Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2]C1C(C2C=CC=CC=2C)=C(Cl)C=CC=1.Br.[H-].[Na+].C(Br)C=C.C(OCC=C)C=C.[CH2:31]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])[C:35]=1[OH:48])[CH:32]=[CH2:33].ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=C(C)C=C(C)C=1>[Cl:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:36]1[C:35]2[O:48][CH:32]([CH2:33][OH:2])[CH2:31][C:34]=2[CH:39]=[CH:38][C:37]=1[Cl:40]
Reactant: C=CCc1ccc(Cl)c(-c2ccccc2Cl)c1O
Reactant: COc1cccc(Cl)c1-c1ccccc1C
Agent: Br
Agent: C=CCOCC=C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C=CCBr
Solvent: Cc1cc(C)cc(C)c1
Product: OCC1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Yield: 74 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (15.6 g, 80.64 mol) generally according to the procedure described for Intermediate 37 afforded 5.0 g (73%) of 6-chloro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (60 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (1.05 g, 26.35 mmol) and allyl bromide (3.19 g, 26.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol (2.8 g, 10.03 mmol) with m-chloroperoxybenzoic acid (4.6 g, 15.0 mmol, 77%) and potassium carbonate (1.6 g, 12.0 mmol) generally according to the procedure described for Intermediate 9 afforded 2.2 g (74%) of (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.6 g, 5.42 mmol) with p-toluenesulfonyl chloride (1.55 g, 8.13 mmol) generally according to the procedure described for Intermediate 10 gave 2.1 g (86%) of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.44 mmol) with sodium azide (0.2 g, 3.08 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.43 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.3 g, 1.14 mmol) generally according to the procedure described for Example 154 provided 0.036 g (24%) of (±)-{[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 221-223° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:14])(OC(C)(C)C)=O.[F:15][C:16]1[C:17](I)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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>[F:15][C:16]1[C:17]([C:14]#[C:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H]3CCCN3)c21
Reaction time: 2.5 h

Procedure:
Using Method C above, (S)-N-Boc-2-ethynyl-pyrrolidine (100 mg, 0.52 mmol) (Example 87B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 40-70% EtOAc in hexanes gradient. The intermediate that was obtained from this operation was directly dissolved at 0° C., in 5 mL of a solution of 50% trifluoroacetic acid in CH2Cl2 that contained 0.2 mL of H2O and stirred for 2.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(pyrrolidin-2-yl)ethynyl]-2H-indol-2-one was obtained after reverse phase column chromatography with 0-90% MeOH in H2O gradient, a silica gel column chromatography with neat THF and a precipitatiion out of THF with excess of hexanes. (Yield 8 mg, 18%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1.Cl[C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(Cl)Cl>ClCCCl>[O:25]=[C:18]([C:8]1[C:9]([O:15][CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=1[O:6][CH3:5])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CCC(=O)Cl
Reactant: COc1cc(OC)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CCC(=O)c1c(OC)cc(OC)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) suspension of AlCl3 (2.036 g; 15.27 mmol) in anh. DCE (10 ml) was treated with commercially available 1,3,5-trimethoxybenzene (1.675 g; 9.96 mmol), and stirring at 0° C., under nitrogen, was continued for 10 min. Commercially available methyl 4-chloro-4-oxobutanoate (1.000 g; 6.64 mmol) was then added, and the mixture was stirred at rt for 24 h. The resulting reaction mixture was poured onto crushed ice (30 g), and DCM (20 ml) was added. The separated aq. layer was further extracted with DCM (3×10 ml). The mixed organic layers were washed successively with water (15 ml) and brine (2×15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 4-oxo-4-(2,4,6-trimethoxyphenyl)butanoate as a colorless oil. LC-MS (conditions D): tR=0.88 min.; [M+H]+: 283.02 g/mol.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([I:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:26][O-:27].[Na+].ClCCl>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([O:27][CH3:26])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([I:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2ccnc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2ccnc2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A heterogeneous mixture containing 3-(4-(1H-imidazol-1-yl)benzyl)-2,4-dichloro-6-iodoquinoline (1.2 g, 2.5 mmol, Intermediate 17: step b) and sodium methoxide (1.6 g, 30 mmol) in toluene (25 mL) was heated to 110° C. After 2 hours, the flask was allowed to cool to 23° C. Dichloromethane (100 mL) was added and the mixture was filtered through Celite®, rinsing the filter cake with dichloromethane. The filtrate was concentrated to provide the title compound as an off-white solid. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=O)=[CH:4][CH:3]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21]C)=[O:20]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:9]/[CH:10]=[CH:23]/[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=CC=O)c2ccc(C)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(C(=C/C=C/C(=O)O)c2ccc(C)cc2)cc1
Yield: 67.4 %

