Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[C:18]([CH2:28]O)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].CS(Cl)(=O)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl.C(N(CC)CC)C.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([C:22]#[C:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:19]=[C:18]([CH2:28][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C#C[Si](C)(C)C)cc(CO)c1
Reactant: C1CCNC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C#C[Si](C)(C)C)cc(CN2CCCC2)c1
Reaction time: 8 h

Procedure:
398 mg of the ethyl (RS)-(4-cyano-phenylamino)-(3-hydroxymethyl-5-trimethylsilanylethynyl-phenyl)-acetate described in Example 156.3 were dissolved in 6 ml of CH2Cl2 g and 0.41 ml of triethylamine followed by 0.1 ml of methanesulphonyl chloride were added dropwise at 0° C. The mixture was stirred overnight and an intermediate was then isolated by extraction. This was taken up in 5 ml of THF and stirred together with 0.41 ml of triethylamine and 0.32 ml of pyrrolidine. By repeat extraction there was obtained a crude product, which was purified by column chromatography (cyclohexan/ethyl acetate). There were obtained 130 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-trimethylsilanylethynyl-phenyl)-acetate as a light brown solid; MS: 460 ([M]+).
Reaction SMILES: FC(F)(F)C(O)=O.CN(C)[CH:10]=[C:11]([N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)[C:12](OCC)=[O:13].[CH:23]1([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([NH:39][NH2:40])[N:36]=[CH:35][N:34]=3)[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH:23]1([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[N:34]=[CH:35][N:36]=[C:37]([N:39]4[C:12](=[O:13])[C:11]([N:17]5[CH:21]=[CH:20][N:19]=[N:18]5)=[CH:10][NH:40]4)[CH:38]=3)[CH2:31][CH2:32]2)[CH2:24][CH2:25][CH2:26]1
Reactant: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid are added to a mixture of 211 mg (1.0 mmol) of the compound from Example 8A and 250 mg (1.0 mmol) of the compound from Example 9A in 4 ml of ethyl acetate, and the mixture is stirred at 100° C. for 20 h. The reaction mixture is concentrated under reduced pressure, more ethyl acetate and trifluoroacetic acid (the same amounts as above) are added and the mixture is stirred at 100° C. for 3 d. The reaction mixture is cooled to RT, and the precipitated solid is filtered off and washed with diethyl ether. The residue is suspended in 2 ml of water, dissolved by adding aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 195 mg (51% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:12][CH3:11])[CH:5]=[O:6]
Reactant: C[S-]
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
A solution of 3-chloro-4-fluorobenzaldehyde (50.0 g) in N,N-dimethylformamide (350 mL) was cooled to −10° C., and sodium methanethiolate (25 g) was added. The reaction solution was warmed to room temperature, and stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (33.6 g, yield 59%) as colorless crystals. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-30:70, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (12.3 g, yield 21%) as colorless crystals. melting point 58-59° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1[C:18]2[CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=O)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].[H][H]>C1COCC1>[CH:7]1[C:18]2[CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1Nc2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCc1ccccc1NC2
Temperature: 25 °C
Yield: 98.5 %

Procedure:
In a two liter three neck round bottom flask (argon atmosphere) was placed 300 ml of dry THF and 30.06 g (0.8 mole) of LAH was added cautiously. The reaction mixture was stirred and a suspension of 89.31 g (0.4 mole) of 11,12-dihydrodibenz[b,f]azocin-6(5H)-one (Aldrich) in 400 ml of hot THF was added dropwise. After the addition, the reaction mixture was stirred and heated to reflux for 8.5 hr. The reaction mixture was cooled to RT and 60 ml of 1N sodium hydroxide was added with caution (hydrogen evolution). The reaction mixture was stirred and heated to reflux for 0.5 hr to give a white suspension. The solid was removed by filtration and washed with several portions of warm THF. The filtrate was concentrated to dryness in vacuo to give 82.5 g of white solid title compound of 99.5% purity by g.c. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19](Cl)=[CH:18][N:17]=[C:16]([NH:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]4[CH3:31])[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:32]NC(C1C2C=C(C3C(C)=CN=C(Cl)N=3)SC=2C=CC=1)=O.C(OC(N1CCN(CCCN)[C@@H](C)C1)=O)(C)(C)C>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([CH3:32])=[CH:18][N:17]=[C:16]([NH:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]4[CH3:31])[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3C)cc12
Agent: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1CCCN
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@@H]4C)ncc3C)cc12

Procedure:
Using the method of (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and (S)-4-(3-aminopropyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 439 [M+H].
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:24]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(N(Cc4ccccc4)Cc4ccccc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 559.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]2[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]2)=[CH:3][CH:2]=1.[BrH:26].C(O)(=O)C>>[BrH:26].[C:1]1([CH3:25])[CH:2]=[CH:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCC(c2ccccc2Sc2ccc(C)cc2)CC1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(Sc2ccccc2C2CCNCC2)cc1
Temperature: 80 °C

