Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH2:48][CH2:49][CH3:50])[CH:45]=3)[CH:40]([C:51]3[CH:56]=[CH:55][C:54]4[O:57][CH2:58][O:59][C:53]=4[CH:52]=3)[CH:39]2[C:60]([O-:62])=[O:61])=[C:34](OS(C(F)(F)F)(=O)=O)[CH:33]=1.[C:71]([O:75]C)(=[O:74])[CH:72]=[CH2:73]>C(N(CC)CC)C.C(#N)C.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:71](/[CH:72]=[CH:73]/[C:34]1[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[CH:36][C:35]=1[CH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH2:48][CH2:49][CH3:50])[CH:45]=2)[CH:40]([C:51]2[CH:56]=[CH:55][C:54]3[O:57][CH2:58][O:59][C:53]=3[CH:52]=2)[CH:39]1[C:60]([OH:62])=[O:61])([OH:75])=[O:74]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1/C=C/C(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,3-bis(diphenylphosphino)propane (0.066 mmol), tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026) and bis(triphenylphosphine)palladium(II) chloride (18 mg, 0.026 mmol), were dissolved in a 4:1 mixture of triethylamine/acetonitrile (5 mL) under argon. After 10 min at room temperature, a solution of methyl (1RS, 2SR, 3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (160 mg, 0.26 mmol) and methyl acrylate (679 mg, 7.89 mmol) was added in the above solvent mixture (3 mL). The reaction mixture was heated to reflux under argon for 20 h, cooled to room temperature and a small aliquot analyzed by 1H NMR, which showed no reaction had taken place. Palladium(II) acetate (6 mg, 0.025 mmol) and methyl acrylate (679 mg, 7.89 mmol) in dry DMF (5 mL) were then added. The reaction mixture was heated to reflux overnight. On cooling the solution was filtered through a short column of silica gel and concentrated to yield an oil. The crude product was purified by flash column chromatography (silica gel, gradient elution: 10% to 20% ethyl acetate/hexanes) to afford the title compound as a tan solid. (87 mg, 62%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][CH:6]([CH2:11][C:12]([OH:14])=O)[C:7]([O:9][CH3:10])=[O:8]>ClCCl.CN(C)C=O>[Br:5][CH:6]([CH2:11][C:12]([Cl:3])=[O:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(Br)CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(Br)CC(=O)Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
Thionyl chloride (6.54 g, 54.9 mmol) in dichloromethane (7 mL) was added dropwise over 30 minutes to a mixture of 1-methyl hydrogen bromobutanedioate (i.e. the product of Step A) (10 g, 47.4 mmol) and N,N-dimethylformamide (5 drops) in dichloromethane (20 mL) heated at reflux. The mixture was heated at reflux for an additional 60 minutes and then allowed to cool to room temperature. The solvent was removed under reduced pressure to leave the title product as an oil (11 g, about 100% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][OH:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][O:13][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)N(CCO)C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Product: CC(C)N(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Yield: 57 %

Procedure:
Reaction of (2-hydroxyethyl)isopropylcarbamic acid tert-butyl ester with N-hydroxyphthalimide following the procedure described for Reference Example 14, except purification by column chromatography (silica gel, 75:25 hexanes/EtOAc to 50:50 hexanes/EtOAc), gave tert-butyl[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethyl]isopropylcarbamate (960 mg, 57%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.15-1.20 (6H, br s), 1.43 (9H, s), 3.48-3.50 (2H, s), 4.08-4.15 (1H, m), 4.25-4.28 (2H, m), 7.74-7.85 (4H m).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]2[NH:7][C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3cc(F)c(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)c(F)cc3n2CCc2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.5 %

