Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=[O:13])=[CH:10][CH:9]=2)[CH2:4]1.[O:19]([CH2:26][CH2:27][S:28][CH2:29][C:30](O)=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]3[O:13][C:30]([CH2:29][S:28][CH2:27][CH2:26][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:4]1
Reactant: O=C(O)CSCCOc1ccccc1
Reactant: CN(C)C1CCN(c2ccc(C(=O)NN)cc2)C1
Product: CN(C)C1CCN(c2ccc(-c3nnc(CSCCOc4ccccc4)o3)cc2)C1

Procedure:
4-(3-Dimethylaminopyrrolidin-1-yl)benzohydrazide was reacted with (2-phenoxy-ethylsulfanyl)acetic acid by Method A. The product with the molecular weight of 424.57 (C23H28N4O2S) was obtained in this way; MS (ESI): 425 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2([CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[CH2:10][CH2:9]2)[CH:7]=1.[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH2:36])[N:27]=1)=[O:25]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[N:36]=[CH:13][C:12]([OH:19])([C:15]([F:18])([F:16])[F:17])[CH2:11][C:8]2([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:20][CH3:21])[CH2:10][CH2:9]2)[N:27]=1)=[O:25]
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: COc1ccc(F)cc1C1(CC(O)(C=O)C(F)(F)F)CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(N=CC(O)(CC3(c4cc(F)ccc4OC)CC3)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 306 mg (1.2 mmol) of 5-{3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propanal is reacted with 170 mg (0.84 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 4.0 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0-70%), 204 mg (49% of theory) of the product is obtained.
Reaction SMILES: [C:1]1([CH2:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(#N)C>[CH:12]1([CH2:11][CH2:10][NH:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NCc1ccccc1
Reactant: BrCCC1CCCC1
Solvent: CC#N
Product: c1ccc(CNCCC2CCCC2)cc1

Procedure:
Combine 10.7 g (0.1 mol) of benzenemethanamine and 17.7 g (0.1 mol) of (2-bromoethyl)cyclopentane in 100 mL of acetonitrile. Heat the mixture to reflux and follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction remove the solvent in vacuo and add 100 mL of saturated sodium bicarbonate solution. Extract the aqueous mixture with three 100 mL portions of diethyl ether. Dry the combined extracts over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: N[C:2]1[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[OH-:14].[Na+].C.Cl>O>[OH:11][C:7]1[C:6]2[C:2](=[O:14])[NH:3][S:4](=[O:13])(=[O:12])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: NC1=NS(=O)(=O)c2cccc(O)c21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1NS(=O)(=O)c2cccc(O)c21
Yield: 92 %

Procedure:
5 gm (25.2 mmols) of 3-amino-4-hydroxy-1,2-benzoisothiazole-1,1-dioxide and 2.02 gm (50.5 mmols) of sodium hydroxide were refluxed in 15 ml of water for 6.5 hours. Subsequently, the solution was treated with activated charcoal at 60° C. and filtered. At 60° C. the filtrate was acidified with concentrated aqueous hydrochloric acid (about 5 ml, 0.06 mol). The resulting precipitate was filtered off, dried and recrystallized from water. 4.62 gm (92% of theory) of 4-hydroxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide were obtained.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]1[N:21]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[CH3:29])[C:20](=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)C1C=CC=CC=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:21]1[C:20](=[O:30])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]1[CH2:11][NH:10][S:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:40])=[O:39]
Reactant: Cc1ccc(-n2c(CNC(=O)OCc3ccccc3)nc3ccccc3c2=O)c(C)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1ccc(-n2c(CNS(=O)(=O)c3ccccc3)nc3ccccc3c2=O)c(C)c1

