Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[OH-].[K+].Br[C:13]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>O.[Cu]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:13]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: COc1ccccc1S
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Sc1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 104.8 %

Procedure:
2-Methoxythiophenol (9.9 ml, 81.29 mmol) was added to a solution of KOH (18.24 g, 325.18 mmol) in water (80 ml) degassed for 15 minutes. 2-Bromo-5-nitrobenzoic acid (20.0 g, 81.29 mmol) and copper bronze (258 mg, 4.06 mmol) were added to the reaction mixture, which was refluxed overnight. The reaction was stopped and the mixture was filtered through a celite pad and washed with 2M NaOH then water (50 ml). The filtrate was acidified (pH 1) with concentrated HCl. The precipitate formed was filtered and dried overnight in a vacuum oven (50° C.) to give the crude title compound (26.0 g) as a pale yellow solid. The product was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])[C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:34]=2[CH2:33][CH2:32]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C.O>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:42][C:39]2[CH:40]=[CH:41][C:34]3[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:37][CH2:36][C:35]=3[CH:38]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: N#CCCOc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OCCC#N)n3)cc2CC1
Yield: 75 %

Procedure:
3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-phenoxy]-propionitrile (84 mg, 0.00021 mol), 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (47 mg, 0.00021 mol), and 10-Camphorsulfonic acid (58 mg, 0.00025 mol) in Isopropyl alcohol (2.0 mL) was irradiated in a CEM microwave (140° C., 30 min). The mixture was diluted with 2 mL water and 0.5 mL satd. sodium bicarbonate, then extracted 2×10 mL DCM, dried over sodium sulfate and conc. onto 1 g Celite. Chromatography (ISCO, Amine-capped SiO2, 14 g, 25-100% EtOAc:Hex) afforded 3-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5-morpholin-4-yl-phenoxy)-propionitrile as a light pink solid (91 mg, 74%). MP: 91-96° C., LCMS 578 (M+H); 1H-NMR (CDCl3): 8.23 (d, 1H, J=8.8 Hz), 8.02 (s, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 7.18 (d, 1H, J=7.9 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.85 (s, 1H), 6.56 (d, 1H, J=8.8 Hz), 6.50 (s, 1H), 4.28 (t, 2H, J=6.3 Hz), 3.88 (m, 4H), 3.53 (t, 2H, J=6.3 Hz), 3.38 (s, 3H), 3.14 (m, 4H), 2.90 (m, 6H), 2.72 (m, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][N:9]([C:11]2[C:24]([F:25])=[CH:23][C:14]([C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[C:13]([F:26])[C:12]=2[F:27])[CH2:8][CH2:7][O:6]1)[CH3:3].CO[CH:30](OC)[N:31]([CH3:33])C.[C:36]1(C)C=CC=C[CH:37]=1>>[CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][N:9]([C:11]2[C:24]([F:25])=[CH:23][C:14]([C:15]([C:17](=[CH:33][NH:31][CH:30]3[CH2:37][CH2:36]3)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[C:13]([F:26])[C:12]=2[F:27])[CH2:8][CH2:7][O:6]1)[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(F)c(N2CCOC(CN(C)C)C2)c(F)c1F
Reactant: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(N2CCOC(CN(C)C)C2)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of 3.88 g of ethyl 4-[2-(dimethylaminomethyl)-morpholino]-2,3,5-trifluorobenzoylacetate and 1.85 g of dimethylformamide dimethylacetal in 20 ml of toluene is refluxed for 6 hours. The reaction mixture is concentrated under reduced pressure and to the obtained residue is added 20 ml of ethanol. After the addition of 0.94 g of cyclopropylamine under ice-cooling, the mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and the obtained residue is purified by chromatography on silica gel to give 4.06 g of ethyl 2-[4-[2-(dimethylaminomethyl)morpholino]-2,3,5-trifluorobenzoyl]-3-cyclopropylaminoacrylate in 89% yield as an oily substance.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:13])[C:5]1=O)[CH:2]=[CH2:3].C1(C)C=CC=CC=1.Cl.O>[Zn].C(O)(=O)C>[CH2:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:13])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1Cc2c(Cl)cccc2C1=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCC1Cc2cccc(Cl)c2C1
Yield: 64.4 %

