Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(=O)CCCC1.[C-]#N.[K+].CN(C)[C:21]1([C:26]#[N:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.C#N>O>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:21]1([C:26]#[N:27])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C)C1(C#N)CCCC1
Reactant: CNCc1ccccc1
Agent: C#N
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: O=C1CCCC1
Product: CN(Cc1ccccc1)C1(C#N)CCCC1
Yield: 84 %

Procedure:
The title compound (15 g; 84%) was prepared from N-methylbenzylamine (10.08 g; 83 mmol), cyclopentanone (7 g; 83 mmol) and potassium cyanide (5.41 g; 83 mmol) in water (45 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.90 (6H, m), 2.20 (3H, s), 2.3 (2H, m), 3.62 (2H, s), 7.25 (1H, m), 7.32 (4H, m); Mass Spectrum (Electrospray LC/MS): Found 188 (MH+−HCN). C14H18N2 requires 214. Ret. time 1.21 min.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=1.[C:16](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(C)n1
Temperature: 25 °C
Yield: 88 %

Procedure:
Concentrated sulfuric acid (2 mL) was added to a solution of 6-methylpicolinic acid (1.97 g; 13.65 mmol) in methanol (50 mL). The resulting mixture was heated at reflux for 22 hours. After cooling to room temperature, the solution was made alkaline by addition of an aqueous solution of sodium carbonate. The methanol was evaporated under reduced pressure, water was added and the mixture was extracted three times with dichloromethane. Combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure to give 1.81 g (88%) of methyl 6-methylpicolinate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([O:22]C(=O)/C=C\N3C=NC(C4C=C(C(F)(F)F)C=C(OC)C=4)=N3)=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[NH2:45][NH2:46]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:45][NH2:46])=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(-c2ncn(/C=C\C(=O)OC(=O)/C=C\n3cnc(-c4cc(OC)cc(C(F)(F)F)c4)n3)n2)cc(C(F)(F)F)c1
Reactant: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 500-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (isobutyl carbonic) (Z)-3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic anhydride was cooled at 0° C. and added hydrazine hydrate (22.32 mL, 5.7 eq.). Reaction mixture was stirred at 0° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% MeOH-dichloromethane as mobile phase. SM Rf=0.6 and Product Rf=0.4. Reaction mixture was filtered through celite bed. Filtrate was poured into ice water (5000 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.920 g of crude compound which was used for next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11]OCC1.[Cl:13][P:14]1[O:19]C(=O)[C:17]2[CH:21]=[CH:22][CH:23]=C[C:16]=2[O:15]1>O1CCOCC1>[Cl:13][P:14]1(=[O:19])[O:15][CH2:16][C:17]2[CH:21]=[CH:22][CH:23]=[CH:11][C:12]=2[O:7]1
Reactant: C1COCCO1
Reactant: O=C1OP(Cl)Oc2ccccc21
Solvent: c1ccncc1
Product: O=P1(Cl)OCc2ccccc2O1

Procedure:
Add into a vial first 2 mL of pyridine/dioxane, 3:1 v/v followed by 100 μL of 1 M 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one solution in dry dioxane to give a 50 mM solution of the phosphitylating reagent, e.g. 2-chloro-4H-1,3,2-benzodioxaphosphorin-2-one, in dioxane/pyridine, 3:1 (v/v). Homogenize the solution by gently shaking. Start the reaction by drawing the 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one solution through the synthesis column from the vial.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].OO.C(=O)([O-])[O-:18].[K+].[K+]>CS(C)=O>[NH2:1][C:2]1[C:3]([C:13]([NH2:14])=[O:18])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(C#N)cc1C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(N)c(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 208 %

