Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][N:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]=2[N:15]=1.[CH2:31]([O:33][C:34](=O)[O:35]CC)[CH3:32]>C1COCC1>[C:27]([O:26][C:24]([N:17]1[C:16]2[N:15]=[C:14]([CH2:13][C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19][CH2:18]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)OCC
Reactant: Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a solution of diisopropylamine (7.24 mL, 55.3 mmole) in dry TBF (50 mL) was added n-BuLi (2.5 M in hexanes, 22 mL, 55.3 mmole) dropwise at 0° C. After 15 min, this solution was added dropwise to a solution of 2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine (4.9 g, 19.7 mmole) and diethylcarbonate (8.86 mL, 73.0 mmole) in dry THF (50 mL) at −78° C. After 30 min, the mixture was quenched with saturated NH4Cl (100 mL), warmed to RT, and extracted with EtOAc (3×200 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (40% EtOAc/hexanes) to give the title compound (5.72 g, 91%) as a light yellow oil: MS (ES) m/e 321 (M+H)+.
Reaction SMILES: CS([O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[CH3:18][C:19]1([CH3:33])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[O:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][C:23]1([CH3:25])[C:19]([CH3:18])([CH3:33])[O:20][B:21]([C:26]2[CH:31]=[CH:30][C:29]([O:5][C@@H:6]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]3)=[CH:28][CH:27]=2)[O:22]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1

Procedure:
(S)-tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (0.53 g, 2.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.48 g, 2.2 mmol) and K2CO3 (0.33 g, 2.4 mmol) in DMF (5 mL) were heated at 85° C. for 1 d. The reaction mixture was concentrated in vacuo and Et2O and water were added. The aqueous phase was extracted with Et2O and the combined organics were washed with 1 M NaOH solution (aq), dried (MgSO4), filtered and concentrated in vacuo to give (R)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([N:21](COCC[Si](C)(C)C)COCC[Si](C)(C)C)=[CH:19][C:18]([CH:38]([NH:40][CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH3:39])=[N:17][C:16]=13)=[CH:5]2.O>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]1[CH:13]=[N:14][N:15]3[C:20]([NH2:21])=[CH:19][C:18]([CH:38]([NH:40][CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[CH3:39])=[N:17][C:16]=13)=[CH:5]2
Reactant: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(NC1CCOCC1)c1cc(N)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 2 h

Procedure:
To a solution of 3-(6-fluoroquinolin-3-yl)-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (84 mg, 0.13 mmol) in TFA (2 ml) was added few drops of water and stifling continued for 2 h at room temperature. LC/MS showed no starting material (M.W=666) remaining. TFA along with water was rotoevaporated, and the crude was dried under the high vacuum for 4 h, which was used without further purification for the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[S-:16][C:17]#[N:18].[NH4+]>CO>[CH3:12][C:11]([C:7]1[CH:8]=[C:9]([S:16][C:17]#[N:18])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Temperature: 0 °C

Procedure:
To a three-necked, round bottom 5 L flask, equipped with a mechanical stirrer, gas inlet, thermometer and gas outlet, was added 2,6-di-tert-butylphenol (474 g, 2.30 mole), ammonium thiocyanate (76.12 g, 4.83 mole) and methanol (1200 mL). The reaction mixture was stirred and cooled to 0° C. in an ice/salt bath. Maintaining the temperature at 0° to 10° C., chlorine gas was slowly bubbled through the mixture for about 1 hour whereupon the reaction mixture was a heterogeneous yellow color. Ammonia was then bubbled through the reaction for about 1 and 1/2 hours, maintaining the reaction mixture at a temperature of between 0° to 10° C. The reaction was stirred for an additional hour at 0° C., poured into 2 L of cold distilled water and refrigerated overnight. The aqueous phase was decanted and the solid taken up in methanol, precipitated by addition of water, filtered and dried for 2 days over phosphorous pentoxide. The resulting gummy yellow solid was recrystallized from 5 pentane and dried in vacuo to yield the product as a white powder, m.p. 61.5°-63° C.
Reaction SMILES: CS(O[CH:6]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1)[CH2:7][O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:14]1[N:13]=[CH:12][N:11]2[CH:6]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[CH2:7][O:8][CH2:9][C:10]=12
Reactant: CS(=O)(=O)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C2COCc3cncn32)cc1
Temperature: 80 °C

