Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH3:16])=[O:14].C(O)(C)(C)C.[K].[CH2:23](I)[CH2:24][CH:25]([CH3:27])[CH3:26]>N>[CH3:1][O:2][C:3]1[C:4]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Reactant: CC(C)CCI
Agent: N
Agent: [K]
Solvent: CC(C)(C)O
Product: COC(=O)C1(CCC(C)C)C(OC)=CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a stirred solution of methyl 2-methoxynaphthoate (1.0 g, 4.6 mmol) and tert-butyl alcohol (0.44 ml, 4.6 mmol) at −78° C. was added liquid ammonia (20 mL). Potassium metal was added in small pieces until the solution stayed dark blue for 30 min. Isoamyl iodide (1.9 mL, 14.8 mmol) was added dropwise (the blue coloration disappeared about half-way through addition) and stirring was continued for 1 hour at −78° C. The solution was allowed to warm to room temperature and purged with nitrogen to remove excess ammonia. To the resulting slurry a solution of saturated sodium bicarbonate (100 mL) was added, and the solution was extracted with ether (3×50 mL). The combined organic phases were washed with 10% Na2S2O3 (aq), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (5%→15% ethyl acetate/hexane) afforded the title compound as a light yellow oil (1.1 g, 85%). 1H NMR (300 MHz, CDCl3) δ ppm 0.55 (m, 1H), 0.75 (dd, J=14.71, 6.62 Hz, 6H), 0.88 (m, 1H), 1.39 (m, 1H), 2.06 (m, 1H), 2.27 (m, 1H), 3.55 (d, J=3.31 Hz, 2H), 3.60 (s, 3H), 3.61 (s, 3H), 5.05 (t, J=3.68 Hz, 1H), 7.16 (m, 4H); MS m/z 289.0 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7](=[O:18])[N:6]([CH3:19])[C:5](=[O:20])[CH:4]=1)[NH2:2].O=P(Cl)(Cl)Cl.[CH3:26]O>CN(C=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[C:3]3[NH:1][N:2]=[CH:26][C:4]=3[C:5](=[O:20])[N:6]([CH3:19])[C:7]2=[O:18])=[CH:11][CH:12]=1
Reactant: CO
Reactant: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn[nH]c32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 6-hydrazinyl-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (0.45 g, 1.6 mmol) in DMF (2 mL), POCl3 (0.3 mL, 3.3 mmol) is added dropwise at 0° C. After the reaction mixture is stirred at 0° C. for 1 hour, the mixture is treated with methanol carefully to give white solid. The solid is further purified by chromatography to give 0.4 g product (Yield: 85%). 1H NMR (DMSO-d6) δ 3.23 (s, 3H), 3.71 (s, 3H), 5.05 (s, 2H), 6.85 and 7.31 (AB, 4H, J=11.6 Hz), 8.47 (s, 1H), 13.5 (br, 1H). MS (FAB) m/z 287.21 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16](OC1C=CC=CC=1C(Cl)=O)(=[O:18])[CH3:17]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Product: CC(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1
Yield: 58 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 2-acetoxybenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (15 then 25%) as eluant to afford product as a tan colored solid (80 mg, 58%). 1H NMR (CDCl3) 2.39 (d, J=1.3, 3 H), 3.62 (s, 3 H), 7.57 (d, J=4.0, 1 H), 7.74 (d, J=4.0, 1 H). 19F NMR −63.1. LC/MS 7.82 min, [M+1]+ 276.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]([CH2:6][C:7](OC)=[O:8])=[CH2:5].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH3:1][O:2][C:3]([CH:4]1[CH2:6][C:7](=[O:8])[N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5]1)=[O:11]
Reactant: NCc1ccccc1
Reactant: C=C(CC(=O)OC)C(=O)OC
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Yield: 96.7 %