Procedure:
Methyl 5-amino-4-cyano-2-methylbenzoate (151 mg, 0.79 mmol) (synthesized according to reagent preparation 41) was dissolved in DMSO (1.5 mL). 30% Aqueous hydrogen peroxide (0.3 mL) and potassium carbonate (35 mg, 0.25 mmol) were added, and the mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted (2×) with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated to a yellow oil which was purified by preparative reverse phase HPLC to afford methyl 5-amino-4-(aminocarbonyl)-2-methylbenzoate (108 mg, 0.52 mmol, 66% yield). NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.45 (br s, 1H), 7.26 (s, 1H), 7.19 (br s, 1H), 6.48 (s, 2H), 3.80 (s, 3H), 2.32 (s, 3H); MS (EI) for C10H12N2O3: 209 (MH+).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:34])[CH2:8][NH:9][C:10]23[CH2:17][CH2:16][C:13]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:23][CH:22]=4)=[O:19])([CH2:14][CH2:15]2)[CH2:12][CH2:11]3)[C@H:4]([C:35]#[N:36])[CH2:3]1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:34])[CH2:8][NH:9][C:10]23[CH2:17][CH2:16][C:13]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=4)=[O:19])([CH2:14][CH2:15]2)[CH2:12][CH2:11]3)[C@H:4]([C:35]#[N:36])[CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C(=O)O)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,4S)-4-Fluoro-1-[[N-[4-[N-[4-(1,1-dimethylethyloxycarbonyl)phenyl]amino]carbonylbicyclo[2.2.2]oc t-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (23.0 mg) was dissolved in dichloromethane (0.2 mL). To this solution, trifluoroacetic acid (0.2 mL) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure to give (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-carboxyphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile trifluoroacetate (24.5 mg).
Reaction SMILES: O.O.Cl[Sn]Cl.[N+:6]([C:9]1[CH:10]=[C:11]([C:15]2([F:33])[C:18]([F:20])([F:19])[C:17]([F:22])([F:21])[C:16]2([F:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[CH:12]=[CH:13][CH:14]=1)([O-])=O.[BH4-].[Na+].[OH-].[Na+]>C(O)C.CCOCC.O>[NH2:29][C:25]1[CH:24]=[C:23]([C:16]2([F:32])[C:17]([F:21])([F:22])[C:18]([F:19])([F:20])[C:15]2([F:33])[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH2:6])[CH:10]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1cccc(C2(F)C(F)(F)C(F)(F)C2(F)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: Nc1cccc(C2(F)C(F)(F)C(F)(F)C2(F)c2cccc(N)c2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a stirred solution of SnCl2.2H2O (83.0 g) and 1,2-bis(meta-nitrophenyl)hexafluorocyclobutane (15.0 g) in 300 mL of ethanol was added NaBH4 (1.5 g) at room temperature over 20 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours and at 60° C. for one hour, and then poured into a mixture water and ether (500 mL/500 mL) and treated with NaOH solution. The ether layer was separated and aqueous layer was extracted with ether (2×300 mL). The combined ether layers were washed with NaOH solution and dried over MgSO4. After removal of the solvent, residue (13.8 g) was purified by bulb-to-bulb distillation (ca. 170° C./0.05 mmHg) twice to give 12.0 g of viscous product. 19F NMR: major isomer: -125.0 (dm J=222 Hz, 2F), -125.9 (dm, J=dm, J 222 Hz, 2F), -160.3 (s, 2F). minor isomer: -122.1 (dd, J=225.1 Hz, J=3.4 Hz, 2F), -128.7 (dd, J=255.1 Hz, J=2.4 Hz, 2F), -165.0 (s, 2F); 1H NMR: major isomer: 7.22 (t, J=7.8 Hz, 2H), 6.96 (d, J=7.8 Hz, 2H), 6.86 (s, 2H), 6.77 (dm, J=8.1 Hz, 2H), 3.76 (s, 4H); minor isomer: 7.04 (t, J=7.1 Hz, 2H), 6.63 (d, J=6.6 Hz, 2H), 6.58 (m, 4H), 3.66 (s, 4H). Anal: Calcd for C16H12F6N2 : C, 55.50; H, 3.49; F, 32.92; N, 8.09. Found: C, 55.47; H, 3.71; F, 31.12; N, 7.90.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[C:29](Cl)[N:28]=[CH:27][C:26]=2[C:25]([CH3:34])([CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[C:29]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:28]=[CH:27][C:26]=2[C:25]([CH3:34])([CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc3c(cn2)C(C)(C)CN3C(=O)OC(C)(C)C)cn1
Temperature: 90 °C
Yield: 81.3 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.609 g, 3.0 mmol), 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.282 g, 1.0 mmol), potassium carbonate (0.414 g, 3.0 mmol), tris(dibenzylideneacetone)-dipalladium (0) (0.091 g, 0.1 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 0.041 g, 0.1 mmol), 1,4-dioxane (6 mL) and water (1.5 mL) was heated at 90° C. for 18 h. The solvent was evaporated, water (30 mL) was added and the product extracted with EtOAc (3×20 mL). Combined organic extracts were dried (MgSO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-100% EtOAc in 40-60 petroleum ether) gave the title compound (0.267 g) as an oil. MS: [M+H]+=329.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:14]=[C:13]2[O:27][CH3:28])=[C:4]([F:29])[CH:3]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:25])([F:26])[C:21]([F:23])([F:22])[F:24])[N:14]=[C:13]2[O:27][CH3:28])=[C:4]([F:29])[CH:3]=1
Reactant: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Product: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(O)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone with concentrated sulphuric acid during 2 minutes at 0° C. there is obtained 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 60 MHz): 7.28 ppm (d,1H), 6.83 ppm (d,1H), 5.10 ppm (s,1H), 4.00 ppm (s,3H);
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[NH2:2].[OH-].[Na+]>O.CO>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[NH2:2]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(N)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(N)=O
Reaction time: 24 h