Procedure:
In the manner described in Example 99, 3,3-bis(4-methylphenyl) -2-propenal (9.45 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (15.3 g) in carbon tetrachloride (95 ml) for 3 days at room temperature. The solvent was removed under reduced pressure and the residue was stirred at reflux in mixture of methanol (40 mL) and 2N NaOH for 45 minutes. The cooled solution was diluted with water (300 ml), extracted with dichloromethane (3×100 mL) to remove non-acidic material, and then acidified with 6N HCI (50 ML) and extracted with dichloromethane. The dried (MgSO4) extracts were evaporated and the crude product was crystallized from 2-propanol to afford 7.5 g of (E)-5,5-bis(4-methylphenyl)-2,4-pentadienoic acid, mp 224 5°-226.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[Cu](C#N)[C:10]#[N:11].ClCCl>C(#N)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)nn1
Reactant: N#C[Cu]C#N
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccc(Cl)nn1
Yield: 89 %

Procedure:
A mixture of 3-chloro-6-iodo-pyridazine (CAS 135034-10-5, 5.5 g, 22.9 mmol; Goodman, A. J.; Stanforth, S. P.; Tarbit, B. Tetrahedron (1999), 55 (52), 15067-15070) and copper cyanide (4 g, 44.7 mmol) in acetonitrile (30 ml) was stirred for 30 min. at 160° C., under microwave irradiation (Milestone MW-oven). The mixture was then poured into dichloromethane (200 ml), filtered over celite, and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; dichloromethane/heptane 1:1 to 7:3) to yield D4 (2.84 g, 89%), as a solid.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:36])[C@H:33]([CH3:35])O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@H:33]([CH3:35])[C:32]([OH:36])=[O:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Product: C[C@@H](Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and (S)-(+)-lactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 112-114° C.; MS m/e 448 (M+);
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][N:4]2[N:3]=1.[C:12](=[O:19])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[NH2:13].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Br:1][C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([NH:13][C:12](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Brc1ccn2nc(Br)nc2c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccn2nc(Br)nc2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To an argon purged solution of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (1.9 g, 6.86 mmol) in dioxane (70.3 ml) are added tert-butyl carbamate (965 mg, 8.23 mmol), cesium carbonate (3.13 g, 9.61 mmol), tris(dibenzylideneacetone)dipalladium(0) (126 mg, 137 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (159 mg, 274 μmol). The resulting mixture is stirred for 18 hours at 100° C. under argon atmosphere. The crude material is loaded on silicagel and purified by chromatography on a 70 g silica column using heptane/ethyl acetate 10-40% as eluent affording tert-butyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (1.39 g, 64.6%) as a white solid. MS: m/z=313.0; 314.9 (M+H+).
Reaction SMILES: [CH2:1]1[C:6]([OH:9])([CH2:7][OH:8])[CH:5]([OH:10])[CH:4]([OH:11])[CH:3]([OH:12])[CH:2]1[NH:13]C1C(O)C(O)C(O)C(CO)=C1>P([O-])([O-])([O-])=O>[CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:11])[C@@H:3]([OH:12])[C@H:2]1[NH2:13]
Reactant: OCC1=CC(NC2CC(O)(CO)C(O)C(O)C2O)C(O)C(O)C1O
Agent: O=P([O-])([O-])[O-]
Product: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 24 h
Yield: 63.7 %

