Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:6][C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:6]/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(C2CCOCC2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(C2CCOCC2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-one (310 mg, 1. mmol) in anhydrous DCM (7.8 mL) was added TiCl4 (1 M solution in DCM, 2 mL, 2 mmol) dropwise within 15 minutes at room temperature. The reaction mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (0.41 g, 0.49 mL, 2.2 mmol) dropwise. The resulting mixture was stirred for 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide (240 mg, 78%), which was used in next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1)([OH:3])=O.[CH2:16]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CC(C)([O-])C.[K+].N1C=CC=CC=1C(OC)=O.[OH-].[Na+]>>[CH2:16]([S:26]([NH:29][C:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)=[O:3])(=[O:27])=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1ncc(C(=O)O)cc1OC
Reactant: CCCCCCCCCCS(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: COC(=O)c1ccccn1
Agent: [K+]
Product: CCCCCCCCCCS(=O)(=O)NC(=O)c1cnc(C(=O)O)c(OC)c1

Procedure:
2.1 g (10 mmol) of methyl 5-carboxy-3-methoxypyridine-2-carboxylate (cf. Example 1d)) were reacted with N,N'-carbonyldiimidazole and 1-decylsulfonamide/potassium tert-butoxide in an analogous manner to that described in Example 1e) and the methyl pyridine-2-carboxylate thus obtained was hydrolyzed with 1N methanolic sodium hydroxide solution. After the aqueous solution had been acidified with cooling, 1.4 g of product were obtained, m.p. 145° C. (with dec.).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:38]=[CH:37][C:20]([O:21][C:22]2[C:27]([C@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34](=[O:36])[CH3:35])[CH2:29]3)=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:19][CH:18]=1>C(Cl)Cl>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]1[CH:38]=[CH:37][C:20]([O:21][C:22]2[C:27]([C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34](=[O:36])[CH3:35])[CH2:29]3)=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:19][CH:18]=1
Reactant: CC(=O)N1CCC[C@H](c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCC[C@@H](c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Yield: 100 %

Procedure:
To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (109 mg, 0.450 mmol), NMP (2 mL) and 1-(3-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone (50 mg, 0.225 mmol) was added cesium carbonate (147 mg, 0.450 mmol). The reaction mixture was stirred and heated in a Biotage Initiator at 160° C. for 60 minutes. LC-MS shows complete conversion. The reaction was filtered through a Acrodisc syringe filter 0.2 mm ultipor nylon membrane. The filtrate was purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column (5 micron, C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with an linear gradient of 10% to 80% MeCN (0.1% TFA) in water (0.1% TFA) over 20 minutes to give the product as a TFA salt. The desired fractions were poured into 10% Na2CO3 (aq)/DCM, and the DCM layer separated, dried over MgSO4, and concentrated in vacuo to give a mixture of (S)-1-(3-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)piperidin-1-yl)ethanone (13.5 mg, 0.030 mmol, 27.0% yield) and (R)-1-(3-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)piperidin-1-yl)ethanone (13.5 mg, 0.030 mmol) as a off white solid. MS (ESI, pos. ion) m/z: 445.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Yield: 33.4 %

Procedure:
A mixture of 10 g (0.06 mol) of 3,5-dihydroxybenzoic acid methyl ester, 16.2 ml (0.06 mol) of 1-bromotetradecane and 8.2 g (0.06 mol) of potassium carbonate in 200 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 24 hours, After the usual workup, the crude product was triturated with hot methylene chloride and filtered. The filtrate was concentrated at reduced pressure and the solid residue was recrystallized from methylene chloride-methanol to give the 3,5-dialkylated product. The filtrate was concentrated and the residue was purified by HPLC using 15% ethyl acetatehexane to give 7.3 g (34% yield, mp 92°-94°) of 3-hydroxy-5-(tetradecyloxy)benzoic acid methyl ester. The nmr spectra was consistent with the structure.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])C=C.CN(C)[C:17]1[CH:22]=CC=C[CH:18]=1>>[CH2:22]([C:12]1[C:5]([OH:4])=[C:6]([CH:9]=[CH:10][C:11]=1[O:13][CH3:14])[CH:7]=[O:8])[CH:17]=[CH2:18]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(OC)ccc1C=O
Product: C=CCc1c(OC)ccc(C=O)c1O

