Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:4]2[CH:3]=[CH:2][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(Nc2cc(Cl)n(-c3ccccc3)n2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Reaction time: 3 h

Procedure:
A solution of 5-chloro-N-(4-methoxyphenyl)-1-phenyl -1H-pyrazol-3-amine (0.2 g) in ethanol (10 ml) and triethylamine (0.2 g) was reduced at atmospheric pressure of hydrogen over 10% palladium/charcoal (0.2 g), with stirring, over 3 hours. The solution was filtered and evaporated to leave the title compound as a colourless solid, mp 96°-98°, the NMR and mass spectra of which were identical to those for the title compound of Example 2.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[O:35]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[O:35]1[CH:39]=[CH:38][C:37]([C:2]2[C:10]3[C:9]([N:11]4[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[N:8][CH:7]=[N:6][C:5]=3[N:4]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:3]=2)=[CH:36]1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Reactant: O=C(NC1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1CCN(c2ncnc3c2c(-c2ccoc2)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C

Procedure:
N-{1-[5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D6 (450 mg), 2-(3-furanyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (240 mg, 1.245 mmol, commercially available from e.g. Maybridge, Sigma-Aldrich or Apollo), potassium phosphate trihydrate (660 mg, 2.5 mmol), palladium tetrakis (30 mg, 0.026 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml) and stirred under nitrogen at 90° C. overnight. Cooled to room temperature, solvent removed in vacuo, water (150 ml) was added extracted with EtOAc (3×150 ml). The combined extracts were washed with brine and dried over MgSO4, concentrated to give crude product which was purified by silica gel column eluting with pet eth/EtOAc 1:1 to give 60 mg of desired product D28. LCMS [MH+] 528.2@1.88 min (5 min run)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl.O>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:21])[CH3:20]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)cc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10 g (59.9 mmol) of methyl 4-aminosalicylate in 100 ml of CH2Cl2 is added 6.8 ml (83.9 mmol) of pyridine in one portion at room temperature. The solution is cooled to 0° C. and 4.7 ml (65.9 mmol) of acetyl chloride is added dropwise. After addition is complete the reaction mixture is let stand 30 minutes at room temperature. The reaction mixture is diluted with water and extracted with CH2Cl2. The combined organic extracts are dried over MgSO4, filtered and concentrated to provide methyl 4-acetylaminosalicylate which is used directly in the next step.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[O:14]=[CH:15][CH2:16][C@H:17]1[O:22][CH2:21][O:20][C@@H:19]([CH2:23][C:24]#[N:25])[CH2:18]1.C(OCC)C>CC(C)=O>[C:24]([CH2:23][C@H:19]1[O:20][CH2:21][O:22][C@@H:17]([CH2:16][C:15]([OH:3])=[O:14])[CH2:18]1)#[N:25]
Reactant: CC(C)=O
Reactant: N#CC[C@H]1C[C@@H](CC=O)OCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: N#CC[C@@H]1C[C@H](CC(=O)O)OCO1
Reaction time: 0.25 h

Procedure:
Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 mL (97.6 mmol), is added dropwise to a 0° C. solution of (±)-cis-6-(2-oxoethyl)-1,3-dioxane4-acetonitrile, 1.29 g (7.6 mmol), dissolved in 50 mL of acetone until the orange color is not discharged. After stirring a further 15 minutes, the mixture is poured into 300 mL of diethyl ether and washed with brine until the aqueous washes are colorless. The diethyl ether layer is dried (magnesium sulfate), filtered, and concentrated to provide 1.2 g of (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid as a colorless solid.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[NH:18][C:19]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=1.O>C(OCC)(=O)C>[C:6]([N:18]([C:19]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[N:20]=1)[C:10]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:8])(=[O:7])[NH2:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cccc([N+](=O)[O-])c1Nc1nc2c(c(C(F)(F)F)n1)CCCC2
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1N(C(N)=O)c1nc2c(c(C(F)(F)F)n1)CCCC2
Reaction time: 1 h

