Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34]C)=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:17](=O)[CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C.CO.[OH-].[Na+]>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([OH:34])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[CH2:17][CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(=O)N(CCN(C)C)c1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCN1CCCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of methyl 14-cyclohexyl-5-[2-(dimethylamino)ethyl]-6-oxo-5,6,7,8-tetrahydroindolo[1,2-e][1,5]benzodiazocine-11-carboxylate (prepared as described in Example 8, Step 7) in THF (0.1 M), BH3.Me2S (20 eq, 2 M solution in THF) was added. The solution was stirred overnight at RT. MeOH was carefully added to the mixture to quench the reaction, followed by an excess of 1 N NaOH (>10 eq). The mixture was heated at 60° C. for 12 h. The solvent was evaporated in vacuo. The crude was then purified by prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (24% over three steps).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1[NH2:25].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[C:3]([NH2:25])[N:4]=2)=[N:9]1
Reactant: OB(O)c1cccnc1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1-c1cccnc1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
Under an argon atmosphere, 140 mg (purity 65%, 0.256 mmol) of 6-chloro-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5-amine were suspended in 5 ml of absolute dioxane. 94 mg (0.767 mmol) of pyridin-3-ylboronic acid, 1.023 ml (1.023 mmol) of 1N aqueous potassium carbonate solution and 14 mg (0.051 mmol) of tricyclohexylphosphine were added and argon was passed through the suspension for 10 min with stirring. Then, 28 mg (0.038 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 30 min in the microwave at 140° C. After cooling, the mixture was filtered over an Extrelut cartridge and after-washed with a mixture of dichloromethane/methanol (v/v=20:1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). 77 mg of the target compound were obtained (65% of theory).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23]O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.Cl.[NH2:32][OH:33].C(=O)(O)[O-].[K+]>O>[CH3:27][Si:2]([CH3:28])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22]/[CH:23]=[N:32]/[OH:33])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: NO
Reactant: CCC(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(C/C=N/O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (60 mg, 0.0002 mol) from Example 498, Step 2 in methanol (2 mL, 0.05 mol) was added hydroxylamine hydrochloride (16 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room temperature for 2 h, water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (1E)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal oxime as a semisolid residue (50 mg, 80%). LC/MS (M+H)+: m/z=415.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].FC(S(O[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)[N:18]=[C:17]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:16]=1)(=O)=O)(F)F.[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:35]1([C:17]2[N:16]=[C:15]([NH:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:22]=3)[N:18]=2)[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: O=S(=O)(Oc1cc(-c2cccc(OCc3ccccc3)c2)nc(N2CCOCC2)n1)C(F)(F)F
Reactant: Nc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: c1ccc(COc2cccc(-c3cc(Nc4cccnc4)nc(N4CCOCC4)n3)c2)cc1
Temperature: 25 °C

