Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[N:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12].O.[OH-].[Na+]>C1COCC1>[CH3:7][O:8][C:9]1[C:10]([CH2:11][OH:12])=[CH:15][CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)c1cccnc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of aluminum lithium hydride (1.43 g) in THF (126 ml) was added a solution of methyl 2-methoxynicotinate (6.3 g) in THF (63 ml) at 0° C. The mixture was stirred at room temperature for 2 hours, and water (6.3 ml), 15% aqueous solution of sodium hydroxide (6.3 ml) and water (18.9 ml) were sequentially added to the solution at 0° C. The mixture was filtered with Celite, and washed with methanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give (2-methoxy-3-pyridinyl)methanol (5.0 g).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Reactant: OCC(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Br)nn(CC(O)CO)c1Br
Temperature: 80 °C
Yield: 63.7 %

Procedure:
A mixture of 3,5-dibromo-4-nitropyrazole (2) (40.0 g; 147 mmol) in DMF (200 ml) was added over 15 minutes to a suspension of NaH (6.5 g, 162 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (320 ml) with stirring and under an inert atmosphere. After stirring for 30 minutes, a solution of 3-bromo-1,2-propanediol (19.4 ml; 221 mmol) in DMF (80 ml) was added dropwise. The reaction mixture was heated at 80° C. for 3 hours and the DMF was then evaporated off under reduced pressure. A mixture of DCM/water (480 ml, 2/1) was added. A yellow solid precipitated out. After washing with ether (50 ml), the 3-(3,5-dibromo-4-nitropyrazol-1-yl)-propane-1,2-diol (32.3 g, 63%) was obtained as a white solid (23.3 g; 48%).
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH2:41][CH:42]2[CH2:48][CH2:47][CH:46]3[CH:44]([C:45]3([F:50])[F:49])[CH2:43]2)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH2:41][CH:42]3[CH2:48][CH2:47][CH:46]4[CH:44]([C:45]4([F:50])[F:49])[CH2:43]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCC3C(C2)C3(F)F)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCC3C(C2)C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 5-chloro-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoate, the title compound was obtained as oil (0.35 g, 48%): MS (ES+) m/z 341.07 (M−55).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][N:12]=2)[CH:7]=[CH:6]1.Cl[C:15](=[O:20])[C:16]([O:18][CH3:19])=[O:17].CO>C(Cl)Cl>[O:20]=[C:15]([C:7]1[C:8]2[C:13](=[N:12][CH:11]=[CH:10][CH:9]=2)[NH:5][CH:6]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(=O)Cl
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(=O)c1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a suspension of aluminum chloride (56.4 g, 423 mmol, 5 equiv.) in DCM (50 mL) was added 7-azaindole (10.0 g, 85 mmol). After 1 h at room temperature the resulting mixture was cooled to 0° C. and methyl chlorooxoacetate (51.9 g, 423 mmol, 5 equiv.) was added dropwise. After a period of 18 h at room temperature the reaction mixture was cooled to 0° C. and methanol (300 mL) was added. After a period of 0.5 h at room temperature, the solvents were evaporated. DCM (500 mL) and saturated NaHCO3 (600 mL) were added. The organic layer was separated and the water extracted with DCM (250 mL). The organic phases were combined and stirred for 18 h with a solution of potassium sodium tartrate (166 g in 500 mL of water). The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography with 50% ethyl acetate in hexane to provide 13 g of the title compound.
Reaction SMILES: [C:1]([O:17]CC)(=[O:16])[CH2:2][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:5]([O:7]CC)=[O:6])[OH:4].[C:20]1(CCO)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(=O)([O-])[O-].[K+].[K+]>[C:20]1([CH2:15][CH2:14][O:13][C:11](=[O:12])[CH2:10][C:3]([CH2:2][C:1]([OH:17])=[O:16])([C:5]([OH:7])=[O:6])[OH:4])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Reactant: OCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)CC(O)(CC(=O)OCCc1ccccc1)C(=O)O
Yield: 69 %

Procedure:
After 300 mg of potassium carbonate were added to 10 g of triethyl citrate and 13.3 g of phenylethyl alcohol, stirring was continued under heating for 6 hours while removing ethanol formed. After the end of the reaction, an ether layer was washed with 50 ml of diethyl ether and with 50 ml of purified water. The ether layer was dried with magnesium sulfide and then concentrated under reduced pressure. Distillation under reduced pressure was further carried out to remove unreacted phenylethyl alcohol and triethyl citrate. As a bottom residue after the distillation, 7.4 g of a citric acid phenylethyl ester derivative were obtained. According to a GC-MS analysis, it was confirmed the production of monophenylethyldiethyl citrate and diphenylethylmonoethyl citrate.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH:1]1([CH:7]([C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)[C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: O=CC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(c2ccc(N)cc2)C2CCCCC2)cc1
Temperature: 110 °C