Procedure:
2.2 ml of chlorosulfonyl isocyanate are added at 3° C. to a solution of 7.0 g of 2-(2-methyl-6-nitrophenylamino)-5,6,7,8-tetrahydro-4-trifluoromethyl-quinazoline in 100 ml of ethyl acetate. The whole is stirred for one hour while cooling on an ice-bath, and subsequently 50 ml of ethyl acetate and 30 ml of water are added. The organic phase is separated off, washed with brine, dried and concentrated in vacuo. The residue is triturated with hexane, the product crystallising out. 7.8 g of the title compound of formula ##STR25## are isolated in the form of crystals having a melting point of 161°-162° C. (decomp.) (comp. No. 1.563).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.CO[C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:13][CH2:14][C:15]([NH:17][NH:18][C:19]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=O)=[O:16].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.[OH2:53]>>[CH3:1][O:53][C:34]1[CH:33]=[C:12]([CH:11]=[CH:10][C:35]=1[O:36][CH3:37])[O:13][CH2:14][C:15]1[O:16][C:19]([C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[N:18][N:17]=1
Reactant: COc1ccc(OCC(=O)NNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Reactant: O
Reactant: Cc1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Product: COc1ccc(OCc2nnc([C@@H]3CCCN3C(=O)OC(C)(C)C)o2)cc1OC
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a toluene (700 ml) solution of the compound (61.0 g) obtained in Example 8-(1), Burgess reagent (45.0 g) was added and the mixture was stirred at 120° C. for 4 hours. After adding water to the reaction mixture, the organic layer extracted with AcOEt was dried (Na2SO4), filtered and had the solvent distilled off under reduced pressure; the resulting residue was purified by silica gel chromatography (AcOEt) to give the titled compound (42.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH:2]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCC1>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1
Reactant: COc1ccc(C=O)cc1-c1cccnc1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: C1CCNC1
Solvent: CCO
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1-c1cccnc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A mixture of 3-(3-pyridyl)-4-methoxybenzaldehyde (0.25 g), 5-chloro-2-oxindole (0.2 g) and pyrrolidine (0.5 ml) in ethanol (2 ml) was placed in a sealed tube and heated to 100° C. A precipitate formed within 10 minutes so the reaction was diluted with another 10 ml of ethanol and heating resumed. After 4 hours, the reaction was cooled and the solid was removed by filtration and washed with ethanol and then hexanes to afford 0.27 g (61%) of 5-chloro-3-(3-(3-pyridyl)-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[C:42]=1[Cl:43])=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[C:42]=1[Cl:43])=[O:32])[CH3:26]
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1Cl
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Temperature: 95 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
0.649 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.53 g of N-(3,6-dichloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 7 ml of 1-methyl-2-pyrrolidone; 0.345 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (185:15:2). The desired fraction was collected and recrystallized from ethyl acetate to yield 0.711 g of the title compound.
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:49]([O:51][CH:52]([Cl:56])[CH:53](C)C)=[O:50]>C(Cl)Cl.C(OCC)(=O)C.O>[Cl:56][CH:52]([O:51][C:49]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:50])[CH3:53]
Reactant: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2=O)cc1
Reactant: CC(C)C(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCN(C(=O)OC(C)Cl)CC3)CC2=O)cc1
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 77.7 %

Procedure:
To a solution of 0.75 g of ethyl 4-[[2-oxo-4-(piperidin-4-yl)-piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in 16 ml of methylene chloride was added 1.11 g of proton sponge under ice-cooling. After stirring for 5 minutes, the mixture was cooled to −40° C., and a solution of 0.322 g of 1-chloro-2-methylpropyl chloroformate in 2 ml of methylene chloride. After stirring for 45 minutes, the reaction mixture was diluted with ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layer collected was washed with saturated aqueous saline, dried over sodium sulfate, and the solvent was removed by distillation. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1-40:1) to give 0.624 g (74%) of ethyl 4-[[4-[1-(1-chloroethoxycarbonyl)piperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:41]=[CH:40][C:17]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=3)[C:30]([NH:32][CH:33]3[CH2:36][CH2:35][CH2:34]3)=[O:31])[CH2:22][CH2:21]2)=[O:19])=[CH:16][C:15]=1[F:42].C(N(C(C)C)C(C)C)C.[CH3:52][C:53]([CH3:57])([CH3:56])[CH2:54][NH2:55]>ClCCl>[CH:33]1([NH:32][C:30](=[O:31])[C:29]2[CH:37]=[CH:38][CH:39]=[C:27]([CH2:26][N:23]3[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]4[CH:40]=[CH:41][C:14]([NH:13][C:1]([NH:55][CH2:54][C:53]([CH3:57])([CH3:56])[CH3:52])=[O:12])=[C:15]([F:42])[CH:16]=4)[CH2:21][CH2:22]3)[CH:28]=2)[CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC4CCC4)c3)CC2)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC4CCC4)c3)CC2)cc1F
Reaction time: 1 h
Yield: 153.5 %