Procedure:
A solution of 158.2 g (1.0 mole) of dimethylitaconate and 107.2 g (1.0 mole) of benzylamine in 750 ml of methanol was let stand at ambient temperature over the weekend. The solution was filtered and the filtrate was concentrated under reduced pressure to give an oil as residue. The oil crystallized when it was triturated with petroleum ether (30°-60° C.). The solid was collected by filtration and dried to yield 225.5 g (97%) of the title compound as a white powder. An analytical sample, m.p. 63°-65° C., was prepared from 2-propyl ether.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
82 mg (55%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(4-chlorophenyl)piperazine (80 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)s (189 mg, 0.891 mmol).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[F:9][C:10]1([F:20])[CH2:12][CH:11]1[C:13](OCCCC)=[O:14].Cl>O1CCCC1.O>[F:9][C:10]1([F:20])[CH2:12][CH:11]1[C:13](=[O:14])[CH2:2][C:1]#[N:3]
Reactant: CCCCOC(=O)C1CC1(F)F
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)C1CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of acetonitrile (0.97 mL, 18.5 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. and treated with n-butyllithium in hexanes (11.7 mL, 19.0 mmol) over 5 minutes. The reaction mixture was stirred for 30 minutes, and then n-butyl 2,2-difluorocyclopropane carboxylate (3.0 g, 16.8 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into water (25 mL) and acidified by addition of 10% aqueous hydrochloric acid. The organic layers were extracted into diethyl ether (3×30 mL), dried (MgSO4) and concentrated to afford crude 3-(2,2-difluorocyclopropyl)-3-oxo-propionitrile (2 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[CH:8]=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=1)#[N:6].[N+]([O-])([O-])=O.[K+]>>[N+:1]([C:12]1[CH:11]=[CH:10][N+:9]([O-:13])=[CH:8][C:7]=1[C:5]#[N:6])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc[n+]([O-])c1
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: N#Cc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 7.5 °C
Reaction time: 0.25 h

Procedure:
One hundred fifty mL of stirred 15% fuming nitric acid is cooled to 5-10° C., and 20.4 grams (0.17 mole) of 3-cyanopyridine N-oxide is added portionwise. Upon completion of addition, the reaction mixture is stirred for about 15 minutes, and then 34.4 grams (0.340 mole) of potassium nitrate is added portionwise. Upon completion of addition, the reaction mixture is warmed to about 100° C. where it is stirred for six hours. The reaction mixture is then poured into about 1000 mL of ice-water. The mixture is stirred until the ice melts, and then the resultant solid is collected by filtration. The solid is dried under reduced pressure at about 100° C., yielding 4-nitro-3-cyanopyridine N-oxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[N+:14]([CH3:17])([O-:16])=[O:15].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=Cc1ccc(Cl)cc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
A mixture of 290 g of p-chlorocinnamic acid methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir for 72 hours. The solution is diluted with ethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-chlorophenyl)butanoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:13]=[CH:12][C:11]2[N:14]=[CH:15][NH:16][C:10]=2[CH:9]=1)=[O:7].Cl[C:18]1([C:24]([O:26][CH3:27])=[O:25])[C:22](=[O:23])[CH:21]=[CH:20][S:19]1>C(Cl)(Cl)Cl>[OH:23][C:22]1[CH:21]=[C:20]([N:16]2[C:10]3[CH:9]=[C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:13]=[CH:12][C:11]=3[N:14]=[CH:15]2)[S:19][C:18]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: COCCNC(=O)c1cc2[nH]cnc2cn1
Solvent: ClC(Cl)Cl
Product: COCCNC(=O)c1cc2c(cn1)ncn2-c1cc(O)c(C(=O)OC)s1

Procedure:
In a similar manner as described for example C3, 1.81 g of 1H-imidazo[4,5-c]pyridine-6-carboxylic acid (2-methoxy-ethyl)-amide and 1.27 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 300 ml chloroform yield the title compound which was used for the next step without further purification (example B8).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:25])=[C:18]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:19]=1)#[CH:13]>CN(C=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.[Cu](I)I>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:13]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([F:25])=[C:18]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:19]=2)=[CH:6][CH:5]=1
Reactant: C#Cc1ccc(F)c(CCCC#N)c1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: N#CCCCc1cc(C#Cc2ccc(OC(F)F)cc2)ccc1F
Temperature: 65 °C
Yield: 90.3 %

