Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:17])[NH:13][NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)[CH3:2].[CH3:18][C:19]([O:21][CH2:22][C@H:23]1[O:28][C@H:27](Br)[C@H:26]([O:30][C:31]([CH3:33])=[O:32])[C@@H:25]([O:34][C:35]([CH3:37])=[O:36])[C@@H:24]1[O:38][C:39]([CH3:41])=[O:40])=[O:20]>O1CCCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[C:12]([O:17][C@@H:27]3[O:28][C@H:23]([CH2:22][O:21][C:19](=[O:20])[CH3:18])[C@@H:24]([O:38][C:39](=[O:40])[CH3:41])[C@H:25]([O:34][C:35](=[O:36])[CH3:37])[C@H:26]3[O:30][C:31](=[O:32])[CH3:33])=[N:13][NH:14][C:15]=2[CH3:16])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCSc1ccc(Cc2c(C)[nH][nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Yield: 37.6 %

Procedure:
To a suspension of 4-[(4-ethylthiophenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (1.6 g) and acetobromo-α-D-glucose (2.9 g) in tetrahydrofuran (30 mL) was added silver carbonate (2.1 g), and the mixture was stirred under shading the light at 60° C. overnight. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran) and further column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3) to give 4-[(4-ethylthiophenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[CH3:12][S:13](Cl)(=[O:15])=[O:14].N1C=CC=CC=1>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][S:13]([CH3:12])(=[O:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A mixture of 3-chloro-4-nitroaniline (4.85 g, 28.1 mmol), methanesulfonyl chloride (3.29 mL, 42.2 mmol) and pyridine (6.82 mL, 84 mmol) in THF (100 mL) was stirred for 24 h. Poured in 1M HCl (500 mL). The resulting precipitate was filtered and air-dried to provide the title compound as a solid (7.03 g, 100%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N-:5]=[C:6]=[O:7].C([NH+](CC)CC)C.C[N:16]1CCC[C:17]1=[O:21]>>[CH2:1]([NH:4][C:17]([NH2:16])=[O:21])[CH2:2][NH:3][C:6]([NH2:5])=[O:7]
Reactant: CN1CCCC1=O
Reactant: NCCN
Reactant: [N-]=C=O
Agent: CC[NH+](CC)CC
Product: NC(=O)NCCNC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.88 g of ethylenediamine (0.031 mol) were added dropwise at room temperature with stirring to 100 ml of a solution of 10 g of triethylammonium isocyanate (0.069 mol) in 100 ml of N-methylpyrrolidone, prepared according to the procedure described in example i. After stirring at room temperature for 24 hours, the reaction mixture was heated to reflux for one hour, the solvent was evaporated and the residue was recrystallized from water. 3.4 g, i.e. 75% of theory, of ethylenediurea were obtained in this way.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:51]([O:55][C:56]([N:58]([CH2:66][C:67]1[CH:68]=[C:69]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH:70]=[CH:71][CH:72]=1)[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[O:57])([CH3:54])([CH3:53])[CH3:52]>CN(C)C=O>[C:62]([O:61][C:59]([N:58]([CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([CH:73]2[CH2:74][CH2:75][N:76]([C:15]([C:11]3[CH:12]=[N:13][CH:14]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:10]=3)=[O:17])[CH2:77][CH2:78]2)[CH:68]=1)[C:56]([O:55][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:57])=[O:60])([CH3:63])([CH3:64])[CH3:65]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCNCC2)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.25 g, 1.1 mmol) in anhydrous dimethylformamide (5 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.42 g, 1.1 mmol) and diisopropylethylamine (0.5 ml, 3 mmol). This mixture was stirred 15 minutes at ambient temperature and then treated with a solution of 4-{3-[N,N-Bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidine (0.39 g, 1.0 mmol) in dimethylformamide (5 ml). After stirring at ambient temperature for 18 hours the reaction mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (15 ml). The organic layer was dried over magnesium sulfate and then concentrated under vacuum. The residue was subjected to chromatography on silica gel eluting with a mixture of dichloromethane and methanol (49:1, v/v) to give N,N-bis-(tert-butoxycarbonyl)-3-[1-(5-phenylethynyl -pyridine-3-carbonyl)-piperidin-4-yl]-benzylamine as a yellow oil (0.25 g). 