Procedure:
A solution of 1.00 mmol of 1-(4-cyanophenyl)-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl methanesulphonate in 5 ml of N,N-dimethylformamide is mixed with 2.50 mmol of caesium carbonate and heated at 80° C. for 6 hours. The reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate (2×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained from the residue as yellowish crystals by flash chromatography (SiO2 60 F). Rf=0.61 (dichloromethane-methanol-25% aqueous ammonia solution 200:10:1); Rt=3.54 (gradient II).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]Br.C(OCC)(=O)C>O1CCCC1.O>[C:3]([CH:2]([CH2:16][C:15]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([Cl:12])[CH:14]=1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(Cl)c(Cl)c1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl acetoacetate (1.0 g) in tetrahydrofuran (20 mL) was added sodium hydride (about 60% oil suspension) (0.37 g) in several portions under ice-cooling under a nitrogen atmosphere. After stirring at room temperature for 1 hr, 3,4-dichlorobenzylbromide (1.4 mL) was added to the reaction mixture. After stirring at room temperature for 2 hr, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic phase was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel by eluting with toluene. An eluted fraction containing the desired product was recovered and evaporated under reduced pressure to give ethyl 2-acetyl-3-(3,4-dichlorophenyl)propanoate (35) (1.6 g).
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[CH3:10][C:11]1([CH3:23])[C@@H:13]([CH:14]([Br:19])[C:15]([Br:18])([Br:17])[Br:16])[C@H:12]1[C:20](O)=[O:21]>C(Cl)Cl>[CH3:10][C:11]1([CH3:23])[C@@H:13]([CH:14]([Br:19])[C:15]([Br:18])([Br:17])[Br:16])[C@H:12]1[C:20]([Cl:8])=[O:21]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C(Br)C(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)Cl)[C@@H]1C(Br)C(Br)(Br)Br
Reaction time: 2 h

Procedure:
A mixture of 0.2 ml of dimethylformamide, 8.5 ml of thionyl chloride and 179 ml of petroleum ether (b.p.=35°-75° C.) was heated to reflux and a mixture of 35.76 g of the product of Step A in 150 ml of methylene chloride was added thereto. The mixture was refluxed with stirring for 2 hours and was then cooled and evaporated to dryness. The residue was taken up in toluene and the mixture was evaporated to dryness under reduced pressure to obtain 38 g of raw (1R,cis) 2,2-dimethyl-3-(1',2',2',2'-tetrabromoethyl)-cyclopropane-1-carboxylic acid chloride with a melting point of 88° C. which was used as is for the next step.
Reaction SMILES: O.NN.P(Cl)(Cl)(Cl)(Cl)Cl.Br.F[C:12]1C=CC(OC)=CC=1C#N.[F:22][C:23]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>CO>[F:22][C:23]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:24]=1[C:25]([O:27][CH3:12])=[O:26]
Reactant: COc1ccc(F)c(C#N)c1
Reactant: O=C(O)c1cc(O)ccc1F
Agent: Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(O)ccc1F

Procedure:
In the presence of hydrazine hydrate/glacial acetic acid, phthalic anhydride (3a) with substituent R was transformed into R-substituted phthalhydrazide (3b), which subsequently generated substituted dichlorophthalazine compounds (3c) under the action of phosphorus pentachloride. In another aspect, under the action of hydrobromic acid, 2-fluoro-5-methoxybenzonitrile (3d) was converted to 2-fluoro-5-hydroxybenzoic acid (3e), which was esterificated with methanol to give methyl 2-fluoro-5-hydroxybenzoate (3f). Under the action of sodium hydride, the prepared dichlorophthalazine compounds with substituent R (3c) was reacted with methyl 2-fluoro-5-hydroxybenzoate (3f) to give methyl 5-((4-chloronaphthyridine-1-yl)oxy)-2-fluorobenzoate with substituent R (3g), 3g was transformed into methyl 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)oxy)benzoate (3h) in the presence of AcOH/NaOAc under the reflux condition, 3h was then hydrolyzed under alkali condition into substituent-contained 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (3i), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R and R′ is as described above.
Reaction SMILES: [C:1]1([C:11]([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:22][CH2:23]Br>ClC(Cl)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[N:14]1([C:13]2([C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:12])[CH2:23][CH2:22]2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: O=C(Cn1cncn1)c1cccc2ccccc12
Reactant: BrCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(c1cccc2ccccc12)C1(n2cncn2)CC1

