Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[S:29][CH:30]=[CH:31][N:32]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:33]([C:36]2[CH:41]=[CH:40][C:39](F)=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:21][CH2:20]4)=[CH:9][CH:8]=1>CN1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[S:29][CH:30]=[CH:31][N:32]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:40][CH:41]=2)(=[O:34])=[O:35])[CH2:21][CH2:20]4)=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Agent: CN1CCCC1
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)cc1)C2
Temperature: 100 °C
Reaction time: 72 h
Yield: 52.9 %

Procedure:
A solution of pyrrolidine (0.046 mL, 0.557 mmol) and (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (0.1 g, 0.186 mmol) in N-methylpyrrolidine (2 mL) was stirred at 50° C. in a sealed vial for 6 hours, then allowed to stand at room temperature for 72 hours. The reaction mixture was then stirred at 100° C. for an additional 5 hours, cooled to room temperature, and purified directly by preparative HPLC (Varian, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 50-70% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a pale yellow solid (58 mg). LCMS (Method F, ES-API): RT 2.81 min, m+H=590.0; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=3.1 Hz), 7.62 (d, 1H, J=3.1 Hz), 7.54-7.50 (m, 2H), 7.45-7.40 (m, 2H), 7.28 (s, 1H), 7.219-7.12 (m, 2H), 6.50-6.45 (m, 3H), 5.46 (dd, 1H, J=12.1, 2.0 Hz), 4.21 (d, 1H, J=16.8 Hz), 3.86-3.80 (m, 1H), 3.35-3.30 (m, 4H), 2.92-2.81 (m, 2H), 2.64 (d, 1H, J=12.2 Hz), 2.52-2.36 (m, 2H), 2.07-2.01 (m, 4H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[C@@H:23]([C@@H:24]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:25]([N:35]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH2:22][O:21][C:20](=[O:58])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:60][CH3:61]>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[C@@H:23]([C@@H:24]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:25]([N:35]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH2:22][O:21][C:20](=[O:58])[C@@H:19]1[CH2:60][CH3:61])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(=O)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H]1C(=O)OC[C@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
Slowly add lithium hexamethyldisilazide (2.28 mL, 2.28 mmol, 1.0 M in tetrahydrofuran) at −78° C. under nitrogen to a solution of (R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-oxomorpholine-4-carboxylic acid tert-butyl ester) (1 g, 1.52 mmol) and iodoethane (1.24 mL, 15.2 mmol) in anhydrous tetrahydrofuran (10 mL). Stir at −78° C. for 45 minutes, remove the bath and stir for 1.5 hours. Add water and ethyl acetate. Separate the organic layer and extract the aqueous layer with ethyl acetate. Combine the organic layers, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 90:10 hexane:ethyl acetate) to give the desired compound as a white solid (848 mg, 82%).
Reaction SMILES: O.[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Na+:7].[Na+].[Na+].[C:10](=O)([OH:12])[O-:11].[Na+]>O>[OH2:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Na+:7].[Na+:7].[Na+:7].[C:10](=[O:12])=[O:11]
Reactant: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C=O

Procedure:
The present invention utilizes the reaction of monobasic sodium phosphate monohydrate and sodium bicarbonate in water to produce dibasic sodium phosphate monohydrate, carbon dioxide (which dissipates) and water, according to the following equation:
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].C(C(CCCC(O)COC1C=CC(F)=CC=1)CCCCCCC(O)=O)(=O)C>>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CCCC(O)CSc1ccc(F)cc1)C(C)=O
Agent: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)CSc1ccc(F)cc1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 1, Step F, except that an equivalent quantity of ethyl 8-acetyl-12-hydroxy-13-(4-fluorophenylthio)tridecanoate is substituted for the ethyl 8-acetyl-12-hydroxy-13-(4-fluorophenoxy)tridecanoate of Example 1, Step F.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][S:12]([C:15]1[CH:44]=[CH:43][C:18]([O:19][C:20]2[C:21]([N:35]3[CH2:39][CH2:38][CH2:37][CH:36]3[CH:40]([OH:42])[CH3:41])=[CH:22][C:23]3[NH:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:25][C:24]=3[CH:34]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13].[Cl-].[NH4+]>C(N(CC)CC)C.C(Cl)Cl>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[C:21]([N:35]3[CH2:39][CH2:38][CH2:37][CH:36]3[C:40](=[O:42])[CH3:41])=[CH:22][C:23]3[NH:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:25][C:24]=3[CH:34]=2)=[CH:43][CH:44]=1)(=[O:14])=[O:13]
Reactant: CC(O)C1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)C1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
0.080 ml of oxalyl chloride and 0.087 ml of dimethylsulfoxide were added in order to 3 ml of methylene chloride at −78° C., and the reaction liquid was stirred at −78° C. for 10 minutes, and then a methylene chloride (2 ml) solution of 146 mg of the diastereomer mixture of 1-(1-(6-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-2-yl)-ethanol obtained in Examples 354 and 355, at −78° C. The reaction liquid was stirred at −78° C. for 30 minutes, and 0.42 ml of triethylamine was added to it, and the reaction mixture was stirred at −78° C. for 10 minutes, and then heated up to room temperature. Aqueous saturated ammonium chloride was added to the reaction liquid, extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[N+:5]([O-])=[CH:6][CH:7]=1.C[Si]([C:20]#[N:21])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:20]([C:11]1[N:10]=[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH:14]=[C:13]([CH3:15])[CH:12]=1)#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccnc(-c2cc(C)cc[n+]2[O-])c1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: Cc1ccnc(-c2cc(C)cc(C#N)n2)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 90.3 %

