Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].Cl>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCCl
Reactant: COc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCCl)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 139.2 %

Procedure:
p-Anisidine (12.3 g) was dissolved in CH2Cl2 (30 ml) and the solution was cooled to 5° C. Aqueous NaOH (6.6 g in 13 ml water) and 3-chloro-propionyl-chloride (19.05 g) were simultaneous added to the above solution over 40 minutes. The two phase mixture was stirred at 5° C. for another 30 min. Water (250 ml) and concentrated HCl (3 ml) were then added. The product was isolated by filtration, washed with water and dried to a constant weight to give N-(4-methoxyphenyl)-3-chloropropionamide (29.7 g, 94.6%) in 99.3% purity by HPLC analysis.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:21][CH2:22][CH:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:14]1([O:13][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][C:4]4[CH:3]=[CH:2][N:21]([CH2:22][CH:23]([OH:25])[CH3:24])[C:5]=43)=[CH:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(O)CN
Reactant: O=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1cc(OC3CCCC3)ccc1C2
Reaction time: 0.75 h
Yield: 48.5 %

Procedure:
A solution of 2.58 g of (RS)-2-(2-oxoethyl)-6-cyclopentoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.44 g (48%) of (RS)-1-(7-cyclopentoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([S-])(=[S:17])OCC.[K+]>N1C=CC=CC=1>[S:17]=[C:13]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[O:12]1
Reactant: CCOC(=S)[S-]
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C

Procedure:
Methyl 3-amino-4-hydroxybenzoate (5.09 g, 30.4 mmol) and potassium O-ethyl carbonodithioate (6.35 g, 39.6 mmol) were combined in pyridine (50 mL) and heated to reflux for two hours. The reaction mixture was cooled to ambient temperature. The mixture was filtered, washed with a 1 N aqueous hydrochloric acid solution, and dried on a vacuum filter overnight to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H) 7.63 (d, J=8.48 Hz, 1 H) 7.69 (d, J=1.70 Hz, 1 H) 7.89 (dd, J=8.82, 1.70 Hz, 1 H); MS (ESI−) m/z 207.87 (M−H)−.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:14]([C:32]2[CH:36]=[CH:35][O:34][C:33]=2[CH:37]=[O:38])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:42]([O:41][C:39]([N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[C:11]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:14]([C:32]2[CH:36]=[CH:35][O:34][C:33]=2[CH2:37][OH:38])=[CH:13][CH:12]=1)=[O:40])([CH3:44])([CH3:45])[CH3:43]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2C=O)c1OS(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccoc2CO)c1OS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
Sodium borohydride (0.304 g) was added to a solution of methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-(2-formylfuran-3-yl)-2-(4-methylbenzenesulfonyloxy)-benzoate (Intermediate 22, 3.9 g) in ethanol (50 mL) and the mixture was stirred for 15 minutes. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-(2-hydroxymethylfuran-3-yl)-2-(4-methylbenzene-sulfonyloxy)-benzoate (3.82 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[N:9][OH:10])[S:4][N:3]=1.Cl[CH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=1.[I-].[K+].N12CCCC1=NCCC2>C(#N)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](=[N:9][O:10][CH2:17][C:18]2[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][N:19]=2)[C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[S:4][N:3]=1
Reactant: Nc1ccnc(CCl)n1
Reactant: ON=C(c1ccsc1)c1snc(Cl)c1Cl
Agent: C1CN=C2CCCN2C1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccnc(CON=C(c2ccsc2)c2snc(Cl)c2Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
To a stirred suspension of 1-(3,4-dichloro-1,2-thiazol-5-yl)-N-hydroxy-1-(3-thienyl)methanimine (1.69 g, 6.06 mmol), 2-(chloromethyl)pyrimidin-4-amine (957 mg, 6.66 mmol) and potassium iodide (1.01 g, 6.06 mmol) in acetonitrile (15 mL) at 0° C. was added 1,5-diazabicyclo(4.3.0)non-5-ene (1.52 mL, 12.7 mmol). The mixture was stirred 10 min at 0° C., then overnight at room temperature. After dilution of the reaction mixture with water and extraction with ethyl acetate, the combined organic layers were dried over MgSO4, concentrated in vacuo, and the residue purified on silica gel to afford 2-[({[(3,4-dichloro-1,2-thiazol-5-yl)(3-thienyl)methylene]amino}oxy)methyl]pyrimidin-4-amine [150 mg, yield 3%].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[O:7])=[CH:2]1.OO.C([O-])(O)=[O:19].[Na+].C(OCC)(=O)C>[NH4+].[OH-].CO>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]([NH2:12])=[O:19])=[O:7])=[CH:2]1
Reactant: O=C([O-])O
Reactant: N#Cc1cccc(C(=O)c2ccsc2)c1
Agent: OO
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cccc(C(=O)c2ccsc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To 1.0 g (4.69 mmol) of 3-(thiophene-3-carbonyl)-benzonitrile in 8 mL of a concentrated NH4OH at room temperature was added 6 mL of 30% H2O2 drop-wise. The white reaction mixture was allowed to stir overnight at room temperature. Next day, to the reaction crude was added 60 mL of a saturated solution of NaHCO3 and 60 mL of ethyl acetate. After removing the aqueous layer, the organic layer was washed with brine, dried over Na2SO4, and concentrated. The concentrated crude was purified by flashy chromatography (dichloromethane:methanol, from 2 to 6% methanol over 16 column volume, then from 6 to 10% methanol over 5 column volume) to obtain 840 mg (77.8% yield) of white solids; 1H NMR 500 MHz (CDCl3) δ 8.27 (m, 2H), 8.15 (m, 2H), 7.93 (m, 1H), 7.74 (m, 1H), 7.65 (t, 1H), 7.55 (m, 2H).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH3:17])[CH3:14]>>[C:1]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[CH2:20][CH2:21]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCN(CC)CC1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCC(CN(CC)CC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-(diethylaminomethyl)piperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[CH2:10]([OH:12])[CH3:11].C(=O)C>Cl.O>[CH3:1][C:2]1([CH2:11][CH:10]=[O:12])[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:3]1[OH:4]
Reactant: Cc1c(O)cccc1O
Reactant: CCO
Agent: CC=O
Agent: Cl
Solvent: O
Product: CC1(CC=O)C(O)=CC=CC1O
Reaction time: 1.5 h