Procedure:
Ethyl 8-carbamoyl-12-acetoxyheptadecanoate (5.50 g., 0.0138 mole) is added to a solution of sodium hydroxide (1.66 g., 0.0414 mole) in water (8 ml.) and methanol (72 ml.). The resulting solution is allowed to stand 24 hours at 25° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][NH:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[O:21]1[CH2:26][CH2:25][N:24]([C:27](Cl)=[O:28])[CH2:23][CH2:22]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][CH2:10][N:11]([C:27]([N:24]1[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1)=[O:28])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN(C)C(=O)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of N-t-butoxycarbonyl-N,N'-dimethylethylenediamine (1.0 g) and triethylamine (537 mg) in methylene chloride (20 ml) which was cooled to 0° C., was added morpholinocarbonyl chloride (794 mg). The mixture was stirred at 0° C. for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 5% hydrochloric acid, 1M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. Evaporation of the solvent gave N-t-butoxycarbonyl-N'-(morpholinocarbonyl)-N,N'-dimethylethylenediamine (1.11 g) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[S:14][C:15]4[C:16]([N:21]=3)=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:9]=[CH:8][C:6]=2[CH:7]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CC#N>[N:31]1([CH2:2][C:3]2[O:4][C:5]3[CH:11]=[C:10]([O:12][C:13]4[S:14][C:15]5[C:16]([N:21]=4)=[N:17][CH:18]=[CH:19][CH:20]=5)[CH:9]=[CH:8][C:6]=3[CH:7]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: ClCc1cc2ccc(Oc3nc4ncccc4s3)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1cnc2nc(Oc3ccc4cc(CN5CCOCC5)oc4c3)sc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.2 %