Procedure:
The synthesis of an amine hardener composition was carried out as follows: Cyclohexane carboxaldehyde (5 g, 44.6 mmol, 1 equiv) and aniline (12.5 g, 134.3 mmol, 3 equiv) were added to a 100 mL two-necked round bottom flask equipped with a condenser and thermocouple. The flask was placed under nitrogen and 0.25 mL concentrated HCl was added. After refluxing at 110° C. for 5 hours, the reaction was allowed to cool to 50° C. and 0.75 mL of 50 wt % aqueous NaOH was added. Ethyl acetate (EtOAc) was added and the solution was washed with water (3×30 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo. The resulting mixture contained residual aniline. Purification of the material was performed via column chromatography (66:33 hexane:EtOAc) to yield a tacky yellow solid, 4,4′-(cyclohexylmethylene)dianiline [Structure (XI)], Rf=0.25.
Reaction SMILES: S(C)C.[CH3:4][O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[N:23]([CH3:24])[C:22](=O)[CH2:21][CH2:20][N:19]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[C:18]=3[N:31]=2)=[C:9]([O:32][CH3:33])[CH:8]=1.Cl>C1COCC1.O>[CH3:4][O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[N:23]([CH3:24])[CH2:22][CH2:21][CH2:20][N:19]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[C:18]=3[N:31]=2)=[C:9]([O:32][CH3:33])[CH:8]=1
Reactant: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CCC(=O)N3C)c(OC)c1
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CCCN3C)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
BH3.SMe2 (1.36 mL, 5.0 M in Et2O, 6.8 mmol) was added to solution of methyl4-[(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzoate (Intermediate 8; 290 mg, 0.68 mmol) in THF (4 mL) and stirred for 5 h at ambient temperature under an atmosphere of nitrogen. HCl (10 mL, concentrated aqueous) was added and the resulting solution was stirred at ambient temperature for 16 h. The HCl solution was then diluted with water (50 mL), and loaded onto an SCX-2 column. The SCX-2 column was then washed with water (50 mL) and MeOH (50 mL). The product was then eluted from the SCX-2 column with NH3 (50 mL, 7M in MeOH). The volatiles were then removed under reduced pressure to afford the title compound (250 mg, 89%) as a solid.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=O)[CH2:8][CH2:7]1)=O)C.[CH2:23]([O:25]C(N1CCC(C(C(OCC)=O)N)(C2C=CC=CC=2C)CC1)=O)C.C(O)(=O)CO.N>Cl>[OH:25][CH2:23][C:13]1[N:12]([CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)[C:16]2[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cccc(C)c32)CC1
Reactant: CCOC(=O)C(N)C1(c2ccccc2C)CCN(C(=O)OCC)CC1
Agent: Cl
Agent: N
Agent: O=C(O)CO
Product: Cc1cccc2nc(CO)n(C3CCNCC3)c12
Temperature: 100 °C
Reaction time: 72 h
Yield: 41 %

Procedure:
The 1-Ethoxycarbonyl-4-(1,3-dihydro-7-methyl-2H-benzimidazol-2-on-1-yl)piperidine (40 mg) obtained in Reference Example 11, (d) was dissolved in 5 N aqueous hydrochloric acid (0.8 ml), added with glycolic acid (16 mg) and stirred at 100° C. for 3 days. The reaction mixture was made alkaline by addition of aqueous ammonia and extracted twice with dichloromethane (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 14.4 mg of the title compound. Yield: 41%.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34](OCC)=[O:35])=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:20][CH:19]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]4[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]5[N:85]=[CH:86][NH:82][N:83]=5)[CH:92]=4)=[O:35])=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1nc2scc(-c3ccc(C)cc3)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: Cc1ccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)cc1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(4-methylphenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 81 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (162.0 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>N1C=CC=CC=1>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:18])=[CH:3][C:2]=1[NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(CC(=O)Nc2cccc(C3CCCCC3)c2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cc(CC(=O)Nc2cccc(C3CCCCC3)c2)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
3-Amino-4-benzyloxy-N-(3-cyclohexylphenyl)phenylacetamide (the compound of Example 33) (200 mg) is dissolved in pyridine (5 ml), and thereto is added dropwise methanesulfonyl chloride (111 mg), and the mixture is stirred for 0.5 hour. Water is added to the mixture, and the mixture is extracted with ethyl acetate. The organic layer is dried under sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-benzyloxy-N-(3-cyclohexylphenyl)-3-methanesulfonylaminophenyl-acetamide (200 mg). This product is dissolved in ethanol (10 ml), and thereto is added 10% palladium on carbon (20 mg). The mixture is subjected to catalytic hydrogenation at 25° C. The catalyst is removed by filtration, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 10% chloroform/methanol) to give the desired compound (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[N:23]1[CH:27]=[C:26]([CH2:28][CH2:29][NH2:30])[NH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.C1COCC1>CO.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:30][CH2:29][CH2:28][C:26]3[NH:25][CH:24]=[N:23][CH:27]=3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: NCCc1cnc[nH]1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCCc3cnc[nH]3)c(Br)c2)c(SC)s1