Procedure:
To a solution of 8-Chloro-7-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.0041 mol) in N-methyl 2-pyrolidone (0.5 mL) was added powdered potassium hydroxide (0.08 g, 0.00143 mol) and allowed to stir for 10 min at RT. 2-trifluoromethyl-5-vinyl pyridine (0.079 g, 0.00046 mol) was added and stirred for further 15 h. at rt, After completion (TLC), reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through preparative HPLC to give the desired compound 10 as light yellow solid (0.02 g, 12% yield), 8-Chloro-7-fluoro-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.02 g, 0.0000485 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.006 g, 0.0000485 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.015 g, 62% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(OC)(O[CH3:16])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Cl)c1N
Temperature: 80 °C
Yield: 96 %

Procedure:
5.13 g (0.03 mol) of 2-amino-3-chlorobenzoic acid, ml of toluene, 0.97 g (0.003 mol) of tetrabutylammonium bromide, and 4.54 g (0.04 mol) of dimethyl sulfate were added to a 100 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer, and a dropping funnel, and a mixture of 4.56 g (0.033 mol) of potassium carbonate and 9 ml of toluene was added dropwise with stirring at 80° C. Then, the mixture was stirred at 80° C. for 1 hour. The solution was analyzed by HPLC by the absolute calibration method, and as a result, the yield was 96%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[CH2:9][OH:10])=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[NH:39][N:38]=2)[CH:32]=1.N>CN(C)C=O.[Cu]I>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[N:39]([C:2]3[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=3)[C:5]([NH:7][C@@H:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH2:9][OH:10])=[O:6])[N:38]=2)[CH:32]=1
Reactant: COc1ccc(C[C@@H](CO)NC(=O)c2ccnc(Br)c2)cc1OC
Reactant: O=c1[nH]nc(-c2cccnc2)c2ccccc12
Agent: [Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H](CO)NC(=O)c2ccnc(-n3nc(-c4cccnc4)c4ccccc4c3=O)c2)cc1OC
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
To a solution of (2S)-2-(2-bromoisonicotinoylamino)-3-(3,4-dimethoxyphenyl)-1-propanol (1.2 g) in dimethylformamide (40 ml) are added potassium carbonate (0.88 g) and copper (I) iodide (0.61 g) at room temperature under nitrogen atmosphere. The mixture is heated with stirring at 120° C. for 30 minutes. To the reaction mixture is added 4-(3-pyridyl)phthalazin-1(2H)-one (1.42 g), and the mixture is heated with stirring at 130° C. for two hours. The reaction mixture is cooled to room temperature, and thereto is added aqueous ammonia. The mixture is extracted with chloroform, and the extract is washed, dried and concentrated. The residue is purified by silica gel chromatography (solvent; chloroform:acetone=1:1) to give (2S)-2-{2-[4-(3-pyridyl)phthalazin-1(2H)-on-2-yl]isonicotinoylamino}-3-(3,4-dimethoxyphenyl)-1-propanol (330 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18](Cl)=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].N1C=CC=CC=1>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18]4[O:19][N:28]=[C:25]([CH3:26])[N:27]=4)=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Reactant: CC(=N)N
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1noc(-c2cnc3cc(C#Cc4cccc(F)c4)ccn3c2=O)n1
Temperature: 70 °C

Procedure:
8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonyl chloride was dissolved in 1,4-dioxane (3 mL). To the solution was added acetamidine hydrochloride (18 mg, 0.162 mmol, 1 equiv) and pyridine (2 mL). The reaction mixture was then heated at 70° C. overnight. After it was cooled to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by preparative TLC to give 2.2 mg of the desired product. MS (ESI): 347 (MH+).
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:22]=[C:21]2[C:10]([C:11]([CH3:24])([CH3:23])[C:12]3[CH:16]=[CH:15][N:14]([CH2:17][C@H:18](O)[CH3:19])[C:13]=32)=[CH:9][CH:8]=1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.CN(C)C=O.O>[N:32]([C@@H:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[C:11]([CH3:24])([CH3:23])[C:10]3[C:21]([C:13]1=2)=[CH:22][C:7]([F:6])=[CH:8][CH:9]=3)=[N+:33]=[N-:34]
Reactant: C[C@@H](O)Cn1ccc2c1-c1cc(F)ccc1C2(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](Cn1ccc2c1-c1cc(F)ccc1C2(C)C)N=[N+]=[N-]
Yield: 55.6 %

