Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([O:10][C:11](=[O:24])[NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:14]=1[I:23])([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl.C1COCC1>[C:6]([O:10][C:11](=[O:24])[NH:12][C:13]1[C:14]([I:23])=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[C:18]=1[Cl:4])([CH3:9])([CH3:7])[CH3:8]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(I)c(OC)c1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(I)c(NC(=O)OC(C)(C)C)c1Cl
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of sulfurylchloride (0.92 ml, 11.0 mmol, 1.16 equiv) in DCM (20 mL) is added dropwise (30 min) to a cold (−15° C.) solution of (2-iodo-3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester (3.6 g, 9.49 mmol) in THF (48 ml), under an argon atmosphere. The reaction mixture is allowed to stir for 1 h at −15° C. and then poured onto a mixture of ice/H2O (100 mL), a saturated aqueous solution of NaHCO3 (80 ml), and EtOAc (100 mL). The layers are separated and the aqueous phase is extracted with EtOAc (2×100 mL). The combined organic phase is washed with H2O (3×60 mL) and brine (60 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM) followed by crystallization from DCM/Hex to afford the title compound. ESI-MS: 411.9, 413.9 [M-H]−, TLC: Rf=0.18 (DCM/Hex, 7:3).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:41]2[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:40])[N:23]([CH:34]2[CH2:39][CH2:38][S:37][CH2:36][CH2:35]2)[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[NH:3][C:4](=[O:7])[O:5][N:48]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:40])[N:23]([CH:34]2[CH2:35][CH2:36][S:37][CH2:38][CH2:39]2)[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCSCC2)c2nc(C)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCSCC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogen carbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-thiopyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.41 g, 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[NH:17][NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])([O-:3])=[O:2].[C:25](Cl)(Cl)=[O:26]>C1(C)C=CC=CC=1>[CH3:22][C:20]([C:19]1[O:24][C:25](=[O:26])[N:17]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:7][C:6]=2[N+:14]([O-:16])=[O:15])[N:18]=1)([CH3:21])[CH3:23]
Reactant: CC(C)(C)C(=O)NNc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nn(-c2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])c(=O)o1
Temperature: 59 °C
Yield: 45.2 %

Procedure:
A mixture of 0.35 g (1 mmol) of N'-(2,6-dinitro-4-trifluoromethylphenyl)-2,2-dimethylpropionhydrazide, 0.3 g (3.1 mmols) of phosgene and 2.1 ml of toluene was heated to reflux for 2.5 hours (inner temperature of 59° C.). A solution (0.7 ml) of 0.1 g (1 mmol) of phosgene in toluene was further added to the reaction mixture followed by heating to reflux for further 2.5 hours. An excess of phosgene and toluene were distilled off and the residue was taken up in 20 ml of ether. After washing with saturated sodium chloride aqueous solution, the solution was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus obtained crude product was subjected to silica gel column chromatography to give 0.17 g of 5-(1,1-dimethylethyl)-3-(2,6-dinitro-4-trifluoromethylphenyl)-1,3,4-oxadiazolin-2-one.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46].CCOCC>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([O:13][N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])=[O:12]
Reactant: O=C(O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(ON1C(=O)CCC1=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 89.8 %

Procedure:
A mixture of 3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoic acid (5.00 g, 15.5 mmol), 1,3-dicyclohexylcarbodiimide (3.72 g, 18.1 mmol) and N-hydroxysuccinimide (2.08 g, 18.0 mmol) in tetrahydrofuran (100 Ml) was stirred at room temperature for 40 h. Ether (100 Ml) was added and the mixture was stirred for 20 min. The white solid was filtered off and discarded. The solvent was evaporated from the filtrate, and the residue was coated onto silica gel and chromatographed (50-75% ethyl acetate/hexanes) to give 1-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedione (5.84 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Na+].[H][H].[CH:20]([CH:22]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH:23]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=O>O1CCCC1.C(O)(=O)C>[OH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:23]1[CH:22]([CH:20]=[CH:4][C:3](=[O:11])[CH:2]([CH3:1])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:30][CH2:29][C:24]21[O:25][CH2:26][CH2:27][O:28]2
Reactant: [H][H]
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: CCCCC(C)C(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(C)C(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethyl 3-methyl-2-oxoheptylphosphonate (5.1 g.; prepared as described in the Specification of Netherlands Patent Application No. 7203126) in dry tetrahydrofuran (20 ml.) was added dropwise to a stirred suspension of sodium hydride (0.52 g.) in dry tetrahydrofuran (150 ml.) at ambient temperature under nitrogen. The reaction mixture was stirred at ambient temperature until hydrogen evolution had ceased, and then treated with a solution of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (5.1 g.) in dry tetrahydrofuran (50 ml.). After stirring for a further period of 2 hours at ambient temperature the reaction mixture was acidified to pH 4 with glacial acetic acid and then concentrated under reduced pressure. The residue was triturated with diethyl ether and filtered. The filtrate was washed with dilute aqueous sodium carbonate solution and water respectively, then dried over sodium sulphate. Removal of the solvent under reduced pressure gave crude 6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (7.6 g.), νmax (liquid film) 3450 cm-1, 1680 cm-1, 1660 cm-1, 1620 cm-1, 1380 cm-1, 1040 cm-1, which was used in the next stage without further purification being necessary.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH2:33])[C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=3)=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]2[NH:23][C:24]([CH:26]([NH:33][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[C:27]3[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=3)=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: Cn1ccc(C(N)c2nc3cc(Cl)ccc3[nH]2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(c2ccn(C)n2)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine with TBTU and DIPEA in THF.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16])([O-:8])=[O:7].[C:18]([OH:22])(=[O:21])[CH:19]=O>>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([CH:16]=[CH:19][C:18]([OH:22])=[O:21])=[O:17])([O-:8])=[O:7]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: O=C(O)C=CC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 30.3 %