Procedure:
4,4′-Dimethyl-2,2′-bipyridyl N-oxide (3.7 g, 18 mmol) was dissolved in nitroethane (50 ml), and trimethylsilyl cyanide (5.5 g, 55 mmol) and N,N-dimethylcarbamoyl chloride (2.9 g, 27 mmol) were added thereto. The mixture was stirred at room temperature for 36 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (3.4 g, 87%) as white crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:23](=[O:24])[C:22]4[C:21]5[C:16](=[CH:17][C:18]([C:25]#[N:26])=[CH:19][CH:20]=5)[NH:15][C:14]=4[C:13]([CH3:28])([CH3:27])[C:12]=3[CH:29]=2)[CH2:4][CH2:3]1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].COC1CCCC1>C(Cl)Cl.CN(C=O)C>[CH3:27][C:13]1([CH3:28])[C:14]2[NH:15][C:16]3[C:21](=[CH:20][CH:19]=[C:18]([C:25]#[N:26])[CH:17]=3)[C:22]=2[C:23](=[O:24])[C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]3)=[CH:29][C:12]1=2
Reactant: CC1(C)c2cc(N3CCC(O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC1CCCC1
Solvent: ClCCl
Product: CC1(C)c2cc(N3CCC(=O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-(4-Hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-7-1, 210 mg, 0.545 mmol), was dissolved in the DCM (2 mL) and DMF (0.6 mL) mixture solvent, added with 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (300 mg, 1.3 eq.), and the mixture was stirred at room temperature for 2 hr. To the reaction solution, 0.25 mol/L aqueous solution of sodium thiosulfate, saturated sodium bicarbonate solution and CPME were added followed by further stirring at room temperature for 1 hr. The reaction solution was filtered and the filtrate was subjected to liquid separation. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (yellowish white powder, 109 mg, 52%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][CH2:9][CH2:10]Br.[CH:12]1([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)[CH:26]=3)=[CH:21][C:18]=2[C:19]#[N:20])[CH2:14][CH2:13]1>CN(C=O)C>[CH:12]1([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:33]=[N:34][N:35]([CH2:10][CH2:9][O:8][CH3:7])[CH:36]=4)[CH:26]=3)=[CH:21][C:18]=2[C:19]#[N:20])[CH2:14][CH2:13]1
Reactant: N#Cc1cc(-c2ccnc(Nc3cn[nH]c3)c2)ccc1OCC1CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCn1cc(Nc2cc(-c3ccc(OCC4CC4)c(C#N)c3)ccn2)cn1
Temperature: 80 °C