Procedure:
A round bottom flask, oven dried and kept under N2 atmosphere was charged with Cs2CO3 (1.4 eq), Pd(OAc)2 (5 mol %), and S-(−)-BINAP (1.5×mol of Pd catalyst). The flask was purged with N2 for about 5-10 min and a solution of 2-morpholin-4-yl-6-[3-(phenylmethoxy)phenyl]pyrimidin-4-yl (trifluoromethyl) sulfonate (1eq) in dry THF (20 mL) was added via a syringe, followed by 3-aminopyridine (2 eq,) in one portion. The flask was equipped with a reflux condenser, purged again with N2 for 5 min and the reaction mixture was refluxed overnight. An efficient stirring is very important. The reaction mixture was cooled down to room temperature and the solvent was evaporated under reduced pressure. The residue was washed with water (x2) and triturated with methanol to afford the desired {2-morpholin-4-yl-6-[3-(phenylmethoxy)phenyl]pyrimidin-4-yl}-3-pyridylamine.
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])([CH3:5])[CH3:4].[Na].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>CN(C)C=O.O>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[Si:3]([CH3:5])([CH3:4])[CH2:2][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: C[Si](C)(CCl)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A mixture of 5.1 g (0.020 mol) of chloromethyl(2,4-dichlorophenyl)dimethysilane and 2.0 g (0.022 mol) of 1,2,4-triazole sodium salt in 10 ml of dry dimethylformamide was stirred at 80°-90° for 2 hours. The resulting slurry was cooled, diluted with water, and washed with ether. The ether extracts were washed with several portions of water and once with brine, dried over magnesium sulfate, and evaporated to leave 4.6 g (81%) of the title compound as a pale yellow liquid: nD23 1.5580; ir (neat) 1550, 1485, 1440, 1345, 1260, 1240, 1130, 1085, 1025, 1005, 835 cm-1 ; nmr (CDCl3) 0.5 (6H, s), 4.1 (2H, s), 7.2-7.5 (3H, m), 7.8 (1H, s), 7.9 (1H, s).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[C:6]([CH:15]2[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16]2)=[C:5]1[CH3:23])(=O)C.[OH-].[K+]>O.C(O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][C:5]([CH3:23])=[C:6]2[CH:15]1[CH:20]2[CH2:19][CH2:18][N:17]([CH2:22][CH2:21]2)[CH2:16]1
Reactant: COc1ccc2c(c1)c(C1CN3CCC1CC3)c(C)n2C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2[nH]c(C)c(C3CN4CCC3CC4)c2c1

Procedure:
200 mg of 3-(1-Acetyl-5-methoxy-2-methyl-3-indolyl)quinuclidine are stirred on a steam bath for 16 hours with 100 mg of KOH in 7 ml of water and 14 ml of ethanol. The mixture is then worked up as is customary. 3-(5-methoxy-2-methyl-3-indolyl)quinuclidine is obtained; hydrochloride, m.p. 231.7°-234.0°.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:17][CH2:18][C:19]([OH:21])=O.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41]>ClCCl>[CH3:25][C:23]1[CH:22]=[C:16]([CH:15]=[C:14]([CH3:13])[CH:24]=1)[O:17][CH2:18][C:19]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[O:21]
Reactant: Cc1cc(C)cc(OCC(=O)O)c1
Reactant: COC(=O)CCCCCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)COc1cc(C)cc(C)c1
Yield: 62.3 %

Procedure:
In a 5L 3-necked flask equipped with a mechanical stirrer and a dropping funnel was placed 1,1′-carbonyldiimidazole (94.4 g, 0.583 mol) in dichloromethane (1 L). A solution of 3,5-dimethylphenoxyacetic acid (Intermediate A77, 95.4 g, 0.53 mol) in dichloromethane (1250 mL) was added over a period of 60 min under argon. Triethylamine (107.1 g, 1.06 mol) was added followed by addition of a suspension of methyl 6-aminohexanoate hydrochloride (101.1 g, 0.555 mol) in dichloromethane (250 mL) in five portions. After 1 hr the reaction mixture was washed with 3 M HCl (1×1L), 2 M ammonium hydroxide (1×1L), and water (1×1L). The organic phase was then filtered through 1PS filter paper and concentrated under reduced pressure to give an oil. Distillation of the oil gave 101.5 g (62%) of the title compound, amide boiling at 197-202° C. (1 mm). The oil solidified on standing.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[C@@H:17]([CH:18]([OH:36])[CH:19]([NH2:35])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)[CH2:16][O:15][C@@H:14]([O:37][CH2:38][C:39]2([CH3:44])[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[C:5]([O:9][C:10]([N:12]1[C@@H:17]([C@@H:18]([OH:36])[C@@H:19]([NH:35][C:1](=[O:3])[CH3:2])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)[CH2:16][O:15][C@@H:14]([O:37][CH2:38][C:39]2([CH3:44])[CH2:40][CH2:41][CH2:42][CH2:43]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC1(CO[C@H]2CN(C(=O)OC(C)(C)C)[C@@H](C(O)C(N)Cc3cccc(OCc4ccccc4)c3)CO2)CCCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1cccc(OCc2ccccc2)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
Add acetyl chloride (0.13 mL, 1.82 mmol) to an ice cold solution of (2R,5R)-5-[2-amino-3-(3-benzyloxyphenyl)-1-hydroxypropyl]-2-(1-methylcyclopentylmethoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.91 g, 1.652 mmol) and N,N-diisopropyl-ethylamine (0.58 mL, 3.30 mmol) in dichloromethane (20 mL). Stir 15 minutes and dilute with ethyl acetate and wash with 1 N hydrochloric acid, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, elutin with dichloromethane/ethyl acetate) to give the desired compound (246 mg).
Reaction SMILES: [N+](C1C=CC(O[C:9]([CH:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:28](=[O:29])[N:17]3[CH:18]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[C:19]([CH3:22])([CH3:21])[S:20][C@H:16]23)=[O:13])=[O:10])=CC=1)([O-])=O.C([N:40](CC)CC)C.C(Cl)(Cl)Cl.N>CO>[C:9]([CH:11]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:12]([NH:14][CH:15]1[C:28](=[O:29])[N:17]2[CH:18]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)[C:19]([CH3:22])([CH3:21])[S:20][C@H:16]12)=[O:13])(=[O:10])[NH2:40]
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccc([N+](=O)[O-])cc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reactant: CCN(CC)CC
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(N)=O)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 4 h

