Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NO.C(=O)([O-])[O-:5].[Na+].[Na+].Cl.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([CH2:20][C:21]([NH2:23])=[NH:22])=[N:12]1>O.C(O)C>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([CH2:20][C:21](=[N:23][OH:5])[NH2:22])=[N:12]1
Reactant: O=C([O-])[O-]
Reactant: N=C(N)Cc1noc2ccccc12
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(Cc1noc2ccccc12)=NO
Temperature: 80 °C
Yield: 84.3 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.17 g) and sodium carbonate (0.13 g) in water (5 ml) was added a solution of 1,2-benzisoxazole-3-acetamidine hydrochloride (0.21 g) in ethanol (10 ml) and the mixture was heated on water bath at 80°C for 1 hour. The solvent was distilled off under a reduced pressure and to the residue was added water. The mixture was made alkaline with sodium bicarbonate and the precipitated crystalline were separated by filtration, washed with water, dried and recrystallized from ethanol to give the desired compound (0.16 g). m.p. 160° to 162°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)(C(O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C[N:43]([CH:45]=[O:46])C>CCOC(C)=O>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([N:43]=[C:45]=[O:46])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)c(Cl)c2)CC1
Reactant: CN(C)C=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N=C=O)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of 358 (187 mg, 0.4997 mmol) in DMF (1.5 mL) at RT under nitrogen was added TEA (167.1 μL, 1.199 mmol) neat via syringe followed by DPPA (129.6 μL, 0.5996 mmol) neat by syringe. The solution was stirred for 2 h at RT then warmed to 60° C. After 3 h at 60° C., the reaction was cooled to RT and diluted to 30 mL with EtOAc. The organic extract was washed with H2O (3×30 mL) and brine (1×30 mL). The organics were dried (MgSO4), filtered and concentrated to afford 170 mg (91%) of tert-butyl 4-(3,4-dichlorophenyl)-4-isocyanatopiperidine-1-carboxylate (360) as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:37])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[C:16]([Cl:37])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)c(F)c2)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(F)c(F)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(3,4-difluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 434 (M+H)+.
Reaction SMILES: C(O)C.[H][H].[CH3:6][C:7]1[C:15]2[C:10](=[C:11]([CH2:19][CH3:20])[C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[NH:9][CH:8]=1>[Fe].C(O)(=O)C>[CH3:6][C:7]1[C:15]2[C:10](=[C:11]([CH2:19][CH3:20])[C:12]([NH2:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: [H][H]
Reactant: CCc1c([N+](=O)[O-])ccc2c(C)c[nH]c12
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(N)ccc2c(C)c[nH]c12
Temperature: 90 °C

Procedure:
A mixture of 0.5 1 of 96° ethanol, 0.5 l of glacial acetic acid and 100 g of hydrogen-reduced pure iron is heated to 90° C. 51 g of 3-methyl-6-nitro-7-ethylindole are added in portions over 15 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1.Cl[C:27]1N=C2C(N=CN2CC)=C(N2CCOC[C@@H]2C)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]2[CH2:11][CH3:27])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1
Reactant: CCn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CCOCC1)n2C
Product: CCn1c(C2(O)CCOCC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
This compound (g-1) was prepared in an analogous fashion to (S)-4-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol, using (S)-4-(2-chloro-9-ethyl-9H-purin-6-yl)-3-methylmorpholine as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 5.65 to 4.75 (broad d, 2H), 4.46 (q, 2H), 4.05 to 3.85 (m, 5H), 3.83 to 3.73 (m, 2H), 3.62 (dt, J=11.6 Hz, 2.6 Hz, 1H), 3.55 to 3.39 (broad s, 1H), 2.59 (s, 1H), 2.46 to 2.34 (m, 2H), 1.87 (d, J=12.8 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H); LC-MS m/z (method B2)=382/384 [M+H]+, RT=1.79 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[CH:25][C:26]([CH2:34]O)=[N:27][C:28]=1[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:23]1[CH:24]=[CH:25][C:26]([CH2:34][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[N:27][C:28]=1[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: COC(=O)CCc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Under an argon atmosphere, to a solution of methyl 3-(3-hydroxyphenyl)propanoate (131 mg), (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (200 mg) and triphenylphosphine (259 mg) in THF (3.0 mL) was added a about 2.2 M solution of diethyl azodicarboxylate in toluene (450 μL), and the mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (249 mg) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH:3](/[C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].O>CN(C)C=O>[CH:3]([C:11]1[N:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C(=C/c1ccc[nH]1)\c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cccc1C=Cc1ccccc1
Yield: 34.5 %