Procedure:
[3-(2,4-Dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]carbamic acid benzyl ester, as prepared above in Example 4, was hydrogenated in a similar manner as described above in Example 6, and then condensed, as described above in Paragraph A, with benzenesulfonyl chloride to yield N-[3-(2,4-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylmethyl]benzenesulfonamide; MS (ESI) 420 (MH+).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Cl[C:11]1[N:16]=[CH:15][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][N:6]([C:11]2[N:16]=[CH:15][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH:7]=1
Reactant: CCCC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCC(=O)c1ccc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
A mixture of 4-(trifluoromethyl)pyrazole (116 mg, 0.85 mmol), 1-(6-chloropyridin-3-yl)butan-1-one (130 mg, 0.71 mmol), and potassium carbonate (294 mg, 2.12 mmol) was stirred 4 h at 50° C. The mixture was cooled to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (200 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.97-8.99 (m. 1H), 8.90-8.91 (m, 1H), 8.39 (dd, J=8.5, 2.4 Hz, 1H), 8.08 (dd, J=8.58, 0.78 Hz, 1H), 7.93 (s, 1H), 2.94 (t, J=7.4 Hz, 2H), 1.74-1.85 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][OH:23])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>CO.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][O:23][CH2:26][CH2:25][C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)CCOCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
A mixture of (1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methanol (50 mg, 0.161 mmol), tert-butyl acrylate (0.059 mL, 0.403 mmol), and Triton B (40% in MeOH) (7 μL, 0.016 mmol) in toluene (1 mL) was stirred at rt for 5 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 (0-30% EtOAc:hexanes) to afford the title compound (61 mg, 85% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.28 (dd, J=9.1, 6.7 Hz, 1H), 7.19-7.13 (m, 2H), 7.12-7.07 (m, 1H), 7.01 (ddd, J=4.4, 3.3, 1.8 Hz, 2H), 6.86 (ddd, J=8.0, 2.4, 1.0 Hz, 1H), 3.92 (s, 2H), 3.65 (t, J=6.3 Hz, 2H), 3.17 (s, 2H), 2.48 (t, J=6.3 Hz, 2H), 2.10-1.95 (m, 4H), 1.86-1.73 (m, 2H), 1.70-1.58 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=O)[O:33]C(C)(C)C)[CH2:27][CH2:26]2)=[O:24])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].Cl.O1[CH2:47][CH2:46]OCC1>C1COCC1>[C:32]([NH:31][CH:28]1[CH2:29][CH2:30][N:25]([C:23]([NH:22][CH2:21][CH2:20][C:7]2([C:5]([NH:4][CH2:3][C:2]([F:40])([F:39])[F:1])=[O:6])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:24])[CH2:26][CH2:27]1)(=[O:33])[C:47]1[CH:46]=[CH:9][CH:8]=[CH:7][CH:5]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)NCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NC1CCN(C(=O)NCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 487 compound (1.1 g, 1.97 mmol) in THF (4 mL) was added 4N HCl in dioxane (9 mL, 36.4 mmol). The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo and then from dioxane (3×10 mL) to give crude title compound (1.46 g) as a white foamy solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1([N:10]2[C:14]3=[N:15][C:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH2:27][CH3:28])[NH:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([N:10]2[C:14]3=[N:15][C:16]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N+:1]([O-:4])=[O:2])=[CH:25][CH:26]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH2:27][CH3:28])[NH:11]2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=[N+]([O-])O
Reactant: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3)nc(=O)c1-2
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc([N+](=O)[O-])cc3)nc(=O)c1-2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
and (b) To 90% HNO3 (95 mL) at -10° to -15° C. was added 1-cyclopentyl-3-ethyl-6-(phenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one (9.62 g, 30 mmol). The reaction mixture was stirred as such for 1.5 hours, and then was poured into ice water. A precipitate formed which was collected by filtration, recrystallized from ethyl acetate and dried at 100° C. and 0.2 mm Hg to afford 2.31 g of 1-cyclopentyl-3-ethyl-6-(4-nitrophenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 221°-223° C. [labelled as Example 25 (a)]. The mother liquors were combined and concentrated in vacuo to afford a mixture of 1-cyclopentyl-3-ethyl-6-(2-nitrophenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one and 1-cyclopentyl-3-ethyl-6-(3-nitrophenylmethyl]pyrazolo[3,4-d]pyrimidin-4-one [labelled as Example 25 (b)].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].OO.[OH-].[Na+].[ClH:15]>O>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cccnc1N
Reactant: Cl
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc(Cl)cnc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
(Step 1) To a solution of 2-aminonicotinamide (0.5 g) in concentrated hydrochloric acid (3 ml) was added dropwise 30% aqueous hydrogen peroxide (0.3 ml). After stirring at 60° C. for 1 hr, the reaction mixture was diluted with water and basified with 1N aqueous sodium hydroxide solution. The mixture was extracted with a mixed solution of ethyl acetate and THF, washed with saturated brine and dried over magnesium sulfate. The reaction solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to give 2-amino-5-chloronicotinamide as crystals (0.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].N1C=CN=C[C:33]=1N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:33][CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: Nc1cnccn1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CCc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (cis)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.14, 1.20, 1.29, 1.95, 2.31, 2.45, 2.73, 2.82, 3.12, 3.48, 3.74, 3.99, 5.42, 5.75, 7.12-7.21, 7.36, 7.51; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1617.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][O:15][S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Cl)nc2)nc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1
Reaction time: 8 h

