Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH:16]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:17][C:18]#[N:19]>C(O)(=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=3)[CH2:17][C:18]#[N:19])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1cc(C(CC#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 56 %

Procedure:
A stirred suspension of 3-nitrophthalic anhydride (0.24 g, 1.13 mmol) and 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanenitrile (0.25 g, 1.13 mmol) in 6 mL of acetic acid was heated to reflux under nitrogen for 12 hours. The acetic acid was removed in vacuo to afford an orange gum which was dissolved in methylene chloride (10 mL) and was washed with a saturated aqueous solution of sodium bicarbonate (2×10 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) and the resulting solid was dried in vacuo (60° C., <1 mm) to afford 0.25 g (56%) of 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile as a yellow solid: mp 155.5°-157° C.; 1H NMR (CDCl3) δ8.20-8.09 (m, 2H), 8.02-7.86 (m, 1H), 7.15-7.02 (m, 2H), 6.88-6.76 (m, 1H), 5.64 (dd, J=6.3, 10.6 Hz, 1H), 4.09 (q, J=7 Hz, 2H), 3.85 (s, 3H), 3.84 (dd, J=10.6, 16.7 Hz, 1H), 3.26 (dd, J=6.3, 16.7 Hz, 1H), 1.46 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ165.3, 162.3, 150.1,148.7, 144.9, 135.7, 133.5, 129.0, 128.1,127.4, 123.2, 120.3, 116.6, 112.1, 111.5, 64.6, 55.9, 51.9, 20.9, 14.7; Anal. calcd for C20H17 N3O6. Theoretical: C, 60.76; H, 4.33; N, 10.63. Found: C, 60.59; H, 4.22; N, 10.65.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:17]2[C:16](=O)[CH2:15][C@@:14]2([CH3:23])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1.Cl.[NH2:25][OH:26].[OH-].[Na+]>O>[OH:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:17]2[C:16](=[N:25][OH:26])[CH2:15][C@@:14]2([CH3:23])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1
Reactant: NO
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=NO)C[C@]12C
Reaction time: 6 h

Procedure:
A solution of (Z)-3α-hydroxy-5α-pregn-17(20)-en-11-one (10.264 g) in warm industrial methylated spirits (320 ml) was heated with hydroxylamine hydrochloride (3.25 g) and sodium hydroxide (5.123 g) in water (10 ml). The mixture was refluxed for 41 hours and, after addition of more hydroxylamine hydrochloride (15.35 g) in water (20 ml) and sodium hydroxide (25.04 g) in water (50 ml) refluxing was continued for a further 6 hours. The mixture was then poured into water and the crystalline material (10.419 g) collected by filtration. Crystallisation of a portion from aqueous ethanol afforded an analytical sample of title compound m.p. 233°-235°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:5]([C:7](=[CH2:11])C(O)=O)=[O:6].[NH2:16][C:17]1[C:18]([CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=1[CH3:23].O=P(Cl)(Cl)Cl.C(N(CC)CC)C.[O:37]1CCC[CH2:38]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:5]([CH:7]=[CH:11][C:38]([NH:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[O:37])=[O:6]
Reactant: C1CCOC1
Reactant: Cc1cccc(C)c1N
Reactant: C=C(C(=O)O)C(=O)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc(C)c1NC(=O)C=CC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
A solution of 6.12 g. (0.025 moles) of 3,4-dichlorobenzoylacrylic acid and 4.0 ml. (3.94 g., 0.0325 moles) of 2,6-xylidine in 125 ml. of tetrahydrofuran is cooled to 5° C. and treated in succession with 3.0 ml. (5 g., 0.0328 moles) of POCl3 and 10 ml. (7.25 g., 0.072 moles) of triethylamine. The temperature rises to 25° C. and then falls to 20° C. After stirring for one hour, the suspension mixture is diluted with water and stripped of solvent. A semi-crystalline solid is obtained which is washed with water, then slurried with ethyl acetate. After filtering and washing with ether, 2.8 g. of 3-(3,4-dichlorobenzoyl)-2',6'-dimethylacrylanilide is obtained having a melting point of 213° C.-215° C.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:10][OH:11])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:20](Cl)(=[O:23])(=[O:22])[NH2:21]>C(COC)OC>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:8][O:9][S:20](=[O:23])(=[O:22])[NH2:21])[CH2:10][O:11][S:20](=[O:23])(=[O:22])[NH2:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC(CO)(c1ccccc1)c1ccccc1
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: NS(=O)(=O)OCC(COS(N)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To a solution of 17.3 g. (0.076 mol.) of 2,2-diphenyl-1,3-propanediol in 200 ml. of dimethoxyethane is added 12.7 g. (0.3 mol.) of 57% sodium hydride followed by an additional 400 ml. of dimethoxyethane. After stirring overnight the suspension is cooled to 4° C. A solution of 31.2 g. (0.27 mol.) of sulfamoyl chloride in 600 ml. of dimethoxyethane is then added dropwise. The suspension is stirred overnight at room temperature. After filtering the mixture the filtrate is concentrated and the residue washed with heptane. Chromatography on SilicAR, CC-7, followed by crystallization affords 2,2-diphenyl-1,3-bis-O-sulfamyl-1,3-propanediol.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=O.[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[NH:1][C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)=[CH:7][CH:8]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: Clc1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
A mixture of 23.2 g (0.10 mole) of 2-amino-4'-chlorobenzophenone and 14.7 g (0.11 mole) of 3-amino-2-chloropyridine (96%) were heated for 1.5 hr at 180° C. under nitrogen atmosphere. The mixture was cooled to room temperature and methylene chloride added. After stirring for 30 min., solids were separated by filtration and triturated in hot 190 proof ethanol. The remaining insoluble material was collected by filtration and recrystallized from benzene-isooctane to give 2.7 g product, m.p. 203°-204.5° C. Drying conditions prior to analyses were: overnight at 97°-98° C./0.1 mm Hg.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]([CH2:18][CH2:19][NH:20][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])([O:16][CH2:14][CH3:15])=[O:21]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)CCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1
Reaction time: 3 h

