Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([C:18](=[CH:21]NC1C=CC=CC=1)[C:19]#[N:20])=[O:17])([O-:12])=[O:11]>C(O)C>[NH2:20][C:19]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:21][C:18]=1[C:16](=[O:17])[C:15]1[CH:29]=[CH:30][CH:31]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1
Reactant: NNc1ccc(F)cc1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: Nc1c(C(=O)c2cccc([N+](=O)[O-])c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 4-fluorophenylhydrazine (2.24 g, 15.57 mmol) and 2-(3-nitrobenzoyl)-3-phenylaminoacrylonitrile (4.15 g, 14.16 mmol) in ethanol (50 ml) was heated at reflux under nitrogen atmosphere. After 1 h, the reaction mixture was cooled to room temperature and stirred for an additional 3 h. The solid was filtered and dried to give 5-amino-1-(4-fluorophenyl)-4-(3-nitrobenzoyl)pyrazole (4.5 g) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:54][C:55](=[O:63])[NH:56][CH2:57][C:58](=[O:62])[O:59]CC)[CH2:12][CH2:13][NH:14][C:15](=[O:53])[CH2:16][N:17]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24][N:23]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:22][CH2:21][N:20]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:19][CH2:18]2)=[O:10])=[CH:4][CH:3]=1.O[Li].O.CCO>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:11]([CH2:54][C:55]([NH:56][CH2:57][C:58]([OH:62])=[O:59])=[O:63])[CH2:12][CH2:13][NH:14][C:15](=[O:53])[CH2:16][N:17]2[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:31])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:25][CH2:24][N:23]([CH2:37][C:38](=[O:39])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])[CH2:22][CH2:21][N:20]([CH2:45][C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[CH2:19][CH2:18]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC(=O)CN(CCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)C(=O)Cc1ccc(O)cc1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCCN(CC(=O)NCC(=O)O)C(=O)Cc2ccc(O)cc2)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 50-mL round bottom flask loaded with tri-tert-butyl 2,2′,2″-(10-(6-(2-(4-hydroxyphenyl)acetyl)-2,8,11-trioxo-12-oxa-3,6,9-triazatetradecyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate 2 (0.260 g, 0.291 mmol) was added LiOH.H2O (0.018 g, 0.437 mmol, 1.5 eq.), 6 mL of EtOH, and 2 mL of H2O. The reaction was stirred at room temperature for 12 hours. After solvent removal in vacuo, purification was achieved by preparative reverse-phase HPLC (gradient from 100% 0.1% formic acid in water to 50% 0.1% formic acid in water/50% CH3CN) to give 3. 65.5% 1H-NMR (300 MHz, CDCl3) δ 8.66 (m, 1H), 8.07 (m, 1H), 7.02 (m, 2H), 6.29 (m, 2H), 6.34 (br s, 1H), 4.20-2.80 (m, 34H), 1.44 (s, 27H); 13C-NMR (75 MHz, CDCl3) δ 174.51, 174.14, 173.70, 173.45, 172.43, 169.80, 167.18, 156.59, 156.45, 130.43, 130.02, 125.93, 116.08, 115.89, 81.89, 81.85, 81.75, 56.42, 55.62, 52.76, 52.32, 51.61, 50.52, 49.67, 49.31, 49.25, 49.12, 47.69, 47.52, 43.54, 43.21, 40.37, 39.38, 38.07, 28.14.
Reaction SMILES: [Cl-].[Li+].C(NC(C)C)(C)C.C([Li])CCC.[OH:15][CH:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]([N:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH3:22])[CH3:18].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[OH:15][CH:16]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:17]([N:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH2:22][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH3:31])[CH3:18]
Reactant: CCC(=O)N(C)C(C)C(O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1CCC(=O)N(C)C(C)C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A dry 2 L 3-necked round-bottomed flask was equipped with a mechanical stirrer, and charged with lithium chloride (25.0 g, 596 mmol, 6.0 equiv), diisopropylamine (31.3 mL, 224 mmol, 2.25 equiv), and tetrahydrofuran (120 mL). The suspension was cooled to -78° C., and n-butyllithium (2.43M in hexanes, 85.1 mL, 207 mmol, 2.08 equiv) was added via cannula. After a brief warming to 0° C., it was recooled to -78° C. [S-[R*,R*]]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl propionamide (22.0 g, 99.41 mmol, 1.0 equiv) was added as a 0° C. solution in tetrahydrofuran (300 mL). The resulting solution was stirred at -78° C. for 1 hour, warmed to 0° C. for 15 minutes, warmed to 23° C. for 5 minutes, and cooled to 0° C. Benzyl bromide (17.74 mL, 149 mmol, 1.5 equiv) was added, and the reaction was stirred at 0° C. The reaction was quenched after 15 minutes with saturated ammonium chloride, and the amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (500 mL, 150 mL, 150 mL). The combined organic extracts were dried over sodium sulfate, and after removal of the solvent under reduced pressure, a yellow solid was obtained. Recrystallization from toluene (100 mL) yielded the desired product as a white powder (27.77 g, 90% yield). GC analysis of the TMS ether indicated a diastereomeric purity of the amide of greater than 99% de: mp 136°-137° C.; 1H NMR (300 MHz, C6D6) δ6.9-7.4 (m, 10 H), 4.45 (m, 1H), 4.25 (br, 1H), 3.96 (m, 1H), 3.80 (m, 1H), 3.36 (dd, 2H, J=13.1 Hz, 6.92 Hz), 3.01 (m, 1H), 2.75 (m, 1H), 2.70 (s, 3H), 2.45-2.59 (m, 3H), 2.08 (s, 3H), 1.05 (d, 3H, J=7.0 Hz), 1.02 (d, 3H, J=6.5 Hz), 0.83 (d, 3H, J=7.0 Hz), 0.59 (d, 3H, J=6.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ178.2, 177.2, 142.3, 141.1, 140.5, 139.9, 129.2, 128.9, 128.6, 128.31, 128.26, 127.5, 126.8, 126.4, 126.2, 76.4, 75.2, 58.0, 40.3, 40.0, 38.9, 38.1, 32.3, 27.1, 17.7, 17.4, 15.5, 14.3; FTIR (neat film) cm-1 3384 (br, m), 3027 (m), 2973 (m), 2932 (m), 1617 (s), 1493 (m), 1453 (m), 1409 (m), 1080 (m), 1050 (m), 701 (s); HRMS (FAB) Calcd for C20H26NO2 (MH+): 312.1965. Found: 312.1972; Anal. Calcd for C20H25NO2: C, 77.14, H, 8.09, N, 4.50. Found: C, 76.87, H, 8.06, N, 4.50.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)[C:49]3=[O:52])=CC=2)=CC=1.COC1C=CC(N=C=S)=CC=1>>[CH3:49][O:52][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Agent: COc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(OC)cc4)cc3)cc2C1=O