Procedure:
Caesium carbonate (0.17 g, 0.54 mmol) and 2-bromoethyl methyl ether (0.045 g, 0.325 mmol) are added to a solution of the 2-cyclopropylmethoxy-5-[2-(1H-pyrazol-4-ylamino)pyridin-4-yl]benzonitrile prepared above (0.09 g, 0.27 mmol) in dry DMF (2 ml). The reaction mixture is warmed at 80° C. for 8 h. Ice is added, and the mixture is extracted with ethyl acetate (2×50 ml). The organic phase is washed with water (1×25 ml) and dried over sodium sulfate. The mixture is then evaporated in a rotary evaporator. The crude product is purified by chromatography, giving 5.8 mg of the desired product as brown solid;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([F:10])=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:19]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>CO.C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:14]2[CH2:15][CH2:16][N:11]([C:4]3[CH:5]=[C:6]([F:10])[C:7]([CH3:9])=[CH:8][C:3]=3[Cl:2])[CH2:12][CH2:13]2)=[O:23])=[C:20]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:19]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(Cl)c(N2CCNCC2)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of 1-Boc-piperazine (1.9 g), 1-bromo-2-chloro-5-fluoro-4-methylbenzene (2.2 g), palladium acetate (112 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (312 mg) and sodium tert-butoxide (1.4 g) was added toluene (20 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform). The obtained compound was dissolved in chloroform (3 mL), 4N hydrogen chloride/ethyl acetate (3 mL) was added, and the mixture was stirred at room temperature for 3 hr. Filtration gave 1-(2-chloro-5-fluoro-4-methylphenyl)piperazine hydrochloride (2 g). To a mixture of 1-(2-chloro-5-fluoro-4-methylphenyl)piperazine hydrochloride (1.1 g), 4-bromo-2-methanesulfonylbenzoic acid (1.1 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.5 g) were added chloroform (50 mL), methanol (50 mL) and N-methylmorpholine (440 μL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform:methanol) to give (4-bromo-2-methanesulfonylphenyl)[4-(2-chloro-5-fluoro-4-methylphenyl)piperazin-1-yl]methanone (1.9 g). To a mixture of (4-bromo-2-methanesulfonylphenyl)[4-(2-chloro-5-fluoro-4-methylphenyl)piperazin-1-yl]methanone (1.9 g), oxazolidin-2-one (418 mg), potassium carbonate (1.7 g) and copper (I) iodide (152 mg) were added toluene (4 mL) and N,N′-dimethylethylenediamine (180 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (0.5 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].[OH-].[Na+].S(=O)(=O)(O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.COC(C)(C)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: OCCCBr
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: O
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a mixture of 0.72 g of 3-bromopropanol, 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of t-butyl methyl ether, 0.06 g of tetra-n-butylammonium bromide and 5.0 g of water was added 0.77 g of a 27% aqueous sodium hydroxide solution. The mixture was heated to 60° C. and stirred for 12 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution was added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.2 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 93%, yield: 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][CH:25]=1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(F)cc2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-fluorophenyl)-boronic acid (CAN 1765-93-1) as starting materials; LC-MS (UV peak area/ESI) 100%, 392.1005 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].C([BH3-])#N.[Na+]>>[CH3:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccccc1C
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccccc1C
Yield: 83 %

Procedure:
Reduction of 2-methylbenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil (83% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.42 (3H, s, CH3), 3.55 (3H, s, OCH3), 4.11 (2H, s, NCH2), 5.64 (1H, s, NH), 7.19-7.32 (4H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 148-150° C. Anal. calcd. for C9H13NO—HCl: C, 57.60; H, 7.51; N, 7.46. Found: C, 57.59; H, 7.69; N, 7.52.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([OH:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][OH:14])=[CH:4][CH:3]=1.[Se](=O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]=[O:14])=[O:15])=[CH:4][CH:3]=1
Reactant: OCc1ccccc1C(O)c1ccc(Cl)cc1
Agent: O=[Se]=O
Solvent: CC(=O)O
Product: O=Cc1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 18.6 g. of 4'-chloro-2-hydroxymethylbenzhydrol in 100 ml. of acetic acid and 10.4 g. selenium dioxide was refluxed for 2 hours. The mixture was poured on ice and made alkaline and extracted with ether. Concentration of the ether solution and addition of petroleum ether gave pale yellow prisms which after recrystallization from a mixture of ether and petroleum ether gave 2-(p-chlorobenzoyl)-benzaldehyde melting at 112°-113°. Ultraviolet inflexion (2-propanol) at 225 mμ (ε = 17,500) and maximum at 259 mμ (ε = 22,500), infrared absorption (CHCl3) at 1670 cm-1 and 1705 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=[O:2].[NH4+].[Cl-]>C(O)(=O)C.O.[Zn]>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1cccc(C(=O)O)c1
Temperature: 0 °C

