Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH:37]=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Br:2][C:1]([Br:5])=[CH:37][C:33]1[O:32][CH:36]=[CH:35][CH:34]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: BrC(Br)=Cc1ccco1
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
To a stirred solution of 9.6 g (29 mmol) of carbon tetrabromide in 120 mL of dry methylene chloride at 0° was added 15.2 g (58 mmol) of triphenylphosphine. After 15 min 3.0 mL (22.5 mmol) of triethylamine was added, and after stirring another 5 min at 0°, the reaction mixture was cooled to −78°. At this temperature 1.50 mL (22.5 mmol) of 2-furaldehyde was added quickly dropwise, and after addition was complete, the mixture was stirred a −70° for 30 min. The reaction mixture was poured onto a rapidly stirring saturated solution of sodium bicarbonate in water. The methylene chloride phase was removed and the aqueous layer was extracted with additional methylene chloride. The combined extracts were evaporated to a solid which was stirred in 500 mL of hexanes for 2 h. After filtration, the filtrate was concentrated to a volume of 50 mL and the filtered again to remove precipitated solid. Final evaporation of the filtrate afforded 3.1 g (58%) of the title compound.
Reaction SMILES: [OH:1][C:2]1([CH3:24])[CH:8](Br)[CH:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:24])[CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(c2ccc(OCc3ccccc3)cc2)C1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(c2ccc(OCc3ccccc3)cc2)C1

Procedure:
The product obtained by reducing 2.0 g of 3-hydroxy-3-methyl-4-bromo-5-(p-benzyloxyphenyl)-5-pentanolide with 5.99 g of tri-n-butyltin hydride in 40 ml of anhydrous tetrahydrofuran according to the method described in Example 2 (a), was separated by a thin layer chromatography into two isomers in a total yield of 1.40 g.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[C:21]([Si:25]([CH3:35])([CH3:34])[O:26][C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)([CH3:24])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C.O>C1COCC1>[C:21]([Si:25]([CH3:35])([CH3:34])[O:26][C:27]1[CH:28]=[C:29]([NH:33][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:5]3[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=3[N+:18]([O-:20])=[O:19])[CH:8]=2)[CH:30]=[CH:31][CH:32]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Reactant: O=C(Cl)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(NC(=O)c2cccc(Oc3ccc(Cl)cc3[N+](=O)[O-])c2)c1
Reaction time: 16 h
Yield: 62 %

Procedure:
To the product from Example 168b (1.3 g, 4.2 mmol) in THF (25 mL) was added 3-(tert-Butyl-dimethyl-silanyloxy)-phenylamine (1.0 g, 4.2 mmol), and N,N-diisopropylethylamine (0.67 g, 5.2 mmol). The reaction was stirred for 16 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer washed with 5% HCL, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (1.3 g, 85%).
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:13](C3C=CC=C(C(F)(F)F)C=3)[OH:14])[CH:9]=2)[N:4]=1.[ClH:25].[OH-].[Na+]>>[Cl:25][C:9]1[C:8]([CH2:13][OH:14])=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][CH:3]=[N:4]2
Reactant: COc1ccc2cc(C(O)c3cccc(C(F)(F)F)c3)ccc2n1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Product: OCc1ccc2ncccc2c1Cl

Procedure:
A mixture of intermediate 28 (1 g) and HCl (25 ml; 3 N) was stirred and refluxed for 2 hours. The solution was basified with NaOH and extracted with CH2Cl2. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the solvent was evaporated, yielding 1.8 g of (±)-6-[hydroxy[3-(trifluoromethyl)phenyl]methyl]-2(1H-quinolinone (intermediate 29).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].CO.Cl>C[O-].[Na+].O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4]
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CCCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 94.1 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) and 4-aminobutyric acid (525 mg, 5.1 mmol) in 0.5 N NaOMe in MeOH solution (6.8 mL, 3.4 mmol) was heated to reflux overnight. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl solution to pH=3-4. Precipitate was collected and rinsed with water. It was dried in vacuo to provide the title compound (117 mg, 0.32 mmol) in 94% yield. LC-MS ESI−: 365.05 (M−1)−.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5](C#N)[C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[OH-].[K+].C(O)CO>O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:6]2([CH2:5][C:4]([OH:22])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C#N)C1(c2ccc(OC)cc2)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc(C2(CC(=O)O)CCCCC2)cc1
Temperature: 180 °C
Yield: 79.8 %