Procedure:
Heat a solution of 125 g of the product obtained in Step A in 300 ml of N,N-dimethylaniline at 200° C. for 15 hours. Then evaporate off the solvent in vacuo and take up the residue in 1 liter of isopropyl ether; extract the solution 10 times using 100 ml of 1N sodium hydroxide solution each time and then acidify the combined extracts using 3N hydrochloric acid. Then extract the aqueous acid solution with dichloromethane, and dry and concentrate the organic phase.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([Br:19])[CH:21]=3)[CH:26]=2)(=[O:31])=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a mixture of 1-tert-butoxycarbonylpiperazine (1.25 g), sodium hydrogen carbonate solution (10 ml) and ethyl acetate (10 ml), was added 6-bromonaphthalene-2-sulfonylchloride (2.05 g), and the mixture was stirred at room temperature for 1 hour and extracted with dichloromethane. The extract was washed with water, dried and concentrated. The residue was crystallized with diisopropylether to give 1-(tert-butoxycarbonyl)-4-(6-bromonaphthalene-2-sulfonyl)piperazine as colorless crystals (2.83 g).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH:10]2[CH2:15][C:14](=O)[CH2:13][CH:12]([C:17]3[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[OH-].[K+].O.NN.C(Cl)Cl>C(O)COCCO>[CH:1]([C:4]1[C:5]([C@H:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([C:17]3[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccnc1C1CC(=O)CC(c2ncccc2C(C)C)N1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: OCCOCCO
Solvent: O
Product: CC(C)c1cccnc1[C@@H]1CCC[C@H](c2ncccc2C(C)C)N1
Temperature: 100 °C
Yield: 98.5 %

Procedure:
To a solution of 3,3″-diisopropyl-2′,3′,5′,6′-tetrahydro-1′H-[2,2′;6′,2″]terpyridin-4′-one (106 mg, 0.314 mmol) in diethylene glycol (3 mL) were added KOH (352 mg, 6.29 mmol) and hydrazine monohydrate (0.61 mL, 12.6 mmol). The reaction mixture was heated to ˜100° C. for 1 h using a sand bath. After 1 h the temperature was raised to 200° C. for about 45 minutes. CH2Cl2 (50 mL) was added to the remaining mixture and was washed with water (3 times 50 mL). The organic layer was dried (MgSO4), filtered and concentrated to provide 100 mg (99%) of 3,3″-diisopropyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (with some DEG). 1H NMR(CDCl3) δ 1.25 (d, 6H, J=9.3 Hz), 1.57-1.65 (m, 2H), 1.68-1.89 (m, 3H), 2.10-2.14 (m, 1H), 3.19-3.30 (m, 3H), 4.33 (br s, 1H), 7.10 (dd, 2H, J=7.8, 4.5 Hz), 7.53 (d, 2H, J=7.8 Hz), 8.46 (d, 2H, J=4.5 Hz).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]3)[N:11]=2)=[CH:2]1.CI.[C:26]([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:26][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]3[CH2:18][CH2:19][C@H:20]([OH:23])[CH2:21][CH2:22]3)[N:11]=2)=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: O[C@H]1CC[C@H](Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccnc(N[C@H]3CC[C@H](O)CC3)n2)c2cccnc21
Temperature: 50 °C