Procedure:
To a stirred solution of 523 mg. (0.001 mole) of 6-(2-[p-nitrophenoxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 101 mg of triethylamine in 50 ml. of chloroform is added 1 ml of a 1M solution of ammonia in methanol, at -30° C. Stirring is continued for 4 hours without external cooling and then evaporation in vacuo leaves the crude product as its triethylamine salt.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][SH:7])=[O:5].[H-].[Na+].Cl[C:11]1[N:16]2[N:17]=[CH:18][N:19]=[C:15]2[N:14]=[C:13]([CH3:20])[CH:12]=1>C(O)C.ClCCl.O>[CH2:2]([O:3][C:4]([CH2:6][S:7][C:11]1[N:16]2[N:17]=[CH:18][N:19]=[C:15]2[N:14]=[C:13]([CH3:20])[CH:12]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)CS
Reactant: Cc1cc(Cl)n2ncnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CSc1cc(C)nc2ncnn12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl thioglycollate, 1.2 g, is dissolved in 30 ml of dry ethanol, to which 400 mg of sodium hydride (60% in an oil) is added under cooling with ice water and stirred for 10 minutes. Then 1.7 g of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine and 10 ml of dry dichloromethane are added and stirred for 16 hours. To the reaction mixture, water and dichloromethane are added and the organic layer is separated. The separated organic layer is washed with saline and dried over anhydrous potassium carbonate. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography [on 40 g of silica gel, developed and eluted with ethyl acetate] to give 2.2 g of the desired compound as a colorless powder.
Reaction SMILES: C1CO[C:3]([CH3:18])([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[O:2]1.C(=O)(O)[O-].[Na+]>Cl>[N:11]1([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3](=[O:2])[CH3:18])=[CH:6][CH:7]=2)[CH2:12][CH:13]=[CH:14][CH2:15][CH2:16]1
Reactant: CC1(Cc2ccc(N3CCC(O)CC3)cc2)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Cc1ccc(N2CC=CCC2)cc1
Yield: 71.6 %

