Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([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>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:9]2[C:8]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]3[CH3:1])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=3)[N:10]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3C)nc2c1
Reactant: OB(O)c1ccc(F)cc1
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: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCC3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a solution of methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (880 mg, crude) in dioxane (25 ml) was added Pd(PPh3)4 (100 mg, 0.09 mmol), 4-fluorophenylboronic acid (485 mg, 3.47 mmol), K3PO4 (735 mg, 3.46 mmol) and water (3 ml). The resulting solution was stirred for 1 hour at 90° C. under an inert atmosphere of nitrogen, and then concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1%-10% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (330 mg).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]2=[CH:15][N:16]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=4)[CH:24]=[C:17]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]2[CH:12]=[N:11]1.O>CN(C)C=O>[Cl:1][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[C:30]2[C:25]=1[CH:24]=[C:17]1[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]3=[CH:15][N:16]12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1N=CN2C1=Cn1c(cc3ccc(Cl)cc31)-c1ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: CN1N=CN2C1=Cn1c(cc3c(Cl)cc(Cl)cc31)-c1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
A solution of 1.91 g N-chlorosuccinimide in 45 ml dimethylformamide was added dropwise to a solution of 3.33 g 1-methyl-12-chloro-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine in 100 ml dimethylformamide. The reaction mixture was stirred for three hours at room temperature. Upon addition of water and stirring overnight, a solid precipitated. This was collected, triturated with hexane and dried to yield 1.72 g. Recrystallization from methanol/water yielded 1.17 g solid;
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@@H:6]1[NH:14]C(=O)OC(C)(C)C)=[O:4].C(O)C>C(Cl)Cl.[Br-].[Br-].[Zn+2]>[NH2:14][C@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C@H:5]1[C:3]([N:2]([CH3:22])[CH3:1])=[O:4]
Reactant: CN(C)C(=O)[C@@H]1Cc2ccccc2[C@@H]1NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=O)[C@@H]1Cc2ccccc2[C@@H]1N
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a stirred solution of tert-butyl rel-{(1R,2R)-2-[(dimethylamino)carbonyl]-2,3-dihydro-1H-inden-1-yl}carbamate (690 mg, 2.15 mmol) in DCM (25.0 mL) was added zinc dibromide (970 mg, 4.31 mmol) and ethanol (0.25 mL, 4.31 mmol), and the mixture was stirred for 18 h. The reaction mixture was quenched by addition of water (20.0 mL) and the resulting mixture was stirred for 2 h. To this mixture was added 1.00 M NaOH (30.0 mL) and extracted with DCM (3×100 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by flash chromatography (10 to 30% Methanol/DCM) to afford the title compound (438 mg, 95%) as a colorless oil. LC/MS: Rt=0.89 min, ES+ 205.2 (AA standard).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][CH:5]([CH2:7][CH2:8][CH2:9][CH:10]([CH2:12][CH:13]=[O:14])[CH3:11])[CH3:6]>CN(C)C=O>[CH3:11][C:10](/[CH:9]=[CH:8]/[CH2:7][CH:5]([CH3:4])[CH2:6][CH2:8][CH2:7][CH:5]([CH3:6])[CH3:4])=[CH:12][C:13]([O:2][CH3:1])=[O:14]
Reactant: CC(C)CCCC(C)CC=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=C(C)/C=C/CC(C)CCCC(C)C
Reaction time: 3 h