Procedure:
A mixture of cyano-[1-(4-methoxy-phenyl)-cyclohexyl]-acetic acid ethyl ester (1.84 g), potassium hydroxide (1.27 g), ethylene glycol (5 ml) and water (0.025 ml) was heated to 180° C. for 21 h. After cooling to room temperature, water was added and washed with diethyl ether. The aqueous phase was acidified using concentrated HCl and extracted with dichloromethane. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness to give the title compound as an off-white solid (1.21 g), MS (ESI−): m/z=247.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][OH:15])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1.[CH2:29]([NH2:33])[CH2:30][CH2:31][NH2:32]>>[NH2:32][CH2:31][CH2:30][CH2:29][NH:33][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][OH:15])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OCCO)ccc3n2)Cc2ccccc21
Reactant: NCCCN
Product: NCCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(OCCO)cc12
Temperature: 150 °C
Yield: 35.8 %

Procedure:
A mixture of 2-{[4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinolin-6-yl]oxy}ethanol (250 mg, 0.6 mmol) and propane-1,3-diamine (88.8 mg, 1.2 mmol) was heated for 1.5 hours at 150° C. under microwave irradiation. The reacting mixture was purified by preparative HPLC and SPE to afford 98.2 mg of the desired product (yield was 35.8%). MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.10-8.02 (d, J=8 Hz, 1 H), 7.88-7.80 (d, J=7.6 Hz, 1 H), 7.77-7.68 (q, J=9.6 Hz, 2 H), 7.60-7.50 (m, 2 H), 7.42-7.38 (m, 1 H), 5.94 (s, 1 H), 5.29 (s, 2 H), 4.55-4.42 (m, 2 H), 4.18-4.10 (t, J=4.4 Hz, 2 H), 3.90-3.85 (t, J=4.4 Hz, 2 H), 3.76-3.68 (t, J=4.4 Hz, 2 H), 3.62-3.55 (t, J=6.8 Hz, 2 H), 3.12-3.05 (t, J=7.6 Hz, 2 H), 2.15-2.00 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]3=[N:9][CH:8]=2)[S:5][CH:6]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:2]2[CH:3]=[C:4]([C:7]3[N:11]4[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[N:15][C:10]4=[N:9][CH:8]=3)[S:5][CH:6]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccn2c(-c3cc(Br)cs3)cnc2n1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccn2c(-c3cc(-c4cccnc4)cs3)cnc2n1
Yield: 79.9 %

