Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[O:19][CH2:20][O:21][CH3:22].CN(C)CCN(C)C.CN(C)[CH:35]=[O:36].Cl>C(OCC)C>[CH3:6][O:7][CH:8]([O:23][CH3:24])[C:9]1[C:10]([O:19][CH2:20][O:21][CH3:22])=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:13][C:14]=1[CH:35]=[O:36]
Reactant: COCOc1c(C(OC)OC)cccc1C(F)(F)F
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1c(C(F)(F)F)ccc(C=O)c1C(OC)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A n-butyl lithium-1.59M n-hexane solution (196 ml, 312 mmol) was added dropwise to a solution of 1-(dimethoxymethyl)-2-(methoxymethoxy)-3-(trifluoromethyl)benzene (39.3 g, 140 mmol) obtained in Example (6-4) and N,N,N′,N′-tetramethylethylenediamine (46.9 ml, 311 mmol) in diethyl ether (410 ml) at −25° C. over 20 minutes. After the reaction mixture was stirred at 0° C. for 30 minutes, it was further stirred at room temperature for 1.5 hours. After the reaction mixture was cooled to −30° C. and N,N-dimethylformamide (41.9 ml, 541 mmol) was added thereto, the mixture was further stirred at room temperature for 1 hour. After the reaction mixture was carefully poured into cold 0.1N hydrochloric acid and the mixture was extracted with ethyl acetate (four times), the organic layer was successively washed with 0.1N hydrochloric acid, water (three times) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude 2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzaldehyde. This compound was used in Example (6-6) without further purification.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1C(O)=O.[OH:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]=1[C:21]([NH2:23])=[O:22]>>[NH:3]1[CH2:2][CH2:7][CH:6]([O:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH2:23])=[O:22])[CH2:5][CH2:4]1
Reactant: NC(=O)c1oc2ccccc2c1O
Reactant: O=C(O)N1CCCCC1Cl
Product: NC(=O)c1oc2ccccc2c1OC1CCNCC1

Procedure:
Referring to Scheme 3, methoxybenzofuran ester 1, for example, is converted to the corresponding hydroxybenzofuran carboxylic acid 2 with boron tribromide. Carboxylic acid 2 is coupled with Hca amine to yield hydroxybenzofuranamide 3. 1-Substituted 4-hydroxypiperidine 4 is coupled with amide 3 to yield (piperidin-4-yloxy)benzofuranamide 5.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:14]=[N:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+].Cl>CO.O.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[C:8]3[CH:9]=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[CH:14]=[N:13]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid ethyl ester (2.75 g, 9.64 mmol) and 85% potassium hydroxide pellets (6.4 g, 84 mmol) in methanol-water was warmed at reflux for 15 minutes and then stirred overnight. The mixture was then diluted with water (300 mL) and then a dilute solution of aqueous HCl (1 equivalent based on mass of KOH) was added in several portions (final pH=5). The resulting solid was collected by filtration and dried by pulling vacuum through the filter cake to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH2:9]([O:16][C:17]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Br)C=C>C1COCC1>[CH2:9]([O:16][C:17]([C:19]1([CH2:8][CH:6]=[CH2:7])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(OCc1ccccc1)C1CCCC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1(C(=O)OCc2ccccc2)CCCC1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Next, to a stirred solution of LDA (4 mmol, 2M in Hexane) in THF (8 mL) at −78° C. is added a solution of cyclopentanecarboxylic acid benzyl ester (817 mg, 4 mmol) in THF (3 mL) dropwise. After the addition, the mixture is stirred at −78° C. for 5 hours then allyl bromide (726 mg, 6 mmol) is added dropwise. The mixture is warmed to room temperature during 4 hours then the reaction mixture is quenched with saturated NaHCO3. Magnesium sulfate (2 g) is added and stirred until all the MgSO4 is dissolved. The mixture is extracted with ethyl acetate and the organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (hep:EtOAc, 10:1) to give 1-allyl-cyclopentanecarboxylic acid benzyl ester. Next, Ozone is bubbled through a solution of 1-allyl-cyclopentanecarboxylic acid benzyl ester in methylene chloride (15 mL) for 30 min then PS-triphenolphosphine (300 mg) is added and the mixture is stirred at room temperature for 5 hours. The resin is filtered and solvent is removed under reduced pressure. The residue is purified by flash chromatography (heptane:EtOAc, 10:1) to give 1-(2-oxo-ethyl)-cyclopentanecarboxylic acid benzyl ester MS 247.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1.[CH:23]([CH:25]=[CH2:26])=[O:24].C(N(CC)CC)C.O>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:26]=[CH:25]/[CH:23]=[O:24])=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1
