Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(#N)C.CO>[NH2:1][C:2]1[N:17]([C@H:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]2)[C:16]2[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=2[N:5]=1
Reactant: N#CBr
Reactant: CCOC(=O)c1ccc(N[C@H]2CC[C@H](O)CC2)c(N)c1
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc(N)n2[C@H]1CC[C@H](O)CC1

Procedure:
5.0 M cyanogen bromide in acetonitrile (1.0 mL) was added to water (35 mL) in a 250 mL round-bottom flask at room temperature with stirring. To this was added dropwise via an addition funnel ethyl 3-amino-4-(trans-4-hydroxycyclohexylamino)benzoate (0.91 g, 0.0033 mol) in methanol (70 mL) over 1 hour. After 3 hours the reaction mixture was concentrated to an off white residue. The residue was triturated with ethyl acetate and dried overnight in vacuo to give the title compound (0.97 g, 98%) as an off white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:10](=[O:11])[CH:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:8](=[O:21])[N:7]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][N:7]1[C:8](=[O:21])[C:9]([N+:1]([O-:4])=[O:2])([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])[C:10](=[O:11])[N:6]1[CH3:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(C2C(=O)N(C)N(C)C2=O)c(C)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(C2([N+](=O)[O-])C(=O)N(C)N(C)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
A quantity of 0.13 ml (3.1 mmols) of fuming nitric acid was added to a solution of 0.70 g (2.8 mmols) of 1,2-dimethyl-4-(2,4,6-trimethylphenyl)pyrazolidine-3,5-dione in 20 ml of chloroform at room temperature. The obtained mixture was stirred at room temperature for 15 minutes. The reaction mixture was washed with water and was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then the residue was purified by column chromatography (benzene:ethyl acetate=3:1) to give 0.53 g (yield 64%) of 1,2-dimethyl-4-nitro-4-(2,4,6-trimethylphenyl)pyrazolidine-3,5-dione in the form of yellowish white crystals.
Reaction SMILES: C([O:3][C:4](=[S:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])C.[OH-].[K+]>CO>[CH2:11]([CH:5]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]([OH:3])=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=S)C(Cc1ccccc1)CC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CC(Cc1ccccc1)C(O)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
400 mg of 2-benzyl-3-tert.-butylthio-propionic acid ethyl ester was dissolved in 1.5 ml of methanol and then reacted with 5 ml of 2N potassium hydroxide solution. The mixture was stirred overnight at room temperature and concentrated by evaporation. The residue was diluted with water and washed with ether. The aqueous layer was acidified to pH 3 with 2N HCl, and then evaporated to give the title compound (280mg, 78% yield). 1H NMR: 300MHz spectrum consistent with proposed structure.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].Br[C:13]1[CH:14]=[C:15]([C:19]([C:24]2[N:25]=[CH:26][N:27]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=2)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:17][CH:18]=1>>[OH:23][C:19]([C:15]1[CH:14]=[C:13]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=2)[CH:18]=[CH:17][CH:16]=1)([C:24]1[N:25]=[CH:26][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=Cc1cccc(B(O)O)c1
Product: CC(C)C(O)(c1cccc(-c2cccc(C=O)c2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 72.8 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using 3-formylphenylboronic acid (0.45 g) and 1-(3bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.05 g), the amorphous title compound (0.80 g) was obtained.