Procedure:
To a solution of 1-Difluoromethoxy-4-iodo-benzene (0.21 g, 0.79 mmol) in DMF (3.5 ml) were added TEA (0.55 mL, 57.4 mmol) and 4-(5-Ethynyl-2-fluoro-phenyl)-butyronitrile (0.48 g, 0.79 mmol). The reaction was degassed by bubbling argon through it for 5 min and then dichlorbis(triphenylphospine)palladium (0.0.28 g, 0.04 mmol), and copper iodide (0.008 g, 0.57 mmol) were added simultaneously. The reaction mixture was heated at 65° C. for 15 min. cooled and quenched with 0.1 N HCl (10 ml). The aqueous layer was extracted with Et2O (3×10 ml). The combined organic extracts were washed with brine (25 ml), dried (MgSO4), and concentrated. The crude material was purified by silica gel chromatography (10-20% Ethyl acetate/Petroleum Ether) to afford the titled compound (0.235 g, 90%) as a brown oil that solidified on standing, and was identified by NMR and mass spectral analyses. MS (EI+): 329 (M+).
Reaction SMILES: [BH4-].[Na+].CC1C=[C:6]([C:21](=O)[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)C)C=CC=1O[Si](C(C)C)(C(C)C)C(C)C.C([OH:41])C>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:27]2([OH:30])[CH2:28][CH2:29][N:24]([CH:22]([OH:41])[CH2:21][CH3:6])[CH2:25][CH2:26]2)=[CH:32][CH:33]=1
Reactant: CCO
Reactant: Cc1cc(C(=O)C(C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CCC(O)N1CCC(O)(c2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of sodium borohydride (0.564 g, 14.92 mmol) and ethanol (60 mL) was stirred 10 minutes and then 1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (7.66 g, 14.92 mmol in 10 mL of ethanol) was added with two 30 mL ethanol rinses. The reaction mixture was stirred at ambient temperature overnight. The white solid that precipitated was collected by filtration and dried to yield 5.72 g (74%) of (1R*, 2R*)-1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl-propan-1-ol, which was suitable for use without further purification and had: m.p. 188-189° C.
Reaction SMILES: [Cl:1][C:2]1[C:23]([O:24]C)=[CH:22][CH:21]=[C:20]([Cl:26])[C:3]=1[NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:9]=[CH:8][C:7]=1[F:19]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:4][CH2:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[CH:9]=[CH:8][C:7]=2[F:19])=[C:20]([Cl:26])[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Solvent: ClCCl
Product: Oc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a solution of 2,6-dichloro-N-[[2-fluoro-5-(3-fluorophenyl)phenyl]methyl]-3-methoxy-aniline (200 mg, 0.5 mmol, 1.0 eq) in DCM (15 mL) at 0° C. was added borontribromide (640 mg, 2.5 mmol, 5.0 eq) portion-wise. The reaction was stirred at room temperature overnight then poured into ice. The mixture was extracted with EtOAc and the combined organic extracts were dried, (Na2SO4) filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (Petroleum ether:EtOAc, 20:1) to give the title compound (150 mg, 77%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>C1(C)C=CC=CC=1.O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of sodium hydride (44.2 g, 60 percent in oil, 1.1 mol) in dry toluene (800 mL) was added dropwise a solution of benzyl alcohol (108 mL, 1.0 mol, in 200 mL of toluene) at 0° C. under nitrogen over 30 min. The resulting mixture was stirred for 3.5 h at rt. The reaction was then cooled with ice water, to which a solution of ethyl bromoacetate (167.6 g, 1.0 mmol, in 200 mL of toluene) was added in 30 min and the resulting mixture was stirred for additional 25 min at 0° C. The reaction mixture was then poured into a mixed solution of 800 mL of cold water and 10 mL of cone HCl, followed by extraction with toluene. The organic layer was washed with saturated aq NaCl and dried over anhydrous MgSO4. Filtration, evaporation, and purification by flash chromatography provided ethyl(benzyloxy)acetate. (98 g, 50.5%). 1H-NMR δ (400 MHz, CDC3): 7.38-7.30 (m, 5H), 4.63 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 4.09 (s, 2H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12](C(=O)C)[CH:11]=[CH:10]2>Cl>[ClH:6].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[C:10]2[CH2:2][C:1]([OH:5])=[O:4]
Reactant: O=CC(=O)O
Reactant: CC(=O)N1C=Cc2cc(Cl)ccc2C1
Agent: Cl
Product: O=C(O)Cc1cncc2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Glyoxylic acid (1.37 g, 9.28 mmol) is added to mixture of 1-(6-chloro-1H-isoquinolin-2-yl)-ethanone [J. Org. Chem., 1980, 45, 1950 ] (1.44 g, 5.90 mmol) in 6N HCl (24 ml). The reaction is heated at 100° C. for 3 hours, cooled to RT, washed with ether and evaporated to 10 ml volume. After overnight refrigeration, the solid is collected by filtration and dried to afford (6-chloro-isoquinolin-4-yl)-acetic acid hydrochloride. 1H NMR (400 MHz, DMSO) δ: 4.45 (s 2H), 8.18 (d J 9 1H), 8.52 (s 1H), 8.70 (d J 8 1H), 8.83 (s1H), 9.96 (s 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)(C)C>[CH3:11][NH:12][C:13]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[S:14]
Reactant: NCCOCc1c[nH]cn1
Reactant: CN=C=S
Solvent: CC(C)O
Product: CNC(=S)NCCOCc1c[nH]cn1
Yield: 23.5 %

Procedure:
4-(2-Aminoethoxymethyl)imidazole (2.24 g.) was caused to react with methyl isothiocyanate (1.21 g.) in isopropyl alcohol (25 ml.) in the usual way. The crude product was purified by chromatography on a column of silica gel with ethyl acetate as eluant and subsequently on a dry column of alumina, using chloroform. The final product was recrystallised from ethyl acetate to give N-methyl-N'-[2-(4-imidazolylmethoxy) ethyl]thiourea (0.80 g.), m.p. 96°-98°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.Cl[S:25]([N:28]=C=O)(=[O:27])=[O:26]>O>[S:25](=[O:27])(=[O:26])([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:28]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Yield: 54.4 %