Procedure:
The compound of example 57 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 4-methoxyphenyl isothiocyanate. The compound of example 57 was used directly without isolation for the preparation of compound of example 58.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:10]C(=O)[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Na+].Cl>O>[NH2:8][C:5]1[C:4]([OH:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(Br)cc1O
Temperature: 10 °C
Yield: 52.9 %

Procedure:
6-Bromooxazolo[4,5-b]pyridine-2(3H)-one (K. Rufenacht and H. Kristinsson, Helv. Chim. Acta 59 (5), 1593 [1976]) (4.3 g; 0.02 mole) sodium hydroxide (5 g; 0.125 mole) and water (50 ml) were stirred on the steam bath for 45 minutes. The solution was cooled to approximately 10° C. and carefully acidified with concentrated HCl (considerable foaming). The resulting solid was collected by filtration, washed with water and dried. The yield was 3.0 g (79 percent) of tan solid melting at 187° to 189° C. Recrystallization from aqueous ethanol afforded 2.0 g of tan crystals, melting point 195° to 197° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3ccc(SCC(=O)C(C)(C)C)cc3)c2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)C(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Dissolve 3-(tert-butoxycarbonyl)-7-chloro-6-[4-(3,3-dimethyl-2-oxobutylthio)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (35 mg, 0.06 mmol) in DCM (0.2 mL). Add 4M hydrogen chloride in dioxane (0.3 mL, 1.3 mmol) and stir at room temperature for 1 h. Concentrate in vacuo and purify by SCX chromatography to obtain the desired intermediate (26 mg, 93%).
Reaction SMILES: [CH:1]1([C:4](=[O:33])[CH:5]([N:13]2[CH2:18][CH2:17][CH:16]([SH:19])/[C:15](=[CH:20]\[C:21]3[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:22]=3)/[CH2:14]2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[F:12])[CH2:3][CH2:2]1.[ClH:34]>C(#N)C>[ClH:34].[C:28]([CH2:27][CH2:26][N:23]1[CH:24]=[CH:25][C:21](/[CH:20]=[C:15]2/[CH2:14][N:13]([CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[F:12])[C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:33])[CH2:18][CH2:17][CH:16]/2[SH:19])=[N:22]1)([OH:30])=[O:29]
Reactant: CCOC(=O)CCn1ccc(/C=C2/CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Agent: Cl
Solvent: CC#N
Product: O=C(O)CCn1ccc(/C=C2/CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Yield: 97 %

