Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Reaction time: 18 h
Yield: 50.6 %

Procedure:
To a solution of methyl 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (550 mg) in ethanol/THF (15 ml/15 ml) was added at room temperature 1N sodium hydroxide solution (1.6 ml), and the mixture was stirred for 18 hours. To the mixture was added 1N hydrochloric acid (1.6 ml), and the mixture was concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with 2-propanol and diethylether to give yellow crystals of 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (268.9 mg). The mother liquor was concentrated, and the resulting solid was collected by filtration (177 mg). (Second crystals, Purity: about 50%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:18][CH2:19][CH2:20][CH2:21]Br>CC(C)=O>[Br:18][CH2:19][CH2:20][CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: BrCCCBr
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Nc1ccc(OCCCBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 500 mL flask was charged with 4-amino-3-nitrophenol (15.4 g, 100 mmol, commercially available from Aldrich). Acetone (300 mL), cesium carbonate (39.09 g, 120 mmol) and 1,3-dibromopropane (40.84 mL, 400 mmol) were added to the flask and stirred at refluxed temperature. The reaction was monitored by LCMS and was complete in 6 hours. The reaction mixture was cooled to room temperature, filtered and washed with excess acetone. The organic layer was removed on a rotary evaporator under reduced pressure and the resulting brown gelatin was purified by silica column chromatography using 40% hexane in dichloromethane as eluent. 20.0 g of 4-(3-bromopropoxy)-2-nitroaniline was obtained as a dark orange liquid which was used without any further purification. MS (EI: 276 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[S:7](=[O:26])(=[O:25])[C:8]2[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=2[C:10]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:4].O.[OH-].[Li+]>CO.O>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=3[S:7](=[O:26])(=[O:25])[N:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:34])[F:35])[C:5]=2[C:3]([OH:4])=[O:2])[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=1
Reactant: COC(=O)C1=C(c2cc(OC)cc(OC)c2)c2ccccc2S(=O)(=O)N1c1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OC)cc(C2=C(C(=O)O)N(c3ccccc3C(F)(F)F)S(=O)(=O)c3ccccc32)c1
Yield: 66 %

Procedure:
The solution of 4-(3,5-dimethoxy-phenyl)-2-(2-trifluoromethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (1.29 g, 2.5 mmol) and lithium hydroxide monohydrate (0.3 g 12.5 mmol) in 30 mL of MeOH and 15 mL water was refluxed for 2.5 hours and evaporated to an oil. The residue was dissolved in water, washed with ethyl ether, and the aqueous layer decanted. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a foam. The residue was chromatographed on 50 g silica gel eluted with chloroform, and the appropriate fractions were concentrated in vacuo and evaporated from ethyl ether giving a solid foam, 1.4 g, 66% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][C:7]([CH3:14])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:14])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)C1(C)CC=C(C(C)=O)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1(C)CCC(C(C)=O)CC1
Yield: 99 %

Procedure:
0.1 g of 10% palladium-carbon was added to a solution of 2.1 g of methyl 4-acetyl-1-methyl-3-cyclohexene-1-carboxylate (Example 34) in 50 ml of ethanol. The solution was reacted for 18 hours under normal-pressure hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. The oily substance obtained was refined by vacuum distillation (Kugelrohl), yielding 2.1 g of methyl 4-acetyl-1-methyl-1-cyclohexanecarboxylate as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:25]([O:15][CH2:14][C@H:11]1[CH2:12][CH2:13][N:9]([C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[CH2:10]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: C[C@H](c1ccccc1)N1CC[C@H](CO)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](c1ccccc1)N1CC[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of {(3S)-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}methanol (6.62 g, 32 mmol) and imidazole (4.77 g, 70 mmol) in N,N-dimethylformamide (90 ml) was added tert-butyldimethylchlorosilane (5.28 g, 35 mmol) at 0° C. and the resulting mixture was warmed to room temperature. The reaction mixture was stirred overnight and poured into water. Extraction with ethyl acetate was performed. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=90/10 to 75/25) to afford (3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[(1R)-1-phenylethyl]pyrrolidine (8.81 g, 27.6 mmol, 86%) as a colorless oil.
Reaction SMILES: Cl[C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4]([Cl:10])([F:9])[CH2:3]2.[Br:11]C1(Cl)CCCC(Cl)(F)C1O.[OH-].[Na+]>O>[Br:11][C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4]([Cl:10])([F:9])[CH2:3]2
Reactant: OC1C(F)(Cl)CCCC1(Cl)Br
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC1(Cl)CCC2OC2(Br)C1
Yield: 80 %

