Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1>>[C:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:28]1[C:23]([O:22][CH2:21][CH2:20][O:19][CH3:18])=[N:24][C:25]([C:34]([F:36])([F:35])[F:37])=[CH:26][CH:27]=1)#[CH:17]
Reactant: COCCOc1nc(C(F)(F)F)ccc1C=CC(=O)O
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OCCOC)cc(F)c1NS(C)(=O)=O
Yield: 70.1 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (45 mg, 0.156 mmol) was reacted with 3-[2-(2-methoxy-ethoxy)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (38 mg, 0.13 mmol) to give the title compound (47 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=4)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[N:18]([CH3:37])[CH:19]=[C:20]([CH2:24][C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[N:27][CH:26]=4)[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Solvent: ClCCl
Solvent: CI
Product: COc1ncc(Cc2cn(C)c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To a solution of 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone (300 mg, 0.561 mmol) and DIPEA (0.294 mL, 1.682 mmol) in DCM (15 mL) was added MeI (0.053 ml, 0.841 mmol). The mixture was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (100 mg, 32.5% yield). LCMS: rt=3.49 min, [M+H+]=549
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[C:14]([N:16]2[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7](OCC)=[O:8])(=[O:4])=[O:3].[CH3:24][C:25]1[C:26]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[CH3:1][S:2]([C:5]1[CH:15]=[C:14]([N:16]2[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7]([N:38]1[CH2:39][CH2:40][N:35]([C:26]2[C:25]([CH3:24])=[CH:30][C:29]([C:31]([F:34])([F:32])[F:33])=[CH:28][N:27]=2)[CH2:36][CH2:37]1)=[O:8])(=[O:3])=[O:4]
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Reactant: CCOC(=O)c1ccc(N2[C@H](C)CCS2(=O)=O)cc1S(C)(=O)=O
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3[C@H](C)CCS3(=O)=O)cc2S(C)(=O)=O)CC1
Yield: 13.9 %

Procedure:
Using ethyl (R)-2-methanesulfonyl-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (361 mg) described in Preparation Example 28 and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (245 mg) described in Preparation Example 84 and by the reaction and treatment in the same manner as in Example 109, the title compound (78 mg) was obtained.
Reaction SMILES: [C-:1]#[N:2].[CH3:3][C@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:5]=[O:6].[NH4+].[Cl-].O>C1(C)C=CC=CC=1>[C:1]([CH:5]([OH:6])[C@@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:3])#[N:2]
Reactant: [C-]#N
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Temperature: -78 °C
Reaction time: 6 h

Procedure:
Diethylalumninum cyanide (4.53 mL, 1M in toluene, 4.53 mmol) was added dropwise to a stirred solution of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry toluene (33 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. Saturated NH4Cl (20 mL) and water (10 mL) were added then the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1 mixture of diastereoisomers. Rf=0.63 (50% EtOAc in hexanes). LCMS calc.=257.1; found=257.1 (M+1)+. 1H NMR (500 MHz, CDCl3) major diastereoisomer: δ 7.39-7.31 (m, 5H), 5.11 (m, 2H), 4.60 br (s, 1H), 3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H), minor diastereoisomer: δ 7.39-7.31 (m, 5H), 5.14 (m, 2H), 4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].IC.[C:12](=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)ccc1Br
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(F)ccc1Br
Temperature: 25 °C
Yield: 111.4 %

Procedure:
In a 250 mL r.b. flask, a solution of 2-bromo-5-fluorophenol (Lancaster: 7.0 mL, 64 mmol, 1.0 equivuiv) in acetone (140 mL) was treated with iodomethane (Aldrich: 4.8 mL, 77 mmol, 1.2 equivuiv), potassium carbonate (8 g), and water (1 mL). The reaction mixture was heated at reflux for 6 h, cooled to rt, clarified with H2O (40 mL), and the bulk of the volatiles was removed under reduced pressure. The reaction mixture was extracted with EtOAc (3×120 mL); the extracts were washed with brine (1×80 mL), combined, dried (K2CO3), filtered, and concentrated to a clear oil. Bulb-to-bulb distillation (60-65° C., 0.7 Torr) afforded 13.22 g (quant) of 2-bromo-5-fluoroanisole as a colorless liquid. Data for 2-bromo-5-fluoroanisole: 1H NMR (400 MHz, CDCl3): 7.46 (dd, J=10.6, 8.7, 1H); 6.64 (dd, J=10.4, 2.8, 1H); 5.58 (dt, J=10.4, 2.4, 1H); 3.88 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:9](=[O:18])[CH:8]([NH:19][C:20](=[O:40])[C@H:21]([NH:26][C:27](=[O:39])[C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:30])[CH3:29])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:7]2.[C:41]1(=O)[O:46][C:44](=[O:45])[CH2:43][CH2:42]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O.C1(C)C=CC=CC=1>[O:45]=[C:44]1[CH2:43][CH2:42][C:41](=[O:46])[N:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:9](=[O:18])[CH:8]([NH:19][C:20](=[O:40])[C@H:21]([NH:26][C:27](=[O:39])[C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:29])[CH3:30])[CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:7]2
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2N(Cc2ccsc2)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3C(=O)CCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 25 °C

