Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:21][CH2:22][CH2:23][CH2:24][C:25](Br)=[O:26]>C(Cl)(Cl)Cl.O>[Br:21][CH2:22][CH2:23][CH2:24][C:25]([NH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=[O:26]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(Br)CCCBr
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCBr
Yield: 63.1 %

Procedure:
To a solution of 2,6-diisopropylaniline (1.77 g, 10 mmol) in chloroform (30 ml) was added triethylamine (1.11 g, 11 mmole), then 4-bromobutyryl bromide (1.95 mg, 10.5 mmol) was slowly dropped thereinto with ice cooling and the mixture was made to react for 20 minutes. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with 0.5N HCl, water, aqueous solution of sodium bicarbonate and saturated sodium chloride solution successively and dried over magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (120 g of silica gel; developing solvent, hexane:acetone=7:1→5:1) and the resulting crude crystals were recrystallized from hexane-acetone to provide 2.06 g (yield 63%) of 4-bromo-N-(2,6-diisopropylphenyl)butyramide as colorless needles.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: NCCCCCO
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(NCCCCCO)c1ccccc1

Procedure:
The preparation is carried out as in Example 1(a) from 353 g (2 mol) of benzenesulphonyl chloride and 216.6 g (2.1 mol) of 5-amino-1-pentanol.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][NH:5][C@H:4]1[C:8]([OH:10])=S)[CH3:2].C[C@@H]1CCN[C@H]1C([OH:19])=S.C(S)C.C(CCC(Cl)=S)(=O)C>>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][NH:5][C@H:4]1[C:8]([OH:10])=[O:19])[CH3:2]
Reactant: C[C@@H]1CCN[C@H]1C(O)=S
Reactant: CC[C@@H]1CCN[C@H]1C(O)=S
Agent: CC(=O)CCC(=S)Cl
Solvent: CCS
Product: CC[C@@H]1CCN[C@H]1C(=O)O

Procedure:
Following the general procedure of Example 79 (a) to (d) but substituting an equivalent amount of ethyl mercaptan for the methanethiol one obtains (trans)-3-ethyl-D,L-proline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([F:41])[CH:36]=1>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].ClCCl>[F:41][C:37]1[CH:36]=[C:35]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][N:19]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Fc1cc(Br)ccn1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccnc(F)c2)c1
Temperature: 86 °C

Procedure:
A mixture of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (8.00 g, 21.1 mmol), PdCl2(dppf)-dichloromethane adduct (0.861 g, 1.06 mmol), 2-methyl-THF (70.0 mL), 2 M sodium carbonate (21.1 mL, 42.2 mmol), and 4-bromo-2-fluoro pyridine (2.40 mL, 23.2 mmol) was heated to 86° C. for 6 hours under an argon atmosphere. The reaction mixture was directly subjected to an extraction where the aqueous and organic layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed sequentially with saturated sodium bicarbonate (40 mL) and saturated aqueous sodium chloride (40 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was triturated with a mixture of ethyl acetate (15 mL), dichloromethane (5 mL), and methanol (2 mL) to afford N-[3-(2-fluoropyridin-4-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine as an off-white solid. MS APCI calc'd for C17H13F4N4 [M+H]+ 349. found 349. 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.84 (d, J=4.9 Hz, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.09 (s, 1H), 7.61 (d, J=6.2 Hz, 2H), 7.39 (s, 1H), 7.34 (s, 1H), 7.29 (d, J=4.9 Hz, 1H), 2.36 (s, 3H).
Reaction SMILES: CN(C=O)C.[CH3:6][CH:7]([OH:16])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>O>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([O:16][CH:7]([CH3:6])[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(O)CCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
To 100 mL of DMF is added α-methyl-4-morpholinepropanol (15.9 g, 0.1 mol) and 7.2 g (50% in mineral oil, 0.15 mol) of NaH followed by 14.1 g (0.1 mol) of 1-fluoro4-nitrobenzene. Heat the reaction at 80° C. and monitor the reaction by thin-layer chromatography. Upon completion of the reaction add 100 mL of water and extract with ether. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: Cl.Cl.[C:3]([NH:11][NH2:12])(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:13]([O-])=O.[Na+].C(OCC)C.C(=O)(O)[O-].[Na+]>O>[CH2:3]([N:11]=[N+:12]=[N-:13])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=NCc1cccnc1
Yield: 86.1 %