Procedure:
The same procedure was followed as for the production of 2e in Example 17: it was performed with 0.20 g (0.75 mmol) of alcohol 1i, 3 cm3 of water and 0.12 g (3 mmol) of sodium hydroxide. Reaction time: 1 h 15 min; ether extraction (4×7 cm3). After treatment, 0.15 g of epoxide 2g were obtained (macrobore GC purity>97.5%), having a yield of 80%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([O:13][Si](C)(C)C)[C:11]#N)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:13])[CH2:11][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: BrCc1ccccc1
Reactant: CSc1ccc(C(C#N)O[Si](C)(C)C)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
The 3-fluoro-4-(methylthio)-a-[(trimethylsilyl)-oxy]-benzeneacetonitrile (40.1 g, 149 mmol) was cooled to −78° C. in tetrahydrofuran(400 mL). Lithium hexamethydisilazide (175 mL of 1.0 M in Hexanes, 175 mmol) was added dropwise over 1 hour. The solution was stirred for 1 additional hour at −78° C. Benzylbromide (24.5 g 149 mmol) was added as a solution in tetrahydrofuran (100 mL) over 25 minutes. The solution was kept at −78° C. for 1 hour, warmed to room temperature, and kept at room temperature for six hours. The solution was poured into ethyl acetate (300 mL). Aqueous 1 N hydrochloric acid (200 mL) was added and the solution stirred for 48 hours at room temperature. The layers were separated and the organic layer collected. The organic layer was mixed with aqueous 15% sodium hydroxide and stirred for 30 minutes. The organic layer was collected washed with saturated ammounium chloride(200 mL) and solution was dried over sodium sulfate and solvent removed at reduced pressure to afford a yellow oil. The product was isolated by preparative silica chromatography followed by crystallization from 2% ethyl acetate and hexanes (400 mL). 1-[3-fluoro-4-(methylthio)phenyl]-2-phenylethanone (21.5 grams, 82.0 mmol) was obtained as white crystals. (55% yield): Mp 77.1-77.2° C. 1H NMR (CDCl3/300 MHz) 7.77, (dd, 1H, J=8.0, 1.8 Hz), 7.64 (dd, 1H, J=10.7, 1.8 Hz), 7.20-7.40 (m, 6H), 4.22 (s, 3H), 2.51 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]2[O:24][CH2:23]2)=[CH:20][CH:19]=1.[H-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:23][CH:22]([C:21]3[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=3)[OH:24])[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: Cc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccc(C)cc2)C1
Yield: 14.3 %

Procedure:
2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (214 mg, 1 mmol), 4-methylstyrene oxide (1 mL, 7.5 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 mL) at 120° C. for 16 h (overnight) to obtain 50 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). 1H NMR (CDCl3, TFA salt) δ (ppm): 13.20 (bs, 1H), 7.4-7.0 (m, 7H), 5.05-4.97 (m, 1H), 4.70 (t, 1H), 4.25-4.10 (m, 3H), 3.70-3.60 (m, 1H), 3.40-3.10 (m, 5H), 2.5 (s, 3H), 2.38 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[CH3:24][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:16]=2)[CH:12]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2n1C
Reaction time: 0.25 h

