mixture of (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-propionic acid methyl ester (0.0834, 0.151 mmol) in THF (1.0 mL) is added LiOH (1 N aqueous, 0.4 mL) and stirred at RT for 1 h. The reaction mixture is acidified with 1N HCl (0.5 mL) and extracted with EtOAc (3×5 mL). Combined organic extracts are dried over MgSO4, filtered, and conc. to provide (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-propionic acid (0.0814 g, 71%) as a white solid. MS (ES): 540.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[NH2:6].C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1>C(Cl)Cl>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:31])=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2ccc(Cl)cc2[N+](=O)[O-])ccc1OCCN1CCCC1
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]aniline (43 mmol, 10.0 g) in DCM was added triethylamine (52 mmol, 5.2 g) and 4-chloro-2-nitrobenzoyl chloride (9.5 g, 43 mmol). The solution was stirred overnight. The reaction mixture was extracted with 2N HCl. The resulting acidic aqueous solution was made basic by adding 2N NaOH. The combined basic aqueous solution was extracted with DCM. The organic phase was washed with brine, dried and concentrated giving the title compound (11.5 g, 69%). 1H NMR (DMSO-D6): δ 1.66 (4H, m), 2.49 (4H, m), 2.75 (2H, t, J=6.0 Hz), 3.72 (3H, s), 4.00 (2H, t, J=6.0 Hz), 6.94 (1H, d, J=8.6 Hz), 7.14 (1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.1 Hz), 7.94 (1H, d, J=8.1 Hz), 8.23 (1H, s), 10.55 (1H, s). LCMS m/z=420 (m+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C@@H:7]1[CH2:11][NH:10][C@H:9]([C:12]#[N:13])[CH2:8]1.C(N(CC)CC)C.S(=O)(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][CH2:2][C:3]([N:10]1[CH2:11][C@@H:7]([F:6])[CH2:8][C@H:9]1[C:12]#[N:13])=[O:4]
Reactant: N#C[C@@H]1C[C@H](F)CN1
Reactant: O=C(Cl)CCl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Temperature: 0 °C
Yield: 55.4 %

Procedure:
Chloroacetyl chloride (11.13 g, 98.5 mmol) was dissolved in 120 mL of dichloromethane with stirring under argon atmosphere. Upon cooling to 0° C., (2S,4S)-4-fluoropyrrolidine-2-carbonitrile 13f (11.4 g, 75.7 mmol) was dissolved in 400 mL of dichloromethane followed by addition of triethylamine (16.1 g, 158.97 mmol). To a solution of chloroacetyl chloride in dichloromethane was added the above mentioned mixture in 30 minutes. The reaction mixture was reacted at 0° C. for 2 hours and diluted with 200 mL of ice water and 150 mL of dichloromethane. The separated organic phase was neutralized with saturated sodium bisulfate, washed with 300 mL of water and 300 mL of saturated brine successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile 13g (8 g, yield 60%) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[N+:9]([O-])([OH:11])=[O:10].OS(O)(=O)=O.O=S(=O)=O>>[Cl:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1cccc(Cl)n1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1ccc(Cl)nc1Cl

Procedure:
reacting 2,6-dichloropyridine with nitric acid in the presence of about 10-65% strength by weight oleum to produce a reaction mixture comprising 2,6-dichloro-3-nitropyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=3)[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.O.[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: CCOC(Cc1ccc(NCCCN2CCOc3cc(F)ccc32)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOC(Cc1ccc(NCCCN2CCOc3cc(F)ccc32)cc1)C(=O)O
Yield: 69.9 %

Procedure:
Methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate (180 mg, 1 eq, 0.43 mmol) obtained in example 16, was hydrolyzed using lithium hydroxide monohydrate (55 mg, 3 eq, 1.2 mmol), in methanol-water at RT till all the starting material is consumed (4 to 5 h). The reaction mixture was diluted with water, acidified (pH ˜4-5) with dil. HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatographed using ethyl acetate and hexanes→methanol and chloroform to afford the title compound (121 mg, yield 70%) as viscous liquid.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:6][CH2:5]1>C(Cl)(Cl)Cl>[Br:1][CH:10]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9]1
Reactant: BrBr
Reactant: CCOC(=O)N1CCCC(=O)CC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=O)C(Br)CC1
Reaction time: 8 h

