Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>P(Cl)(Cl)(Cl)=O.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: C1=COCCC1
Reactant: OCCCCCBr
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: BrCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 36 g of 5-bromopentan-1-ol were added 24.72 ml of 2,3-dihydropyran and 3 drops of phosphorus oxychloride under cooling in an ice bath, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with 5% aqueous potassium hydroxide, water, a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1:19) as eluent to give 49.5 g of the subtitle compound having the following physical characteristics:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+].Cl>C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:15])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2noc(C)n2)c(C=O)cc1OCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-c2noc(C)n2)c(C(O)c2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzaldehyde (reference example 15-1) (450 mg) and tetrahydrofuran (5.6 mL) was added dropwise phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 1.4 mL) in an ice salt bath. After stirring at the same temperature for 30 minutes, an aqueous solution of ammonium chloride, 2 mol/L hydrochloric acid and ethyl acetate were added to the mixture. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (564 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[NH:18][C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(OCc2ccccc2)c(Cl)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Yield: 74.8 %

Procedure:
A mixture of 4.27 g (10.3 mmol) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy)phenyl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione and 420 mg of 10% palladium on charcoal in 70 mL of ethyl acetate was placed in a Paar bottle and was agitated under 45 psi hydrogen over a 16 hour period. It was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo and the resultant crude product flash chromatographed over silica gel, eluting with a 95:5 v:v mixture of dichloromethane and methanol to give 2.50 g of the title compound as a pale orange solid, m.p.: 68°-72° C.; 1H-NMR (DMSO-d6): ppm 7.5 (d, 1H), 7.0 (d, 1H), 6.4 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10]([CH2:12][CH:13]([CH3:15])[CH3:14])=[O:11].Cl[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20].[Cl-].[NH4+]>CO>[CH3:14][CH:13]([CH3:15])[CH2:12][C:10]([C:3]1[C:2]([OH:1])=[C:7]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:6]([OH:8])=[C:5]([CH2:7][CH:2]=[C:3]([CH3:10])[CH3:4])[C:4]=1[OH:9])=[O:11]
Reactant: CC(C)=CCCl
Reactant: CC(C)CC(=O)c1c(O)cc(O)cc1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)=CCc1c(O)c(CC=C(C)C)c(O)c(C(=O)CC(C)C)c1O
Yield: 17.1 %

Procedure:
Under an atmosphere of nitrogen, 441 mg (11.1 mmol, 2.06 equivalents) of an oily 60% sodium hydride was washed with dry hexane to remove paraffin. To this was added 6.0 ml of dry methanol cooling with ice and stirred. Then, a methanol (6.0 ml) solution of 1.135 g (5.400 mmol) of (2-methylpropyl) (2,4,6-trihydroxyphenyl) ketone (5) was added dropwise to the solution. Further, a methanol (5.0 ml) solution of 1.205 g (11.52 mmol, 2.130 equivalents) of 1-chloro-3-methyl-2-butene was slowly added dropwise. The mixture was stirred cooling with ice for 1.5 hours, then added 50 ml of a saturated aqueous ammonium chloride solution, and extracted from ether. The ether layer was washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to remove the solvent and obtain 1.752 g of a crude product in the form of a red viscous oily substance. This crude product was subjected to silica gel column chromatography (40 g of Wako Gel C-300 and eluted sequentially with 200 ml each of petroleum ether:ether at varying ratios=19:1, 18:2, 17:3, and 16:4). From the eluate of the column, various fractions were sequentially obtained. As the first fraction, 160 mg of {3,5-bis(3-methyl-2-butenyl)-2,4,6-trihydroxyphenyl} (2-methylpropyl) ketone (15) was obtained in the form of light yellow crystals shaped fine needles.
