Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]=[C:11]([NH2:18])[CH:10]=1.CO[CH:21](OC)[CH2:22]Br.O1CCOCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([S:15][CH2:16][CH3:17])[N:12]2[CH:21]=[CH:22][N:18]=[C:11]2[CH:10]=1
Reactant: COC(CBr)OC
Reactant: CCSc1nc(N)cc(-c2ccc(Cl)cc2Cl)n1
Solvent: O
Solvent: C1COCCO1
Product: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12

Procedure:
48.5 g (161.55 mmol) of 6-(2,4-dichlorophenyl)-2-(ethylthio)pyrimidine-4-amine (Example 3A) and 163.84 g (969.32 mmol) of bromoacetaldehyde dimethyl acetal are introduced into a mixture of 1164 ml of dioxane and 291 ml of water and heated under reflux for 16 h. The dioxane is substantially removed in vacuo, and 1000 ml of ethyl acetate and 1000 ml of saturated aqueous sodium bicarbonate solution are cautiously added. The phases are separated and a further extraction with ethyl acetate is carried out. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and then freed of solvent. The residue is purified by silica gel chromatography. 16.6 g (27% of theory) of the product are obtained and are reacted further in this form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:59]=[CH:58][C:55](CO)=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][C:55]2[CH:58]=[CH:59][C:52]([F:51])=[CH:53][CH:54]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: OCc1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4ccc(F)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 73.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (82 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (111 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-fluorobenzyl alcohol (40 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 68%).
Reaction SMILES: C1(C2N=C([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:14])C=CC=2)C=CC=CC=1.[C:27]1([C:33]2[CH:37]=[C:36](C(O)=O)[NH:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([C:33]2[CH:37]=[C:36]([C:13]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:14])[NH:35][N:34]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(C(=O)c2cccc(-c3ccccc3)n2)cc(OC)c1OC
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]1
Product: COc1cc(C(=O)c2cc(-c3ccccc3)n[nH]2)cc(OC)c1OC

Procedure:
(3-Phenyl-1H-pyrazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1k) was prepared using the same method as used of compound 1c from 3-phenyl-1H-pyrazole-5-carboxylic acid. 1H NMR (500 MHz, CDCl3 δ 10.97 (br, 1H), 7.77 (s, br, 2H), 7.48-7.38 (m, 5H), 7.14 (s, br, 1H), 3.96 (s, 3H), 3.94 (s, 6H); MS (ESI) m/z 361.1 (M+Na)+, 337.0 (M−H)−.
Reaction SMILES: C(OC([N:6]=[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][CH:29]([CH3:31])[CH3:30])=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:32][CH3:33])[CH:11]=1)([CH3:9])=[O:8])=O)C.C(O)C.[O-]CC.[Na+]>ClCCl.CO>[CH:29]([NH:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([O:17][CH2:16][C:12]3[CH:11]=[C:10]([S:7]([CH3:9])(=[NH:6])=[O:8])[CH:15]=[CH:14][CH:13]=3)=[C:19]([O:32][CH3:33])[CH:20]=2)[N:25]=[CH:24][N:23]=1)([CH3:30])[CH3:31]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2c(NC(C)C)ncnc2cc1OCc1cccc(S(C)(=N)=O)c1
Temperature: 80 °C
Yield: 36 %