Procedure:
Validoxylamine G (100 mg) was dissolved in 0.05 M phosphate buffer (pH 7.0) (20 mL) and wet cells of Flavobacterium saccharophilum IFO 13984 (about 2 g) were added to the solution, followed by incubation at 27° C. for 24 hours with stirring. The reaction mixture was centrifuged for removal of cells, and the supernatant was adsorbed onto a column (50 mL) of Amberlite IRC-50 (NH4+ form, manufactured by Rohm & Haas Co.), followed by washing with water and elution aqueous ammonia. The eluate was concentrated to dryness under reduced pressure, and the residue was adsorbed again onto a column (50 mL) of Amberlite IRC-50 (NH4+ form) and eluted with 0.1N aqueous ammonia. In succession to the fractions containing valienamine (eluate fractions 120-140 mL), the fractions containing valiolamine were eluted (eluate fractions 340-430 mL). The fractions containing valiolamine were concentrated to dryness under reduced pressure, and the residue was submitted to column chromatography on Dowex 1× 2 (OH- form, manufactured by Dow Chemicals Co.; 2 mL) followed by concentration of the eluate to dryness under reduced pressure, to give white powders of valiolamine (35 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCOC(C)=O>CN(C=O)C>[CH3:12][O:11][C:9](=[O:10])[CH:8]([N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]1)[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
2.97 g of potassium carbonate and 1.97 g of methyl 2-bromopropanoate are added to a solution of 2 g of tert-butyl piperazine-1-carboxylate in 36 ml of DMF, and then it is heated at 60° C. for 1 hour. After it returns to RT, 150 ml of EtOAc is added, it is washed with water, with brine, dried over Na2SO4 and then evaporated to dryness. 2.8 g of the expected compound is obtained in the form of a colorless oil.
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>Br>[CH2:16]([N:11]1[C@@H:12]2[C@@H:8]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([OH:2])[C:15]=3[CH2:14][CH2:13]2)[CH2:9][CH2:10]1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCc1ccccc1
Temperature: 0 °C
Yield: 98 %

Procedure:
2.88 g (0.00936 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenethyl-1H-benzo[e]indole were dissolved in 0.106 l of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was poured into an ice-cold aqueous solution of 37.4 g (0.936 mol) of NaOH. Then, solid NaHO3 was added thereto and the mixture was extracted three times with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered and concentrated. By chromatography of the residue over silica gel with cyclo-hexane/ethyl acetate 1:1 there were obtained 2.69 g (98%) of oily rac-cis-2,3,3a,4,5,9b-hexahydro-3-phenethyl-1H-benzo[e]indol-6-ol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:18]#[C:19][CH3:20].O>ClCCl>[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:6][CH:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)NC(CO)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a 0° solution of D-serine methyl ester hydrochloride (0.62 g, 4 mmol) in 5 mL of dichloromethane was added triethylamine (1.67 mL,12 mmol) followed by a dichloromethane (6 mL) solution of 4-(2-butynyloxy)-benzenesufonyl chloride (0.98 g, 4 mmol). The reaction was stirred at room temperature overnight and then the mixture was poured into water. The organic layer was washed with 2N citric acid, water and brine, dried over sodium sulfate, filtered and concentrated to give 1.16 g of methyl 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-hydroxypropanoate. Yield˜89.2%. mp 72-74° C. Electrospray Mass Spec 328.2 (M+H)+.
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.Cl[Si](C)(C)C.[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1>[NH2:6][C:7]1[S:8][C:9]([C:18]([OH:19])([CH3:20])[CH3:17])=[CH:10][N:11]=1
Reactant: Nc1nccs1
Reactant: CC(C)=O
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cnc(N)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Add n-Butyl lithium (1.6 M solution in hexane, 24 mL, 38 mmol, 2.0 eq.) in a dropwise manner at −78° C. under nitrogen to the solution of 2-amino thiazole (1.90 g, 18.97 mmol, 1.0 eq.) in anhydrous THF (80 mL). Add chlorotrimethyl silane (4.8 mL, 38 mmol, 2.0 eq.) to the mixture slowly at −78° C. Let the reaction mixture warm up to 0° C. slowly and stir the mixture at 0° C. for 10 minutes. Cool the solution to −78° C. and add n-Butyl lithium (1.6 M solution in hexane, 12 mL, 19 mmol, 1.0 eq.) in a dropwise manner. Add acetone (1.4 mL, 19 mmol, 1.0 eq.) last. Stir the reaction mixture at −78° C. for 10 minutes, then at room temperature for 30 minutes. Quench with ammonium chloride (sat. 10 mL) at −78° C. Then warm up to room temperature. Add ethyl acetate (200 mL). Wash the organic layer with aqueous saturated sodium chloride (3×30 mL), water (2×30 mL). Dry the organic phase over MgSO4 and filter the drying reagent off. Concentrate in vacuo. Purify by column chromatography (0%→5% methanol in dichloromethane→10% methanol in dichloromethane) to afford product (1.38 g, 46%). MS(ES), m/z 159 (M+1).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([C:29]#[C:30][CH2:31][OH:32])=[CH:26][CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(Cl)Cl.CO.[Pd]>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([CH2:29][CH2:30][CH2:31][OH:32])=[CH:26][CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(C#CCO)ccc34)nn2)cc1)N1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(CCCO)ccc34)nn2)cc1)N1CCOCC1
Yield: 38.5 %