Procedure:
tert-Butyl 1-((2R)-1-(8-amino-2-oxo-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (100 mg) and succinic anhydride (21 mg) were added to toluene (1 mL), and the mixture was refluxed for two hours while being stirred. The reaction mixture was concentrated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (ethyl acetate, chloroform:methanol (5:1)), whereby the Compound A (114 mg) was yielded. The Compound A (110 mg), sodium acetate (75 mg), and acetic anhydride (1 mL) were added to toluene (1 mL), and the mixture was stirred at 80° C. for 20 minutes. The mixture was cooled to room temperature, and water was added thereto. The mixture was extracted with ethyl acetate twice, and the organic layers were combined. The combined organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure, whereby the title compound (100 mg) was yielded.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17](Br)=[C:16]([CH3:21])[N:15]([C@H:22]([CH3:26])[CH2:23][O:24][CH3:25])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:29][CH:30]([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:30]([F:40])[F:29])[CH:36]=3)=[C:16]([CH3:21])[N:15]([C@H:22]([CH3:26])[CH2:23][O:24][CH3:25])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1cccc(C(F)F)c1
Reactant: COC[C@@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c(Br)c1C
Product: COC[C@@H](C)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c(-c2cccc(C(F)F)c2)c1C

Procedure:
Example 44 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 43c and replacing 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid. ESI mass spectrum: [M+H]+=519; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:39]=[CH:38][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[CH:15]=[C:14]2[C:33](OCC)=[O:34])=[CH:10][CH:9]=1>C(OCC)C>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[CH:15]=[C:14]2[CH2:33][OH:34])=[CH:38][CH:39]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(Cn2c(CO)cc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
Lithium aluminum hydride (0.244 g, 6.1 mmol) was added portionwise to a stirring solution of ethyl 1-(4-methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indole-2-carboxylate (2.0 g, 4.4 mmol) in ethyl ether (17 mL) at 0° C. under a nitrogen atmosphere over a period of 5 minutes. The mixture was then warmed up to room temperature. After the reaction mixture was stirred at room temperature for 5 hour, the reaction was carefully quenched with water then filtered. The filtrate was extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to afford the title compound as a white solid (1.56 g, 86%). Mass spectrum (ESI, [M+H]+) m/z 412. 1HNMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.76 (d, 2H, J=6.71 Hz), 7.45-7.35 (m, 4H), 7.08 (d, 2H, J=7.74 Hz), 6.96 (d, 2H, J=8.09 Hz), 6.50 (s, 1H), 5.44 (s, 2H), 5.35 (t, 1H), 4.60 (d, 2H), and 2.23 ppm (t, 3H). Elemental Analysis for C24H20F3NO2: Calculated: C, 70.07; H, 4.90; N, 3.40. Found: C, 69.80; H, 4.75; N, 3.34.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:24](/[CH:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1)=[CH:25]\[CH2:26][CH2:27][CH3:28].O>COC(C)(C)C.O1CCCC1>[CH3:2][O:3][CH:4]=[C:32]1[CH2:33][CH2:34][CH:29](/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31]1
Reactant: CCC/C=C/C1CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CCC/C=C/C1CCC(=COC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7 g of methoxymethyl-triphenylphosphonium chloride were suspended in 35 ml of t-butyl methyl ether and the suspension was treated at -20° C. with 2.43 g of potassium t-butylate. The mixture was stirred for a further 1 hour at room temperature, then treated dropwise at -20° C. with a solution of 2 g of 4-(1E-pentenyl)cyclohexanone in 18 ml of tetrahydrofuran and the mixture was stirred for a further 1 hour at room temperature. The reaction mixture was subsequently treated with water and extracted three times with 50 ml of diethyl ether each time. The extracts were washed with water and the wash-water was back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate and freed from solvent. The residue was dissolved in ethyl acetate and the solution was diluted with petroleum ether, freed from precipitated triphenylphosphine oxide by filtration and the filtrate was concentrated. This procedure for the separation of triphenylphosphine oxide was repeated twice and the crude product of 1-(methoxymethylene)-4-(1E-pentenyl)cyclohexane obtained was processed without additional purification.
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:29][CH2:28]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:29][CH2:28]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCO)CC1