Procedure:
To a solution of nicotinic acid hydrazide dihydrochloride (2 g) in water (10 ml) was added a solution of sodium nitrite (1.6 g) in water (10 ml), keeping the temperature below 20° C. Diethyl ether (50 ml) was then added and the mixture basified by the careful addition of solid sodium bicarbonate. The organic layer was separated, washed with water (20 ml), dried over anhydrous magnesium sulphate and evaporated to dryness under vacuum to give nicotinyl azide (1.1 g) m.pt. 54° C. This azide (1.1 g) was stirred in dry toluene (10 ml) and heated at 100° C. under a nitrogen atmosphere for 8 hr to give a solution containing 3-pyridyl isocyanate. A portion of this solution (1 ml) was reacted with 5-oximino-25-cyclohexyl-22,23-dihydroavermectin B1 monosaccharide (Example 5) (100 mg), in toluene (10 ml) at room temperature for 1 hr before pouring into a diethyl ether-water mixture (1:1, 30 ml). The organic layer was separated, dried over anhydrous magesium sulphate and evaporated to dryness under vacuum to give a residue (130 mg) which was purified by high pressure liquid chromatography on a Dynamax (trade mark) column (41.4×250 mm, 8 μm, ODS-silica, Rainin) eluting at 45 ml per minute with a methanol-water 85:15 mixture, changing to 87:13 after 15 mins. Appropriate fractions were combined and evaporated under vacuum to yield the title compound as a white powder (52 mg). Mass and NMR spectra were fully consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([O:13][C:14]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:21]2[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]=[O:17])[C:14]=2[O:13][CH2:11][CH3:12])[CH:3]=1
Reactant: CCOc1c(O)cccc1C=O
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Yield: 82.9 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.35 g, 2.2 mmol), 2-ethoxy-3-hydroxybenzaldehyde (0.37 g, 2.2 mmol) and cesium carbonate (0.73 g, 2.2 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 19 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(2-ethoxy-3-formylphenoxy)benzonitrile (0.55 g, 82%) as a tan solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N1C=CC=CC=1.[CH2:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1)[CH3:16].CCCCCC.CCOC(C)=O>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Br:1][CH:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[N:21][CH:22]=1)[CH3:16]
Reactant: CCc1ccc(C(F)(F)F)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(Br)c1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Bromosuccinimide (1.78 g, 0.01 mol) was added to anhydrous fresh methylene chloride (60 mL) at room temperature under an atmosphere of nitrogen. Once dissolved, the solution was cooled to 0° C. The 5-ethyl-2-trifluoromethyl-pyridine pyridine (1.75 g, 0.01 mol) was dissolved in a small amount of anhydrous methylene chloride and was added via syringe followed by zirconium tetrachloride (117 mg, 0.5 mmol). The ice bath was taken away and the mixture allowed to stir at room temperature overnight. TLC showed complete reaction (9:1, hexane:EtOAc). The reaction mixture was quenched with saturated sodium bicarbonate (25 mL). The organic layer was separated and washed with brine and dried (MgSO4). The residue was purified by column chromatography (1:20, EtOAc:Hex) to give the product, 2.04 g (80%), as a pale yellow liquid; 1H NMR (CDCl3) δ 8.77 (s, 1H), 7.97 (d, 1H), 7.69 (d, 1H), 5.21 (q, 1H), 2.08 (d, 3H).
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([C:33]([F:36])([F:35])[F:34])[C:29]([NH2:32])=[N:30][CH:31]=2)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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]>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([C:7]2[S:6][C:5]3=[N:4][CH:3]=[C:2]([C:26]4[CH:27]=[C:28]([C:33]([F:36])([F:35])[F:34])[C:29]([NH2:32])=[N:30][CH:31]=4)[N:9]3[N:8]=2)[CH:11]=[N:12][CH:13]=1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: COc1cncc(-c2nn3c(I)cnc3s2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1cncc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 120 °C
Yield: 41.9 %

