Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SiH3]O[SiH3].[C:4]1([C@H:10]([CH3:13])[CH2:11][OH:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([CH:10]([CH3:13])[CH2:11][OH:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@H](CO)c1ccccc1
Agent: [SiH3]O[SiH3]
Product: CC(CO)c1ccccc1

Procedure:
Furthermore, the purificative deprotections of the chiral silylethers (1f and 1m) were examined in the presence of the corresponding enantiomerically pure alcohols using the triphasic system of FIGS. 2 and 3. The deprotection reaction of 1f (1.0 equiv) proceeded in the presence of (R)-(+)-1-(2-naphthyl)ethanol (1.0 equiv), and 1-(2-naphthyl)ethanol was obtained in 83% total yield in a ratio with 41/59 in P-/S-phases (entry 5). The enantiomeric excess (ee) values of 1-(2-naphthyl)ethanol obtained were >97% and 90% in P- and S-phases, respectively. The chiral silyl ether 1m (1.0 equiv) also underwent the purificative deprotection in the presence of (S)-(−)-2-phenylpropanol (1.0 equiv), and 2-phenylpropanol was obtained in 76% total yield in a ratio with 39/61 in P/S-phases. The ee values of 2-phenylpropanol were 89% and 87% in P- and S-phases, respectively.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Na+].C([Li])CCC.[C:17]1([CH:23]=[CH:24][CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O1CCCC1.CCCCCC.C(OCC)C.O>[CH3:1][O:2][C:3](=[O:9])[CH:4]=[C:5]([OH:8])[CH:6]([CH3:7])[CH:25]([OH:26])[CH:24]=[CH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CC=Cc1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)C=C(O)C(C)C(O)C=Cc1ccccc1
Yield: 114.5 %

Procedure:
13.0 g 3-Oxo-pentanoic acid methyl ester were added to a suspension of 4.4 g of sodium hydride in 250 ml tetrahydrofurane at 0° C. within over a period of about ten minutes and the reaction mixture is stirred for an additional ten minutes. Subsequently, 42.4 ml of butyl lithium in n-hexane (2.5 molar) were added at 0° C. over a period of fifteen minutes and the reaction mixture was stirred for ten minutes. 14.5 g of 3-phenyl-propenal is then added. After stirring, the reaction mixture for ten minutes, 20 ml concentrated hydrochloric acid, 50 ml water and 350 ml diethylether were added successively. The organic phase was separated off, washed and dried. The solvent was removed in vacuo to yield 30 g of an oil having a refraction index of 1.547 at 20° C. The oil was used for the preparation of 7-phenyl-3,5-dimethoxy-4-methyl-hepta-2,6-dienoic acid methyl esters without further purification.
Reaction SMILES: [ClH:1].CCOCC.[CH3:7][N:8]1[CH2:40][CH2:39][C@:10]2([N:14](C(OC(C)(C)C)=O)[C@@H:13]([C:22]3[N:27]=[C:26]([CH3:28])[CH:25]=[C:24]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:23]=3)[CH2:12][CH2:11]2)[C:9]1=[O:41]>C(Cl)Cl>[ClH:1].[CH3:7][N:8]1[CH2:40][CH2:39][C@:10]2([NH:14][C@@H:13]([C:22]3[N:27]=[C:26]([CH3:28])[CH:25]=[C:24]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)[N:23]=3)[CH2:12][CH2:11]2)[C:9]1=[O:41]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc([C@H]2CC[C@@]3(CCN(C)C3=O)N2C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc([C@H]2CC[C@@]3(CCN(C)C3=O)N2)n1
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
1M HCl in Et2O (3.07 mL, 3.07 mmol) was added to a solution of the (2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one (1.2 g, 3.07 mmol) in DCM (20 mL) at 20° C. and the reaction stirred for 5 mins. The solvent was evaporated and the residue was trituated from Et2O and dried under vacuum at 40° C. to afford the (2R,5S)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one hydrochloride (E1) (1.07 g, 2.7408 mmol, 89.2% yield) as an off white solid with 5 mol % ether present;
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=C[C:3]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]2([CH3:24])[CH3:23])=[CH2:9].C(N(CCCC)CCCC)CCC.[C]=O.[C:40]([O:43][CH2:44]C)(=[O:42])[CH3:41]>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:19]1[C:10]([C:8]([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:41]=2[C:40]([O:43][CH3:44])=[O:42])=[CH2:9])=[CH:11][C:12]2[C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][C:16]([CH3:21])([CH3:22])[C:17]=2[CH:18]=1