Product: O=C(OCc1ccccc1)N1CCC(CCCCCBr)CC1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 4-(5-hydroxypentyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH2:1]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:31][N:32]=2)=[CH:24][CH:23]=1>C1COCC1>[Br-:20].[C:33]1([C:30]2[O:29][C:28]([C:25]3[CH:24]=[CH:23][C:22]([CH2:21][N:17]4[CH:18]=[CH:19][N+:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:16]4)=[CH:27][CH:26]=3)=[N:32][CH:31]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCCCCCCCCCCCCn1ccnc1
Reactant: BrCc1ccc(-c2ncc(-c3ccccc3)o2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC[n+]1ccn(Cc2ccc(-c3ncc(-c4ccccc4)o3)cc2)c1
Product: [Br-]
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a round-bottomed flask previously purged with anhydrous argon are added 1-tetradecylimidazole [2-5] (1.023 g, 3.9 mmol), 2-(4-bromomethyl-phenyI)-5-phenyl-oxazole (1.215 g, 3.9 mmol) and anhydrous THF (15 mL). The reaction mixture is stirred at 80° C. for 12 hours. The solvent is removed in vacuo and the product is washed with 3 times 10 mL Et2O and dried under reduced pressure at ambient temperature. The product is purified by flash chromatography (silica gel column, elution with DCM-MeOH, MeOH 1% to 7%) and characterized as being an imidazolium salt.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>CN(C=O)C.CCOCC.O>[CH2:1]([O:8][C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2cccnc2Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Cc1noc(-c2cccnc2OCc2ccccc2)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl alcohol (1.5 eq) in DMF (0.4M) was added NaH (1.5 eq, 60%) followed by 2-chloro-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine (1 eq) in DMF (0.5M) after 30 min.). The reaction was stirred at 20° C. for 1 h, diluted with Et2O and water. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 80:20) afforded the title compound.
Reaction SMILES: O.[OH-].[Li+].O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=1)[CH:10]=[C:9]2[C:25]([O:27]C)=[O:26]>O1CCCC1>[C:25]([C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([Cl:5])[CH:7]=2)[N:11]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:10]=1)([OH:27])=[O:26]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Reaction time: 16 h
Yield: 87.9 %

Procedure:
0.42 g (15 mmol) of lithium hydroxide monohydrate and 50 cm3 of water are added to 1.13 g (3.35 mmol) of 5-chloro-3-methoxycarbonyl-1-(quinolin-4-yl)-1H-indole dissolved in 50 cm3 of tetrahydrofuran at a temperature in the region of 20° C. After stirring for 16 hours at the reflux temperature of the solvent, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 10 cm3 of 1N hydrochloric acid, the suspension is then filtered, and the solid residue is dried under atmospheric pressure at a temperature in the region of 60° C., giving 0.95 g of 3-carboxy-5-chloro-1-(quinolin-4-yl)-1H-indole in the form of a cream-colored solid, which is used directly in the following step.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].[CH:10]1[CH:11]=[CH:12][C:13]2N(O)N=N[C:14]=2[CH:15]=1.C(N(CC)CC)C.[C:27]([O:31][C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34])([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[CH2:27]([O:31][C:32]([NH:1][C@H:2]([C:7]([NH:34][C@@H:33]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:36])[CH3:35])=[O:9])[CH2:3][CH2:4][S:5][CH3:6])=[O:36])[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:15]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 109.3 %

Procedure:
Z-Protected L-methionine (10 g) was dissolved in DMF (200 ml) and 1-[3-(diemthylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.13 g) was added followed by HOBT (5.72 g) and triethylamine (19.7 ml). The mixture was stirred for 1 h then L-alanine tert-butyl ester (7.7 g) was added and stirring continued for 18 h. The mixture was evaporated under reduced pressure and partitioned between diethyl ether and water. The separated organic phase was washed with hydrochloric acid (1M), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (11.9 g) as an orange oil which crystallised on standing.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]([C:13]([OH:15])=O)[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>O1CCCC1>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:13]([CH:5]2[C:4]3[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=3[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]2=3)=[O:15])[CH2:22][CH2:23]1
Reactant: CN1CCC(N)CC1
Reactant: O=C1Nc2ccccc2C(C(=O)O)c2ccccc21
Solvent: C1CCOC1
Product: CN1CCC(NC(=O)C2c3ccccc3NC(=O)c3ccccc32)CC1
Temperature: 40 °C
Yield: 68.7 %

