Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[C:26]([F:28])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:22]=[C:21]([NH2:23])[C:20]([O:24][CH3:25])=[CH:19][N:18]=3)=[N:10]2)=[C:6]([F:29])[CH:5]=1)[CH3:2].Cl.Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>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]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:29])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:22]=[C:21]([NH:23][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[C:20]([O:24][CH3:25])=[CH:19][N:18]=3)=[N:10]2)=[C:26]([F:28])[CH:27]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(N)n3)c3c2CCC3)c(F)c1
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3c2CCC3)c(F)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
1.74 g of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazol-3-yl]-5-methoxypyrimidin-4-amine 1-4-1 (4.34 mmol, 1.00 eq.), 1.26 g of 4-bromopyridine hydrochloride (1:1) (6.50 mmol, 1.50 eq.), 540 mg of (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphtyl (0.867 mmol, 0.20 eq.), 1.66 g of sodium-tert-buylat (17.3 mmol, 4.00 eq.) and 198 mg of tris(dibenzylideneacetone)dipalladium(0) (0.867 mmol, 0.20 eq.) were suspended in 23 mL of dry DMF and stirred under nitrogen atmosphere at 100° C. bath temperature for 24 h. The reaction mixture was partitioned between half saturated aqueous ammonium chloride solution and DCM/isopropanol (4:1). The separated aqueous layer was extracted twice with DCM/isopropanol (4:1). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Toluene was added and concentrated in vacuo. The residue was purified by flash chromatography (hexane (50-100%)/ethyl acetate and ethyl acetate (0-100%)/methanole): 655 mg (1.29 mmol, 30%) of analytically pure target compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[N:4][CH:5]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 7 °C

Procedure:
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 125 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinoyl chloride (49.3 g, 235 mmol, Intermediate 4: step a), dichloromethane (493 mL), and N,O-dimethylhydroxylamine hydrochloride (25.63 g, 258.8 mmol). After the mixture was cooled to 7° C., diisopropylethylamine (90.26 mL, 517.6 mmol) was added such that the addition temperature did not exceed 16° C. After the addition, the reaction was allowed to warm to room temperature. The reaction was then transferred to a reparatory funnel and the organic layer was washed with saturated aqueous NaHCO3 (2×100 mL) followed by water (100 mL) and then dried over sodium sulfate and filtered. Removal of solvent afforded a brown oil as the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][NH2:20])[C:14]=2[C:21]([F:24])([F:23])[F:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]([F:38])([F:37])[CH2:33][C:34](Cl)=[O:35]>CCOC(C)=O.C1COCC1>[F:31][C:32]([F:38])([F:37])[CH2:33][C:34]([NH:20][NH:19][C:15]1[C:14]([C:21]([F:24])([F:22])[F:23])=[C:13]([NH:12][CH2:11][C@H:9]2[CH2:10][C@@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][N:16]=1)=[O:35]
Reactant: NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Reactant: O=C(Cl)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CC(F)(F)F)NNc1nccc(NC[C@H]2C[C@@H]2c2ccc(F)cc2)c1C(F)(F)F
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