Reactant: C=CC=O
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(/C=C/C=O)cc1)c1ccnc(C#N)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 50.6 %

Procedure:
4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile (1.3 g, 2.5 mmoles), acrolein (0.5 ml, 7.4 mmoles), and triethylamine (0.4 ml, 3.1 mmoles) are dissolved in 25 ml of acetonitrile and Pd(OAc)2 (27 mg, 0.12 mmoles) is added at rt. The mixture is stirred at 80° C. for 18 h. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 423 mg of desired 4-{(2,2-dimethyl-propyl)-[4-((E)-3-oxo-propenyl)-benzyl]-amino}-pyrimidine-2-carbonitrile in 39% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.CC(C)([O-])C.[K+].[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]1([C@H:14]([N:10]2[CH2:11][CH2:12][O:13][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:7][CH:6]=3)[CH2:9]2)[CH3:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1ccccn1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Solvent: C1COCCO1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Nc3ccccn3)cc2)C1
Yield: 35.6 %

Procedure:
A solution of (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (1.5 g, 5.31 mmol), 2-chloropyridine (1.21 g, 10.6 mmol), tris(dibenzylideneacetone)-dipalladium(0) (52.6 mg, 0.05 mmol), potassium tert-butoxide (0.88 g, 7.8 mmol) and 1,3-bis(2,6-di-i-propylphenyl)imidazolium chloride (89.6 mg, 0.21 mmol) in dioxane (17 ml) was stirred at 90° C. for 15 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane-ethyl acetate, 1:2) to afford N-(4-((2S)-4-((1R)-1-Phenylethyl)-morpholin-2-yl)phenyl)pyridin-2-amine (0.68 g, 36%) as red crystals.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[F:13][C:14]([F:31])([C:20]([F:30])([F:29])[C:21]([F:28])([F:27])[C:22]([O:24][CH2:25][CH3:26])=O)[C:15]([O:17]CC)=[O:16]>O1CCCC1>[CH2:25]([O:24][CH:22]1[C:21]([F:27])([F:28])[C:20]([F:29])([F:30])[C:14]([F:13])([F:31])[CH:15]([OH:16])[O:17]1)[CH3:26]
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)C(=O)OCC
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC1OC(O)C(F)(F)C(F)(F)C1(F)F
Temperature: -70 °C
Reaction time: 2 h

Procedure:
A solution of 30.3 g. (0.015 mol.) of Vitride (70% in benzene) in 30 ml. of dry tetrahydrofuran (THF) was added dropwise over 45 min. to a stirred solution of 25.0 g. (0.084 mol.) of diethyl perfluoroglutarate in 200 ml. of THF at -70° C. The mixture was stirred for an additional 2 hours at -70° C. followed by decomposing the Vitride as described in Example 1 to give 16.8 g. (87% by weight) of the title compound as a pale yellow liquid. Distillation afforded a colorless oil: boiling range 65°-70° C. (1.7 mm); nD26 1.3671; νmaxneat 3350 (broad) cm-1 ; nmr (CDCl3) δ 1.20 (t,3H,J=6.5 Hz), 3.46-4.10 (m,2H,J=4 Hz) 5.07-5.26 (m,2H), 8.33 (bd s, 1H, exch.) which on prolonged storage (1 month) solidified to a white crystalline product; melting range 84°-6° C. (C6H6).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH:26]1([N:29]([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=2)[CH2:28][CH2:27]1>>[CH:26]1([N:29]([CH3:37])[C:30]2[N:31]=[CH:32][C:33]([NH:36][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Br:22])=[N:13][C:12]=3[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:34][CH:35]=2)[CH2:28][CH2:27]1
Reactant: CCCc1nc(-c2ccccc2Br)oc1C(=O)ON1C(=O)CCC1=O
Reactant: CN(c1ccc(N)cn1)C1CC1
Product: CCCc1nc(-c2ccccc2Br)oc1C(=O)Nc1ccc(N(C)C2CC2)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-cyclopropyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H23BrN4O2 (m/e) 455, obsd 456 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH:7]=[CH:6][C:5]=1[F:17].[AlH4-].[Li+]>O1CCCC1>[F:17][C:5]1[CH:6]=[CH:7][C:8]([NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)OC)c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-Fluoro-5-(propane-1-sulfonylamino)-benzoic acid methyl ester (670, 1.20 g, 0.00436 mol) in tetrahydrofuran (100.0 mL) was added lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 10.0 mL) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. To the reaction was added Na2SO4.10H2O (5 g), and then stirred at room temperature for 1 hour. The reaction was filtered, concentrated and purified with silica gel column chromatography eluting with 50% ethyl acetate in hexane to give the compound (671, 0.90 g, 83%). MS (ESI) [M−H+]−=246.