Procedure:
Sodium hydride (0.3 g, 0.0063 mol) was washed with petrol 60°-80° and suspended in dimethylformamide (DMF, 25 ml). The (E)-2-styrylpyrrole (1.0 g, 0.006 mol) in DMF (10 ml) was added dropwise at room temperature. After stirring for 11/2 hours, methyl bromoacetate (0.56 ml, 0.006 mol) in DMF (5 ml) was added dropwise. After 16 hours it was poured into water (200 ml) and extracted with ether (3×100 ml). The extracts were washed with brine dried and evaporated under reduced pressure to give a brown oil. Purification by column chromatography using silica gel with ethyl acetate: petrol 60°-80°, (1:1) as the eluent gave methyl (2-styrylpyrrol-1-yl)acetate (0.5 g, 30% yield) as a buff amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[NH:16][C:17]([CH3:28])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24](O)=[O:25])[NH:20][C:19]2=[O:27].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.N>CN(C)C=O>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:15]1[NH:16][C:17]([CH3:28])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24]([NH2:35])=[O:25])[NH:20][C:19]2=[O:27]
Reactant: Cc1[nH]c(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c(=O)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(N)=O)[nH]c(=O)c12
Yield: 0 %

Procedure:
A mixture of Example 40 (0.05 g, 0.105 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.048 g, 0.126 mmol), N-ethyl-N-isopropylpropan-2-amine (0.092 mL, 0.527 mmol) and 0.5 M ammonia (1.054 mL, 0.527 mmol) in dimethylformamide (1 mL) was stirred at ambient temperature for 4 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. Purification by reverse phase chromatography (C18, CH3CN/10 mM ammonium acetate in water, 10-100% gradient) afforded the title compound (0.011 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ 8.96-9.08 (m, 1H), 8.00 (d, J=2.37 Hz, 1H), 7.96-7.99 (m, 1H), 7.82 (dd, J=8.48, 2.37 Hz, 1H), 7.44-7.63 (m, 3H), 7.28 (s, 1H), 7.18-7.27 (m, 1H), 6.99 (d, J=7.46 Hz, 1H), 3.26 (s, 3H), 2.67 (s, 3H). MS (ESI+) m/z 474 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:9]([O:11][C:12]([N:14]=[C:15]=[O:16])=[O:13])[CH3:10]>C(N(CC)CC)C.C(Cl)Cl>[CH2:1]([O:3][P:4]([C:15]([NH:14][C:12](=[O:13])[O:11][CH2:9][CH3:10])=[O:16])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=O)P(=O)(OCC)OCC

Procedure:
To a solution of 11.0 parts of diethylphosphite in 175 parts of methylene chloride and 4 drops of triethyl amine was added 10.0 parts of ethoxycarbonyl isocyanate. The solution was refluxed for 3 hours. Removing the solvent under reduced pressure left 18.5 parts of colorless oil which partially crystallized. The crystals were washed with cyclohexane to give 7.3 parts of ethyl N-(diethylphosphonocarbonyl)carbamate, m.p. 75° -64° , The proton nmr spectrum was consistent with this structure (δNH = 10.0 ppm)
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]1([O-:24])[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[N+:25]([C:12]1[CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:8]([O-:24])[CH:13]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)c1ccc[n+]([O-])c1C(=O)OCC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c[n+]([O-])c1C(=O)OCC
Temperature: 0 °C
Yield: 78 %

