Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]C(N)=O.[N:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16](F)(F)F)=[C:6]=[S:7]>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:5][C:6]([NH2:1])=[S:7])=[C:9]([CH3:16])[CH:10]=1
Reactant: NC(N)=O
Reactant: COc1ccc(N=C=S)c(C(F)(F)F)c1
Product: COc1ccc(NC(N)=S)c(C)c1

Procedure:
The title compound is prepared as described in Example 1 for [4-2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using 1-isothiocyanato-4-methoxy-2-trifluoromethyl-benzene. Title compound: ES-MS: 251.0 [M+H]+; single peak at tR=3.13 min (System 2).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:29]#[N:30])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([C:29]#[N:30])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1ccc(C(=O)C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
p-Toluoyl cyanide was prepared according to the general procedure reported by Olah et al. [supra]. Under dry conditions, 1.35 mL of p-toluoyl chloride (98%, Aldrich) (10.2 mmol), 26 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.53 mL of trimethylsilyl cyanide (11.5 mmol) were added to a 100-mL round bottom flask. To this solution 0.25 mL of tin (IV) chloride (2.1 mmol) was added. This mixture was stirred for 2 hr at room temperature. During the 2 hr, the color of the solution changed from pale yellow to dark brown. After 2 hr the reaction mixture was quenched with 75 mL of ice-cold water and then extracted with two 75-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 75-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield a dark brown oil which solidifed on standing. This crude product was dissolved in hexanes and filtered. The solvent was removed by rotary evaporation to yield 1.266 g (86%) of p-toluoyl cyanide as a yellow solid: IR (CCl4) (partial) 2220, 1685, 1607 cm-1.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=2[C:6]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[N+:22]([O-:27])([N+]([O-])=O)=[O:23]>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[O:3][C:2]([N+:22]([O-:27])=[O:23])=[C:6]([C:7]3[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:17]=1
Reactant: O=C(O)Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1cccc(-c2c([N+](=O)[O-])oc3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-bromo-5-chloro-3-benzofuranyl)phenylacetic acid in chloroform with 1.5 equivalents of cyclonexene is treated with 1.5 equivalents of dinitrogen tetroxide and stirred for about 20 hours at room temperature. The mixture is washed with water, extracted with saturated sodium bicarbonate solution, then the aqueous extracts are acidified. The mixture is extracted with dichloromethane, which is dried and concentrated. The residue is recrystallized from a mixture of benzene and hexane to provide 3-(5-chloro-2-nitro-3-benzofuranyl)phenylacetic acid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=2)[CH:15]=[C:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:31]=[CH:30][CH:29]=[C:14]([CH:15]=[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH:13]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl 4-(3-(5-isopropoxypyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.5 g, 1.17 mmol) in CH2Cl2 (3 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.46 mL, 5.97 mmol). The resulting mixture was stirred for 2 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.38 g, 99%). 1H NMR (500 MHz, CDCl3): δ 8.94 (m, 2H), 7.35 (m, 2H), 7.0 (m, 2H), 6.90 (s, 1H), 6.47 (s, 1H), 4.53 (m, 1H), 3.50 (m, 2H), 3.32 (m, 2H), 2.76 (m, 2H), 2.65 (m, 2H), 1.35 (d, J=6 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:23]1[CH2:26][CH:25](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:24]1>CN(C)C=O.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:25]2[CH2:26][O:23][CH2:24]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: Oc1ccc(Cc2cc(Br)ccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Br)cc1Cc1ccc(OC2COC2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 4-(5-bromo-2-fluoro-benzyl)-phenol (1.1 g, 3.9 mmol) and cesium carbonate (1.91 g, 5.87 mmol) in N,N-dimethylformamide (15.0 mL) at room temperature was added a solution of toluene-4-sulfonic acid oxetan-3-yl ester (1.34 g, 8.0 mmol) in N,N-dimethylformamide (10.0 mL). The reaction mixture was then stirred overnight at 65° C. After a total of 18 hours, the reaction mixture was cooled to room temperature, diluted with brine and extracted 3 times with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 30% ethyl acetate in heptane to afford 0.948 g (72% yield) of the desired product as a white solid.