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=2)[O:29][C@@H:30]([CH3:35])[C:31]([O:33]C)=[O:32])[C:20]([CH3:39])=[C:19]3[CH3:40])=[O:15])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=2)[O:29][C@@H:30]([CH3:35])[C:31]([OH:33])=[O:32])[C:20]([CH3:39])=[C:19]3[CH3:40])=[O:15])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(OC(C)C)c4)ccc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C)n(Cc2cccc(O[C@@H](C)C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(OC(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-methyl 2-(3-((5(((S)-1-(3-isopropoxyphenyl)ethyl) carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate (70 mg, 0.13 mmol, 1 equiv) in THF (2 mL) was added a 1 N LiOH aqueous solution of (1 mL). The reaction mixture was stirred 6 h at room temperature, then acidified with a 0.5 N HCl aqueous solution. The mixture was filtered and the precipate was dissolved in methanol and concentrated to obtain the crude product which was purified by prep. HPLC (MeOH/Acetonitrile/water 0.1% TFA) to obtain the title compound.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[C:16]([CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:26]1([CH2:32][CH2:33][N:23]2[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:17]=3)[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(-c2cc(CCC3CCNCC3)c3ccccc3n2)cc1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CCN2CCC(CCc3cc(-c4ccccc4)nc4ccccc34)CC2)cc1

Procedure:
The operation is as in Example 21, starting from 9.3 g of the monohydrochloride of 2-phenyl-4-[2-(4-piperidyl)-ethyl]-quinoline, prepared as indicated in Example 16, 7.3 g of 2-phenyl-ethyl bromide and 18.1 g of potassium carbonate, in suspension in 130 ml of dimethylformamide. 8.3 g are obtained of 4-{2-[1-(2-phenyl-ethyl)-4-piperidyl]-ethyl}-2-phenyl-quinoline melting at 80° C.
Reaction SMILES: [CH3:1]OC(C)(C)C.C[Zn]C.[Br:10]/[CH:11]=[C:12]1/[C@H:13]2[C@:17]([CH3:21])([CH2:18][CH2:19][CH2:20]/1)[C:16]([CH:22]=[O:23])=[CH:15][CH2:14]2>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.[C@@H]1(NS(C(F)(F)F)(=O)=O)CCCC[C@H]1NS(C(F)(F)F)(=O)=O.C(OCC)(=O)C>[Br:10]/[CH:11]=[C:12]1\[CH2:20][CH2:19][CH2:18][C@@:17]2([CH3:21])[C@H:13]\1[CH2:14][CH:15]=[C:16]2[C@@H:22]([OH:23])[CH3:1]
Reactant: C[C@]12CCC/C(=C\Br)[C@@H]1CC=C2C=O
Reactant: COC(C)(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: C[Zn]C
Agent: O=S(=O)(N[C@@H]1CCCC[C@H]1NS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@H](O)C1=CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: 50 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(1R)-trans-N,N′-1,2-cyclohexanediylbis(1,1,1-trifluoromethanesulfonamide) (2.3 mg, 0.006 mmol) was placed in a reaction vessel. After replacing the atmosphere with nitrogen, t-butyl methyl ether (0.03 ml) was added thereto and dissolved. To the solution, tetraisopropoxy titanium (0.0177 ml, 0.06 mmol) was added at room temperature, and the resulting mixture was heated at 50° C. for 30 minutes. After cooling to room temperature, dimethylzinc (1.0 M in heptane, 0.12 ml, 0.12 mmol) was added thereto. The obtained reaction mixture was added to (3aR,4E,7aS)-4-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-7a-methyl-3H-indene-1-carbaldehyde (Compound 29: 15.3 mg, 0.06 mmol). After stirring the reaction solution at room temperature for 1 hour, ethyl acetate (30 ml) was added thereto, and the resulting mixture was washed with 2N hydrochloric acid, saturated brine and with saturated aqueous sodium hydrogen carbonate solution, respectively. The organic layer was dried over sodium sulfate, and the solvent was evaporated to obtain the reaction mixture. The reaction mixture was purified by preparative TCL to obtain (S)-1-{(3aS,7E,7aR)-7-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-3a-methyl-1H-indene-3-yl}ethanol (18.4 mg, 100%). The spectrum data thereof agreed with the data described in Example 4.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.B(Br)(Br)Br>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(NC(C)=O)cc1-c1ccnn1C
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