Procedure:
A mixture of 3-(4-bromothien-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (104 mg, 0.3 mmol), pyridine-3-boronic acid-1,3-propanediol cyclic ester (73 g, 0.45 mmol), cesium carbonate (0.29 g, 0.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) in 1,4-dioxane (5 ml) and H2O (0.5 ml) were degassed with a stream of N2 for 10 min. The reaction mixture was then heated at reflux for 1 h. The mixture was concentrated under reduced pressure to remove the organic solvents and H2O (20 ml) was added. The organics were extracted with dichloromethane (2×50 ml) and concentrated under reduced pressure while dry loading onto silica. The resulting crude residue was purified by column chromatography on silica using 70% EtOAc in hexanes containing 1% Et3N and 1% MeOH as the eluent. The resulting material was taken up in MeOH and was poured onto a strong cation exchange cartridge and eluted with methanol. The product was then eluted with 2.0M NH3 in MeOH and evaporated to give 3-[4-(pyridin-3-yl)thien-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (83 mg, 80%): δH (400 MHz, d6-DMSO) 7.46-7.53 (1H, m), 7.60 (1H, d, J 7.1), 8.18 (1H, d, J 1.5), 8.22-8.30 (1H, m), 8.26 (1H, d, J 1.5), 8.42 (1H, s), 8.56-8.60 (1H, m), 9.10 (1H, s), 10.20 (1H, d, J 7.1); m/z (ES+) 346 (M+).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:14]=[CH:15][CH:16]=3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[O:37][CH:38]=[CH:39][N:40]=1)CCC.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:37]1[CH:38]=[CH:39][N:40]=[C:36]1[C:2]1[C:10]2[C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])[CH:14]=[CH:15][CH:16]=3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(Br)cn3COCC[Si](C)(C)C)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(-c2ncco2)cn3COCC[Si](C)(C)C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of N-(3-(5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide (249 mg, 0.51 mmol) in toluene (10 mL) under nitrogen, was added 2-(tributylstannyl)-1,3-oxazole (548 mg, 1.53 mmol), Pd2(dba)3 (93 mg, 0.10 mmol), and X-Phos (95 mg, 0.20 mmol). The resulting solution was stirred overnight at 60° C. and then concentrated in vacuo, and the resulting crude reaction was extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-100% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(5-(oxazol-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a yellow oil. LRMS (ESI) calc'd for C25H30N5O3Si [M+H]+: 476, found 476.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]Br)=[C:9]([Cl:15])[CH:8]=2)[CH:6]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[Cl:15][C:9]1[CH:8]=[C:7]([N:5]2[CH:6]=[C:2]([Cl:1])[CH:3]=[N:4]2)[CH:12]=[CH:11][C:10]=1[CH2:13][C:16]#[N:17]
Reactant: [C-]#N
Reactant: Clc1cnn(-c2ccc(CBr)c(Cl)c2)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(-n2cc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 99.5 %

