Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([N:14]([S:37]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])[C:15](=[CH2:36])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:21]=1)=[O:17])[CH3:13].O.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[CH2:12]([N:14]([S:37]([C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])[C:15](=[CH2:36])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N+:23]([O-:9])=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:21]=1)=[O:17])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C(=O)NCc1cc[n+]([O-])c(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
3-Chloro perbenzoic acid (1.5 mol eq, 100 mg) was added to a solution of Example 1 (200 mg, 0.39 mmol) in CHCl3 (10 mL) and the mixture was stirred at r.t. for 24 hours. Then 10% water solution of K2CO3 was added to wash the organic phase that was then dried over Na2SO4 and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (EtOAc 6/petroleum ether 4) to obtain a white solid (60 mg, 29% yield). 1HNMR (DMSO, 200 MHz) δ 1.09 (3H, t, J=7.2 Hz), 3.40 (2H, q, J=6.8 Hz), 4.40 (2H, d, J=6 Hz), 5.14 (1H, s), 6.10 (1H, s), 7.36 (1H, dd, J=4.8 Hz, J′=1.2 Hz), 7.46 (2H, t, J=8.8 Hz), 7.63 (1H, d, J=2.2 Hz), 7.83 (4H, m), 8.05 (2H, d, J=8 Hz), 8.34 (1H, d, J=6.8 Hz), 8.82 (1H, bt) [M+1] 524.6 (C24H21F4N3O4S requires 523.50).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[C:9](OC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: COCCOc1ccc(C(=O)OC)cc1OCCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOc1ccc(CO)cc1OCCOC
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of methyl 3,4-bis{[2-(methyloxy)ethyl]oxy}benzoate, (1.1 g, 3.9 mmol) at 0° C. was added a solution of lithium aluminum hydride in tetrahydrofuran (1.0M, 5.0 mL, 5.0 mmol) and the resulting mixture was stirred for one hour. It was then quenched with ethyl acetate (2 mL) and 5% sodium hydroxide solution (2 mL), diluted with ether (100 mL), and filtered. The filtrate was washed water and brine (100 mL each), dried over sodium sulfate, filtered and concentrated to give (3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)methanol (0.82 g, 3.2 mmol, 82% yield). 1H NMR (400 MHz, CDCl3): 6.93 (s, 1H), 6.87 (s, 2H), 4.59 (s, 2H), 4.16-4.13 (m, 4H), 3.77-3.74 (m, 4H), 3.44 (s, 6H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16].Br[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: BrCC1CCCO1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31 M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid (696 mg, 3.39 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of 2-bromomethyl-tetrahydro-furan (672 mg, 4.07 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. The excess solvent was removed in vacuo. The residue was diluted with water (50 mL) and was treated with a 1N aqueous hydrochloric acid solution until the solution was acidic. The resulting solution was extracted into ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate with glacial acetic acid) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid (692.3 mg, 70.8%) as a white solid: mp 100–102° C.; FAB-HRMS m/e calcd for C13H14Cl2O3 (M+H)+ 289.0399, found 289.0404.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23](Br)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[CH:25][N:24]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: COc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1OC

Procedure:
Synthesized using 3,4-dimethoxyphenylboronic acid (610 mg, 3.36 mmol) and 1a (400 mg, 1.68 mmol) according to Method C. Yellow solid. Yield: 470 mg, 1.58 mmol, 94%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.93 (s, 3H), 3.98 (s, 3H), 5.16 (s, 2H), 6.92 (br, s, 1H), 6.94 (d, J=8.5 Hz, 1H), 7.11 (bs, 1H), 7.46 (dd, J=8.5, 2.2 Hz, 1H), 7.47 (dd, J=8.5, 2.2 Hz, 1H), 7.58 (bs, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 56.0, 56.0, 113.3, 110.0, 111.1, 119.0, 119.5, 120.0, 129.4, 130.3, 131.4, 135.7, 148.4, 149.4, 150.3, 157.3; MS (ESI): m/z=296.17 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[H][H]>C(OCC)(=O)C.C(O)C.O=[Pt]=O>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccccc2Br)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Brc1ccccc1CC1CCNCC1
Reaction time: 18 h
Yield: 260 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-[(2-bromophenyl)methylene]-piperidine (XI, 8 g, 22.7 mmole) in ethyl acetate (75 ml) and ethanol (75 ml) was shaken with PtO2 (0.75 g) and hydrogen (60 psi) for 15 min. Two further batches of 1-(tert-butoxycarbonyl)-4-[(2-bromophenyl)-methylene]-piperidine (8 g each, 24 g total) were similarly reduced and the mixtures were filtered. The filtrates were combined and concentrated in vacuo. The residue (X) was dissolved in dioxane (200 ml) and 3N HCl (100 ml) and stirred for 18 hr. The solution was concentrated in vacuo and the residue was made basic with 50% sodium hydroxide. The mixture was extracted with CH2Cl2. The extracts were dried over Na2SO4 and concentrated in vacuo to give a yellow oil that was purified by short path vacuum distillation to give 4-(2-bromobenzyl)piperidine (VI) as a oil (15 g, 86.6%). The oil converted to the fumarate salt using fumaric acid (6.85 g) in 2-propanol to give 4-(2-bromobenzyl)piperidine fumarate as a white solid (15.8 g, 62.6% overall, mp: 164-165° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([SH:18])[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1.[CH2:27](I)[CH2:28][CH3:29].C(=O)([O-])O.[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>CN(C)C=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:27][CH2:28][CH3:29])[N:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:14]=2[CH:25]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccccc3)c2c1
Reactant: CCCI
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
100 mg of 6-[[2-mercapto-1-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 2 ml of N,N-dimethylformamide, mixed with 40 μl of propyl iodide, 57 mg of potassium hydrogen carbonate and 10 mg of dicyclohexano-18-crown-6, and the mixture was stirred for 15 hours at 20° C. It was filtered, and the filtrate was concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 103 mg was obtained.
Reaction SMILES: C1(C2CCCCCCCC2)BCCCCCCC1.[CH3:19][O:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][O:31][CH3:32])[CH:26]=[CH:25][C:24]=1[CH:33]1[CH2:38][CH2:37][CH2:36][C:35](=[CH2:39])[CH2:34]1.OO.[OH-].[Na+].S(S([O-])=O)([O-])(=O)=[O:45].[Na+].[Na+]>O1CCCC1.O>[CH3:19][O:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][O:31][CH3:32])[CH:26]=[CH:25][C:24]=1[CH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][OH:45])[CH2:34]1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: C=C1CCCC(c2ccc(OCOC)cc2OCOC)C1
Agent: B1CCCCCCCC1C1CCCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(C2CCCC(CO)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
9-Borabicyclononane (2.7 ml of a 0.5M solution in tetrahydrofuran) was added to a stirred solution of (±)-2,4-bis(methoxymethoxy)-1-(3-methylenecyclohexyl)benzene (80 mg) in tetrahydrofuran (2 ml) at 0° C. under argon. After 1 hr at 0° C., the reaction mixture was allowed to warm to ambient temperature and stirring continued. After 2 hr, the reaction mixture was cooled to 0° C. and water (0.1 ml) was added. After the effervescence had subsided, hydrogen peroxide (1 ml of a 30% w/v solution) and sodium hydroxide (1 ml of a 2M solution) were added and the mixture was allowed to warm to