Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)=[N:21][CH:22]=2)=[CH:13][CH:12]=1.[NH2:32][CH2:33][C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(N(CC)C(=O)C1C(=CC=CC=1)O)C.N>CN(C=O)C.[Cu]I.CCOC(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:25]3[CH:30]=[CH:29][C:28]([NH:32][CH2:33][C@@H:34]4[CH2:38][CH2:37][CH2:36][N:35]4[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:27][CH:26]=3)=[N:21][CH:22]=2)=[CH:13][CH:12]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc(I)cc3)nc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Agent: [Cu]I
Agent: CCN(CC)C(=O)c1ccccc1O
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
4.90 g (20.00 mmol) of potassium phosphate monohydrate were added under argon to a mixture of 4.16 g (10.00 mmol) of 5-(4-chlorophenyl)-2-(4-iodophenylethynyl)pyridine, 3.10 g (15.00 mmol) of tert-butyl (S)-2-aminomethylpyrrolidine-1-carboxylate, 194 mg (1.00 mmol) of CuI, 0.77 g (4.00 mmol) of N,N-diethylsalicylamide in 10 mL of DMF and the mixture was stirred for 16 hours at 100° C. The reaction mixture was combined with 100 mL of 5% aqueous ammonia, stirred, and the precipitate was filtered off. The precipitate was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). 2 fractions were isolated. Fraction 1: yield: 0.48 g (10% of theoretical); C29H30ClN3O2 (M=488.020) molpeak (M+H)+: 488/490 (Cl); found: molpeak (M+H)+: 488/490 (Cl); Rf value: 0.60 (silica gel, PE/EtOAc 1:1).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
A solution of KOH (0.37 g, 6.54 mmol) in ethanol (5 mL) was added to a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-malonic acid diethyl ester (2.18 g, 5.95 mmol) in ethanol (25 mL) and methylene chloride (10 mL) at 0° C. The mixture was stirred for 18 h at room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in water. The aqueous layer was washed with ether, acidified to pH 4 by 1M HCl and extracted with methylene chloride. The organic layer was washed with water, brine and dried. After filtration and concentration under reduced pressure, the crude product was purified by flash chromatography (methanol/CH2Cl2, 1:20) to yield 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.00 g, 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:10]=[C:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]#[N:17])[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(S)cc1C
Reactant: C=C(C#N)CCC#N
Solvent: CCO
Product: Cc1ccc(SCC(C#N)CCC#N)cc1C

Procedure:
A mixture of 3,4-dimethylbenzenethiol (0.59 ml), 2-methyleneglutaronitrile (0.48 ml), ethanol (10 ml), and triton B (40% ethanol solution, 5 drops) was refluxed for 5 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was dissolved in chloroform, washed with water, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was purified by flash column chromatography on silica by eluting with benzene/ethyl acetate (7:1) to give 1.18 g of 2-(3,4-dimethylphenylthiomethyl)glutaronitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>C(OCC)(=O)C>[Cl:8][C:5]1[CH:4]=[C:3]([OH:9])[C:2]([Cl:1])=[CH:7][C:6]=1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(Cl)c1cc(Cl)c(O)cc1Cl
Temperature: 80 °C
Yield: 80.6 %