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[N:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:4]2[CH2:3][CH2:2]1.C1COCC1.[CH3:17][O:18][C:19]1[CH:60]=[CH:59][C:22]([CH2:23][N:24]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[C:25]2[N:30]=[C:29]([CH3:31])[N:28]=[C:27]([C:32]3[C:33]([NH:40][C:41]4[CH:42]=[N:43][C:44]([O:48][CH3:49])=[C:45]([F:47])[CH:46]=4)=[N:34][CH:35]=[C:36]([CH:39]=3)[CH:37]=O)[N:26]=2)=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:11]=[S:1]1(=[O:10])[N:5]2[CH2:6][CH2:7][N:8]([CH2:37][C:36]3[CH:39]=[C:32]([C:27]4[N:28]=[C:29]([CH3:31])[N:30]=[C:25]([N:24]([CH2:23][C:22]5[CH:59]=[CH:60][C:19]([O:18][CH3:17])=[CH:20][CH:21]=5)[CH2:50][C:51]5[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=5)[N:26]=4)[C:33]([NH:40][C:41]4[CH:42]=[N:43][C:44]([O:48][CH3:49])=[C:45]([F:47])[CH:46]=4)=[N:34][CH:35]=3)[CH2:9][CH:4]2[CH2:3][CH2:2]1
Reactant: O=S1(=O)CCC2CNCCN21
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH3-]C#N
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN5C(CCS5(=O)=O)C4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a stirred mixture of hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide (ref: WO2007028654, 0.180 g, 1.021 mmol) in THF (2.50 mL, 30.5 mmol) was added 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (preparation previously described, 0.3042 g, 0.511 mmol) and titanium (IV) ethoxide (0.529 mL, 2.55 mmol) and the mixture was heated at 70° C. overnight. The resulting mixture was cooled to 0° C. and excess sodium cyanoborohydride (0.160 g, 2.55 mmol) was added and the entire mixture was stirred at the same temperature for 1 h prior to being quenched with MeOH (1.0 mL). The mixture was concentrated and adsorbed onto a plug of silica gel and chromatographed through a silica gel column (100% DCM to 70% ethyl acetate in DCM to obtain the desired product 4-(5-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)-2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.297 g, 77%) as a yellow syrup. m/z (ESI, +ve ion) 756 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28](=[O:31])[C:27]=1[CH3:32].O.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Ce+3].CO.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([OH:31])[C:27]=1[CH3:32]
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(=O)CC1)C(=O)OC2
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(O)CC1)C(=O)OC2
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
A mixture of 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-one (0.17 g) and cerium trichloride heptahydrate (0.172 g) in tetrahydrofurn/methanol (12 mL, 4/1) was trea=ed with sodium borohydride (0.035 g). After 0.5 hours, the reaction was diluted with ethyl acetate and washed with brine. Drying over magnesium sulfate was followed by filtration and solvent removal. Chromatography (hexanes/methylene chloride/ether, 1/1/1) gave the product 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ol (0.088 g) as a solid m.p. 108.0°-111.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].N1C=CC(C(O)=O)=C1.[Cl:19][C:20]1[N:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:22]([C:21]2[C:20]([Cl:19])=[N:28][CH:27]=[CH:26][CH:25]=2)=[O:23])=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCOC(=O)c1cc[nH]c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(O)c1cc[nH]c1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)c1c[nH]cc1C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a mixture of 1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 14.4 mmol) (synthesized from 1H-pyrrole-3-carboxylic acid suing the same procedure as in Example 30) and 2-chloronicotinoyl chloride (4.4 mg, 25 mmol) in dry benzene (10 mL) at 0° C. was added dropwise a solution of tin (IV) chloride (0.7 g) in dry benzene (5 mL). The mixture was allowed to warm up slowly to room temperature and stirred for overnight. The reaction was diluted with ethyl acetate, washed with brine and concentrated. The residue was purified on a silica gel column to give 402 mg (10%) of 4-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:15][C:16]([O:18][C:19]1([CH3:29])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2)=[O:17]>C(OCC)C.CC(C)=O.CN(C=O)C>[CH3:29][C:19]1([O:18][C:16](=[O:17])[CH2:15][O:5][C:1](=[O:4])[CH2:2][OH:3])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2
