Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9](O)(=O)[CH3:10].[CH:13](=O)[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>ClCCl>[Br:8][C:6]1[CH:7]=[C:2]([N:1]([CH2:9][CH3:10])[CH2:13][CH3:14])[CH:3]=[N:4][CH:5]=1
Reactant: CC=O
Reactant: CC(=O)O
Reactant: Nc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: CCN(CC)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
A solution of 3-amino-5-bromopyridine (Aldrich, Buchs, Switzerland, 400 mg, 2.31 mmol), acetic acid (0.4 ml, 6.99 mmol) and acetaldehyde (Fluka, Buchs, Switzerland, 153 mg, 3.47 mmol) in dichloromethane was stirred for 1.5 h at rt then was added sodium triacetoxyborohydride (980 mg, 4.62 mmol). The reaction mixture was stirred 17.5 h at rt then were added at 1.5 h interval acetaldehyde (153 mg, 3.47 mmol) and sodium tracetoxyborohydride (490 mg, 2.31 mmol). The RM was stirred 7 h at rt then were added at 1.5 h interval acetaldehyde (77 mg, 1.75 mmol) and sodium tracetoxyborohydride (490 mg, 2.31 mmol). After 15 h stirring at rt, the reaction mixture was diluted with dichloromethane and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (DCM/iPrOH 1% to 3.5%) to give the title compound as a yellowish oil. (HPLC: tR 2.31 min (Method A); M+H=229, 231 MS-ES)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)=[O:13])[CH2:6]2)#[N:2].N.CO.O1CCCC1.CO>[Ni].O>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)=[O:13])[CH2:6]2
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C#N)cc3C2)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(CN)cc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Cyano-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (0.04 g, 0.115 mmol) and 7M ammonia-methanol/tetrahydrofuran/methanol (4 mL) were added to Ra—Ni 2800, water slurry (0.080 g, 1.363 mmol) in a 50 ml pressure bottle and stirred for 16 hours at 30 psi and room temperature. The mixture was filtered through a nylon membrane, concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, Methanol-d4) δ ppm 7.76-7.79 (m, 2H), 7.60-7.63 (m, 2H), 7.31-7.35 (m, 3H), 4.82 (s, 4H), 3.86 (s, 2H), 3.30-3.33 (m, 2H), 1.53-1.75 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 425 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][C:11]([CH2:13][CH2:14][N:15]2[C@H:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:10][NH:9]1)C1C=CC=CC=1.CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[CH3:34][C:33]1[C:28]([C@H:16]2[CH2:17][CH2:18][CH2:19][C@@H:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:15]2[CH2:14][CH2:13][C:11]2[CH:12]=[N:8][NH:9][CH:10]=2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCC1=CNN(Cc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCc1cn[nH]c1
Temperature: 140 °C
Yield: 64.4 %

Procedure:
To a solution of (2′R,6′S)-1′-[2-(2-benzyl-1 H-pyrazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.130 g, 0.288 mmol) in dry DMSO (0.70 mL) and THF (12 mL) was added 4 Å molecular sieve (˜1 g) pre-heated at 140° C., and KOtBu (0.600 g, 5.35 mmol). The solution was bubbled with air (pre-dried by passing through a NaOH column) at room temperature for 1 h. Saturated aqueous NH4Cl (20 mL) was then added. The mixture was filtered through a celite cake and the cake was washed with EtOAc throughout. The organic layer in the filtrate was collected, and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (200:10:1 CH2Cl2/CH3OH/NH4OH), affording a pale yellow solid (0.067 g, 64%) after precipitation from CH2Cl2/hexanes by evaporation under vacuum. 1HNMR(CDCl3) δ 1.60-1.85 (4H), 2.00-2.15 (m, 2H), 2.25-2.62 (m, 10H), 4.10-4.20 (m, 2H), 6.73 (s, 2H), 7.07-7.12 (m, 2H), 7.43 (d, 2H, J=7.2 Hz), 8.45 (s, br. 2H); 13C NMR (CD2Cl2) δ 19.02, 21.33, 25.61, 30.31, 50.86, 64.12, 118.85, 122.40, 132.22, 132.65, 138.78, 147.03, 160.46. ES-MS m/z 362 (M+H). Anal. Calcd. for C22H27N5.0.2H2O: C, 72.38; H, 7.56; N, 19.18. Found: C, 72.31; H, 7.70; N, 18.98.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21](=[O:29])[O:20]2)[CH2:16][CH2:15]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:15][CH2:16][C:17]4([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21](=[O:29])[O:20]4)[CH2:18][CH2:19]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(N3CCC4(CC3)OC(=O)Nc3ccccc34)nn2)n1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