Procedure:
To a solution of 621 g. of 2-methylresorcinol in 1 l. of ethanol were added 209 g. of acetaldehyde and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated with stirring in an oil bath and, when the reaction mixture began to boil under reflux through exothermic reaction, heating was reduced and then heating under reflux was continued as it was for further 90 minutes. After completion of the reaction, the reaction mixture was poured into 5 l. of a cold water with stirring to give a pale brown powdery resin.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(O)cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(O)cc2)C1

Procedure:
The title compound is prepared from a mixture of 4-(3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)phenol, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: OCC1CO1
Product: OCC(O)CNCc1ccccc1

Procedure:
Glycerol glycid and benzylamine are reacted in a known manner to give 3-benzylamino-1,2-propanediol (boiling point 160°-170° C./0.01 mm Hg),
Reaction SMILES: [PH4+].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:12]([C@H:14]1[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][C@@H:17]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][C:36](=[O:56])[C@H:37]([CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)C2C=CC=CC=2)[NH:38][C:39]([O:41][CH3:42])=[O:40])[O:16][CH2:15]1)=O>C1COCC1>[CH3:42][O:41][C:39]([NH:38][C@H:37]([C:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C@H:17]1[O:16][CH2:15][C@@H:14](/[CH:12]=[CH:27]\[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18]1)=[O:56])[CH:43]([C:53]1[CH:52]=[CH:51][CH:50]=[CH:55][CH:54]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:40]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C=O)CO1)C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [PH4+]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](/C=C\Cc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) suspension of phosphonium salt triphenyl(2-phenylethyl)phosphonium iodide (2.5 eq) in THF (0.1M) was added dropwise a solution of 1M lithium bis(trimethylsilyl)amide (3 eq) in THF. The reaction mixture was stirred at that temperature for 30 min then cooled to −78° C. A solution of tert-butyl (2R,5S)-5-formyl-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq) in THF (1M) was added dropwise. The reaction mixture was stirred at that temperature for 30 min then allowed to warm to rt for 30 min, quenched with water and the organic layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 0% to 70% of EtOAc/Hex to afford the desired compound.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].Cl>P([O-])([O-])([O-])=O>[C:1]([NH:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)c1ccccc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: CC(=O)N[C@@H](C)c1ccccc1
Temperature: 20 °C
Reaction time: 27 h
Yield: 49.6 %