Procedure:
15 g of 4-chloro-1-(4-bromomethyl-3-chlorophenyl)pyrazole are added to 2.8 g of sodium cyanide in 67 ml of dimethylsulfoxide and stirred for 6.5 hours at room temperature. 300 ml of water are added dropwise and 12.3 g of 2-chloro-4-(4-chloropyrazol-1-yl)phenylacetonitrile are thus obtained. Chromatographing the latter with a mixture of cyclohexane/ethanol/ethyl acetate on silica gel, yields a product with a m.p. 139.5° to 140° C. (As by-product, 1,2-bis-[2-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid nitrile has formed; from this by-product the appropriate amide with m.p. 248° to 249.5° C. is obtained by saponification with concentrated sulfuric acid.)
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1>C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[F:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[NH:26][C:14]1[CH2:15][CH2:16][C:11]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:12][C:13]2=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: Fc1ccc2[nH]c3c(c2c1)CC1(CC3)OCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of MgSO4 (18.4 g, 0.154 mol) in DCM (500 ml) were added 1,4-dioxaspiro[4.5]decan-8-one (48.0 g, 0.308 mol) and 4-fluorophenylhydrazine hydrochloride (50.0 g, 0.308 mol). Then, TEA (43.8 ml, 0.308 mol) was added dropwise over 5 min. The internal temperature went up from 17° C. to 25° C. upon addition of TEA. The resulting suspension was allowed to stir at rt for 4 h and filtered. The white solid was washed twice with DCM and the filtrate was concentrated in reduced pressure. The orange slurry was suspended in toluene (500 ml) and ZnCl2 (38.6 g, 0.283 mol) was added. The resulting dark orange solution was stirred at reflux using a Dean-Stark apparatus for 12 h. After cooling to rt, the resulting black mixture was filtered over celite. The solid was washed with isopropyl acetate, the organic filtrate was basified with 1N NaOH (until pH ˜12). The aqueous phase was extracted with isopropyl acetate, the combined organic extracts were passed through celite, dried over Na2SO4, filtered and concentrated in vacuo to yield the titled compound as a dark brown solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[C:27]1[O:31][N:30]=[C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=1>C1COCC1>[Br:5][CH2:1][C:27]1[O:31][N:30]=[C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=1
Reactant: CCOC(=O)c1cc(CO)on1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CBr)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
Carbon tetrabromide (5.44 g; 16.39 mmol) was added to the solution of triphenylphosphine (4.34 g, 16.39 mmol) in THF (50 mL) and the resulting mixture was stirred at room temperature for 15 min. To this green suspension was added a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (1.87 g, 10.93 mmol) in THF (10 mL) and the resulting reaction mixture was stirred overnight at room temperature. The solid material was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: 15 to 100% dichloromethane in heptane) to afford 1.73 g (68%) of ethyl 5-(bromomethyl)isoxazole-3-carboxylate as a solid.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH2:25][C:26](=[CH2:28])[CH3:27])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].CCN(CC)CC>CCOC(C)=O.[Pd]>[CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH2:25][CH:26]([CH3:27])[CH3:28])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:20])[F:22])[CH3:2]
Reactant: C=C(C)CN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1CC(C)C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of (R)-3-ethyl-3,4-dihydro-8-isopropoxy-4-methallyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.010 g, 0.025 mmol in 1.5 mL EtOAc and 0.1 mL Et3N was added 10% Pd on carbon (0.006 g) and the mixture was vigorously stirred under H2 atmosphere for 1 h. The reaction mixture was filtered through Celite and concentrated to afford 0.010 g (100% yield) of (R)-3-ethyl-3,4-dihydro-4-isobutyl-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. This material (0.010 g, 0.025 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with conc. HCl (0.5 mL) in AcOH (1.0 mL) and heated at 95° C. to afford Compound 115 (0.008 g, 89% yield) as a yellow solid. Rf 0.5 (9:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 11.81 (broad s, 1H), 7.11 (s, 1H), 7.00 (d, 1H, J=9.0), 6.92 (d, 1H, J=9.0), 4.33 (dd, ABX, 1H, J=10.4, 1.2), 3.98 (dd, ABX, 1H, J=10.4, 2.3), 3.23 (dd, ABX, 1H, J=14.5, 4.8), 3.15–3.10 (m, 1H), 2.80 (dd, ABX, 1H, J=14.5, 9.8), 2.07–1.97 (m, 1H), 1.62–1.49 (m, 2H), 1.01 (d, 3H, J=6.5), 0.98–0.92 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C@H:28]([NH2:30])[CH3:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:30][C@@H:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[CH3:29])[N:3]=1
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](Nc1nc(N)nc(-c2ccco2)c1C#N)c1ccc2ccccc2c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (R)-(−)-1-(2-naphthyl)ethylamine and DBU in DME. ES-MS m/e (%): 356 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[O-]CC.[Na+].[Na].Cl[CH2:23][CH:24]([OH:26])[CH3:25]>C(O)C>[CH3:23][CH:24]([OH:26])[CH2:25][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:3]=[C:2]([F:1])[CH:15]=[C:14]([F:16])[CH:13]=2)=[CH:11][CH:10]=1
Reactant: CC(O)CCl
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(O)COc1ccc(Oc2cc(F)cc(F)c2)cc1
Yield: 59.2 %

Procedure:
4-(3,5-Difluorophenoxy)phenol (3.0 g, 13.5 mmol) was added to an ethanolic solution of sodium ethoxide prepared from ethanol (15 ml) and sodium (313 mg, 13.6 mmol). To the resultant solution, 1-chloro-2-propanol (1.60 g, 16.9 mmol) was dropwise added with stirring under reflux. After completion of the addition, the resultant mixture was stirred under reflux for 5 hours. After allowed to cool, ethanol was removed, and the residual oil was dissolved in toluene. The toluene layer was washed with water once, a 20% aqueous potassium hydroxide solution two times and a saturated aqueous sodium chloride solution once in order and dried over anhydrous magnesium sulfate. Removal of the solvent gave 1-methyl-2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (2.24 g).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Fe].Cl[Cu].O>[C:2]1([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:1])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Agent: Cl[Cu]
Agent: [Fe]
Solvent: O
Product: CC(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 71.1 %

