Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].O.[OH-].[Li+]>C1OCCOC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:25][CH:26]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:27]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH2:11][CH2:12]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(C(=O)c4cccc(F)c4)C3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(C(=O)c4cccc(F)c4)C3)CC2)cc1
Temperature: 70 °C
Yield: 74.3 %

Procedure:
To a solution of methyl 6-((5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinamido)methyl)nicotinate (D160) (40.5 mg, 0.079 mmol) in a mixture 1-4 dioxane/water (1.5 ml/0.5 ml), lithium hydroxide hydrate (10 mg, 0.24 mmol) was added. The reaction mixture was heated to 70° C. under microwave irradiation for 20 min (4 cycles of 5 min each). After solvent evaporation the residue was taken in water (5 ml) and 1M HCl (5 ml) and extracted with ethylacetate (3×10 ml). Collected organics after solvent evaporation afforded the title compound (E25) (29 mg)
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:28][CH2:27][C:23]1[O:22][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccco1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccco3)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of 2-furylmethyl amine and 3.5 of triethyl amine and worked up. Melting point: 154° C (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:3]=1[CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7]>O1CCCC1.C(O)C.[Pd]>[NH2:14][C:12]1[CH:11]=[CH:10][C:3]([CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[C:2]([F:1])[CH:13]=1
Reactant: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1ccc(N)cc1F
Reaction time: 15 h
Yield: 86.5 %

Procedure:
To a stirred solution of N-(2-fluoro-4-nitrobenzyl)methanesulfonamide (250 mg, 1.007 mmol) in tetrahydrofuran and ethanol as co-solvent were added 10% Pd/C (25 mg). The mixture was charged with H2 (gas) balloon. The resulting mixture was stirred for 15 h, then filtered by using celite. The filtrate was removed in vacuo. The crude was purified by column chromatography. N-(4-Amino-2-fluorobenzyl)methanesulfonamide (190 mg) was obtained as 86% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[CH:11]([F:13])[F:12].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:1][C:2]2[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)[CH:11]([F:12])[F:13]
Reactant: Nc1cccc(S)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: FC(F)C(F)(F)Oc1cccc(CNc2cccc(S)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
EX-473A) 3-Aminobenzenethiol (2.4 mL, 22.5 mmol) and 3-(1,1,2,2-tetrafluoro-ethoxy)benzaldehyde (5 g, 22.5 mmol) were dissolved in 40 mL of dichloroethane and acetic acid (1.35 mL, 23.7 mmol), then solid NaBH(OAc)3 (6.2 g, 29.3 mmol) was added. The mixture was stirred at room temperature for 18 hours, then quenched with water and diluted with dichloromethane. The organic layer was washed with aqueous saturated sodium bicarbonate, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give 5.36 g (72%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzenethiol product as a brown oil. 1H NMR (CDCl3) δ3.4 (s, 1H), 4.4 (s, 2H), 5.9 (tt, 1H), 6.4 (dd, 1H), 6.55 (m, 1H), 6.65 (d, 1H), 7.05 (t, 1H), 7.2-7.4 (m, 4H).
Reaction SMILES: [ClH:1].[CH2:2]([C:11]1[NH:12][NH:13][C:14]2[CH:20]=[CH:19][N:18]=[CH:17][C:15]=2[N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[ClH:1].[CH2:2]([C:11]1[NH:12][N:13]([C:21](=[O:23])[CH3:22])[C:14]2[CH:20]=[CH:19][N:18]=[CH:17][C:15]=2[N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC1=Nc2cnccc2NN1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CCCCCCCCCC1=Nc2cnccc2N(C(C)=O)N1
Temperature: 80 °C
Yield: 73 %

Procedure:
A mixture of 6 g (0.02 moles) of 1,2-dihydro-3-nonylpyrido[3,4-e]-as-triazine hydrochloride and 80 ml of acetic anhydride is maintained at 80° C. for 2 hours. The product separates upon cooling. 5 g (73%) of 3-nonyl-1-acetyl-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride are obtained; m.p.: 209°-210° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I-:16].O>C(#N)C.[Ag+].FC(F)(F)C([O-])=O>[I:16][C:7]1[CH:6]=[CH:5][C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])=[CH:3][C:2]=1[F:1]
Reactant: [I-]
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
In 300 ml of acetonitrile was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF3COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33]Br)[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:17][C:18](=[O:38])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][CH2:33][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OC)ccc(C(C)=O)c1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOc1c(C(C)=O)ccc(OCC(=O)OC)c1CCC
Yield: 57.3 %