Procedure:
To 1 g (6.13 mmol) racemic N-acetyl 1-phenylethylamine (+/−)-1a, partially dissolved in 100 ml 0.1 M phosphate buffer pH 7.0, 100 ml (25.3 units) acylase from Arthrobacter aurescens Ac5R is added and the mixture is shaken (100 rpm) at 20° C. for 27 hours. After acidification (pH 2) by addition of HCl the reaction mixture is extracted three times with 100 ml dichloromethane. The combined organic layers are dried (MgSO4) and the solvent is distilled off after filtration, yielding 0.496 g (49.6%) of (S)-N-acetyl 1-phenylethylamine (−)-1a ([α]D20=−138.0° (c=1.0 EtOH), enantiomeric ratio S/R=96.8:3.2) as a white solid. The aqueous phase is neutralized by addition of NaHCO3 and extracted again with dichloromethane. Usual workup leads to 0.323 g (43.5%) of (R)-1-phenylethylamine (+)-1b ([α]D20=+29.4° (c=2.2 EtOH), enantiomeric ratio R/S=99.7:0.3) as colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:21]=[CH:22][C:23]3[C:28]([C:4]=2[NH:3]1)=[CH:27][CH:26]=[CH:25][CH:24]=3.[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=2)[C:5]2[CH:21]=[CH:22][C:23]3[C:28]([C:4]=2[NH:3]1)=[CH:27][CH:26]=[CH:25][CH:24]=3
Reactant: CCOC(=O)c1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Yield: 82.2 %

Procedure:
Ethyl 4-[2,4-Dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoate (1.19 g, 3.18 mmol) obtained in Example 102, (3), and 8 N aqueous sodium hydroxide (1.00 mL, 8.00 mmol) were stirred at room temperature in ethanol (10 mL) and water (5 mL). After the disappearance of the starting materials was confirmed, a post-treatment was performed in a conventional manner to obtain the title compound (905 mg, yield 82%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. EI-MS m/e (%): 288 (M+, 100), 287 ([M—H]+, 60).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]3[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (300 mg; 1.01 mmol), N-methylpiperazine (132 mg; 1.32 mmol) and K2CO3 (168 mg; 1.22 mmol) in DMF (4 ml) are heated to 80° C. for 45 minutes. The reaction mixture was diluted with MeOH, filtered and purified via chromatography (SiO2; CH2Cl2/MeOH/NH3conc 95:5:0.5) to yield the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 7.63 (d, 2H); 7.33 (d, 2H); 3.47 (s, 1H); 2.34 (bs, 8H); 2.16 (s, 3H); 1.30 (s, 12H). MS (m/z) ES+: 317 (MH+).
Reaction SMILES: [Na].[CH:2]([CH:6]([C:11]([O:13]C)=O)[C:7]([O:9]C)=O)([CH2:4][CH3:5])[CH3:3].[NH2:15][C:16]([NH2:18])=[O:17]>C(O)C>[CH:2]([CH:6]1[C:7](=[O:9])[NH:18][C:16](=[O:17])[NH:15][C:11]1=[O:13])([CH2:4][CH3:5])[CH3:3]
Reactant: CCC(C)C(C(=O)OC)C(=O)OC
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: CCC(C)C1C(=O)NC(=O)NC1=O
Yield: 43.4 %

Procedure:
110 mL of anhydrous ethanol was reacted with 7.72 g of sodium metal. Subsequently 17.6 g (0.1 mol) of dimethyl secbutylmalonate was added, followed (after about 5 minutes) by urea (6.72 g). The reaction mixture was refluxed for 15 hours and 60 mL of ethanol was distilled off. 200 mL of water was added to the residue followed by 20 mL of concentrated sulfuric acid. Precipitated crystals were filtered off. The product was then recrystallized from water to yield 8 g of colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@@H:7](O)[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(NC(C)C)(C)C.[CH3:33][C:34]([C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2)=[O:35]>C1COCC1.CCCCCC>[C:36]12([C:34](=[O:35])[CH2:33][C@@H:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH3:8])[CH2:43][CH:42]3[CH2:41][CH:40]([CH2:39][CH:38]([CH2:44]3)[CH2:37]1)[CH2:45]2
Reactant: C[C@H](O)c1ccncc1
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H](CC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 18 %

Procedure:
The method followed that described in Example 9 but using (-)-(S)-1-(4-pyridyl)ethanol (1.84 g, 15.0 mmol) in THF (80 ml), butyllithium (1.6M; 9.4 ml, 15.0 mmol) in hexane, p-toluenesulfonyl chloride (2.86 g, 15.0 mmol), diisopropylamine (6.31 ml, 45.0 mmol) in THF (120 ml), butyllithium (1.6M; 28.12 ml, 45.0 mmol) in hexane and 1-adamantyl methyl ketone (8.0 g, 45 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:50:1 gave the title compound (765 mg, 18%), which crystallised from hexane. m.p. 46°-48° C.; [α]D +6.8° (c 1.0, MeOH). IR, NMR and MS data were the same as given in Example 14.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](=O)[C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][NH:7][CH:6]=1)=[O:4].CN(C=O)C.S(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:10]([Cl:23])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)c1c[nH]cc(C(=O)OC)c1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(C(=O)OC)c1Cl
Yield: 41 %