Procedure:
1.27 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 2.0 g of (R)-1-(7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 4.52 ml of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloro-methane, washed twice with 60 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 60 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 1.07 g of sodium azide and the reaction mixture was heated to 60° for 16 hours while stirring. After cooling, the solution was poured into 80 ml of water and extracted three times with 70 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.22 g (54%) of (S)-1-(2-azido-propyl)-7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=1.[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:14]1([C:15]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:8]([C:4]3[CH:3]=[C:2]([N:39]4[C:40]5[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=5[C:33]5[C:38]4=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:7]=[CH:6][CH:5]=3)=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[CH:20]3)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3cccc(-n4c5ccccc5c5ccccc54)c3)c3ccccc23)cc1
Yield: 73.4 %

Procedure:
Into a 200 mL three-neck flask were put 1.3 g (3.3 mmol) of 9-(3-bromophenyl)-10-phenylanthracene (abbr.: mPA), 0.55 g (3.3 mmol) of 9H-carbazole, and 0.63 g (6.6 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, 40 mL of toluene and 0.40 mL of tri(tert-butyl)phosphine (10 wt % hexane solution) were added to this mixture. This mixture was stirred to be degassed while the pressure was reduced. After the degassing, 95 mg (0.17 mmol) of bis(dibenzylideneacetone)palladium(0) was added to this mixture. This mixture was stirred under a nitrogen stream at 110° C. for 8 hours. After the stirring, this mixture was subjected to suction filtration through Celite (Wako Pure Chemical Industries, Ltd., catalog No.: 531-16855), alumina, and Florisil (Wako Pure Chemical Industries, Ltd., catalog No.: 540-00135). The obtained filtrate was concentrated to give a light-yellow oily substance. The obtained oily substance was recrystallized from toluene/hexane to give 1.2 g of a light-yellow solid, which was the object of the synthesis, in a yield of 71%.
Reaction SMILES: [Na].[N+:2]([CH3:5])([O-:4])=[O:3].[CH3:6][C:7]1([CH3:14])[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.C(O)(=O)C>C(O)C.O>[CH3:6][C:7]1([CH3:14])[CH2:12][CH2:11][C:10]([CH2:5][N+:2]([O-:4])=[O:3])([OH:13])[CH2:9][CH2:8]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: C[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CCC(O)(C[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of sodium (0.2 g, 0.009 mol) and ethanol (5 mL, 0.08 mol) was added a solution of nitromethane (0.77 g, 0.013 mol) and 4,4-dimethyl-cyclohexanone (1 g, 0.008 mol) in ethanol (1 mL) dropwise. The mixture was stirred at room temperature for 4 hours. Acetic acid (2 mL) and water (10 mL) were added and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with brine (30 mL×3), dried over sodium sulfate, and purified by flash chromatography to afford the desired product as a clear oil. (1.5 g, 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][NH2:34].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:32][C:28]1[CH:27]=[C:26]([S:23]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:9]3[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=3[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH3:33])[N:7]=3)[CH:17]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CNc1nccc(-c2sc(C(C)C)nc2-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol), methylamine (2.0M in THF, 2.0 mL, 4.0 mmol) and K2CO3 (283 mg, 2.0 mmol) in 1-butanol (5 mL) the title compound was obtained as a white powder (100 mg, 0.21 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.57-7.65 (m, 2H), 7.48-7.53 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.19-7.22 (m, 4H), 6.04 (s, 1H), 3.23-3.30 (m, 1H), 2.76 (s, 3H), 1.36 (d, J=6.7 Hz, 6H); m/z (ESI): 485.3 [M+H]+.
Reaction SMILES: [Na+].[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([C:12]([O-:14])=O)=[N:9][C:8]=2[CH:15]=1.[C:18]([O:22][C:23](=[O:45])[C@@H:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH:25]([CH3:27])[CH3:26])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C=O)C>[Cl-].[Na+].O>[C:18]([O:22][C:23](=[O:45])[C@@H:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:12]([C:10]3[S:11][C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:17])[F:16])=[CH:15][C:8]=4[N:9]=3)=[O:14])=[CH:42][CH:43]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH:25]([CH3:27])[CH3:26])([CH3:20])([CH3:21])[CH3:19]
Reactant: O=C([O-])c1nc2cc(C(F)(F)F)ccc2s1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4cc(C(F)(F)F)ccc4s3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
To 5-trifluoromethyl-benzothiazole-2-carboxylic acid sodium salt (260 mg, 0.97 mmol) was added (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (469 mg, 1.2 eq), BOP (515 mg, 1.2 eq) and 5 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine, and extracted with ethyl acetate. The combined organic layers were washed with brine and water. Removal of solvent gave the crude product, which was purified by column chromatography on silica gel to give 230 mg of (S)-3-methyl-2-{4′-[(5-trifluoromethyl-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][N:24]1[C:28]([Sn](CCCC)(CCCC)CCCC)=[CH:27][N:26]=[CH:25]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][O:21][C:4]1[CH:3]=[C:2]([C:28]2[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1
Reactant: CNc1nc(Nc2ccc(Br)cc2OC)ncc1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(-c3cncn3C)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 42.3 %