Reactant: CCOC(C)=O
Reactant: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1C(=O)OC

Procedure:
A solution of 6-[1-(2-iodophenyl)vinyl]-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (17.2 g, 40 mmol), palladium diacetate (1.02 g, 4.5 mmol) and tributylamine (21.9 ml, 92 mmol) in methanol (500 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:11][CH2:12][NH:14][CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccn1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccc2cc[nH]c2c1)c1ccccn1

Procedure:
[3-(1H-Indol-6-yl)-3-pyridin-2-yl-propyl]-methyl-amineCLXIX was prepared as a hydrochloride salt from 3-(1H-indol-6-yl)-N-methyl-3-pyridin-2-yl-propionamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=266.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[SH:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].[OH-].[Na+]>CN(C)C=O>[NH2:8][C:7]1[C:6]2[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CS
Reactant: N#Cc1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc(Br)cc2c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of 5-bromo-2-fluorobenzonitrile (13.5 g, 67.5 mmol) in N,N-dimethylformamide at 0° C. was added methyl 2-mercaptoacetate (6.45 mL, 70.88 mmol). The mixture was stirred at 0° C. for 30 minutes and 5N sodium hydroxide (20.25 mL) added. After stirring at 0° C. for 3 hours, the mixture was quenched with ice-water and the resulting precipitate collected by filtration and dried to give 18.5 g (96%) of a white solid. LCMS (APCI) m/z: 287(M+H)+.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:10]=1N.[CH3:19][S:20]SC>[Cu]>[CH3:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:10]=1[S:20][CH3:19]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: CSSC
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1c(C)cccc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
226 g (1.97 mmol) of tert-butyl nitrite and 100 g of copper powder are initially-charged in 300 ml of dimethyl disulfide, and a solution of 200 g (1.32 mol) of 2-methyl-6-nitroaniline in 700 ml of dimethyl disulfide is added dropwise at 50-55° C. The mixture is then stirred at 75° C. for 8 hours. For work-up, the solid is filtered off with suction and the solution is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over sodium sulfate, filtered off and concentrated using a rotary evaporator. Excess dimethyl disulfide is removed under oil pump vacuum. This gives 271 g (99%) of a dark-red oil, purity according to HPLC 87%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([C:20]([OH:22])=[O:21])[C:6]=2[CH:23]=1.S(Cl)(Cl)=O.[CH2:28](O)[CH3:29]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[C:7]([C:20]([O:22][CH2:28][CH3:29])=[O:21])[C:6]=2[CH:23]=1
Reactant: CCO
Reactant: COc1ccc(CCc2oc3ccc(Br)cc3c2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1c(CCc2ccc(OC)cc2)oc2ccc(Br)cc12

Procedure:
1H-NMR (DMSO-d6) δ: 3.00 (2H, m), 3.35 (2H, m), 3.69 (3H, s), 6.80 (2H, d, J=8.0 Hz), 7.07 (2H, d, J=8.0 Hz), 7.50 (1H, dd), 7.55 (1H, d), 8.00 (1H, d) d) 64.2 g of 5-bromo-2-[2-(4-methoxyphenyl)-ethyl]-3-benzofurancarboxylic acid obtained in the above step c) was suspended in 900 ml of ethanol. 30 ml of thionyl chloride was added dropwise to the above suspension with ice cooling. After refluxing under heating for 5 hours, 50 ml of thionyl chloride was further added dropwise to the resulting reaction mixture, followed by additional refluxing under heating for 3 hours. The reaction solution thus obtained was concentrated to dryness, and the resulting residue was mixed with water to collect insoluble materials by filtration. The thus collected insoluble materials were dissolved in ethyl acetate and washed with a saturated sodium bicarbonate aqueous solution, water, a saturated sodium chloride aqueous solution in that order, followed by drying to distill off the solvent. Thereafter, the resulting residue was suspended in ethanol and then collected by filtration to obtain 59.23 g of ethyl 