Procedure:
The reaction was conducted following the procedure for Example 156: step a, using. 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2: step c), 2-(3H-imidazol-4-yl)-ethylamine (0.027 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (0%–6% MeOH/DCM) yielded the title compound. ESI-MS (m/z): Calcd. for C17H17BrN4O4S3: 518.44 (M+H); found 517.0, 519.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]=[C:31]=[O:32])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: COc1cc(N=C=O)cc(OC)c1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: COc1cc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)cc(OC)c1

Procedure:
59.2 mg of solid beige-coloured 3-{4-[3-(3,5-dimethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3,5-dimethoxyphenyl isocyanate.
Reaction SMILES: [Mg].CN(C)P(N(C)C)(N(C)C)=O.Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Cl.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].C([O-])(O)=O.[Na+]>>[CH3:23][Si:22]([CH3:25])([CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)Cl
Reactant: Clc1ccccc1Cl
Agent: O=C([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C[Si](C)(C)c1ccccc1[Si](C)(C)C
Temperature: 70 °C
Yield: 54.13 %

Procedure:
Magnesium (9.72 g, 400 mmol), hexamethylphosphoramide (HMPA) (80 mL, 460 mmol), 1,2-dichlorobenzene (14.76 g, 100 mmol), and a catalytic amount of 12 were combined in a 500 mL round bottomed flask and heated to 70° C. with stirring. Chlorotrimethylsilane was added dropwise to the solution at 70° C. The solution was stirred for an additional 30 minutes and then heated to 100° C. for 48 h. After cooling, the reaction mixture was poured over ice and NaHCO3. The Mg and precipitate were filtered off and the filtrate was extracted with ether (3×, 200 mL). The organic phase was washed with water (2×, 400 mL) and brine (1×, 400 mL) and dried with Na2SO4 and concentrated. The product was distilled under reduced pressure at 128-133° C. to yield a light yellow oil (12.0426 g, 54.13%). 1H NMR (300 MHz, CDCl3) δ 7.85 (dd, 2H, J=3.4 Hz, J=5.5 Hz, ArH), 7.49 (dd, 2H, J=3.4 Hz, J=5.5 Hz, ArH), 0.55 (s, 18H, CH3); 13C NMR (300 MHz, CDCl3) δ 145.98, 135.17, 127.76, 1.96
Reaction SMILES: C(OC(N1CCCC(NC2N=C(C)C=C(C)N=2)C1C)=O)(C)(C)C.C(OC([N:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=2)[C@@H:32]1[CH3:45])=O)(C)(C)C>>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([NH:37][C@@H:33]2[CH2:34][CH2:35][CH2:36][NH:31][C@H:32]2[CH3:45])=[N:39][CH:40]=1
Reactant: C[C@H]1[C@H](Nc2ccc(Cl)cn2)CCCN1C(=O)OC(C)(C)C
Agent: Cc1cc(C)nc(NC2CCCN(C(=O)OC(C)(C)C)C2C)n1
Product: C[C@@H]1NCCC[C@H]1Nc1ccc(Cl)cn1

