Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2](Br)C.[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:12][C:13]=1[N:14]([C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])[CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:8].C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl.[Zn]>[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:12][C:13]=1[N:14]([C:22]([CH:24]1[CH2:25][CH2:26][CH:27]([CH3:30])[CH2:28][CH2:29]1)=[O:23])[CH:15]1[CH2:20][CH2:19][C:18](=[CH2:2])[CH2:17][CH2:16]1)=[O:8]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Reactant: CC(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)OC)CC1
Temperature: -40 °C
Yield: 80.5 %

Procedure:
To a suspension of zinc dust (2.87 g, 44.0 mmol) and dibromoethane (1.00 mL, 14.4 mmol) in tetrahydrofuran (20 mL) stirred under a nitrogen atmosphere at −40° C. was added titane tetrachloride (10 mL of a solution 1M in dichloromethane, 10 mmol). The mixture was then allowed to warm to room temperature and was stirred for two days at this temperature. This methylation reagent (2.5 eq) was added to a solution of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.440 mmol, 1 eq) in dichloromethane (2 mL) and the resulting mixture was stirred 3 h at room temperature. A saturated solution of sodium bicarbonate was then added and reaction mixture was extracted with dichloromethane (3×30 mL). Organic phases were combined, dried over sodium sulfate and concentrated. The crude was purified by chromatography (30% ethyl acetate/hexanes) to give 160 mg (81%) of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-methylene-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as a white solid. NMR 1H (CDCl3, 400 MHz) 7.63 ppm (d, 2H); 7.40 ppm (m, 3H); 6.98 ppm (s, 1H); 4.82 ppm (tt, 1H); 4.78 ppm (d, 2H); 3.85 ppm (s, 3H); 2.20 ppm (m, 4H); 2.05 ppm (m, 2H); 1.90 ppm (d, 1H); 1.65 ppm (m, 4H); 1.42 ppm (m, 1H); 1.30 ppm (m, 2H); 1.00 ppm (m, 2H); 0.78 ppm (d, 3H); 0.64 ppm (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[CH:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[N:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]([C:27]([NH2:29])=[O:28])[NH2:26]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[CH:17]=[C:18](/[C:21](=[N:26]/[NH:25][C:27]([NH2:29])=[O:28])/[CH3:22])[CH:19]=[N:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=O
Reactant: CC(=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2c1
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2c1
Yield: 8.9 %

Procedure:
A solution of 1-(3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyrimidin-6-yl)ethanone (40 mg, 0.132 mmol) and hydrazinecarboxamide hydrochloride (14.9 mg, 0.198 mmol) in methanol (3 mL) was stirred at 40° C. for 2 h. The solvent was removed in vacuo and the residue was purified by HPLC to afford 4.2 mg (8.8%) of the title compound as white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.45 (s, 1H), 9.24 (d, 1H), 8.91 (d, 1H), 8.86 (dd, 1H), 8.30 (d, 1H), 7.98 (d, 1H), 7.89 (s, 1H), 7.72 (dd, 1H), 7.52-7.49 (m, 2H), 6.65 (s, 2H), 4.59 (s, 2H), 2.18 (s, 3H). LCMS (method A): [MH]+=360, tR=2.95 min.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>C(Cl)Cl>[C:27]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:30])[CH:28]=[CH2:29]
Reactant: CC(C)(C)OC(=O)NCc1cc([N+](=O)[O-])ccc1N
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc([N+](=O)[O-])cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of tert-butyl 2-amino-5-nitrobenzylcarbamate (200 mg, 0.75 mmol) and triethylamine (76 mg, 0.75 mmol) in DCM was added acryloyl chloride (102 mg, 1.12 mmol). The mixture was stirred at rt for 48 h, and purified with column chromatography to give tert-butyl 2-acrylamido-5-nitrobenzylcarbamate. The tert-butyl 2-acrylamido-5-nitrobenzylcarbamate was dissolved in EtOH/HCl and stirred at rt for 1 h. Diethyl ether was then added and the solid formed was collected by filtration to yield the HCl salt of N-(2-(aminomethyl)-4-nitrophenyl)acrylamide (46 mg, 0.18 mmol).
Reaction SMILES: N[CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.C(N(CC)CC)C.N[C@H](C)[CH2:32][OH:33]>CCO>[OH:33][CH2:32][C@H:3]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1)[CH3:2]
Reactant: C[C@@H](N)CO
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](CO)n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 100 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethyl-1H-pyrimidine-2,4-dione (Intermediate A step 3) (200 mg 0.59 mmol), triethylamine (82 μl, 0.59 mmol) and (R)-2-aminopropan-1-ol (45 mg, 0.59 mmol) (commercial) were combined in EtOH (2 mL). The mixture was heated at 100° C. under microwave irradiation for 1 hour. The solvent was evaporated under reduced pressure. The solid residue dissolved in DCM and water and extracted (×3). The combined organic phases were washed with water, passed through a hydrophobic frit and evaporated under reduced pressure to afford the title compound as an off-white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([O:26]C3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=O)=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][NH:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[CH3:38][O:39][C:40]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:41]=1[CH2:42][N:43]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)[S:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[N:14][CH:15]=[CH:16]2)(=[O:25])=[O:26]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)nccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)nccc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of perfluorophenyl 1-(pyrrolidin-2-yl)isoquinoline-6-sulfonate 2,2,2-trifluoroacetate (Intermediate ZZZ; 0.350 g, 0.627 mmol) and N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.173 g, 0.689 mmol) in tetrahydrofuran (6.27 ml) was cooled in a dry ice-acetone bath for 10 min. Lithium bis(trimethylsilyl)amide (1M in THF) (1.316 ml, 1.316 mmol) was added drop wise, then the reaction was stirred for 5 minutes. The cooling bath was removed and the reaction was stirred for 30 minutes. The reaction was warmed to room temperature and quenched with saturated ammonium chloride solution (aq), diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by chromatography on an 80-g silica gel column with 0-100% EtOAc/Heptane followed by a 20% 2.0M ammonia in MeOH/DCM flush to afford N-(2,4-dimethoxybenzyl)-1-(pyrrolidin-2-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. m/z (ESI) 511.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].CC1(C)N([Br:24])C(=O)N(Br)C1=O>>[Br:24][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Product: COc1cc(C(=O)O)c(Br)c(OC)c1OC
Reaction time: 25 h