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-3-benzofurancarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@H:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:36][OH:37])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(N[C@@H](CO)c1ccccc1)c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H](CO)c3ccccc3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (R)-2-bromo-N-(2-hydroxy-1-phenylethyl)benzenesulfonamide. MS (ESI): mass calcd. for C24H21FN4O3S, 464.13; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36-8.32 (m, 1H), 8.07-8.01 (m, 2H), 7.75 (t, J=8.2, 1H), 7.60-7.54 (m, 1H), 7.49-7.44 (m, 1H), 7.25-7.18 (m, 4H), 7.07-7.00 (m, 3H), 6.98-6.92 (m, 1H), 4.19 (t, J=6.6, 1H), 3.69-3.58 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[K+].Cl.[CH3:18][N:19](C)C.C(=O)(O)[O-].[Na+]>O.CN(C=O)C>[O:13]=[C:9]1[CH2:10][CH2:11][CH2:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:18]#[N:19])[CH2:8]1
Reactant: CN(C)C
Reactant: O=C1C=C(c2ccccc2)CCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccccc2)CCCC(=O)C1
Temperature: 93 °C
Yield: 92 %

Procedure:
A mixture of 3-phenylcyclohex-2-enone (14.3 mmol), potassium cyanide (1.92 g) and trimethylamine hydrochloride (2.06 g, 21.5 mmol) in H2O (10 mL) and DMF (57 mL) was heated at 93° C. for 6 hr. After cooling down to room temperature, saturated sodium bicarbonate was added and the organic layer was separated. The aqueous layer was extracted with diethyl ether 3 times. The combined organic layers were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under vacuum to get 2.62 g of the crude 3-oxo-1-phenylcyclohexanecarbonitrile which was directly taken to the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[C:10][C:11]2[CH:12]=[N:13][C:14]([NH:17][CH3:18])=[CH:15][CH:16]=2)=[C:7]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([F:28])[CH:20]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[CH2:1]([C:3]1[C:8]([C:9]#[C:10][C:11]2[CH:12]=[N:13][C:14]([NH:17][CH3:18])=[CH:15][CH:16]=2)=[C:7]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:34]3[CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32][CH2:33]3)=[O:24])=[C:21]([F:28])[CH:20]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(NC)nc1
Reactant: CCN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(CC)CC3)c(F)c2)c1C#Cc1ccc(NC)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 100 mg (0.28 mmol) 4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-benzoic acid (A-46) using 55 μL (0.33 mmoL) N-ethyl piperazine, 101 mg (0.27 mmol) HATU and 50 μL DIPEA in 1.5 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 82 mg (65%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH3:12])[C:9]([C:13]([OH:15])=O)=[CH:8]2)=[O:2].N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1.Cl.[NH2:60][C:61]1[C:62]([O:76][CH3:77])=[C:63]([NH:71][S:72]([CH3:75])(=[O:74])=[O:73])[CH:64]=[C:65]([C:67]([CH3:70])([CH3:69])[CH3:68])[CH:66]=1>CN(C)C=O.C(OCC)(=O)C.O>[C:67]([C:65]1[CH:64]=[C:63]([NH:71][S:72]([CH3:75])(=[O:74])=[O:73])[C:62]([O:76][CH3:77])=[C:61]([NH:60][C:13]([C:9]2[N:10]([CH3:12])[C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[CH:1]=[O:2])=[O:15])[CH:66]=1)([CH3:70])([CH3:68])[CH3:69]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cn1c(C(=O)O)cc2cccc(C=O)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2cc3cccc(C=O)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
1.45 g 7-formyl-1-methyl-1H-indole-2-carboxylic acid (salt with N-methyl-morpholine) are dissolved in 8 ml N,N-dimethylformamide and combined with 2.72 g O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU), 2.45 ml N,N-diisopropyl-ethylamine (DIEA) as well as 324 mg 1-hydroxy-7-azabenzotriazole (HOAT). The mixture is left for 15 minutes at ambient temperature with stirring and then 1.47 g N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulphonamide hydrochloride are added. The reaction is heated to 50° C. for 12 hours and then divided between water and ethyl acetate. The organic phase is washed successively with 1 N hydrochloric acid, water and saturated aqueous sodium chloride solution and dried on magnesium sulphate. After elimination of the solvents in vacuo the residue is chromatographed on silica gel with cyclohexane/ethyl acetate (70:30 to 20:80).