Procedure:
2,5-Dichlorophenol (1.00 g, 6.17 mmol) was gradually added to chorosulfonic acid (2 mL, 30.85 mmol) at 0° C. Then it was heated at 80° C. for 1 hour. Then it was cooled at room temperature and poured onto crushed ice. Then ethyl acetate was added. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 1.30 g (81%) of the title compound as a white solid, which was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N+:10]([O-:12])=[O:11])=[CH:16][CH:15]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1CBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1CSc1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-1-(bromomethyl)-2-nitrobenzene (0.60 g) in tetrahydrofuran (10 ml) was added 4-fluorothiophenol (1.2 ml) and diisopropylethylamine (0.45 ml). After stirring for 2 h the mixture was concentrated under vacuum and purified by column chromatography on silica, eluting with petroleum ether (40-60°):dichloromethane (9:1 to 8:1) to give the title compound (0.52 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[NH:5]C(=O)OCC1C=CC=CC=1.C(N(CC)CC)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl.[Pd]>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:5][C@@H:3]2[CH2:4][C@H:2]2[CH3:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: C[C@@H]1C[C@H]1NC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C[C@H]1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of benzyl ((1R,2R)-2-methylcyclopropyl)carbamate (1.68 g, 8.2 mmol) in DCM (55 mL) was charged with 10 wt % Pd/C, then degassed and charged with hydrogen (50 PSI). The reaction was complete after 30 min and so was filtered over celite, rinsing with DCM (15 mL). The liquor was cooled to 0° C., and treated with triethylamine (3.43 mL, 24.6 mmol) and 4-bromobenzene-1-sulfonyl chloride (2.20 g, 8.61 mmol). The cold bath was removed and the reaction was stirred for 1 h. At completion, the reaction was washed with 0.5 M aq. HCl (2×20 mL) and brine (20 mL), dried over MgSO4 and concentrated to provide 4-bromo-N-((1R,2R)-2-methylcyclopropyl)benzenesulfonamide (2.06 g, 87% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74-7.80 (m, 1H), 7.66-7.72 (m, 1H), 4.90 (br. s., 1H), 1.94 (dt, J=3.5, 1.8 Hz, 1H), 1.41 (t, J=7.3 Hz, 1H), 0.89-1.01 (m, 3H), 0.70-0.81 (m, 1H), 0.35-0.45 (m, 1H).
Reaction SMILES: C(OC([NH:11][C@:12]1([PH:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]1([PH:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[CH2:17][CH2:16][CH2:15][N:14]([NH2:18])[C:13]1=[O:19]
Reactant: CCCN[PH](=O)[C@@]1(NC(=O)OCc2ccccc2)CCCN(N)C1=O
Agent: [Pd]
Solvent: CO
Product: CCCN[PH](=O)C1(N)CCCN(N)C1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Palladium black (16 mg) was added to a solution of (3S)-3-benzyloxycarbonylamino-1-amino(n-propylamino)phosphinyl-2-piperidone (161.1 g, 0.4373 mmol) in methanol (3 mL), and the resulting mixture was stirred at room temperature for 50 minutes under a hydrogen atmosphere.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15]O)[C@@H:12]([OH:13])[C@H:10]1[OH:11].S(Br)([Br:29])=O.S(Cl)(Cl)=O>>[Br:29][CH2:15][C@H:14]1[O:17][C@@H:9]([N:8]2[C:18]3[N:19]=[C:2]([Cl:1])[N:3]=[C:4]([NH:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:5]=3[N:6]=[CH:7]2)[C@H:10]([OH:11])[C@@H:12]1[OH:13]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=S(Br)Br
Solvent: O=S(Cl)Cl
Product: O[C@@H]1[C@H](O)[C@@H](CBr)O[C@H]1n1cnc2c(NN3CCCCC3)nc(Cl)nc21
Yield: 9 %