Procedure:
Using the procedure described herein above in Example 1, Method E, 3,4,5-trimethoxybenzoic acid was brominated with DBDMH to provide the following results (assay yields) after reacting for 25 hours at 20°-25° C.:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5](=[CH2:7])[CH3:6])[CH3:2].[CH3:8][O:9][SiH:10]([O:13][CH3:14])[O:11][CH3:12]>[Pt]>[CH2:1]([NH:3][CH2:4][CH:5]([CH3:6])[CH2:7][Si:10]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:8])[CH3:2]
Reactant: C=C(C)CNCC
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Product: CCNCC(C)C[Si](OC)(OC)OC
Temperature: 88 °C
Reaction time: 1 h
Yield: 150 %

Procedure:
To a 500 gallon reactor were added 489 kg (4.94 kmols) of N-ethylmethallylamine and 1425 g of platinum catalyst. The resulting solution was heated to 88° C. and 725 kg (5.94 kmols) of trimethoxysilane were added at such a rate to keep the temperature under 105° C. After addition was complete, the contents were heated to 110° C. for one hr. The low boiling byproducts were then removed by overhead stripping. The mixture was then cooled and approximately 60 L of methanol were added, and the reaction mixture was agitated at 50° C. for 1 hour before stripping the excess methanol. The resulting crude material (>97% purity) was then transferred from the reactor. The process was repeated without cleanup of the reactor to yield a combined total of 1638 kg (7.41 kmol) of N-ethyl-3-trimethoxysilyl-2-methylpropanamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[Br:18]
Reactant: Nc1ccc(CCO)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CCO)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of 2-(4-amino-phenyl)-ethanol (5.10 g, 37.2 mmol) in 37 mL of DMF was added NBS (6.60 g, 37.1 mmol) and the mixture stirred overnight at RT. The reaction was diluted with 100 mL of water and extracted with EtOAc (3×100 mL). The organic layer was washed with brine (200 mL) and dried over Na2SO4. The title compound was purified by silica gel flash chromatography eluting with 50% EtOAc/hexanes to give 5.10 g (64%) of a white solid. Mass spectrum (ESI, m/z): Calcd. for C8H10BrNO, 216.0 (M+H), found 216.1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11][C:12]1[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=1)=[CH:6][CH:5]=2.[CH3:30][O:31][CH2:32][CH:33]=O>>[CH3:30][O:31][CH2:32][CH2:33][N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][O:22][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)=[N:13][CH:14]=[N:15]3)=[CH:20][CH:19]=2)[CH2:25][CH2:26]1
Reactant: COCC=O
Reactant: Cc1cc2cc(Oc3ncnc4cc(OCC5CCNCC5)ccc34)ccc2[nH]1
Product: COCCN1CCC(COc2ccc3c(Oc4ccc5[nH]c(C)cc5c4)ncnc3c2)CC1
Yield: 46.4 %