ambient temperature. After a further 16 hr, the reaction mixture was cooled to 0° C. Saturated aqueous sodium metabisulfite was added until no oxidant could be detected by starch iodide paper, and the reaction mixture was extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with water (20 ml), dried over magnesium sulfate, and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as a pale brown oil (46 mg, 54%); m/z (ES+) 311 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.O>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(Br)nc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a reaction container equipped with a dropping funnel, 8 g of 2,5-dibromopyridine and 90 ml of diethyl ether were added. The obtained solution was cooled at −70° C. and then, 21.37 mL of butyl lithium (1.58 M/hexane solution) was added dropwise thereto. The obtained mixture was stirred for 1 hour and 30 minutes and then, a solution obtained by dissolving 4.32 mL of trimethylchlorosilane in 6.2 mL of diethyl ether was added dropwise thereto. The obtained mixture was stirred for 2 hours and 40 minutes and then, 60 mL of water was added dropwise thereto at 0° C. The obtained mixture was stirred at room temperature overnight and then, 30 mL of diethyl ether was added thereto. The obtained solution was extracted three times with 30 mL of diethyl ether. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography to obtain 5.96 g of 2-bromo-5-trimethylsilylpyridine. Purity: 90% (area percentage value obtained by gas chromatography analysis).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10].[I-].[Na+].[O:15]=[S:16]1(=[O:33])[CH2:21][CH2:20][N:19]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:18]2=[N:17]1.[OH-].[Na+]>CS(C)=O>[CH2:9]([CH:8]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]2[C:18]3=[N:17][S:16](=[O:33])(=[O:15])[CH2:21][CH2:20][N:19]3[CH:22]=[CH:23][CH:24]=2)=[CH:31][CH:30]=1)[CH2:11][CH3:12])[CH3:10]
Reactant: CCC(Br)CC
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CC)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 9.6 %

Procedure:
A mixture of potassium carbonate (750 mg), 3-bromopentane (820 mg), sodium iodide (814 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) in DMSO (5 mL) was stirred at 150° C. for 3 hr. The mixture was poured into 1N NaOH aq. and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give a solid. This material was purified by preparative HPLC (C18, eluted with H2O in acetonitrile containing 0.1% TFA). The desired fraction was neutralized with sat. NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (36.1 mg) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:5]=1[NH:20]C(=O)C.[ClH:25]>>[ClH:25].[ClH:25].[NH2:20][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][C:4]=1[C:3]([OH:24])=[O:2]
Reactant: COC(=O)c1cc(OCCCN2CCCCC2)ccc1NC(C)=O
Agent: Cl
Product: Nc1ccc(OCCCN2CCCCC2)cc1C(=O)O
Yield: 100 %

Procedure:
2-Acetylamino-5-(3-piperidin-1-ylpropoxy)benzoic acid methyl ester (1.34 g, 4.0 mmol) was treated with 6N HCl (aq.) (20 mL) and heated at reflux temperature for 8 h. The mixture was then cooled and concentrated in vacuo to afford 2-amino-5-(3-piperidin-1-ylpropoxy)benzoic acid dihydrochloride (1.4 g, 4.0 mmol, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([O:29][CH3:30])[C:26]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:31]([OH:34])([CH3:33])[CH3:32])=[C:27]([O:29][CH3:30])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: COc1nc(Cl)ccc1C(C)(C)O