Procedure:
To a solution 2-(2-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine (110 mg, 0.3 mmol) in MeCN (3 mL) was added DIEA (209 μL, 0.155 mg, 0.8 mmol) followed by morpholine (27 μL, 27 mg, 0.3 mmol) and stirred (rt, 12 h). The reaction mixture was partitioned between DCM (15 mL) and saturated NaHCO3 (5 mL). The organic layer was washed with saturated NH4Cl (10 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography to provide the title compound as colorless crystals (41 mg, 37%). MS (ESI): mass calcd. for C19H17N3O3S, 367.1; m/z found, 368.1.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.01 (dd, J=7.9, 1.7, 1H), 7.59-7.51 (m, 2H), 7.28-7.25 (m, 1H), 7.20 (dd, J=8.0, 4.8, 1H), 6.65 (s, 1H), 3.75 (dd, J=15.5, 10.8, 4H), 3.70 (s, 2H), 2.62-2.49 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[Si]([O:32][CH2:33][CH2:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.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].O>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[C:3]([O:23][CH3:24])=[C:2]([C:38]4[CH:37]=[N:36][N:35]([CH2:34][CH2:33][OH:32])[CH:39]=4)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=3)[CH3:11])[N:13]=[C:14]([CH3:22])[C:15]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1cnn(CCO)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.026 g, 0.062 mmol) (chiral pure, first peak from Step 2), 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.024 g, 0.069 mmol), sodium carbonate (13 mg, 0.12 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (6.1 mg, 0.0075 mmol) in acetonitrile (0.5 mL)/water (0.1 mL) was degassed and then refilled with N2. The reaction mixture was stirred at 95° C. for 2 hours, then treated with conc. HCl (0.1 mL) and then stirred at room temperature for 1 hour. The crude mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a single enantiomer. LCMS calculated for C21H25ClN7O2 (M+H)+: m/z=442.2; Found: 442.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:25])=[C:4]([CH:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([OH:11])=[C:6]([C:9]=1[CH3:10])[CH:7]=[O:8].P(=O)(O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:25])=[C:4]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([OH:11])=[C:6]([C:9]=1[CH3:10])[CH:7]=[O:8]
Reactant: CCCCCCCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CCCCCCCCCCC=Cc1c(O)c(Cl)c(C)c(C=O)c1O
Temperature: 25 °C
Yield: 76.4 %

Procedure:
5-Chloro-2,4-dihydroxy-3-(1-hydroxydodecyl)-6-methylbenzaldehyde (33 mg, 0.089 mmol) was stirred in acetic acid (2 ml) in the presence of 85% phosphoric acid (0.024 mmol) at a reflux temperature for 1.5 hours. The reaction mixture was cooled to room temperature. After extractive workup with ethyl acetate, the crude product was purified by silica gel thin-layer chromatography (chloroform) to obtain 5-chloro-3-(1-dodecenyl)-2,4-dihydroxy-6-methylbenzaldehyde (24 mg, yield 76%).
Reaction SMILES: [CH2:1]([N:3]([CH3:30])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].ClC[C@@H](O)CO>>[CH2:1]([N:3]([CH3:30])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2]
Reactant: CCN(C)c1cc(-c2nc(-c3cc(C)c(OC[C@H](O)CO)c(C)c3)no2)cc(C)n1
Agent: OC[C@H](O)CCl
Product: CCN(C)c1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(C)c3)no2)cc(C)n1

Procedure:
(S)-3-(4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propane-1,2-diol is prepared in analogy to (R)-3-(4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propane-1,2-diol using (S)-3-chloro-1,2-propanediol; LC-MS: tR=0.75 min; [M+1]+=413.18.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:16])[CH:8]=[CH:7][C:6]([C:9]([NH:11][CH2:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:5][CH:4]=1.I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[C:13]([CH:12]([NH:11][C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH3:16])=[CH:8][CH:7]=1)=[O:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:15])[CH3:14]
Reactant: CC(=O)CNC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(C)(C)OCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OCCCCCCC(NC(=O)c1ccc(C)cc1)C(C)=O
Yield: 73 %