Reaction SMILES: COC([CH:5]1[C:20](=[O:21])[CH2:19][C:8]2([CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[NH:7][C:6]1=[O:22])=O>C(#N)C.O>[C:15]([O:14][C:12]([N:10]1[CH2:11][C:8]2([CH2:19][C:20](=[O:21])[CH2:5][C:6](=[O:22])[NH:7]2)[CH2:9]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C1C(=O)CC2(CN(C(=O)OC(C)(C)C)C2)NC1=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)CC(=O)N2)C1

Procedure:
6,8-Dioxo-2,5-diaza-spiro[3.5]nonane-2,7-dicarboxylic acid 2-tert-butyl ester 7-methyl ester (1.1 g; 3.5 mmol) is refluxed in acetonitrile/water (18 ml/2 ml) for 50 minutes and evaporated to dryness. The residue is triturated with CH2Cl2 to deliver the title compound as colorless crystals. 1H-NMR (400 MHz; DMSO-d6): Keto-enol tautomerism. 10.70 (s, 1H); 8.75 (s, 0.5H); 7.55 (s, 0.5H); 4.85 (s, 1H); 3.94 (bd, 2H); 3.86 (bd, 2H); 3.78 (bs (2H); 1.40 (s, 9H); MS (m/z) ES+: 255 (25; MH+); 199 (100).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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)(C)C.O>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:26])([F:25])[F:27])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(-c4ccccc4F)ncc3n2)ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[1,2-a]pyrazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0516 g, 0.13 mmol), 2-fluorophenylboronic acid (Combi-Blocks, 32 mg, 0.26 mmol), Na2CO3 (0.0413 g, 0.39 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.009 g, 0.01 mmol), and isopropanol-water (1 mL, 3:1). The mixture is stirred at 70° C. for 16 hr. The reaction mixture is concentrated, taken up into EtOAc and CH2Cl2 (1:1) and purified by preparative plate TLC (1:1 Hexanes:EtoAc) to give the title compound (6 mg, 10% yield). LCMS m/z=457.5 [M+H]+, tR=3.06 min. (compound same as Example 86)
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1.Cl[C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+]>C1COCC1.CCOC(C)=O>[N:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:5]3[N:6]([CH:36]=[C:3]([CH2:2][O:1][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:8][N:9]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(-c4ccncc4)c4nc(CO)cn34)cn2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(-c4ccncc4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of compound 87d (80.0 mg, 0.164 mmol), 2-chloroquinoline (40.3 mg, 0.246 mmol) and 18-crown-6 (43.8 mg, 0.164 mmol) in 5 mL of THF at rt was added potassium tert-butoxide (0.328 mL, 0.328 mmol, 1.0M in t-BuOH). The resulting mixture was heated to 60° C. and continued to stir for 0.5 h. After cooling to rt, the mixture was treated with 30 mL of EtOAc and washed with water (2×10 mL) and brine (10 mL). Removal of the solvent under reduced pressure followed by purification of the resultant residue by flash column chromatography on silica gel (0-4% MeOH/DCM) gave compound 87e as a yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.82 (br. s., 2H), 8.70 (br. s., 2H), 8.51 (br. s., 1H), 7.91-8.09 (m, 3H), 7.70-7.91 (m, 3H), 7.64 (t, J=7.2 Hz, 1H), 7.41 (t, J=6.8 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 5.84 (s, 2H), 3.70 (br. s., 4H), 3.60 (br. s., 4H), 1.51 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calcd. for C35H34N8O3, 615.3 (M+H). found 615.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:21][CH:20]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ncc(N)cn2)C1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 81.4 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyrimidin-2-yl)piperidin-3-ylcarbamate (440 mg, 1.5 mmol) to afford the desired product (462 mg, 80%) as a yellow solid: ESI MS m/z 567 [C27H31BrN6O3+H]+.
