Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[C:29]1[C:34]([N+:35]([O-:37])=[O:36])=[C:33]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=[C:31]([CH3:43])[N:30]=1)(=O)=O>C1(C)C=CC=CC=1>[CH2:39]([NH:38][C:33]1[CH:32]=[C:31]([CH3:43])[N:30]=[C:29]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:34]=1[N+:35]([O-:37])=[O:36])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCNc1cc(C)nc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-]
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCNc1cc(C)nc(N(Cc2ccccc2)Cc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.4 %

Procedure:
Dibenzylamine (1.04 g, 5.28 mmole), triethylamine (0.53 g, 5.28 mmole), 4-butylamino-6-methyl-3-nitro-2-pyridinyl trifluoromethanesulfonate (1.72 g, 5.28 mmole) and toluene (45 mL) were combined and heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature then filtered through a layer of silica gel. The silica gel was eluted with methylene chloride. The combined organic filtrates were evaporated to provide 2.08 g of an oily semisolid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([CH3:16])[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:16])[CH3:15])=[O:31]
Reactant: CNc1cnccc1-c1ccc(F)cc1C
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of 4-(4-fluoro-2-methylphenyl)-N-methylpyridin-3-amine (60 mg, 0.28 mmol, example 23, intermediate a) and DIPEA (97 μL, 0.56 mmol) was added 3,5-dichlorobenzoyl chloride (87 mg, 0.42 mmol, CAS RN 2905-62-6) in CH2Cl2 (2 mL). After stirring for 16 hours, the reaction mixture was loaded directly onto a silica gel column and elution with EtOAc gave the title compound (43 mg, 40%). MS (ESI): m/z=388.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH:25]3[C:30]([OH:32])=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41]>C1COCC1>[C:40]([NH:44][C:45]([N:27]1[CH2:28][CH2:29][C@@H:24]([NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C@@H:25]([C:30]([OH:32])=[O:31])[CH2:26]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCNCC3C(=O)O)cc2)c2ccccc2n1
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(=O)NC(C)(C)C)C[C@@H]3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a solution of 0.5 g (1.1 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid (Example 29, Step 1) and triethylamine (0.3 mL, 2.197 mmol) in THF (10 mL) at 0° C. was added tert-butylisocyanate (0.130 g, 1.32 mmol). The reaction mixture was allowed to warm to 25° C. and then stirred for 19 h. The THF was removed in vacuo and the resulting oil was diluted with ethyl acetate (100 mL). The organics were washed with saturated aqueous sodium chloride (2×30 mL), dried over MgSO4, filtered and concentrated to obtain a crude solid (0.580 g). The crude product was purified by reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting an acetonitrile:water gradient, to afford (3S,4R)-1-tert-butylcarbamoyl-4-[4-(2-methyl-quinolin-4-yl methoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid as an amorphous white solid (0.5 g, 88.5%). MS: 555 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:9]2=[O:14])([O-])=O.O.O.[Sn](Cl)Cl.O1CCCC1>>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:9]2=[O:14]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1CC1CCOCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc2c(=O)n(CC3CCOCC3)ccc12

Procedure:
5-Nitro-2-(tetrahydro-pyran-4-ylmethyl)-2H-isoquinolin-1-one (0.78 g, 0.0027 mol) and tin dichloride dihydrate (2 g, 0.01 mol) were stirred in tetrahydrofuran (10 mL, 0.1 mol) at room temperature for 24 hours. The mixture was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 solution, separated. The aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, and purified via flash chromatography (40 g of silica gel, 0-100% EtOAc/Hexanes) to give a yellow solid. MS m/z (M+H) 259.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10](O)([CH3:13])([CH3:12])[CH3:11].C(OCC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:10]([O:8][C:7]([CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)=[O:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)O
Reactant: O=C1CCC(C(=O)O)C1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(=O)C1