Procedure:
To a solution of 3-chlorosulfonylbenzoic acid (3-1) (Maybridge Chemicals) (1.10 g, 5 mmoles) and β-alanine ethyl ester (0.85 g, 5.5 mmoles) in CHCl3 (20 ml) at room temperature was added triethylamine (1.52 g, 15 mmoles). After stirring for 3 hrs the solvent was removed, the residue was taken up in EtOAc, washed with H2O, 10% KHSO4 solution, H2O, brine and dried (Na2SO4). Solvent removal gave a residue that was purified by flash chromatography on silica gel eluting with CHCl3 (97)/MeOH(3) to give pure 3-2.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:24][CH2:25]Br)=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:27][NH:28][CH3:29]>C1COCC1>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:24][CH2:25][N:28]([CH3:29])[CH3:27])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CNC
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCBr)o1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCN(C)C)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To a solution of 2-bromoethyl 5-(tetradecyloxy)furan-2-carboxylate (0.186 g, 0.43 mmol) (prepared in Example 5) in THF at 0° C. was added dimethylamine (1 mL of a 2M solution in THF, 2.15 mmol) with stirring. The solution was allowed to warm to room temperature and stirring was continued for 12 hrs at which time the reaction was concentrated to dryness. The crude material was purified by flash chromatography eluting with ethyl acetate in hexanes (5-35%) to yield 0.121 g (71%) of the title compound as a waxy, colourless solid. MS (m/z, ES+): 396.29 (M+1, 100%); 1H NMR (400 MHz, DMSO-d6) δ: 7.2 (d, 1H), 5.6 (d, 1H), 4.23 (t, 2H), 4.13 (t, 2H), 2.53 (t, 2H), 2.18 (s, 6H), 1.7 (p, 2H), 1.2-1.5 (m, 22H), 0.85 (t, 3H).
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][CH2:11][C@H:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1)[C:13]([O:15]C)=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C>O1CCCC1.O>[C:3]([O:7][C:8]([NH:10][CH2:11][C@H:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:27])[CH:24]([CH3:25])[CH3:26])[CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(C(=O)C(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C(=O)N1CCN([C@@H](CNC(=O)OC(C)(C)C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10 ml (10 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1N are added to a solution of 2.0 g (5.6 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoate in 40 ml of tetrahydrofuran and 8 ml of water, and then the reaction medium is stirred at ambient temperature for 20 h. After the addition of an aqueous solution of acetic acid having a concentration of 1N, the product is extracted with n-butanol. The organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum, 1.5 g (78%) of (S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[C:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:26][CH:25]=[CH:24][N:23]=1>>[CH:28]1([C:27]2[C:22]([O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:9][CH:10]=3)=[N:23][CH:24]=[CH:25][N:26]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Clc1nccnc1C1CCCC1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: c1ccc(Nc2ccc(Oc3nccnc3C3CCCC3)cc2)nc1
Temperature: 120 °C