Procedure:
A mixture of 5-Iodo-2-(5-methoxy-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (26 mg, 0.073 mmol, 1.0 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -3-trifluoromethyl-pyridin-2-ylamine (27 mg, 0.096 mmol, 1.3 eq), PdCl2(dppf) (12 mg, 0.015 mmol, 0.2 eq), sat. K2CO3 (0.5 mL) in DME (4 mL) was heated under microwave irradiation at 120° C. for 30 min. The solvent was removed and the residue was diluted with DCM and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography (Isolute Si II; MeOH in DCM, 0 to 3%) to give the desired product (12 mg, 42%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.76 min, [M+H]+ m/z 393.0; 1H NMR (300 MHz, DMSO) δ 8.87 (d, J=1.8 Hz, 1H), 8.75 (d, J=1.7 Hz, 1H), 8.53 (d, J=2.8 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.85 (m, 2H), 6.76 (s, 2H), 3.96 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].N1C=CC=CC=1.[Br:18]Br>ClCCl>[Br:18][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7][OH:8]
Reactant: BrBr
Reactant: COc1cccc(CCO)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Br)c(CCO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
To a stirred mixture of 3-methoxyphenethyl alcohol (1.18 g, 7.8 mmol) and pyridine (0.75 ml, 9.3 mmol) in dry dichloromethane (10 ml) was added bromine (0.47 ml, 18.0 mmol) dropwise under nitrogen at 0° C. The orange solution was stirred at room temperature for 4 hours (hr). The reaction mixture was quenched by the addition of 10% sodium bisulfite aqueous solution., and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate, and concentrated to give crude products, which were purified by silica-gel column chromatography eluted with gradient of hexane and ethyl acetate (10:1, 8:1, 5:1) to give the title compound as a colorless oil (1.5 g, 83.2%). 1H-NMR (CDCl3): 7.43 (d, J=8.8 Hz, 1H), 6.83 (d, J=3.3 Hz, 1H), 6.67 (dd, J=8,8, 3.3 Hz, 1H), 3.91-3.81 (m, 2H), 3.78 (s, 3H), 2.99 (t, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:4]=1)#[N:2].[CH2:16]([NH2:19])[CH2:17][CH3:18].[OH-].[Na+]>O1CCCC1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:19][CH2:16][CH2:17][CH3:18])=[C:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:4]=1)#[N:2]
Reactant: CC(C)Cc1nc(C#N)c(C#N)nc1Cl
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCNc1nc(C#N)c(C#N)nc1CC(C)C
Yield: 85.5 %

Procedure:
2,3-Dicyano-5-chloro-6-isobutylpyrazine (1.10 g; 0.005 mole) was dissolved in 20 ml of tetrahydrofuran. The solution was worked up in the same way as in Example 13 using 0.30 g (0.005 mole) of n-propylamine and 0.02 g (0.005 mole) of sodium hydroxide to afford 1.04 g (yield 85%) of 2,3-dicyano-5-n-propylamino-6-isobutylpyrazine.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][NH:19][C:20]([C:22]1[S:23][C:24]([Cl:27])=[CH:25][CH:26]=1)=[O:21])[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]1[CH3:17])=[O:10])(C)(C)C.B(Br)(Br)Br.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[NH2:7][C@H:8]([C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]1[CH3:17])=[O:10])[CH2:18][NH:19][C:20]([C:22]1[S:23][C:24]([Cl:27])=[CH:25][CH:26]=1)=[O:21]
Reactant: C[C@H]1COCCN1C(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NC(=O)OC(C)(C)C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H]1COCCN1C(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
Intermediate 2 (306 mg, 0.708 mmol) from step 1.2 was dissolved in 3 ml of DCM, cooled to 0° C. and slowly treated with 1.42 ml (1.42 mmol) of a BBr3-solution (1M in DCM). After 2 h at 0° C. 7 ml sat. aq NaHCO3-solution and 3 ml H2O were added and the reaction was stirred for 15 min at RT. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic layers were washed with H2O, dried with MgSO4, filtered and evaporated to dryness. 191 mg of crude product were obtained and used without further purification in step 1.8.
Reaction SMILES: COC1C=C(C=CC=1OCCCC)[CH2:6][N:7]([C@H:18]([CH3:30])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:10].[H-].[Na+].N1C(C)=CC=CC=1C.C(Cl)(Cl)=[O:50]>C1(C)C=CC=CC=1>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH2:19][C@H:18]([N:7]2[CH2:8][C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[O:10][C:6]2=[O:50])[CH3:30])[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: CCCCOc1ccc(CN(CC(O)c2cccc(Cl)c2)[C@H](C)Cc2ccc(OC)c(OC)c2)cc1OC
Reactant: O=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@@H](C)N2C[C@@H](c3cccc(Cl)c3)OC2=O)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5.0 g. of (R)-N-(3-methoxy-4-n-butoxybenzyl)-N-[2-(3-chlorophenyl)-2-hydroxyeth-1-yl]-1-(3,4-dimethoxyphenyl)-prop-2-ylamine (obtained in Example 2) in 45 mL of toluene is added to 406 mg. of sodium hydride at room temperature. The mixture is stirred for one hour, 1.29 mL of 2,6-lutidine are added, and stirring is continued for 30 minutes. The reaction mixture then is added with stirring to 5.74 mL of a 20% solution of phosgene in toluene which has been cooled to 0° C. Excess phosgene is destroyed with 3N sodium hydroxide and the reaction mixture diluted with toluene, washed sequentially with 3N sodium hydroxide and brine, dried over magnesium sulfate, and evaporated to yield (R,R)-3-[1-(3,4-dimethoxyphenyl)prop-2-yl]-5-(3-chlorophenyl)oxazolidin-2-one. This is further purified by stirring in heptane at 55° C. for 15 minutes, filtering, washing with additional heptane, and recrystallization from 5:4 ethyl acetate:heptane to yield white crystals. Gas chromatography indicates the chemical purity is 99.3% and HPLC indicates the de is 99.6%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[OH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+].O.O>CN(C)C=O.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]>[OH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)=[CH:34][CH:33]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Nc1cncc(-c2ccc(CO)cc2)n1)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 80 °C
Yield: 32.5 %