Procedure:
A mixture of 2 g (0.0088 mol) of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 3.39 g (0.0088 mol) of [4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester and 1.8 g (0.013 mol) of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux for 20 hours. An additional 1.0 g of potassium carbonate was added and reflux was continued for a total of 35 hours. The hot reaction mixture was filtered and filtrate was concentrated in vacuo to an oil which was dissolved in ethyl acetate and washed with 1N sodium hydroxide and sodium chloride solution. The crude oil obtained on concentration of the ethyl acetate solution was purified by HPLC, eluting with 30% ethyl acetate in hexane to yield 2.7 g (58% yield) of [4-acetyl-3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester as a pale yellow oil.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](#[N:17])[CH:15]=[CH2:16].C[O-].[Na+]>>[CH2:1]([S:13][CH2:16][CH2:15][C:14]#[N:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCSCCC#N

Procedure:
β-n-Dodecylmercaptopropionitrile was prepared according to the procedure of Example 1 using 1-dodecanethiol (24.75 g; 0.12 moles), acrylonitrile (6.4 g; 0.21 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]([NH2:9])[C:7](=[O:10])[CH:6]=[C:5]([CH3:11])[N:4]=1.[F:12][C:13]([F:21])([CH2:19][CH3:20])[C:14](OCC)=O.Cl>O1CCOCC1.C(O)C>[F:12][C:13]([C:14]1[N:2]=[C:3]2[N:4]=[C:5]([CH3:11])[CH:6]=[C:7]([OH:10])[N:8]2[N:9]=1)([F:21])[CH2:19][CH3:20]
Reactant: CCOC(=O)C(F)(F)CC
Reactant: Cc1cc(=O)n(N)c(N)n1
Agent: Cl
Agent: [Na]
Solvent: C1COCCO1
Solvent: CCO
Product: CCC(F)(F)c1nc2nc(C)cc(O)n2n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of NaEtO prepared from sodium (FLUKA, 0.152 g, 6.62 mmol) and ethanol (25 mL), Intermediate 1 (0.773 g, 5.52 mmol) was added, and the mixture was heated at 80° C. for 30 min. Then, the reaction was cooled down to room temperature and ethyl 2,2-difluorobutanoate (FLUOROCHEM, 1007 mg, 6.62 mmol) was added and the reaction mixture was stirred at 80° C. for 3 h. A solution of HCl (1.655 mL, 6.62 mmol) in dioxane was added and a white solid was formed. The residue was purified (silica gel column, eluting with DCM:MeOH mixtures from 100:0 to 90:10%) to obtain Intermediate 6 as a white solid.
Reaction SMILES: C(OC(=O)N[CH2:8][CH:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[N:10]1[CH3:26])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([N:12]2[C:13](=[O:14])[C:9](=[CH2:8])[N:10]([CH3:26])[C:11]2=[O:25])[CH:20]=[CH:19][C:18]=1[C:21]#[N:22]
Reactant: Cc1c(N2C(=O)C(CNC(=O)OC(C)(C)C)N(C)C2=O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C1C(=O)N(c2ccc(C#N)c(Cl)c2C)C(=O)N1C
Yield: 33.8 %

Procedure:
A solution of the N-Boc-protected amine 13B (300 mg, 0.763 mmol) in CH2Cl2 (3 mL) and TFA (3 mL) was stirred at rt for 1 h. The solution was then concentrated under reduced pressure and the residue azeotroped with a 1:1 solution of CH2Cl2/toluene (3×10 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/CH3OH, 100:0 to 80:20 gradient) to afford the title compound (71 mg) as a white solid. 1H NMR (DMSO-d6) δ 2.21 (s, 3H), 3.12 (s, 3H), 5.16 (d, J=2.2 Hz, 1H), 5.39 (d, J=2.2 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H); 13C NMR (DMSO-d6) δ 15.70, 26.73, 95.59, 113.18, 115.83, 128.79, 132.09, 136.03, 136.37, 136.54, 136.68, 151.88, 160.56; HPLC a) column: Phenominex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.70 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.59 min retention time (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:26](Br)[CH:27]=[CH2:28].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:28]([C@H:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:12]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:11]1=[O:25])[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O