Procedure:
A mixture of 4-(pyridin-2-ylamino)phenol (0.30 g, 1.60 mmol), cesium carbonate (1.56 g, 4.80 mmol), and 2-chloro-3-cyclopentylpyrazine (0.29 g, 1.60 mmol) under argon was heated to 120° C. for 20 h. The mixture was cooled to RT and partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with aqueous 1N sodium hydroxide (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give N-(4-(3-cyclopentylpyrazin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 333.3 (M+1). IC50 (uM) 0.012.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:12]([C:10]1[S:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)=[O:14]
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNC(=O)c2ccc(-c3ccccn3)s2)c(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 5-pyridin-2-yl-thiophene-2-carboxylic acid and 2,4-dimethoxy-benzylamine. MS (M+H, 355.2).
Reaction SMILES: [C:1]([CH:4]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:5][CH:6]=[CH2:7])(=O)[CH3:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:5]([C:4]1[N:8]=[C:9]([CH:10]([CH3:11])[CH3:12])[O:13][C:1]=1[CH3:2])[CH:6]=[CH2:7]
Reactant: C=CCC(NC(=O)C(C)C)C(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCc1nc(C(C)C)oc1C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
6.63 g of the above prepared N-(1-acetyl-but-3-enyl)-isobutyramide(33.61 mmol) were treated with 37 ml of trifluoroacetic acid (483 mmol) and 28.03 ml of trifluoroacetic anhydride (6 eq.) and kept for 3 h at 40°, when TLC indicated the disappearance of starting material. The reaction mixture was then poured onto crashed ice/NaHCO3, the aqueous layer (pH ˜8) extracted twice with AcOEt, washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=92/8) yielded 3.92 g of the title compound as yellowish oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:18][C:19](=O)[CH:20]([CH3:22])[CH3:21])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.N[N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C[N:33](C)C=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:19]([CH:20]([CH3:22])[CH3:21])[N:33]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:25]3)[C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Reactant: NN1CCCCCC1
Reactant: CN(C)C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1C1CCCCCN1

Procedure:
1.7 ml of conc. hydrochloric acid are added to 5 g (16.7 mmol) of the compound from Example 2 and 5.7 g (50.1 mmol) of N-amino-hexahydroazepine in 100 ml of toluene AR and 80 ml of dimethylformamide and the mixture is boiled in a water separator for 24 hours. The mixture is cooled, diluted using 200 ml of ethyl acetate and extracted three times using 1N hydrochloric acid and twice using saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 1:9).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:33][C:34]1[CH:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[N:41]2)=[CH:36][CH:35]=1>ClCCCl.CN(C=O)C>[N:41]1[C:42]2[C:37](=[CH:36][CH:35]=[C:34]([NH:33][C:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][N:7]=4)[CH2:14][CH2:13]3)=[O:17])[CH:43]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: Nc1ccc2cccnc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2cccnc2c1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C

Procedure:
1-(5-Trifluoromethylpyrid-2-yl)-piperidine-4-carboxylic acid (D101) (100 mg, 0.36 mmol) was treated with oxalyl chloride (63 ul, 0.72 mmol) and catalytic DMF in 1,2-dichloroethane (3.5 ml) at 60° C. for 0.75 h. On cooling to room temperature the solvent was removed in vacuo and the residue was dissolved in DCM (2 ml). Triethylamine (30 ul, 0.2 mmol) and 7-aminoquinoline (D55) (27 mg, 0.19 mmol) were added and the reaction stirred at room temperature until complete by tlc. The resultant precipitate was collected by filtration to give the title compound as an off-white solid. MS(ES): MH+ 401, M-H+ 399.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]3=[N:22][C:23](Cl)=[N:24][C:25](Cl)=[C:20]3[CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[CH3:28][OH:29]>>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]3=[N:22][C:23]([O:29][CH3:28])=[N:24][C:25]([O:2][CH3:1])=[C:20]3[CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)nc(Cl)nc32)CC1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1nc(OC)c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1

Procedure:
Sodium methoxide (4 mmol) is added to a mixture of 4-(4,6-dichloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 24; 1 mmol) in methanol. The resulting mixture is heated at reflux for 8 h and then cooled. The solvent is evaporated, and ethyl acetate and water are added. The organic layer is washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography on silica gel to give 4-(4,6-dimethoxy-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][CH2:31][C:32]1[N:33]=[CH:34][N:35](C(OC(C)(C)C)=O)[CH:36]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][CH2:31][C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)n1cnc(CCCN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCCc3cccnc32)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2N(CCCc1c[nH]cn1)Cc1nc2ccccc2[nH]1
Yield: 94.1 %