Procedure:
(Z)-1-[2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-4-sulfanylpiperidine (the free base described in Example 171, 158 mg) was treated with 3N hydrochloric acid (5 ml) at 50° C. for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 35/65, v/v) to afford the title compound (156.6 mg, yield: 97%) as a colourless amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:11][CH2:10]1.[OH-].[Na+].Cl>C(OCC)(=O)C.O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 40 °C

Procedure:
To a round 25 ml bottomed flask containing trans-methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate (60 mg, 0.23 mmol) and water (4 ml) was added sodium hydroxide (32 mg, 0.78 mmol) and the solution heated to 40° C. for 1 hr. The solution was poured into a separating funnel containing ethyl acetate (15 ml) and water (10 ml). To the aqueous layer was then added aqueous hydrochloric acid (10 ml, 1.0M) and ethyl acetate (20 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (15 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound (34 mg, 60%) as a solid. m/z (ES+) 251 (M+H+); δH(CD3OD) 1.20 (2H, m), 1.48 (2H, m), 1.89 (4H, m), 2.25 (2H, d), 2.81 (1H, m), 6.27 (2H, m), 6.91 (1H, m).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:29]#[N:30])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH:14]=2)=[O:9])C.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:29]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:32])([CH3:31])[C:4]([OH:33])=[O:3])=[O:9])[N:11]=1)#[N:30]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(C)cc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(Oc2ccc3c(O)c(C(=O)NCC(C)(C)C(=O)O)nc(C#N)c3c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-[(1-Cyano-4-hydroxy-7-p-tolyloxy-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-propionic acid ethyl ester (18 mg, 0.04 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 9 mg. MS: (−) m/z 417.99 (M−1).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH:12][C:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:12]([C:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=1)[C:11]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:9]([O:8][CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)[CH:10]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(NC2=CC(=O)CC2)cc1OC1CC2CCC1C2
Product: COc1ccc(N(Cc2ccccc2)C2=CC(=O)CC2)cc1OC1CC2CCC1C2
Yield: 92.3 %

Procedure:
According to the same procedure as in Example 26, using 3-[3-[(1RS,2RS,4SR)-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyanilino]2-cyclopenten-1-one produced in Example 8(3) instead of 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one, and using benzyl bromide instead of methyl iodide, the title compound (yield 92.3%) was obtained as a light yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[O:13]=[C:14]1[C@:22]2([CH2:24][C@@H:23]2[C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15]1>>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([C@H:23]2[C@@:22]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:12])=[CH:5][CH:6]=4)[C:14]3=[O:13])[CH2:24]2)=[CH:32][CH:31]=1)#[N:30]
Reactant: N#Cc1ccc([C@H]2C[C@]23C(=O)Nc2ccccc23)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: N#Cc1ccc([C@@H]2C[C@@]23C(=O)N(Cc2ccc(C(=O)O)cc2)c2ccccc23)cc1

Procedure:
The title compound was prepared in analogy to Example 1 starting from 4-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-4-(2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)benzonitrile prepared as in Scheme 1. LC/MS m/e calcd. for C25H18ClN2O3: 394, observed (M+H)+: 395.2 1H NMR (400 MHz, DMSO-d6) δppm 2.11-2.20 (m, 1 H) 2.43-2.50 (m, 1 H) 5.10 (s, 2 H) 6.16 (d, 1 H) 6.70 (t, 1 H) 6.92 (d, 1 H) 7.08 (t, 1 H) 7.43 (d, 2 H) 7.55 (d, 2 H) 7.80 (d, 2 H) 7.93 (d, 2 H).
Reaction SMILES: B(F)(F)F.CCOCC.[Si]([O:17][C@@H:18]([C@@H:20]1[C@@H:23]([CH:24]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[S:27])[CH3:25])[NH:22][C:21]1=[O:34])[CH3:19])(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(#N)C>[OH:17][C@@H:18]([C@@H:20]1[C@@H:23]([CH:24]([C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[S:27])[CH3:25])[NH:22][C:21]1=[O:34])[CH3:19]
Reactant: CC(C(=S)c1ccccc1)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C(=S)c1ccccc1)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
1.3 ml of boron trifluoride etherate were added to a solution of 1.37 g of (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1RS)-1-(phenylthiocarbonyl)ethyl]-2-azetidinone in 33 ml of acetonitrile, cooled in ice-water, and the mixture was stirred for 15 minutes at 0° to 5° C. 2.94 g of sodium bicarbonate were added to the reaction mixture, then a saturated aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was stripped off, giving 0.95 g of (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1RS)-1-(phenylthiocarbonyl)ethyl]-2-azetidinone, which was used in the following reaction.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:29][C@H:23]2[O:24][C:25]([CH3:28])([CH3:27])[O:26][C@H:22]2[CH:21]1OC(OC1C=CC=CC=1)=S)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:27][C:25]1([CH3:28])[O:24][C@@H:23]2[O:29][C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:21][C@@H:22]2[O:26]1
Reactant: CC1(C)O[C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(OC(=S)Oc3ccccc3)[C@@H]2O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC1(C)O[C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C[C@@H]2O1
Temperature: 130 °C
Yield: 88.9 %