Procedure:
The crude 2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethanol from step C is dissolved in methylene chloride (50 mL), then TsCl, DMAP and triethyl amine are added and stirred overnight. The reaction mixture is washed with water, brine and concentrated. Column chromatography on silica gel gave the title compound (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:18](=[O:20])[CH3:19])[C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].[NH2:21]/[C:22](/[CH3:31])=[CH:23]\[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(O)CCC>[C:18]([C:10]1[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([CH3:31])[NH:21][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16])(=[O:20])[CH3:19]
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)CCCCCl
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Solvent: CCCCO
Product: CC(=O)C1=C(CCCCCl)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1Cl

Procedure:
25 g (70 mmol) 6-(2,3-dichlorophenyl-methylene)-1-chloro-5,7-octanedione and 22 g (0.14 mol) tert-butyl β-amino-crotonate are boiled under reflux in 200 ml 1-butanol for 6 h. The mixture is concentrated and the residue is prepurified by chromatography with toluene/acetone=8/2. The product thus obtained is chromatographed again over silica gel with toluene/acetone=99/1. The title compound is obtained as a yellow oil. Yield: 5.8 g (18%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:21])O)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl.[OH-].[Na+]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1C(O)c1ccc2[nH]cc(C#N)c2c1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CC1Cc1ccc2[nH]cc(C#N)c2c1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of the 2-[(3-cyano-1H-indol-5-yl)-hydroxy-methyl]-cyclopropane-carboxylic acid ethyl ester (1.0 g, 3.5 mmol), dichloromethane (25 ml), and trifluoroacetic acid (5 ml) was cooled to 0° C. and treated with triethylsilane (0.57 g, 5.0 mmol). The solution was stirred for 30 min and then diluted with an additional 50 ml dichloromethane and neutralized with 1 N sodium hydroxide. The organic layer was washed with brine (1×50 ml) and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo to a deep amber oil. Silica gel column chromatography (hexanes, ethyl acetate 1:1) afforded 2-(3-cyano-1H-indol-5-ylmethyl)-cyclopropane-carboxylic acid ethyl ester (0.62 g, 56%) as a light yellow oil. LC-MS: 1.38 min; 269.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2N(C)C(=O)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[CH3:21][O:22][C:23](=[O:26])OC>>[CH3:21][O:22][C:23]([C:9]1[NH:8][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]2[C:5]=1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20]2)=[O:26]
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: COC(=O)OC
Product: COC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
The starting material can be prepared from 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and dimethylcarbonate in a manner analogous to that described in Example 1. After recrystallization from acetone, there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid methyl ester; melting point 208°-210° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH:17]=O)[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:44])[CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:21]>ClCCl>[CH2:20]([O:22][C:23](=[O:44])/[CH:24]=[CH:17]/[C@H:14]1[CH2:15][CH2:16][C@H:11]([CH2:10][CH2:9][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[CH3:8])[CH2:12][CH2:13]1)[CH3:21]
Reactant: CN(CC[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Yield: 75.5 %