Temperature: 2 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a cold (ice bath) solution of 3-oxo-1-cyclopentanecarboxylic acid (1.50 g), tert-butylalcohol (1.05 g) and 4-dimethylaminopyridine (140 mg) in dichloromethane (9 mL) was added a solution of dicyclocarbodiimide in dichloromethane (9 mL). The mixture was stirred 3 hours at ca. 2° C. then diethylether (30 mL) was added and the precipitate was filtered off and discarded. The solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (9:1 v/v) as eluant to afford the title compound (1.80 g, 96%) as colorless oil. MS (EI): 111 (M-OtBu.)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:20][C:21]1[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH2:20][C:21]3[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:31])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cccc2cc(CCl)c(-c3ccccc3Cl)nc12
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3ccc(=O)c4c(N)ncnc43)c(-c3ccccc3Cl)nc12
Temperature: 140 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1 g, 0.616 mmol), Cs2CO3 (0.3013 g, 0.925 mmol, 1.5 eq), and KI (0.0102 g, 0.0616 mmol, 0.1 eq) in DMF (2 mL) was added 3-(chloromethyl)-2-(2-chlorophenyl)-8-methyl-quinoline (0.2049 g, 0.678 mmol, 1.1 eq) and the mixture was stirred at 140° C. for 2.5 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 10 min as eluent to provide 4-amino-8-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one as white solid. The white solid was triturated with EtOAc-Hexane (1:1) and filtered to provide 4-amino-8-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3Kδ IC50=58 nM] as white solid. 1H NMR (DMSO-d6) δ ppm 9.53 (1 H, d, J=4.7 Hz), 8.13 (1 H, s), 8.04-8.11 (2 H, m), 7.84 (1 H, d, J=7.8 Hz), 7.78 (1 H, d, J=7.8 Hz), 7.64 (1 H, d, J=7.0 Hz), 7.38-7.59 (5 H, m), 6.12 (1H, d, J=7.8 Hz), 5.40 (2 H, d, J=6.3 Hz), 2.64 (3 H, s). Mass Spectrum (ESI) m/e=428.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][O:24][CH3:25])=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]2([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[CH3:26])=[CH:4][CH:3]=1.[H-].[Na+].[C:39]([O:43][C:44](=[O:47])[CH2:45]Br)([CH3:42])([CH3:41])[CH3:40].O>O1CCCC1>[C:39]([O:43][C:44]([CH2:45][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][O:24][CH3:25])=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]2([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:31][CH:32]=2)[CH3:26])=[CH:4][CH:3]=1)=[O:47])([CH3:42])([CH3:41])[CH3:40]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCc2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
To a solution of 4-[4-(4-hydroxyphenyl)-1-butyl]-7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman (481 mg, 0.976 mmol) in dry tetrahydrofuran (8 ml) was added sodium hydride (22.7 mg, 1.418 mmol) at room temperature and stirred for 20 minutes. Bromoacetic acid tert-butylester (276.7 mg, 1.418 mmol) was added thereto at the same temperature and stirred for 20 minutes. After the reaction was completed, water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 589 mg (yield: quant.) of the title compound as a colorless oil. The resulting compound was used in the next reaction without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)C.[H][H]>C1(C)C=CC=CC=1.[Pt]>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reaction time: 4 h
Yield: 108.8 %

Procedure:
tert-Butyl [4-(7-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate (20.36 g, 43.6 mmol) was slurried in toluene (450 mL) and added to a Parr vessel charged with 5% platinum on carbon (4.3 g) and a small amount of toluene. 2-Propanol (50 mL) was added, and the vessel was charged with hydrogen (30 psi, 2.1×105 Pa). The hydrogen was replaced three times. After 4 hours, the catalyst was removed by filtration through a layer of CELITE filter aid, and the filter cake was rinsed with toluene (0.5 L), 50% toluene/2-propanol (0.5 L), and 2-propanol (0.25 L). The filtrate was concentrated under reduced pressure, and the residue was mixed with toluene and concentrated under reduced pressure to provide 20.7 g of tert-butyl [4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]carbamate as a viscous, black oil.
