Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([CH2:9][CH3:10])[C:7]#[N:8])=[CH:2]1.[Li+].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH3:12][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([CH2:9][CH3:10])[C:7]#[N:8]
Reactant: CCC(C#N)c1ccsc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCC(C)(C#N)c1ccsc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A cooled solution of 2-(thiophen-3-yl)butanenitrile (708 mg, 4.682 mmol) in THF (15 mL) under nitrogen was treated with LHMDS in THF (4.375 g, 4.916 mL of 1 M, 4.916 mmol) dropwise. After 1 hour the reaction was treated with iodomethane (731.0 mg, 320.6 μL, 5.150 mmol) and then allowed to warm to RT. After 2.5 hours the reaction was quenched with MeOH and then concentrated in vacuo. The mixture was diluted with EtOAc/water and the two layers separated. The combined organics were dried (MgSO4), filtered, concentrated and purified by column chromatography (5:1 Petroleum ether/EtOAc) to give the product as a colourless oil (693 mg, 90% Yield).
Reaction SMILES: C[Si](C)(C)CCOC[O:7][C:8]1[CH:13]=[C:12]([O:14]COCC[Si](C)(C)C)[CH:11]=[CH:10][C:9]=1[C:23]1[C:24](=[O:47])[O:25][C:26]2[C:31]([C:32]=1[CH2:33][C:34](=[O:37])[CH2:35][Cl:36])=[CH:30][CH:29]=[C:28]([O:38]COCC[Si](C)(C)C)[CH:27]=2>Cl.C(OCC)(=O)C>[Cl:36][CH2:35][C:34](=[O:37])[CH2:33][C:32]1[C:31]2[C:26](=[CH:27][C:28]([OH:38])=[CH:29][CH:30]=2)[O:25][C:24](=[O:47])[C:23]=1[C:9]1[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=1[OH:7]
Reactant: C[Si](C)(C)CCOCOc1ccc(-c2c(CC(=O)CCl)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)c(OCOCC[Si](C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(CCl)Cc1c(-c2ccc(O)cc2O)c(=O)oc2cc(O)ccc12

Procedure:
3-[2,4-Bis-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-4-(3-chloro-2-oxo-propyl)-7-(2-trimethylsilanyl-ethoxymethoxy)-chromen-2-one (0.846 g, 1.13 mmol) in HCl (1N, 40 mL 1:1 THF:iPrOH) was stirred overnight at 25° C. The reaction mixture was then diluted with ethyl acetate (10 mL) and washed with brine (2×30 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried, concentrated and purified by silica gel column chromatograph (5% MeOH/DCM) to yield the title compound as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[S:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].O>C1(C)C=CC=CC=1>[F:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH3:18])[CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:34]=[O:35])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(SC(c2cnc(Br)cc2C)c2cc(F)ccc2F)ccc1F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(SC(c2cnc(C=O)cc2C)c2cc(F)ccc2F)ccc1F
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
A solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-fluoro-3-methylphenyl)thio]methyl]-4-methylpyridine (2.0 g, 4.6 mmol) in toluene (50 ml) was cooled to −78° C., and in an argon atmosphere, n-butyllithium (1.54 M hexane solution, 3.6 ml, 5.5 mmol) was added thereto. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C., stirred for 30 minutes, and cooled again to −78° C., and then N,N-dimethylformamide (424 μl, 5.5 mmol) was added. After stirring for 30 minutes at the same temperature, water was added thereto, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=95:5 was concentrated under reduced pressure to obtain the title compound (1.1 g, 2.8 mmol, 63%) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.N#N.[CH:25]1([C:28]#[CH:29])[CH2:27][CH2:26]1.C(N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu]I.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>[CH:25]1([C:28]#[C:29][C:2]2[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH2:27][CH2:26]1
Reactant: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(=NOCc1csc(C#CC2CC2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.5 %