A mixture of N-(((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)-2-hydrazinyl-3-(trifluoromethyl)pyridin-4-amine (0.38 g, 1.117 mmol) in EtOAc (3 mL) and THF (3 mL) and sat'd aqueous sodium carbonate (3 mL) was stirred as 3,3,3-trifluoropropanoyl chloride (0.213 g, 1.452 mmol) was added slowly. The mixture was stirred for 10 min. The reaction was diluted with EtOAc, washed with aqueous sodium bicarbonate, dried with brine, and concentrated. The crude product was purified by silica gel chromatography using 0-100% ethyl acetate/hexane as the eluent to give 3,3,3-trifluoro-N′-(4-((((1S,2S)-2-(4-fluorophenyl)cyclopropyl)methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)propanehydrazide as an off-white solid (0.4 g, 71.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) d 7.87 (d, J=6.3 Hz, 1H), 7.08-6.92 (m, 4H), 6.23 (d, J=6.3 Hz, 1H), 5.35 (d, J=3.8 Hz, 1H), 3.35-3.12 (m, 4H), 1.89 (dt, J=9.1, 4.9 Hz, 1H), 1.44-1.31 (m, 1H), 1.07 (dt, J=8.4, 5.5 Hz, 1H), 0.98 (dt, J=8.9, 5.5 Hz, 1H). LCMS M+1=451.1.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([O:9]CC)=[O:8]>CO>[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)c1csnn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1csnn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
1 N Aqueous solution of sodium hydroxide (6.7 ml.) was added to a solution of ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (syn isomer) (1.2 g.) in methanol (10 ml.) and the mixture was stirred for 1.5 hours at ambient temperature. Methanol was distilled off from the reaction mixture and water was added to the residue. The mixture was washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give prisms of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.7 g.), m.p. 110° to 113° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=O)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Br.[NH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:54]=[C:55]([CH:58]=[CH:59][CH:60]=1)[C:56]#[N:57]>Cl.O>[C:56]([C:55]1[CH:54]=[C:53]([CH:60]=[CH:59][CH:58]=1)[O:52][CH2:51][CH2:50][NH:49][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:18][CH:17]=1)#[N:57]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: CCOC(=O)c1ccc(Nc2ccncc2)cc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cccc(OCCNC(=O)c2ccc(Nc3ccncc3)cc2)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
180 mg (0.743 mmol) of ethyl 4-[(pyridine-4-yl)amino]benzoate was dissolved in 5 ml of concentrated hydrochloric acid, and the solution was stirred at 70° C. for 15 hours. The solvent was evaporated, and the residue was dissolved in 5 ml of dichloromethane. 0.23 ml (1.64 mmol) of triethylamine, 156 mg (0.82 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 208 mg (0.82 mmol) of 1-hydroxybenzotriazole and 199 mg (0.82 mmol) of 3-(2-aminoethoxy)benzonitrile hydrobromide were added to the solution, and they were stirred for 16 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was successively washed with water, 1 N sodium hydroxide and saturated aqueous NaCl solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33]>CN(C=O)C.C(OCC)(=O)C>[C:28]1(=[O:33])[N:27]([O:10][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[C:31](=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 4-hydroxyphenylacetic acid (3.0 g, 20 mmol) in DMF was added HOBT (3.7 g, 24 mmol) followed by EDC (4.2 g, 22 mmol) and the mixture was stirred at room temperature for 30 min. N-hydroxysuccinimide (2.3 g, 20 mmol) was added and stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate (150 ml), extracted with 5% citric acid (2×), saturated NaHCO3 (2×) and brine (1×) and was dried over anhydrous Na2SO4. Following removal of the solvent in vacuo the product was dissolved in CH2Cl2 and precipitated with hexanes to afford 4-hydroxyphenylacetic acid succinimidyl ester (3.9 g, 78%). 1H NMR (300 MHz, DMSO-d6): 2.79 (s, 4H), 3.93 (s, 2H), 6.72 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 9.41 (s, 1H).