Procedure:
(RS)-N-(Ethoxycarbonyl)-S-[3-({[4-(isopropylamino)-6-methoxyquinazolin-7-yl]oxy}-methyl)phenyl]-S-methylsulphoximide (105 mg, 0.22 mmol) is introduced into 2.5 ml of ethanol. 1.0 ml of a 1-molar ethanolic sodium ethoxide solution is added and the mixture is heated to 80° C., until starting material is no longer present according to TLC checking (eluent dichloromethane/methanol 10:1). The reaction solution is concentrated in vacuo, and the residue is taken up in ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is dried over sodium sulphate and concentrated. The crude product is purified by preparative HPLC and the desired product is obtained in 36% yield (32 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[C:32]([Cl:34])[CH:33]=1>CO.C(Cl)Cl>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[O:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[O:19])=[CH:16][CH:17]=3)=[CH:4][C:3]1=2
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Reactant: Oc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(Oc3cc(Cl)cc(Cl)c3)CCN4)cc2)CC1
Yield: 82 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (20 mg) was reacted with 3,5-dichlorophenol (27.7 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (82% yield). LCMS: m/z=497.12 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.02-2.13 (m, 1H), 2.24-2.35 (m, 1H), 2.33 (s, 3H), 2.35-2.60 (m, 4H), 3.40-3.66 (m, 4H), 3.70-3.92 (m, 2H), 5.30 (bs, 1H), 5.37 (t, J=3.3 Hz, 1H), 6.93 (d, J=1.6 Hz, 2H), 7.02 (dd, J=1.6 and 1.6 Hz, 1H), 7.44-7.51 (m, 4H), 7.60 (d, J=2.1 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H).
Reaction SMILES: [BrH:1].C([N:9]1[CH2:14][C@@H:13]([CH2:15][OH:16])[C@H:12]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C@@H:11]([OH:24])[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[BrH:1].[OH:16][CH2:15][C@@H:13]1[CH2:14][NH:9][CH2:10][C@H:11]([OH:24])[C@H:12]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1
Reactant: OC[C@@H]1CN(Cc2ccccc2)C[C@H](O)[C@H]1c1ccc(O)cc1
Agent: [Pd]
Agent: Br
Solvent: CO
Product: OC[C@@H]1CNC[C@H](O)[C@H]1c1ccc(O)cc1
Yield: 89.1 %

Procedure:
The solution of 18.6 g (47.2 mmol) of crude (3R,4R,5S)-1-benzyl-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrobromide in 250 ml of methanol was flushed with argon, treated with 1.5 g of palladium-on-charcoal (10%) and exhaustively hydrogenated at room temperature under normal pressure during 18 hours. The reaction mixture was filtered over Dicalit and the residue washed twice with 100 ml of warm methanol. The methanol solutions were combined and evaporated under reduced pressure to yield 12.79 g of (3R,4R,5S)-5-hydroxymethyl-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrobromide [MS: 223 (M)+] as a yellowish foam which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][NH2:21])=[O:19]>CCOCCO>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][N:21]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([OH:1])[CH3:11])=[O:19]
Reactant: CC(O)C(=O)c1ccccc1
Reactant: NNC(=O)c1ccccn1
Solvent: CCOCCO
Product: CC(O)C(=NNC(=O)c1ccccn1)c1ccccc1
Reaction time: 2 h
Yield: 46.7 %

Procedure:
21.5 g of 2-hydroxypropiophenone and 20.6 g of picolinic acid hydrazide are stirred in 250 ml of ethyl cellosolve for 18 hours at 110° C. and then for 2 hours at room temperature. The light yellow solution is concentrated on a rotary evaporator to approx. 50% of its volume. The yellow crystals which have precipitated are isolated by filtration and washed with isopropanol and then with water. After the crystals have been dried under vacuum at 50° C., 18 g of 2-hydroxypropiophenone picolinoylhydrazone are obtained which gives the following microanalysis:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[CH3:21][C:22]([CH3:24])=[O:23]>>[CH2:10]([O:9][CH:8]([O:12][CH2:13][CH3:14])[C:5]1[CH:6]=[CH:7][C:2]([C:22]([OH:23])([CH3:24])[CH3:21])=[CH:3][C:4]=1[F:15])[CH3:11]
Reactant: CCOC(OCC)c1ccc(Br)cc1F
Reactant: CC(C)=O
Agent: [Li]CCCC
Product: CCOC(OCC)c1ccc(C(C)(C)O)cc1F