Reaction SMILES: [F:1][C:2](=[C:10]([F:12])[F:11])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1>CN(C)C=O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:5]([CH2:4][CH2:3][C:2]([F:1])=[C:10]([F:11])[F:12])([C:6]#[N:7])[C:8]#[N:9])=[CH:18][CH:19]=1)#[N:24]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: N#CC(C#N)CCC(F)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(C#N)(C#N)CCC(F)=C(F)F)cc1
Yield: 63.2 %

Procedure:
Using 0.20 g of (3,4,4-trifluoro-3-butenyl)malononitrile, 5 ml of N,N-dimethylformamide, 50 mg of sodium hydride (60% in oil), and 0.25 g of α-bromo-p-tolunitrile, and according to the process described in the Production Example 1, there was obtained 0.21 g of 2-(4-cyanobenzyl)-2-(3,4,4-trifluoro-3-butenyl)malononitrile (the present compound (68)).
Reaction SMILES: [N+](C1C=CC(S([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:15][CH2:14]2)(=O)=O)=CC=1)([O-])=O.[OH-].[NH4+].[OH-].[K+]>CCOCC.[Cl-].[Cl-].[Cl-].[Ti+3]>[Cl:25][C:21]1[CH:20]=[C:19]([N:16]2[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3cccc(Cl)c3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: Clc1cccc(N2CCNCC2)c1

Procedure:
1-[(p-Nitrophenyl)sulfonyl]-4-(m-chlorophenyl)piperazine is reduced with aqueous titanium trichloride in ether solution by dropwise addition of aqueous TiCl3 until the purple color is no longer discharged. The reaction progress is followed by thin layer chromatography. Work-up with concentrated ammonium hydroxide and subsequently aqueous potassium hydroxide followed by isolation, drying, and concentration of the organic layer gives 1-[p-aminophenyl)sulfonyl]-4-(m-chlorophenyl)piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11](C3SC=CC=3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O)(=O)=O.C[C:26]1(C)[O:30][CH:29]([CH2:31]O)CO1.O>CN(C)C=O>[NH:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:31][CH:29]2[O:30][CH2:26]2)=[CH:7][CH:6]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(p-hydroxyphenyl)-4-(2-thienyl)imidazole (19.5 g, 0.08 m) in dimethylformamide (65 ml) is added to a stirred suspension of sodium hydride (4.8 g, 0.10 m, 50% dispersion in mineral oil) in dimethylformamide (20 ml) at 80° C. After stirring at 80° C. for 0.5 hours, a solution of 2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane methanesulfonate, (I) (16.82 g, 0.08 m) in dimethylformamide (20 ml) is added rapidly and the mixture is stirred under nitrogen at 80° C. for 17 hours. The reaction mixture is poured into H2O (400 ml) and extracted with ether (3×350 ml). The combined extracts are washed with 5% NaOH solution (2×250 ml) and with H2O (3X), dried, and the solvent is evaporated under reduced pressure to yield crude (II) (14.22 g) which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7]C1C=CC=C2C=1/C(=C/C1NC=CC=1OC)/C(=O)N2.[F:27][C:28]1[C:29](I)=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:38]\[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7][C:29]1[C:28]([F:27])=[CH:36][CH:35]=[C:34]2[C:30]=1/[C:31](=[CH:38]/[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44])/[C:32](=[O:37])[NH:33]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (57.5 mg, 0.51 mmol) (see Example 42 supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) (Aldrich) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[2,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 15 mg, 21%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:16])[CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:31]2[CH2:36][CH2:35][CH:34]([C:37]([O:39]CC)=[O:38])[CH2:33][CH:32]=2)O1.[Li+].[OH-]>O1CCOCC1.O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:31]1[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=[O:38])[CH2:33][CH:32]=1)[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10]2