Procedure:
Using an analogous procedure to that described for Example 71, 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.386 mmol), (prepared as described in Example 122), was reacted with methoxyacetaldehyde (83 mg, 0.772 mmol), (prepared as described for the starting material in Example 71), to give 7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4(2-methylindol-5-yloxy)quinazoline (80 mg, 46%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[CH3:14][C:15]1[C:23]2[C:22]([N:24]3[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]3)=[N:21][CH:20]=[N:19][C:18]=2[S:17][C:16]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(O)C.CS(C)=O>[OH:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:22]2[C:23]3[C:15]([CH3:14])=[C:16]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[S:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:25][CH2:26]1
Reactant: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(N)CC3)c12
Reactant: OCc1cccc(OCC2CO2)c1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)sc2ncnc(N3CCC(NCC(O)COc4cccc(CO)c4)CC3)c12
Yield: 36 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 35 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-methyl-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 36% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: C(O[CH:4]([O:8][CH2:9][CH3:10])[O:5]CC)C.[CH3:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22](=O)C)[CH:16]=[CH:15]2.II>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[CH2:9]([O:8][C:4](=[O:5])[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:22])[CH:18]=2)[CH:13]=1)[CH3:10]
Reactant: CC(=O)c1ccc2cc(C)ccc2c1
Reactant: CCOC(OCC)OCC
Agent: [Ag+]
Agent: II
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cc1ccc2cc(C)ccc2c1
Temperature: 80 °C

Procedure:
Triethylorthoformate (1.5 ml) and 1-(6-methylnaphthalen-2-yl)ethanone (1.0 mmol) were dissolved in ethanol (4 ml). To the reaction mixture were added AgNO3 (2.1 mmol) and I2 (1.05 mmol) and the reaction mixture was heated to 80° C. for 20 hours. The reaction mixture was cooled to ambient temperature and concentrated to dryness. The residue was diluted eith EtOAc and filtered through celite. The combined organics were washed with saturated sodium bicarbonate solution and brine. The organic layer was then dried over MgSO4, filtered and concentrated to dryness. The crude residue was chromatographed on silica gel using 5% EtOAc in hexanes as the eluant to yield the title compound (50).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH3:12]>O1CCOCC1>[Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: Clc1nccc2scc(Br)c12
Reactant: N
Solvent: C1COCCO1
Product: Nc1nccc2scc(Br)c12
Temperature: 150 °C
Reaction time: 96 h

Procedure:
To the solution of 3-bromo-4-chloro-thieno[3,2-c]pyridine (3.2 g) in dioxane (30 ml) was added 28% ammonia solution (10 ml) in an autoclave and put into the oil bath. The reaction mixture was allowed to heat up to 150° C. and stir for 4 days at 150° C. The resultant mixture was concentrated in vacuo and the residue was purified by chromatography on a silica gel column to afford 3-bromo-thieno[3,2-c]pyridin-4-ylamine (1.7 g) 1H NMR (400 MHz, DMSO-d6) ppm 7.84 (d, J=5.6 Hz, 1H), 7.78 (s, 1H), 7.27 (d, J=5.6 Hz, 1H), 6.51 (s, 2H). MS: m/z 229, 231 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>C(Cl)Cl>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)=[O:10]
Reactant: COC(CN)OC
Reactant: O=C=Nc1cccc(I)c1
Solvent: ClCCl
Product: COC(CNC(=O)Nc1cccc(I)c1)OC
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A suspension of 3-iodophenylisocyanate (1.1 g) in DCM (10 ml) was treated with aminoacetaldehyde dimethyl acetal (0.49 ml) and stirred under nitrogen at 20° C. for 24 h. The reaction mixture was quenched by adding MeOH. The solvents were removed under reduced pressure to give the title compound (1.35 g) LCMS RT=2.92 min.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([O:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:9][C:8]=1[O:20][CH3:21])(C)(C)C.S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[CH2:29]([O:17][C:15](=[O:16])[CH:14]([O:18][CH3:19])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([O:20][CH3:21])[CH:9]=1)[CH3:30]
Reactant: COc1cc(CC(OC)C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (356 mg, 1.05 mmol) in absolute ethanol (8 mL) was added concentrated sulfuric acid (0.033 mL, 0.63 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The solution was concentrated under vacuum, and water (10 mL) and solid NaHCO3 were added to neutralize the residue. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated to produce 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid ethyl ester (260 mg, 98%). 1H-NMR (200.15 MHz, CDCl3): δ 6.83 (d, 1H, J=8.1 Hz), 6.76–6.69 (m, 2H), 4.19 (q, 2H, J=7.3 Hz), 3.97–3.90 (m, 1H), 3.87 (s, 3H), 3.36 (s, 3H), 2.96–2.92 (m, 2H), 1.25 (t, 3H, J=7.3 Hz).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[O:37]=[C:38]1[CH2:42][CH2:41][CH2:40][N:39]1[CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:45][CH2:44][CH:43]([N:39]4[CH2:40][CH2:41][CH2:42][C:38]4=[O:37])[CH2:48][CH2:47]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27]
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Reactant: O=C1CCCN1C1CCNCC1
Product: Cc1ccccc1-c1cc(N2CCC(N3CCCC3=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 38.8 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (47.6 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (38.0 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (23.1 mg, 39%).
Reaction SMILES: [C:1]([CH:3]([NH:9][CH:10]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:12](#[N:15])[CH:13]=[CH2:14].FC(F)(F)C(O)=O>ClCCCl>[NH2:2][C:1]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:9][CH:10]=[CH:14][C:13]=1[C:12]#[N:15]
Reactant: C=CC#N
Reactant: CCOC(=O)C(C#N)NC=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)c1nccc(C#N)c1N
Yield: 20.9 %