Procedure:
To a solution of 225 ml of glacial acid and 8.5 ml of concentrated sulfuric acid is added 49.54 g (0.30 mol) of 2'-nitroacetophenone and 47.02 g (0.50 mol) of glyoxylic acid (hydrated). The mixture is heated at 100° C. 16 hours. The mixture is cooled and poured over crushed ice. After the ice melts, the mixture is filtered and the solid washed with cold water. The solid is dried and recrystallized from dichloromethane-hexane to give 20.1 g of 3-(2-nitrobenzoyl)acrylic acid as white crystals, m.p. 153°-158° C. A solution of the preceding compound (9.0 g) in 80 ml of ethanol and 1.6 g of palladium-on-carbon is hydrogenated in a Parr hydrogenator under 30 pounds per square inch of hydrogen for 20 hours. The mixture is filtered through diatomaceous earth and the solvent is removed. The residue (7.0 g) is chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 4.0 g of 3-(2-aminobenzoyl)acrylic acid as an orange solid, m.p. 103°-107° C. A 0.50 g sample of the preceding compound, 0.36 ml of triethylamine and 0.43 ml of diethoxyphosphinyl cyanide in 20 ml of dichloromethane is stirred at room temperature for 5 days. The solvent is removed, ethyl acetate is added and the mixture washed with water, 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue purified by chromatography over silica gel with ethyl acetate-hexane (1:1) as solvent to give 0.190 g of light brown crystals, m.p. 168°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[CH2:22]([N:24](CC)CC)C.O>CCOCC>[CH3:17][S:18]([O:7][CH:6]([C:22]#[N:24])[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
The cyanohydrin of 4-fluoro-3-phenoxybenzaldehyde (0.038 mol) is dissolved in 150 ml ether and cooled to 0° in an ice bath. To this is slowly added methanesulfonyl chloride in 20 ml ether. The mixture is stirred for 10 minutes then triethylamine in 20 ml ether is added dropwise. The solution turns white, and a precipitate appears. The reaction mixture is kept at 0° over-night and is then worked up with water and extracted with ether. The ether phase is washed with 30% sodium bisulfite solution (2×), ether and water (2×), and dried over sodium sulfate. The mixture is filtered and the filtrate concentrated to give α-cyano-4 fluoro-3-phenoxybenzyl methanesulfonate.
Reaction SMILES: [C:1](OC(N1CC[C@H](NC2C=CC(N)=CN=2)C1)=O)(C)(C)C.[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=2)[CH2:26]1)=[O:24].COC([C@@H]1CC[C@H](NC2C=CC([N+]([O-])=O)=CN=2)C1)=O>>[CH2:21]([O:22][C:23]([C@@H:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=2)[CH2:26]1)=[O:24])[CH3:1]
Reactant: COC(=O)[C@@H]1CC[C@H](Nc2ccc(N)cn2)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Agent: COC(=O)[C@@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Product: CCOC(=O)[C@@H]1CC[C@H](Nc2ccc(N)cn2)C1

Procedure:
With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (1R,3S)-3-(5-amino-pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester was prepared by the hydrogenation of (1R,3S)-3-(5-nitro-pyridin-2-ylamino)-cyclopentanecarboxylic acid methyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=1)[CH2:3][CH3:4].O.NN.[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([S:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Sc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)Sc1ccc(OCCN)cc1