Procedure:
A solution of 4.02 g (14.9 mmol) trans-[2-(4-formyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester and 5.47 g (14.9 mmol) of (triphenyl-phosphoranylidene)-acetic acid ethyl ester in 40 ml of dichloromethane was stirred at room temperature for 60 hours. After concentration under reduced pressure, the crude product was chromatographed on silica gel with a 9:1 v/v mixture of hexane and ethylacetate as the eluent giving 3.82 g (75.4%) of pure trans-3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-(E)-acrylic acid ethyl ester as colorless viscous oil, MS: 340 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]5[CH3:59])=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([CH2:27]O)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CS([Cl:73])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]5[CH3:59])=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([CH2:27][Cl:73])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CO)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CCl)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of Intermediate 61e (124 mg, 0.15 mmol) in DCM (1.5 mL) at 0° C. was treated with DIPEA (79 μL, 0.45 mmol) then methanesulfonyl chloride (23 μL, 0.30 mmol) and the mixture was stirred at RT for 1 h. The mixture was cooled to 0° C. and treated with another portion of DIPEA (40 μL, 0.23 mmol) and methanesulfonyl chloride (12 μL, 0.15 mmol) and stirred at RT for 30 min. The mixture was diluted with DCM and a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with water, a saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-4% MeOH in DCM, to give the title compound (34 mg, 27%). LCMS (Method 3): Rt 5.56 min, m/z 839 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:7]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:6][C:5]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=2)=[C:4]([Cl:57])[C:3]=1[OH:58].Br[CH2:60][CH2:61][OH:62].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:7]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:9]2)=[CH:6][C:5]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=2)=[C:4]([Cl:57])[C:3]=1[O:58][CH2:60][CH2:61][OH:62]
Reactant: OCCBr
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(O)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCCO)c2Cl)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
To a solution of crude compound 78 (2.67 g, 3.1 mmol) in acetone (30 mL) were added 2-bromoethanol (0.33 mL, 4.63 mmol) and K2CO3 (640 mg, 4.63 mmol) at 0° C. The mixture was stirred at 50° C. for 15 hours. The mixture was filtrated and concentrated in vacuo. The resultant was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 79 (2.68 g, 95%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[N:40]([CH3:41])[C:23]2=[N:24][C:25]([S:28][C:29]3[CH:34]=[C:33]([CH3:35])[C:32]([N+:36]([O-:38])=[O:37])=[C:31]([CH3:39])[CH:30]=3)=[CH:26][CH:27]=[C:22]2[N:21]=1>CN(C)C=O>[CH3:39][C:31]1[CH:30]=[C:29]([S:28][C:25]2[N:24]=[C:23]3[N:40]([CH3:41])[C:20]([CH2:19][O:3][C:4]4[CH:17]=[CH:16][C:7]([CH2:8][CH:9]5[S:13][C:12](=[O:14])[NH:11][C:10]5=[O:15])=[CH:6][CH:5]=4)=[N:21][C:22]3=[CH:27][CH:26]=2)[CH:34]=[C:33]([CH3:35])[C:32]=1[N+:36]([O-:38])=[O:37]
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: Cc1cc(Sc2ccc3nc(CCl)n(C)c3n2)cc(C)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Sc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3n2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (0.12 g, 55% w/w) in N,N-dimethylformamide (6 ml) was added 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (0.31 g). The mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added dropwise a solution of 2-chloromethyl-5-(3,5-dimethyl-4-nitrophenylthio)-3-methyl-3H-imidazo[4,5-b]pyridine (0.51 g) in anyhdrous N,N-dimethylformamide (14 ml). The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated and neutralized with 3N hydrochloric acid and sodium bicarbonate and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant to afford the desired compound (0.39 g, Rf=0.60: thin layer chromatography on a silica gel plate using ethyl acetate as the eluant).