Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][CH2:20][C:21]2[C:22]([NH:29][CH3:30])=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=2)=[C:12]([CH3:31])[CH:11]=1.CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N:19]2[CH2:20][C:21]3[C:22](=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=3)[N:29]([CH3:30])[C:4]2=[O:3])=[C:12]([CH3:31])[CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1cc([N+](=O)[O-])c(F)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1cc([N+](=O)[O-])c(F)cc1C)C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of diphosgene (0.85 mL, 7.2 mmol) in anhydrous dioxane (20 mL) was added a solution of 5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (2.2 g, 6.5 mmol) and Et3N (1.32 g, 13 mmol) in anhydrous dioxane (50 ml) at 0° C. After the addition, the resulting mixture was stirred at 50° C. overnight. Water was added and the mixture was neutralized with saturated Na2CO3 solution to pH 8. The dioxane was removed in vacuo, and the aqueous layer was extracted with EtOAc (3×60 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was washed with ether and dried in vacuo to afford 3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (2 g, 84%). 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1 H), 7.97 (d, J=8 Hz, 1 H), 7.18 (d, J=12 Hz, 1 H), 4.73 (d, J=14.8 Hz, 1 H), 4.42 (d, J=14.8 Hz, 1 H), 3.40 (s, 3 H), 2.52 (s, 3 H), 2.25 (s, 3 H); MS (ESI) m/z: 364.1 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[O:13][CH2:12][C@@H:11]([S:14]C(=O)C)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CO.Cl.C(O)(C)C>O1CCCC1>[O:1]([CH2:8][C@@H:9]1[O:13][CH2:12][C@@H:11]([SH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](COc2ccccc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CO
Product: S[C@@H]1CO[C@@H](COc2ccccc2)C1
Yield: 70.1 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.532 g of product from Example 23, 506 microliter of 25% sodium methoxide/methyl alcohol, 7.5 ml of tetrahydrofuran, and 1.18 ml of 1.86N hydrochloric acid/isopropyl alcohol to give 0.311 g of the desired product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N+:22]([O-:24])=[O:23])[C:6]([C:13](=[O:21])[CH2:14][C:15]2[N:19]=[CH:18][N:17](C)[N:16]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.N1CCC[C@H:35]1C(O)=O>CS(C)=O>[F:2][C:3]1[CH:4]=[C:5]([N+:22]([O-:24])=[O:23])[C:6]([C:13](=[O:21])/[C:14](/[C:15]2[N:16]([CH3:35])[N:17]=[CH:18][N:19]=2)=[CH:30]/[C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C(=O)Cc1ncn(C)n1
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C(=O)/C(=C/c1ccc(F)cc1)c1ncnn1C
Temperature: 45 °C
Reaction time: 48 h
Yield: 39.7 %

Procedure:
To a stirred solution of methyl 5-fluoro-2-(2-(1-methyl-1H-1,2,4-triazol-5-yl)acetyl)-3-nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in dimethylsulfoxide (2 mL) was added L-proline (230 mg, 2 mmol). The resulting mixture was kept with stirring at 45° C. for 48 hours. The reaction system was then partitioned between ethyl acetate (50 mL) and water (30 mL), and the organic phase was washed with water (20 mL×3), dried with Na2SO4, concentrated in vacuo, and purified by column chromatography (ethyl acetate:petroleum ether=1:3) to give the title compound (9) as a pale yellow foam (340 mg, yield 40%). LC-MS (ESI) m/z: 429 (M+1)+. 1H-NMR (400 MHz, DMSO-d6); δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, 1H), 8.08 (s, 1H), 8.26 (dd, 1H), 8.56 (dd, 1H).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[Si:31]([CH2:38][O:39][CH2:40]/[CH:41]=[C:42](/[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53](/[C:56](/[CH3:60])=[CH:57]/[CH2:58]O)=[CH:52][CH:51]=2)=[CH:46][CH:45]=1)\[CH3:43])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C1COCC1.O.C(OCC)(=O)C>[CH2:21]([O:20][C:18](=[O:19])[C@@H:17]([O:16][CH2:14][CH3:15])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:58]/[CH:57]=[C:56](/[C:53]2[CH:54]=[CH:55][C:50]([C:47]3[CH:48]=[CH:49][C:44](/[C:42](/[CH3:43])=[CH:41]/[CH2:40][O:39][CH2:38][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[CH:45][CH:46]=3)=[CH:51][CH:52]=2)\[CH3:60])=[CH:28][CH:29]=1)[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccc(/C(C)=C/COC[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/COC[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (0.91 g, 3.62 mmol) was added at 0–5° C. to a stirred solution of tributylphosphine (0.89 mL, 3.62 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.60 g, 2.53 mmol) and (E)(E) 3-(4′-{3-[(tert-butyidimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-en-1-ol (1.02 g, 2.41 mmol) in dry THF (15 ml). The mixture was warmed to room temperature, and