Procedure:
To a solution of the above phthalimide (6.84 g, 19.7 mmol) in 100 mol of ethanol, heated to 60°, is added hydrazine hydrate (2.0 ml, 41.0 mmol) with stirring. Additional ethanol (100 ml) is added and the mixture is stirred overnight at 60°. After cooling, 5% sodium hydroxide is added and the basic mixture is extracted with ether. The combined organic layers are washed with water and brine, dried and rotoevaporated to give 2-[4-(1-methylpropylthio)phenoxy]ethylamine.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Mg].[CH2:6]([C:9]1([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH2:7][CH3:8]>CCOCC>[CH2:6]([C:9]1([CH:13]([OH:14])[CH2:3][C:2]#[CH:1])[CH2:12][CH2:11][CH2:10]1)[CH2:7][CH3:8]
Reactant: C#CCBr
Reactant: CCCC1(C=O)CCC1
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)C1(CCC)CCC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 250.6 %

Procedure:
Propargyl bromide (0.27 mL, 2.4 mmol) was added to a mixture of magnesium (1.1 g, 45 mmol) and mercuric chloride (30 mg, 0.117 mmol) in Et2O (60 mL). The mixture was warmed to 40° C. until bubbling commenced. The remainder of the propargyl bromide (2.1 mL, 19 mmol) was added in small portions. After ˜1.5 h the reaction became cloudy white. A solution of the aldehyde 3 (0.8 g, 7 mmol) in Et2O (4 mL) was added and the reaction was stirred for 16 h. The reaction was then quenched by cautiously adding saturated aqueous NH4Cl. The resultant mixture was extracted with Et2O. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 1:1 pentane/CH2Cl2) gave 1.0 g (94%) of the alcohol 4.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)#[CH:23]>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.C(N(CC)CC)C>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:23]#[C:22][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:3][N:4]2[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: C#Cc1ccccn1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc([N+](=O)[O-])cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1nc(C#Cc2ccccn2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Iodo-6-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (838 mg, 2.0 mmol), 2-ethynyl-pyridine (242 μL, 2.4 mmol), and triethylamine (6.0 mL), were degassed and flushed with argon, then treated with Cul (8 mg, 0.042 mmol), and Pd(PPh3)2Cl2 (16 mg, 0.023 mmol). The resulting mixture was stirred overnight at room temperature, at which time HPLC indicated all starting material had been consumed. The mixture was purified by stripping of volatiles under high vacuum, then passing through a plug of silica eluted with ethyl acetate. The resulting product was used in the next step without further purification. ESIMS (M+H+): 395.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:27][C:12]2=[CH:13][C:14]3[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH2:36][CH:37]([NH2:39])[CH3:38].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH2:36][CH:37]([NH:39][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:27][C:12]2=[CH:13][C:14]3[C:15](=[O:26])[N:16]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:38]
Reactant: CN(C)CCN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Reactant: CC(N)Cc1cc(F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Yield: 85.2 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.59 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.44 g, 2.59 mmol), n-butanol (50 mL) and N,N-diisopropylethylamine (10 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a brown solid product, 1.15 g, 85.2% yield. MS: 521.2 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 13.43 (s, 1H), 11.31 (d, 1H, J=6.0 Hz), 10.98 (d, 1H, J=7.5 Hz), 8.16 (s, 1H), 8.01 (s, 1H), 7.42-7.35 (m, 2H), 7.20-7.13 (m, 1H), 7.10-7.02 (m, 1H), 6.18 (d, 1H, J=7.2 Hz), 4.16 (m, 1H), 3.95 (t, 2H, J=6.0 Hz), 3.33 (m, 2H), 3.10-2.96 (m, 2H), 2.81 (s, 6H), 1.33 (d, 3H, J=6.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:13][CH2:14][CH:15]1[N:25]2[C:26]3[C:21]([C:22](=[O:32])[C:23]([C:27](OCC)=[O:28])=[CH:24]2)=[CH:20][C:19]([I:33])=[CH:18][C:17]=3[CH2:16]1)(=O)C>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:27]([C:23]2[C:22](=[O:32])[C:21]3[C:26]4=[C:17]([CH2:16][CH:15]([CH2:14][OH:13])[N:25]4[CH:24]=2)[CH:18]=[C:19]([I:33])[CH:20]=3)=[O:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)CC2COC(C)=O
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(I)cc3c1=O)CC2CO
Temperature: 100 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 4-chlorobenzylamine (2 mL) and ethyl 2-((acetyloxy)methyl)-8-iodo-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate (Preparation 9, 0.70 g) is heated to 120° C. under a stream of nitrogen for 7 h, to 100° C. for 18 h, and then to 130° C. for 8 hours. Upon cooling, the mixture is diluted with a mixture of CH2Cl2, EtOAc, and methanol (2/2/1) and absorbed onto silica gel. This material is chromatographed eluting with 0-4% methanol in CH2Cl2 to give a wet brown solid. The crude product is recrystallized by dissolving in hot acetic acid and slowly adding water until cloudiness persisted. Upon standing, crystals form which are collected to provide 340 mg (43%) of the title compound as a tan solid. Physical characteristics: M.p. 222-223° C.; MS (ESI+) m/z 495 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH2:6])=[O:4].[CH3:7][N:8]([CH3:22])[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=O)[CH:18]=2)[NH:13][CH:12]=1>CO>[CH3:1][O:2][C:3]([NH:5][N:6]=[CH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:10][CH2:9][N:8]([CH3:22])[CH3:7])=[O:4]
Reactant: COC(=O)NN
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Solvent: CO
Product: COC(=O)NN=Cc1ccc2[nH]cc(CCN(C)C)c2c1
Yield: 104 %