Procedure:
Sodium methoxide (1.2 g. of sodium and 30 ml. of methanol) is added slowly to a mixture of 5 g. of dihydrocitronellal and 10 g. of diethyl 3-methoxycarbonyl-2-methylprop-2-enyl phosphonate (about 77% trans) in 50 ml. of dimethylformamide, under nitrogen and at about 0°, with stirring. After addition is complete, the reaction is left three hours at room temperature and then worked up by extraction with hexane/ether to yield cis/trans methyl 3,7,11-trimethyldodeca-2,4-dienoate, mostly the trans,trans isomer.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>O.CO.C1COCC1>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:2])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
Sodium periodate (1.23 g, 5.76 mmol) in water (2.0 mL) was added to a solution of the above thioether (1.08 g, 4.80 mmol) in methanol/THF (2:1, 15 mL). The mixture was stirred at 50° C. for 24 h, then the solvent was concentrated in vacuo. The residue was diluted with diethyl ether and washed with water and saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the crude product by silica-gel chromatography (methylene chloride—50% ethyl acetate in methylene chloride) provided 4-tert-butyl-1-methanesulfinyl-2-nitro-benzene (1.05 g, 91%) as a white solid.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])[C:4]=2[CH2:3][S:2]1(=O)=O.C[Al](C)C.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH:30][C:31](=O)[O:32]C)[N:23]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([O:21][CH3:20])[N:23]=[C:24]([NH:30][C:31]([NH:13][S:10]([C:9]2[C:4]3[CH2:3][S:2][CH2:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])=[O:32])[N:25]=1
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Reactant: NS(=O)(=O)c1cccc2c1CS(=O)(=O)C2
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccc3c2CSC3)n1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
A suspension of 0.74 g of the sulfonamide prepared in Example 13 in 50 ml of methylene chloride was cooled to 10° to 15° under nitrogen, and 1.7 ml of a 2M solution of trimethylaluminum in toluene was added slowly. The suspension was allowed to warm to room temperature, 0.67 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate was added, and the reaction mixture was heated at reflux overnight. The turbid solution was cooled to 0°-5° and 50 ml of 5% hydrochloric acid was added dropwise. The two-phase suspension was allowed to warm to ambient temperature, then filtered. The solid was washed with 1-chlorobutane and dried giving 0.31 g of 1,3-dihydro-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzo[c]thiophene-4-sulfonamide, 2,2-dioxide, m.p. 170°-173°(d).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>CN(C=O)C.O>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:18][CH:19]=1)=[O:22]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 70 °C
Yield: 84.3 %

Procedure:
K2CO3 (450 mg, 3.27 mmol) and 6-chloronicotinonitrile (270 mg, 1.97 mmol) were added to 4-hydroxy-benzaldehyde (200 mg, 1.64 mmol) in DMF (2 mL) and the resulting mixture was heated to 70° C. for 3 hrs. The reaction mixture was then diluted with water and the resulting was filtered and dried to afford 310 mg (79.1% yield) of 6-(4-formyl-phenoxy)nicotinonitrile. LCMS Purity: 97.3%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](C=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-:13].[K+].C(Br)(Br)Br.[OH-].[K+].CO.[O:23]1[CH2:28][CH2:27][O:26][CH2:25]C1>CO>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:27]([O:26][CH3:25])[C:28]([OH:23])=[O:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: [OH-]
Reactant: C1COCCO1
Agent: [K+]
Solvent: CO
Solvent: BrC(Br)Br
Product: COC(C(=O)O)c1ccc(OC(C)C)cc1
Reaction time: 18 h

Procedure:
An oven-dried flask was charged with 4-isopropoxybenzaldehyde (4.9 g, 29.9 mmol), anhydrous methanol (30 mL) and anhydrous dioxane (30 mL) then fitted with an addition funnel. The addition funnel was charged with a solution of KOH (8.4 g, 149.5 mmol) in anhydrous methanol (30 mL) and an aliquot (˜2 mL) was added to the reaction mixture. Bromoform (3.4 mL, 38.8 mmol) was added to the reaction mixture then the remaining KOH/MeOH solution was added dropwise over 10 minutes. After stirring for 18 hours, the mixture was concentrated in vacuo. The residue was diluted with water and the pH was adjusted to ˜2 using concentrated HCl then extracted with EtOAc. The combined organics were dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo gave 2-(4-isopropoxyphenyl)-2-methoxyacetic acid as a light yellow solid (6.8 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[SH:9])=[CH:4][CH:3]=1.Br[C:13]1C=CC(C(O)(C)C)=CC=1.[P:23]([S-:29])(=[S:28])([O:26][CH3:27])[O:24][CH3:25].[K+]>>[P:23]([S:29][CH2:13][S:9][C:8]([CH3:11])([CH3:10])[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[S:28])([O:26][CH3:27])[O:24][CH3:25]
Reactant: CC(C)(O)c1ccc(Br)cc1
Reactant: CC(C)(S)c1ccc(Br)cc1
Reactant: COP(=S)([S-])OC
Agent: [K+]
Product: COP(=S)(OC)SCSC(C)(C)c1ccc(Br)cc1