stirred for 18 h. The resulting mixture was diluted with water and ethyl acetate, the aqueous layer collected and further extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica using heptane/ethyl acetate (4:1) as eluent to give 1.18 g (76%) of (E)(E)(S) 3-{4-[3-(4′-{3-[(tert-butyldimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=6)=[C:23]([C@H:32]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:50]([N:57]1[CH2:60][CH:59](I)[CH2:58]1)([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CN(C=O)C>[C:39]([O:38][C@@H:32]([C:23]1[C:22]([CH3:43])=[CH:21][C:19]2[N:20]=[C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[N:1]([CH:59]4[CH2:58][N:57]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:60]4)[N:2]=[CH:3]5)[CH:15]=3)[S:17][C:18]=2[C:24]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C5CN(C(=O)OC(C)(C)C)C5)c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of (S)-ethyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (110 mg, 0.18 mmol) in DMF (3 mL) was added Cs2CO3 (117 mg, 0.36 mmol) and 1-Boc-3-iodoazetidine (76 mg, 0.27 mmol). The reaction mixture was heated at 60° C. overnight. The reaction mixture was washed by saturated NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down, purified by silica gel column, eluting by 0-60% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C42H44ClN5O5S: 766.3 (M+H+); found: 766.3.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[C:51]1([N:57]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]([CH2:66][NH2:67])=[N:58]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH3:17][CH:16]([CH3:18])[CH2:15][C@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[C:12](=[O:14])[NH:67][CH2:66][C:59]1[C:60]2[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=2)[N:57]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:58]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: NCc1nn(-c2ccccc2)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NCc1nn(-c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.45 g, 1.8 mmol, Example 1, Step B) was dissolved in dry DMF (6 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N-methylmorpholine (0.68 mL, 6.1 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.70 g, 1.8 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; then a solution of C-(1-phenyl-1H-indazol-3-yl)-methylamine monohydrochloride (0.45 g, 1.8 mmol) in dry DMF (8 mL) was added. After additional 20 minutes stirring at 0° C., the ice-water bath was removed, and the reaction mixture was stirred and allowed to warm up to ambient temperature for 15 minutes. The reaction mixture was poured into 50 mL of EtOAc; the resulting mixture was successively washed with 3% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo affording an amber oil which was further purified by flash chromatography (80% EtOAC in hexanes). Finally, recrystallization from EtOAc-Hexanes afforded 0.39 g (48%) of the pure titled compound as a off-white solid: mp 135-136° C. APCI-MS m/z 462.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][CH2:16][O:17][CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: COCCNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting 2-methoxyethylamine for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.91 (m, 1H), 7.75 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.55 (s, 4H), 3.35 (s, 3H), 2.19 (s, 3H). ESHRMS m/z 464.1142 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1.O[C:21]1([C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[C:24]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:23]([CH3:46])[NH:22]1>C(Cl)Cl>[CH3:46][C:23]1[NH:22][C:21]([C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=2)=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[C:24]=1[C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: CCOC(=O)C1=C(C)NC(O)(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(c2ccc([N+](=O)[O-])cc2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
Trifluoroacetic anhydride (0.65 ml, 4.63 mmoles) was added with stirring to pyridine (0.75 ml, 9.26 mmoles) and diethyl 1,2,3,4-tetrahydro-2-hydroxy-6-methyl-4-(3-nitrophenyl)-2-(4-nitrophenyl)-3,5-pyridinedicarboxylate (2.31 g, 4.63 mmoles) in methylene chloride (60 ml). After stirring for 2.5 hours, the solution was washed with water, dilute hydrochloric acid (x3), water, saturated sodium bicarbonate solution, water and dried (Na2SO4). The solvent was removed in vacuo and the residue recrystallised from ethanol to give the title compound (1.77 g) as a yellow solid, mp 176°-7°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.Cl[CH2:45][C:46]1[O:50][C:49]([C:51]([O:53][CH3:54])=[O:52])=[CH:48][CH:47]=1.COC1C=CC(CCl)=CC=1>>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[O:50][C:49]([C:51]([O:53][CH3:54])=[O:52])=[CH:48][CH:47]=1