Reaction SMILES: [C:1]([O:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[C:7](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]1=[O:27])(=[O:3])[CH3:2].[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>>[C:1]([O:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)/[C:7](=[C:17](/[NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:6]1=[O:27])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(OC(C)=O)c2cc([N+](=O)[O-])ccc21)c1ccccc1
Product: COC(=O)c1ccc(N/C(=C2\C(=O)N(OC(C)=O)c3cc([N+](=O)[O-])ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetoxy-3-(1-ethoxy-1-phenyl-methylidene)-6-nitro-2-indolinone and methyl 4-aminobenzoate without subsequent hydrogenation
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH2:7])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:19]2)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](=[S:19])[NH2:7]
Reactant: NC(=O)CCC(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)CCC(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of 4,4,4-trifluorobutanamide (17.9 g), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (51.3 g) and toluene (400 mL) was stirred at 80° C. for 3 hr. The reaction mixture was purified by aminopropylsilane-bonded silica gel column chromatography (ethyl acetate), and again purified by aminopropylsilane-bonded silica gel column chromatography (ethyl acetate/hexane) to give the title compound (14.6 g) as a solid.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]2[CH:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=3[N+:17]([O-])=O)[CH2:7][CH2:8][C:2]=12.CCO>C1COCC1.[Pd]>[NH2:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[CH:6]1[N:3]2[CH:4]=[N:5][CH:1]=[C:2]2[CH2:8][CH2:7]1)[C:13]#[N:14]
Reactant: N#Cc1ccc(C2CCc3cncn32)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(C2CCc3cncn32)c(N)c1
Reaction time: 8 h

Procedure:
4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-nitrobenzonitrile (0.054 g, 0.212 mmol) is dissolved in THF (2 mL) and EtOH (2 mL) and 5% palladium on carbon (wet) (15 mg) is then added. The mixture is placed under an atmosphere of hydrogen overnight. The mixture is then filtered and concentrated. The residue is purified via HPLC (reversed phase, CH3CN/H2O) to give 3-amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile as a solid. MS (ESI) m/z 225.0 (M+H); 1H NMR (400 MHz, CH3CN) (TFA salt) δ ppm 2.45-2.57 (m, 1 H), 2.99-3.16 (m, 3 H), 4.47 (br s, 2 H), 5.68-5.75 (m, 1 H), 6.69 (d, J=7.8 Hz, 1 H), 6.98 (d, J=1.5 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 7.21 (s, 1 H), 8.32 (s, 1 H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([Si](C(C)C)(C(C)C)C(C)C)[CH:31]=[CH:30]2)#[N:20]>C1COCC1.[Cl-].[Na+].O>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)#[N:20]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccccc3C#N)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
Tetra-n-butylammonium fluoride (8.0 mmoles, 8 ml of 1.0M solution in THF) was added to 5-(2-Cyanophenyl)-1-triisopropylsilylindole (4 mmole, 1.5 g) in 5 ml THF and stirred at room temperature for 5 minutes. The reaction was added to brine and extracted with ether. The ether solution was dried over sodium sulfate and concentrated. The residue was chromatographed over silica gel eluted with chloroform to yield 0.69 g of 5-(2-cyanophenyl)indole. (MS)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[C:58](OC(=O)C)(=[O:60])[CH3:59]>ClCCl>[C:58]([O:50][CH:45]1[CH2:44][CH2:43][CH:42]([CH:41]=[C:40]([CH:24]2[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28](=[O:29])[CH:30]([CH2:35][CH:36]=[CH2:37])[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]3[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]3[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]3[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:21](=[O:22])[O:23]2)[CH3:51])[CH2:47][CH:46]1[O:48][CH3:49])(=[O:60])[CH3:59]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: CC(=O)OC(C)=O
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: ClCCl
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(C)=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 5 h

Procedure:
To a solution of the FR-900506 substance (10.4 mg) in dichloromethane (0.2 ml) were added Dvridine (0.1 ml) and acetic anhydride (0.05 ml) at room temperature, and the mixture was stirred for 5 hours. The solvent was removed from the reaction mixture under reduced pressure. The residue was subjected to silica gel thin layer chromatography (developing solvent: diethyl ether and dichloromethane, 1:2 v/v) to give 12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (6.0 mg).