Procedure:
To a solution of hydrazinecarboxylic acid methyl ester (0.90 g, 10 mmol) in methanol (10 ml) is added 3-(2-Dimethylamino-ethyl)-1H-indole-5-carbaldehyde (2.16 g, 10 mmol), and the mixture obtained is heated at reflux for 20 hours. After removal of the solvent, a yellow oil (3.0 g) is obtained, which is chromatographed on silica (chloroform:methanol 9:1 v:v to 4:1 v:v) to give 1.6 g (55.4%) of the product as a colourless foam. 1H-NMR (CDCl3, 300 MHz) δ 2.26 (s, 6H, N(CH3)2); 2.57, 2.84 (2 m, 2H each, CH2CH2NHMe2); 3.79 (s, 3H, OCH3); 6.90 (s, 1H, H-2); 7.11 (d, 1H, J=8.5 Hz, H-7); 7.45 (dd, 1H, J=1.5 Hz, H-6); 7.62 (br s, 1H, H-4); 7.77 (s, 1H, N═CH); 9.04 (br s, 1H, H-1); 9.33 (br s, 1H, NH). 13C-NMR (CDCl3, 75 MHz) δ 23.73 (CH2); 45.51 (N(CH3)2); 53.04 (OCH3); 60.39 (CH2NMe2); 112.07 (C-7); 114.66 (C-3); 119.52 (C-4); 120.72 (C-6); 123.14 (C-2); 125.14 (C-5); 127.52 (C-9); 137.71 (C-8); 147.25 (N═CH); 155.02 (NC═O).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.C(OC(=O)C)(=O)C.P(=O)(O)(O)O>O>[CH2:7]1[CH2:8][C:9](=[O:11])[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6]1
Reactant: O=C(O)CCCc1cccs1
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1CCCc2sccc21
Yield: 88.9 %

Procedure:
4-(2-Thienyl)butyric acid (28.42 g, 167 mmol) was placed in a round bottom flask with acetic anhydride (30 mL) and phosphoric acid (0.6 mL), and heated to reflux for 3.2 hours. The reaction mixture was poured into 100 mL of water, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (22.60 g) which was vacuum distilled (1 mm Hg, 107-115° C.) to give a white solid (13.08 g, 51%): mp 34-40° C.); 1H NMR (CDCl3) 300 MHz 7.29 (d, J=5.2 Hz, 1H), 6.99 (d, J=5.2 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H), 2.47 (m, 2H), 2.13 (m, 2H). M+H=153.
Reaction SMILES: C(C1C=CC(CN)=CC=1)(C)(C)C.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]=[C:40]=[O:41])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].[NH2:42][CH2:43][C:44]1[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([CH3:57])[CH:45]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([CH2:38][NH:39][C:40](=[O:41])[NH:42][CH2:43][C:44]2[CH:49]=[C:48]([CH:50]=[CH2:51])[C:47]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[C:46]([CH3:57])[CH:45]=2)=[CH:36][CH:37]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Reactant: C=Cc1cc(CN)cc(C)c1NS(C)(=O)=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)c1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(C)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 23.9 %

Procedure:
4-tert-Butyl-benzylamine (1.5 eq, 71.91 μl, 0.44 mmol) was added in CH2Cl2 and then BOC2O (1.5 eq, 0.44 mmol, 101.19 μl) and DMAP (0.2 eq, 0.06 mmol, 7.08 mg) were slowly added. After confirming the synthesis of the 1-tert-Butyl-4-isocyanatomethyl-benzene, N-(4-Aminomethyl-2-methyl-6-vinyl-phenyl)-methanesulfonamide (1 eq, 0.29 mmol, 70.5 mg) and TEA (2 eq, 0.58 mmol, 80.84 μl) were added into the reaction mixture. The reaction mixture was stirred for 12 hr. The reaction mixture was purified according to step 9 of example 7 to obtain N-{4-[3-(4-tert-Butyl-benzyl)ureidomethyl]-2-methyl-6-vinylphenyl}methanesulfonamide (29.75 mg, 23.9%).