Procedure:
The title compound was prepared as described in Example 15, Step 3 using 4-bromo-1-(diethoxymethyl)-2-fluorobenzene (2.8 g, 0.01 mol), n-BuLi (4.8 mL of 2.5M, 0.012 mol), and acetone (0.96 mL, 0.013 mol) as starting materials. 1H NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 7.47 (d, 1H), 7.26 (s, 1H), 7.28 (d, 1H), 5.74 (s, 1H), 3.62 (s, 2H), 3.47-3.52 (m, 2H), 1.48 (s, 6H), 1.16 (t, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[C:19]1([S:16]([NH:15][C:10]2[CH:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][C:30]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[O:31])=[N:6][C:5]=3[CH3:7])[CH:13]=[N:12][C:11]=2[Cl:14])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1
Reactant: O=C(Cl)c1ccco1
Product: Cc1nc(NC(=O)c2ccco2)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1

Procedure:
Using an analogous method to that described in Example 51, N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]benzenesulfonamide was reacted with 2-furoyl chloride. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 8.0 minutes); 1H NMR Spectrum: (DMSOd6+D2O) 8.57 (1H, d); 8.27 (1H, d); 8.05 (2H, d); 7.83 (1H, t); 7.76 (1H, d); 7.69 (2H, t); 6.75 (1H, d); 6.55 (1H, dd); 2.25 (3H, s); Mass Spectrum: M+H+ 475.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.S(Cl)([Cl:16])=O.Cl.[CH:19]([NH:22][OH:23])([CH3:21])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:16])=[O:8])=[C:4]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[Cl:1][C:2]1[S:6][C:5]([C:7]([N:22]([OH:23])[CH:19]([CH3:21])[CH3:20])=[O:9])=[C:4]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1
Reactant: C[Si](C)(C)c1cc(Cl)sc1C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CC(C)NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)N(O)C(=O)c1sc(Cl)cc1[Si](C)(C)C
Product: C[Si](C)(C)c1cc(Cl)sc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Chloro-3-(trimethylsilyl)-2-thiophenecarboxylic acid chloride was prepared by the reaction of 1 g 5-chloro-3-(trimethylsilyl)-2-thiophenecarboxylic acid (prepared as in Example 263) and 6 mL thionyl chloride, using the procedure of step a in Example 248. This product was dissolved in CH2Cl2 at 0° C. and added to a mixture of N-isopropylhydroxylamine hydrochloride (0.55 g, 5 mmol) and 4 g NaHCO3 in 20 mL CH2Cl2 and 20 mL water. The resulting reaction mixture was stirred at RT for additional 3 h. The organic layer was separated, washed with brine, dried and concentrated. The residue was purified by flash chromatography with 8% ethyl acetate/hexane to give 80 mg of the title compound. m.p. 146-150° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:11].[NH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([OH:24])[C:19]=2[OH:23])[C:14]1=[O:25]>C(O)C.[Pd]>[BrH:11].[C:1]1([CH2:7][CH2:8][CH2:9][NH:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:24])[C:19]=3[OH:23])[C:14]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Reactant: O=CCCc1ccccc1
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: O=C1c2ccc(O)c(O)c2CCC1NCCCc1ccccc1

Procedure:
In 300 volume parts of ethanol is dissolved 5 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide and, after the addition of 50 parts of β-phenylpropionaldehyde, catalytic reduction is carried out at ordinary temperature and pressure using palladium-on-carbon as a catalyst. When a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The procedure yields 3.5 parts of 2-(3-phenylpropyl)amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide as colorless crystals melting at 215°-217° C.
Reaction SMILES: [CH2:1]([N:3]1[C@@H:11]2[C:6]3=[C:7]([CH:20]=[C:21]([CH3:23])[CH:22]=[C:5]3[C@H:4]1[CH2:24][CH2:25][CH3:26])[C:8]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH2:10]2)[CH3:2].CCOCC>CC(C)=O>[CH2:1]([N:3]1[C@H:11]2[C:6]3=[C:7]([CH:20]=[C:21]([CH3:23])[CH:22]=[C:5]3[C@@H:4]1[CH2:24][CH2:25][CH3:26])[C:8]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[CH2:10]2)[CH3:2]
Reactant: CCC[C@@H]1c2cc(C)cc3c2[C@H](Cc2ccc(OC)c(OC)c2-3)N1CC
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCC[C@H]1c2cc(C)cc3c2[C@@H](Cc2ccc(OC)c(OC)c2-3)N1CC