1H NMR [(CD3)2SO, 500 MHz]: δ 8.82 (s, 1H), 8.62 (s, 1H), 8.02 (s, 1H), 7.61 (m, 2H), 7.45 (m, 3H), 7.30 (m, 1H), 7.20 (m, 1H), 7.15 (m, 1H), 7.04 (m, 1H), 4.68 (s, 2H), 4.62 (br m, 1H), 3.60 (br m, 1H), 3.23 (br m, 1H), 2.85 (m, 2H), 1.83 (br m, 1H), 1.65 (m, 3H), 1.39 (s, 18H). MS(EI): 596(M++H).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][C:36]([F:39])([F:38])[F:37])[N:23]=[CH:24][C:25]=3[CH:26]3[CH2:28][CH2:27]3)=[CH:15][C:14]=2[CH3:40])[CH3:12])=[CH:6][C:5]=1[O:41][CH3:42].[OH-].[Na+].C1COCC1.Cl>O.CO>[CH:26]1([C:25]2[CH:24]=[N:23][N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][C:36]([F:37])([F:38])[F:39])[C:21]=2[CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([O:41][CH3:42])[CH:6]=3)[CH3:12])=[C:14]([CH3:40])[CH:15]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(CN(C)c2ccc(OCc3c(C4CC4)cnn3-c3ccccc3OC(F)(F)F)cc2C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CN(C)c2ccc(OCc3c(C4CC4)cnn3-c3ccccc3OC(F)(F)F)cc2C)ccc1C(=O)O
Yield: 96.1 %

Procedure:
A mixture of 4-[({4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methoxy-benzoic acid methyl ester (0.30 g, 0.51 mmol), sodium hydroxide (5 N, 0.5 mL), THF (3 mL) and methanol (3 mL) is heated to reflux for 1 h. The reaction is cooled and acidified with 5 N HCl, then diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4 to give the tile compound (285 mg, 97%) as an off-white foam. LC-ES/MS m/e 582.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.Cl[C:31]([O:33][CH3:34])=[O:32].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][C:8]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[C:31]([O:33][CH3:34])=[O:32])([CH3:10])[CH3:9])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Br)c1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 850 mg of tert-butyl[2-(3-bromophenyl)propan-2-yl]carbamate in 8.5 ml of THF was added 4.1 ml of a 1.65 M n-butyllithium/hexane solution at −78° C., followed by stirring at the same temperature for 30 minutes. Then, 0.85 ml of methyl chloroformate was added dropwise thereto at −78° C., followed by stirring at the same temperature for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 199 mg of methyl 3-{2-[(tert-butoxycarbonyl)amino]propan-2-yl}benzoate.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.CN(C)NC(Cl)=O.[CH2:14]([NH:16][C:17]1[CH:18]=[N+:19]([O-])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH3:15]>CN(C=O)C.C(Cl)Cl.O>[CH2:14]([NH:16][C:17]1[C:18]([C:5]#[N:6])=[N:19][CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH3:15]
Reactant: CCNc1c[n+]([O-])ccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)NC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCNc1c([N+](=O)[O-])ccnc1C#N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
TMSCN (1.1 ml, 8.33 mmol) and dimethyl amino carbamoyl chloride (0.76 mL, 8.33 mmoL) are added to a solution of 3-ethylamino-4-nitro-pyridine-1-oxide (1 g, 6.94 mmol) in anhydrous DMF (10 mL) were added. The reaction mixture is stirred overnight at 80° C., cooled to room temperature, and diluted with CH2Cl2 and water. The combined organic layer is washed with water, brine, dried over Na2SO4, and concentrated. The residue is chromatographed eluting with 40% EtOAc-hexanes to afford 3-ethylamino-4-nitro-pyridine-2-carbonitrile as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 7.82 (d, J=4.5 Hz, 1H), 7.50 (d, J=4.5 Hz, 1H), 3.70 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).
