Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=2)O1.[C:38]([O-:41])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:31]=[C:32]([CH2:35][N:7]([CH3:8])[CH2:6][CH2:5][O:41][CH3:38])[S:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cs1
Temperature: 150 °C
Yield: 14 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (100 mg, 0.27 mmol) in dioxane and water (3 mL/1 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (116 mg), Pd(PPH3)4 (30 mg) and K2CO3 (112 mg). The reaction mixture was heated to 150° C. for 900 seconds in microwave. The organic phase was separated, concentrated, and redissolved in DMSO (3 mL). The resulting solution was split to two. NaBH3CN (30 mg), ZnCl2 (30 mg) and N-methyl-2-(methyloxy)ethanamine (50 mg) were added. The mixture was heated to 100° C. for 30 minutes in microwave which was then purified by HPLC with TFA to afford the title compound (9 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[N:13]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)[Cl:18]>O.Cl>[ClH:18].[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][NH2:13]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: O=N[O-]
Reactant: Nc1ccccc1OC(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccccc1OC(F)(F)F
Reaction time: 8 h
Yield: 68.8 %

Procedure:
2-(Trifluoromethoxy)aniline (2.00 mL, 15.0 mmol) was cooled and conc hydrochloric acid (10 mL) added. After recooling to 0° C. a solution of the sodium nitrite (1.25 g, 18.0 mmol) in water (10 mL) was added dropwise. The reaction was stirred at the same temp for 30 min when tin chloride (8.53 g 45.0 mmol) in hydrochloric acid (10 mL) was added dropwise again keeping temp ca 0° C. The reaction was stored in a fridge overnight and then recooled to 0° C. The resulting solid was filtered off, washed with saturated NaCl (10 mL) and then ether:hexane 1:2 before drying to give a solid (2.36 g, 69%)
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13](=[O:25])[NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][N:16]=3)[CH:10]=[C:9]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:7]=2[CH:8]=1.CO.C1COCC1>O>[CH3:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13](=[O:25])[NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]=3)[CH:10]=[C:9]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:7]=2[CH:8]=1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)c3cc(C)oc3c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(OCC(C)C)cc(C(=O)Nc3ccc(C(=O)O)cn3)cc2o1
Temperature: 25 °C

Procedure:
Sodium hydroxide solution (0.94 ml of 1M, 0.94 mM) was added to a solution of 2-methyl-4-isobutoxy-6-[N-(5-methoxycarbonylpyridin-2-yl)carbamoyl]benzofuran (Method 1; 120 mg, 0.314 mM) in a methanol/THF mixture (1 ml+4 ml), and the resulting solution stirred at ambient temperature. After 4 hrs the reaction mixture was diluted with water (5 ml) and concentrated to half volume in vacuo. The resulting mixture was acidified to pH6 with 1M HCl. The resulting solid precipitate was filtered, washed with water, and dried to give a pale cream solid. This was chromatographed (10 g Bondelut), eluting with DCM containing methanol (0-10% gradient) to give the title compound as a colourless solid. NMR: 1.03 (d, 6H), 2.09 (sept, 1H), 2.45 (s, 3H), 3.97 (d, 2H), 6.66 (s, 1H), 7.44 (s, 1H), 7.85 (s, 1H), 8.31 (t, 2H), 8.87 (s, 1H), 11.10 (bs, 1H); m/z 367 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][N:22]=2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[O:29]1CC[CH2:31][CH2:30]1.C(O)CO>C(N(CC)CC)C>[CH2:30]1[O:29][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:10]2[CH:20]=[CH:21][N:22]=[C:8]([C:6](=[O:7])[C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)[O:12][CH2:31]1
Reactant: C1CCOC1
Reactant: O=C(Nc1ccccc1)c1ccnc(C(=O)c2ccc(Cl)cc2)c1
Solvent: OCCO
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1cc(C2(Nc3ccccc3)OCCO2)ccn1
Reaction time: 0.33 h
Yield: 80 %

Procedure:
2-(4-Chlorobenzoyl)-isonicotinanilide (11 g) was reacted with thionyl chloride as in Synthesis 1. To the resulting product, tetrahydrofuran (150 ml) and ethylene glycol (30 ml) were added and the mixture was stirred for about 20 minutes under cooling with ice. To the resulting solution, triethylamine (25 ml) was added dropwise. After completion of the addition, the solution was stirred for 1 hour, followed by stirring at room temperature for another 4 hours. The resulting solution was treated as in Synthesis 1 to produce the titled compound in an amount of 10.2 g (yield: 80%). m.p. 102°-103° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][C@H:10]([N:12]=[N+]=[N-])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][C@H:10]([NH2:12])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C