Reaction SMILES: [CH3:1]C[O-].[Na+].[NH2:5][C:6]1[C:21]([I:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:7]=1[C:8]([NH:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[O:9].C(OCC)=O>C(O)C>[Cl:23][C:19]1[CH:18]=[C:7]2[C:6](=[C:21]([I:22])[CH:20]=1)[N:5]=[CH:1][N:10]([CH:11]([CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH3:17])[C:8]2=[O:9]
Reactant: CCCC(CCC)NC(=O)c1cc(Cl)cc(I)c1N
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC=O
Product: CCCC(CCC)n1cnc2c(I)cc(Cl)cc2c1=O

Procedure:
Poured into a solution of 4.43 g of sodium ethylate in 250 cm3 of ethanol is a solution of 3.21 g of 2-amino-5-chloro-3-iodo-N-(1-propylbutyl)benzamide in 120 cm3 of ethanol then 3.3 cm3 of ethyl formate. The reaction mixture is heated under argon at reflux for 16 h. It is then cooled in order to be evaporated using a rotary evaporator under reduced pressure (5 kPa). 200 cm3 of dichloromethane and 150 cm3 of water are added, while stirring, to the concentration residue. The aqueous phase is extracted with 50 cm3 of dichloromethane. The organic phases are combined, washed with 50 cm3 of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The ochre product obtained is purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 100% dichloromethane). After concentrating the fractions under reduced pressure, 2.09 g of 6-chloro-8-iodo-3-(1-propylbutyl)quinazolin-4(3H)-one are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]
Reactant: Nc1ccccc1
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(CCN1C(=O)c2ccccc2C1=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propanoic acid (40 g, 182.49 mmol, 1.00 equiv) in water (250 mL). This was followed by the addition of aniline (17 g, 182.55 mmol, 1.00 equiv). To this was added sodium carbonate (9.6 g, 90.57 mmol, 0.50 equiv). The resulting solution was stirred for 3 h at 25° C. The pH value of the solution was adjusted to 5-6 with hydrochloric acid (1 mol/L). The solids were collected by filtration. The filter cake was washed with 1×200 mL of water. This resulted in 40 g (74%) of 3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-phenylpropanamide as a white solid. MS (ESI) m/z 295 ([M+H]+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH3:11])[CH:5]=2)[CH2:3][CH2:2]1.[N:12]([O-])=O.[Na+]>CC(O)=O.O>[CH:1]1([C:4]2[CH:5]=[C:6]3[CH:11]=[N:12][NH:10][C:7]3=[CH:8][N:9]=2)[CH2:3][CH2:2]1
Reactant: O=N[O-]
Reactant: Cc1cc(C2CC2)ncc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1n[nH]c2cnc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 6-cyclopropyl-4-methylpyridin-3-amine (130 mg, 0.88 mmol) in AcOH (10 mL) was treated with a solution of sodium nitrite (61 mg, 0.88 mmol) in water (0.5 mL). The reaction mixture was stirred at RT for 15 min and then was allowed to stand at RT for 24 h. AcOH was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The organic solution was washed with water and brine, then dried (Phase separator) and concentrated under. MS (LC-MS): 160 [M+H]+, tR (HPLC conditions c): 2.07 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)[CH3:2]>CO.CCOCC.[Pd]>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:12][CH:11]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C=Cc1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)CCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
The compound 34-2 (64 mg) according to the same procedure as described in Step 1 was dissolved in methanol (10 ml) and to the solution was added a catalytic amount of 10% palladium/carbon, followed by stirring at room temperature under hydrogen gas atmosphere for 2 hours. The resulting mixture was diluted with ether, filtered through celite, and then concentrated under reduced pressure to yield the compound 34-3 (60 mg, 93%)
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24](=[O:27])[N:25]([CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])[N:26]=2)=[CH:17][CH:16]=1
Reactant: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Reactant: CC1(C)Oc2ccncc2C2OC21
Product: CC1(C)Oc2ccncc2C(n2nc(-c3ccc(Cl)cc3)ccc2=O)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 6-(4-chloro-phenyl)-2H-pyridazin-3-one as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][N:6]2[CH:13]=1.S(Cl)([Cl:16])=O>ClC(Cl)Cl>[ClH:16].[Cl:1][CH2:11][C:9]1[CH:8]=[CH:7][N:6]2[CH:13]=[C:3]([CH3:2])[N:4]=[C:5]2[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cn2ccc(CO)cc2n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1cn2ccc(CCl)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred mixture of 10.7 parts of 2-methylimidazo-[1,2-a]pyridine-7-methanol monohydrochloride and 150 parts of trichloromethane were added dropwise 9.6 parts of thionyl chloride. The resulting solution was stirred for 15 minutes at room temperature. The reaction mixture was evaporated in vacuo and the residue was stirred in 80 parts of 2-propanone. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 11.8 parts (100%) of 7-(chloromethyl)-2-methylimidazo-[1,2-a]pyridine monohydrochloride; mp. 178.5 (intermediate 16).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:7][CH2:6]2.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C1C(=O)[N-]C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd+]>[Cl:19][C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][CH:21]=1)[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:7][CH2:6]2