3-Chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (690 mg) obtained in Example 43(2), spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (1 g) and triethylamine (1.4 mL) were suspended in N,N-dimethylformamide (20 mL), and the suspension was stirred at 160° C. under irradiation of microwave for 15 min. The mixture was cooled to room temperature, water (200 mL) was added and the resulting precipitate was collected by filtration. The precipitate was recrystallized from ethanol to give the object product (550 mg, 42%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH2:20][CH2:21][C:22]([NH:24][NH2:25])=[O:23])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH3:8])[CH3:7].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:19][C:16]([C:13]1[CH:12]=[C:11]([CH2:20][CH2:21][C:22]2[O:23][C:1](=[S:2])[NH:25][N:24]=2)[CH:10]=[C:9]([C:6]([CH3:5])([CH3:7])[CH3:8])[C:14]=1[OH:15])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CCc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 15.8 %

Procedure:
Thiophosgene (0.55 mL, 6.80 mmol) is added dropwise to a -78° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide (2.0 g, 6.8 mmol) in tetrahydrofuran (200 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a heavy oil which is crystallized from ethyl acetate/hexane. The product is chromatographed on a column of silica with ethyl acetate/dichloromethane (5/95) and recrystallized from dichloromethane/hexane to afford 0.36 g (16%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]-1,3,4-oxadiazole-2(3H)-thione, mp 164.5°-165.5° C.
Reaction SMILES: [C:1]1([C:7]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:22])[CH2:18][C:19]([CH3:21])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:29]/[C:30](/[CH3:36])=[CH:31]\[C:32]([O:34][CH3:35])=[O:33].[N+:37]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)([O-:39])=[O:38]>C(O)(C)C>[CH3:35][O:34][C:32]([C:31]1[CH:44]([C:43]2[CH:46]=[CH:47][C:40]([N+:37]([O-:39])=[O:38])=[CH:41][CH:42]=2)[C:18]([C:17]([NH:16][CH2:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:12][CH2:11]2)=[O:22])=[C:19]([CH3:21])[NH:29][C:30]=1[CH3:36])=[O:33]
Reactant: CC(=O)CC(=O)NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)NCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
A solution of acetoacetic acid N-[3-(4,4-diphenylpiperidin-1-yl)propyl]amide (365 mg, 0.964 mmol, 1.0 equiv), methyl 3-aminocrotonate (138 mg, 1.20 mmol, 1.2 equiv, Aldrich), and 4-nitrobenzaldehyde (181 mg, 1.20 mmol, 1.2 equiv, Aldrich) in isopropanol was refluxed under argon for 60 hours. The mixture was cooled to room temperature and concentrated, and the residue was diluted with CH2Cl2, washed with water, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc, followed by EtOAc-MeOH, 19:1 and 9:1) to give 147.8 mg (25%) of yellow solid: 1H NMR (300 MHz, CDCl3) δ1.55 (m, 2H), 2.14 (s, 3H), 2.15-2.50 (m, 10H), 2.32 (s, 3H), 3.20 (m, 1H), 3.37 (m, 1H), 3.54 (s, 3H), 5.00 (s, 3H), 5.48 (br s), 6.98 (br t, J=4.9 Hz, 1H), 7.14-7.30 (m, 10H), 7.39 (dm, J=8.7 Hz, 2H), 8.05 (dm, J=8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ18.74, 20.64, 25.61, 36.77, 40.20, 42.26, 45.03, 51.16, 51.61, 58.08, 100.65, 109.71, 124.35, 126.46, 127.61, 128.84, 129.06, 135.52, 146.96, 147.10, 154.55, 168.22, 168.70; IR (neat) 1680, 1610, 1515, 1340 cm−1; MS (FAB) m/e 609 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([NH:30][CH3:29])=[O:23])[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)O)c3)nc2N1C1CCCC1
Reactant: CN
Agent: Cl
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)NC)c3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 39, with (R)-1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-imidazole-4-carboxylic acid (Example 37) instead of (R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44), and with methylamine hydrochloride instead of dimethylamine hydrochloride. 1H NMR (CDCl3) δ: 8.52 (s, 1H), 8.34 (s, 1H), 7.76 (s, 1H), 4.30-4.41 (m, 2H), 3.46 (s, 3H), 3.30 (s, 3H), 3.01 (s, 3H), 1.73-2.16 (m, 10H), and 0.87 ppm (t, J=7.7 Hz, 3H); LCMS: 398.1 m/z (M+H)+; ret. Time: 3.367 min (Analytical Method A).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[N:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Oc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccncc2)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
tert-Butyl 3-hydroxyazetidine-1-carboxylate (4.0 g) and pyridin-4-ol (1.8 g) were mixed with THF (50 ml), and triphenylphosphine (6.23 g) was added thereto. A 1.9 M DIAD/toluene solution (12.5 ml) was added dropwise, followed by stirring at 55° C. overnight. Triphenylphosphine (5 g) and a 1.9 M DIAD/toluene solution (10 ml) were added to the reaction mixture, followed by stirring at 55° C. overnight. The reaction mixture was concentrated under reduced pressure, and a liquid separation operation was carried out by the addition of EtOAc and 0.5 M hydrochloric acid. The aqueous layer was adjusted to a pH of around 10 by the addition of a 4 M aqueous NaOH solution, and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (4.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=O)[CH3:2].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:20]1([NH:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[O-:27])[CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCCCCI
Reactant: ONC1CCCCC1
Reactant: CCOc1cc(C=O)ccc1O
Product: CCCCCCOc1ccc(C=[N+]([O-])C2CCCCC2)cc1OCC

Procedure:
The title compound was prepared according to the procedure described in Example 28 using 3-ethoxy-4-hydroxybenzaldehyde, 1-iodohexane and N-cyclohexylhydroxylamine. The title compound was isolated in 41.3% yield as a solid, m.p. 67.3° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][S:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:21][C:8]1=2)([OH:3])=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:9]2[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]([S:6][CH2:5][CH2:4][C:1]([NH:34][C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[O:3])[C:8]=2[CH:21]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
0.92 g of 11-(2-carboxyethylthio)-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Example 11, 0.21 g of 5-aminotetrazole and 0.5 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.25 g of 4-dimethylaminopyridine dissolved in 20 ml of methylene chloride were stirred at room temperature for 2 days. After this reaction mixture was washed with 1N-hydrochloric acid and a saturated saline solution, the organic layer was dried over anhydrous sodium sulfate. The residue obtained by condensation was applied to silica gel column chromatography and the resulting solid was recrystallized from methanol to obtain 0.5 g of the title compound as slightly brown powder.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[O:31][N:30]=1.CC#N>CCOC(C)=O>[F:20][C:2]([F:1])([F:19])[CH2:3][C:4]1[N:5]([CH2:28][C:29]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=3)[O:31][N:30]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(cc(CC(F)(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
A mixture of 2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 374A) (0.080 g, 0.27 mmol), K2CO3 (0.042 g, 0.30 mmol), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.143 g, 0.54 mmol) and CH3CN (5 mL) was stirred at 60° C. for 6 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.031 g, 22%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.69-7.63 (m, 2H), 6.94 (s, 1H), 5.56 (s, 2H), 3.96 (q, 2H); MS m/z 517 (M−H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.O[CH2:21][C@H:22]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[C@@H:23]1[CH2:27][C@@H:26]([CH3:28])[C:25](=[O:29])[O:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:28][C@@H:26]1[CH2:27][C@@H:23]([CH:22]2[CH2:21][N@@:30]2[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[O:24][C:25]1=[O:29]
Reactant: C[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 0.08 h

Procedure:
1.6 ml of a solution of diethyl azodicarboxylate in toluene (40%) (3.48 mmol) was added to a solution of 1.00 g of N-{(S)-2-hydroxy-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (76f) (2.90 mmol) and 0.91 g of triphenylphosphine (3.48 mmol) in tetrahydrofuran (30 ml) under ice-cooling over five minutes, and the mixture was stirred at the same temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 0.82 g of the title compound (yield: 87%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:24]([N:31]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37]2)=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]2=[C:8]([C:35]3[CH:36]=[CH:37][C:38]4[C:33]([CH:34]=3)=[N:32][N:31]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:39]=4)[CH:9]=[C:10]([CH2:11][CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC(Cc2cc(Br)c3c(N)ncnn23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 94.3 %

Procedure:
To a stirred, degassed mixture tert-butyl 3-[(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]azetidine-1-carboxylate (397 mg, 1.04 mmol), Intermediate C (521 mg, 1.56 mmol), Na2CO3 (330 mg, 3.12 mmol) and H2O (1.6 mL) in DMF (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol). The reaction was heated (110° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and H2O (50 mL). The layers were separated and the aqueous was further extracted with ethyl acetate (1×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified via ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 500 mg (80%) of the desired product, which contained trace impurities.