Procedure:
20.7 g (0.1 mol) of (1, 2, 4-triazol-1-yl)-methyl 1-naphthyl ketone in 100 ml of dichloroethane, 0.3 g of benzyltriethyl-ammonium chloride and 27 ml of 50% strength sodium hydroxide solution were placed in a reaction flask, and, under reflux, 20.7 g (0.11 mol) of 1, 2-dibromoethane were added dropwise over 15 minutes. The mixture was refluxed for a further 5 hours, cooled, diluted with water and extracted with di-chloroethane. After drying and removing the solvent, 10.6 g (45% of theory) of the title compound were obtained as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:32])=O>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(Oc3ccc4c(c3)OCO4)cc2c1O
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc4c(c3)OCO4)cc2c1O

Procedure:
Prepared in analogy to example 31f from 6-(benzo[1,3]dioxol-5-yloxy)-4-hydroxy-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester and POBr3. ESI MS (m/z): 460 (M+H)+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]4[O:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[C:27]=4[C:34]=3[CH3:35])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.O>C1COCC1>[CH:1]1([C:28]2([OH:33])[C:27]3[C:34]([CH3:35])=[C:23]([N:20]4[CH2:21][CH2:22][N:17]([C:14]5[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=5)[CH2:18][CH2:19]4)[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]=3[O:30][C:29]2([CH3:31])[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: Br[Mg]C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(C3CCCCC3)C(C)(C)O4)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Cyclohexyl magnesium bromide (THF solution 1.0 M, 35 mL, 35 mmol) was added to a solution of 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine (1.00 g, 2.53 mmol) obtained in Reference Example 13 in THF (10 ml) under ice cooling and the reaction mixture was allowed to warm to room temperature. After stirring for one hour, the resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to obtain 970 mg (yield 80%) of the title compound via recrystallization (hexane). mp. 166–167° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[S:24][C:18]2[CH:19]([CH3:23])[NH:20][CH2:21][CH2:22][C:17]=2[CH:16]=1>>[Br:14][C:15]1[S:24][C:18]2[CH:19]([CH3:23])[N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:21][CH2:22][C:17]=2[CH:16]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(Br)sc21
Product: CC1c2sc(Br)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2-bromo-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1)=[O:7].[CH3:23]I.O>C1COCC1>[CH3:3][O:4][N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH3:23])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:9]1)=[O:7]
Reactant: CI
Reactant: CON(C)C(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1CCCC(N(C)C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a suspension of NaH (60%, 340 mg, 8.38 mmol) in THF (10 mL) was added dropwise a solution of tert-butyl 3-{[methoxy(methyl)amino]carbonyl}cyclohexylcarbamate (2.00 g, 6.98 mmol) in THF (10 mL)followed by methyl iodide (1.09 g, 7.68 mmol). The mixture was stirred at 60° C. for 0.5 hr. After cooled to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1) to give tert-butyl N-[3-(N-methoxy-N-methyl-carbamoyl)cyclohexyl]-N-methylcarbamate as a colorless oil (1.94 g, yield; 93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[F:14][C:11]1([F:13])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([CH2:15][OH:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a THF (30 ml) solution of (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (3.77 g, 15 mmol) at 0° C., BH3.THF solution (1.0 M in THF, 45 ml) was added dropwise over 20 minutes. The reaction mixture was allowed to warm to room temperature and stirring was continued for a total of 16 hours. Reaction went to completion as monitored by LC-MS. The reaction mixture was quenched by the addition of saturated aqueous solution of NaHCO3 (60 ml) at room temperature and the stirring was continued at room temperature for 4 hours. Most THF was removed in vacuo and the mixture was extracted with EtOAc (˜60 ml), two layers were separated, organic layer was washed with brine (˜50 ml), repeat the extraction/wash cycle one more time. Organic layers were combined, dried (Na2SO4), filtered, solvent was removed in vacuo. Crude product was purified by silica gel chromatography (Hexane/EtOAc, gradient from 100:0 to 50:50). Compound (S)-tert-butyl 4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate was obtained as a colorless oil: 2.6473 g (74% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=O.C[Si](C)(C)N[Si](C)(C)C.[Na]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2ccccc21
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
To a solution at 0° C. containing 5-fluorooxindole (0.30 g, 1.99 mmol) and phthalide (0.400 g, 2.98 mmol) in 5.0 mL DMF was added 4.2 mL of sodium hexamethyldisilazane (1.0 M in THF) over 5 min. The solution was stirred at room temperature for 3 h and then quenched into cold 1.0 M aqueous HCl solution to give a yellow solid. The solid was collected and then purified by chromatography (silica gel, hexanes/EtOAc, 4:1) to afford the title compound (32 mg, 6%) as a yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@@:26]2([CH3:27])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:15]3[CH2:16][CH:17]=[C:18]2[C@H:19]([OH:21])[CH3:20])[CH2:10][C@@H:9]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42][CH:43]1[O:47][C:44]1([CH3:46])[CH3:45].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[Si:5]([O:6][C@@H:7]1[C@@:26]2([CH3:27])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:15]3[CH2:16][CH:17]=[C:18]2[C@H:19]([O:21][CH2:42][CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[CH3:20])[CH2:10][C@@H:9]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:8]1)([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:38])[CH3:37]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC1(C)OC1CBr
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 82.7 %

