Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH2:15][C:16](=[CH:20][O:21][C:22]3[CH:34]=[CH:33][C:25]4[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=4[CH:23]=3)[CH:17]=[CH:18][CH:19]=2)=[C:9]([CH3:35])[CH:8]=1)[CH3:2].S(O[O-])([O-])(=O)=[O:37].[K+].[K+].[OH2:44]>CO>[CH2:1]([S:3]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:35])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:34]=[CH:33][C:25]4[C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][O:28][C:24]=4[CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)(=[O:37])=[O:44])[CH3:2]
Reactant: O
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCSCCOc1cc(C)c(C2=CC=CC(=COc3ccc4c(c3)OC[C@H]4CC(=O)O)C2)c(C)c1
Agent: [K+]
Solvent: CO
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a solution of [(3S)-6-({4′-[2-(ethylthio)ethoxy]-2′,6′-dimethylbiphenyl-3-yl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid (0.304 g, 0.617 mmol) in methanol (10 mL) was added dropwise a solution of potassium peroxysulfate (trade name: OXONE, 0.569 g, 0.926 mmol) in water (5 mL) under ice-cooling, and the mixture was stirred for 12 hr, during which the mixture was allowed to gradually warm to room temperature. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC, and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.237 g, yield 73%) as colorless crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CCCCC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC(Cn1ccnc1)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 40 ml of nitric acid and 10 ml of sulfuric acid, 14.8g (0.0498 mole) of 1-[β-(2,4-dichlorophenyl)hexyl]imidazole in 30 ml of sulfuric acid is added at less than 5°. The reaction is stirred for 1/2 hour and then it is poured into iced water. The oily solid which separates is isolated by decanting off the dilute acid solution. The residue is washed and then treated with ammonium hydroxide solution.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C@H:8]2[CH2:12][CH2:11]C(=O)[N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1.[NH2:25][NH2:26]>C1COCC1>[C:17]([O:16][C:14](=[O:15])[NH:9][C@@H:8]([CH2:7][C:6]1[CH:21]=[CH:22][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=1)[CH2:12][CH2:11][NH:25][NH2:26])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)cc1
Reactant: NN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCNN)Cc1ccc(C(F)(F)F)cc1
Yield: 91.4 %

Procedure:
(R)-tert-Butyl 2-(4-(trifluoromethyl)benzyl)-5-oxopyrrolidine-1-carboxylate (1.46 g, 4 mmol) (prepared as shown in Scheme 15) was treated with hydrazine (0.5 mL, 16 mmol) at 50° C. in THF for 30 minutes. The mixture was partitioned between EtOAc and saturated aqueous ammonium chloride, and dried over sodium sulfate. Evaporation provided the desired product as a white amorphous solid (1.27 g, 87%). LCMS (API-ES) m/z: 276 (M-Boc+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7][C:6]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:5]2.[C:20]([O-])(=O)[CH3:21].[Na+:24].[N+:25]([C:28]1[CH:29]=[C:30]([C:37](Cl)=[O:38])[CH:31]=[C:32]([C:34](Cl)=[O:35])[CH:33]=1)([O-:27])=[O:26]>O>[Na+:24].[Na+:24].[Na+:24].[Na+:24].[N+:25]([C:28]1[CH:29]=[C:30]([C:37]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:20][CH:21]=2)[C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:7][C:6]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:5]3)=[O:38])[CH:31]=[C:32]([C:34]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:7][C:6]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:5]3)=[O:35])[CH:33]=1)([O-:27])=[O:26]
Reactant: Nc1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccc2c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc2c1)c1cc(C(=O)Nc2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2)cc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
An 18.18 g portion of 6-amino-1,3-naphthalenedisulfonic acid is suspended in 200 ml of water and the pH is adjusted to 7.0 giving a solution. A 5.6 g portion of sodium acetate is dissolved in this solution and 8.18 g of 5-nitro-1,3-benzenedicarbonyl dichloride is added. The mixture is stirred for one hour, filtered and the filtrate is treated with activated carbon. The filtrate is reduced to a low volume on a rotary evaporator producing crystals. The crystals are recrystallized from water giving 6,6'-[5-nitro-1,3-phenylenebis(carbonylimino)]bis[1,3-naphthalenedisulfonic acid] tetrasodium salt.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[C:22]1([C:28]([NH2:31])([CH3:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:31][C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH3:30])[CH3:29])=[O:16])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: O=C(O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylic acid (50 mg, 0.17 mmol, 1 equiv) in DCM (2 mL) was added 2-phenylpropane-2-amine (27 μL, 0.18 mmol, 1.05 equiv), DIEA (30 μL, 0.17 mmol, 1 equiv) and HATU (68 mg, 0.18 mmol, 1.05 equiv). The reaction mixture was stirred 2 h at room temperature.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43]N)=[CH:39][CH:38]=1>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:40](=[CH:41][CH:42]=1)[NH:43][C:22]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[C:21]2[CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:33])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 555.6 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]=[CH2:4].C([Li])CCC.[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=[CH:2][CH2:3][CH3:4])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
In a stream of argon, 2.9 g (7.5 mmol) of allyltriphenylphosphonium bromide was suspended in 10 ml of anhydrous tetrahydrofurane, and thereto 4.3 ml of butyllithium a was added dropwise under cooling with ice. After stirring the mixture at room temperature for 30 minutes, thereto was added dropwise a solution of 1 g (5.3 mmol) of 1-benzyl-4-piperidone in anhydrous tetrahydrofurane under cooling with ice and the obtained mixture was stirred at room temperature for 15 hours. The reaction solution was filtrated, and ethyl acetate and water were added to the filtrate, and the organic phase was taken out. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting oily matter was subjected to a column chromatography using 40 g of silica gel and eluted with ethyl acetate-hexane (1:1 to 1:3) to obtain 200 mg of 1-benzyl-4-propylidenepiperidine.
Reaction SMILES: [C:1]([C:6]1[O:10][C:9]([CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[O:15]1CCOCC1>>[C:1]([C:6]1[O:10][C:9]([CH:11]=[C:12]([CH3:13])[CH:14]=[O:15])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(C=C(C)C)o1
Reactant: C1COCCO1
Product: CCOC(=O)c1ccc(C=C(C)C=O)o1
Temperature: 90 °C
Yield: 44 %