Procedure:
74.3 g (211 mM) of (±)-(4R*,5aS*)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-2-methyl-4-n-propyl-dibenz[cd,f]indole are dissolved in 600 ml acetone and a solution of 81.67 g (211 mM) of (-)-di-O,O'-p-toluoyl-L-tartaric acid monohydrate in 300 ml acetone is added with stirring. The mixture is further stirred for one hour at room temperature, a total of 1 liter ether being added in portions during this period. The resultant precipitate is filtered off, washed with ethyl acetate until it remains light yellow, and dried.
Reaction SMILES: [Na].[F:2][C:3]([F:14])([F:13])[C:4]1[CH:8]=[C:7]([NH:9][C:10](=O)C)[O:6][N:5]=1.C1C=CC=CC=1.S(OC)(OC)(=O)=O>CO>[F:14][C:3]([F:2])([F:13])[C:4]1[CH:8]=[C:7]([NH:9][CH3:10])[O:6][N:5]=1
Reactant: CC(=O)Nc1cc(C(F)(F)F)no1
Agent: [Na]
Solvent: c1ccccc1
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: CNc1cc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium metal (0.28 g, 12.3 mmole) was dissolved in dry methanol (12.3 ml) and to this solution was added 3-trifluoromethyl-5-acetylaminoisoxazole (2.38 g, 12.26 mmole). After stirring at room temperature for 15 minutes, the mixture was concentrated in vacuo and dry benzene (12.3 ml) was added to the residue. The mixture was concentrated in vacuo and dry benzene (18.4 ml) and dimethyl sulfate (1.55 g, 12.3 mmole) were added to the residue, followed by refluxing for 2 hours. After cooling, the precipitated crystals were filtered off. The filtrate was washed with a 8% solution of sodium bicarbonate and concentrated in vacuo. A 5% solution of sodium hydroxide (11.8 g) was added to the residue and the mixture was sitrred at room temperature for 2 hours. It was extracted with methylene chloride and the methylene chloride layer was dried with anhydrous sodium sulfate. The extract was concentrated in vacuo and the resulting residue was recrystallized from cyclohexane to give the title compound as colorless columns. Yield: 1.41 g (65.4%). m.p. 48.5°-50.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CS(O[C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]1)(=O)=O>CN(C=O)C>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([C@H:35]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34]3)[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:18]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reactant: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc([N+](=O)[O-])cc3)c3c(N)ncnc32)C1
Reaction time: 6 h
Yield: 51.8 %

Procedure:
A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.62 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 6 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford (S)-tert-butyl 3-(4-amino-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.43 g, 52% yield). ESI-MS m/z [M+H]+ found 426.7, calculated 426.2.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[O:27][CH3:28])[N:9]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:6][O:7][C:8]1[C:13]([NH:14][C:1](=[O:4])[CH2:2][CH3:3])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:18][C:17]=2[O:27][CH3:28])[N:9]=1
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c(N)cc1C
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Reaction time: 3 h