Procedure:
79.9 g (500 mmol) bromine are added to a solution of 92.7 g (500 mmol) ethyl 4-oxo-azepan-1-carboxylate in 350 mL chloroform and the reaction is stirred overnight. The reaction solution is washed three times with saturated NaHCO3 solution, the organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. The product is further reacted without purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[NH2:12][C:13]1[N:17]=[C:16]([SH:18])[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][S:18][C:16]2[N:17]=[C:13]([NH2:12])[NH:14][N:15]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: Nc1n[nH]c(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SCCOc2ccc(Cl)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.1 %

Procedure:
A mixture of 1-(2-bromoethoxy)-4-chlorobenzene (2.0 g, 8.49 mmol), 3-amino-5-mercapto-1,2,4-triazole (1.04 g, 8.92 mmol), potassium carbonate (2.34 g, 16.98 mmol), and anhydrous N,N-dimethylformamide (4 mL) was added to a 50 mL RBF with a magnetic stirring bar. The mixture was allowed to stir at ambient temperature for 3 days. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm (Rt=6.04 min). The mixture was diluted with 40 mL of water and allowed to stir for 5 min. A precipitate was isolated by filtration, rinsed with 25 mL of water, and allowed to dry under reduced pressure. The solid material was >98% pure by analytical HPLC and afforded the title compound as a white powder (2.21 g, 96% yield). EM (calc.): 270.7; MS (ESI) m/e: 271.0 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 12.00 (br s, 1H), 7.32 (d, 2H), 7.00 (d, 2H), 6.04 (s, 2H), 4.19 (t, 2H), 3.30 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]2=[N:4][C:3]=1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.BrC(C)C(=O)C=CC1C=CC(C#N)=CC=1.NC1C=C(C(OC)=O)C=CN=1.[CH2:50]([O:52][C:53]([CH2:55][CH2:56][NH:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:54])[CH3:51].C(OCC)(=O)C.C(O)C.N>S(Cl)(Cl)=O>[C:58]1([N:57]([CH2:56][CH2:55][C:53]([O:52][CH2:50][CH3:51])=[O:54])[C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([CH3:1])=[C:3]([CH2:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=4)[N:4]=[C:5]3[CH:10]=2)=[O:12])[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: Cc1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)ccn12
Reactant: CCOC(=O)CCNc1ccccc1
Agent: CC(Br)C(=O)C=Cc1ccc(C#N)cc1
Agent: COC(=O)c1ccnc(N)c1
Agent: N
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Reaction time: 1 h

Procedure:
1.4 g (4.6 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]imidazo[1,2-a]pyridin-7-yl-carboxylic acid (prepared from 4-bromo-l-(4-cyanophenyl)-1-penten-3-one and methyl 2-aminopyridine-4-carboxylate analogously to Y. Katsura et al., Chem. Pharm. Bull. 1992, 40, 1424-1438) were suspended in 15 mL of thionyl chloride and heated to boiling for 1 hour until fully dissolved. After the thionyl chloride had been distilled off, the acid chloride was dissolved in 15 mL of pyridine without any further purification and at 0° C. mixed with 1.0 g (5.2 mmol) of N-(2-ethoxycarbonylethyl)aniline. After 1 hour, the solvent was distilled off, the residue was taken up in 30 mL of methylene chloride, washed with 15 mL of 1N hydrochloric acid, and dried with sodium sulfate. After distillation of the solvent and chromatography (silica gel; methylene chloride/ethanol=0 to 2%), a brown oil was obtained. Yield: 1.48 g (64% of theory); Rf value: 0.73 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1).