Procedure:
A mixture of 8.2 g (0.042 mol) of 1-(5-carbethoxy-2-furanyl)-2-methyl-1-propene, 10.0 g of SeO2 (0.09 mol) and 120 mL of dioxane was degassed three times under argon and heated at 90° C. for 1.5 h. The reaction mixture was cooled, filtered through Celite and evaporated to remove most of the dioxane. The residue was filtered again and washed with 50 mL of dioxane. The filtrate and washings were concentrated to a small volume and chromatographed on 170 g of silica gel (25% Et2O/hexane) to give 3.9 g (44% yield) of a white solid. Recrystallization from EtOAc/hexane gave long white needles, mp 83° C.; IR (mull) 1740, 1690, 1650, 1320, 1280, 1240, 1200, 1040, 980, 780 cm-1 ; 1H NMR (CDCl3) δ1.43 (t, J=7 Hz, 3, CH2CH3), 2.18 (s, 3, C=CCH3), 4.48 (q, J=7 Hz, 2, CH2CH3), 6.88 and 7.35 (2d, J=4 Hz, 2, 3', 4'H), 7.15 (s, 1, C=CH), 9.60 (s, 1, CHO); MS calcd for C11H12O4 208.0736, found 208.0728.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=1[N:44]=[C:45]=[O:46]>O1CCCC1>[S:23]1[CH:24]=[CH:25][C:21]([C:19]([NH:18][C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:6]4[CH:5]=[CH:4][C:3]([NH:2][C:45]([NH:44][C:35]5[CH:36]=[C:37]([C:40]([F:41])([F:43])[F:42])[CH:38]=[CH:39][C:34]=5[F:33])=[O:46])=[CH:8][CH:7]=4)=[CH:10][CH:11]=3)[NH:15][N:14]=2)=[O:20])=[CH:22]1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 24 °C
Reaction time: 3.5 h

Procedure:
A solution of 1.72 g of 6-(4-aminophenyl)-3-[(thiophen-3-yl)carbonylamino]-1H-indazole hydrochloride and 0.65 mL of triethylamine in 70 mL of tetrahydrofuran is admixed slowly under an argon atmosphere with 0.67 mL of 2-fluoro-5-trifluoromethylphenyl isocyanate. The reaction mixture is stirred at 24° C. for 3.5 hours and then concentrated under reduced pressure. The residue is purified by flash chromatography on a silica column (60; 35-70 μM), eluting with a dichloromethane/methanol (97/3 by volume) mixture, to give 0.4 g of 1-(4-{3-[(thiophen-3-yl)carbonylamino]-1H-indazol-6-yl}phenyl)-3-(2-fluoro-5-trifluoromethylphenyl)urea, whose characteristics are as follows:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22]C=C)[C@@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[F:25][C:26]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43])[C:31]([O:33]CC)=[O:32].ICCCC(F)(F)C(F)(F)F.C(OCC)(=O)CC(OCC)=O.ICCCCCCC=C>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:30]([CH2:29][CH2:28][CH2:27][C:26]([F:25])([F:48])[C:44]([F:45])([F:46])[F:47])[C:31]([OH:33])=[O:32])[C@@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CC[C@H]1c2ccc(OC)cc2SC[C@@]1(C)c1ccc(OC)cc1
Agent: C=CCCCCCCI
Agent: FC(F)(F)C(F)(F)CCCI
Solvent: CCOC(=O)CC(=O)OCC
Product: C[C@@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@@H]1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the (3R,4R)-7-methoxy-3-(4-methoxy-phenyl)-3-methyl-4-(2-propenyl)thiochroman prepared in Example 2 and ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate separately prepared from 1-iodo-4,4,5,5,5-pentafluoropentane, diethyl malonate and 1-iodo-7-octene, a procedure analogous to that as shown in Example 2 or 3 was repeated to give 11-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:12]=[CH:11][C:9](N)=[C:8]([O:13][C:14]([F:17])([F:16])[F:15])[CH:7]=1.[Br-:18]>>[Br:18][C:9]1[CH:11]=[CH:12][C:6]([CH:2]=[O:1])=[CH:7][C:8]=1[O:13][C:14]([F:17])([F:16])[F:15]
Reactant: [Br-]
Reactant: Nc1ccc(C2OCCO2)cc1OC(F)(F)F
Product: O=Cc1ccc(Br)c(OC(F)(F)F)c1