Procedure:
A mixed solution of 1α,3β-bis(tert-butyldimethyl-silyloxy)-20(R)-hydroxypregna-5,7,16-triene (51 mg, 0.0911 mmol), sodium hydride (50 mg, 2.08 mmol) and 4-bromo-2,3-epoxy-2-methylbutane (75 mg, 0.455 mmol) in tetrahydrofuran (2ml) was heated under reflux for 1.5 hours and combined with 1M lithium tri-s-butylborohydride solution in tetrahydrofuran (0.9 ml, 0.900 mmol), and the mixed solution was heated under reflux for 20 minutes. The reaction solution was stirred with 3N aqueous sodium hydroxide solution and 30% aqueous hydrogen peroxide at room temperature for 30 minutes, then diluted with ethyl acetate, washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by preparative thin layer chromatography (0.5 mm×1, hexane:ethyl acetate=10:1, developed twice) to give the title compound as a colorless oil (48.6 mg, 83%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[C:21]([CH3:38])=[CH:20][N:19]=1>CN(C=O)C>[CH3:34][N:30]1[C:29]2[C:35]([CH3:37])=[CH:36][C:26]([C:24]([C:22]3[C:21]([CH3:38])=[CH:20][N:19]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:23]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: Cc1cnc(Cl)cc1C(=O)c1cc(C)c2c(c1)oc(=O)n2C
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc1C(=O)c1cc(C)c2c(c1)oc(=O)n2C
Temperature: 250 °C

Procedure:
0.26 g (1.2 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.13 g (0.40 mmol) 6-(2-chloro-5-methyl-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one (mixture) were combined and heated to 250° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11](I)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:15]([C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23][OH:24])=[CH:19][CH:18]=1)#[CH:16].N1CCCCC1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([C:16]#[C:15][C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23][OH:24])=[CH:19][CH:18]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(OCCO)cc1
Reactant: Clc1ccc(-c2cnc(I)cn2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: OCCOc1ccc(C#Cc2cnc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under an argon atmosphere 49 mg (0.06 mmol) of PdCl2(dppf) and 11 mg (0.06 mmol) of CuI were added to a repeatedly degassed solution of 535 mg (3.30 mmol) of 2-(4-chlorophenyl)-5-iodopyrazine, 950 mg (3.30 mmol) of 2-(4-ethynylphenoxy)ethanol, and 0.59 mL (6.00 mmol) of piperidine in 50 mL of THF and the mixture was stirred for 4 hours at RT. The precipitate was suction filtered and washed with acetonitrile. The mother liquor was concentrated, and the precipitate formed was filtered off and washed with acetonitrile. The precipitates were combined. Yield: 700 mg (67% of theoretical); C20H15ClN2O2 (M=350.798); calc.: molpeak (M+H)+:351/353 (Cl); found: molpeak (M+H)+:351/353 (Cl); Rf value: 0.30 (silica gel, PE/EtOAc 1:1).