Procedure:
To a stirred solution of N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (1 g, 2.63 mmol, 1 eq.) in 20 ml dry THF “degassed” with N2, was added cyclopropylacetylene (70%, 0.996 g, 10.54 mmol, 4 eq.) followed by N-ethyldiisopropylamine (1.36 g, 10.54 mmol, 4 eq.), Copper(I) Iodide (0.025 g, 0.132 mmol, 0.05 eq.) and Tetrakis(triphenylphosphine)palladium (0.152 g, 0.132 mmol, 0.05 eq.). The reaction was stirred for 20 hrs at room temperature for complete conversion. The reaction mixture was diluted with EtOAc (50 ml), filtered through “Chem Elut” cartridge, washed with fresh EtOAc (2×20 ml) and the filtrate was evaporated. The residue was purified by chromatography on silica gel to give N-{[2-(cyclopropylethynyl)-1,3-thiazol-4-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.57 g, 60% yield, single stereoisomer) as a brown gum.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:13]([O:15][C:16](=[O:22])[CH:17](Cl)[O:18][CH2:19][CH3:20])[CH3:14]>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:18][CH2:19][CH3:20])[N:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]1=[O:3])[CH3:14]
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: CCOC(=O)C(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OCC)n1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.228 g=0.74 g NaH) was suspended in DMF (45 ml) under an argon atmosphere. The stirred suspension was cooled to 0° C. and 2-hydroxy-3-nitropyridine (4 g) was added portion wise over a period of 45 min. The mixture containing a compact yellow precipitate was then stirred at r.t. for 30 min and was cooled again to 0C. A solution of 2-chloro-2-ethoxyacetic acid ethyl ester (4.99 g) in DMF (5 ml) was then added and stirring at r.t. was continued for 2 h 30. The mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica gel, gradient cyclohexane=>cyclohexane/EtOAc 3:2) to give (RS)-ethoxy-(3-nitro-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (4.32 g) as yellow solid. MS 270.1 ([M]+)
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1CC1N2CCN(C)C(=O)C2=C(O)C(=O)N=1>>[C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:12]1[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]2=[C:9]([OH:8])[C:14](=[O:15])[N:13]=1
Reactant: CC(C)N1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(O)c2C1=O
Yield: 19.1 %

Procedure:
6-Biphenyl-2-ylmethyl-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-03) (17 mg, 19%) was synthesized as an off-white solid from 9-benzyloxy-6-biphenyl-2-ylmethyl-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-03) (110 mg, 0.229 mmol) following the procedure as described for 6-biphenyl-2-ylmethyl-9-hydroxy-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-01).
Reaction SMILES: C12OC(CC1)CN(C1N=C(C3C=CC(N)=CC=3)N=C3N(CC(F)(F)F)N=CC=13)C2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[O:42]1[CH2:47][CH2:46][N:45]([C:48]2[N:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1.[N:55]([C:58]1[CH:63]=[CH:62][C:61]([C:64]2[N:69]=[C:68]3[N:70]([CH2:73][C:74]([F:77])([F:76])[F:75])[N:71]=[CH:72][C:67]3=[C:66]([N:78]3[CH2:84][CH:83]4[O:85][CH:80]([CH2:81][CH2:82]4)[CH2:79]3)[N:65]=2)=[CH:60][CH:59]=1)=[C:56]=[O:57]>ClCCl.C(N(CC)CC)C>[N:45]1([C:48]2[N:53]=[CH:52][C:51]([NH:54][C:56]([NH:55][C:58]3[CH:63]=[CH:62][C:61]([C:64]4[N:69]=[C:68]5[N:70]([CH2:73][C:74]([F:76])([F:77])[F:75])[N:71]=[CH:72][C:67]5=[C:66]([N:78]5[CH2:84][CH:83]6[O:85][CH:80]([CH2:81][CH2:82]6)[CH2:79]5)[N:65]=4)=[CH:60][CH:59]=3)=[O:57])=[CH:50][CH:49]=2)[CH2:46][CH2:47][O:42][CH2:43][CH2:44]1
Reactant: O=C=Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: Nc1ccc(N2CCOCC2)nc1
Agent: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1)Nc1ccc(N2CCOCC2)nc1
Reaction time: 8 h