Procedure:
In Scheme 31 are shown 2 methods that may be used for the synthesis of 4-bromo-3-(trifluoromethoxy)benzaldehyde or 4-chloro-3-(trifluoromethoxy)benzaldehyde. Method 1: Commercially available 4-amino-3-(trifluoromethoxy)benzoic acid can be converted into the ester followed by a Sandmeyer reaction, described in Scheme 30, to provide the bromide or chloride. Reduction of the ester provides 4-bromo-3-(trifluoromethoxy)benzyl alcohol. The alcohol can be oxidized to the aldehyde to give the desired substituted benzaldehyde. Method 2: Commercially available 4-bromo-2-(trifluoromethoxy)aniline can be protected on the amino group with a suitable amino protecting groups well known to those skilled in the art of organic chemistry. The bromine can then be converted to the lithio or magnesio derivative and reacted directly with dimethylformamide to provide the 4-aminoprotected-3-(trifluoromethoxy)benzaldehyde derivative. Removal of the N-protecting group followed by protection of the aldehyde provides 4-(1,3-dioxolan-2-yl)-2-(trifluoromethoxy)aniline. Conversion of the amine to a bromide via the Sandmeyer method of Scheme 30 followed by hydrolysis of the dioxolane provides 4-bromo-3-(trifluoromethoxy)benzaldehyde.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][N:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:22]=2)[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5]1=[O:11]
Reactant: Cn1cc(Br)n2cncc2c1=O
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)n2cncc2c1=O
Temperature: 25 °C
Yield: 18.8 %

Procedure:
A solution of compound from Example 129, step 1 (80 mg, 0.35 mmol), (3-methylsulfonylphenyl)boronic acid (77 mg, 0.6 mmol), Na2CO3 (106 mg, 1 mmol), Pd(PPh3)2Cl2 (30.0 mg) in dioxane (3 mL) and water (0.5 mL) was stirred at 120° C. for 18 h under N2. After cooling to room temperature, the mixture was filtered, concentrated and purified by prep-HPLC to give the title compound (20.0 mg, 20%). 1H NMR (Methanol-d4 400 MHz): δ 8.70-8.65 (m, 1H), 8.30-8.20 (m, 2H), 8.16 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.22 (s, 1H), 3.56 (s, 3H), 3.24 (s, 3H). LCMS (M+H)+ 304.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:25]1([CH2:31]Br)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3CCCCC3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: BrCC1CCCCC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(CC3CCCCC3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(CC3CCCCC3)c3c2CCNCC3)cc1
Yield: 53.5 %

Procedure:
The title compound (0.09 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 170 mg) using cyclohexylmethyl bromide (2 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-cyclohexylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H26ClN3, 343.18. found, m/z 344.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37 (d, J=6.6 Hz, 2H), 7.32 (d, J=6.6 Hz, 2H), 3.94 (d, J=7.3 Hz, 2H), 3.44-3.40 (br m, 2H), 3.35-3.32 (br m, 2H), 3.17-3.14 (br m, 2H), 3.01-2.99 (br m, 2H), 1.74-1.53 (m, 4H), 1.52 (d, J=11.2 Hz, 2H), 1.17-1.10 (m, 3H), 0.94-0.90 (m, 2H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCOCC1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Nc2ccccc2N)cc1
Yield: 97.4 %

Procedure:
33.1 g (0.3 mol) of 1,2-phenylenediamine was dissolved in 200 ml of dioxane. A solution of 20.87 g (0.1 mol) of 4-methoxybenzenesulfonyl chloride in 110 ml of dioxane was added thereto under stirring. The resulting mixture was stirred at room temperature overnight. 12.1 g (0.12 mol) of triethylamine was added thereto. After concentration followed by addition of an aqueous citric acid solution and ethyl acetate, the organic layer was separated, concentrated and purified by silica gel column chromatography to obtain 27.1 g of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:3]1=2.C(N(CC)CC)C.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>C(Cl)Cl>[O:1]=[S:2]1(=[O:16])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:24]([CH:25]([CH3:27])[CH3:26])=[O:28])[CH:13]=[CH:14][C:3]1=2
Reactant: Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Yield: 46.1 %