Procedure:
Into a solution of ethyl 6-(4-methylphenyl)-1H-indole-2-carboxylate (0.9 g) in DMF (10 ml) was added at 0° C. sodium hydride (60%, 0.14 g), and the resulting mixture was stirred for 15 minutes. Into the reaction mixture was added methyl iodide (0.22 ml), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration of the organic layer under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:4) and further to recrystallization (ethyl acetate/hexane) to obtain ethyl 1-methyl-6-(4-methylphenyl)-1H-indole-2-carboxylate (0.80 g) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])/[C:9]1=[O:32])=O)(C)(C)C.[F:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:49])=[C:38]([CH:40]=[N:41][C:42]([O:44][Si](C)(C)C)=[CH2:43])[CH:39]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:32])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:43][C:42](=[O:44])[NH:41][CH:40]3[C:38]3[CH:39]=[C:34]([F:33])[CH:35]=[CH:36][C:37]=3[CH3:49])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cc(Cl)ccc2OCS(C)(=O)=O)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Yield: 5.8 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-(5-chloro-2-methanesulfonylmethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (600 mg, 1.2 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (5 mmol) in toluene to give the title compound as a white solid (40 mg).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.NC1C2C(=CC=CC=2)N=C(C)C=1C(=O)C.BrC1C=CC(CBr)=C([Cl:48])C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[C:22]([Cl:48])[CH:23]=1
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Reactant: Clc1cc(Br)ccc1CBr
Agent: CC(=O)c1c(C)nc2ccccc2c1N
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1Cl

Procedure:
1-(4-(4-Bromo-2-chlorobenzylamino)-2-methylquinolin-3-yl)ethanone was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from 1-(4-amino-2-methylquinolin-3-yl)ethanone and 4-bromo-2-chlorobenzyl bromide. MS(FAB+): 403/405.
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[C:6](=[C:7]([C:13]([OH:15])=O)[CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH3:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:13]([NH:21][C@@H:20]([CH3:22])[C:19]([O:18][CH2:16][CH3:17])=[O:23])=[O:15])[C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c3c([nH]c12)CCC3
Reactant: CCOC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NC(=O)c1cccc2c3c([nH]c12)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a stirred, cooled (0° C.) solution of crude 1,2,3,4-tetrahydrocyclopenta[b]indole-5-carboxylic acid (60 mmol, 12 g), L-alanine ethyl ester (72 mmol, 11 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (72 mmol, 14 g), 1-hydroxybenzotriazole (HOBT) (72 mmol, 10 g) in CH2Cl2 (100 mL) was slowly added diisopropylethylamine (360 mmol, 46 g). The reaction mixture was stirred overnight while warming to room temperature. The reaction was concentrated in vacuo and the resulting oil was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous NH4Cl, NaHCO3, and brine, dried over MgSO4, filtered and concentrated to a brown oil. The crude material was purified by chromatography through silica gel (Biotage) eluting with 15% ethyl acetate-hexanes to afford a yellow oil (8.4 mmol, 2.5 g, 16% yield over 2 steps).
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:17]=[C:16](I)[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19].[CH3:20][N:21]([CH3:29])[C:22](=[O:28])[CH2:23][O:24][CH2:25][C:26]#[CH:27]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:19][C:10]1[C:11]2[O:15][CH2:14][O:13][C:12]=2[C:16]([C:27]#[C:26][CH2:25][O:24][CH2:23][C:22]([N:21]([CH3:29])[CH3:20])=[O:28])=[CH:17][C:9]=1[Cl:8]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCOCC(=O)N(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CN(C)C(=O)COCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: -20 °C
Yield: 81.9 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.236 g), cuprous iodide (0.96 g) and diisopropylamine (0.47 ml) were added to a stirred solution of 5-chloro-7-iodo-1,3-benzodioxol-4-amine (0.500 g) and N,N-dimethyl-2-(prop-2-yn-1-yloxy)acetamide (0.474 g) in ethyl acetate (8 ml) cooled to −20° C. under a nitrogen atmosphere; the resultant mixture was stirred for 4 hr at ambient temperature. The reaction mixture was filtered through Celite, ethyl acetate (12 ml) was then added and the resultant solution washed with saturated aqueous sodium bicarbonate (20 ml). The aqueous layer was re-extracted with ethyl acetate (20 ml). The combined organic extracts were washed with brine (20 ml), dried over sodium sulphate and then evaporated. The residue was purified by column chromatography on silica using ethyl acetate as eluent. There was thus obtained the title compound as a solid (0.428 g). NMR Spectrum: (CDCl3) 2.96 (s, 3H), 3.02 (s, 3H), 4.06 (s, 2H), 4.31 (s, 2H), 4.52 (s, 2H), 6.02 (s, 2H), 6.89 (s, 1H); Mass Spectrum: M+H+ 311 and 313.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][NH:40][CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[C:53](Cl)(=[O:55])[CH3:54]>ClCCl>[C:53]([N:40]1[CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][N:32]([C:21]3[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]4[CH:4]=[C:3]([C:2]([F:44])([F:1])[F:45])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=4)([CH3:43])[CH3:42])=[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[CH3:31])[CH:22]=3)[CH2:33][CH:34]2[CH2:41]1)(=[O:55])[CH3:54]
Reactant: CC(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN2CCN(c3cc(-c4ccc(F)cc4C)c(N(C)C(=O)C(C)(C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cn3)CC2C1
Reaction time: 2 h