Procedure:
This compound was prepared by general method C, described in more detail in Example 2. 2-Chloro-N-(1-piperidinyl)adenosine [WO 93/08206 (Novo Nordisk A/S)] (3.08 g, 8 mmol) was subjected to the same reaction conditions described above, except that thionyl bromide was substituted for thionyl chloride. The procedure provided the desired 5'-bromo-2-chloro-5'-deoxy-N-(1-piperidinyl)adenosine as a foam (0.19 g, 9%) after column chromatography, 1H-NMR (400 MHz, DMSO-d6) δ1.37 (2H, br, piperidine C--H), 1.62 (4H, m, piperidine C--H), 2.80 (4H, br, piperidine C--H), 3.72, 3.82 (2H, ABX, H-5'a and H-5'b), 4.10 (1H, dt, H-4'), 4.17 (1H, dt, H-3'), 4.68 (1H, q, H-2'), 5.50, 5.62 (1H, 2d, 2'- and 3'-OH), 5.88 (1H, d, H-1'), 8.38 (1H, s, H-8), 9.36 (1H, br, NH). HPLC retention time 11.06 min. (gradient elution over 30 min.; 20-80% acetonitrile/0.1% TFA in water, 96.4% purity at 250 nm). C15H20N6BrClO3.1.3 H2O requires C, 38.2; H, 4.8; N, 17.8. Found: C, 38.7; H, 4.7; N, 17.3%.
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:29])[CH3:12].CN(C)CCCN=C=NCC.[CH3:42][C:43]1[N:44]=[C:45]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)[S:46][C:47]=1[C:48](O)=[O:49]>C(OCC)(=O)C.C(OCC)C>[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:48]([C:47]3[S:46][C:45]([C:51]4[CH:52]=[CH:53][C:54]([C:57]([F:60])([F:58])[F:59])=[CH:55][CH:56]=4)=[N:44][C:43]=3[CH3:42])=[O:49])[CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:29])[CH3:12]
Reactant: CCOC(=O)COc1cc(C2CCCNC2)ccc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
(2-methyl-5-piperidin-3-yl-phenoxy)-acetic acid ethyl ester L-tartaric acid salt (147 mg, 0.34 mmol) was dissolved in 50 mL ethyl acetate and washed with 50 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 2 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (132 mg, 0.69 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (99 mg, 0.34 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 24 h. The reaction was diluted with 100 mL diethyl ether and washed with water (100 mL), 0.5 N HCl (2×100 mL), saturated aqueous NaHCO3 (2×100 mL), dried over Na2SO4 and concentrated under reduced pressure to yield (2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-acetic acid ethyl ester (146 mg, 76%) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH:4]([CH3:10])[C:3]1=[O:11].[CH3:13][Li].Cl>CCOCC>[OH:11][C:3]1([CH3:13])[CH:4]([CH3:10])[C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7][C:2]1([CH3:1])[CH3:12]
Reactant: [Li]C
Reactant: CC1C(=O)C(C)(C)CCC1(C)C
Agent: Cl
Solvent: CCOCC
Product: CC1C(C)(C)CCC(C)(C)C1(C)O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
26 g of 2,2,5,5,6-pentamethylcyclohexanone are dissolved in 500 ml of ether and treated slowly at -20° C. with 113.5 ml of methyl lithium (1.5 molar in ether). After stirring for 3.5 hours at 0° C., the mixture is poured on to ice, acidified with 1N hydrochloric acid, extracted with ethyl acetate, dried and evaporated. Distillation of the crude product gives 25.9 g of 1-hydroxy-1,2,2,5,5,6-hexamethylcyclohexane as a colourless liquid of boiling point 87°-92° C./10 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22].F[C:24]1C=C(C(O)C)C=C(F)C=1C1N=C(C(O)=O)C=CC=1F.[H-].[Na+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][CH3:24])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: CC(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)O)cc2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)OC)cc2F)n1
Reaction time: 0.03 h
Yield: 63 %

Procedure:
To a solution of methyl 6-[2,6-difluoro-4-(1-hydroxyethyl)phenyl]-5-fluoro-pyridine-2-carboxylate (1.21 mmol, 376 mg; penultimate intermediate en route to Intermediate 136) in N,N-dimethylformamide (50 mL) at 0° C. was added sodium hydride (60 mass % in mineral oil, 1.5 equiv., 1.81 mmol, 72.5 mg). The mixture was stirred for 2 minutes, then iodomethane (3.0 equiv., 3.62 mmol, 0.226 mL) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to provide methyl 6-(2,6-difluoro-4-(1-methoxyethyl)phenyl)-5-fluoropicolinate (392 mg, 63%). This ester was diluted with MeOH (15 mL) and water (5 mL) and lithium hydroxide (60 mg) was added. The mixture was stirred overnight at rt. The reaction was quenched by the addition of 1 N HCl(aq), then the mixture was diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (quant) which was used without purification.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][S:14]([CH2:17][C@H:18]([NH:29][C:30]([NH:32][C@@H:33]1[CH2:48][C:47]2=[CH:49][CH:50]=[C:44]([CH:45]=[CH:46]2)[O:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][CH2:37][C@H:36]([CH:51]([CH3:53])[CH3:52])[NH:35][C:34]1=[O:54])=[O:31])[C:19]([O:21]CC1C=CC=CC=1)=[O:20])(=[O:16])=[O:15])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH2:12][CH2:13][S:14]([CH2:17][C@H:18]([NH:29][C:30]([NH:32][C@@H:33]1[CH2:48][C:47]2=[CH:46][CH:45]=[C:44]([CH:50]=[CH:49]2)[O:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][CH2:37][C@H:36]([CH:51]([CH3:52])[CH3:53])[NH:35][C:34]1=[O:54])=[O:31])[C:19]([OH:21])=[O:20])(=[O:16])=[O:15]
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CS(=O)(=O)CCNC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CS(=O)(=O)CCN)C(=O)O)C(=O)N1
Reaction time: 48 h
Yield: 16.3 %