Procedure:
A solution of 4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine (50 mg, 0.12 mmol) in dichloromethane (4 mL) was treated with triethylamine (0.16 mL), followed by a solution of triphosgene (19 mg, 0.064 mmol) in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 6-morpholinopyridin-3-amine (86 mg, 0.48 mmol)—was added to the 3-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After being left overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile over 30 minutes to provide 1-(6-morpholin-4-ylpyridin-3-yl)-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea.TFA (18 mg, 21%). MS (ES+): 610.2 (M+H)+
Reaction SMILES: [C:1]([CH2:3][S:4]([N:7]([CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8])(=[O:6])=[O:5])#[N:2].[H-].[Na+].[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36](Br)=[CH:37][CH:38]=2)[C:33]([CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])=[CH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1.COCCOC.C(O)C>[CH2:24]([N:31]1[C:39]2[C:34](=[CH:35][C:36]([CH:3]([C:1]#[N:2])[S:4]([N:7]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:8])(=[O:5])=[O:6])=[CH:37][CH:38]=2)[C:33]([CH2:41][CH2:42][N:43]([CH3:44])[CH3:45])=[CH:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)CCc1cn(Cc2ccccc2)c2ccc(Br)cc12
Reactant: CN(C(c1ccccc1)c1ccccc1)S(=O)(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CCc1cn(Cc2ccccc2)c2ccc(C(C#N)S(=O)(=O)N(C)C(c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
To a stirred solution of 1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (see Example 2(c), 2.36 g, 7.9 mmol) in a mixture of toluene (4 ml) and ethylene glycol dimethylether (1 ml) at 0-5° C. under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil) (577 mg, 14.4 mmol) portionwise, maintaining the temperature below 5° C. Upon completion of the addition, the dark brown solution was warmed to ambient temperature over a 30 min period, before tetrakis(triphenylphospline) palladium(0) (529 g, 0.46 mmol) was added in one portion. A solution of 1-benzyl-5-bromo-3-[2-(dimethylamino)ethyl]-1H-indole (from step (c), 2.34 g, 6.6 mmol) in toluene (2 ml) was then added dropwise to the brown slurry and the mixture was warmed to reflux. Reflux was maintained for 2 hr after which time the dark brown solution was cooled to ambient temperature. The reaction mixture was then poured into water (25 ml) and extracted with ethyl acetate (3×5 ml). The organic extracts were combined and evaporated in vacuo to yield a brown oil. This was re-dissolved in absolute ethanol (8 ml) and stirred for 18 hr over which time precipitation occurred. The solid was filtered and dried in vacuo at 50° C. overnight to yield the subtitle compound (1.3 g, 35%) as a cream solid. m.p. 98-100° C.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:30])[C:24]=2[CH:23]=[CH:22]1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:30][C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH:23]=[CH:22][NH:21]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccc2[nH]ccc12
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: ClCCl
Product: O=C(Nc1cccc2[nH]ccc12)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77 %

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 110 mg; 0.40 mmol) in DCM was treated with polymer-supported Mukaiyama reagent (1.1 g) followed by 1H-indol-4-amine (Aldrich, 58.2 mg; 0.44 mmol). After stirring at RT for 72 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (120 mg, 77%).
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH:9]=[O:10])[CH:5]=1)([CH3:3])[CH3:2].[CH3:11][Mg]Br.O>O1CCOCC1.O1CCCC1>[CH:1]([C:4]1[O:8][N:7]=[C:6]([CH:9]([OH:10])[CH3:11])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(C)c1cc(C=O)no1
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)O)no1
Reaction time: 1 h

Procedure:
5.70 g of 5-i-propylisoxazole-3-carbaldehyde was dissolved in 82 ml of 1,4-dioxane, and 48 ml of a 0.93 M solution of methylmagnesium bromide in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.66 g of 1-(5-i-propyl-isoxazol-3-yl)ethanol.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:6]1([O:5][CH2:4][CH:3]([OH:1])[CH2:2][N:25]2[CH2:26][CH2:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCO
Product: OC(COc1cccc2ccccc12)CN1CCC(c2ccccc2)CC1

Procedure:
To a solution of 5.0 parts of 1,2-epoxy-3-(1-naphthoxy)propane in 79 parts of ethanol is added 5.0 parts of 4-phenylpiperidine. The resulting mixture is then refluxed for 24 hours. Evaporation of the solvent from the reaction mixture under reduced pressure affords 1-(1-naphthoxy)-3-(4-phenylpiperidino)-2-propanol. This free amine is then dissolved in isopropanol and treated with a solution of hydrochloric acid in isopropanol. The resulting salt is separated by filtration and recrystallized from a mixture of ethanol and ethyl ether to give 1-(1-naphthoxy)-3-(4-phenylpiperidino)-2-propanol hydrochloride. This compound melts at 195°-197° C. and is represented by the following structural formula ##STR6##
Reaction SMILES: C([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:8][C@@H:7]([O:34]C(=O)C)[CH2:6]1)(=O)C.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)(=O)C>[OH:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:8][C@@H:7]([OH:34])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)COC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@H](COC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 1.5 g. of (20S)-1α,3β-diacetoxy-20-methyl-21-tetrahydropyranyloxypregna-5-ene in 25 ml. of absolute ether was added 0.3 g. of lithium aluminum hydride and the suspension was stirred at room temperature for 1 hour. After cooling to 0°, 2 ml. of ethyl acetate was added and the mixture poured onto ice-water. The insoluble part was extracted with ethyl acetate, the organic solution was washed with water and dried over sodium sulfate. By filtration and evaporation under vacuum 1.4 g. of crystalline (20S)-1α,3β-dihydroxy-20-methyl-21-tetrahydropyranyloxypregna-5-ene was obtained. Recrystallization from methanol gave white crystals, m.p. 138°-141°; [α]D =-48.8° (c=0.5, chloroform).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19].[H-].[Na+]>C1COCC1>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][O:19][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (0.5, 2.207 mmol) and 2-(dimethylamino)ethanol (0.393 g, 4.41 mmol) in THF (10 mL) was added NaH (0.177 g, 4.41 mmol) at 0° C. The resulting mixture was stirred at rt. After 5 h, TLC analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (DCM/MeOH=20/1) to yield a white solid of N,N-dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethanamine (0.5 g, 1.717 mmol, 78.0% yield): 1H NMR (400 MHz, CD3OD) δ 9.25 (d, J=2.4 Hz, 1H), 8.74 (d, J=2.4 Hz, 1H), 4.73 (t, J=5.4 Hz, 2H), 2.88 (t, J=5.4 Hz, 2H), 2.37 (s, 6H); ES-LCMS m/z 280.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:32]([O:31][C:29](=[O:30])[C:28]([O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:35])[CH3:34])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(O)c2)n1
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Reaction time: 2 h
Yield: 36.9 %