Procedure:
5,5-Dioxo-2-aminodibenzothiophene (J Med Chem, (1994), 37 (13), 2085-9; 231 mg, 1.0 mmol) was suspended in a solution of DCM (10 ml) and triethylamine (111 mg, 1.1 mmol). iso-Butyrylchloride (106.5 mg, 1.0 mmol) was added dropwise and the resultant mixture was stirred for 16 hours at ambient temperature. The mixture was evaporated in vacuo and the residue was purified by chromatography (Bond Elut column) eluting with 0-2.5% methanol in DCM to give the product as a colourless solid (139 mg). NMR: 10.38 (brs, 1H), 8.37 (s, 1H), 7.85-8.00 (m, 3H), 7.80 (d, 1H), 7.74 (d, 1H), 7.63 (t, 1H), 2.66 (m, 1H), 1.13 (d, 6H); m/z 302.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.[F:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH:15](C)[CH2:16]Cl)=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[F:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH:15]([CH3:16])[CH2:1][N:3]2[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)=[CH:12][CH:11]=1
Reactant: O=CN1CCNCC1
Reactant: CC(CCl)Oc1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CN1CCNCC1)Oc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-Formyl piperazine (2.8 g) and 2-(4-fluorophenoxy)propyl chloride (4.7 g) were dissolved in dimethylformamide (60 ml), and sodium iodide (3.2 g) and triethylamine (4.4 ml) were added thereto, and the mixture was stirred overnight at 50 to 70° C. The organic layer was partitioned by adding water and ethyl acetate, washed with brine, dried over sodium sulfate anhydrous, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (ethyl acetate). The resulting yellow oil (12.3 g) was dissolved in methanol (20 ml), and 5N aqueous sodium hydroxide (10 ml) was added thereto and then stirred for 1 hour under reflux. The reaction mixture was evaporated, then the organic layer was partitioned by adding water and ethyl acetate, washed with brine, and dried over sodium sulfate anhydrous. The residue obtained by evaporation was purified by Cromatorex NH silica gel column chromatography (ethyl acetate/methanol system), whereby the title compound (2.2 g, 38%) was obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18]CC3C=CC=CC=3)=[C:13]3[CH:26]=[CH:27][CH:28]=[CH:29][C:12]3=[C:11]([O:30]CC3C=CC=CC=3)[C:10]=2[C:9]1=[O:38].B(Br)(Br)Br>C(Cl)Cl>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]4[CH:26]=[CH:27][CH:28]=[CH:29][C:12]4=[C:11]([OH:30])[C:10]=3[C:9]2=[O:38])=[C:2]([Cl:1])[CH:3]=1)[CH3:44]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCc3ccccc3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(O)c4ccccc4c3O)C2=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 9.8 %

Procedure:
To a solution of ethyl (3-chloro-4-{1,3-dioxo-4,9-bis[(phenylmethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (0.505 g, 0.84 mmol) in DCM (30 ml), cooled to −78° C. under an atmosphere of argon, was added boron tribromide (0.24 ml, 2.50 mmol) drop wise. Stirred at −78° C. for 25 minutes. The reaction mixture was quenched with water and warmed to room temperature. This was extracted X2 with DCM using a hydrophobic frit. The organic phase was evaporated to an orange solid. Hot trituration in DCM resulted in a yellow solid which was collected by filtration (0.189 g, 0.44 mmol, 53%). The filtrate was purified by chromatography on silica gel, eluting with ethyl acetate (0-70%) in hexane to give the title compound as a yellow solid (0.035 g, 0.082 mmol). LC/MS: Rt=3.22, [MH]+ 426.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([OH:11])[CH:3]=1.[S-:12][C:13]#[N:14].[K+].BrBr>O.CN(C)C=O.N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[N:5]=[C:4]([OH:11])[C:3]=1[S:12][C:13]#[N:14]
Reactant: Nc1cc(O)nc(C2CC2)n1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: N#CSc1c(N)nc(C2CC2)nc1O
Temperature: 40 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a mixed solution of the compound (0.30 g) obtained in Step 1, potassium thiocyanate (0.77 g) and N,N-dimethylformamide (6.0 ml) was added pyridine (0.29 ml) at 90° C. After allowing to cool to 40° C., a mixed solution of bromine (0.15 ml) and N,N-dimethylformamide (1.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. Under ice-cooling, water (12 ml) was added to the reaction solution, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (0.40 g).