Procedure:
To a flask was added compound 18 (17 mg), methyl iodide (7.8 mg), K2CO3 (10 mg), and DMF (1 mL). The mixture was heated to 50° C. for 2 hrs, then poured into water and extracted with EtOAc. The organic layer was separated, dried with MgSO4, then concentrated and the residue was purified by flash chromatography [DCM:MeOH/9.5:0.5] to afford 14 mg (82%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.70 (d, 1 H), 8.40 (d, 1 H), 8.20 (d, 1 H), 7.85 (s, 1 H), 7.20 (dd, 1 H), 6.80 (d, 1 H), 5.00 (m, 1 H), 4.30 (m, 1 H), 3.96 (s, 3 H), 3.70 (m, 1 H), 2.30 (m, 2 H), 2.10 (m, 2 H), 1.70 (br s, 1 H), 1.50 (m, 2 H), 1.35 (m, 2 H). MS (ESI) m/I: 324 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16](=O)[C:15]2(C2C=CC(F)=CC=2)[CH2:27]O)=[CH:10][CH:9]=1.[OH2:36].[OH-].[Na+]>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)([CH:15]2[CH2:27][CH2:18][N:17]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16]2)[OH:36])=[CH:10][CH:9]=1
Reactant: O=C1N(Cc2ccccc2)CC(c2ccc(F)cc2)C1(CO)c1ccc(F)cc1
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred slurry of 7.6 g (0.02 mole) of lithium aluminum hydride in 150 ml of freshly distilled tetrahydrofuran was added dropwise, over a 45 min period, a solution of 38.5 g (0.098 mole) of 4-[bis(4-fluorophenyl)hydroxymethyl-1-(phenylmethyl)-2-pyrrolidinone in 150 ml of tetrahydrofuran. After the addition was complete, the mixture was heated at reflux for 2 hr and then let stir at ambient temperature overnight. The excess lithium aluminum hydride was decomposed by the successive addition of 8 ml of water, 8 ml of a 15% sodium hydroxide solution, and 24 ml of water. The mixture was stirred for 30 min and filtered. The filtrate was concentrated under reduced pressure and the residue crystallized when triturated with petroleum ether (30°-60° C.). The solid was collected by filtration and recrystallized from 2-propanol to yield 30.3 g (81%) of the title compound as a white solid, mp 99°-100° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CN.CC([O-])=O.[K+].[CH3:18][N:19](C=O)C>O.[Cu]I>[CH3:18][NH:19][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: CN
Solvent: O
Product: CNc1ccc(C(C)C)cc1
Temperature: 100 °C
Yield: 34 %

Procedure:
A mixture of 1-bromo-4-isopropylbenzene (1.0 g, 5.03 mmol), methylamine (25 mL, 50.0 mmol), CuI (1.15 g, 6.0 mmol), KOAc (1.24 g, 12.6 mmol) and DMF (30 mL) in a sealed tube under N2 was heated to 100° C. overnight. The mixture was cooled to r.t., diluted with water (100 mL), and extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated, and purified by silica gel chromatography (PE:EtOAc=10:1) to give 254 mg (34%) of the title compound as a yellow oil. [M+H] Calc'd for C10H15N, 150. Found, 150.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[Cl:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[Cl:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(C)cc(Cl)c2[nH]1
Product: CCOC(=O)c1cc2cc(C)cc(Cl)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 7-chloro-5-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25].O>CC(C)=O>[CH2:17]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:16]
Reactant: CCOCCOCCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCOCCOCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Yield: 87.3 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 3-[(2-ethoxy)ethoxy]-1-propylamine (4.41 g, 0.030 mol) was heated at 140° C. for 5 hours. The reaction mixture was dissolved in acetone (20 mL) and the solution poured into water (120 mL). The solid that formed was collected by filtration and dried under ambient conditions to give 3.0 g (87%) of material. Recrystallization from isooctane gave 2.45 g of the product; mp 65°-66° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[N:23]=[C:22]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl>C(OCC)(=O)C>[ClH:31].[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:15]=2)[CH2:21][C:22]([C:32]([F:38])([F:37])[C:33]([F:35])([F:36])[F:34])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(N3CCNCC3)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 223.9 %

Procedure:
5-[3-(4-BOC-piperazin-1-yl)-phenyl]-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (600.0 mg, 1.1 mmol) prepared in Example 119 was added to a saturated solution of hydrochloric acid in ethyl acetate (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give 610.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([CH2:24][OH:25])[CH:17]=3)[CH:11]=[CH:12][CH:13]=2)OCC[O:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CC(C)=O>[OH:25][CH2:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:10]2[CH:9]=[C:8]([C:3](=[O:4])[CH2:1][CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][OH:23]
Reactant: CCC1(c2cccc(CCc3ccc(CO)c(CO)c3)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)c1cccc(CCc2ccc(CO)c(CO)c2)c1
Reaction time: 5 h