Procedure:
To a solution of [(3aS,5R,6aS)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-6-yl]oxy-phenoxy-methanethione (compound 25c, 17 g, 30 mmol) in toluene (150 mL) was added tri(trimethylsilyl)silane(16.4 g, 66 mmol) and azodiisobutyronitrile (98 mg, 0.6 mmol), the mixture was heated at 130° C. under nitrogen for 3 hours. After the reaction was completed, the reaction was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:10 EtOAc in petroleum ether) to afford 11 g of [(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methoxy-tert-butyl-diphenyl-silane (compound 25d).
Reaction SMILES: [CH2:1]([C:3]1([CH2:27][CH3:28])[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:12]=[CH:13][C:14]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37](=[O:40])[CH2:38][CH3:39].O>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:12]=[CH:13][C:14]=2[N:15]2[CH2:16][CH2:17][N:18]([CH2:36][C:37](=[O:40])[CH2:38][CH3:39])[CH2:19][CH2:20]2)[CH2:5][CH2:4]1)[CH3:28]
Reactant: CCC1(CC)CCC(c2cc(N3CCOCC3)ccc2N2CCNCC2)CC1
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)CN1CCN(c2ccc(N3CCOCC3)cc2C2CCC(CC)(CC)CC2)CC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-[3-(4,4-diethylcyclohexyl)-4-piperazin-1-ylphenyl]morpholine (20 mg, 0.052 mmol) produced in Example (84b) in dimethylformamide (1 mL) were added potassium carbonate (11 mg, 0.078 mmol) and 1-bromo-2-butanone (9.4 mg, 0.063 mmol), followed by stirring for 2 hours and 5 minutes at an external temperature of 80° C. After air-cooling, water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and then filtered through Celite, and the filtrate was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[4-[2-(4,4-diethylcyclohexyl)-4-morpholin-4-ylphenyl]piperazin-1-yl]butan-2-one. This compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate (0.020 mL, 0.080 mmol) was added. The solution was concentrated under reduced pressure, and then hexane was added to the obtained residue to produce a solid. The solid was triturated by sonication and the supernatant hexane solution was removed. The obtained solid residue was dried under reduced pressure to give 25 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]Cl)[CH:12]=3)[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.[I-:37].[Na+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][I:37])[CH:12]=3)[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1
Reactant: [I-]
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCl)c2cc1OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Yield: 93.8 %

Procedure:
But using 2 g of 5-fluoro-2-[1-(2-chloroethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.85 g of sodium iodide in 100 ml of 2-butanone. 2.2 g of 5-fluoro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([O:19]CC)=O)=[CH:4][CH:3]=1.[NH3:22].C>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:22])=[O:19])=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Agent: C
Solvent: CO
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 600 mg of ethyl 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate in 62 mL of a 3N solution of ammonia in methanol are added 11 mL of 22% aqueous ammonia solution. The reaction mixture is stirred for 20 hours in an autoclave at 80° C. (12 bar) and then concentrated under reduced pressure. The residue obtained is diluted in 100 mL of methanol, treated with carbon black and refluxed for 30 minutes. The mixture is filtered while hot through Celite and then rinsed with 2×10 mL of methanol. The filtrate is concentrated under reduced pressure to give 490 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide in the form of a foam, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:21]1([CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To an ice-cooled solution of ethyl 4-hydroxybenzenepropanoate (0.40 g, 2.1 mmol) in N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.11 g, 2.7 mmol), and the mixture was stirred for 30 min. 1-Bromo-3-phenylpropane (0.53 g, 2.7 mmol) was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.29 g, yield 46%). oil.