Procedure:
Amalgamated zinc (prepared from zinc powder (6 g), mercuric chloride (0.6 g)) was heated under reflux for 7 hours with 2-allyl-4-chloro-indan-1-one (3 g), toluene (20 ml), conc. hydrochloric acid (20 ml), water (8 ml) and acetic acid (2 ml). Upon cooling conventional work-up gave a crude product which was purified by chromatography (silica/hexane) to give a 2-allyl-4-chloroindane (1.8 g). 2-Allyl-4-chloroindane (0.8 g) in dry methanol (10 ml) and dry dichloromethane (2 ml) was reacted at -35° with ozone until the blue colour persisted. After purging with nitrogen the solution was stirred 16 hours with dimethyl sulphide (2.58 g). The volatiles were removed and the residue taken up in tetrahydrofuran (10 ml) and heated under reflux with 4-toluenesulphonic acid (30 mg) and water (circa 0.5 ml) for 2 hours. After conventional work up the product, 2-(4-chloro-2-indanyl) ethanol, was obtained as a yellow oil (0.8 g).
Reaction SMILES: ClC(=C)[C:3]#[N:4].[C:6]1([CH2:12][NH:13][CH2:14][CH2:15][OH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][C:18](C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1COCC1>[C:6]1([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH:15]([C:3]#[N:4])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCNCc1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: C=C(Cl)C#N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
A 500 mL reactor under nitrogen was successively loaded with toluene (50 mL) and 2-chloro-2-propenenitrile (14.26 mL, 179 mmol) at 25° C., and then 2-[(phenylmethyl)amino]ethanol (25.4 mL, 179 mmol) was added over 15 minutes. The reaction mixture was post-agitated at 25° C. for 16 hours. The mixture was diluted with toluene (100 mL), cooled to −5° C., and potassium tert-butoxide (20.04 g, 179 mmol) in THF (90 mL) was slowly added over 30 minutes, maintaining the temperature at −5° C. to 0° C. The mixture was post-agitated at about −5° C. to 0° C. for 1 hour, then quenched by the addition of water (150 mL), and the mixture was allowed to warm to 25° C. The aqueous was extracted with EtOAc (4×150 mL), dried (Na2SO4), filtered, and concentrated to afford the title compound (36 g) as a brown solid. LC-MS (ES) m/z=203 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[CH:22]=[CH:21][C:10]3[CH2:11][CH:12]([C:17]([O:19]C)=[O:18])[S:13][CH2:14][C:15](=[O:16])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].O>CO>[CH:1]1([C:7]2[CH:22]=[CH:21][C:10]3[CH2:11][CH:12]([C:17]([OH:19])=[O:18])[S:13][CH2:14][C:15](=[O:16])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1Cc2ccc(C3CCCCC3)cc2C(=O)CS1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CSC(C(=O)O)Cc2ccc(C3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
In methanol (150 ml) was suspended methyl 7-cyclohexyl-1,2,4,5-tetrahydro-3-benzothiepin-5-one-2-carboxylate (40 g) followed by addition of 2N-KOH (100 ml), and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into water, acidified and extracted with etyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 7-cyclohexyl-1,2,4,5-tetrahydro-3-benzothiepin-5-one-2-carboxylic acid (27.5 g, yield 72%). Recrystallization from ethyl acetate gave colorless plates.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[O:6].C(N(CC)CC)C.Cl[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.[Cl-].[Na+].O>[OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:11]=1)=[O:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(CCCO)c1c[nH]cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
4-Hydroxy-1-(1H-imidazol-4-yl)butan-1-one (9.23 g) was dissolved in N,N′-dimethylformamide (120 ml), and triethylamine (12.5 ml) and chlorotriphenylmethane (16.69 g) were added. The mixture was stirred at room temperature for 2 h. Brine was added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=9:1) to give the title compound (25.22 g) as an orange oil.
Reaction SMILES: [CH:1]([S:4][C:5]1[C:10]([C:11]#N)=[CH:9][C:8]([CH3:13])=[CH:7][N:6]=1)([CH3:3])[CH3:2].[OH-:14].[K+].Cl.[OH2:17]>CS(C)=O>[CH:1]([S:4][C:5]1[N:6]=[CH:7][C:8]([CH3:13])=[CH:9][C:10]=1[C:11]([OH:17])=[O:14])([CH3:3])[CH3:2]
Reactant: Cc1cnc(SC(C)C)c(C#N)c1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(SC(C)C)c(C(=O)O)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
After 2-isopropylsulfanyl-5-methyl-pyridine-3-carbonitrile (0.186 g, 0.97 mmol) obtained in Step A was dissolved in water (0.4 mL) and DMSO (0.04 mL), KOH (0.76 g) was added thereto, and the mixture was stirred at 100° C. for 16 hours. After the termination of the reaction, 6N HCl aqueous solution was added thereto to adjust the pH of the reactant to 2, and the mixture was extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.15 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1Br)[C:6]([O:8][CH3:9])=[O:7].[F-].[K+].[CH2:18]([O:20][C:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22])[CH3:19]>C1(C)C=CC=CC=1.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>[CH2:21]([O:20][C:18]([C:12]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[O:14][CH3:15])=[CH2:19])[CH3:22]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(OC)c(Br)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(OC)cc(C(=O)OC)cc1OC
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Methyl 3,5-dimethoxy-4-bromobenzoate (500 mg) was dissolved in toluene in a nitrogen atmosphere, and 1-ethoxyvinyltributyltin (742 μL) and tetrakis(triphenylphosphine)palladium (211 mg) were added to it, and stirred overnight at 110° C. The reaction liquid was cooled to room temperature, then aqueous potassium fluoride solution was added to it, and stirred at room temperature. The reaction liquid was filtered through Celite, the Celite was washed with ethyl acetate, and the filtrate was washed with saturated saline water. The organic layer was dried with sodium sulfate, the sodium sulfate was removed through filtration, the filtrate was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 85/15) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[C:30]([O:32]C)=[O:31].[OH-].[Na+].CO>C1COCC1>[CH3:1][C:2]1([CH3:34])[S:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:3]1[C:30]([OH:32])=[O:31]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)CCSC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)C1C(=O)O
Yield: 84.1 %