Procedure:
To a stirred solution of bis(trichloromethyl) carbonate (0.331 mmol, 98 mg) in dichloromethane (10 mL) was added a solution of 3-((4-(4-amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-cyclobutylbenzamide (0.974 mmol, 400 mg) and N-ethyl-N-isopropylpropan-2-amine (2.144 mmol, 0.354 mL, 277 mg) in dichloromethane (10 mL) (dropwise). The reaction mixture was stirred for 1 hour then 2,2-dimethylpropan-1-amine (1.169 mmol, 0.137 mL, 102 mg) was added. The reaction mixture was stirred for 20 hours. Chromatography on silica (eluting with dichloromethane to dichloromethane/methanol (1% to 3%)) gave the title compound (266 mg).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:27][CH3:28])[CH2:5][CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([N+:16]([O-])=O)=[C:11]3[Se:19][C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=4[C:9]([C:10]=23)=[N:8]1)[CH3:3].Br[CH2:30][CH2:31][N:32]1C(=O)C2=CC=CC=C2C1=O.[Cl:43]CCCl.C(N(C(C)C)CC)(C)C>[Pd].CN(C)C=O.ClCCl>[ClH:43].[ClH:1].[ClH:43].[NH2:32][CH2:31][CH2:30][NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:7]([CH2:6][CH2:5][N:4]([CH2:27][CH3:28])[CH2:2][CH3:3])[N:8]=[C:9]3[C:21]4[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:20]=4[Se:19][C:11]=1[C:10]=23
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)[Se]c1ccc(O)cc1-2
Reactant: ClCCCl
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)[Se]c1ccc(O)cc1-2
Temperature: 110 °C
Reaction time: 13 h

Procedure:
A suspension of 4.28 g (0.009 mole) of 2-[2-(diethylamino)ethyl]-5-nitro-2H-[1]benzoselenino[4,3,2-cd]indazol-9-ol, hydrochloride and 0.650 g of 20% palladium on carbon in 100 ml N,N-dimethylformamide is hydrogenated at atmospheric pressure for 13 hours. An additional 0.25 g of catalyst is added and the hydrogenation continues for another 24 hours. The mixture is filtered through a Celite pad and the filtrate is concentrated in vacuo to 4.74 g of a dark orange-brown oil. To this oil is added 2.67 g (0.011 mole) of N-(2-bromoethyl)phthalimide and the mixture is heated under argon in a 110° C. oil bath for 20 hours. To the resulting solid is added 200 ml of 1,2-dichloroethane and 3.3 ml of diisopropylethylamine. The mixture is heated under reflux in an argon atomosphere for two hours, diluted further with dichloromethane, and washed once with a saturated solution of aqueous sodium bicarbonate. The organic layer is separated, dried over sodium sulfate, filtered, and concentrated to a crude solid. The solid is dissolved in dichloromethane and filtered through a small column of Florisil with a 1:9 (v/v) solution of methanol and 1,2-dichloroethane. The effluent is concentrated and the resulting solid is triturated with hot 2-propanol to give 1.98 g of the dried product; mp 203°-205° C.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.Cl>C1(C)C=CC=CC=1.C1COCC1>[NH2:1][C@@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1N
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (3R,4R)-4-azido-1-benzylpyrrolidin-3-ylcarbamate (7.0 g, 22.0 mmol) in 250 mL toluene, PPh3 6.0 g, 23.0 mmol) was added and the mixture was refluxed for 1 hour. The mixture was cooled down to room temperature, diluted with 250 mL THF, water (0.54 g, 30.0 mmol) was added and the mixture was refluxed for an additional 1 hour. 4N HCl was added, the aqueous acidic layer was separated, washed with CHCl3 and basified with aqueous NH3 to pH 9-10. The product was extracted with CHCl3, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 10% MeOH in CHCl3 giving the title mono-Boc protected diamine.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH:10]1[CH:11]=[CH:12][C:13]2[NH:18][CH:17]=[C:16]([CH2:19][CH2:20][OH:21])[C:14]=2[CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]1([CH3:5])[C:17]2[NH:18][C:13]3[C:14]([C:16]=2[CH2:19][CH2:20][O:21]1)=[CH:15][CH:10]=[CH:11][CH:12]=3)[CH3:9]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Reaction time: 0.17 h