Procedure:
255 ml of acetic anhydride were added to a mixture of 203.2 g (0.85 mol) of diethyl pyridine-2,3-dicarboxylate-N-oxide in 1.2 l of glacial acetic acid. 68.3 g (1.06 mol) of 98% strength nitric acid were then added in the course of 40 minutes at from 20° to 28° C. with gentle cooling and stirring and the mixture was stirred at 30° C. for 12 hours. The reaction solution was poured into 3.5 l of ice-water and extracted with methylene chloride. The organic phase was extracted in succession with water, saturated sodium hydrogencarbonate solution and sodium chloride solution, dried over magnesium sulfate and filtered off with suction through silica gel. After concentration, 177.6 g (78% of theory) of diethyl 5-nitropyridine-2,3-dicarboxylate-N-oxide were obtained of nD25 =1.5290. A sample crystallized after relatively long standing; m.p. 84°-86° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH:18]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C#N)cn1
Yield: 57 %

Procedure:
A suspension of 3-cyano-4-fluoronitrobenzene (831 mg, 5 mmol), of 4-methylimidazol (821 mg, 10 mmol) and of potassium carbonate (1382 mg, 10 mmol) in acetonitrile (10 mL) was stirred over the weekend at room temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1N aqueous NaOH solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was crystallized from ethanol/water to yield the title compound (650 mg, 57%) as an off-white solid. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=8.95 (s, 1H), 8.62 (d, 1H), 8.16 (s, 1H), 7.93 (d, 1H), 7.49 (s, 1H), 2.21 (s, 3H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:24]([NH:26][C@H:27]([C:33]([OH:35])=[O:34])[CH2:28][CH2:29][C:30](=[O:32])[OH:31])=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])[CH2:3][OH:4]>CO.C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:24]([NH:26][C@H:27]([C:33]([OH:35])=[O:34])[CH2:28][CH2:29][C:30](=[O:31])[OH:32])=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:15])=[O:16])=[O:6])[CH2:3][OH:4]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 8 h

Procedure:
4.03 Grams of Z-Ser-Lys(Tos)-Glu-OH was dissolved in a mixture of 60 ml of methanol with 40 ml of 10%-acetic acid and a small amount of palladium black was added and stirred overnight under introducing hydrogen gas. After completion of the reaction, the catalyst was removed by vacuum filtration, and the filtrate was distilled under a reduced pressure, then the residue was poured into water and was lyophilized to obtain the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].II>>[CH3:1][N:2]([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1
Reactant: CNc1cccc(F)c1
Reactant: Fc1ccc(CCl)cc1
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Product: CN(Cc1ccc(F)cc1)c1cccc(F)c1

Procedure:
N-methyl-N-p-fluorobenzyl-m-fluoroaniline was prepared from 26.3 grams (0.21 mole) of N-methyl-m-fluoroaniline, 30.6 grams (0.21 mole) p-fluorobenzyl chloride (Aldrich), 17.8 grams anhydrous sodium acetate and 0.18 grams iodine according to the procedure described in Example III. Yield 35.4 grams (72 percent), boiling point 131°-137° C. at 0.2 mmHg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1I)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:42])[CH2:24][C:25]1[CH:26]=[C:27]([C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])[CH2:8][CH3:9])[C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH3:21]
Reactant: CCN(Cc1cc(Br)ccc1I)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (5-bromo-2-iodo-benzyl)-ethyl-carbamic acid tert-butyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH:3]=[CH2:4].[CH:18](=[O:22])/C=C/C>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[CH:5]([CH2:1][CH2:2]/[CH:3]=[CH:4]/[CH:18]=[O:22])[CH2:14][CH2:13]2
Reactant: C/C=C/C=O
Reactant: C=CCCC1CCc2cc(OC)ccc2C1=O
Product: COc1ccc2c(c1)CCC(CC/C=C/C=O)C2=O