Procedure:
A mixture of 3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol [945 mg, 2.42 mmol, Example 35(i)], PS-TBD (3.38 g, 5 mmol), ethyl 2-bromoisobutyrate (888 mL, 605 mmol) and acetonitrile (20 mL) is heated to reflux and stirred for 2 hours. The heating is turned off and the mixture is stirred overnight at ambient temperature. The reaction mixture is filtered to remove the resin and the resin is washed with MeOH (20 mL) and with acetonitrile (20 mL). The combined filtrate and washings are concentrated by rotary evaporator. The residue is subjected to flash column chromatography on silica (40 g) eluting with 20 to 50% EtOAc in heptane gradient to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid ethyl ester [450 mg, 37%, Example 42] as a solid. LCMS: RT=2.9 minutes, MS: 504 (M+H).
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]([O:7][C:8]([CH:10]1[CH:18]2[C:13]3([CH:22]=[CH:21][CH:20]=[CH:19][C:14]3=[N:15][CH2:16][CH2:17]2)[S:12][CH2:11]1)=[O:9])[CH3:6].[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH2:5]([O:7][C:8]([CH:10]1[CH:18]2[C:13]3([CH:22]=[CH:21][CH:20]=[CH:19][C:14]3=[N:15][CH2:16][CH2:17]2)[S:12][CH:11]1[C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23])=[O:9])[CH3:6]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(C(=O)c2ccccc2Cl)SC23C=CC=CC2=NCCC13
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To 30 ml of chloroform were added 0.60 g of 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester synthesized in Example 1, 0.64 ml of triethylamine, and 523 mg of 2-chlorobenzoyl chloride, and the mixture was stirred for one hour at room temperature. The reaction mixture was washed with ml of water and then with 30 ml of an aqueous sodium hydrogencarbonate solution having a pH of 9.0, and also with 30 ml of water. The chloroform layer was dried by sodium sulfate and the solvent was distilled off under reduced pressure to provide 614 mg (yield of 67%) of 2 -(2-chlorobenzoyl)-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([NH2:26])=[C:19]2[N:18]=1.CCN(C(C)C)C(C)C.Cl[C:37](=[O:42])[C:38]([O:40][CH3:41])=[O:39]>>[F:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([NH:26][C:37](=[O:42])[C:38]([O:40][CH3:41])=[O:39])=[C:19]2[N:18]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
A DCM (5 mL, 0.7928 mmol) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 250 mg, 0.7928 mmol) and DIEA (0.2071 mL, 1.189 mmol) was first cooled in an ice-water bath, then methyl 2-chloro-2-oxoacetate (0.07657 mL, 0.8325 mmol) was added to reaction drop-wise. Ice bath was removed and the reaction was stirred at ambient temperature for approx. 10 minutes to reach completion. The reaction was washed with 10% citric acid (aqueous). The aqueous layer was back-washed with DCM. The combined organic layer was washed with 1:1 water/brine, dried (Na2SO4) and concentrated. The crude oil residue was directly purified by silica chromatography, eluting with EtOAc/hexanes 1:1 to 2:1, yielding the final product as a pale-yellowish foamy powder (270 mg, 85% yield). MS (apci) m/z=402.2 (M+H).