Reaction SMILES: [OH:1][CH:2]([C:20]1[N:21]=[CH:22][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:24]=1[CH3:25])[CH:3]1[C:18](=[O:19])[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][CH3:17])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3>C(O)(=O)C.O>[OH:1][CH:2]([C:20]1[N:21]=[CH:22][NH:23][C:24]=1[CH3:25])[CH:3]1[C:18](=[O:19])[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][CH3:17])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CCCc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: CC(=O)O
Solvent: O
Product: CCCc1c2n(c3ccccc13)C(=O)C(C(O)c1nc[nH]c1C)CC2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of 8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-propylpyrido[1,2-a]-indol-6(7H)-one (1.65 g) in a mixture of acetic acid and water (4:1, 90 ml) was stirred at 60° C. for 4 hours. After evaporation of the solvent, the residue was diluted with as aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The crystalline residue was suspended in a mixture of methanol and chloroform and filtered to give one isomer of 8,9-dihydro-7-[(hydroxy)(5-methyl-1H-imidazol-4-yl)methyl]-10-propylpyrido[1,2-a]indol-6(7H)-one with an upper Rf value in silica gel thin layer chromatography (TLC) (6% methanol-chloroform) (0.27 g), which was designated as the isomer A. The filtrate was evaporated and purified by silica gel column chromatography (6% methanol-methylene chloride). The fractions eluted first contained the isomer A and the fractions eluted later contained another isomer of 8,9-dihydro-7-[(hydroxy)(5-methyl-1H-imidazol-4-yl)methyl]-10-propylpyrido[1,2-a]indol-6(7H)-one with a lower Rf value in TLC, which was designated as the isomer B.
Reaction SMILES: [C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([O:32]C)=[O:31])[CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@](c2ccc(-c3ccccc3)cc2)(S(=O)(=O)CCC)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@](c2ccc(-c3ccccc3)cc2)(S(=O)(=O)CCC)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-(propylsulfonyl)pyrrolidine-2-carboxylate (1.52 g, 2.372 mmol) in THF (20.00 mL) and MeOH (20 mL) was added pre-made solution of lithium hydroxide (0.199 g, 4.74 mmol) in water (20.00 mL). The formed cloudy solution was stirred at rt for 3 h. Removed the volatiles in vacuo. The residue was acidified with 1M HCl to pH 3, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated in vacuo to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-(propylsulfonyl)pyrrolidine-2-carboxylic acid (1.45 g, 2.198 mmol, 93% yield) as a white foam. 1H NMR (400 MHz, MeOD) δ ppm 0.97 (t, J=7.53 Hz, 3 H) 1.36-1.55 (m, 12 H) 1.55-1.82 (m, 4 H) 2.10 (q, J=6.61 Hz, 2 H) 2.81 (dd, J=8.66, 6.65 Hz, 2 H) 2.91 (dd, J=12.92, 10.42 Hz, 1 H) 3.28 (d, J=7.28 Hz, 1 H) 4.20 (dd, J=9.91, 7.40 Hz, 1 H) 4.37 (d, J=11.04 Hz, 1 H) 4.52 (t, J=6.90 Hz, 1 H) 4.95 (dd, J=10.16, 1.13 Hz, 2 H) 4.98-5.07 (m, 1 H) 5.13 (d, J=11.04 Hz, 1 H) 5.77-5.94 (m, 1 H) 7.33-7.42 (m, 1 H) 7.48 (t, J=7.53 Hz, 2 H) 7.65 (d, J=7.53 Hz, 2 H) 7.72-7.78 (m, 2 H) 7.93 (d, J=8.28 Hz, 2 H). LC-MS (retention time: 1.99 min, method A), MS m/z 627 (M+H).