Reaction SMILES: [OH:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]#[N:9])[S:4](=[O:11])(=[O:10])[N:3]=1.[Na].[Na].[N+]([O-])([O-])=O.[Ag+:18]>O>[Ag:18].[Ag:18].[OH:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]#[N:9])[S:4](=[O:11])(=[O:10])[N:3]=1
Reactant: [Ag+]
Agent: N#CC1=C(O)C(O)=NS1(=O)=O
Agent: O=[N+]([O-])[O-]
Agent: [Na]
Solvent: O
Product: [Ag]
Reaction time: 2.5 h

Procedure:
To a solution of disodium 3,4-dihydroxy-5-cyanoisothiazole-1,1-dioxide (7.4 g, 34 mmol) in water (60 ml) there was added a solution of silver nitrate (11.5 g, 68 mmol) in water (40 ml). The resulting suspension was stirred for 2-3 hours and the precipitate collected by filtration and washed with ethanol, diethyl ether and dried to give 11.4 g of title compound which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC(C)Oc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC(C)C)ncn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
In 0.5 ml of tetrahydrofuran was suspended 0.02 g of sodium hydride (60% in oil), to which 0.1 ml of a solution containing 0.02 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature. After stirring at room temperature for 20 minutes, 0.1 ml of a solution containing 0.05 g of 4-chloro-6-(isopropyloxy)pyrimidine in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 2 hours. The mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.05 g of 4-(2-butynyloxy)-6-isopropoxypyrimidine (the present compound (1)).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(Cl)Cl>[N+:17]([C:4]1[CH:3]=[C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][C:5]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])([O-:19])=[O:18]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(N2CCNCC2)ccc1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 4-fluoro-2-nitro-1-(phenylsulfonyl) benzene (1.0 g, 3.6 mmol), piperazine (0.37 g, 4.3 mmol), and potassium carbonate (0.79 g, 5.7 mmol) is stirred in 35 mL of acetonitrile overnight at reflux. The mixture is cooled to rt and 35 mL of water and CH2Cl2 are added. The layers are separated and the aqueous layer extracted with CH2Cl2 (3×35 mL). The combined organics are dried over MgSO4, filtered, and concentrated. Purification via flash column chromatography (15% MeOH/CH2Cl2) gives 1.1 g (92%) of title compound as a solid, mp 180-182° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH:5]=[CH:6][C:7]=1[S:8](=[O:21])(=[O:20])[NH:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:17][O:16][B:15]([OH:18])[C:14]=2[CH:19]=1.C([Sn](CCCC)(CCCC)/[CH:34]=[CH:35]/[O:36][CH2:37][CH3:38])CCC.CN(CCO)C>CN1C(=O)CCC1.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]>[CH2:37]([O:36]/[CH:35]=[CH:34]/[C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:28])[C:24]([F:26])([F:27])[F:25])[CH:5]=[CH:6][C:7]=1[S:8](=[O:20])(=[O:21])[NH:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:17][O:16][B:15]([OH:18])[C:14]=2[CH:19]=1)[CH3:38]
Reactant: CCCC[Sn](/C=C/OCC)(CCCC)CCCC
Reactant: O=C(Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(Br)c1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CN(C)CCO
Solvent: CN1CCCC1=O
Product: CCO/C=C/c1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 100 °C

Procedure:
The mix of N-(3-bromo-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2,2,2-trifluoroacetamide (87 mg, 0.182 mmol), (E)-tributyl(2-ethoxyvinyl) stannane (71 mg, 0.196 mmol), dimethylamino ethanol (17.9 mg, 0.2 mmol) and Pd(dppf)2Cl2 in NMP (2 ml) was degassed and heated to 100° C. overnight. The crude product was purified by prep-HPLC to give (E)-N-(3-(2-ethoxyvinyl)-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2,2,2-trifluoroacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:40][C:12]3[C:13](=[O:39])[N:14]([CH2:17][C:18]4[N:23]=[C:22]([O:24][CH2:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][N:27]5C(OC(C)(C)C)=O)[CH:21]=[CH:20][CH:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:40][C:12]3[C:13](=[O:39])[N:14]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([O:24][CH2:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]5)[N:23]=4)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc3cnn(Cc4cccc(OC[C@@H]5CCCCN5C(=O)OC(C)(C)C)n4)c(=O)c3s2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cc3cnn(Cc4cccc(OC[C@@H]5CCCCN5)n4)c(=O)c3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (2S)-2-{[(6-{[2-(4-methoxyphenyl)-7-oxothieno[2,3-d]pyridazin-6(7H)-yl]methyl}pyridin-2-yl)oxy]methyl}piperidine-1-carboxylate (354 mg, 0.629 mmol) was dissolved in DCM (7 ml) and TFA (1 ml) was added. The reaction was stirred at rt. for 30 min and the solvent evaporated in vacuo. To the resultant oil was added DCM (100 ml) and 5% Na2CO3 (aq) (100 ml), the phases separated and the aqueous phase extracted with DCM (100 ml). The combined organics were dried through a phase separator and evaporated in vacuo yielding the title compound as a light yellow solid. Yield: 290 mg (100%). MS (ESI+) 463.23 (M+1H+)
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([C@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)[C:12]([O:14]C)=[O:13])=[O:10])([CH3:7])([CH3:6])[CH3:5].C1COCC1>O>[C:4]([O:8][C:9]([C@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)[C:12]([OH:14])=[O:13])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)[C@@H](Cc1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
LiOH—H2O (0.6246 g, 14.88 mmol) was added to a solution of (R)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)propanoate (1.646 g, 4.961 mmol) in 1:1 THF:H2O (26 mL). The reaction mixture was stirred at room temperature for 2 hours, after which it was diluted with H2O and washed with EtOAc. The aqueous layer was then acidified with solid KHSO4 and extracted with DCM. The combined extracts were dried (Na2SO4), filtered, concentrated, and then re-concentrated from DCM/hexanes to give (R)-2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)-propanoic acid (1.31 g, 83.10% yield) as a white powder. LCMS (APCI) m/z 316 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[N:4]1)[CH3:2].[CH2:17]([C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][N:20]1C(OC(C)(C)C)=O)[CH3:18]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:22]2[N:23]=[CH:24][C:6]3[CH:5]=[N:4][N:3]([C:1]4[CH:2]=[CH:18][CH:17]=[C:19]([N:23]5[CH2:22][CH2:21][NH:20][C@H:19]([CH2:17][CH3:18])[CH2:24]5)[N:20]=4)[C:7]=3[CH:21]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CC[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC[C@@H]1CN(c2cccc(-n3ncc4cnc(-c5cnn(CC)c5)cc43)n2)CCN1
Yield: 10 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and (R)-tert-butyl 2-ethylpiperazine-1-carboxylate, 142 was obtained as an off-white solid (12.7 mg, 10%) over 2 steps. 1H NMR (400 MHz, DMSO) δ 9.18-9.06 (s, 1H), 8.67-8.59 (s, 1H), 8.56-8.49 (s, 1H), 8.31-8.25 (s, 1H), 7.95-7.90 (s, 1H), 7.78-7.70 (t, J=8.1 Hz, 1H), 7.23-7.15 (d, J=7.7 Hz, 1H), 6.84-6.76 (d, J=8.5 Hz, 1H), 4.27-4.15 (m, 4H), 3.10-3.03 (d, J=11.7 Hz, 1H), 3.01-2.93 (td, J=11.8, 3.0 Hz, 1H), 2.86-2.77 (td, J=11.6, 3.0 Hz, 1H), 2.68-2.56 (m, 2H), 1.48-1.38 (m, 5H), 0.94-0.87 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 403.2 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH:3]=1.[CH3:16][N:17]([CH3:29])[C:18]([CH2:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)=[O:19]>>[CH3:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[NH:8][C:4]1[CH:3]=[C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:18](=[O:19])[N:17]([CH3:16])[CH3:29])=[CH:28][CH:27]=2)[N:7]=[CH:6][N:5]=1
