Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[C:8]1[CH:9]2[C:17](=[O:18])[O:16][C:14](=O)[CH:10]2[CH2:11][CH2:12][CH:13]=1.[C:19](OCC)(=O)C.O>O1CCCC1>[CH3:19][C:12]1[CH2:11][C@H:10]([CH2:14][OH:16])[C@H:9]([CH2:17][OH:18])[CH2:8][CH:13]=1
Reactant: CCOC(C)=O
Reactant: CC1=CCCC2C(=O)OC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=CC[C@@H](CO)[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 300 ml of tetrahydrofuran at 0° C. was added 16.0 g (0.42 mol) lithium aluminum hydride portionwise keeping the reaction temperature between 0° C. and 5° C. A solution of 33.0 g (0.20 mol) of 4-methyl-4-cyclohexene-2,3-dicarboxylic anhydride in 100 ml of tetrahydrofuran was added dropwise over 2 hours keeping the temperature between 0° C. and 10° C. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction was cooled to 0° C. and 35 ml of ethyl acetate was added dropwise, followed by dropwise addition of 35 ml isoropanol and 35 ml water. The reaction mixture was filtered through celite using acetone, dried with MgSO4, filtered, and concentrated to 33.0 g of oil. Flash chromatography in 3:1 hexanes-ethylacetate, followed by 1:1 hexanes-ethylacetate and finally ethylacetate alone yielded 18.2 g of oil.
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]2[CH2:7][CH2:8][CH2:9][C:3]=12.C([Li])CCC.C(O[B:19]([O:24][CH:25]([CH3:27])[CH3:26])[O:20][CH:21]([CH3:23])[CH3:22])(C)C.OC(C(O)(C)C)(C)C.C(O)(=O)C>C1COCC1>[CH3:27][C:25]1([CH3:26])[C:21]([CH3:22])([CH3:23])[O:20][B:19]([C:2]2[CH:6]=[N:5][N:4]3[CH2:7][CH2:8][CH2:9][C:3]=23)[O:24]1
Reactant: Brc1cnn2c1CCC2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)OB(c2cnn3c2CCC3)OC1(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (73.5 g, 390 mmol) in THF (600 mL) was slowly added n-butyllithium (1.6 M in hexanes, 300 mL, 480 mmol) at −78° C. After 45 minutes, triisopropylborate (111 mL, 480 mmol) was added at −78° C., and the reaction mixture was allowed to warm to ambient temperature. After 1 hour, pinacol (1.8 M in THF, 300 mL, 540 mmol) was added. After 5 minutes, acetic acid (24 mL, 420 mmol) was added. After 30 minutes, the reaction mixture was filtered through CELITE, washed with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (2×500 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole. MS ESI calc'd. for C12H20BN2O2 [M+H]+ 235. found 235. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 4.12 (t, J=6.9 Hz, 2H), 2.97 (t, J=6.9 Hz, 2H), 2.60 (t, J=6.9 Hz, 2H), 1.29 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[C:18]4[CH3:24])[CH:9]=2)=[C:4]([CH3:25])[CH:3]=1.[CH:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH3:25][C:4]1[CH:3]=[C:2]([NH:1][CH2:26][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30][CH2:29]2)[CH:7]=[CH:6][C:5]=1[C:8]1[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[CH3:24])[CH:9]=1
Reactant: Cc1cc(N)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(4-amino-2-methylphenyl)-4-(3-methyl-1H-indazol-5-yl)pyrimidin-2(1H)-one (25 mg, 0.06 mmol) in 6 mL dichloroethane were added tert-butyl 4-formylpiperidine-1-carboxylate (76.6 g, 0.36 mmol), NaBH(OAc)3 (76 mg, 0.36 mmol), and 500 μL acetic acid. The reaction mixture was stirred at room temperature for 2 hours and diluted with saturated aqueous NaHCO3 (15 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford tert-butyl 4-((3-methyl-4-(6-(3-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydropyrimidin-4-yl)phenylamino)methyl)piperidine-1-carboxylate, which was submitted to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1.O>C1COCC1>[Br:11][C:12]1[N:13]=[C:14]([NH:1][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cc1ccnc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(Br)n2)n1
Temperature: 55 °C

Procedure:
A solution of 2-amino-4-methylpyrimidine (980 mg, 8.86 mmol) in THF (10 ml) was added dropwise to a cooled suspension of NaH (60% on oil, 1 g, 25.32 mmol) in THF (15 ml) under inert atmosphere. The reaction mixture was heated at 55° C. for 2 hours. The reaction was cooled down to 0° C. and a solution of 2,6-dibromopyridine (2 g, 8.44 mmol) in THF (20 ml) was added. The reaction mixture was heated at 80° C. for 5 hours. The reaction was cooled down to 0° C. and hydrolysed carefully with water (50 ml). After extraction with EtOAc (2×100 ml), the combined extractions were dried over MgSO4. After filtration and evaporation, N-(6-bromopyridin-2-yl)-4-methylpyrimidin-2-amine was obtained and purified dry flash chromatography over SiO2 eluting with DCM/MeOH(1%)/NEt3 (0.5%) (0.846 g, 38%). 1H NMR (300 MHz, DMSO-d6) δ 10.12 (br s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.36 (d, J=8.3 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.18 (dd, J=7.6, 0.6 Hz, 1H), 6.91 (d, J=5.0 Hz, 1H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([CH:61]=1)[O:45][C:46]1[N:51]=[C:50]2[S:52][C:53]([NH:55][C:56]([CH:58]3[CH2:60][CH2:59]3)=[O:57])=[N:54][C:49]2=[CH:48][CH:47]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([O:45][C:46]2[N:51]=[C:50]3[S:52][C:53]([NH:55][C:56]([CH:58]4[CH2:60][CH2:59]4)=[O:57])=[N:54][C:49]3=[CH:48][CH:47]=2)[CH:61]=1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: CC(C)(C)Oc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(OC(C)(C)C)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
To a solution of 3-tert-butoxybenzoic acid (64 mg, 0.330 mmol) in pyridine (3.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (125 mg, 0.330 mmol), and the mixture was stirred at room temperature for 10 min. N-[5-(5-Amino-2-methylphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (102 mg, 0.30 mmol) was added to the obtained solution, and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (100 mL)/tetrahydrofuran (10 mL), washed with 1% aqueous citric acid solution (100 mL), 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diisopropyl ether to give the title compound (88 mg, 57%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH:21]1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:18])([CH3:15])([CH3:14])[CH3:13].O1CCCC1.C(N(CC)CC)C>O>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:21]1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CC1NCCCC1NC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC1C(NC(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Benzyloxycarbonyl chloride (2.55 mL) was added dropwise to the compound 12 (3.40 g), tetrahydrofuran (50 mL) and triethylamine (4.15 mL) with stirring at 0° C. The reaction solution was stirred at 0° C. for 20 minutes, added water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to obtain the title compound (4.81 g) having the following physical properties.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6](Cl)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>N1C=CC=CC=1.O>[SH:4][C:3]1[N:5]=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:1][N:2]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NNC(N)=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Sc1n[nH]c(-c2cccnc2)n1

Procedure:
To a solution of 19 g (0.200 mol) of thiosemicarbazide in 175 ml of dry pyridine, 29 g (0.200 mol) of nicotinoyl chloride was slowly added at 10° C. After reflux for 40 min. the reaction mixture was concentrated to half the original volume, 500 ml of water was added, and stored in the cold overnight. The precipitate formed was removed by filtration, and the filtrate was evaporated in vacuo. The resulting heavy, yellow oil was dissolved in 300 ml of water, and 64 g (0.600 mol) of sodium carbonate in 400 ml of water was added. After reflux for 4 h the solution was cooled and acidified with conc. hydrochloric acid to pH=4. The formed, colorless precipitate, 65, was isolated by filtration and dried in vacuo. Yield: 35 g (0.297 mol, 98%).