Procedure:
6.4 g (18.7 mmol) of (4-{2-[3-(2-ethyl-[1,3]dioxolan-2-yl)phenyl]ethyl}2-hydroxymethyl-phenyl)methanol are dissolved in a mixture of 40 ml of water and 40 ml of acetone. 650 mg of paratoluene-sulfonic acid are added, and the medium is stirred for 5 hours. After the usual treatment, the desired product is pure without purification, and obtained in the form of colorless oil (m=5.57 g; Y=100%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=[N:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1OCCCN1CCOCC1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCCc1ccccc1)c1ccccc1OCCCN1CCOCC1
Yield: 76.5 %

Procedure:
2-[3-(4-Morpholinyl)propoxy]benzaldehyde (31.7g) is reacted with 15.8g of phenethylamine in 130 ml of toluene following the procedure described in Example 1A to yield 34.3g of product as an oil, boiling point 215°-219° C at 0.2-0.3 mm of Hg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([CH2:11][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7]2)[CH2:2]1.S(O[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:26][CH:25]=1)(=O)(=O)C.C(=O)(O)[O-].[Na+].[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>C(O)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[CH3:34][S:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][N:1]2[CH2:6][CH2:5][CH2:4][C:3]3([CH2:11][C:10](=[O:12])[C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[O:7]3)[CH2:2]2)=[CH:25][CH:26]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reactant: O=C1CC2(CCCNC2)Oc2ccccc21
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(CCN2CCCC3(CC(=O)c4ccccc4O3)C2)cc1
Temperature: 25 °C

Procedure:
A solution of 560 mg (258 mmole) of 3,4-dihydrospiro-[(2H)-1-benzopyran-2,3'-piperidine]4-one in 20 mL ethanol was treated with 880 mg (3 mmoles) of 2-(4-methanesulfonamidophenyl)ethyl mesylate and 0.5 g sodium bicarbonate and heated to reflux for 48 hours. The reaction was cooled to room temperature, poured into saturated sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was treated with 1 eq. oxalic acid and the salt was recrystallized from acetone to give product with mp=204°-210° C. Elemental analysis for C22H26N2O4S·C2H2O4 · 1/2H2O Calcd: N, 5.45; C, 56.12; H, 5.69. Found: N, 5.52; C, 56.35; H, 5.54.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH:26](O)[CH2:27][CH:28]=[CH2:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH:28]=[CH2:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)c1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCc1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Reaction time: 1.25 h
Yield: 99.1 %

Procedure:
1-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)but-3-en-1-ol (3.7 g, 9.4 mmol) was dissolved into 10 mL CH2Cl2 and treated with Et3SiH (12 mL, 94.4 mmol.). To this clear, colorless solution was added trifluoroacetic acid (TFA) (10.5 mL, 142 mmol) neat over 3 minutes which darkened the solution and exothermed. The reaction vessel was placed in a room temperature water bath and let stir for 1.25 h. The reaction was concentrated to yellow oil via rotary evaporation and the residue dissolved in 100 mL methyl t-butyl ether (MTBE). To this was added 50 mL 2.5 M K2CO3, the layers separated and the aqueous phase extracted 3×50 mL MTBE. The combined organics were washed with 50 mL saturated aqueous NaCl, dried over Na2SO4 and concentrated to give 1-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-3-butene, (3.6 g) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ=7.51 (d, 4H), 7.44-7.35 (m, 6H), 5.90 (m, 1H), 5.06 (d, 1H), 4.97 (d, 1H), 4.78 (s, 2H), 4.74 (s, 2H), 2.74 (m, 2H), 2.27-2.24 (m, 9H) ppm.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[C:32](Cl)(=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O.O1CCOCC1>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([C:32](=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:22][CH2:21]4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Clc1cccc(Nc2ncnc3[nH]nc(N4CCNCC4)c23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCC(=O)N1CCN(c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)CC1

Procedure:
Analogously to Example 26, 100 mg (0.248 mmol) of 4-(3-chloro-phenylamino)-3-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrmidine dihydrochloride and 103 mg (0.74 mmol) of potassium carbonate in 10 ml of water are reacted with 81.5 mg (0.37 mmol) of lauric acid chloride in 10 ml of dioxane and extracted. Column chromatography (SiO2; methylene chloride/ethyl acetate/acetic acid=50:50:1) yields 4-(3-chloro-phenylamino)-3-(4-[n-dodecanoyl]-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=22.6; FAB-MS: (M+H)+=512.