Procedure:
A mixture of 16.38 g (77.6 mmol) of 4-oxo-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester (prepared according to the method described in S. Zupancic, Heterocycles; 2000; 2033–2042) and 0.5 ml of DMF in 150 ml of thionyl chloride is heated at reflux for 2 hours. Excess thionyl chloride is removed under vacuum and the residue is added to aqueous NaHCO3, and extracted in ethyl acetate. The phases are separated and the organic layer is dried and evaporated. The residue is washed with aqueous K2CO3 and water, and dried. There is obtained 7.35 g (41% yield) of white solid (M+1=230).
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>C(O)(C)(C)C>[N+:1]([C:4]1([CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C1CCCCC1
Reactant: C=CC(=O)OCC
Solvent: CC(C)(C)O
Product: CCOC(=O)CCC1([N+](=O)[O-])CCCCC1
Yield: 87 %

Procedure:
99.5 g of nitrocyclohexane was dissolved in 40 ml of t-butanol, and 83.4 ml of ethyl acrylate was added thereto in the presence of 7 ml of 40% Triton B. The mixture was reacted at room temperature to give 153 g (yield: 87%) of 1-nitro-l-(2-ethoxycarbonylethyl)cyclohexane. Then, 20 g of this substance was dissolved in ethanol and 3.6 g of Raney nickel was added thereto. The mixture was strongly stirred in the presence of hydrogen gas (70 kg/cm2), and then the Raney nickel was removed. The reaction solution was refluxed under heating for 5 hours. Then, ethanol was distilled off to give 8.0 g (yield: 62%) of 1-aza-2-oxospiro[4.5]decane8.0 g of this substance was dissolved in 30 ml of THF, and 3.6 g of LiAlH4 was added thereto. The mixture was reacted at room temperature for 15 hours to give 7.4 g (yield: 83%) of 1-azaspiro[4.5]decane.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[C:29]3[CH:28]=[C:27]([C:30]4[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=4)[N:26]=[CH:25][C:24]=3[CH:23]=[N:22]2)[N:16]=1.O1CCOCC1.Cl>>[CH3:36][C:32]1[N:31]=[C:30]([C:27]2[N:26]=[CH:25][C:24]3[CH:23]=[N:22][N:21]([C:17]4[N:16]=[C:15]([CH:3]5[CH:2]([OH:1])[CH2:7][CH2:6][NH:5][CH2:4]5)[CH:20]=[CH:19][CH:18]=4)[C:29]=3[CH:28]=2)[CH:35]=[N:34][CH:33]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CN(C(=O)OC(C)(C)C)CCC3O)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CNCCC3O)n2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 4-hydroxy-3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperidine-1-carboxylate (35 mg, 0.072 mmol) in 1,4-dioxane (2.00 mL, 23.4 mmol) was added hydrogen chloride (4 mol/L) in 1,4-dioxane (1.00 mL, 4.00 mmol). The reaction was stirred at RT 18 h. The reaction was concentrated and purified by reverse phase HPLC to yield 265. MS (ESI) m/z: 388.1.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[C:11]1[C:12]([NH2:33])=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=2[CH3:32])[N:16]=1>C1COCC1>[CH3:32][C:18]1[CH:19]=[CH:20][C:21]([S:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)[C:12]([NH2:33])=[N:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(Cl)n1
Reactant: Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(Nc2cccnc2)n1

Procedure:
A suspension of NaH (60% dispersion in oil) (12 mg, 0.298 mmol) is stirred in THF (3 ml). Pyridine-3-ylamine (28 mg, 0.293 mmol) is added and gas evolved. Once all gas production is stopped 3-Chloro-5-[2-methyl-5-(morpholine-4-sulfonyl)-phenyl]-pyrazin-2-ylamine (Intermediate M) (100 mg, 0.271 mmol) in THF (3 ml) is added. The reaction mixture is microwaved at 120° C. for 10 minutes. More NaH (60%) (33 mg, 0.813 mmol) is added to the reaction mixture and the sample is microwaved at 120° C. for 40 minutes. The reaction is quenched with water (100 ml) and evaporated to dryness in vacuo. The brown residue is purified by reverse phase column chromatography to yield the title compound as a brown glass. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (1H, d), 8.99 (1H, s), 8.38-8.33 (3H, m), 7.81 (1H, s), 7.70 (1H, d), 7.66-7.60 (5H, m), 3.64 (4H, t), 2.88 (4H, t), 2.54 (3H, s); MS m/z 427 [M+H]+