Reaction SMILES: N1C=CC=CC=1[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30])([O-:22])=[O:21].O>C(Cl)Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:23]1([N+:20]([O-:22])=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]1[S:29]([NH:9][C:8]1[CH:7]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:30])=[O:31]
Reactant: c1ccncc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccccc1-c1ccccn1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])C1(c2ccccn2)C=CC=CC1S(=O)(=O)Nc1ccccc1
Temperature: 23 °C
Yield: 74.4 %

Procedure:
To 2-(2-pyridinyl)aniline (S1) (851 mg, 5.00 mmol, 1.00 equiv) in CH2Cl2 (10 mL) at 0 ° C. was added pyridine (1.60 mL, 20.0 mmol, 4.00 equiv) and 2-nitrobenzenesulfonyl chloride (2.20 g, 10.0 mmol, 2.00 equiv). The reaction mixture was warmed to 23 ° C. and stirred for 2.0 hr before the addition of water (10 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×8 mL). The combined organic phases were washed with brine (30 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 3:7 (v/v) to afford 1.33 g of the title compound as a pale-yellow solid (75%). Rf=0.12 (hexanes/EtOAc 7:3 (v/v)). Melting Point: 91-94 ° C. NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 8.73 (d, J=5.0 Hz, 1H), 7.94 (dd, J=7.5 Hz, 2.0 Hz, 1H), 7.82 (dd, J=8.0 Hz, 1.0 Hz, 1H), 7.74 (ddd, J=7.5 Hz, 7.5 Hz, 2.0 Hz, 1H), 7.63-7.52 (m, 5H), 7.38 (ddd, J=7.5 Hz, 7.5 Hz, 1.5 Hz, 1H), 7.27-7.24 (m, 1H), 7.18 (ddd, J=7.5 Hz, 7.5 Hz, 1.0 Hz, 1H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 156.9, 156.2, 148.0, 137.9, 136.4, 133.6, 132.2, 131.0, 130.0, 129.0, 127.1, 125.0, 124.7, 122.4, 121.9, 121.9, 110.9. Mass Spectrometry: HRMS-FIA (m/z): Calcd for [C17H13N3O4S+H], 356.06995. Found, 356.07008.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1ccc(OC)cc1

Procedure:
Ethyl p-methoxy-α-methylcinnamate (39.1 g) is dissolved in 186 ml of 2B ethanol. This solution is shaken with 1.5 g of 10% palladium on carbon at an initial pressure of 60 psi until the uptake of hydrogen is 100%. The reaction mixture is removed on an evaporator leaving ethyl β-(p-methoxyphenyl)-α-methylpropionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:10][CH2:11][C@@H:12]2[C@@H:16]([OH:17])[C@:15]([F:19])([CH3:18])[C@H:14]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([NH:31][C:32]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:24][C:25]=4[O:29][CH3:30])[O:13]2)=[CH:5][CH:4]=1.[CH:69]1[CH:74]=[CH:73][C:72]([CH2:75][O:76][C:77](Cl)=[O:78])=[CH:71][CH:70]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:77](=[O:78])([O:17][C@H:16]1[C@:15]([F:19])([CH3:18])[C@H:14]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([NH:31][C:32]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:24][C:25]=3[O:29][CH3:30])[O:13][C@@H:12]1[CH2:11][O:10][C:9]([C:61]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=1)([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[O:76][CH2:75][C:72]1[CH:73]=[CH:74][CH:69]=[CH:70][CH:71]=1
Reactant: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](O)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](OC(=O)OCc5ccccc5)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of nucleoside 114 (2.52 g, 2.75 mmol) in anhydrous DCM (8 mL) was added DMAP (1.01 g, 8.2 mmol) and the solution was cooled at 0° C. in an ice-water bath. Cbz-Cl (0.77 g, 4.2 mmol) was added via a syringe to the mixture and resulted in a cloudy reaction mixture. The mixture was stirred at room temperature for 24 hours and sat. NaHCO3 (10 mL) was added. The mixture was partitioned in DCM and water. The organic layer was dried over Na2SO4 and concentrated to a white foam solid. The residue was purified via column chromatography (1060% EtOAc in hexanes) to afford 2.74 g product, 115, as a white foam solid (yield, 95%).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[C:35]([CH3:36])=[N:34][CH:33]=[CH:32][N:31]=3)[N:28]=[CH:29][C:22]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[CH:17]([O:16][CH2:15][C@H:4]([O:3][C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[C:35]([CH3:36])=[N:34][CH:33]=[CH:32][N:31]=3)[N:28]=[CH:29][C:22]=12)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6])([CH3:19])[CH3:18]
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC(C)C)cn1
Reactant: Cc1nccnc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2nccnc2C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