Reaction SMILES: [N:1]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].CCN(C(C)C)C(C)C.Cl.[Cl:27][C:28]1[CH:39]=[CH:38][C:31]2[NH:32][C:33]([C@@H:35]([NH2:37])[CH3:36])=[N:34][C:30]=2[CH:29]=1>CN(C=O)C>[Cl:27][C:28]1[CH:39]=[CH:38][C:31]2[NH:32][C:33]([C@@H:35]([NH:37][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][C:2]4=[O:7])=[CH:16][CH:15]=3)[CH3:36])=[N:34][C:30]=2[CH:29]=1
Reactant: O=C(O)c1ccc(N2CCOCC2=O)cc1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CCOCC2=O)cc1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
254 mg (1.15 mmol) 4-(morpholin-3-on-4-yl)-benzoic acid (prepared by synthesis sequence analogously to Example 30a, 2d and 21a) are placed in 5 ml DMF and 428 mg (1.0 mmol) PfTU and 514 μl (3.0 mmol) DIPEA are added. After stirring at ambient temperature for 10 minutes 232 mg (1.0 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine-hydrochloride are added and the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is filtered through basic aluminium oxide and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/methanol 100:0->90:10), the corresponding fractions are evaporated down i. vac., the residue is dissolved in acetonitrile/water and lyophilised.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23]C)=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29].[OH-].[K+].Cl>O.CO>[NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:13][CH:14]=2)[C:6]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[Cl:29]
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 111.1 %

Procedure:
5-Aminomethyl-2-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (1.64 g. 3.98 mmol, 1 eq), 0.5N KOH in methanol (11.96 mL, 5.98 mmol, 1.5 eq), water (1.0 mL) and methanol (20 mL) were mixed and refluxed under N2 overnight. The solution was then brought to neutrality with 1N HCl and the solvents removed in vacuo. The residue was taken up in DMF and the salts filtered off. The DMF was then removed in vacuo to yield 1.76 g of a glass. NMR (200 MHz, DMSO-d6) δ 7.50 (d, 1H, J=7 Hz); 7.40-7.18 (m, 5H); 6.92 (d, 2H, J=8 Hz); 6.50 (bm, 3H); 5.26 (s, 2H); 3.60 (s, 2H); 2.55 (t, 2H, J=7 Hz); 1.51 (t of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:21]([NH:20][CH2:18][CH3:19])=[O:22])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Reactant: CCN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A suspension of 5-chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine, which may be produced as in Example 1A (210 mg, 0.86 mmol), ethylisocyanate (600 mg, 8.6 mmol), and dibutyltin diacetate (2 drops) in a mixture of toluene and THF (1:1, 10 mL) was heated at 110° C. with stirring in a sealed tube for 5 h. The homogeneous reaction mixture was cooled to RT. The solvent was removed under reduced pressure and the resulting solid was triturated with chloroform (10 mL) and hexanes (250 mL). The solid was filtered, washed with hexanes, and dried to obtain 1-(5-Chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-ethyl-urea LCMS (APCI+) 317.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH2:15](Br)[CH:16]1[O:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[O:20]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:15][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: BrCC1CCCO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CC3CCCO3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), tetrahydrofurfuryl bromide (51 mg, 0.31 mmol, Alfa Aesar, Cat. No. A15192), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with ethyl acetate. The organic solution was washed with water and brine, and dried over Na2SO4. After filtration the filtrate was concentrated to yield 51 mg of the product.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[N:10][CH2:9][CH:8]2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]1([CH:7]2[O:12][C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[N:10][CH2:9][CH:8]2[O:18][C:26](=[O:27])[NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: OC1CN=C(c2cccs2)OC1c1ccccc1
Product: O=C(Nc1ccccc1)OC1CN=C(c2cccs2)OC1c1ccccc1
Yield: 77.4 %

Procedure:
Working in a manner similar to that described in Example 12, but starting with (5RS, 6SR)-6-phenyl-2-(2-thienyl)-5,6-dihydro-4H-1,3-oxazin-5-ol (1.55 g) and phenyl isocyanate (0.8 g), and after recrystallization in isopropanol, (5RS, 6SR)-6-phenyl-5-phenylcarbamoyloxy-2-(2-thienyl)-5,6-dihydro-4H-1,3-oxazine (1.75 g), m.p. 98° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][N:37]3[CH:38]=[C:34]([C:33]([F:43])([F:32])[F:44])[CH:35]=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cn1cc(C(F)(F)F)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)cn3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79.1 μmol), (4-trifluoromethyl-pyrazol-1-yl)-acetic acid (20.7 mg, 106.9 μmol) and DIPEA (48 μL, 276.8 μmol) in THF (3 mL), T3P (166 μL, 276.8 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (71%, 35 mg).