Procedure:
A solution of 0.418 g (0.817 mmol) of methyl 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate, 4.0 mL (4.08 mmol) of 1N NaOH, 4.0 mL of methanol and 4.0 mL of THF was heated to reflux for 5 h. The reaction was concentrated and the residue was diluted with water, acidified to pH5 and extracted with ethyl acetate. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 0.342 g (84%) of 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid as a colorless oil. Electrospray Mass Spec: 496.5 (M−H)−
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[C:6]([CH2:8]P(=O)([O-])[O-])[N:7]=1)[CH3:2].[H-].[Na+].[CH3:15][O:16][CH2:17][O:18][C:19]1[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]=1.O>O1CCCC1>[CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:24]\[C:23]2[C:19]([O:18][CH2:17][O:16][CH3:15])=[N:20][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(CP(=O)([O-])[O-])co1
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCOC)co1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a solution of diethyl ([(2-ethyl-1,3-oxazol-4-yl)methyl]phosphonate (2.97 g) in tetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.32 g) was added to the reaction mixture and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-3:7, v/v) to give 2-ethyl-4-{(Z)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole as a pale-yellow oil (0.24 g, yield 7.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:5][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COc1ccccc1C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A solution of 1-methoxy-2-(trifluoromethyl)benzene (10.0 g, 56.8 mmol) in dry chloroform (76 mL) was cooled to 0° C. and treated with chlorosulfonic acid (7.55 mL, 113.5 mmol) drop-wise under argon. After the addition was completed, the reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction was quenched by pouring the mixture slowly onto ice. The separated, aqueous phase was extracted with chloroform (3×). The combined organic phase was washed sequentially with a saturated, aqueous sodium chloride solution (2×) and water. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the title compound (8.77 g. 31.9 mmol, 56%) as a gray solid;
Reaction SMILES: [Na].Cl[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][N:17]=[C:12]3[CH:11]=[N:10]2)[CH:8]=1.[CH:18]([OH:22])([CH2:20][CH3:21])[CH3:19]>>[CH:18]([O:22][C:16]1[N:17]=[C:12]2[CH:11]=[N:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:8]=3)[C:13]2=[N:14][CH:15]=1)([CH2:20][CH3:21])[CH3:19]
Reactant: CCC(C)O
Reactant: Clc1cccc(-n2ncc3nccnc32)c1
Agent: [Na]
Product: CCC(C)Oc1cnc2c(cnn2-c2ccccc2)n1
Yield: 53 %

Procedure:
In 50 ml of sec.-butanol was dissolved 2.1 g (0.091 mole) of metallic sodium, and then, 10.0 g (0.043 mole) of 5-chloro-phenyl-1H-pyrazolo[3,4-b]pyrazine was added to the solution. The mixture was heated under reflux for 2 hours. After completion of the reaction, the excessive amount of sec.-butanol was removed by distillation under a reduced pressure. The residue was washed with water, dried and then recrystallized from hexane to obtain 6.2 g (the yield was 53%) of 5-sec.-butoxy-1-phenyl-1H-pyrazolo[3,4-b]pyrazine in the form of a colorless needle crystal.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C[O-].[Na+].Cl[CH:13](Cl)[C:14]([O:16][CH3:17])=[O:15].Cl>CO.O>[CH3:17][O:16][C:14]([CH:13]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)=[O:15]
Reactant: COC(=O)C(Cl)Cl
Reactant: Oc1ccccc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1Oc2ccccc2O1
Temperature: 25 °C