Procedure:
Using p-bromo-α,α-dimethyl-α-toluenethiol prepared from p-bromo-α,α-dimethylbenzyl alcohol by the procedure of Example 1, and using potassium O,O-dimethyl phosphorodithioate in place of potassium O,O-diethyl phosphorodithioate, the procedure of Example 6 gives the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]3=[CH:12][S:13][C:14](=S)[N:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:16].C(I)C.C(#N)C.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(N(CC)CC)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]3=[CH:12][S:13][C:14](=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])[N:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:16]
Reactant: Fc1ccc2c(c1F)OCc1csc(=S)n1-2
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CC#N
Solvent: CCI
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)=C1SC=C2COc3c(ccc(F)c3F)N21
Reaction time: 5 h
Yield: 63.8 %

Procedure:
6,7-Difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazine-1-thione (0.4 g) prepared in Reference Example 18 and ethyl iodide (1.9 g) were added to acetonitrile (10 ml) and the mixture was stirred at 75° to 78° C. for 5 hours. Then diethyl malonate (0.5 g) and triethylamine (0.62 g) were added and the mixture was refluxed for 24 hours. After the reaction mixture was evaporated to dryness under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silica-gel column chromatography (Silica gel 60, 230-400 meshes, made by Merck Co., 130 g, eluent; chloroform) under medium pressure and recrystallized from a mixed solvent of hexane-ethyl acetate to give the title compound (0.38 g) as pale yellow crystals. The compound had physical properties identical to those of diethyl (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate prepared in Reference Example 6.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[C:23](=[O:26])([O-:25])[O-].[Cs+].[Cs+].[C:29]([O:33]CC)(=[O:32])[CH:30]=[CH2:31]>C(#N)C.CN(C=O)C.O>[C:29]([OH:33])(=[O:32])[C:23]([OH:25])=[O:26].[CH:18]1[C:19]2[C:20]3[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=3[N:13]3[C:14]=2[C:15]([C:29](=[O:32])[CH2:30][CH2:31]3)=[CH:16][CH:17]=1
Reactant: C=CC(=O)OCC
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccccc3c2CC1
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C(=O)O
Product: O=C1CCn2c3c(c4cccc1c42)CCNCC3
Temperature: 50 °C
Yield: 166.8 %

Procedure:
A mixture of 3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5.00 g, 17.2 mmol), cesium carbonate (5.61 g, 17.2 mmol), and ethyl acrylate (1.90 mL, 17.5 mmol) in acetonitrile (250 mL) was heated under N2 at 50° C. for 5 h (reaction can also be run in DMF at room temperature). Cooled to room temperature, diluted with H2O, and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with EtOAc/hexanes (2:1) to give 4.82 g (72%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 7.57-7.38, 7.32, 7.23-7.07, 4.49-4.33, 4.20-4.02, 3.77-3.66, 3.28-3.13, 2.94, 2.72, 1.24; IR (liq.) 2981, 1731, 1631, 1467, 1445, 1422, 1381, 1368, 1349, 1319, 1295, 1272, 1242, 1187, 742, 707 cm−1; MS (ESI) 391.0 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C[CH2:12][C:13](=O)[C:14]([O-:16])=[O:15].N1CCCC[CH2:19]1>CO>[CH3:19][O:16][C:14]([C:13]1[CH:12]=[CH:4][C:3]2[C:2](=[CH:9][C:8]([NH2:10])=[CH:7][CH:6]=2)[N:1]=1)=[O:15]
Reactant: CCC(=O)C(=O)[O-]
Reactant: C1CCNCC1
Reactant: Nc1ccc(C=O)c(N)c1
Solvent: CO
Product: COC(=O)c1ccc2ccc(N)cc2n1