Reaction SMILES: O=O.[O:3]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([NH:7][CH3:8])=[O:6].CO.[H][H]>Cl.C(Cl)Cl>[OH:3][C@H:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([NH:7][CH3:8])=[O:6]
Reactant: [H][H]
Reactant: CNC(=O)C(=O)C(C)(C)C
Agent: Cl
Agent: O=O
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)[C@H](O)C(C)(C)C
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
A catalyst solution was prepared in a glove box (O2 content<1 ppm) by dissolving 385 mg (0.5 mmol) of [Ru(OAc)2((R)-BIPHEMP)] in 40 ml of a 0.025 molar methanolic hydrochloric acid solution and 40 ml of methylene chloride, subsequently stirred at 20° C. for 1.5 hours and thereafter transferred into a pressure-tight catalyst supply vessel. A 2 l steel autoclave was charged with 71.6 g (0.5 mol) of 2-keto-3,3,N-trimethyl-butyramide and 310 ml of methanol and sealed. After replacement of the atmosphere with hydrogen the catalyst solution was allowed to flow from the catalyst supply vessel into the autoclave with slight over-pressure and the hydrogenation was carried out while stirring at 60° C. and at a pressure of 60 bar (6 MPa). After 20 hours the hydrogenation was interrupted and the reaction mixture was evaporated. From a solution of the residue in 250 ml of diisopropyl ether there firstly separated at room temperature 1.2 g of crystalline product with ee=3% and a melting point of 135-137° C. By adding 275 ml of cyclohexane and stirring the mixture in an ice bath for 3 hours there were isolated 43.9 g (60.5%) of (R)-2-hydroxy-3,3,N-trimethyl-butyramide; m.p. 69-71° C.; [α]=+61.0° (c=1, CHCl3), ee=98.7% (measured by GC on an OV-61/p-DiMe-β-CD chiral column).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH:36]1(O)[CH2:40][CH2:39][CH2:38][CH:37]1[OH:41]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][C:32]2([O:41][C@H:37]3[CH2:38][CH2:39][CH2:40][C@H:36]3[O:35]2)[CH2:33][CH2:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: OC1CCCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)O[C@H]2CCC[C@H]2O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 135.5 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.75 g), cyclopentane-1,2-diol (0.42 g), p-toluenesulfonic acid monohydrate (0.018 g) and toluene (30 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: C1COCCN1
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCOCC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to morpholine via General Procedure B. The product was purified via reverse phase HPLC to give 8.7 mg of 252. MS (Q1) 450.8 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:25]2[C:24](=[O:26])[C:23]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]3[C:21]2=[O:31])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of 1-tert-butoxycarbonyl-4-(2-mesyloxyethyl)piperidine (1.20 g) and potassium phthalimide (0.80 g) in N,N-dimethylformamide (15 ml) was stirred at 40° C. for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate and evaporated in vacuo to give N-[2-[1-tert-butoxycarbonylpiperidin-4-yl]ethyl]phthalimide (1.12 g).