Reaction SMILES: O=[O+][O-].C=[C:5]1[CH2:10][N:9]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][N:7]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:6]1.C(=O)=[O:36].CC(C)=O.CSC>O=O.CC(C)=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:9]2[CH2:10][C:5](=[O:36])[CH2:6][N:7]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:8]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: C=C1CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C=O
Agent: O=O
Agent: O=[O+][O-]
Solvent: CSC
Solvent: CC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A stream of ozone in oxygen was bubbled into a solution of hexahydro-5-(methylene)-1,3-bis(4-nitrobenzenesulfonyl)pyrimidine (0.6 g, 1.3 mmol) in 150 mL acetone at −78° C. (dry ice-acetone bath) until a blue color persisted for 5 minutes. The reaction was stirred for 15 minutes under a nitrogen atmosphere. Next, 2.0 mL of dimethyl sulfide was added. After stirring for 10 minutes, the solvent was removed and the solid dried under reduced pressure to give 0.5 g (83%) of tetrahydro-1,3-bis(4-nitrobenzenesulfonyl)pyrimidin-5(4H)-one. [1H NMR (acetone-d6): δ3.95 (s, 4H), 5.25 (s, 2H), 8.20, 8.48 (AB q, J=9.0 Hz, 8H); 13C NMR (DMSO-d6): δ53.8, 58.8, 124.8, 129.3, 141.9, 150.4, 196.2].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].CS(O[CH2:15][C:16]1[C:17]2[CH:25]=[C:24]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[S:23][C:18]=2[N:19]=[C:20]([CH3:22])[N:21]=1)(=O)=O.Cl>O.CN(C=O)C.C1COCC1>[CH:26]1([C:24]2[S:23][C:18]3[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([CH2:15][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]4=[O:7])[C:17]=3[CH:25]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCCCC3)sc2n1
Reactant: O=C1CCCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(CN2CCCCC2=O)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
To a mixture of piperidin-2-one (100 mg), THF (4 mL), and DMF (1 mL) was added NaH (60% oil, 40 mg), followed by stirring at room temperature for 30 minutes, and then (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl methanesulfonate (150 mg) was added thereto, followed by further stirring at room temperature for 1 hour. To the reaction mixture were added water and 1 M hydrochloric acid, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain 1-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]piperidin-2-one (13 mg).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]([F:20])([F:19])[C:9]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=1.CI.O>O1CCCC1>[CH3:1][N:12]1[CH:13]=[C:9]([C:8]([F:7])([F:19])[F:20])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(C)cc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of potassium t-butoxide (4.5 g, 0.04 mol) in tetrahydrofuran is treated dropwise with a solution of ethyl 4-(trifluoromethy1)pyrrole-3-carboxylate (8.3 g, 0.04 mol) in tetrahydrofuran over a 20 minute period at 20°-25° C., stirred for 30 minutes, treated dropwise with methyl iodide (5.7 g, 0.04 mol), stirred at room temperature for 24 hours and poured into water. The resultant mixture is extracted with ether and the combined extracts are washed with brine, dried (MgSO4) and concentrated in vacuo to afford a brown oil residue. The residue is distilled using a Kugelrohr distillation apparatus to give a gummy solid at 80° to 85° C./0.2 mm Hg. The solid is purified using ether and basic alumina to yield the title compound as a clear oil, 6.37 g (72%), identified by NMR and elemental analyses.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[C:12]([NH:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN1C(=O)CCC1>[CH3:8][C:6]1[CH:7]=[C:2]([N:18]2[CH2:19][CH2:20][CH:16]([NH:15][C:12](=[O:14])[CH3:13])[CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)NC1CCNC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(C)c2)C1
Temperature: 95 °C
Yield: 97.6 %

Procedure:
After dissolving 15.5 g of 5-fluoro-2-nitrotoluene (0.1 mol) and 12.8 g of 3-acetamido-pyrrolidine (0.1 mol) in 75 ml of NMP, 15.8 g of potassium carbonate (0.12 mol) are added under a nitrogen atmosphere and the mixture is heated at 95° C. for 20 h. The reaction medium is allowed to cool and is then poured into 600 ml of saturated aqueous sodium chloride solution. The yellow precipitate formed is filtered off, washed with 15% NaCl solution until a pH equal to 7 is obtained for the washing waters, and washed with petroleum ether and then dried in a vacuum oven over P2O5. 25.7 g (98%) of N-[1-(3-methyl-4-nitrophenyl)pyrrolidin-3-yl]acetamide are thus obtained in the form of a yellow solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([NH:15][CH:16]1[CH2:44][CH2:43][CH:19]2[CH:20]([CH3:42])[NH:21][C:22]3[C:27]([CH:18]2[CH2:17]1)=[C:26]([O:28][C:29](=[O:31])[CH3:30])[CH:25]=[C:24]([S:32][CH:33]([CH:35]([CH3:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:34])[CH:23]=3)(=[O:14])[CH3:13].C(Cl)(Cl)Cl>C(O)(=O)C>[C:12]([NH:15][CH:16]1[CH2:44][CH2:43][CH:19]2[CH:20]([CH3:42])[NH:21][C:22]3[C:27]([CH:18]2[CH2:17]1)=[C:26]([O:28][C:29](=[O:31])[CH3:30])[CH:25]=[C:24]([S:32]([CH:33]([CH:35]([CH3:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:34])=[O:9])[CH:23]=3)(=[O:14])[CH3:13]
Reactant: CCCCCC(C)C(C)Sc1cc2c(c(OC(C)=O)c1)C1CC(NC(C)=O)CCC1C(C)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)C(C)S(=O)c1cc2c(c(OC(C)=O)c1)C1CC(NC(C)=O)CCC1C(C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Equimolar amounts of m-chloroperbenzoic acid and dl-9-acetamido-1-acetoxy-6-methyl-3-(3-methyl-2-octylthio)5,6,6a,7,8,9,10,10a-octahydrobenzo[c]quinoline are added to a mixture of chloroform and acetic acid (2:1 v/v) and the mixture stirred at room temperature for one hour. The reaction mixture is washed with water, the organic phase dried over magnesium sulfate and evaporated to dryness at reduced pressure to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[N:39]=[C:38](Cl)[CH:37]=[CH:36][N:35]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([C:36]2[CH:37]=[CH:38][N:39]=[C:34]([Cl:33])[N:35]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1ccnc(Cl)n1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Yield: 31.7 %

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 3.9 g, 8.9 mmol) was reacted with 2,4-dichloropyrimidine (3.06 g, 20.5 mmol). The crude residue was purified by flash chromatography on silica, eluting with ethyl acetate/isohexane (1:1) to give the title compound (1.2 g, 32%); NMR Spectrum: (DMSO-d6) 1.45 (s, 9H), 7.23 (m, 2H), 7.57 (t, 2H), 8.15 (d, 2H), 8.29 (d, 1H), 8.38 (d, 2H), 8.73 (s, 1H), 8.91 (d, 1H), 10.00 (s, 1H); Mass Spectrum: M−H− 423.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][C:43]=1[F:49].[CH2:51]([C:53]([C:72]1[CH:85]=[CH:84][C:75]([O:76][CH2:77][CH:78]([OH:83])[C:79]([CH3:82])([CH3:81])[CH3:80])=[C:74]([CH3:86])[CH:73]=1)([C:56]1[CH:61]=[CH:60][C:59](B2OC(C)(C)C(C)(C)O2)=[C:58]([CH3:71])[CH:57]=1)[CH2:54][CH3:55])[CH3:52]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:59]2[CH:60]=[CH:61][C:56]([C:53]([C:72]3[CH:85]=[CH:84][C:75]([O:76][CH2:77][C:78](=[O:83])[C:79]([CH3:81])([CH3:80])[CH3:82])=[C:74]([CH3:86])[CH:73]=3)([CH2:54][CH3:55])[CH2:51][CH3:52])=[CH:57][C:58]=2[CH3:71])=[CH:44][C:43]=1[F:49]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
A solution of palladium acetate (3.8 mg, 0.017 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (14.0 mg, 0.034 mmol) and potassium phosphate (72.3 mg, 0.34 mmol) in water (0.050 mL) and toluene (0.200 mL) was stirred for three minutes. A solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 37.0 mg, 0.18 mmol) and 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol (Example 30-(2); 60.0 mg, 0.12 mmol) in toluene (0.3 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for one hour. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (5% ethyl acetate/hexane) to give the title compound (38.6 mg, 59%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[CH3:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1)(=[O:16])=[O:15].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][N:21]=2)[CH:7]=1