Procedure:
A quantity of 3.5 gm (0.022 mol) of N,N'-carbonyldiimidazole is added to a suspension of 5 gm (0.02 mol) of 5,11-dihydro-6-oxo-6H-dibenz[b,e]azepin-11-carboxylic acid in 100 ml of tetrahydrofuran, and the mixture is heated to 40° C. for 30 minutes. Then, 2.5 gm (0.022 mol) of 4-amino-1-methylpiperidine are added, and the mixture is heated for a further two hours at 40° C. After cooling, the solvent is removed in vacuo, and the residue is purified by column chromatography on silica gel [ethylene chloride/methanol (9:1)]. Subsequently, 4.8 gm (68%) of the desired compound, M.p.: 230°-231° C., are obtained from the eluate. According to the mixed melting point, thin layer chromatography, and IR spectrum, the substance is identical to the product obtained in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[C@H:10]([CH2:23][C:24]([OH:26])=[O:25])[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=O)C(Cl)=O.CO>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[C@H:10]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=N[C@H]2CC(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetic acid (100 mg, 0.27 mmol) and N,N-dimethylformamide (1 drop) in dichloromethane (10 mL) was added oxalyl chloride (56 mg, 0.40 mmol) dropwise at 0° C. The mixture was stirred for 0.5 hour at room temperature. The solution was cooled to 0° C. and methanol (100 mL) was added. The mixture was stirred for 0.5 hour at room temperature. The mixture was concentrated in vacuo, and the residue was diluted with water (5 mL), and extracted with ethyl acetate (10 mL×3). The combined organic layers were dried by sodium sulfate, concentrated in vacuo and the residue was purified by column chromatography (silica-gel, petroleum:ethyl acetate=2:1) to give methyl 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetate (80 mg, 77%) as a light yellow solid. LC/MS m/z 380 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH2:7]([NH2:11])[CH2:8][C:9]#[CH:10]>C(OCC)C>[CH2:7]([NH:11][C:5]([NH:4][CH2:3][CH2:2][Cl:1])=[O:6])[CH2:8][C:9]#[CH:10]
Reactant: O=C=NCCCl
Reactant: C#CCCN
Solvent: CCOCC
Product: C#CCCNC(=O)NCCCl
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Add chloroethyl isocyanate (5.25 g, 50 mmol) dropwise to a solution of but3-ynyl-amine (3.4 g, 50 mmol) (prepared by following the procedure described in Tetrahedron Lett. 1987, 43, 5145) in ethyl ether (100 mL). Stir the suspension for 30 min and filter the solid to obtain the desired intermediate (8.7 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[C:9]([CH3:25])[S:8][C:7]=2[C:26]=1[O:27]S(C1C=CC(C)=CC=1)(=O)=O.CO>C1COCC1.[OH-].[Na+]>[OH:27][C:26]1[C:7]2[S:8][C:9]([CH3:25])=[C:10]([C:11](=[O:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)c2c(C)sc3c(OS(=O)(=O)c4ccc(C)cc4)c(OC)ccc23)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(C)sc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 30 °C
Reaction time: 8 h
Yield: 279.4 %

Procedure:
A mixture of the product of Example 41 (0.035 g; 0.00645 mmol) in THF (0.5 ml) and 1% NaOH in MeOH (0.52 ml; 0.0129 mmol) was stirred overnight at 30° C. under N2 and acidified with the drop of CF3 CO2H. This was evaporated to dryness and diluted to 15 ml with diethyl ether, washed with 0.1 M HCl (2 ml), 5% NaHCO3 (2 ml), brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, CH2Cl2) to give pure title compound (0.007 g; 28%), as a colourless crystals. 1H-NMR (CDCl3) 2.47 (s, 3H); 3.83 (s, 6H); 3.92 (s, 6H); 5.94 (s, 1H); 6.93 (d, 1H, J=8.69 Hz); 7.05 (d, 1H, J=8.69 Hz); 7.1 (s, 2H).