Sodium hydride (22.06 mg, 0.55 mmol) was added to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate C8) (110 mg, 0.46 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate I4) (125 mg, 0.51 mmol) in THF (2 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Further sodium hydride (22.06 mg, 0.55 mmol) was added and the reaction stirred for another hour at room temperature. The reaction mixture was neutralised with 1M citric acid, and then diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford (2S)-3-isopropoxy-N-(5-methylpyrazin-2-yl)-2-(1-(3-methylpyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (98 mg, 47.4%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][CH2:8]2)[C:5]2[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:4]=2[NH:3]1.[OH-].[K+].CC(O)C>O>[NH:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:5]3[CH:18]=[CH:19][C:20]([C:22]([F:24])([F:23])[F:25])=[CH:21][C:4]=3[NH:3][C:2]2=[O:1])[CH2:8][CH2:9]1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)ccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1C1CCNCC1

Procedure:
A mixture of 26 parts of ethyl 4-[1,3-dihydro-2-oxo-5-(trifluoromethyl)-2H-benzimidazol-1-yl]-1-piperidinecarboxylate, 30 parts of potassium hydroxide, 176 parts of 2-propanol and 4 parts of water is stirred and refluxed for 20 hours. The reaction mixture is evaporated. The residue is dissolved in water, acidified with a concentrated hydrochloric acid solution, while cooling, and alkalized with a concentrated ammonium hydroxide solution. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanol. The product is filtered off and dried, yielding 1,3-dihydro-1-(4-piperidinyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one; mp. 198° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]([CH3:15])([N+:12]([O-:14])=[O:13])[CH3:11].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1>[CH3:11][C:10]([N+:12]([O-:14])=[O:13])([CH3:15])[CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CC(C)(COc1ccccc1Br)[N+](=O)[O-]
Reactant: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(COc1ccccc1N1CCNCC1)[N+](=O)[O-]
Yield: 73.2 %

Procedure:
A solution of 1-bromo-2-(2-methyl-2-nitro-propoxy)-benzene (2.30 g, 8.4 mmol), piperazine (1.8 g, 20 mmol), Pd2dba2 (384 mg, 0.4 mmol), BINAP (784 mg, 1.26 mmol), and NaOtBu (1.13 g, 12 mmol) in 34 mL of toluene was heated to 90° C. for 5 hrs. The solution was concentrated, dissolved in CH2Cl2 and filtered through celite. Purification by silica gel chromatography (4×20 cm SiO2, 0,1,2,3,4,5,7,9,11% 2M NH3 in MeOH/CH2Cl2 step gradient, 12 min each at 35 mL/min) afforded 1.72 g (6.15 mmol, 73%) of 1-[2-(2-methyl-2-nitro-propoxy)-phenyl]-piperazine as a yellow oil. LRMS (electrospray): 280.1 [M+1].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][O:35][CH3:36]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:28]5[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:26]([O:25][CH3:24])[CH:27]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COCCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 2-[3-methoxy-4-(2-methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Stage 30.1.1, 39 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: tR 2.71 min (Method A); M+H=474 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.15-8.02 (m, 2H), 7.97-7.89 (m, 1H), 7.59-7.51 (m, 1H), 7.11-7.02 (m, 2H), 7.00-6.94 (m, 1H), 4.16-4.07 (m, 2H), 3.94-3.84 (m, 6H), 3.70-3.64 (m, 2H), 3.58 (s, 3H), 3.31 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][O:19][CH3:20])=[C:8]([C:21](OC)=[O:22])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].CC(C[Al]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][O:19][CH3:20])=[C:8]([CH2:21][OH:22])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncc(C(=O)OC)c1-c1ccc(Cl)cc1OCOC
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCn1ncc(CO)c1-c1ccc(Cl)cc1OCOC
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of Methyl 1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-yl carboxylate (10.00 g, 0.028 mol) in 200 mL of CH2Cl2 at 0° C. was added 85.2 mL of 1.5 M Dibal-H in toluene. After string for 1 h, the reaction was quenched with MeOH (100 mL) followed by addition of 35 mL of conc. HCl in 200 mL of water. The resulting mixture was stirred for 15 min. and extracted with CH2Cl2 (3×200 mL). The combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 9.50 g (97%) of the title compound as a oil: MS (ESI) m/z 325 (M+H)+; 1H NMR (400 MHz, CDCl3) d 7.63 (s, 1H), 7.13-7.29 (m, 3H), 5.09 (s, 2H), 4.36 (dd, 2H). 3.80-3.98 (m, 2H), 3.35 (s, 3H), 1.70 (m, 2H), 1.18 (m, 2H), 0.81 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[N-:25]=[N+:26]=[N-:27].[Na+].CN(C=O)C>O>[N:25]([C:7]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:19]([F:20])([F:22])[F:21])[N:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:26]=[N-:27]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OC)c1N=[N+]=[N-]
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of 15.13 g (0.040 mol) of product of Example 27, 2.85 g (0.040 mol) of sodium azide and 175 ml of DMF was stirred for 1 hour and poured into 500 ml of water. The mixture was extracted with ether. The ether extract was washed several times with water, dried (MgSO4) and concentrated to give 14.4 g (93.7%) of product; mp 46°-47° C.