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: CS(=O)(=O)c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1nnc(Cl)cc1Nc1ccc(S(C)(=O)=O)cn1
Temperature: 100 °C
Yield: 18.7 %

Procedure:
A flask was charged with methyl 4,6-dichloropyridazine-3-carboxylate (200 mg, 0.966 mmol), 5-(methylsulfonyl)pyridin-2-amine (183 mg, 1.06 mmol), Pd2(dba)3 (88.5 mg, 0.097 mmol), xantphos (112 mg, 0.193 mmol) and cesium carbonate (944 mg, 2.9 mmol). 1,4-Dioxane (6.0 mL) was added and argon was bubbled through it while sonicating the flask for 5 min. The flask was sealed and heated at 100° C. for 1 h. After cooling the mixture was filtered through celite and the filter cake washed with CH2Cl2. The filtrates were concentrated in vacuo then purified by chromatography (spherical silica 20-45 μM, 23 g, Versaflash Supelco, 0 to 100% ethyl acetate in hexanes, 30 min) to give methyl 6-chloro-4-(5-(methylsulfonyl)pyridin-2-ylamino)pyridazine-3-carboxylate (62 mg, 19%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.18 (s, 1H) 9.31 (s, 1H) 8.98 (d, J=2.27 Hz, 1H) 8.19 (dd, J=8.59, 2.53 Hz, 1H) 7.09 (dd, J=8.84, 0.76 Hz, 1H) 4.15 (s, 3H) 3.15 (s, 3H). LCMS (EI/CI) m/z: 342.9 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[CH3:16][NH:17][CH2:18][CH2:19][CH3:20].[I-].[K+]>CC(C)=O>[CH3:12][C:11]([CH3:14])([CH3:13])[C:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:17]([CH3:16])[CH2:18][CH2:19][CH3:20])[N:8]=1)=[O:15]
Reactant: CC(C)(C)C(=O)Nc1cccc(CCl)n1
Reactant: CCCNC
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(C)Cc1cccc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C

Procedure:
N-(6-chloromethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.66 g), methyl-propylamine (0.33 mL), KHCO3 (0.32 g) and a catalytic amount of potassium iodide in acetone (10 mL) were heated to reflux for 6 h. The-reaction mixture was cooled to RT and partitioned between water and AcOEt, the layers were separated, the organic layer dried over MgSO4, filtered and evaporated to give 2,2-dimethyl-N-{6-[(methyl-propyl-amino)-methyl)-pyridin-2-yl}-propionamide (0.75 g) as a brown oil. MS (ESI): 264.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Nc1ccccc1O
Reactant: COc1cc(C(=O)O)ccc1C
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2ccccc2O)ccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxy-4-methyl benzoic acid (1.2 g, 7.2 mmol) and thionyl chloride (10 mL) was heated to reflux conditions under argon until no starting material was observed by TLC. After cooling mixture to rt and concentration in vacuo, the resulting brown oil was dissolved in THF (15 mL) and slowly added to a cooled mixture of 2-aminophenol (780 mg, 7.1 mmol), diisopropylethyl amine (1.5 mL, 8.6 mmol) and THF (20 mL) at 0° C. Reaction mixture was allowed to warm to rt. After one hour, no starting material acid was observed by TLC. After concentrating reaction mixture in vacuo, the resulting brown oil was purified by flash chromatography on silica gel, using 1:4 EtOAc:hexanes. This afforded the desired intermediate, N-(2-hydroxyphenyl)-3-methoxy-4-methylbenzamide, as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]2C2CCCCO2)=[C:9]([NH2:24])[N:8]=1)[CH3:2].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[NH:8][C:9]([NH2:24])=[C:10]2[C:14]([N:15]=1)=[N:13][C:12]([O:22][CH3:23])=[N:11]2)[CH3:2]
Reactant: CCOCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCOCCOc1nc2nc(OC)nc-2c(N)[nH]1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-{[2-(Ethyloxy)ethyl]oxy}-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (4.78 g, 14.2 mmol) was dissolved in MeOH (30 ml) and TFA (7.5 ml) was added with stirring at 0° C. The mixture was left standing at room temperature for 1 day. A white solid was formed. The solid was filtered off and washed with ethyl acetate and dried in vacuo. This gave product (4 g, 80.5%).