Procedure:
A solution of 3-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-6-yl)prop-2-yn-1-ol (40 mg; 0.09 mmol; 1.0 eq.) in DCM (2.0 mL) and MeOH (2.0 mL) was passed through a Pd/C cartridge at RT with full H2 at 1 mL/min in the H-cube. Solvents were removed under reduced pressure and the crude obtained was purified by preparative HPLC to give the title compound as a white solid (15 mg, 37%). 1H NMR (300 MHz, DMSO-d6) δ 13.23 (brs, 1H), 9.37 (s, 1H), 8.24 (d, J=8.3 Hz, 1H), 8.15 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.37 (m, 1H), 7.12 (dd, J=8.3 Hz, 1.1 Hz, 1H), 4.52 (t, J=5.1 Hz, 1H), 3.64 (m, 6H), 3.42 (m, 2H), 2.94-2.75 (m, 4H), 1.85-1.72 (m, 2H). HPLC (max plot) 98.3%; Rt % 2.69 min. UPLC/MS: (MS+) 433.1, (MS−) 431.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[C:6]=2[N:7]=1.Cl[C:24]1[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[CH2:33][CH2:32]2)[CH:25]=1>>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][CH:22]=[C:11]([C:8]3[C:6]4[N:7]=[C:2]([NH:1][C:24]5[CH:25]=[C:26]([N:31]6[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[CH2:33][CH2:32]6)[N:27]=[C:28]([CH3:30])[N:29]=5)[N:3]=[CH:4][C:5]=4[S:10][CH:9]=3)[CH:12]=2)[CH2:18][CH2:19]1
Reactant: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Reactant: Nc1ncc2scc(-c3cccc(C(=O)NC4CC4)c3)c2n1
Product: Cc1nc(Nc2ncc3scc(-c4cccc(C(=O)NC5CC5)c4)c3n2)cc(N2CCN(CCO)CC2)n1
Yield: 47.1 %

Procedure:
N-Cyclopropyl-3-(2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide (16 mg, 47% yield) was prepared in the same manner as Step 10 of Example 1 using 3-(2-aminothieno[3,2-d]pyrimidin-7-yl)-N-cyclopropylbenzamide (20 mg, 0.064 mmol) and 2-(4-(6-chloro-2-methylpyrimidin-4-yl)piperazin-1-yl)ethanol (17 mg, 0.064 mmol).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][SiH:5]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:3]1.[Mg].P(OCC)(OCC)(OCC)=O.I[CH2:24][CH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>[Cu]I.C1COCC1>[CH2:8]([Si@H:5]1[CH2:6][CH2:7][C@H:2]([CH2:24][CH2:25][C@H:26]2[CH2:27][CH2:28][C@H:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[C:40]([F:48])[CH:39]=4)=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)[CH2:3][CH2:4]1)[CH2:9][CH3:10]
Reactant: CCC[SiH]1CCC(Br)CC1
Reactant: Fc1cc(-c2ccc([C@H]3CC[C@H](CCI)CC3)cc2)ccc1C(F)(F)F
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(C(F)(F)F)c(F)c4)cc3)CC2)CC1

Procedure:
22.1 g (0.1 mol) of 1-bromo-4-n-propyl-4-silacyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 47.6 g (0.1 mol) of 4-(trans-4-(2-iodoethyl)cyclohexyl)-3'-fluoro-4'-trifluoromethylbiphenyl. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-3'-fluoro-4'-trifluoromethylbiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 35.5 g (yield 72.3%) of the trans isomer.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([OH:15])[CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[Cl:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:14][C:13]=1[O:15][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]
Reactant: Nc1nccc(Nc2ccc(Cl)c(O)c2)n1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ccnc(N)n2)ccc1Cl
Yield: 41 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 5-(2-aminopyrimidin-4-ylamino)-2-chlorophenol (13 mg, 0.06 mmol) and Cs2CO3 (18 mg, 0.06 mmol) in acetone (1 mL) was treated with 4-bromo-2-methyl-2-butene (6.5 μL, 0.41 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/9) in 41% yield (7 mg).