Procedure:
To a solution of crude 2-[3,5-bis(trifluoromethyl)phenyl]-N-[4-(4-fluoro-2-methylphenyl)-6-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-3-pyridinyl]-N,2-dimethylpropanamide (prepared with an analogous procedure to that described for D80, 89 mg, 0.14 mmol) in 5 mL of dichloromethane were added at 0° C. triethylamine (197 μL, 1.41 mmol) and acetyl chloride (75 μL, 1.0 mmol). The reaction was left at room temperature for 2 h. It was diluted with dichloromethane, extracted with sat NaHCO3 solution, the organics dried (Na2SO4), and the solvent was removed. The product was purified by flash chromatography (silica, cyclohexane: EtOAc 50:50 to EtOAc). Obtained 60 mg.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:38])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)=[O:4].[C:39](Cl)(=[O:42])[CH:40]=[CH2:41].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:37][C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([NH:5][C:3]([C@@H:2]([NH:1][C:39](=[O:42])[CH:40]=[CH2:41])[CH3:38])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)[C@H](C)N
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N[C@@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCOC
Yield: 24 %

Procedure:
205 mg of (2S)-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-propionamide as a starting material was dissolved in 10 ml of a mixture of THF and water (3:1), and reacted with 0.047 ml of acryloylchloride at room temperature for 1 hour after adding 97 mg of sodium bicarbonate. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (55 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:13]=3[NH2:14])=[CH:10][N:9]([CH3:23])[C:8]=12.[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1.[Na].C(O)(=O)C>ClCCl>[CH:24]1([CH2:27][NH:14][C:13]2[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:12]=2[C:11]2[C:7]3[C:8](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=3)[N:9]([CH3:23])[CH:10]=2)[CH2:26][CH2:25]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N)cn(C)c12
Reactant: O=CC1CC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CC3)cn(C)c12
Yield: 99.6 %

Procedure:
The product from Example 44A (0.1 g, 0.302 mmol), cyclopropanecarboxaldehyde (0.063 g, 0.905 mmol) and sodium triacetoxyhydroborate (0.192 g, 0.905 mmol) were combined in dichloromethane (1.0 mL) and acetic acid (1.0 mL) under nitrogen, stirred for 6 hours and partitioned into water/ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (0.116 g, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]3[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:23]=1.C(=O)([O-])[OH:25].[Na+]>O1CCOCC1.O>[I:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:23]=[C:3]([CH2:2][OH:25])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: O=C([O-])O
Reactant: ClCc1cn2c(n1)CN=C(c1ccccn1)c1cc(I)ccc1-2
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cn2c(n1)CN=C(c1ccccn1)c1cc(I)ccc1-2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
A solution of 1.15 g of 2-chloromethyl-8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine in 40 ml of dioxan was treated with a solution of 0.28 g of sodium hydrogen carbonate in 10 ml of water and stirred at 80° C. for 1.5 h. The mixture was evaporated in a vacuum. The residue was partitioned between chloroform and aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with chloroform. The chloroform extracts were dried over sodium sulphate, concentrated to 30 ml in a vacuum and chromatographed over 50 g of silica gel. 1.05 g of the desired product were eluted with chloroform/ethanol mixtures containing 3 to 7% ethanol. After recrystallization from ethyl acetate/diethyl ether there was obtained 0.955 g of 8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 206-207° C. which was converted into the hydrochloride (dec. above 300° C.).