Reaction SMILES: ClN1C(=O)CCC1=O.[N:9]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=[N:25][OH:26])=[CH:16][CH:15]=2)[CH:13]=[N:12][CH:11]=[N:10]1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([C:36]([F:39])([F:38])[F:37])=[CH2:35])[CH:31]=[C:30]([Cl:40])[CH:29]=1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[C:32]([C:34]2([C:36]([F:39])([F:37])[F:38])[O:26][N:25]=[C:24]([C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]([N:9]4[CH:13]=[N:12][CH:11]=[N:10]4)=[CH:15][CH:16]=3)[CH2:35]2)[CH:31]=[C:30]([Cl:40])[CH:29]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1ccc(-n2cncn2)c2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(-n3cncn3)c3ccccc23)=NO1
Reaction time: 0.75 h
Yield: 64.1 %

Procedure:
N-chlorosuccinimid (220 mg) is added to a solution of 4-[1,2,4]triazol-1-yl-naphthalene-1-carbaldehyde oxime (390 mg) in DMF (5 ml). After 45 minutes at 40° C., the reaction is cold down to 0° C., and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (394 mg, Example 1, step A) and triethylamine (0.25 ml) are added. The reaction is then further reacted at room temperature for 3 hours. Water is added (50 ml) and the reaction mixture is extracted two times with ethyl acetate. The organic phase is extracted, with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC: to yield 1-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalen-1-yl}-1H-[1,2,4]triazole (500 mg) as beige crystals. MS (HPLC/MS): 477 (MH+). Retention time: 5.20 min.
Reaction SMILES: O[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([I:12])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:15]>CN(C)C=O>[Cl:15][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([I:12])=[CH:4][N:3]=1
Reactant: Oc1ncc(I)cc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(I)cnc1Cl
Temperature: 130 °C
Yield: 50 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis (diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=[C:9]12.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.NCC(C1NC2C(C=1)=C(OC)C=CN=2)OC1CCCCO1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][NH:12][C:11](=[O:14])[N:10]2[C:15]3[N:21]=[CH:20][CH:19]=[C:18]([O:25][CH3:23])[C:16]=3[CH:17]=[C:9]12
Reactant: O=C1NCC(OC2CCCCO2)c2cc3cccnc3n21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: COc1ccnc2[nH]c(C(CN)OC3CCCCO3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc2c1cc1n2C(=O)NCC1OC1CCCCO1
Yield: 63 %

Procedure:
Following the same procedure as for 10a, from triphosgene (20 mg, 0.07 mmol) in CH2Cl2 (3 ml), 9b (58 mg, 0.20 mmol) and DIPEA (34 μl, 0.20 mmol) in CH2Cl2 (3 ml). Reaction time 30 min. at room temperature. The crude mixture was purified by flash column chromatography. Elution with CH2Cl2/MeOH (98/2) gave a diastereomeric mixture (1:1) of 10b (40 g, 63%).
Reaction SMILES: [CH2:1]([Br:4])[C:2]#[CH:3].[CH2:5]([O:7][CH:8](OCC)[O:9][CH2:10][CH3:11])[CH3:6]>[I-].[Zn+2].[I-]>[Br:4][CH2:1][C:2]#[C:3][CH:8]([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6]
Reactant: C#CCBr
Reactant: CCOC(OCC)OCC
Agent: [I-]
Agent: [Zn+2]
Product: CCOC(C#CCBr)OCC

Procedure:
4-Bromo-1,1-diethoxy-2-butyne (Reagent L) was prepared according to the procedure of R. Epsystein and S. Marszak, Bull. Soc. Chim. Fr., I, pp. 313-17 (1968). A total of 74.1 g. (0.40 mole) of propargyl bromine, 59.28 g. (0.40 mole) of triethylorthoformate, and 3.2 g. (0.010 mole) of zinc iodide were combined in a reaction flask fitted with a packed distillation column and a stillhead. The mixture was heated to 100°-110° C. and ethanol was removed by slow distillation over 2.5 hours. Hexane (96 ml.) was added as required to maintain the stillhead temperature below 80° C. The pot residue was diluted with 200 ml. methylene chloride, washed with water and brine, dried with magnesium sulfate, filtered, and then distilled. A forerun of ethylorthoformate was collected, followed by the acetal at 50°-77° C./5-10 mm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=1)[CH:19]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:19][C:18]2[CH:21]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[CH3:22])=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1ccc(F)cc1C=O
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(F)ccc2C)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 5-fluoro-2-methyl-benzaldehyde (1.38 g, 10 mmol) in ethanol (10 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(5-fluoro-2-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.0 g, 70%) as a white solid: LC/MS m/e calcd for C17H16FNO2 (M+H)+: 285.3, observed: 286.3.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][OH:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>ClCCl.B(F)(F)F.CCOCC>[OH:13][CH:8]([C:7]([O:32][CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCO)cc1OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(O)C(OCCc1ccc(OC)c(OC)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
7 g (27.5 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.5 g (30.2 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml of dichloromethane and, at room temperature, 5 drops of boron trifluoride etherate were added. The solution was stirred for 2 hours. The solvent was then distilled off, and the residue (10.7 g, 89%) was immediately reacted further.