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(CCl)ccc21
Reactant: OB(O)c1cccc(Cl)c1
Agent: Br[Pd+]
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)[N-]1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)NC1CCc2cc(Cc3cccc(Cl)c3)ccc21
Temperature: 60 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A mixture of N-(5-(chloromethyl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (50 mg, 0.174 mmol), 3-chlorophenylboronic acid (54.3 mg, 0.347 mmol), trans-Bromo(N-succinimidyl)bis(triphenylphosphine)palladium(II) (7.04 mg, 8.69 μmol), and Sodium carbonate (36.8 mg, 0.347 mmol) in degassed Tetrahydrofuran (1 mL) and Water (1 mL) was stirred at 60° C. for 5 h. The Reaction mixture was then filtered and partitioned between H2O and EtOAc, the organic layer separated and evaporated in vacuo. Purification by flash chromatography (0-100% EtOAc in heptane) afforded the title compound as a colourless oil (43 mg, 68%). MS (ESI): m/z [M−H]− 362.0
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.CN(C)[CH:12]=[O:13]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:13][C:12]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1Br
Product: Brc1ccccc1COc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture is stirred at room temperature and 37.2 g of 2-bromobenzyl bromide in solution in 15 ml of dimethylformamide are introduced at 5° C. After 2 hours at 20° C., the reaction medium is poured over ice-cold water and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 36 g of oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH3:22])[CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CI.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[C:8]([CH3:22])[CH:9]=[CH:10][C:11]=2[N:13]([CH3:30])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-4-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (7.8 g), methyl iodide (1.7 ml), potassium carbonate (2.9 g) and N,N-dimethylformamide (14 ml) was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with aqueous citric acid solution, water and saturated brine,*dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with diethyl ether-hexane to give the title compound (6.85 g, yield 85%) as colorless needle crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Cl[CH2:13][CH:14]=[C:15]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[Cl:24])[CH3:16]>C(O)C>[CH3:7][C:5]([CH:4]([CH2:13][CH:14]=[C:15]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[Cl:24])[CH3:16])[C:3]([O:9][CH2:10][CH3:11])=[O:8])=[O:6]
Reactant: CC(=CCCl)c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC=C(C)c1cc(Cl)ccc1Cl)C(C)=O
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 0.8 gram (0.021 mole) of sodium hydride (60% in mineral oil) in 40 mL of ethanol is stirred for about 15 minutes, and a solution of 2.8 grams (0.021 mole) of ethyl acetoacetate in 5 mL of ethanol is added dropwise. Upon completion of addition, the reaction mixture is stirred at ambient temperature for one hour. After this time a solution of 5.0 grams (0.021 mole) of 1-chloro-3-(2,5-dichlorophenyl)-2-butene in 10 mL of ethanol is added dropwise. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 18 hours. The reaction mixture is then concentrated under reduced pressure to a residue. The residue is stirred with 50 mL of an aqueous 10% acetic acid solution and then is extracted with two 30 mL portions of diethyl ether. The combined extracts are washed with an aqueous solution saturated with sodium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 5.2 grams of ethyl 2-methylcarbonyl-5-(2,5-dichlorophenyl)-4-hexenoate. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1>O>[Cl:11][C:4]1[N:3]=[C:2]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)nc1N1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
2,6-Dichloro-3-nitropyridine (10 g, 51.8 mmol) and sodium carbonate (8.8 g, 82.9 mmol) were added to anhydrous N,N-dimethylformamide (250 ml). 1,2,3,4-tetrahydroisoquinoline (7.14 ml, 82.9 mmol) was added at 0° C. to the reaction mixture, which was then stirred for 2 hours at 0° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 10 g of the titled compound as yellow solid. (Yield: 81%).