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: COc1ccc(CCl)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1

Procedure:
Following the procedure as described in EXAMPLE 7 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and methyl 5-(chloromethyl)-2-furoate to replace 4-methoxybenzyl chloride, methyl 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate was obtained (92%) as a colorless solid: mp 88-92° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.28 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.17 (dd, J=7.2, 0.9 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H), 7.06 (ddd, J=7.8, 7.8, 0.9 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.37 (d, J=3.6 Hz, 1H), 6.24 (s, 1H), 5.12 (d, J=16.5 Hz, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.90 (d, J=16.5 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.18 (m, 2H), 4.14-4.10 (m, 2H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.2, 158.9, 155.3, 153.4, 144.8, 144.4, 141.4, 138.4, 132.2, 129.1, 124.1, 123.9, 120.9, 119.1, 111.7, 110.3, 109.1, 99.5, 80.1, 64.6, 64.0, 58.1, 52.1, 37.4; MS (ES+) m/z 433.9 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH:13]C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 18a (3.26 g, 11.37 mmol) in 10 mL of DCM, was added TFA (5 mL, 64.9 mmol). The mixture was stirred at room temperature for 2 h and the solvent were evaporated. The residue was dissolved in DCM and a saturated solution of NaHCO3 and 1N NaOH were added until pH was 8. The layers were separated and the aqueous layer was extracted with 3:1 DCM:IPA (3×40 mL). The organic extracts were combined, dried, filtered and evaporated to afford 1.89 g (89%) of 18b.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])C.[CH2:26]([O:28][C:29]([C:31]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].ClC1C=CC(C2N(C3C=CC=CC=3Cl)N=C(C(N3CCN(C4C=CC=CC=4)CC3)=O)C=2CC#N)=CC=1>>[CH2:26]([O:28][C:29]([C:31]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:32][CH2:33][N:34]([C:4]([C:6]2[C:10]([CH3:11])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:7]=2)=[O:5])[CH2:35][CH2:36]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: N#CCc1c(C(=O)N2CCN(c3ccccc3)CC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Product: CCOC(=O)C1(c2ccccc2)CCN(C(=O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1

Procedure:
The ester compound [A1] was hydrolysed according to the procedure for the last step in the synthesis of [1.1]. The resulting acid was coupled with 4-phenyl-piperidine-4-carboxylic acid ethyl ester according to the procedure for the synthesis of [C1] to give 1-[1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-1H-pyrazole-3-carbonyl]-4-phenyl-piperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:39][C:15]3([CH2:18][N:17]([CH2:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:16]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].C1(C)C=CC=CC=1>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:39][C:15]3([CH2:16][N:17]([CH2:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:18]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCOCCC(=O)OC(C)(C)C)c4)C3)C2)cs1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCOCCC(=O)O)c4)C3)C2)cs1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3-(3-(2-(8-(2-isopropylthiazole-4-carbonyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethyl)phenethoxy)propanoate (460 mg) (example 176 step g) in DCM (6 mL) was treated with TFA (2 mL) and the solution allowed to stand at RT for 1 hour. Toluene (10 mL) was added and the solvents were evaporated under reduced pressure and the residue dissolved in acetonitrile and the solution evaporated under reduced pressure to afford the subtitled compound. Yield 500 mg.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:23]=[O:24])C>>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH:23]=[O:24])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1[nH]c2ccccc2c1C=O
Temperature: 40 °C

Procedure:
2-Ethylindole (0.5 g, 3.4 mmol) dissolved in DMF (2 mL) was added to a cold (0° C.) premixed (30 minutes) mixture of DMF (1.15 mL) and phosphorous oxychloride (0.64 g, 4.16 mmol). After addition of 2-ethylindole, the mixture was heated to 40° C. for 1 h, water (5 mL) was added and the pH adjusted to 5 by means of 1 N sodium hydroxide. The mixture was subsequently extracted with diethyl ether, the organic phase isolated, dried with MgSO4 and evaporated to dryness affording 2-ethylindole-3-carbaldehyde (300 mg).