Procedure:
Prepared analogous to Example 1 substituting (±)-tert-butyl-3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylpiperidine-1-carboxylate with the title compound from Step A.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[O:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[CH:17]=2)[CH:9]=1)=[O:4].[OH-].[Na+]>CS(C)=O.O>[O:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=[C:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:25])[N:7]=1
Reactant: COC(=O)c1cc(-c2ccccc2-c2cc3ccccc3o2)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1nc(-c2ccccc2-c2cc3ccccc3o2)cc1C(=O)O
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A suspension of 0.90 g (2.71 mmol) of 5-(3-benzofuran-2-yl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (6′A) in 8.50 ml of DMSO was treated at RT with 1.35 ml (5.42 mmol) of aqueous 1N NaOH. After 2 h, reaction was diluted with chilled water and extracted 1× with Et2O. The water phase was acidified with aqueous 10% KHSO4 and extracted with Et2O (2×). These organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.84 g (97%) of the title compound as white powder. MS: 317.1 (M−H−).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C(Cl)Cl>[C:7]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCO
Solvent: ClCCl
Product: O=C(NCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A CH2Cl2 solution (300 mL) of 3-aminopropanol (10 g, 0.133 mole) and TEA (20 g, 0.2 mole) was cooled to OC, followed by slow addition of CH2Cl2 solution (25 mL) of benzyl chloroformate (25 g, 0.147 mole). The resulting solution was gradually warmed to room temperature. The stirring was continued at room temperature overnight. The reaction mixture was washed with H2O, dried and purified by flash column chromatography (on silica gel, CH3OH—CH2Cl2) to yield 16.4 g, 58.9% of title compound. 1H NMR (CDCl3): δ 7.26-740 (m, 5H), 5.10 & 5.0-5.10 (s+m, 3H), 3.68 (q, 2H), 3.36 (q, 2H), 2.58 (t, 1H), 1.70 (p, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:3].[OH-].[Na+].O.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O1CCCC1.CCOCC>[CH2:25]([O:24][C:22]([N:15]1[CH2:14][CH2:13][CH:12]([S:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=2)[CH2:17][CH2:16]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(C)Cc1ccc(SC2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN(C)Cc1ccc(SC2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
250 mg (1 mmol) of 4-[4-(dimethylaminomethyl)phenylthio]piperidine in 20 ml tetrahydrofuran are combined with 2 ml 2N sodium hydroxide solution and 5 ml water. At ambient temperature 200 mg (1.2 mmol) of benzyl chloroformate in 5 ml tetrahydrofuran are slowly added dropwise. After 1.5 hours at ambient temperature some benzyl chloroformate and sodium hydroxide solution are again added. After the addition of 100 ml ether the mixture is washed with saturated saline solution, the organic phase is dried with magnesium sulphate and concentrated by evaporation. The product obtained after purification by column chromatography (aluminium oxide, petroleum ether/ethyl acetate=4:1, v:v) is converted into the hydrochloride with ethereal hydrochloric acid. 190 mg (45.1% of theory) of the title compound are obtained as a colourless powder, melting point 144° C.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:27]([CH3:29])[CH3:28].C(Cl)Cl.CCOCC.CO>CN(C)C=O>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:27]([CH3:29])[CH3:28])=[C:4]([NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Cc1cccnc1CNc1nc(F)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cccnc1CNc1nc(F)nc2c1ncn2C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-fluoro-N-(3-methylpyridin-2-yl)methyl-9H-purin-6-amine (0.3 g, 1.17 mmol) in dimethylformamide (10 ml) at room temperature under an argon atmosphere, was added powdered, anhydrous K2CO3 (0.8 g, 5 eq, 5.85 mmol), followed by 2-bromopropane (1.15 ml, 11.7 mmol). The reaction mixture was stirred at room temperature for 24 h, when DCM:ether:MeOH (55:40:5), indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between EtOAc (50 ml) and water (50 ml). The aqueous phase was extracted with more EtOAc (2×50 ml) and the combined organic phase washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with CHCl3:MeOH (98:2) to afford the title compound as a slightly yellow film (170 mg, 48%). δH (CDCl3, 500 MHz) 1.51 (6 H, d, J 7.5, CH[CH3]2), 2.28 (3 H, s, CH3), 4.68-4.65 (3H, m, NHCH2 and CHMe2), 7.08-7.05 (1 H, m, ArH), 7.4 (1 H, d, J 5, ArH), 7.72 (1 H, s, ArH), 7.93 (1H, s, br, NH), 8.34 (1 H, d, J 5, ArH); δC (CDCl3, 500 MHz) 160.09 (C), 158.43 (C), 155.97 (C), 154.06 (C), 145.85 (CH), 137.73 (CH), 137.54 (CH), 130.67 (C), 122.28 (CH), 118.73 (C), 47.28 (CH), 42.87 (CH2), 22.43 (2×CH3), 17.66 (CH3); 19F NMR δ −50.20; m/z 301.2 (M+H)