Procedure:
For example, 2,4-diaminobenzaldehyde 24.7 (Apin Chemicals) is reacted with one molar equivalent of methylpyruvate 24.2 in methanol, in the presence if a base such as piperidine, to afford methyl-7-aminoquinoline-2-carboxylate 24.8. Basic hydrolysis of the product, employing one molar equivalent of lithium hydroxide in aqueous methanol, then yields the carboxylic acid 24.9. The amino-substituted carboxylic acid is then converted into the diazonium tetrafluoborate 24.10 by reaction with sodium nitrite and tetrafluoboric acid. The diazonium salt is heated in aqueous solution to afford the 7-hydroxyquinoline-2-carboxylic acid, 24.11, Z=OH. Alternatively, the diazonium tetrafluoborate is heated in aqueous organic solution with one molar equivalent of cuprous bromide and lithium bromide, to afford 7-bromoquinoline-2-carboxylic acid 24.11, X=Br. Alternatively, the diazonium tetrafluoborate 24.10 is reacted in acetonitrile solution with the sulfhydryl form of an ion exchange resin, as described in Sulfur Lett., 2000, 24, 123, to prepare 7-mercaptoquinoline-2-carboxylic acid 24.11, Z=SH.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:44](COCC[Si](C)(C)C)[CH:43]=[N:42][C:5]=2[C:6]([CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:12][C:11]=1[C:29]([F:32])([F:31])[F:30])#[N:2].O.C(=O)(O)[O-:55].[Na+]>S(=O)(=O)(O)O>[Cl:41][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([Cl:40])[C:34]=1[CH2:33][C:6]1[C:5]2[N:42]=[CH:43][NH:44][C:4]=2[C:3]([C:1]([NH2:2])=[O:55])=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[CH:12][C:11]=2[C:29]([F:31])([F:32])[F:30])[N:7]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)c4ncn(COCC[Si](C)(C)C)c4c3C#N)c(C(F)(F)F)c2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Nc2ccc(N3CCNCC3)cc2C(F)(F)F)nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c12
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product of Example 22B (150 mg, 0.2 mmol) in concentrated sulfuric acid (5 mL) was added water (1 mL) at 0° C. and the mixture was stirred at 95° C. for 20 minutes. After cooling to ambient temperature, water (3 mL) was added. The mixture was adjusted to pH 8-9 with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3×20 mL). The organic layers were concentrated and the residue was purified by preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 13.51 (br, 1 H), 11.64 (s, 1 H), 9.52 (br, 1 H), 8.80 (s, 2 H), 8.61(s, 1 H), 7.81 (s, 1-H), 7.62 (d, J=9 Hz, 1 H), 7.56-7.53 (m, 2 H), 7.43-7.41 (m, 1 H), 7.07 (d, J=2.1 Hz, 1 H), 6.72 (dd, J=9, 2.1 Hz, 1 H), 4.83 (s, 2H), 2.75-2.67 (m, 8 H). MS: 564 (M+H+).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([CH:13]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18](=[O:23])[CH:17]([O:24][SiH:25]([CH3:27])[CH3:26])[CH2:16][CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].Cl>O1CCCC1.CCOCC>[C:1]1([C:18]2([OH:23])[CH2:19][CH2:20][CH2:21][CH2:22][CH:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[CH2:14][CH2:15][CH2:16][CH:17]2[O:24][SiH:25]([CH3:27])[CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C[SiH](C)OC1CCCC(C(C)(C)C)CCCCC1=O
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[SiH](C)OC1CCCC(C(C)(C)C)CCCCC1(O)c1ccccc1
Temperature: 40 °C