Reactant: CC1(OC(=O)CCl)C2CC3CC(C2)CC1C3
Reactant: O=C(O)CO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC1(OC(=O)COC(=O)CO)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
37.6 g (494 mmol) of glycolic acid, 700 mL of DMF, 86.5 g (626 mmol) of potassium carbonate, and 28.3 g (170 mmol) of potassium iodide were added to a 2 L three-neck flask equipped with a thermometer, a cooling pipe, and a stirring apparatus, and then stirred for 30 minutes at room temperature. Subsequently, a solution of 300 mL of dimethylformaldehyde with 100 g (412 mmol) of 2-methyl-2-adamantyl chloroacetate was gradually added thereto. Then, the resultant was heated at 40° C., and stirred for 4 hours. After the reaction, 2,000 mL of diethylether was added thereto and filtrated, thereby obtaining the solution (filtrate). The solution thus obtained was washed three times using 500 mL of distilled water. Thereafter, crystallization was conducted using a mixture solvent of 300 mL of toluene and 200 mL of heptane, thereby obtaining 78 g of the intended compound in the form of a colorless solid (yield: 67%, GC purity: 99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:74](=[O:81])([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])[NH2:75].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([NH:75][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:81])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Temperature: 100 °C
Reaction time: 15 h
Yield: 32.5 %

Procedure:
A suspension of Intermediate 1 (137 mg) obtained in Example 1, Step A, tris(dibenzylideneacetone)dipalladium(0) (55 mg, Aldrich), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (37 mg, Aldrich), tert-butyl carbamate (70 mg, Aldrich), and cesium carbonate (196 mg, Aldrich) in toluene (5 ml) is stirred at 100° C. for 15 hours. The reaction mixture is cooled to room temperature, and then added with ethyl acetate (5 ml), and the insoluble matters are removed by filtration through Celite. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (48 mg (predictive yield)).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]2[NH:32][C:33](=[O:35])[NH:34][C:30]=2[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C(=O)C>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:27][C:28]2[CH:37]=[CH:36][C:31]3[NH:32][C:33](=[O:35])[NH:34][C:30]=3[CH:29]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(Nc3ccc4[nH]c(=O)[nH]c4c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-amino-1,3-dihydro-2H-benzimidazol-2-one (33.5 mg, 0.225 mmol), cesium carbonate (92 mg, 0.281 mmol), N,N-dimethylacetamide (DMA) (2 mL), palladium(II) acetate (2.52 mg, 0.011 mmol) and Xantphos (10.83 mg, 0.019 mmol) wherein the reaction temperature was 150° C. and reaction time was 8 h. The final product was collected as 25 mg (27%). LCMS E-S (M+H)=487.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.61 (m, 6 H), 2.13 (s, 3 H), 2.23 (s, 3 H), 4.38 (d, J=5.0 Hz, 2 H), 5.20 (quin, J=6.6 Hz, 1 H), 5.90 (s, 1 H), 6.79-6.91 (m, 2 H), 8.04 (d, J=8.3 Hz, 1 H), 8.26-8.33 (m, 2 H), 8.84 (t, J=5.0 Hz, 1 H), 11.50 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)[N:5]=[CH:4][N:3]=1.Cl.[N:34]1([CH2:38][CH2:39][N:40]2[CH:44]=[C:43]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[C:47]([Cl:52])[CH:46]=3)[N:42]=[C:41]2[CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:56]2[CH2:57][CH2:58][CH:53]([C:41]3[N:40]([CH2:39][CH2:38][N:34]4[CH2:37][CH2:36][CH2:35]4)[CH:44]=[C:43]([C:45]4[CH:50]=[CH:49][C:48]([F:51])=[C:47]([Cl:52])[CH:46]=4)[N:42]=3)[CH2:54][CH2:55]2)[N:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1Cl
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Agent: Cl
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 4-[1-(2-Azetidin-1-yl-ethyl)-4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine hydrochloride instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=481, obsd.=481).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH2:10])[CH2:7][CH2:8][CH3:9]>ClCCl.C(Cl)(Cl)Cl>[CH2:6]([NH:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