Procedure:
A solution (4S)-1-(tert-butyloxycarbonyl)-4-azido-L-proline tert-butyl ester (185 mg, 0.611 mmol) in 90% ethanol (15 mL) was hydrogenated in the presence of 10% palladium-on-charcoal (40 mg) under a balloon atmosphere of hydrogen gas for one hour. The catalyst was removed by filtration through Celite, the filter washed with methanol, and the combined filtrate and washings evaporated. The title compound was obtained as a colorless oil after drying under high vacuum; yield 145 mg (86%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13].[Cl:14][C:15]1[C:16]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])=[N:17][NH:18][C:19]=1[CH3:20].Cl>C(OCC)(=O)C>[Cl:8][CH2:9][CH2:10][NH:11][C:12]([N:18]1[C:19]([CH3:20])=[C:15]([Cl:14])[C:16]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])=[N:17]1)=[O:13]
Reactant: Cc1[nH]nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Reactant: O=C=NCCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)c(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Triethylamine (0.10 g, 1.0 mmol) and 2-chloroethyl isocyanate (0.12 g, 1.1 mmol) were added to a solution of 4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.35 g, 1.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-(2-chloroethyl)-4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.44 g, yield: 97.6%). mp: 141-143° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.62 (s, 3H), 3.55-3.65 (m, 4H), 6.80-7.05 (m, 1H), 7.67 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1cccc(C(F)(F)F)c1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-(trifluoromethyl)benzylamine (47 mg, 0.39 mmol). The title compound was obtained as a solid (87 mg, 52% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.48 (1H, m), 8.99 (2H, s), 8.47 (1H, s), 7.64 (2H, m), 7.57 (1H, m), 4.56 (2H, m). MS m/z: 506.07, 508.07 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15].C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl.O1CCOCC1>[OH:5][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 40.2 %

Procedure:
A mixture of (S)-(−)-3-chloro-1-phenyl-1-propanol (0.426 g, 2.50 mmol, 99%ee), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.565 g, 2.00 mmol), diisopropylethylamine (1.29 g, 10.0 mmol), dioxane (5.0 mL) and catalytic amount of tetrabutylammonium iodide was stirred at 90° C. for 72 hrs. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (306 mg, 39.3% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.42 (d, 4H, J=8.1 Hz), 7.35 (m, 1H), 7.30 (d, 1H, J=8.0 Hz), 7.23 (t, 1H, J=8.1 Hz), 7.12 (s, 1H), 6.96 (apparent dd, 1H, J=8.0 Hz), 5.0 (apparent dd, 1H, J=4.4, 8.3 Hz), 3.18 (apparent dd, 2H, J=2.5, 12.5 Hz), 2.74 (m, 2H), 2.50 (m, 2H), 2.3-2.1 (m, 6H), 1.8 (m, 2H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 389.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:28])([C:5]([F:27])([F:26])[C:6]([F:25])([F:24])[C:7]([F:23])([F:22])[C:8]([F:21])([F:20])[C:9]([F:19])([F:18])[C:10]([F:17])([F:16])[C:11]([F:15])([F:14])[CH2:12][OH:13])[CH2:3][OH:4].[OH-].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([O:13][CH2:12][C:11]([F:15])([F:14])[C:10]([F:16])([F:17])[C:9]([F:18])([F:19])[C:8]([F:20])([F:21])[C:7]([F:22])([F:23])[C:6]([F:25])([F:24])[C:5]([F:26])([F:27])[C:2]([F:28])([F:1])[CH2:3][OH:4])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry 5 mL round bottom flask was charged with 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorodecane-1,10-diol (2.2 mmol, 1.0 g), dry DMF (2.5 mL), and crushed potassium hydroxide (2.2 mmol, 121 mg). The mixture was flushed with argon and benzyl bromide (0.7 mmol, 123 mg) was added dropwise over 15 minutes. The solution was allowed to stir overnight at room temperature under argon. The reaction mixture was concentrated in vacuo, and the residue was partitioned between aqueous saturated ammonium chloride and ethyl acetate. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with water then brine, dried over MgSO4, and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel using 5% EtOAc in petroleum ether as the eluent. The product was isolated as colorless oil; upon drying under high vacuum for 12 h, the oil solidified (90%). 1H NMR (CDCl3): δ7.36 (m, 5H), 4.68 (s, 2H), 4.10 (td, 2H, J=14, 6), 3.94 (t, 2H, J=14), 1.96 (t, 1H, J=7); 13C NMR (CDCl3): δ136.6, 128.8, 128.5, 128.0, 74.7, 66.9, 60.9; 19F NMR (CDCl3): δ −119.8, −122.3, −122.8, −123.7, −123.9.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29]C)=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[C:32]([F:38])=[CH:33][CH:34]=[CH:35][C:36]=3[F:37])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2c(F)cccc2F)ccc2cc(O)ccc12
Yield: 54 %