Procedure:
4-[4-(2,2-Ethylenedioxypropyl)phenyl piperidin-4-ol (0.9 g) was dissolved in 50% hydrochloric acid solution, and heated under reflux for 4 hr. The solution was cooled, basified with 1.2M sodium bicarbonate solution and extracted with ethylacetate (3×50 ml). The organic extract was dried (magnesium sulphate), filtered and evaporated in vacuo, to give an oil which was chromatographed on silica. Elution with chloroform:methanol (97:3) gave 4-(1,2,3,6-tetrahydropyridyl) phenyl propan-2-one (0.5 g).
Reaction SMILES: [OH:1][CH2:2][C:3]12[N:10]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][O:5][CH2:4]2.[CH3:17]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]12[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][O:5][CH2:4]2)=[O:1]
Reactant: CC(C)OC(=O)N1C2CCC1(CO)COC2
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1(C=O)COC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of isopropyl 5-(hydroxymethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (73 mg, 0.3 mmol) in DCM (mL) was added Dess-Martin (191 mg, 0.45 mmol) at ice-bath. The mixture was allowed to warm to room temperature while stirred for 2 h. Then the mixture was diluted with DCM (50 mL) and washed with saturated NaHCO3 (50 mL) three times and water (50 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford tert-butyl 5-formyl-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate (71 mg, 98%) which was used for next step without further purification. MS: calc'd (MH+) 242, measured (MH+) 242.
Reaction SMILES: C(OC([C:7]1([O:17][CH2:18][C:19]#[CH:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH2:8]1)=O)C#C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[O:28]1CCC[CH2:29]1>>[CH2:18]([O:17][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:29][OH:28])[C:19]#[CH:20]
Reactant: C#CCOC(=O)C1(OCC#C)CC=Cc2ccccc21
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: C#CCOc1c(CO)ccc2ccccc12

Procedure:
14.55 g of 1-(2-propynyloxy)-naphthoic acid 2-propynyl ester dissolved in 50 ml of absolute tetrahydrofuran are cautiously added at -10° C. under a nitrogen atmosphere to a suspension of 2.09 g of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran. After completion of the addition is complete, the mixture is left to react at about 0° C. for a further 1 hour. To hydrolyze, water is cautiously added dropwise at -10° C. with stirring while the temperature is maintained at 0° C. or below. The mixture is filtered using a filter aid (Celite) and the filtrate is concentrated. The residue is dissolved in ethyl acetate and washed, in sequence, with 2 N hydrochloric acid solution, 10% potassium bicarbonate solution, semi-saturated and saturated sodium chloride solution. The residue is dried over sodium sulfate and evaporated. Pure [1-(2-propynyloxy)-2-naphthyl]methanol, m.p. 65°-68° C. (from hexane/ethyl acetate), is obtained by recrystallization. This material is reacted with cyclopropane carboxylic acid chloride in the procedure described in Example 2 to yield cyclopropane carboxylic acid [1-(2-propynyloxy)-2-naphthyl]methyl ester; nD20 =1.5902.
Reaction SMILES: C(O)(=O)C.[OH:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:15]([NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[NH:34])=[CH:31][CH:30]=2)[C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:17]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>CS(C)=O>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[OH:5][CH2:6][C:7]1[CH:8]=[C:9]([C@H:15]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([NH2:35])=[NH:34])=[CH:36][CH:37]=2)[C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:17]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: COc1cc(CO)cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CO)cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1