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Oc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=C(O)C1CC=C(c2nc3ccc(O)cc3nc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
2-Chloro-3-(trifluoromethyl)quinoxalin-6-ol (Intermediate 14, 109 mg) was suspended with K2CO3 (97 mg), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (117 mg), PdCl2(dppf) (13 mg) in dioxane (1 mL) and water (0.2 mL) in a sealed microwave tube and heated at 100° C. over 40 min with microwave. The resultant mixture was diluted with water (5 mL) and MeOH (2 mL) and treated with LiOH (65 mg) overnight. After filtration through a pad of Celite, the clear aqueous layer was acidified with 1N HCl to pH 3. After the suspended solution was stirred over 1 h, filtration and rinsing with water afforded the desired product (125 mg). 1H NMR (DMSO-d6 300 MHz): δ 12.30 (1H, s), 10.93 (1H, s), 8.04 (1H, d, J=9 Hz), 7.59 (1H, dd, J=3, 9 hz), 7.35 (1H, d, J=3 Hz), 5.84 (1H, s), 2.58 (1H, m), 2.34 (4H, m), 2.07 (1H, m), 1.75 (1H, m) ppm. MS (ESI): m/z 339.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:12][N:13]([CH3:40])[CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[CH:22][C:21]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:40][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][N:17]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][N:23]=1)[C:7](=[O:8])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: CN(C)CCCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)N(CCCN(C)C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A solution of 6.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane is added to a solution of 2 mmol of 10-[[6-[3-(dimethylamino)propylamino]-3-pyridinyl]carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 5 ml of diisopropylethylamine in 75 ml of dichloromethane. The solution is stirred 16 hours at room temperature, washed with water, dried (MgSO4) and the solvent removed. The residue is purified by column chromatography over silica gel with 30% methanol in chloroform as eluent to give 0.75 g of solid; mass spectrum (CI) 525 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[N:23](C5CCCCO5)[CH:22]=[N:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=2)[NH:6][C:5](=[O:30])[CH2:4]1)[CH3:2].[ClH:31]>C(O)C.O1CCOCC1>[ClH:31].[N:21]1[N:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:10]3[N:11]=[C:12]4[N:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:30])[NH:6][C:7]4=[N:8][CH:9]=3)=[CH:14][CH:15]=2)[NH:23][CH:22]=1
Reactant: CCN1CC(=O)Nc2ncc(-c3ccc(-c4nncn4C4CCCCO4)cc3)nc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCN1CC(=O)Nc2ncc(-c3ccc(-c4nnc[nH]4)cc3)nc21
Temperature: 75 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
4-Ethyl-6-(4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one in ethanol was treated with 2 N hydrogen chloride in dioxane. The solution was stirred at 75° C. for 1 h. The solution was condensed partially and cooled. Cold ethanol was added to the slurry and the resulting precipitate filtered and washed with additional cold ethanol followed by hexanes to afford the title compound as the hydrochloride salt in 82% yield. 1H NMR (400 MHz, METHANOL-d4) δ (ppm) 9.18 (s, 1H), 8.22 (d, J=8.59 Hz, 2H), 8.04-8.09 (m, 3H), 7.66-7.74 (m, 1H), 7.58-7.64 (m, 1H), 4.24 (s, 2H), 3.74 (q, J=7.03 Hz, 2H), 1.29 (t, J=7.03 Hz, 4H), 0.79-0.98 (m, 4H); MS (ESI) m/z 322.2 [M+1]+.