Procedure:
The crude ethyl 4-(2-(4-tolylsulfanyl)phenyl)-piperidin-1-carboxylate as a red oil from example 3 was mixed in a stirred reactor with hydrobromic acid in acetic acid (40%, 545 mL, 3.11 mol). The mixture was heated at 80° C. for 18 hours. The reaction mixture was cooled down to room temperature. During the cooling the product crystallises out. After 1 hour at room temperature ethyl ether (800 mL) was added to the reaction mixture, and the mixture was stirred for another hour. The product was filtered off, washed with ethyl ether and dried in a vacuum oven at 50° C. until constant weight.
Reaction SMILES: CC(C)=O.S([O-])([O-])(=O)=O.[Mg+2].P(O)([O-])([O-])=O.[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[Na+].[OH:24][CH:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][O:28][C:27]2[CH:36]=[CH:37][C:38]([CH2:40][CH2:41][O:42][C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:39][C:26]1=2>CO.O>[O:24]=[C:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][O:28][C:27]2[CH:36]=[CH:37][C:38]([CH2:40][CH2:41][O:42][C:43]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:39][C:26]1=2
Reactant: OC1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: O=C1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 80.3 %

Procedure:
In this process, 10 g of 11-hydroxy-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in a solution comprising 800 ml of acetone, 1000 ml of water, 20 ml of saturated aqueous magnesium sulfate solution and 0.2 g of disodium phosphate. To the solution is dropwise added 2.6 g of aqueous sodium permanganate solution and the mixture is stirred at room temperature for 4.5 hours. Then, 100 ml of methanol is added thereto and the mixture is heated at reflux for 3 hours. After allowing the mixture to stand for cooling, the mixture is filtered and the filtrate is extracted with 1000 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the resultant crude product is recrystallized from isopropanol to obtain 8.0 g of the desired product having melting point of 132-134° C. as a white crystal.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[C:21]1([NH:20][S:9]([C:8]2[CH:13]=[CH:14][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:11])=[O:10])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Acetylsulfanilyl chloride 1 (55 g, 236 mmol) was added in portion to a stirring, 0° C. suspension of sodium acetate (48.4 g, 590 mmol) and aniline 2 (22 mL, 236 mmol) in ethanol (300 mL). The reaction mixture was stirred at room temperature overnight and then poured into ice-cold water (1.5 L) with vigorous stirring. After stirring for 1 h, the white solid that gradually precipitated was collected by filtration. The filter cake was washed with ice-cold water, dried under vacuum, and recrystallized from hot ethanol to give N-[4-[(phenylamino)sulfonyl]phenyl]acetamide (3) (also called 137-19 or LED137) (41 g, 60%) as a white solid, mp 209-210° C. 1H NMR (CD3OD, 400 MHz) δ 7.64 (br s, 4H), 7.18 (t, J=7.6 Hz, 2H), 7.06-7.00 (m, 3H), 2.10 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(I)cc2)CC1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
4-Iodobenzoyl chloride (7.99 g) and piperazine-1-carboxylic acid tert-butyl ester (5.87 g) were dissolved in tetrahydrofuran (75 ml), 1N aqueous sodium hydroxide solution (36 mL) was added, and the mixture was stirred at room temperature. The reaction mixture was poured into water under cooling and 1N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, then washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. To the residue was added hexane and the mixture was stirred at room temperature. The crystals were collected by filtration to give the title compound (11.67 g).
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][C:13]#[N:14].C(OCC)(=O)C.Cl.O1CCCC1.P([S-])(OCC)(OCC)=[S:28]>O>[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][C:13](=[S:28])[NH2:14]
Reactant: N#CCN1C(=O)c2ccccc2C1=O
Reactant: CCOP(=S)([S-])OCC
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=S)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
To a mixture of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetonitrile (15 g), 4 mol/L hydrogen chloride-ethyl acetate solution (40 mL) and tetrahydrofuran (50 mL) was added O,O-diethyl dithiophosphate (15 mL), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and tetrahydrofuran. The extract was washed twice with water, and then washed with saturated brine and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as white crystals (yield 9.0 g, 51%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:41]([CH3:42])=[CH:40][N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:41]([CH3:42])=[CH:40][N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)c(C)cn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (233 mg, 0.75 mmol) and 3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K17) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white foam (240 mg, 57%).
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[CH:16]=[CH:15][C:14]=1[O:24][CH3:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[C:16]([N+:1]([O-:3])=[O:2])=[CH:15][C:14]=1[O:24][CH3:25])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])c(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
69% Nitric acid (10 mL, 155 mmol) was added to a mixture of (E)-2-(benzyloxy)-1-methoxy-4-(2-nitrovinyl)benzene described in Production Example 1-1 (10 g, 35.1 mmol) and acetic acid (70 mL) under nitrogen atmosphere at 25° C., and the mixture was stirred at 40° C. for 3 hours. The reaction mixture was poured onto ice and the precipitate was collected by filteration and then washed with ethanol to obtain the title compound (10.5 g, 91%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]2[O:11][C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:9]=2[CH:8]=1)(=O)C.[OH-].[Na+]>C(O)C>[OH:4][CH2:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]2[O:11][C:12]([S:14](=[O:16])(=[O:17])[NH2:15])=[CH:13][C:9]=2[CH:8]=1
Reactant: CC(=O)OCCc1ccc2oc(S(N)(=O)=O)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cc2cc(CCO)ccc2o1