Procedure:
To a solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one (1481 mg, 3957 μmol; Example 35, Step A) and allyl bromide (360 μl, 4155 μmol) in THF (16 mL, 0.25 M) was added dropwise lithium bis(trimethylsilyl) amide (1M solution in THF, 4352 μl, 4352 μmol) at −78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH:8]2[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([NH:27][C:28]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH:8]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=O
Reactant: COc1cccc2c1CCNC2c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: COc1cccc2c1CCN(C(=O)NC(C)(C)C)C2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 50 mL round-bottomed flask was added 5-methoxy-1-(4-(trifluoromethyl)-phenyl)-1,2,3,4-tetrahydroisoquinoline (44 mg, 143 μmol, from step 3), CH2Cl2 (2 mL), t-butylisocyanate (16 μL, 143 μmol, Aldrich). The solution was stirred at RT for 5 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give N-tert-butyl-5-methoxy-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide. MS (ESI pos. ion) m/z: 407 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[OH-].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCn1ncc2c(Cl)c(C(=O)O)cnc21
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A solution of Intermediate 1 (3.5 g) in dioxane (28 ml) was treated with potassium hydroxide (6.3 g) as a solution in water (20 ml). The mixture was stirred for 2 h, then concentrated in vacuo, acidified to pH 3 with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The layers were separated, the organic layer dried over sodium sulphate, then concentrated in vacuo to afford Intermediate 11 as a white solid (2.4 g). LCMS showed MH+=226; TRET=2.62 min.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].CO[CH:8](OC)[CH2:9][CH2:10][Si:11]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:13][O:12][Si:11]([O:16][CH3:17])([O:14][CH3:15])[CH2:10][CH2:9][CH:8]1[S:5][CH2:1][CH2:2][CH2:3][S:4]1
Reactant: COC(CC[Si](OC)(OC)OC)OC
Reactant: SCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CO[Si](CCC1SCCCS1)(OC)OC