Procedure:
To a degassed solution of (S)—N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-3-(trifluoromethyl)benzamide (210 mg, 0.5 mmol), 4-(hydroxymethyl)phenylboronic acid (152 mg, 1 mmol) and aqueous sodium carbonate (0.62 mL, 2M, 1.55 mmol) in N,N-dimethyl formamide (3 mL) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium(II) (24 mg, 0.03 mmol) and the mixture was heated at 80° C. for 18 hours in a sealed tube. After this time the mixture was allowed to cool, was poured into a mixture of brine/water (2:3, 50 mL) and was extracted with a mixture of ethyl acetate/tetrahydrofuran (4:1, 3×30 mL). The combined organic extracts were concentrated under reduced pressure and the residue was taken up in ethyl acetate (50 mL), dried (Na2SO4) and concentrated under reduced pressure to give a black oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give (S)—N-(3-(1-(6-(4-(hydroxymethyl)phenyl)pyrazin-2-ylamino)ethyl)phenyl)-3-(trifluoromethyl)benzamide (80 mg, 33%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[N+]([O-])([O-])=[O:20].[Na+].F[P-](F)(F)(F)(F)F.[H+]>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:20])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(N)cnc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [H+]
Solvent: O
Product: Cc1cc(O)cnc1-c1ccc(C(F)(F)F)cc1
Temperature: -15 °C
Yield: 79.9 %

Procedure:
5-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine (2.74 g, 10.87 mmol) is suspended in hydrochloric acid (21.74 mL, 5N) and the solution is cooled to −15° C. in a brine/ice bath. Sodium nitrate (0.9 g, 13.04 mmol) in water (10 mL) is added slowly to the mixture. The reaction is allowed to stir at −15° C. for ten minutes after complete addition. Hexafluorophosphoric acid (5 mL, 21.74 mmol of a 60% wt. solution in water) is added slowly to the mixture. The resulting slurry is filtered, rinsed with cold water, methanol, and diethyl ether, and dried under vacuum. This solid is added in small portions to a round bottom containing acetic acid (10 mL) at 105° C. This solution is cooled to room temperature then treated with sodium hydroxide (25 mL, 5N) for 30 min. The pH of this solution is adjusted to 6 with hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, then filtered and concentrated to provide the title product (2.2 g, 8.69 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(=O)[nH]cc1Cl
Yield: 52 %

Procedure:
A 5.00 g quantity of 5-chloro-4-hydroxy-2-pyridone and 3.66 ml of acetyl chloride were stirred in 250 ml of pyridine at room temperature for 3 hours. The reaction mixture was then concentrated and the concentrate was washed with ethyl acetate and water to produce 3.39 g of the title compound in a yield of 52%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29](/[CH:31]=[CH:32]/[C:33](OC)=[O:34])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29](/[CH:31]=[CH:32]/[CH2:33][OH:34])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC/C=C/c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 67 %

Procedure:
To a stirring and cold (0° C.) solution of methyl (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]acrylate (400 mg, 0.77 mmol, 1 equiv) in THF (10 mL) was added diisobutylaluminum hydride in THF (1M, 3 mL, 3 mmol, 4 equiv). The resulting mixture was stirred at rt for 20 hn and it was then poured into the aq Rochelle's salt solution and EtOAc. This was filtered a pad of Celite®. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated and residue was triturated with hexane and ether to yield (250 mg, 67% yield). 1H-NMR (DMSO-d6) δ 8.93 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 8.1 (d, 1H), 7.67 (d, 1H), 7.60 (dd, 1H), 7.46 (dd, 1H), 7.39 (m, 1H), 7.24 (m, 2H), 7.17 (d, 1H), 7.10 (m, 1H), 6.49-6.65 (m, 2H), 5.20 (s, 2H), 4.90 (s, 1H), 4.11 (d, 2H); LCMS RT=3.71 min, [M+H]+=492.1.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[C:8]#[N:9])=[CH:4][CH:3]=1.Cl.[CH2:15]([OH:17])[CH3:16]>>[ClH:1].[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:10])([CH3:11])[C:8](=[NH:9])[O:17][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(C)(C#N)Oc1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=N)C(C)(C)Oc1ccc(Cl)cc1

Procedure:
Commercially available 2-(4-chlorophenoxy)-2-methylpropanenitrile (Maybridge), HCl gas and ethanol were processed using the method described for Example 4A to obtain the titled compound. MS (ESI+) m/z 242 (M+H)+.