Procedure:
As an alternative method of forming azo compounds, nitroso compounds are coupled to amines in glacial acetic acid by the Mills reaction. Badger, G. et al., Aust. J. Chem. 17: 1036 (1964). Nitroso compounds are made by the method of Coleman et al., Organic Synthesis Collective Vol. III: p668. For example, 3-nitrobenzoic acid (Aldrich Chem. Co., Milwaukee, Wis.) (2.44 mmoles) and a solution of 150 mg of NH4Cl in 5 ml of water are combined in a 50 ml round-bottomed flask and stirred vigorously. Zinc dust (372 mg) is added in small portions over 5 minutes. After the addition of zinc is complete the temperature begins to rise, but is kept between 50 and 55° C. by the use of an ice bath. The mixture is stirred at that temperature for 20 minutes and then the zinc residues are filtered and washed with boiling water. The combined filtrate and washings are cooled to 0° C. in a beaker by the addition of ice. To this cold mixture of the hydroxylamine, a cold solution of sulfuric acid (750 μl of concentrated acid plus enough ice to bring the temperature to −5° C.) is added with stirring. An ice-cold solution of 170 mg of sodium dichromate dihydrate in 750 μl of water is added all at once with stirring. The resulting 3-nitrosobenzoic acid thus obtained is combined with one-half of an equivalent of benzidine, 2,7-diaminofluorene or another benzidine derivative in glacial acetic acid and warmed to 70-80° C. for 7 hrs and then allowed to stand at room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate giving 4,4′-bis(3-carboxy-phenylazo)-biphenyl), 2,7-bis(3-carboxy-phenylazo)-fluorene, or the corresponding bis(3-carboxy-phenylazo) derivative of the particular benzidine derivative employed.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[F:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1>C(N(CC)CC)C>[CH:10]1[C:11]([O:14][C:4]([CH2:3][CH2:2][Cl:1])=[O:5])=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=1
Reactant: O=C(Cl)CCCl
Reactant: Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Product: O=C(CCCl)Oc1ccc(F)cc1
Temperature: 60 °C
Yield: 97.8 %

Procedure:
3-Chloropropionyl chloride (391.5 g) and 3 drops of triethylamine is added to 4-fluorophenol (308.3 g) under stirring at 60° C. After heating to 100° C. for 1.5 hrs, distillation gives 544.7 g of (I) boiling at 126°-130° C. 10 mm Hg.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:15]([O:17]C)=[O:16])[C:6]2[C:11]([C:12]=1[O:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:2].C1COCC1.[OH-].[Na+]>O>[CH3:2][O:1][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=[O:16])[C:6]2[C:11]([C:12]=1[O:13][CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1cc(OC)c(OC)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c2ccccc2c1OC
Yield: 92.3 %

Procedure:
A solution of methyl 3,4-dimethoxyl-1-naphthalenecarboxylate (2.93 g, 11.9 mmol), THF (145 mL), water (58 mL), and 1N NaOH (25 mL, 25.0 mmol) was stirred at room temperature overnight. The THF was removed in vacuo and the mixture acidified to pH 1 with 1N HCl. The resulting white precipitate was extracted with EtOAc (2×50 mL), dried (MgSO4) and filtered to give the product as a white solid (2.55 g, 92%). 1H NMR (DMSO) δ 13.19 (s, 1H), 8.89 (d, 1H), 8.13 (d, 1H), 8.08 (s, 1H), 7.54 (m, 2H), 3.97 (s, 3H), 3.98 (s, 3H); MS (APCI) m/z 231 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[S:27](N)([NH2:30])(=[O:29])=[O:28]>O1CCOCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][N:24]([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: NS(N)(=O)=O
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Solvent: C1COCCO1
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCN(S(N)(=O)=O)CC3)cc12
Temperature: 90 °C

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (10.0 mg, 0.0256 mmol), sulfamide (4.92 mg, 0.0512 mmol) and dioxane (2 mL) was heated to 90° C. for 16 h in a sealed tube. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.87 (d, J=7.1 Hz, 3 H), 2.40-2.60 (m, 2 H), 3.32-3.35 (m, 2 H), 3.77 (q, J=2.6 Hz, 2 H), 5.26 (q, J=7.1 Hz, 1 H), 5.90-5.96 (m, 1 H), 7.19 (t, J=8.6 Hz, 1 H), 7.29 (s, 1 H), 7.37 (d, J=1.5 Hz, 1 H), 7.42 (br. s., 1 H), 8.28 (br. s., 1 H). MS (ES+): m/z 469.00 (100) [MH+]. HPLC: tR=3.42 min (ZQ3, polar—5 min).