Reaction SMILES: [CH3:1]/[C:2](/[C:9]1[S:10][C:11]([CH2:14][CH:15](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:16])=[CH:12][CH:13]=1)=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O>[N:28]([CH:15]([CH3:16])[CH2:14][C:11]1[S:10][C:9](/[C:2](/[CH3:1])=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:13][CH:12]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C=C(\C)c1ccc(CC(C)OS(=O)(=O)c2ccc(C)cc2)s1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)/C=C(\C)c1ccc(CC(C)N=[N+]=[N-])s1

Procedure:
For the preparation of the amine starting material of Examples 6 and 10g, 5-[(RS)-2-hydroxypropyl]-2-thienyl methyl ketone and triethyl phosphonoacetate were reacted in ethanol in the presence of sodium ethylate to give ethyl (E)-5-[(RS)-2-hydroxypropyl]-β-methyl-2-thiopheneacrylate. With p-toluenesulfonyl chloride, there was obtained therefrom ethyl (E)-β-methyl-5-[(RS)-2-[(p-toluenesulphonyl)oxy]propyl]-2-thiopheneacrylate (m.p. 121°, from methylene chloride-alcohol. Reaction with sodium azide in dimethylsulfoxide gave ethyl (E)-5-[(RS)-2-azido-propyl]-β-methyl-2-thiopheneacrylate. Reduction with triphenylphosphine and hydrolysis yielded ethyl (E)-5-[(RS)-2-aminopropyl]-β-methyl-2-thiopheneacrylate, ε320 =17970.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[O:11][C:12]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[N:13][N:14]=2)=[O:8])=[CH:4][CH:3]=1.O1C=CC=C1C1OC([NH:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35](I)[CH:34]=2)=O)=NN=1.C(C1C=CC(B(O)O)=CC=1)#N>>[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:2]2[S:6][C:5]([C:7]([NH:9][C:10]3[O:11][C:12]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)=[N:13][N:14]=3)=[O:8])=[CH:4][CH:3]=2)=[CH:35][CH:34]=1)#[N:30]
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1ccc(Br)s1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cccc(I)c1
Agent: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(C(=O)Nc3nnc(-c4ccco4)o3)s2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 5-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-2-thiophenecarboxamide prepared in Reference Example 4 instead of N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-3-iodobenzenecarboxamide and using commercially available 4-cyanophenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [N:1]1[CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[N:4]=[N:3][N:2]=1.CC1(C)C(C)(C)OB(C2C=CC([C:41]3[S:42][CH:43]=[CH:44][C:45]=3[NH:46][S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])=CC=2)O1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CN(C=O)C.O.CCOC(C)=O>[N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:41]3[S:42][CH:43]=[CH:44][C:45]=3[NH:46][S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=S(=O)(Oc1ccc(-c2ccc(CC3N=NN=N3)cc2)cc1)C(F)(F)F
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(Cc3nn[nH]n3)cc2)cc1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
Deoxygenate and heat a mixture of trifluoro-methanesulfonic acid 4′-(5H-tetrazol-5-ylmethyl)-biphenyl-4-yl ester (48mg, 0.2 mmol), propane-2-sulfonic acid {2-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide (95 mg, 0.24 mmol, 1.2 eq.), barium hydroxide octahydrate(189 mg, 0.6 mmol, 3 eq.) and Pd(dffp)(29 mg, 0.04 mmol, 0.2 eq.) in 2 ml DMF and water mixture (4/1, v/v) to 80° C. overnight. Cool the mixture to room temperature and dilute with 30 mL EtOAc. Wash with water (3×10mL) and saturated aq. sodium chloride, dry, and remove solvent. Purification by flash chromatography (Silica gel-CH2Cl2:MeOH(1/50, v/v)) affords the title compound 50 mg(53%). MS (m/e): 441.1(M+1).