Procedure:
Convert [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,6-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-methanone (2.5 g, 4.8 mmol) into the hydrochloride salt and charge a flask with the solid salt. Dissolve the material in 200 mL methylene chloride and chill in ice. Add to this mixture boron tribromide (5.0 mL, 53.0 mmol) while swirling. Stir the reaction at room temperature for one hour and pour into a two phase system of saturated sodium bicarbonate and an organic layer consisting of a 3/1 mixture of chloroform/isopropanol. Shake to extract the product, separate the organic layer, dry over 3 Å molecular sieves and evaporate the solvent under vacuum. Purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (54%) of the title compound: 1H-NMR (CDCl3, 400 MHz) δ 7.79-7.74 (d, 1H); 7.58 (d, J=8.4 Hz, 2H); 7.50 (d, J=8.8 Hz, 1H); 7.33-7.30 (d, 1H); 7.17 (d, J=2.4 Hz, 1H); 7.16-7.08 (m, 1H); 6.99-6.95 (dd, 1H); 6.77-6.73 (m, 2H); 6.68 (d, J=9.2 Hz, 2H); 4.11 (t, J=6.0 Hz, 2H); 3.05-2.99 (t, 2H); 2.90-2.84 (m, 4H); 1.71-1.71 (m, 4H); 1.63-1.60 (m, 4H).
Reaction SMILES: [F:1][C:2](F)(F)[CH2:3][C:4]([NH2:6])=O.FC1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=CC=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:20]([CH2:19][NH:6][C:4]1[CH:3]=[C:2]([F:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(F)cc1
Reactant: NC(=O)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1cc(F)ccc1C#N
Yield: 115.1 %

Procedure:
Dissolve the 2-trifluoromethylacetamide-4-fluorobenzonitrile (1 g, 4.3 mmol) in dimethylformamide (4 mL) under an atmosphere of nitrogen. Add ethyl bromoacetate (0.954 mL, 8.6 mmol), potassium carbonate (1.1 g, 8.6 mmol) and heat to 50° C. for 2.5 hours. Dilute the reaction with ethyl acetate and rinse the organic phase with water. Dry the organic phase, filter and concentrate in vacuo to yield the title compound (1.1 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.COC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.FC(F)(F)S(OC1C=CC([Cl:63])=CC=1)(=O)=O>>[Cl:63][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])=[N:7][CH:2]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Reactant: O=S(=O)(Oc1ccc(Cl)cc1)C(F)(F)F
Agent: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(Cl)cn1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (100 mg, 0.28 mmol) was reacted with 4-chlorophenyl trifluoromethanesulfonate (74 mg, 0.28 mmol) to afford the desired 2-[4-(5-chloropyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.69–8.68 (d, 1H), 7.98 (s, 2H), 7.94–7.90 (m, 2H), 7.86–7.78 (m, 1H), 7.74–7.73 (m, 1H), 7.65–7.58 (m, 1H), 7.40–7.37 (m, 2H), 4.03 (s, 3H). MS (ESI) 337 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(C=O)[CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:22][CH2:23][CH3:24])=[O:21].[C:45]1(C)C=CC=CC=1>>[C:10]([CH2:9][CH2:8][C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:45]=[CH:25][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:11]
Reactant: N#CCCC(C=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=CC(CCC#N)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 4,4-diphenyl-4-formylbutyronitrile (8.04 g) and (carbethoxymethylene)-triphenylphosphorane (20.85 g) in toluene (200 mL) was heated under reflux for 3 days. The reaction mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography to give the desired product as a yellow-orange oil (12.10 g): MS showed (M+NH4)+ @ 337; 1H-NMR (CDCl3, δ): 1.25-1.32 (t. 3H), 2.10-2.18 (m, 2H), 2.65-2.75 (m, 2H), 4.15-4.23 (q, 2H), 5.60-5.66 (d. 1H), 7.05-7.75 (m. I 1H).
Reaction SMILES: BrCCBr.[Cl:5][C:6]([Cl:12])(Cl)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>O1CCCC1.CCCCCC.[Zn]>[Cl:5][C:6]([Cl:12])=[C:7]([O:9][CH3:10])[O:8][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CCCCCC
Product: COC(O[Si](C)(C)C)=C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a suspension of 5.9 g (0.091 g-atom) of zinc powder (−325 mesh) in 40 mL of tetrahydrofuran was added 0.2 mL of 1,2-dibromoethane. The mixture was heated at gentle reflux for 30 minutes. The mixture was cooled to room temperature and 7.1 mL (0.06 mole) of methyl trichloroacetate was added dropwise, followed by 9.1 mL (0.097 mole) of trimethylsilyl chloride at rate such the internal temperature was below 50 degrees. The mixture was stirred at room temperature for 1 hour and then diluted with hexane. The resulting solid was removed by filtration, and the filtrate concentrated under reduced pressure. Solids were removed by filtration, washing with hexane. The filtrated was concentrated under reduced pressure and the residue was then distilled under vacuum to give 8.0 g of (2,2-dichloro-1-methoxy-vinyloxy)-trimethyl-silane as a colorless oil. Bp 45-48 degrees at 1 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]12[O:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-:3])=[O:2].[C:19](#[N:22])[CH:20]=[CH2:21].O>CN(C=O)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][CH2:20][C:19]#[N:22])[C:8](=[O:13])[C:7]12[O:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-:3])=[O:2]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C12OCCCO2
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCN1C(=O)C2(OCCCO2)c2cc([N+](=O)[O-])ccc21
Temperature: 52 °C
Yield: 101.4 %

