Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[C:66]([O:70][C:71]([N:73]1[CH2:77][C@@H:76]([OH:78])[C@H:75]([NH2:79])[CH2:74]1)=[O:72])([CH3:69])([CH3:68])[CH3:67]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[C:66]([O:70][C:71]([N:73]1[CH2:77][C@@H:76]([OH:78])[C@H:75]([NH:79][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:74]1)=[O:72])([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.024 g (0.12 mmole) of (3R,4R)-3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.053 g of (3R,4R)-3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (I-103) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1c(C)ncnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ncnc(C)c1C(=O)O
Temperature: 50 °C

Procedure:
The crude methyl 4,6-dimethylpyrimidine-5-carboxylate from the previous example to 20° C. was cooled and water (86 ml) was charged. 25% sodium hydroxide solution (75.5 ml) was charged and the batch was warmed to 50° C. for 90 minutes. The batch was cooled to between −5 and 0° C. and concentrated hydrochloric acid was charged slowly keeping the temperature within the range of −5 to +5° C. until a pH of 1.5 was reached. The batch was agitated for at least one hour at 0° C. The batch was filtered and the product washed with ice cold water (2×43 ml). The batch was dried under vacuum at 40–45° C. Yield of 4,6-dimethylpyrimidine-5-carboxylic acid was 59 g. m. p. 203–204° C., 1H NMR (D2O): δ2.57 (6H, s, CH3), δ9.00 (1H, s, ArH). 13H CMR (D2O): δ170.00, δ164.39, δ151.29, δ133.47, δ20.85. HR-MS; Calculated for C7H9N2O2, m/z=153.0664. Found 153.0667.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:7]([OH:19])[CH2:6]1)=[O:4].[CH3:20]I>ClCCl.[Ag-]=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C@H:7]([O:19][CH3:20])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C1
Reactant: CI
Agent: O=[Ag-]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](OC)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of alcohol (d) (6.5 g, 24 mmol), silver(I) oxide (16.5 g, 72 mmol), methyl iodide (4.5 ml) and 3 A molecular sieves (10 g) in dichloromethane (100 ml) was stirred at room temperature for 18 hours. The mixture was filtered and evaporated. The residue was chromatographed on silica eluting with 1:2 ethyl acetate:petrol affording an oil (5.47 g, 80%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:22]3[N:23]=[C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:29][CH:28]=4)[N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)[CH:12]=1)C.O>C(OCC)C>[N:36]1([CH2:35][CH2:34][O:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:24]3[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=[C:17]([C:13]5[CH:12]=[C:11]([CH2:10][OH:9])[CH:16]=[CH:15][CH:14]=5)[N:22]4[N:23]=3)=[CH:32][CH:31]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCOC(=O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a slurry of lithium aluminium hydride (82.6 mg, 2.12 mmol) in diethylether (10 mL) was added 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid ethyl ester (0.50 g, 1.06 mmol) portionwise. The mixture was stirred at room temperature for 6 hrs. Water was added to quench the hydride and the aqueous layer was removed. The organic layer was concentrated in vacuo, and the crude product loaded onto an SCX column, which was washed with methanol and the product eluted with 2M ammonia in methanol, then concentrated in vacuo. Yield: 0.35 g, 76%. A small amount was purified by preparatory HPLC. RT: 2.32, MI: 430, Method: 2.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[C:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(OC)(OC)OC.ClCCl.CO>[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:15]1[CH:10]2[CH2:11][CH2:12][CH:13]1[CH2:14][C:8](=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:9]2
Reactant: Cc1ccccc1C=O
Reactant: c1ccc(C(=C2CC3CCC(C2)N3)c2ccsc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: CO
Product: Cc1ccccc1CN1C2CCC1CC(=C(c1ccccc1)c1ccsc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 mg (355 μmol) of 3-(phenyl-thiophen-3-yl-methylene)-8-aza-bicyclo[3.2.1]octane in 1 mL of trimethyl orthoformate was added 62 μL (533 μmol) of 2-methylbenzaldehyde, 173 mg (817 μmol) of sodium triacetoxyborohydride, 34 μL of glacial acetic acid at room temperature. The reaction mixture was allowed to stir overnight at room temperature. Next day, the crude was diluted with 1 mL of dichloromethane and 0.5 mL of methanol. The diluted suspension was filtered and the precipitates were washed with dichloromethane. The combined filtrates were concentrated. The concentrated sample was purified by reverse phase chromatography (20×100 mm J'sphere H-80 YMC column using a gradient of 0.1% TFA/water to 5% water/0.1% TFA/acetonitrile). The eluent was evaporated to yield the title compound as a white solid; MS m/z (MH+) 386; 1H NMR 300 MHz (MeOD-d4) δ 6.86-7.51 (m, 12H), 4.26 (s, 2H), 4.05-4.11 (m, 2H), 2.03-2.89 (m, 11H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16]OC)[C:7]1=2)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[C:28]1[N:29]=[CH:30][C:31]([C:34]([NH2:36])=[O:35])=[N:32][CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19][C:28]3[CH:33]=[N:32][C:31]([C:34](=[O:35])[NH2:36])=[CH:30][N:29]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: NC(=O)c1cnc(Br)cn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(COC)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(N)=O)cn3)cc(C)c21
Temperature: 80 °C
Yield: 49.4 %