Procedure:
83 mg of 5% palladium/C were added to a solution of 198 mg (0.26 mmol) of benzyl(R)-3-(2-benzyloxycarbonylaminoethanesulfonyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]propionate in 10 ml of methanol, and the mixture was hydrogenated under a hydrogen atmosphere (balloon pressure). After leaving to stand for 2 days, the mixture was filtered, concentrated and purified by preparative HPLC. The required fractions were combined and freeze dried after addition of 1N hydrochloric acid. 23 mg of the title compound were obtained as hydrochloride.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:1][N:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)N(C)C)cc3)cc2)CC1
Yield: 34.2 %

Procedure:
The title compound (29 mg, 27%) was prepared as a white solid from {4-[(dimethylamino)carbonyl]phenyl}boronic acid (39 mg, 0.2 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.63-7.42 (m, 6H), 6.96 (d, 2H, J=8.8 Hz), 4.98-4.81 (m, 1H), 4.20 (bs, 2H), 3.84 (d, 2H, J=6.4 Hz), 3.13 (s, 3H), 3.04 (s, 3H), 2.84-2.74 (m, 2H), 2.08-1.92 (m, 1H), 1.90-1.80 (m, 2H), 1.37-1.14 (m, 8H); LRMS (ESI), m/z 425 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:38]=[C:37]([CH3:39])[C:14]2[N:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:17]=[N:18][C:13]=2[CH:12]=1>CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]2[CH:38]=[C:37]([CH3:39])[C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH2:30][CH2:31][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)(=[O:27])=[O:28])=[CH:24][CH:25]=4)[N:17]=[N:18][C:13]=3[CH:12]=2)[CH:4]=1
Reactant: Cc1cc(-c2cc([N+](=O)[O-])ccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)NCCN4CCCC4)cc3)nc12
Solvent: CO
Product: Cc1cc(-c2cc(N)ccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)NCCN4CCCC4)cc3)nc12
Reaction time: 4 h

Procedure:
4-[7-(2-chloro-5-nitro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.41 mmol, 1.0 equiv) was dissolved in 20 mL of MeOH, and the reaction was evacuated of air by vacuum and placed under a blanket of argon. Pd/C (10% by wt) was added to the reaction, followed by another evacuation of argon, and by blanketing with hydrogen. The reaction was stirred under hydrogen blanket for 4 h, filtered through Celite, and concentrated by reduced pressure to give a crude residue, which was precipitated using EtOAc/hexanes (1:5 v/v) to give 4-[7-(5-amino-2-chloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, as a dark green solid (89.4 mg, 41% yield). 1H NMR (DMSO-d6): δ 1.61 (m,4H), 2.34 (m, 4H), 2.42 (t, J=6.9 Hz, 2H), 2.71 (s, 3H), 2.85 (t, J=7.1 Hz, 2H), 5.43 (s, 1H), 6.65 (dd, J=8.7 Hz, J=2.8 Hz, 1H), 6.73 (d, J=2.7 Hz,1H), 7.21 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.9 Hz, 2H), 7.89 (s, 1H), 8.15 (s, 1H), 8.21 (d, J=8.8 Hz, 2H). MS (ES+) m/z=538, LC retention time 2.13 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9]/[CH:10]=[CH:11]\[C:12]([O:14]C(C)(C)C)=[O:13])=[CH:7][CH:6]=1.Cl>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9]/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: COCCc1ccc(O/C=C\C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COCCc1ccc(O/C=C\C(=O)O)cc1