Procedure:
Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for thirty minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 21/2 hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid ethyl ester, as an oil, γmaxCHCl3 1715 cm-1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][CH2:2][CH2:3][C:4]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[C:10]([O:15][CH3:16])[CH:11]=1)=[O:5]
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCCl)cc1OC

Procedure:
Further, Patent Document 2 discloses that 3-chloropropionyl chloride was reacted with 1,2-dimethoxybenzene in the presence of aluminum chloride to produce 3-chloro-3′,4′-dimethoxypropiophenone in situ. To the reaction mixture concentrated sulfuric acid was added and the reaction was allowed to proceed at 70° C. The resulting product was then purified by silica gel column chromatography to give 5,6-dimethoxy-1-indanone with a yield of 40%. However, silica gel chromatography as used in the above method is a cumbersome method, and further, a problem of the above method is low yield.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH:7]2[C:5]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)([CH2:6]2)[CH2:4]1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>C(O)C>[CH:1]([N:3]1[CH2:8][CH:7]2[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:22][CH3:23])=[CH:11][CH:10]=3)([CH2:6]2)[CH2:4]1)=[O:2]
Reactant: CCI
Reactant: O=CN1CC2CC2(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccc(C23CC2CN(C=O)C3)cc1
Yield: 27.2 %

Procedure:
To a stirred mixture of 1.0 g of 3-formyl-1-(p-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane and 0.7 g of potassium carbonate in 25 ml of absolute ethanol is added a solution of 3.2 g of ethyl iodide in 10 ml of absolute ethanol. The mixture is refluxed for 2 hours and then is filtered and evaporated. The residual mixture of crystals and liquid is combined with water and this is extracted with chloroform and the extract is dried over magnesium sulfate and evaporated to give 1.0 g of a colorless, viscous liquid, which crystallizes on standing. Recrystallization from hexane gives 0.31 g of 3-formyl-1-(p-ethoxyphenyl)-3-azabicyclo[3.1.0]hexane as colorless crystals, m.p. 48°-51° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[N:13]=[CH:14][CH:15]=[CH:16][C:7]1=2)=[O:5].O.O.[Cl-]>CO>[NH2:21][C:19]1[CH:18]=[CH:17][C:3]([C:4]([N:6]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3[N:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)=[O:5])=[C:2]([Cl:1])[CH:20]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2ncccc21
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Nc1ccc(C(=O)N2CCCCc3ncccc32)c(Cl)c1
Yield: 85.7 %

Procedure:
A mixture of 3.31 g of 6,7,8,9-tetrahydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrido[3,2-b]azepine and 6.78 g of stannus chloride dihydrate (SnCl2.2H2O) in 200 ml of methanol is refluxed for 2 hours under argon. The solvent is removed under vacuum and 5 ml of saturated NaHCO3 solution and solid NaHCO3 added to bring the pH to 7. The mixture is extracted with ethyl acetate, the extract filtered through diatomaceous earth and the filtrate washed with saturated NaHCO3, H2O, brine and dried (Na2SO4). The filtrate is passed through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness to give 2.58 g of an amorphous solid. Anal. Calc'd for C16H16ClN3O; C,59.9; H,5.7; N,13.1; C1, 11.1 Found: C,60.5; H,5.0; N,12.9; Cl,11.6.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]=[C:7]([OH:15])[C:6]([OH:16])=[N:5]2.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:15][C:7]1[C:6]([OH:16])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=2)[N:8]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cc2nc(O)c(O)nc2cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc2nc(O)c(O)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A mixture of 500 mg (1,9 mmol) 6-brom-2,3-dihydroxy-7-nitroquinoxaline (ex. 1) in 10 ml dry dimethylformamide and 20 ml dry triethylamine is added 4 mg palladium(II)acetate, 8 mg triphenylphosphine and 600 l (4,3 mmol) trimethylsilylacetylene. The mixture is refluxed for 2.5 h under nitrogen. After cooling to room temperature, the reaction mixture is evaporated in vacuo. The residue is stirred with water, filtered and washed with water to give 500 mg of a crude product. The crude product is dissolved in ethyl acetate and purified by column chromatography (silica gel) to give 400 mg (70%) of 2,3-dihydroxy-6-trimethylsilylethynyl-7-nitroquinoxaline.