Procedure:
A suspension of (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (150 mg, 0.600 mmol) and Cs2CO3 (430 mg, 1.32 mmol) in DMF (4 mL) was treated with 5-bromo-pyrazine-2-carboxylic acid amide (158 mg, 0.780 mmol) at room temperature and the reaction was heated to 80° C. for 2 h. The reaction mixture was concentrated to dryness. The residue was diluted with water and adjusted to pH 2 with 1N HCl. The aqueous phase was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=1:2 to DCM/MeOH=10:1) to afford the title compound as a white solid (110 mg). 1H NMR (300 MHz, CD3OD) δ 8.90 (s, 1H), 8.34 (s, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 7.08 (s, 1H), 5.70 (s, 1H), 5.69-5.66 (m, 1H), 4.21 (q, 2H), 3.14-3.12 (m, 1H), 2.49-2.41 (m, 1H), 2.37 (s, 3H), 1.26 (t, 1H). MS found: (M+H)+: 372.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.Br[CH2:12][C:13]#[N:14]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][CH2:12][C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#CCBr
Solvent: C1CCOC1
Product: COc1ccc(CNCC#N)cc1
Temperature: 10 °C
Reaction time: 12 h
Yield: 76.4 %

Procedure:
A mixture of TEA (55.9 ml, 401 mmol), (4-methoxyphenyl)methanamine (50 g, 364 mmol) and 2-bromoacetonitrile (43.7 g, 364 mmol) in THF (500 ml) was stirred at about 10° C. for about 12 h in a 500 ml round-bottomed flask. The reaction was filtered through a pad of silica gel. The crude material was deposited onto silica gel, loaded onto a silica gel column and eluted with Hex/EtOAc (1:1) to afford the title compound (49 g, 278 mmol, 76% yield). 1H-NMR (CDCl3, 400 MHz): δ=3.55 (s, 2H), 3.81 (s, 3H), 3.87 (s, 2H), 6.88 (d, 2H, J=8.4 Hz), 7.26 (d, 2H, J=8.0 Hz)
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22]C(C)([O-])C.[K+].CCl.Cl>C(O)(C)(C)C.O>[CH3:22][C:11]1[C:12](=[O:20])[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]=1[CH2:9][CH2:8][C@@H:7]1[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]1[CH2:5][CH2:4][C:3]2=[O:21]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[O-]
Agent: CCl
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O