Procedure:
(E)/(Z)-tert-butyl 3-(4-(2-methoxyethyl)phenoxy)acrylate (0.57 g) was suspended in a mixture of THF (5 mL)/HCl (2 M, 5 mL) and placed in the microwave reactor (T=100° C., 15 sec). THF was removed by rotary evaporation and the mixture was extracted with CH2Cl2 (10 mL). (E)/(Z)-3-(4-(2-methoxyethyl)phenoxy)acrylic acid was obtained as a white solid after purification by column chromatography using a mixture of hexane/ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[CH:16](OC)=[O:17]>COC(C)(C)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH:16]=[O:17]
Reactant: COc1ccc(F)c(Cl)c1
Reactant: COC=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: COc1ccc(F)c(Cl)c1C=O
Reaction time: 3 h

Procedure:
To a solution of 3-chloro-4-fluoroanisole (28.5 g, 178 mmol) in t-butyl methyl ether (200 mL, dried over anhydrous MgSO4) at −78° C. was added 2.5 M n-butyl lithium in hexanes (107 mL, 267.5 mmol). After 3 h, methyl formate (18.76 mL) was added drop-wise while keeping the temperature below −60° C. The reaction mixture was quenched with sat. aq. ammonium chloride (250 mL) after 45 minutes and the organic layer was separated. The aq. layer was extracted with ethyl acetate (2×100 mL) and the combined organic layer was washed with water (200 mL) followed by brine, dried (Na2SO4) and concentrated to give a residue which on trituration with hexanes gave solids. The solids were filtered, taken again in hexanes and heated over steam bath. It was cooled, the light yellow desired product filtered and air dried to give the title compound. 1H NMR (400 MHz, CDCl3): δ=10.48 (d, J=0.8 Hz, 1H), 7.31 (dd, J=9.4, 7.8 Hz, 1H), 6.88 (dd, J=7.8, 3.8 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:9]=2[N:8]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]1=[O:24])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Na+].O.Cl>CO.C(Cl)(Cl)Cl>[CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=2[N:8]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]1=[O:24])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)n(CCC(C)C)c(=O)n2CCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)CCn1c(=O)n(CCC(C)C)c2cc(C(=O)O)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
In 7 ml of methanol is dissolved 0.34 g of methyl 1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate. After adding 1.5 ml of 1 mol/L solution of sodium hydroxide, the mixture is stirred at 50° C. for one hour. Water and chloroform are successively added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 0.29 g of 1,3-diisopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid is obtained as a white solid product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH3:13])=O.P(Cl)(Cl)(Cl)=O.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]([NH:32][NH2:33])=[O:31])[CH:26]=2)[N:21]=1.[OH-].[Na+]>ClCCl.C(Cl)(Cl)Cl.O>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]([NH:33][NH:32][C:30]([C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH3:19])[CH:29]=[CH:28]2)=[O:31])=[N:12][CH3:13]
Reactant: CNC(=O)CCCC1OCCCO1
Reactant: Cc1ccc2cc(C(=O)NN)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN=C(CCCC1OCCCO1)NNC(=O)c1ccc2nc(C)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
4-[1,3]Dioxan-2-yl-N-methyl-butyramide (1 g, 5.35 mmol) was cooled to −78° C. in dry dichloromethane (10 ml) under argon and phosphorus oxychloride (0.65 ml, 7 mmol) was added dropwise. The mixture was warmed to room temperature to give an amber solution which was re-cooled to 0° C. This solution was added dropwise to a suspension of 2-methyl-quinoline-6-carboxylic acid hydrazide (1 g, 5 mmol) in chloroform (20 ml) and the mixture stirred at room temperature overnight. The mixture was poured into water (300 ml), basified with sodium hydroxide solution (5M) and extracted with dichloromethane (3×200 ml). The combined organic portions were dried (Na2SO4), filtered and evaporated to give the desired compound as a brown oil (1.28 g, 83%).