Procedure:
A mixture of N2-(4-bromo-2-methoxyphenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (0.151 g, 0.4 mmol), Pd(dppf)Cl2 (33 mg, 0.04 mmol) and 1-methyl-5-(tributylstannyl)-1H-imidazole (297 mg, 0.8 mmol) in dioxane (5 mL) was degassed under a stream of nitrogen for 10 min. The reaction tube was sealed and heated at 100° C. during 18 hours. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL) and the product extracted into ethyl acetate (2×20 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via preparative HPLC afforded N2-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine as a beige solid (64 mg, 42%). LCMS (10 cm_ESCI_Bicarb_MeCN): [MH+]=379 at 3.59 min. 1H NMR (400 MHz, DMSO): δ 8.33 (d, J=8.3, 1H); 8.21 (s, 1H); 8.10 (s, 1H); 7.72 (s, 1H); 7.23 (d, J=5.2, 1H); 7.16-7.07 (m, 3H); 3.95 (s, 3H); 3.74 (s, 3H); 2.96 (d, J=4.3, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:19]1[C:6]2[C:5]3[CH:22]=[CH:23][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][C:4]=3[CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:8][C:7]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1-c1ccc(N)cc1C(c1ccccc1)O2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1-c1ccc(NS(C)(=O)=O)cc1C(c1ccccc1)O2
Yield: 79 %

Procedure:
The solution of Example 5F (200 mg. 0.66 mmole), pyridine (300 mg) and methanesulfonyl chloride (227 mg., 2.00 mmole) in chloroform (3 mL) was stirred for 1 hour, washed with aqueous HCl (1M), dried (Na2SO4), filtered and concentrated under reduced pressure. Toluene was added and then concentrated. Heptane was added and concentrated under reduces pressure to provide the titled compound (199 mg. 80%). 1H NMR (300 MHz, CDCl3) δ 2.95 (s, 3H), 3.94 (s, 3H), 6.00 (s, 1H), 6.30 (s, 1H), 6.61 (d, J=2 Hz, 1H), 6.62 (dd, J=10 Hz, 2 Hz, 1H), 6.69 (dd, J=9 Hz, 1 Hz, 1H), 7.15 (t, J=9 Hz, 1H), 7.25 (dd, J=9 Hz, 2 Hz, 1H), 7.32-7.39 (m, 5H), 8.45 (d, J=9 Hz, 1H); MS (APCI) m/e 382 (M+H), 399 (M+NH4).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)C.[OH-].[Na+]>C1COCC1>[O:11]=[C:12]([CH2:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)Cc1cccc(C)c1
Reactant: CC#N
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)CC#N)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.5 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 11 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of m-tolyl-acetic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered. The organic layer is concentrated in vacuo, and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-oxo-4-m-tolyl-butyronitrile in the amount of 2.5463 gms.