Procedure:
Catechol (10.26 g, 93.2 mmol), sodium methoxide (25% by weight in methanol, 40.3 g, 186 mmol), and methyl dichloroacetate (13.3 g, 93.2 mmol) were combined in dry methanol (100 mL). The solution was heated to reflux overnight. The reaction was cooled to room temperature, acidified by addition of concentrated hydrochloric acid and then reduced in volume under vacuum to about 50 mL. Water was added and the mixture was extracted with diethyl ether (3×100 mL). The combined organic solution was dried with MgSO4, concentrated to a brown solid, and chromatographed (2% ethyl acetate in hexane) to yield benzo[1,3]dioxole-2-carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=[N:2]1.[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:15]([F:17])([F:16])[CH:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[OH:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1-n1cccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1-n1cccn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.9 %

Procedure:
To 2-pyrazol-1-yl-benzaldehyde (0.344 g, 2 mmol) in THF (8 ml) was added trifluoromethyl trimethyl silane (0.341 g, 2.4 mmol). The mixture was cooled to 0-5° C. (ice water bath) and tetra-n-butyl ammonium fluoride (0.035 ml, 0.035 mmol, 1M in THF) was added. The ice bath was removed, and the mixture was stirred at room temperature for 6 h. 2N HCl (5 ml) was added and the reaction mixture was further stirred at room temperature for 3 h. Solvent was removed on the rotavap under reduced pressure. The residue was dissolved in DCM (30 ml), washed with water (20 ml), brine (20 ml) and dried over sodium sulfate. The solvent was removed in vacuo to give crude 2,2,2-trifluoro-1-(2-pyrazol-1-yl-phenyl)-ethanol (0.45 g, 93%) which was directly used in the following experiment.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:24]=C[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])=[CH:9][C:8]=1O)=[O:5].ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:64](CC)CC)C>C(#N)C.O>[Cl:1][C:2]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)[CH:27]=[CH:26][C:3]=1[C:4]1[O:5][C:8]2[CH:9]=[C:10]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[CH3:14])[N:64]=[CH:24][C:7]=2[N:6]=1
Reactant: C[C@@H](COc1ccc(NC(=O)c2ccc(OCC3CC3)cc2Cl)c(O)c1)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCC4CC4)cc3Cl)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl ((2S)-1-(4-((2-chloro-4-(cyclopropylmethoxy)benzoyl)amino)-3-hydroxyphenoxy)propan-2-yl)carbamate (200 mg), hexachloroethane (241 mg) and triphenylphosphine (321 mg) in acetonitrile (3 mL) was added triethylamine (0.454 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (65 mg).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:39]=[C:38]([CH3:40])[C:31]3[N:32]([CH2:36][CH3:37])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:36]([N:32]1[C:31]2[C:38]([CH3:40])=[CH:39][C:28]([C:26]([C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:3]4[CH2:4][CH2:5][CH:6]([N:9]5[C:17]6[C:12](=[N:13][CH:14]=[CH:15][CH:16]=6)[NH:11][C:10]5=[O:18])[CH2:7][CH2:8]4)[CH:21]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35])[CH3:37]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CCn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(C)c21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(=O)oc2cc(C(=O)c3cc(N4CCC(n5c(=O)[nH]c6ncccc65)CC4)ncn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
47 mg (0.20 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 50 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3-ethyl-4-methyl-3H-benzoxazol-2-one and 0.11 mL (0.64 mmol) DIPEA were combined in 2.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined, the organic solvent was evaporated down and the residue was neutralised with 1N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15]([CH3:20])([CH3:19])[C:14]=1/[CH:21]=[CH:22]/[C:23]#[C:24]C1C=NC=C(C=1)C(OCC)=O.Cl[C:37]1([CH:47]=[CH:46][CH:45]=[N:44][CH2:43]1)[C:38]([O:40][CH2:41][CH3:42])=[O:39].O>C(OCC)C>[O:6]1[C:13]2([CH3:12])[CH2:18][CH2:17][CH2:16][C:15]([CH3:20])([CH3:19])[C:14]12/[CH:21]=[CH:22]/[C:23]#[C:24][C:45]1[CH:46]=[CH:47][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:43][N:44]=1
Reactant: CCOC(=O)C1(Cl)C=CC=NC1
Reactant: CCOC(=O)c1cncc(C#C/C=C/C2=C(C)CCCC2(C)C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(C#C/C=C/C23OC2(C)CCCC3(C)C)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.106 g (0.310 mmol) of 50% meta-chloroperoxybenzoic acid (MCPBA) was added to a solution of 0.1 g (0.310 mmol) of ethyl 5-[(3E)-4-(2,6,6-trimethyl-1-cyclohexenyl)but-3-en-1-ynyl)nicotinate (used as a mixture with 0.6 g (0.310 mmol) of ethyl 3-chloronicotinate), in 10 mL of anhydrous diethyl ether under argon was stirred at ambient temperature for 18 hours. The solution was treated with 10 mL of water and extracted with 3×50 mL ether.