Procedure:
A solution of androst-4-ene-3,17-dione in t-butanol was heated to boiling and added to a boiling solution of potassium t-butoxide in t-butanol. Methyl chloride in t-butanol was added slowly. The solution was cooled, acidified with concentrated hydrochloric acid, and diluted with water. The excess t-butanol was removed under vacuum and the aqueous layer extracted with ethylacetate. The combined extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel and eluted with hexane/ethylacetate. The eluant was evaporated and the residue crystallized from ether to yield 4-methylandrost-4-ene-3,17-dione; I.R. (KBr): 1735 (17-oxo), 1660 (3-oxo), 1620 cm-1 (Δ4).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[NH:12][CH:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl>[F:36][C:2]([F:35])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]([C:46](=[O:48])[CH3:47])[CH:13]([CH3:30])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[C:10]3=[N:9]2)=[CH:33][CH:34]=1
Reactant: CC(=O)Cl
Reactant: CC1Nn2c(nn(Cc3ccc(C(F)(F)F)cc3)c2=O)C(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(C)C(c2ccc(Cl)cc2)=C(c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n21
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (8 mg, 0.015 mmol), prepared as described in Example 469 in CH2Cl2 (0.2 mL) at RT was added diisopropyl ethyl amine (5.8 mg, 0.045 mmol), followed by acetyl chloride (2.4 mg, 0.030 mmol). The reaction was stirred at RT for 2 h. LC-MS showed the completion of the reaction. The solvent was evaporated and the residue was purified using reverse phase HPLC to give the title compound, 2-(4-(Trifluoromethyl)benzyl)-5-acetyl-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (6 mg, 70%) as a white solid. HPLC retention time: 4.23 min; MS [M+H]+: found 573. 1H NMR (CDCl3, 400 MHz) δ 7.65 (d, 2H), 7.51 (d, 2H), 7.30-7.22 (m, 4H), 7.17 (dd, 2H), 7.06 (dd, 2H), 5.70 (q, 1H), 5.14-5.11 (m, 2H), 2.28 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.CN1CCCC1=O.[C:47]([OH:54])(=[O:53])/[CH:48]=[CH:49]\[C:50]([OH:52])=[O:51]>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:47]([O-:54])(=[O:53])/[CH:48]=[CH:49]\[C:50]([O-:52])=[O:51]
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
Nilotinib base (3.85 g, 7.27 mmol) was suspended in TFE (19 ml, 5V) and the mixture was heated to 40° C. with stirring. To the resulting cloudy yellow solution, maleic acid (0.84 g, 7.27 mmol) was added in one portion, followed by TFE (19 ml, 5V) at 45-50° C. Dissolution of the solid was achieved after about 5 min stirring at the same temperature. The resulting clear yellow solution was then stirred at 45° C. for about 3 h, and then at room temperature overnight (about 19 h). MTBE (10V) was added with stirring, leading to immediate precipitation. The resulting slurry was stirred for 1 h at room temperature and then the solid was separated from the mother liquors by filtration. The yellow solid was isolated and dried in a vacuum oven (35 mmHg) at 40° C. for 18.5 h to give Nilotinib maleate form IV (3.49 g, 74%) as a pale yellow solid.
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][NH:7][CH:8]=1)([CH3:3])[CH3:2].[Br:13]N1C(=O)CCC1=O>N1C=CC=CC=1>[Br:13][C:8]1[NH:7][CH:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c[nH]cc1C(C)C
Solvent: c1ccncc1
Product: COC(=O)c1c[nH]c(Br)c1C(C)C
Yield: 63.9 %

Procedure:
Using methyl 4-isopropyl-1H-pyrrole-3-carboxylate (3.5 g), N-bromosuccinimide (3.74 g) and pyridine (0.5 mL), a procedure as in Reference Example 40 was performed to give the title compound as colorless crystals (yield 3.29 g, 64%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([CH:28]4[CH2:31][CH2:30][CH2:29]4)[N:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=34)[CH:13]=2)[CH:5]=1.[NH3:33]>CO>[NH2:27][C:23]1[C:22]2[N:21]([C:20]([CH:28]3[CH2:31][CH2:30][CH2:29]3)=[N:19][C:18]=2[C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:33])=[O:2])[CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)c1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)c1
Temperature: 60 °C

Procedure:
3-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxymethyl]-benzoic acid methyl ester (150 mg, 0.35 mmol) was dissolved in a sealed tube with 2.0 ml of 7N NH3 in MeOH and heated to 60° C. overnight. LC/MS analysis indicated that the reaction was incomplete, therefore NH3 gas was bubbled into the solution and the reaction was run at 100° C. in a 100 mL Parr pressure vessel. The product was chromatographed on silica gel [Jones Flashmaster, 5 g cartridge, eluting with 2% NH3 in MeOH:CH2Cl2] to yield the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 1.99-2.08 (m, 1H), 2.13-2.25 (m, 1H), 2.46-2.55 (m, 2H), 2.55-2.65 (m, 2H), 3.78-3.87 (m, 1H), 5.21 (s, 2H), 6.95 (d, J=5.2 Hz, 1H), 7.08-7.11 (m, 1H), 7.13 (d, J=5.6 Hz, 1H), 7.22-7.24 (m, 2H), 7.42-7.51 (m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.80-7.83 (m, 1H), 7.94 s, 1H); MS (ES+): m/z 414.21 (100) [MH+].
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH3:26])[N:19]=2)O)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C1CCCCC1>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([Cl:4])[C:18]2[N:19]=[C:20]([O:25][CH3:26])[C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1nc(C(O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: COc1nc(C(Cl)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reaction time: 17 h
Yield: 96 %