Procedure:
After adding trifluoroacetic acid to a suspension of 28.5 mg of 4-{[(3-hydroxymethyl-5-methoxyphenyl)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzamidine acetate in 2.85 ml of DMSO, the mixture was concentrated under reduced pressure. The residue was optically resolved using a SUMICHIRAL OA-2500 column, and the first fraction was obtained. This was dissolved in a trifluoroacetic acid:acetonitrile:water=1:50:50 mixed solvent and concentrated, and the first fraction (9.80 mg) of the title compound was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:25][CH2:26][C:27]1([NH2:31])[CH2:30][O:29][CH2:28]1>>[NH2:31][C:27]1([CH2:26][NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:30][O:29][CH2:28]1
Reactant: NCC1(N)COC1
Reactant: O=S1CCN(c2cc(Cl)c3cc(Cl)ccc3n2)Cc2ccccc21
Product: NC1(CNc2cc(N3CCS(=O)c4ccccc4C3)nc3ccc(Cl)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide in Example 18-1 by using 2,4,6-trichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide) and 3-aminomethyloxetan-3-ylamine. MS obsd. (ESI+) [(M+H)+] 443, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (d, J=2.02 Hz, 1 H), 7.77 (d, J=7.83 Hz, 1 H), 7.71 (d, J=8.59 Hz, 1 H), 7.52-7.34 (m, 4 H), 6.22 (s, 1 H), 5.25 (d, J=15.92 Hz, 2 H), 4.78 (brs, 2 H), 4.65-4.52 (m, 4 H), 3.66 (s, 2 H), 3.47-3.38 (m, 2 H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[N:18]=[C:19]3[C:25]([NH:26][C:27](=[O:54])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=[CH:30][C:29]=4[N:41]([CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)C(=O)C(F)(F)F)=[N:24][N:23](C(=O)C4C=CC(N5CCN(C)CC5)=CC=4N(C4CCOCC4)C(=O)C(F)(F)F)[C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1>CO>[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[N:18]=[C:19]3[C:25]([NH:26][C:27](=[O:54])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[CH:30][C:29]=4[NH:41][CH:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)c4ccc(N5CCN(C)CC5)cc4N(C(=O)C(F)(F)F)C4CCOCC4)c4ncc(Sc5cc(F)cc(F)c5)nc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)nc34)c(NC3CCOCC3)c2)CC1
Temperature: 65 °C
Yield: 57 %

Procedure:
0.27 ml (1.95 mmol) of triethylamine is added to 0.21 g (0.19 mmol) of a solution of N-(5-(3,5-difluorophenylthio)-1-(4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoyl)-1H-pyrazolo[3,4-b]pyrazine-3-yl)-4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzamide in 5 ml of methanol. The reaction medium is heated at 65° C. for 4 hours, and then overnight at room temperature. After evaporation of the solvent, the product is extracted several times with ethyl acetate. The organic phases are combined, washed with saturated sodium bicarbonate solution, dried on magnesium sulfate and concentrated. The residue is purified by silica gel chromatography (95:4:1 dichloromethane/methanol/ammonium as eluent) to yield 0.065 g (57%) of N-(5-(3,5-difluorophenylthio)-1-H-pyrazolo[3,4-b]pyrazine-3-yl)-4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH2:9][C:10]([OH:12])=O)#[N:8].[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:27])[CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C=O)C>[C:7]([CH2:9][C:10]([NH:27][CH:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][O:14][CH3:13])=[CH:22][CH:21]=1)[CH2:24][CH2:25][CH3:26])=[O:12])#[N:8]
Reactant: N#CCC(=O)O
Reactant: CCCC(N)c1ccc(OCOC)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCC(NC(=O)CC#N)c1ccc(OCOC)cc1
Temperature: 25 °C
Yield: 102.4 %

Procedure:
Oxalyl chloride (1.03 g, 8.15 mmol) was added drop-wise at ice bath temperature under nitrogen to a stirred solution of cyanoacetic acid (0.67 g, 7.9 mmol) in tetrahydrofuran (15 mL) to which 1-2 drops of DMF had been added. The mixture was stirred for an hour, then added slowly in one portion to a stirred solution of 1-(4-(methoxymethoxy)phenyl)butan-1-amine (1.1 g, 5.3 mmol) in THF (15 mL) at ice bath temperature under nitrogen. The mixture was allowed to warm gradually to room temperature and after 20 hours was stirred into 50 mL of saturated aq sodium bicarbonate and extracted 3× with dichloromethane. The combined extracts were washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo, leaving 1.5 g of dark violet syrup. The product was flash chromatographed on a column (50×70 mm) of silica gel (43-60 μm) eluting with Hxa/EtOAc 1:1 to afford 1.0 g (69%) of clear, dark oil; homogeneous by TLC.