Product: COc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C(C)(C)O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (60 mg, 0.19 mmol) and 2-(6-chloro-2-methoxypyridin-3-yl)propan-2-ol (39 mg, 0.19 mmol) as starting materials.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH:24]=O.[NH2:26][CH2:27][CH:28]1[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C1(OC2C=CC(C=O)=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH:28]1([CH2:27][NH:26][CH2:24][CH2:23][CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:14]4=[CH:15][C:16]5[O:20][CH2:19][O:18][C:17]=5[CH:21]=[C:13]4[O:12][CH2:11]3)[C:2]2=[O:1])[CH2:30][CH2:29]1
Reactant: NCC1CC1
Reactant: O=CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=Cc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1N(CCCNCC2CC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanal (0.07 g, 0.20 mmol) in THF (5.00 mL) was added (aminomethyl)cyclopropane (0.30 mmol) and MP-triacetoxyborohydride (0.26 g, 0.60 mmol). After overnight shaking, the polymer-bound 4-phenyloxybenzaldehyde (0.25 g, 0.18 mmol) was added. After another overnight shaking, the mixture was diluted with ether (10.0 mL) and filtered. The filtrate was concentrated in vacuo to dryness. The residue was recrystallized to give the title compound (0.05 g) in 62% yield as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.32-6.92 (m, 4H), 6.49 (s, 1H), 6.12 (s, 1H), 5.83 (m, 2H), 4.86 (m, 1H), 4.64 (m, 1H), 3.97-3.77 (m, 2H), 2.87-2.80 (m, 2H), 2.66-2.56 (m, 2H), 1.02-0.94 (m, 1H), 0.56-0.47 (m, 2H), 0.25-0.18 (m, 2H); MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1B(O)O
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1nccc1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C

Procedure:
(1-Methyl-1H-pyrazol-5-yl)boronic acid (C1) (1.00 g, 7.94 mmol), 2-bromo-5-(trifluoromethyl)pyridine (1.79 g, 7.92 mmol), dichlorobis(triphenylphosphine)palladium(II) (279 mg, 0.397 mmol), and sodium carbonate (3.37 g, 31.8 mmol) were combined in 1,2-dimethoxyethane (30 mL) and water (3 mL), and the reaction mixture was heated at reflux for 18 hours. After the reaction had cooled to room temperature, it was concentrated in vacuo, diluted with additional water, and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product. Yield: 630 mg, 2.77 mmol, 35%. 1H NMR (400 MHz, CD3OD) δ 3.95 (s, 3H), 6.60 (d, J=2.2 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.94 (br d, J=8.2 Hz, 1H), 8.19-8.23 (m, 1H), 8.89 (br d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.C(O[C:17](=[O:19])[CH3:18])(=O)C>>[C:17]([N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:1])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CNC1CCCc2ccccc21
Product: CC(=O)N(C)C1CCCc2ccccc21

Procedure:
N-Methyl-1,2,3,4-tetrahydro-1-naphthylamine is stirred with acetic anhydride to afford N-acetyl-N-methyl-1,2,3,4-tetrahydro-1-naphthylamine, which is oxidized to N-acetyl-N-methyl-1,2,3,4-tetrahydro-4-oxo-1-naphthylamine by the method of Example 1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O-].[Na+].[CH3:10][C:11]([CH3:19])([CH3:18])[C:12]#[C:13][C:14]#[C:15][CH2:16][OH:17].C(OCC)(=O)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:26]/[C:14](/[C:13]#[C:12][C:11]([CH3:19])([CH3:18])[CH3:10])=[CH:15]\[CH2:16][OH:17]
Reactant: CC(C)(C)C#CC#CCO
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C#C/C(Cl)=C/CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A solution of lithium aluminum hydride (11.4 mmol; 1M solution in tetrahydrofuran, (hereafter THF) was added to a stirred suspension of sodium methoxide (1.23 g, 22.8 mmol) in 18 ml of dry THF and the mixture was stirred at room temperature for 1/2 hour. 6,6-Dimethyl-2,4-heptadiyn-1-ol (777 mg, 5.71 mmol) was added and the mixture stirred at room temperature overnight. The mixture was cooled to 0° C. and dry ethyl acetate (1.0 g, 11.4 mmole) was added dropwise. Hexachloroethane (4.05 g, 17.13 mmole) was then added and the mixture was