Procedure:
The procedure and apparatus of Example 1 were used with 22.4 g (0.207 m) of propane-1,3-dithiol, 46.4 g (0.207 m) of (3,3-dimethoxypropyl)trimethoxysilane, 0.14 g of p-toluenesulfonic acid, and 100 ml of xylenes solvent. Methanol was removed by distillation as the contents of the flask were heated at reflux (143°) for 2 hours. The crude product, excluding solvent, contained 75% of the title product and 7.4% of the monosubstituted product, (MeO)3Si(CH2)2CH(OMe)S(CH2)3SH, as determined by GC/MS.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[CH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](=[O:43])[C:27]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=3)([CH3:32])[CH2:28][O:29]2)=[CH:24][CH:23]=1>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][C:26]1([OH:43])[C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:20][O:19][CH3:18])=[CH:23][CH:24]=2)[O:29][CH2:28][C:27]1([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:37][CH:38]=1)[CH3:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
4-(t-Butyldimethylsilyloxy)-1-butyne (1.17 g, 6.4 mmol) was dissolved in dry tetrahydrofuran (20 ml) under argon atmosphere, which was then cooled down to −78° C. n-Butyllithium (2.29 ml, 5.72 mmol, 2.5M solution in tetrahydrofuran) was slowly added dropwise thereto, and the mixture was stirred at −78° C. for 30 minutes. To this mixture was added dropwise 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-one (1.14 g, 3.18 mmol) dissolved in dry tetrahydrofuran (10 ml) at −78° C., and the resulting reaction mixture was stirred at room temperature for 3 hours, and the reaction mixture was cooled to 0° C. The reaction was quenched with water, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (1.6 g, yield 93%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[C:33]1([C@@H:39]2[CH2:41][C@H:40]2[C:42](Cl)=[O:43])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42]([C@H:40]4[CH2:41][C@@H:39]4[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:43])=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@H]1C[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.162 g, 0.371 mmol) in pyridine (2 mL) at 0° C. was treated with trans-2-phenyl-1-cyclopropylcarbonyl chloride (0.134 g, 0.742 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0° C., the ice bath was removed and the reaction mixture stirred at room temperature for 5 h. Additional trans-2-phenyl-1-cyclopropylcarbonyl chloride (0.034 g, 0.186 mmol) was added and the reaction mixture stirred for 1 h. The organic layer was removed under reduced pressure, and dichloromethane (15 mL) was then added. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel using 15% methanol in dichloromethane then 20% methanol in dichloromethane as eluent. The column afforded 0.150 g (70%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(1S,2S)-2-phenylcyclopropane-1-carboxamide. A hot solution of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(1S,2S)-2-phenylcyclopropane-1-carboxamide (0.147, 0.253 mmol) in ethyl acetate was treated with a hot solution of maleic acid (0.088 g, 0.759 mmol) in ethyl acetate. The precipitate formed was filtered under nitrogen and dried under high vacuum to give 0.204 g of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(1S,2S)-2-phenylcyclopropane-1-carboxamide tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 9.64 (s, 1H), 8.23-8.21 (m, 2H), 7.33-7.29 (m, 2H), 7.24-7.17 (m, 4H), 6.16 (s, 6H), 4.69-4.66 (m, 1H), 3.90 (s, 3H), 2.90-2.60 (m, 7H), 2.37-2.35 (m, 2H), 2.10-1.99 (m, 8H), 1.70-1.50 (m, 3H), 1.32 (m, 1H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.346 min (97%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][CH:15]=[C:14]([CH3:20])[C:13]=3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:28][CH3:29]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:20])[CH:15]=[N:16][C:17]=3[O:19][CH2:28][CH3:29])[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1C1C(C#N)=C(C)Nc2c(C)c[nH]c(=O)c21
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C#N)=C(C)N2
Temperature: 140 °C

Procedure:
3620 mg (10.83 mmol) of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonitrile are suspended in 150 ml (901 mmol) of anhydrous triethyl orthoformate. The reaction mixture is heated to 140° C. Then 10 drops of concentrated sulfuric acid are added each hour. After complete reaction has been detected (analytical HPLC; reaction time about 36 h), the reaction mixture is cooled to room temperature and the precipitated product is filtered off. The precipitate is washed with ethyl acetate and diethyl ether and then purified by flash chromatography (silica gel; mobile phase: initially dichloromethane, then isohexane/ethyl acetate 1:1). The product fractions are combined and concentrated in a rotary evaporator, and the residue is then crystallized from ethyl acetate. Drying under high vacuum results in 1160 mg (30% of theory) of the title compound in the form of yellowish crystals.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][C:9]1([CH3:23])[C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:20][CH3:21])[CH:16]=2)[NH:11][C:10]1=[O:22].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH3:8][C:9]1([CH3:23])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:20][CH3:21])[CH:16]=2)[NH:11][C:10]1=[O:22]
Reactant: CSc1ccc2c(c1)C(=O)C(C)(C)C(=O)N2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc2c(c1)CC(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylsilane (34.75 ml, 49.1 g, 0.042 mol) was added dropwise to a stirred solution of 3,3-dimethyl-6-methylthio-2,4(1H,3H)-quinolinedione (12.79 g, 0.054 mol) in trifluoroacetic acid (520 ml) under nitrogen at 60° C. The reaction was then allowed to cool slowly to room temperature and was stirred for 16 hr. The solvent was then evaporated in vacuo to afford a yellow residue. The residue was then poured into saturated potassium carbonate solution (200 ml). The product was extracted with ethyl acetate (3×150 ml) The organic extracts were combined, washed with water (200 ml), dried and concentrated in vacuo to afford 3,4-dihydro-3,3-dimethyl-6-methylthio-2(1H)-quinolinone as a yellow solid. Mp 154° C.