Procedure:
The procedure of Example I was repeated except that the reaction mass contained 150 ml water, 5.6 g iron (99.9+% pure), 0.2 g CuCl (99.9% pure), and 25.4 g benzyl chloride. The reaction period was for 3 hr. 13.0 g of crude diphenylethane product was obtained. This represents a 71.4% yield.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([NH:9][CH:10]2[CH2:12][CH2:11]2)[N:6]=[C:5]([NH:13][CH:14]([CH3:16])[CH3:15])[N:4]=1.[CH3:17][OH:18]>>[CH3:17][O:18][C:3]1[N:8]=[C:7]([NH:9][CH:10]2[CH2:12][CH2:11]2)[N:6]=[C:5]([NH:13][CH:14]([CH3:16])[CH3:15])[N:4]=1
Reactant: CC(C)Nc1nc(Cl)nc(NC2CC2)n1
Reactant: CO
Agent: [Na]
Product: COc1nc(NC(C)C)nc(NC2CC2)n1
Temperature: 25 °C

Procedure:
2.1 g of sodium was added in portions to 400 ml of stirred anhydrous methanol. The solution was allowed to cool to room temperature, then 16.5 g of 9B was added and the mixture was refluxed for 2 hours. The solvent was evaporated, and the residue was washed with water, then extracted with ether. The extract phase was dried (MgSO4) and stripped of solvent to give 2-methoxy-4-(cyclopropylamino)-6-(1-methylethylamino)-1,3,5-triazine (13A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(O)(=O)C>O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9])[NH2:12]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1ccc(N)cc1F
Temperature: 95 °C
Yield: 89.8 %

Procedure:
A mixture of 3-fluoro-4-(methylsulfonyl)nitrobenzene (8 g, 36.5 mmol), iron powder (22 g, 394 mmol), and acetic acid (0.3 mL) in water (200 mL) was heated at 95° C. for 3 hours. After cooling, insolubles were filtered off by Celite. The filtrate was extracted with ethyl acetate (200 mL×2), the combined organic layer washed with water, brine, dried over MgSO4, and concentrated in vacuo. Chromatographic purification of the residue eluting with ethyl acetate/hexane (1/1) provided the subtitle compound (6.2 g, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2I)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:17][C:18]1[CH:19]=[C:20]([C:15]2[N:14]3[C:10]([O:11][CH:12]=[CH:13]3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(F)c2)OC1(C)C
Reactant: Fc1ccc(-c2nc3occn3c2I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2c(-c3ccc(F)cc3)nc3occn23)cc1F
Temperature: 100 °C
Yield: 83.4 %

Procedure:
A mixture of 6-(4-fluorophenyl)-5-iodo-imidazo[2,1-b]oxazole (10.0 g, 27.4 mmol; Preparation #A.1), 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (11.9 g, 41.1 mmol; Preparation #B.1), Cs2CO3 (28.6 g, 87.8 mmol), tetrakis(triphenylphosphine)palladium(0) (3.17 g, 2.74 mmol; Strem), DME (150 mL) and water (30.0 mL) was added to a flask with screw-thread top. The flask was sealed and heated at about 100° C. for about 16 h. After cooling to ambient temperature the reaction was concentrated under reduced pressure to remove organic solvent. The resulting mixture was diluted with water (200 mL) and EtOAc (200 mL) then filtered to remove insoluble material. The layers were separated and the aqueous layer was extracted with additional EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude material was purified by silica gel chromatography using DCM to give the title compound (7.80 g, 78%): LC/MS (Table 1, Method b) Rt=2.19 min; MS m/z: 342.1 (M+H)+.