allowed to warm to room temperature. After 4.5 hours, additional hexachloroethane (1.35 g, 5.71 mmol) was added to the reaction mixture which was then stirred for 68 hours. The mixture was partitioned between ether and dilute aqueous hydrochloric acid, and the aqueous layer was extracted 3 times with ether. The combined ethereal extract was washed with water an brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3.43 g of crude product. This mixture was purified by chromatography on a column (2.5×47 cm) of silica gel eluting with ethyl acetate-hexane, 5/95. Combination and concentration of the appropriate fractions afforded 404 mg of the desired (Z)-3-chloro-6,6-dimethyl- 2-hepten-4-yn-1-ol.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][N:11]=3)[N:6]([C@H:13]3[CH2:16][C@H:15]([NH:17][C:18]4[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=4)[CH2:14]3)[C:5]2=[O:26])[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:38]2C=C[CH:41]=[CH:42][C:37]=2[N:36]=N1.C(N(C(C)C)CC)(C)C.Cl.NC1(C#N)CC1>C(Cl)Cl>[C:38]([C:37]1([NH:36][C:23]([C:20]2[S:19][C:18]([NH:17][C@H:15]3[CH2:16][C@H:13]([N:6]4[C:7]5=[N:8][CH:9]=[CH:10][N:11]=[C:12]5[N:4]([CH:1]5[CH2:2][CH2:3]5)[C:5]4=[O:26])[CH2:14]3)=[N:22][CH:21]=2)=[O:24])[CH2:41][CH2:42]1)#[N:34]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)c1cnc(N[C@H]2C[C@H](n3c(=O)n(C4CC4)c4nccnc43)C2)s1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CC1(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)c2cnc(N[C@H]3C[C@H](n4c(=O)n(C5CC5)c5nccnc54)C3)s2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxylic acid, (EXAMPLE 149), (0.070 g, 0.188 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.147 g, 0.282 mmol), diisopropylethylamine (0.049 ml, 0.282 mmol), and 1-amino-1-cyclopropanecarbonitrile hydrochloride (0.033 g, 0.282 mmol) in DCM (5 mL) was stirred at room temperature for 12 hours. Purification of the reaction mixture using silica chromatography with ISCO eluting with 0-80% EtOAc/hexanes gave the title compound N-(1-cyanocyclopropyl)-2-((trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)amino)thiazole-5-carboxamide (0.060 g, 0.137 mmol, 73.1% yield). m/z: 437 (M+1); 1H NMR (400 MHz, DMSO-d6) δ: ppm 8.78 (s, 1 H) 8.32 (d, J=6.65 Hz, 1 H) 7.93-8.05 (m, 2 H) 7.40 (s, 1 H) 5.18 (quin, J=8.51 Hz, 1 H) 4.31-4.53 (m, 1 H) 3.21-3.41 (m, 2 H) 2.88-3.05 (m, 1 H) 2.29-2.44 (m, 2 H) 1.44-1.60 (m, 2 H) 1.23-1.35 (m, 2 H) 0.93-1.10 (m, 4 H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1.Cl>[CH2:16]([O:15][C:13](=[O:14])[C:12]([OH:18])=[C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2]1)[CH3:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCOc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(O)=C1COc2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
A solution of sodium 1,1,1,3,3,3-hexamethyldisilylazide (1.0 mol dm-3 ; 35 cm3) in THF was added at -78° C. under nitrogen to a stirred solution of 4-chromanone (5.0 g) in dry THF (100 cm3). The bright orange solution was stirred at -78° C. for 20 minutes, followed by addition of diethyl oxalate (4.75 cm3). The mixture was warmed to room temperature, becoming a thick, red gel. The gel was diluted with hydrochloric acid (1.0 mol dm-3 ; 200 cm3) and extracted with ethyl acetate (200 cm3). The extracts were dried (MgSO4), filtered and concentrated to give hydroxy-(4-oxo-chroman-3-ylidene)-acetic acid ethyl ester (8.3 g; 97%) as a bright yellow, waxy solid; δH (250 MHz; d6 -DMSO) 1.30 (3H, t, J 7.5, CO2 CH2CH3), 4.30 (2H, q, J 7.5, CO2CH2CH3), 5.18 (2H, s, OCH2C), 7.04 (1H, d, J 8.5, 1 of ArH), 7.12 (1H, dd, J 8.5 and 8.5, 1 of ArH), 7.58 (1H, dd, J 8.5 and 8.5, 1 of ArH) and 7.79 (1H, d, J8.5, 1 of ArH); m/z (CI+ ; NH3) 249 (MH+ ; 28%) and 205 (100).