Procedure:
A mixture composed of 215 mg of 2′-nitrobiphenyl-4-ol and 1 ml of toluene was cooled with ice, and 148 mg of chlorosulfonyl isocyanate was added dropwise thereto, followed by refluxing for 17 hours. After water was added to the reaction mixture under cooling with ice, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 160 mg of 2′-nitrobiphenyl-4-yl sulfamate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][CH:12]=[CH:13][CH:14]=2)=[C:6]([F:15])[C:5]=1[F:16])[CH3:2].[Li][CH2:18]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH3:18])=[CH:13][CH:14]=2)=[C:6]([F:15])[C:5]=1[F:16])[CH3:2]
Reactant: CCOc1ccc(-c2ccc[se]2)c(F)c1F
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCOc1ccc(-c2ccc(C)[se]2)c(F)c1F
Temperature: -70 °C
Reaction time: 22 h

Procedure:
6.25 g (20.7 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)selenophene are initially introduced in 50 ml of diethyl ether, and 16.9 ml (26.9 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −70° C. 7.0 ml (0.11 mol) of methyl iodide are added in one portion, and the mixture is warmed to RT and stirred for 22 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added, and the batch is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1→5:1). The further purification is carried out by recrystallisation from n-heptane; 2-(4-ethoxy-2,3-difluorophenyl)-5-methylselenophene is obtained as a colourless solid (m.p. 76° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][O:13][CH3:14])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=4[N:10]=[C:9]3[CH2:12][O:13][CH3:14])[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: COCc1nc2c(OC)cccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: COCc1nc2c(OC)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 53.2 %

Procedure:
[step 3] Using 4-methoxy-2-(methoxymethyl)-1H-benzo[d]imidazole (1.3 g, 6.8 mmol) obtained in step 2 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (2.5 g, 7.0 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, (E)-2-(3-fluoro-8-{[4-methoxy-2-(methoxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (1.7 g, 53%) was obtained.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:47]([O:49][CH3:50])=[O:48])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:25])[CH:16]([CH2:26][N:27]([CH3:46])[CH2:28][CH2:29][N:30]([CH3:45])[CH2:31][CH2:32][CH2:33][S:34](=[O:44])(=[O:43])[NH:35]C(=O)OC(C)(C)C)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][S:34]([CH2:33][CH2:32][CH2:31][N:30]([CH3:45])[CH2:29][CH2:28][N:27]([CH2:26][CH:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:47]([O:49][CH3:50])=[O:48])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:20]2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]1[CH3:25])[CH3:46])(=[O:43])=[O:44]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)N(C)c1ccccc1-3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(N)(=O)=O)N(C)c1ccccc1-3

Procedure:
Methyl 13-cyclohexyl-5-methyl-6-(2,5,13,13-tetramethyl-9,9-dioxido-11-oxo-12-oxa-9-thia-2,5,10-triazatetradec-1-yl)-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in DCM (0.05M) and TFA was added. The mixture was left standing at RT. After 1 h all volatiles were evaporated in vacuo. The residual material was coevaporated with toluene. Methyl 6-{[{2-[[3-(aminosulfonyl)propyl]-(methyl)amino]ethyl}(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was obtained as a reddish sticky solid. The material was dissolved in MeOH/THF (0.05 M) and 1M aqueous KOH solution (4 eq.) was added. The mixture was stirred at RT overnight and then warmed for 5 h to 70° C. After cooling to RT the solution was diluted with water and adjusted with 1M aqueous HCl to pH 6. The resulting suspension was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. All volatiles were evaporated in vacuo. The residual material was used without further purification in the next reaction (95%). (ES+) m/z 611 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:28](=O)[O:29][CH2:30][C:23]=12.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:28]1[C:24]2[C:23](=[N:22][CH:27]=[CH:26][CH:25]=2)[CH2:30][O:29]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2ncccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2ncccc21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (453 mg, 3.0 mmol.) in THF (3 mL) is placed under an Argon atmosphere and cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (6.0 mL of a 1M in THF, 6.0 mmol, 3 eq.) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is removed and a solution of 7H-furo[3,4-b]pyridin-5-one (270 mg, 2.0 mmol) in THF (6 mL) is added dropwise to the reaction mixture. The resulting solution is stirred at room temperature for 4 h and poured into a 10% aqueous HCl solution (50 mL). After 10 min at room temperature, the reaction is heated to ˜90° C. for 45 min. and then let stir at room temperature for 36 h. The solid which forms is collected by filtration and washed sequentially with MeOH, EtOAc, Et2O (3×5 mL) and dried under vacuum to give the title compound (200 mg, 37%).