Procedure:
Saponification of 5-(2-acetoxyethyl)-2-sulfamoylbenzo[b]furan in ethanol with 10% aqueous NaOH at reflux provides the title compound.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CN=CC=1>C1COCC1>[CH2:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCCCCCCCI
Solvent: c1cnccn1
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccccc1
Yield: 71 %

Procedure:
1-Iododecane (134.1 mg, 0.5 mmol) and a THF solution (0.77 mL, 0.97 M, 0.75 mmol) of phenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of phenylmagnesium bromide was added dropwise at 40° C. over 2 hours. 1H-NMR analysis was conducted using pyrazine (29.0 mg, 0.36 mmol) as an internal standard (yield 71%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23].[OH-].[Na+]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([C:25]([F:26])([F:27])[F:28])(=[O:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(Oc2ccc3ccccc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)C(F)(F)F)c(Oc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(2-(naphth-2-yloxy)-4-nitrophenyl)-N,N-bis(trifluoromethanesulfonyl)amine (o.428 g, 0.79 mmol) in THF (10 mL) was added excess aqueous sodium hydroxide (2 mL, 10% aqueous NaOH). The resulting solution was stirred for 10 minutes at ambient temperature and quenched by adding excess 10% aqueous HCl. The two phased solution was partitioned between ethyl acetate and water. The organic layer was washed (2x, brine) dried (Na2 SO4), filtered and concentrated in vacuo. Recrystallization from ether/hexanes afforded the title compound. mp 117-120° C.; 1HNMR (300 MHz, CDCl3) δ 7.21(dd; J=9.3 Hz; 1H), 7.53 (d; J=2.5 Hz; 1H), 7.56-7.59 (m; 2H), 7.64 (d; J=2.5 Hz; 1H), 7.83 (d; J=9 Hz; 1H), 7.86-8.03 (m=3H); Anal. Calcd for C17H11N2O5 F3S: C, 49.52; H, 2.69; N, 6.79. Found: C, 49.52; H, 2.69; N, 6.75.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[O:21]C)[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:23]([O:27][C:28](N1C2=NC=C(Br)C=C2C(C(C2C(O)=CC=C(F)C=2Cl)C)=C1)=[O:29])([CH3:26])([CH3:25])[CH3:24].BrC1C=C2C(C(C3C(OC)=CC=C(F)C=3Cl)C)=CNC2=NC=1>>[C:23]([O:27][C:28]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]2[C:10]([CH:11]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=2[OH:21])[CH3:12])=[CH:9]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1c(F)ccc(Cl)c1C(C)c1c[nH]c2ncc(Br)cc12
Reactant: CC(c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: COc1ccc(F)c(Cl)c1C(C)c1c[nH]c2ncc(Br)cc12
Product: CC(c1c(Cl)ccc(F)c1O)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12

Procedure:
The title compound was prepared from 5-bromo-3-[1-(6-chloro-3-fluoro-2-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine following the procedures described for the preparation of 5-Bromo-3-[1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester from 5-bromo-3-[1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine. 1H NMR (CDCl3, 300 MHz): δ=8.42 (d, J=2.1 Hz, 1H), 7.62-7.59 (m, 2H), 6.97-6.93 (m, 2H), 5.37 (d, J=5.1 Hz, 1H), 4.87 (q, J=7.2 Hz, 1H), 1.79 (d, J=7.2 Hz, 3H), 1.68 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3].[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(C)(C)C
Reactant: NCCc1ccc(O)cc1
Product: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)C(C)(C)C
Yield: 91 %

Procedure:
tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-carbamic acid allyl ester from the above reaction was coupled with tyramine following procedure F to give the title product in 91% yield. LC-MS showed the product had the expected M+H+ of 461. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.3 (d, 1H)) 7.9 (m, 2H) 7.4 (m, 1H) 7.3 (m, 1H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.9 (m, 1H) 5.3 (m, 2H) 5.1 (m, 2H) 4.7 (s, 2H) 4.6 (d, 2H) 3.7 (m, 2H) 2.9 (m, 2H) 1.41 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.FC(F)(F)C(O)=O.[H][H]>[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: Cc1nnc2ccc(-c3cccc([N+](=O)[O-])c3)nn12
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2ccc(-c3cccc(N)c3)nn12

Procedure:
A mixture of 5.1 g. of 3-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as in Example 23), 60 ml. of trifluoroacetic acid and 0.9 g. of 10% palladium catalyst on carbon is shaken in a Parr hydrogenator under about 35 pounds of hydrogen pressure until hydrogen uptake is complete. The catalyst is filtered off and the reaction mixture is concentrated. The residue is dissolved in water and adjusted to pH 5 by addition of 5N NaOH. The insoluble material is filtered off and washed with water to obtain 6-(m-aminophenyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine, m.p. 193° C.