To a suspension of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (2.57 g, 10.48 mmol) in 1,2-dichloroethane (75 mL) was added BBr3 (10 mL, 106 mmol) and stirred for three hours. The nonhomogeneous suspension was heated to reflux for 15 minutes and then cooled to room temperature. The reaction was quenched by slow addition of methanol. The resulting material was purified by HPLC. The product was dried in vacuo to afford N-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide as a white solid (508 mg, 21%). LCMS (%)=232 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) δ: 9.77 (bs, 1H), 9.66 (bs, 1H), 7.44-7.40 (m, 3H), 6.89 (d, J=8.85 Hz, 1H), 6.37 (d, J=1.81 Hz, 1H), 3.66 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:3]=1
Reactant: CCCCCCCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CCCCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(octylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-octylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:24][CH2:25][NH-:26]>>[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:24][CH2:25][NH:26][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: [NH-]CCc1cc(F)cc(F)c1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCc3cc(F)cc(F)c3)s2)c(C)[nH]c1=O
Yield: 15 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (3,5-difluorobenzyl)methylamide as described in Step 5, Example 24 to give the title compound as a solid (15% yield). LC/MS: RT 3.30 min; m/e 439 (M+H); 1H NMR (δ, ppm): 11.82 (1H, s), 7.72 (1H, d), 7.37 (1H, s); 7.28 (1H, d); 7.03 (3H, m), 4.26 (2H, s), 2.71 (3H, s), 2.37 (2H, q), 2.34 (3H, s), 1.11 (3H, t); 19F NMR −109.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:29][CH:30]([F:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[F:40][CH:30]([F:29])[C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1
Reactant: FC(F)c1nc2ccccc2[nH]1
Product: FC(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine from Example 126 (0.07 g) was reacted with 2-(difluoromethyl)-1H-benzo[d]imidazole via General Procedure D to produce 10.7 mg of 172 following reverse phase HPLC purification. MS (Q1) 537.2 (M)+
Reaction SMILES: O[C:2]1C=CC=C[C:3]=1N1C=CC=C1.ClC1C=CC(O)=C(N2C=CC=C2)C=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][C:34]([CH3:39])([C:36]([OH:38])=[O:37])[C:33]3=[CH:40][CH:41]=[CH:42][N:32]3[C:31]=2[CH:43]=1>>[CH2:2]([O:37][C:36]([C:34]1([CH3:39])[C:33]2=[CH:40][CH:41]=[CH:42][N:32]2[C:31]2[CH:43]=[C:27]([Cl:26])[CH:28]=[CH:29][C:30]=2[O:35]1)=[O:38])[CH3:3]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CC1(C(=O)O)Oc2ccc(Cl)cc2-n2cccc21
Agent: Oc1ccc(Cl)cc1-n1cccc1
Product: CCOC(=O)C1(C)Oc2ccc(Cl)cc2-n2cccc21

Procedure:
In the same manner but replacing N-(2-hydroxyphenyl)-pyrrole with an equivalent amount of N-(5-chloro-2-hydroxyphenyl)-pyrrole, 8-chloro-4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-carboxylic acid, m.p. 153° - 154° C (dec), νmaxCHCl3 1,725, 1,510, 1,330cm-1, is obtained via the intermediate ester, 8-chloro-4-methyl-4H-pyrrolo-[2,1-c][1,4]benzoxazine-4-carboxylic acid ethyl ester, νmaxCHCl3 1,735 cm-1.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[S:12][CH:13]=1)(=O)=O.[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([C:11]2[S:12][CH:13]=[C:9]([CH2:8][CH2:7][CH2:6][N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH2:6][CH2:7][CH2:8][C:9]4[N:10]=[C:11]([C:14]5[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=5)[S:12][CH:13]=4)[CH2:28][CH2:27]3)[N:10]=2)[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2nc(CCCOS(C)(=O)=O)cs2)cc(OC)c1OC
Product: COc1cc(-c2nc(CCCN3CCCN(CCCc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-(3-Methanesulfonyloxypropyl)-2-(3,4,5-trimethoxy-phenyl)thiazole (152 mg) and homopiperazine (20 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2>CCO.O=[Pt]=O>[CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccccc3)c(C)cc2c1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
PtO2 (10 mg) was added to a solution of 37 (490 mg, 1.27 mmol, 1 equiv) in EtOH (5 mL). The reaction mixture was stirred under an atmosphere of H2 (50 psi) for 1.5 h. The mixture was then filtered thru a pad of celite and concentration down to provide 38 (452 mg, 100%) as a clear oil. 1HNMR (400 MHz, DMSO-d6): δ 7.61 (m, 2H), 7.32-7.23 (m, 4H), 7.16 (m, 2H), 7.02 (m, 1H), 6.32-6.26 (m, 4H), 5.74 (br s, 2H), 3.85 (s, 3H), 2.14 (s, 3H). MS m/z 356.2 (M+H)+.