Procedure:
A solution of 2-{[[3-(1-tert-butoxycarbonyl-1H-imidazol-4-yl)-propyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (39 mg, 0.066 mmol) in 3:1 TFA/CH2Cl2 (4 mL) was stirred at room temperature for 30 minutes then concentrated in vacuo. The residue was partitioned between CH2Cl2 (15 mL) and 1 N NaOH(aq) (10 mL), and the aqueous phase was extracted with CH2Cl2 (15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford COMPOUND 38 as a yellow foam (24 mg, 80%). 1H NMR (CDCl3) δ 1.67 (m, 3H), 1.86 (m, 1H), 2.00 (m, 1H), 2.16 (m, 1H), 2.42-2.87 (m, 6H), 4.01 (m, 3H), 6.51 (s, 1H), 7.15 (m, 3H), 7.42 (m, 2H), 7.53 (m, 2H), 8.54 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 21.66, 23.85, 24.01, 28.39, 29.50, 49.64, 50.78, 62.36, 115.22, 118.74, 122.23, 122.74, 134.47, 135.25, 135.58, 138.03, 139.02, 146.88, 156.37, 157.69. ES-MS m/z 387 (M+H). Anal. Calcd. for C23H26N6.0.4CH2Cl2.0.9CH4O: C, 64.96; H, 6.82; N, 18.70. Found: C, 65.13; H, 6.93; N, 18.91.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[C:13]=2[S:20][CH3:21])[CH:4]=1.[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:1])[C:13]=2[S:20][CH3:21])[CH:4]=1
Reactant: N
Reactant: CSc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CSc1c(CN)cccc1Oc1cc(Cl)ccc1C#N
Reaction time: 17 h

Procedure:
7N Ammonia in methanol (30 mL, 210 mmol) was added to 4-chloro-2-(3-chloromethyl-2-methysulfanyl-phenoxy)-benzonitrile (240 mg, 0.8 mmol). After stirring for 17 h, TLC still showed some 4-chloro-2-(3-chloromethyl-2-methysulfanyl-phenoxy)-benzonitrile. The reaction mixture was concentrated to about 10 mL by evaporation in vacuo, concentrated ammonia (7 mL) was added and the mixture was heated with stirring at 60° C. for 17 h. Sodium carbonate solution (4 mL) and ethyl acetate (6 mL) were added and the organic layer was separated and dried with MgSO4. To this, was added fumaric acid (84 mg, 0.64 mmol) in methanol (3 mL). Immediately, the solvent was removed in vacuo and diethyl ether (40 mL) was added to the residue. After stirring for 17 h, 4-chloro-2-(3-aminomethyl-2-methysulfanyl-phenoxy)-benzonitrile fumarate (134.7 mg, 53%) was filtered off as a white solid.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2([CH:22]([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25])[OH:21])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].Cl>C(O)(C)C.O1CCCC1.CCOCC>[ClH:4].[C:1]([O:21][C:16]1([CH:22]([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C2CCCCC2(O)C(C)CN(C)C)cc1OC
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1ccc(C2CCCCC2(OC(C)=O)C(C)CN(C)C)cc1OC

Procedure:
The procedure of Example I(c) is followed using 6.5 ml acetyl chloride and 11.5 g 2-(3,4-Dimethoxyphenyl)-1-(2-dimethylamino-1-methylethyl)cyclohexanol and a reaction time of 6 hours to give 9.5 g. crude HCl salt which is dissolved in 50 ml isopropanol and diluted with 440 ml tetrahydrofuran and 60 ml ether to give 7.1 g product, m. 200°.
Reaction SMILES: [C:1]([O:5][CH2:6]C)(=[O:4])[CH:2]=[CH2:3].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:21][CH2:3][CH:2]([C:1]([O:5][CH3:6])=[O:4])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=CC(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl acrylate (86 g, 1.0 mole) in dichloromethane (2 L) was cooled to 0° C. and treated with N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (compound D17 of EP 0363085) (300 g, 80% pure by 1H NMR, 1 mole) with stirring over a period of 10 min whilst maintaining the temperature between -5° C. and 0° C. A solution of trifluoroacetic acid in dichloromethane (100 ml, 1 molar) was added at such a rate that the temperature did not rise above 5° C. and the reaction allowed to warm to room temperature overnight. The solution was then washed with saturated aqueous potassium carbonate solution, dried over sodium sulphate and concentrated in vacuo to a gum. The glum was distilled in vacuo to afford the title compound. (D4) as a single main fraction. Bpt 150°-160° at 8 mm (232 g, 100%).