Procedure:
Sulfuryl chloride (0.37 mL) was added to a solution of (4-tert-butylphenyl)(5-chloro-6-methoxypyridin-2-yl)methanol obtained in Example 7-4(1) (200 mg) and triethylamine (0.27 mL) in cyclohexane (4 mL) at room temperature, and then the mixture was stirred at the same temperature for 17 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give 6-[(4-tert-butylphenyl)(chloro)methyl]-3-chloro-2-methoxypyridine as a colorless oil (203 mg, 96%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=O)C.ClC1C=CC(CC2C=CC=C3C=2C2C(COC)=C(C=[N:50][OH:51])N=CC=2N3)=CC=1>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17]1[C:18]([CH2:19][O:20][CH3:21])=[C:6]([CH:4]=[N:50][OH:51])[N:7]=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c2c1COC
Reactant: COCc1c(C=NO)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Product: COCc1c(C=NO)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12

Procedure:
The preparation takes place from 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester over alcohol and aldehyde, such as described for 5-(4-chlorobenzyl)-4- methoxymethyl-β-carboline-3- carbaldehyde-oxime, melting point 209°-212° C.
Reaction SMILES: C([O:7][CH:8]1[CH2:11][CH:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9]1)(=O)C(C)(C)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Si:13]([O:12][CH:10]1[CH2:11][CH:8]([OH:7])[CH2:9]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)OC1CC(O[Si](C)(C)C(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CC(O)C1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(tert-butyldimethylsilyloxy)cyclobutyl pivalate (4.32 g, 15 mmol) in THF (20 ml) at 0° C. was added diisobutylaluminum hydride, 1.0 m solution in hexanes (48 ml, 48 mmol) dropwise. The reaction was stirred in 1 h, then slowly quenched with Rochelle's salt. The quenched mixture was stirred and layers were separated. The organic layer was dried over MgSO4 and concentrated to give the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15](=[O:36])[CH2:16][O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25]2[O:26][C:27]3[N:28]=[C:29](Cl)[N:30]=[CH:31][C:32]=3[N:33]=2)=[CH:20][C:19]=1[CH3:35])([CH3:13])([CH3:12])[CH3:11]>CC(N(C)C)=O>[C:10]([O:14][C:15](=[O:36])[CH2:16][O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25]2[O:26][C:27]3[N:28]=[C:29]([O:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:30]=[CH:31][C:32]=3[N:33]=2)=[CH:20][C:19]=1[CH3:35])([CH3:13])([CH3:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
19 mg of sodium hydride were added under an argon atmosphere to a solution of 38 mg of phenol in 5 ml of dimethylacetamide. After stirring for 30 min at room temperature, a solution of 156 mg of [4-(5-chloro-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid tert-butyl ester in 3 ml of dimethylacetamide was added slowly. The mixture was allowed to stir for 1.5 h at room temperature. Upon consumption of the starting ester an aqueous solution of citric acid (100 g/l) was added until the pH was neutral. The aqueous layer was extracted twice with 15 ml ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvents were removed in vacuo. The title compound was isolated by silica gel chromatography (heptane/ethyl acetate gradient). Yield: 77 mg of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:35]([O:37][C:38]([C:40]([NH2:43])([CH3:42])[CH3:41])=[O:39])[CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH:43][C:40]([C:38]([O:37][CH2:35][CH3:36])=[O:39])([CH3:42])[CH3:41])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: CCOC(=O)C(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)NC(=O)c1ccc(S(=O)(=O)n2c(=O)n(C3CCCCC3)c3cc(OCC)ccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
500 mg of the compound obtained in Example 13, 300 mg of 1-ethoxycarbonyl-1-methylethylamine hydrochloride and 550 mg of BOP were mixed with 2 ml of DIPEA and 50 ml of DCM and the reaction medium was stirred for 30 minutes at room temperature. It was then concentrated under vacuum and the residue was taken up with water and then extracted with AcOEt, washed successively with 1N HCl , with 1N NaOH and then with water, dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on a silica column using a DCM/AcOEt mixture (97/3; v/v) as the eluent. 170 mg of the expected product were obtained in the form of a white solid by crystallization from an AcOEt/iso ether mixture (10/90; v/v). M.p.=202° C.