Procedure:
Propionyl chloride (0.058 ml, 0.67 mmol) is added to a solution of 2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-ylamine (0.2 g, 0.61 mmol) and diisopropylethylamine (0.13 ml, 0.73 mmol) in CH2Cl2 (1.5 ml) at room temperature. The mixture is kept at room temperature for 3 hours, and is then diluted with EtOAc The mixture is washed with 1N NaOH and brine. After drying over Na2SO4, the solvent is removed under reduced pressure and the residue is purified by flash column chromatography (hexane/EtOAc=4:1) to give the N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propionamide. Rf (hexane/EtOAc=4:1)=0.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)C1C=CC=CC=1.[C:17](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])OC(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)C.[Pd]>[C:17]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:28]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 1-benzyl-3,3-dimethylpiperidin-4-one (0.217 g, 1.00 mmol, 1.0 eq) in ethyl acetate-ethanol (1:1, 10 mL) was added palladium on carbon (approximately 0.100 g). The reaction was purged with nitrogen followed by hydrogen and stirred under an atmosphere of hydrogen for 1 hour. The reaction was purged with nitrogen and di-tert-butyl carbonate (0.327 g, 1.50 mmol, 1.5 eq) and sodium carbonate (0.212 g, 2.00 mmol, 2.0 eq) were added. The solution was stirred at room temperature for 1.5 hours and the reaction filtered through Celite®, eluting with EtOAc (4×20 mL). The filtrate was concentrated under reduced pressure. MPLC (15→50% EtOAc-hexane) yielded the title compound (0.206 g, 91%) as a white solid; 1H nmr (CDCl3) δ 3.69 (2H, dd, J 6.5, 6.0 Hz, pipH-6), 3.40 (2H, s, pipH-2), 2.46 (2H, t, J 6.5 Hz, pipH-5), 1.46 (9H, s, C(CH3)3), 1.08 (6H, s, 2×CH3); 13C nmr (CDCl3) δ 177.2, 154.7, 80.1, 54.9, 46.5, 43.4, 37.6, 28.3, 22.4; m/z 172 [M+H—C4H8]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.O1CCCC1>C(N(CC)CC)C>[C:4]([NH:6][C:7](=[S:8])[O:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: OCc1ccc(Cl)cc1
Reactant: CCOC(=O)N=C=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=S)OCc1ccc(Cl)cc1
Yield: 58.2 %

Procedure:
90 g of ethoxycarbonyl isothiocyanate were added dropwise to a mixture of 85 g of p-chlorobenzyl alcohol, 600 ml of tetrahydrofuran and 4 ml of triethylamine and the mixture was refluxed for 24 hours and was then evaporated to dryness under reduced pressure. The residue was added to isopropyl alcohol and the precipitate formed was recovered by vacuum filtration to obtain 95 g of p-chlorobenzyl N-carbethoxy-thiocarbamate melting at 95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].[OH:29][CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:20]([N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][OH:29])[CH2:32][CH2:33]3)=[O:21])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: OCC1CCNCC1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)N3CCC(CO)CC3)nc12

Procedure:
Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine, phenyl chloroformate and 4-hydroxymethyl-piperidine, the title compound was prepared as white crystals (87% yield). Mp. 202-203.5° C., MS: m/e=406(M+H+).
Reaction SMILES: F[C:2](F)(F)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].O.Cl.NO.[C:17]([O-:20])(O)=O.[Na+].[C:22]1(C)[CH:27]=CC=C[CH:23]=1>C(O)C>[CH2:23]([C:2]1[C:17]([OH:20])=[C:9]([CH2:8][CH2:7][CH3:6])[CH:10]=[CH:5][C:3]=1[OH:4])[CH2:22][CH3:27]
Reactant: Cc1ccccc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1ccc(O)c(CCC)c1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
The crude solid trifluoroacetophenone from Step 1 (11.54 kg) is dissolved in 48 L of ethanol and is charged into a 100 L round-bottom flask. Water (8L) is then added. Hydroxylamine hydrochloride (NH2OH.HCl, 11.05 kg) is added to the stirred mixture, followed by the addition of NaHCO3 (13.36 kg). The heterogeneous solution is stirred at 60° C. overnight. The reaction is complete within 24 hours by LC assay. Work-up consists of the addition of 40L of water and 25L of toluene, followed by transfer to an extractor. The flask is rinsed with an additional 25L of toluene, which is also transferred to the extractor. The layers are separated, and the organic layer is extracted with one washing of 60L of 1N NaOH. The layers are separated, and the NaOH layer is neutralized with 12N HCL to pH=6.1. The aqueous layer is then extracted with 60L of toluene. The layers are separated and the aqueous layer is extracted a second time with toluene. The combined organic layers are washed with 4L of water. The organic layer is concentrated to a crude solid which can be used in the next step without further purification. Alternatively, the product can be crystallized from a toluene/heptane mixture. The product is predominantly the E oxime (shown in the equation above) rather than the Z oxime and is obtained in 85% yield from 2,4-dipropylresorcinol.