Methanesulfonyl chloride (6.76 ml., 87.3 mmole, 1.0 eq.) was dissolved in distilled dichloromethane (44 ml., 0.5M). The solution was cooled in an ice bath and treated dropwise with n-butylamine (17.3 ml., 175 mmole, 2.0 eq.). After the addition was complete, the clear solution was stirred overnight at room temperature. The mixture was diluted with chloroform (200 ml.), dried, washed with 0.5N HCl (2×200 ml.) and saturated NaCl solution (200 ml.), dried (MgSO4) and freed of solvent in vacuo leaving an oil. This was purified by distillation to give N-butylmethanesulfonamide (11.4 g., 86%,. b.p. 106°-110°/0.5 mm) which solidified on standing.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:9]=1[CH2:8][CH2:7]3.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:1][N:2]1[CH2:6][C:5]23[CH:11]([CH2:12][CH2:13][CH:4]2[CH2:3]1)[C:10]1[CH:14]=[CH:15][C:16]([C:31]2[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)=[CH:17][C:9]=1[CH2:8][CH2:7]3
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN1CC2CCC3c4ccc(OS(=O)(=O)C(F)(F)F)cc4CCC23C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CC2CCC3c4ccc(-c5ccc(C#N)cc5)cc4CCC23C1
Temperature: 90 °C
Reaction time: 20 h
Yield: 30.9 %

Procedure:
Trifluoro-methanesulfonic acid 8-methyl-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrol-2-yl ester (Example 1D) (23.0 mg, 0.061 mmol) and 4-cyanophenylboronic acid (18 mg, 0.122 mmol) were dissolved in toluene (2 mL) and ethanol (0.5 mL). 0.15 mL of 1M Na2CO3 solution was added. Nitrogen was bubbled through the reaction mixture for 10 min. Tetrakis(triphenylphosphine)palladium (7.1 mg, 0.006 mmol) was then added. The mixture was stirred at 90° C. for 20 h. The reaction mixture was quenched with water (2 mL), extracted with CH2Cl2 (5 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel twice using 10% methanol in dichloromethane and 0.5% ammonium hydroxide and 5% methanol in dichloromethane, providing 6.2 mg (30.8%) of the title compound 1E.
Reaction SMILES: N1C=CC=CC=1.CN(C1C=CC=CN=1)C.C1(P(Cl)Cl)C=CC=CC=1.C(OC[CH:31]1[CH2:38][N:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[CH:41][CH:40]=2)[CH2:36][CH:35](COCCCC)[O:34][P:33](=[O:70])([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[O:32]1)CCC>ClCCl>[CH2:46]([O:45][C:42]1[CH:43]=[CH:44][C:39]([N:37]2[CH2:36][CH2:35][O:34][P:33](=[O:70])([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[O:32][CH2:31][CH2:38]2)=[CH:40][CH:41]=1)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCCCCCCCCCOc1ccc(N2CC(COCCCC)OP(=O)(c3ccccc3)OC(COCCCC)C2)cc1
Agent: CN(C)c1ccccn1
Agent: ClP(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOc1ccc(N2CCOP(=O)(c3ccccc3)OCC2)cc1
Yield: 21 %

Procedure:
It is prepared from 4-dodecyloxy-N,N-di(2-hydroxy)ethyl aniline (3.66 g, 10 mmol), pyridine (2 g, 25 mmol), dimethylaminopyridine (0.2 g) and phenylphosphonous dichloride (2.15 g, 11 mmol) in dichloromethane as described for compound 200 to obtain a white solid 1 g (21%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH:15]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:20]2[CH2:21][CH2:22][N:23]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:24][CH2:25]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: C1CCC(N2CCNCC2)C1
Agent: Cl
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CCCC2)CC1

Procedure:
This example was prepared according to Example 4 utilizing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-cyclopentylpiperazine dihydrochloride, which was prepared according to Zaragoza, et. al. J. Med. Chem. 2004, 47, 2833-2838. m/z (ES+) M+1=299.2; HPLC tR=1.61 min. 1H NMR (500 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.21-7.15 (m, 1H), 7.10 (d, J=7.0 Hz, 2H), 3.72-3.57 (m, 4H), 2.53-2.42 (m, 6H), 1.98-1.93 (m, 1H), 1.88-1.79 (m, 2H), 1.73-1.61 (m, 3H), 1.59-1.49 (m, 2H), 1.44-1.35 (m, 2H), 1.25 (ddd, J=8.3, 6.3, 4.4 Hz, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=2)[N:11]=1.[OH-].[Na+].Cl>CO.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3nc4ccccc4s3)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
To a solution of methyl 2-(1,3-benzothiazol-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (50 mg, 0.13 mmol) in methanol (30 mL), was added sodium hydroxide (50 mg, 1.25 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 6 with 3 N HCl and filtered to give 2-(1,3-benzothiazol-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (19.4 mg, 40%).