Procedure:
A stirred solution of ethyl 2-cyano-2-(formyl-amino)acetate (J. Org. Chem., 1979, 44, 3835; 0.47 g, 0.003 mol), acrylonitrile (1.2 ml, 0.018 mol) and tri-fluoroacetic acid (0.02 ml, 0.0003 mol) in 1,2-dichloroethane (4 ml) was heated under reflux for 3 days. The solvent was removed by evaporation under vacuum, the residue dissolved in dichloromethane (30 ml) and the resulting solution washed with saturated aqueous sodium bicarbonate solution (30 ml). The aqueous phase was washed with dichloromethane (30 ml) and the organic solutions then combined, dried (MgSO4) and evaporated under vacuum. Chromatography of the residue on silica gel (12 g), eluting with dichloromethane:methanol (100:1), followed by crystallization from acetone:hexane, gave the title compound as a colourless solid (0.12 g, 21%), m.p. 114-116° C.
Reaction SMILES: [Li].[H-].O1CCCC1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1)#[N:9]>C(O)C>[NH2:9][CH2:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: N#Cc1ccccc1-n1cccc1
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1ccccc1-n1cccc1

Procedure:
To a well stirred suspension of (0.05 mol) of lithium alumunium hydride in 100 ml of anhydrous tetrahydrofuran, (0.043 mole) of 1-(2-cyanophenyl)pyrrole were added by small portions. Then the mixture was maintained with stirring at room temperature for 18 hours. Addition of aqueous ethanol to destroy the excess lithium aluminium hydride, followed by filtration afforded a solution, which was then evaporated in vacuo. The residue was extracted with ethyl ether, the organic layer washed with water and dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave a crude product, which was purified by passing through an alumina column eluting with chloroform to give 1-(2-aminomethylphenyl)pyrrole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Br:12][C:13]1[C:14]([CH3:24])=[N:15][C:16]2[N:17]([N:20]=[C:21]([CH3:23])[CH:22]=2)[C:18]=1Cl>O1CCCC1>[Br:12][C:13]1[C:14]([CH3:24])=[N:15][C:16]2[N:17]([N:20]=[C:21]([CH3:23])[CH:22]=2)[C:18]=1[O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1cc2nc(C)c(Br)c(Cl)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2nc(C)c(Br)c(Oc3ccc(F)cc3F)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
A solution of 2,4-difluorophenol (0.156 mL, 0.960 mmol) in tetrahydrofuran (3.0 mL) was treated with sodium hydride (0.0242 g, 0.960 mmol) at 0° C. The resultant reaction mixture was warmed to RT and stirred at that temperature for 30 min. The reaction mixture was then cooled to 0° C., treated with 6-bromo-7-chloro-2,5-dimethylpyrazolo[1,5-a]pyrimidine (0.125 g, 0.480 mmol), warmed to RT and stirred at RT for 14 h. The reaction mixture was cooled to 0° C., quenched with saturated ammonium chloride solution, and diluted with ethyl acetate. Layers were separated and the organic layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% Et2O/hexanes) gave the desired product (162 mg, 95%) as a white solid. LCMS calculated for C14H11BrF2N3O (M+H)+: m/z=354.0, 356.0. found: 353.9, 356.0.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)=[C:3]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1cccc(OC)c1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of ethyl (1RS)-1-hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (150 mg, 0.35 mmol) in CH2Cl2 was added triethylsilane (67 μl, 0.42 mmol), followed by boron trifluoride etherate (213 μl, 1.73 mmol). The reaction mixture was allowed to stir for 30 min, at which time was added slowly 5% aqueous HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to provide the title compound (45 mg, 31%) as a mixture of Δ1 and Δ2 double bond isomers.