Reactant: CN(C)C(=O)COc1ccc(N)cc1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC(=O)N(C)C)cc3)ncn2)c1
Yield: 15 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(3'-methylanilino)pyrimidine (0.410 g) was reacted with 4-(N,N-dimethylcarbamoylmethoxy)aniline (0.420 g). The product was chromatographed on silica and recrystallised from a mixture of methylene chloride and hexane to give 4-(3'-methylanilino)-6-[4'-(N,N-dimethylcarbamoylmethoxy)anilino]pyrimidine in 15% yield, m.p. 135°-138° C.;
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[S:13][C:14](Br)=[CH:15][C:16]=1[Br:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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>[Br:17][C:16]1[CH:15]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:13][C:12]=1[CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1sc(Br)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: CCOC(=O)C(OC(C)(C)C)c1sc(-c2ccccc2)cc1Br
Temperature: 60 °C
Yield: 64.7 %

Procedure:
To a solution of ethyl 2-(tert-butoxy)-2-(3,5-dibromothiophen-2-yl)acetate (10c) (70 mg, 0.17 mmol) in tetrahydrofuran (1 mL) were added tripotassium phosphate (111 mg, 0.52 mmol), phenylboronic acid (23 mg, 0.19 mmol) and a solution of palladium acetate (1.2 mg, 5.2 μmol) and xantphos (3.0 mg, 5.2 μmol) in tetrahydrofuran (1 mL) previously stirred for 5 minutes. The reaction mixture was heated at 60° C. for 3 hours. The mixture was then filtered and the precipitate was rinsed with dichloromethane (5 mL). The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (cyclohexane/ethyl acetate 80/20) to provide the desired product (10d) (45 mg, 0.11 mmol, 65%).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]2[C@H:5]1[C@@H:6]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]2)(=[O:3])[CH3:2].[CH3:24][CH2:25][CH:26]([OH:29])[CH2:27][CH3:28]>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[C:1]([NH:4][C@@H:5]1[C@@H:6]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C@H:10]1[O:29][CH:26]([CH2:27][CH3:28])[CH2:25][CH3:24])(=[O:3])[CH3:2]
Reactant: CCC(O)CC
Reactant: CCOC(=O)C1=C[C@H]2[C@@H]([C@@H](NC(=O)OC(C)(C)C)C1)N2C(C)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 60 %

Procedure:
To a solution of aziridine 13 (16 mg; 0.05 mmol) in 3-pentanol (1 mL) was added Cu(OTf)2 (3 mg; 0.008 mmol). After 16 h the reaction mixture was quenched by addition of saturated solution of NaHCO3 (0.1 ml) and concentrated. Chromatography of residue [hexane-ethyl acetate (3:1)→(2:1), 4.5 ml silica] afforded 12 mg (60%) of compound 15 as white solid: m.p.=144-145° C. (CHCl3); RF=0.3 (ethyl acetate-hexane 1:2); [α]20D=−21.54 (c=0.5, CHCl3); IR (KBr, cm−1) ν 3324, 2976, 3966, 2933, 2877, 2855, 1720, 1687, 1658, 1587, 1536, 1459, 1384, 1297, 1250, 1176, 1146, 1130, 1086, 1054, 1019, 948; 1H NMR (CDCl3, 600 Mhz) δ 6.81 (s, 1H), 5.80 (d, J=9.6 Hz, 1H), 5.11 (d, J=9.0 Hz, 1H), 4.22 (m, 2H), 4.08 (ddd, J=2 x≈4.8, 9.3 Hz, 1H), 3.97 (m, 1H), 3.81 (ddd, J=5.1, 2×9.6 Hz, 1H), 3.37 (qui, J=5.7 Hz, 1H), 2.76 (dd, J=4.8, 17.7 Hz, 1H), 2.31 (m, 1H), 2.00 (s, 3H), 1.51 (m, 4H), 1.44 (s, 9H), 1.30 (t, J=7.2 Hz, 3H), 0.90 (m, 6H); 13C NMR (CDCl3, 150 Mhz) δ 170.85, 165.98, 156.35, 137.65, 129.34, 82.21, 79.73, 76.00, 61.00, 54.47, 49.00, 31.01, 28.33, 26.12, 25.69, 23.41, 14.20, 9.54, 9.21.