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.C(NC(C)C)(C)C.[Cl:38][CH2:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42].Cl>ClCCl>[CH2:11]([CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3][CH:2]1[NH:1][C:41](=[O:42])[C:40]([CH3:45])([CH3:44])[CH2:39][Cl:38])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N)C3)c1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(NC(=O)C(C)(C)CCl)C3)c1
Temperature: 25 °C

Procedure:
To a solution of N-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (40.5 mg, 0.095 mmol; see example 193) in dry dichloromethane (2 ml) containing diisoproylamine (0.025 ml, 0.142 mmol) and under argon was added a solution of 3-chloropivaloyl chloride (0.019 ml, 0.142 mmol) in dichloromethane and stirred at room temperature over night. Added 0.5M hydrochloric acid and extracted with dichloromethane, co extracted aqueous layer with dichloromethane and the combined organic layers were washed with sodium bicarbonate and brine, dried over sodium bicarbonate, filtered and evaporated to obtain the desired N-(1-benzyl-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-yl)-3-chloro-2,2-dimethylpropanamide as yellow oil. m=51 mg (quant.) that was used without further purification for the next steps.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18]CC)=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[CH3:21][CH2:22]N(C(C)C)C(C)C.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>ClCCl>[CH2:21]([CH:15]([N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:2][N:3]([C:37](=[O:38])[NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:4][CH2:5][C:6]1=2)[C:16]([OH:18])=[O:17])[CH3:22]
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCC(C(=O)O)n1c2c(c3ccccc31)CN(C(=O)Nc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step a): To a stirred solution of Intermediate 1 (20 mg, 0.068 mnol) and DIEA (35 μl, 0.20 mmol) in dichloromethane (1 ml) is added phenyl isocyanate (8.2 μl, 0.075 mmol). The reaction mixture is kept stirring at rt for 1 h, then 1N HCl (2 ml) was added. The aqueous layer is extracted twice with dichloromethane. The organic layers are combined and the solvent is evaporated to give crude ethyl (2-phenylcarbamoyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetic acid: tR (LC-2) 2.23 min; ESI-MS (positive ion): m/z 400.39 [M+Na]+ (calcd 377.44 for C22H23N3O3); 1H-NMR (CDCl3): 1.19 (t, J=7.0 Hz, 3H); 2.77 (t, J=5.3 Hz, 2H); 3.91 (t, J=5.3 Hz, 2H); 4.14 (q, J=7.0 Hz, 2H); 4.65 (s, 2H); 4.68 (s, 2H); 6.46 (s, 1H); 6.98 (t, J=7.0 Hz, 1H); 7.04-7.09 (m, 1H); 7.14-7.16 (m, 2H); 7.20-7.26 (m, 2H); 7.32-7.35 (m, 2H); 7.40 (d, J=7.6 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.Cl.[F:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:49]4[CH2:50][CH2:51][CH:46]([F:45])[CH2:47][CH2:48]4)[S:7][C:8]=3[N:9]=2)[CH3:36])[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: FC1CCNCC1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCC(F)CC3)sc2n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (140 mg, 269 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (112 μL, 807 μmol) and 4-fluoropiperidine hydrochloride (113 mg, 807 μmol), and the mixture was stirred at 60° C. for 20 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (79 mg, 50%) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([C:19]1([OH:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)#[CH:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH2:9][N:22]2[CH2:23][CH2:24][C:19]([C:17]#[CH:18])([OH:25])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC=C(c1ccccc1)c1ccccc1
Reactant: C#CC1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC1(O)CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A solution of 16.5 g of 3,3-diphenyl-2-propenyl bromide in 70 ml of acetone is added dropwise to a mixture of 7.5 g of 4-ethynyl-4-hydroxypiperidine, 8.5 g of anhydrous potassium carbonate and 75 ml of anhydrous acetone at room temperature over 45 minutes, then the reaction mixture is stirred at room temperature for one hour. After filtering off the inorganic salts the solution is evaporated under reduced pressure. The residue is taken up in benzene, washed with water, dried over anhydrous sodium sulfate and the solution is evaporated under reduced pressure. After recrystallizing the residue from acetonitrile the title product is obtained in 68.4% yield, m.p.: 122°-123° C.