Procedure:
At room temperature, to a mixture of 5′-nitrospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one(1.75 g, 6.99 mmol) and benzyltrimethylammonium hydroxide (40% aqueous solution, 0.110 mL, 0.699 mmol, 0.1 mole %) in DMF (31 mL) was added acrylonitrile (0.921 mL, 14.0 mmol, 2 eq) drop-wise. and the mixture was heated at 52° C. for 2 hr. The reaction was cooled to room temperature and poured into H2O (160 mL). The reaction mixture was extracted with Et2O. The combined organic extracts were washed with brine and concentrated. The crude product was purified on Biotage KP silica gel eluting with 96/4 CH2Cl2/CH3CN to give the title compound as a yellow solid (2.15 g, 100% ). NMR (300 Mz, DMSO-d6): consistent
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.C(O)(=[O:37])C.O.B(O[O-])=O.[Na+]>CCO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:37])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: CC(=O)O
Agent: O=BO[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Temperature: 0 °C

Procedure:
4.41 g (8.72 mmol) {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester is dissolved in 10 ml EtOH and 2.20 ml glacial acetic acid and 2.20 ml water are added. The funnel is rinsed with 7.50 ml EtOH. Then, 2.28 g (14.8 mmol) sodium perborate is added in portions at r.t. and the mixture is stirred. After complete addition, 1.40 ml water and 1.6 ml toluene is added. The organic phase is separated and 1.60 ml water is added. After cooling to 0° C., the 2-phasic mixture is seeded and stirring is continued. The precipitated product is filtered off, washed with cold toluene and dried. Yield: 2.86 g; Rf=0.22 (silica gel, PE/EtOAc=7/3); Mass spectrum (ESI): m/z=359 [M+H]+.
Reaction SMILES: O.Cl.Cl.[CH2:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[NH:13][C:14]1[N:15]=[CH:16][C:17]2[CH2:22][NH:21][CH2:20][C:18]=2[N:19]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>ClCCl>[Cl:30][CH2:31][C:32]([N:21]1[CH2:22][C:17]2[CH:16]=[N:15][C:14]([NH:13][CH:5]3[CH2:4][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6]3)=[N:19][C:18]=2[CH2:20]1)=[O:33]
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CNC3)C2
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCl)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: -30 °C
Yield: 83.5 %

Procedure:
Stir a suspension of N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrate (14.4 g, 41.9 mmol) and triethylamine (14.3 g, 19.7 mL, 141.4 mmol) in dichloromethane (200 mL) at 23° C. for 10 minutes, then cool to −30° C. Add 2-chloroacetyl chloride (5.49 g, 3.86 mL, 48.6 mmol) over two minutes and warm to 23° C. over 10 minutes. Add methanol (5 mL) and remove the solvent in vacuo. Slurry the crude reaction mixture in methanol (30 mL), add 50 g silica gel and remove solvent in vacuo. Load the resulting residue onto a loading column and purify via silica gel column chromatography (gradient elution: 50% ethyl acetate in hexanes to ethyl acetate to 10% methanol in ethyl acetate) to give the title compound (11.5 g, 84%). MS (m/z): 329(M+1).