Procedure:
21 ml of a solution (1.0 M) of phenylmagnesium bromide in tetrahydrofuran was dissolved in 50 ml of anhydrous ether, and to the solution was added 1.5 g of the above product (b). The reaction solution was stirred at 40° C. for three and a half hours. The reaction solution was poured into ice water and adjusted to pH 4 by addition of 2N HCl, and extracted with ether. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was subject to column chromatography on silica gel, and the eluate with ethyl acetate-hexane (1:20) was collected, to afford 1.1 g of the titled compound (c) as a colorless oily matter.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13](O)(=O)[CH3:14].[CH3:17][N+:18](C)=[CH2:19].[I-]>C1(C)C=CC=CC=1>[CH3:17][N:18]([CH3:19])[CH2:13][CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: C=[N+](C)C
Reactant: CC(=O)O
Agent: [I-]
Solvent: Cc1ccccc1
Product: CN(C)CCc1c[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
Warm mixture of 5-nitroindole (10 g, 62 mmol) and 200 mL glacial acetic acid to 70° C. and treat with Eschenmoser's salt (12 g, 65 mmol). Concentrate after 1 hour the reaction under vacuum to dryness. Mix the residue with 200 mL toluene, reconcentrate to dryness then partition between 200 mL concentrated ammonium hydroxide and 200 ml, EtOAc. When all solids dissolved, Separate the layers and extract the aqueous layer 200 mL EtOAc. Dry the combined organic layer over MgSO4 and concentrate to give N,N-dimethyl-5-nitrotryptamine as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=[N:11]1.[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OCC)C>CN(C)C=O.O>[Cl:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:10]2[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([C:18]([F:20])([F:21])[F:19])[CH:12]=[N:11]2)=[CH:4][C:5]=1[O:9][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)COc1cc(-n2ncc(C(F)(F)F)c(C)c2=O)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
Then, 3.2 g (9.9 mmol) of 2-[2-fluoro-4-chloro-5-hydroxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one was dissolved in about 50 ml of N,N-dimethylformamide, to which 0.44 g (11 mmol) of sodium hydride (60 wt % oil dispersion) was added at room temperature. The mixture was left stand at room temperature for 30 minutes and then cooled with ice, to which 1.8 g (11 mmol) of ethyl bromoacetate was added. The mixture was stirred at room temperature for 1 hour, to which diethyl ether and water were added in this order to make an extraction. The organic layer was washed with 10% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure, and the residue was subjected to silica gel column chromatography, which afforded 2.4 g (5.5 mmol) of ethyl 2-chloro-4-fluoro-5-(4-methyl-5-trifluoromethyl-3-pyridazinon-2-yl)phenoxyacetate (compound [1] wherein R is ethyl; hereinafter referred to as compound A), m.p., 102.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([N:13]=[C:14](Cl)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC(C=CS(N)(=O)=O)=CC=1)([O-])=[O:25].C(Cl)(=O)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([NH:13][C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(C=CS(=O)(=O)N=C(Cl)c2ccccc2)cc1
Solvent: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 76 %

Procedure:
N-(4-Nitrostyrylsulfonyl)benzimidoyl chloride. A mixture of 4-nitrostyrylsulfonamide (18.2 g., 0.08 mole), benzoyl chloride (12.6 g., 0.09 mole) and phosphorus oxychloride (13.8 g., 0.09 mole) is heated at steam bath temperature for 1.5 hr. The reaction mixture diluted with 20 ml. of ethyl acetate, cooled and filtered affords 19.0 g. (76% yield) of N-(4-nitrostyrylsulfonyl)benzamide, m.p. 192°-195° C., from ethyl acetate-hexane.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:13]1([CH3:16])[CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.[C:17]([NH:24][C@@H:25](C(O)=O)[C:26]([CH3:29])(C)C)(OC(C)(C)C)=O.[CH2:33]([N:35]1[CH:39]=[C:38]([C:40]2[N:45]=[C:44]3[C:46](C(O)=O)=[CH:47][N:48](COCC[Si](C)(C)C)[C:43]3=[N:42][CH:41]=2)[CH:37]=[N:36]1)[CH3:34]>>[CH3:16][C:13]1([C@@H:9]([NH:8][C:6]([C:46]2[C:44]3[C:43](=[N:42][CH:41]=[C:40]([C:38]4[CH:37]=[N:36][N:35]([CH2:33][CH3:34])[CH:39]=4)[N:45]=3)[NH:48][CH:47]=2)=[O:7])[C:10](=[O:12])[N:24]2[CH2:17][CH2:29][CH2:26][CH2:25]2)[CH2:14][CH2:15]1
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1(C)CC1
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCCC4)C4(C)CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting (R)-tert-butoxycarbonylamino-(1-methyl-cyclopropyl)-acetic acid for Boc-D-tert-leucine and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2, 3-1)]pyrazine-7-carboxylic acid. MS: (M+H)+=422.