Procedure:
A suspension (70 ml) of 1.81 g of 60% sodium hydride in N,N-dimethylformamide was cooled to −18° C. with ice-sodium chloride bath, and 21 ml of a solution of 8.67 g of 1-(p-toluoylamino)-2-propanone in N,N-dimethylformamide was added slowly. After 1-hour-stirring, 21 ml of a solution of 14.10 g of ethyl 2-(6-iodohexyloxy)-2-methylpropionate in N,N-dimethylformamide was added dropwise slowly. The bath was removed and the mixture was stirred for additional-18 hours at room temperature. The reaction solution was, after addition of ice-cold water, extracted with ethyl acetate, washed with water and brine sequentially, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide 12.20 g of the objective compound as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([N:8]([CH3:26])[CH:9]2[CH2:10][CH2:11][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH2:13]3)[CH2:24][CH2:25]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Yield: 55.4 %

Procedure:
To a suspension of tert-butyl 8-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (3.8 B: 0.30 g, 0.72 mmol) in n-BuOH (4.0 mL) was added 1-methyl-1H-pyrazol-4-amine hydrochloride (0.19 g, 1.44 mmol) and DIPEA (0.37 g, 2.89 mmol). The mixture was stirred in a sealed tube and heated to 150° C. for 12 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EA/PE (v/v)=4/1) to afford 3.9 B as a light yellow solid (0.19 g, 55%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[CH:16]=[C:15](F)[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=1.C[C:20](C)([O-:22])C.[K+]>>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[CH:16]=[C:15]([O:22][CH3:20])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=1
Reactant: CC(C)(C)[O-]
Reactant: C[C@@H]1CN(c2cc(F)c(C#N)c(F)c2)[C@@H](C)CN1
Agent: [K+]
Product: COc1cc(N2C[C@@H](C)NC[C@@H]2C)cc(F)c1C#N

Procedure:
The compound was synthesized in the similar manner as in Reference Example 4-1 using 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2,6-difluorobenzonitrile and 1 equivalent of potassium tert-butoxide.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][C:15]1([CH3:57])[CH2:20][O:19][CH:18]([CH:21]([C@@H:23]2[C@:40]3([CH3:41])[C@H:26]([C@H:27]4[C@H:37]([CH2:38][CH2:39]3)[C@:35]3([CH3:36])[C:30]([CH2:31][C@@H:32]([O:47][C:48]([O:50][CH3:51])=[O:49])[CH2:33][C@@H:34]3[O:42][C:43]([O:45][CH3:46])=[O:44])=[CH:29][C@H:28]4OC(OC)=O)[CH2:25][CH2:24]2)[CH3:22])[O:17][CH2:16]1>O1CCOCC1>[CH3:57][C:15]1([CH3:14])[CH2:16][O:17][CH:18]([CH:21]([C@@H:23]2[C@:40]3([CH3:41])[C@H:26]([C:27]4[C@H:37]([CH2:38][CH2:39]3)[C@:35]3([CH3:36])[C:30]([CH2:31][C@@H:32]([O:47][C:48]([O:50][CH3:51])=[O:49])[CH2:33][C@@H:34]3[O:42][C:43]([O:45][CH3:46])=[O:44])=[CH:29][CH:28]=4)[CH2:25][CH2:24]2)[CH3:22])[O:19][CH2:20]1
Reactant: COC(=O)O[C@@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: CCCCP(CCCC)CCCC
Solvent: C1COCCO1
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
In 10 ml of dioxane was dissolved 25 mg of tris(dibenzylideneacetone)dipalladium(chloroform), followed by addition of 45 μl of tri-n-butylphosphine. The mixture was stirred in an atmosphere of argon gas at room temperature for 10 minutes. To this mixture was added a solution of 270 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β,7α-tris(methoxycarbonyloxy)pregn-5-ene in 10 ml of dioxane and the mixture was refluxed for 12 hours. The resulting reaction mixture was cooled to room temperature and filtered with the aid of Florisil. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography. The procedure yielded 118 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene showing the same physical properties as the compound obtained in Example 124.