Procedure:
The title compound 76 is prepared according to the procedure reported in step C of Example 8 with tetralone 75 (130 mg, 0.56 mmol) and crotonaldehyde (0.19 mL, 2.24 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum/diethyl ether=1:1) afford the title compound 76 as an off-white solid. (Yield 121 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COc1ccc(CO)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(C(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
4-Methoxybenzyl alcohol (11.9 mL, 95.2 mmol) was dissolved in DMF (150 mL), and at 0° C., 55% sodium hydride (4.15 g, 95.2 mmol) was added thereto, followed by stirring at room temperature for 1 hour. A DMF (10 mL) solution of 6-chloronicotinic acid (5.00 g, 31.7 mmol) was added to the reaction mixture, followed by stirring at 80° C. for 2 hours. Water (200 mL) was added to the reaction mixture, and 4 mol/L hydrochloric acid (30 mL) was added dropwise thereto, and the precipitated solid was collected by filtration to afford 6-(4-methoxybenzyloxy)nicotinic acid (8.15 g, 99%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])[NH2:26].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:25]([NH2:26])=[O:27])=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
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: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1cccc(C(N)=O)c1)nn2C1CCCC1
Yield: 93.2 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (120 mg) obtained in Step C of Example 12, (3-carbamoyl phenyl)boronic acid (81.0 mg), tetrakis(triphenylphosphine)palladium(0) (38.0 mg) and 2M aqueous sodium carbonate solution (0.821 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (103 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][O:13][C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:12]
Reactant: COC(=O)Cl
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2ccccc21
Reaction time: 16 h
Yield: 99.3 %

Procedure:
A mixture of indoline (11.97 g, 0.1 mol), methyl chloroformate (15.45 mL, 0.2 mol), triethylamine (40.4 g, 0.4 mol), and DMAP (0.5 g, 0.004 mol) in CH2Cl2 (100 mL) was stirred for 16 hours. The reaction mixture was quenched with water (10 mL). The reaction was extracted with CH2Cl2 (1×40 mL). The organic layer washed with water (1×50 mL), dried over anhydrous magnesium sulfate, filtered and the resultant filtrate was concentrated in vacuo to provide the title compound (17.6 g, 99%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[C:5](=[O:23])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[CH:7][NH:8]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][CH2:32][CH2:33][C:34]#[N:35]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[C:5](=[O:23])[C:6]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[CH:7][N:8]2[CH2:31][CH2:32][CH2:33][C:34]#[N:35]
Reactant: N#CCCCCl
Reactant: COc1ccc(-c2c[nH]c3c(OC)ccc(OC)c3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(CCCC#N)c3c(OC)ccc(OC)c3c2=O)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
400 mg (1.28 mmol) of compound 29 are added to 10 ml of anhydrous N,N-dimethylformamide under a nitrogen atmosphere. 1.35 g of anhydrous potassium carbonate (7.5 eq) and then 0.35 ml of 4-chlorobutyronitrile (3 eq) are successively added to this suspension. The reaction is stirred at 90° C. for 18 hours. The solvents are evaporated off. The residue is taken up in CH2Cl2 and washed twice with water. The organic phase is dried over MgSO4 and then evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica treated with triethylamine (eluent: 7/3 CH2Cl2/EtOAc) to give 180 mg (37%) of compound 80 and 274 mg (56%) of derivative 81.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[C:30][C:31]1[C:32]([O:41][CH3:42])=[CH:33][C:34]([O:39][CH3:40])=[C:35]([CH:38]=1)[CH:36]=O.C[O-].[Li+]>CN(C=O)C.CO>[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[C:30][C:31]1[C:32]([O:41][CH3:42])=[CH:33][C:34]([O:39][CH3:40])=[C:35](/[CH:36]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH:38]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)NCCCn2ccnc2)cc1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)NCCCn3ccnc3)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
Ex-50A: A solution of 4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A, 312 mg, 1.02 mmol) and 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 287 mg, 1.02 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (155 mg, 4.08 mmol). The reaction mixture was stirred at room temperature for 16 h under nitrogen. The reaction mixture was quenched with water (25 mL) and extracted with (3:1) ethyl acetate/THF (3×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (0–7.5% MeOH in dichloromethane) to give 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxy-phenyl]acryloyl}-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (309 mg, 53%) as a yellow oil. 1H-NMR (3.00 MHz, DMSO-d6) 8.28 (d, 2H, J=7.80), 8.20 (s, 1H), 8.01 (d, 1H, J=15.0 Hz), 7.86 (m, 5 H), 7.51 (s, 1H), 7.16 (d, 1H, J=7.5 Hz), 7.23 (m, 2H), 6.79 (d, 2H, J=10.8 Hz), 6.72 (d, 1H, J=8.1 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.45 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.92 (m, 4H), 1.77 (quintet, 2H, J=6.6 Hz).