Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:13]([C:14]([O:16]C)=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>S1(CCCC1)(=O)=O.O>[CH2:26]([O:19][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C(O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Yield: 68.8 %

Procedure:
A mixture of methyl gentisate (16.8 g) and anhydrous potassium carbonate (7.0 g) in dry sulpholane (150 ml) was treated, with stirring, with benzyl chloride (12.7 g), and the mixture was stirred and heated at 100° C. for 4 hours. The mixture was then poured into water (800 ml) and the separated solid was filtered off and recrystallized from ethanol (with the aid of charcoal) to give methyl 5-benzyloxysalicylate (10.7 g), m.p. 108°-112° C. This ester (9.2 g) was heated at 150° C. for 3 hours with a mixture of anhydrous potassium carbonate (2.5 g) and benzyl chloride (4.52 g) in dry sulpholane (100 ml) and the mixture was then cooled and poured into a mixture of ice and water (700 ml), and the mixture was extracted with diethyl ether (2 × 300 ml). The ether extracts were combined and evaporated, the residual oil was triturated with water (100 ml), the oil was separated and the aqueous layer was extracted with diethyl ether (25 ml). The combined oil and extracts were washed with brine, dried over magnesium sulphate and evaporated to give crude methyl 2,5-dibenzyloxybenzoate (12.7 g). This ester (12.4 g) was heated at reflux with aqueous sodium hydroxide solution (2N; 400 ml) for 2 hours and allowed to cool. The separated sodium salt was filtered off and ground with hydrochloric acid (6N; 100 ml), the mixture was heated at reflux for 5 minutes and then cooled. The solid which separated was filtered off, washed with water and dried to give 2,5-dibenzyloxybenzoic acid (8.2 g), m.p. 107°-108.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[CH:55]=[CH:54][CH:53]=[CH:52][C:47]=1[C:48]([O:50][CH3:51])=[O:49].BrCC1OC(C(F)(F)F)=CC=1>>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[CH:55]=[CH:54][CH:53]=[CH:52][C:47]=1[C:48]([O:50][CH3:51])=[O:49]
Reactant: COC(=O)c1ccccc1CBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and methyl 2-(bromomethyl)benzoate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (79%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.04 (dd, J=7.7, 1.3 Hz, 1H), 7.43 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.38-7.29 (m, 1H), 7.22-7.11 (m, 3H), 7.07-6.99 (m, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.55 (s, 1H), 6.43 (s, 1H), 5.52-5.34 (m, 2H), 5.00 (d, J=8.9 Hz, 1H), 4.74 (d, J=8.9 Hz, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.95 (s, 3H), 3.08-2.94 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.2, 167.5, 161.8, 161.4, 142.3, 137.5, 132.8, 132.7, 131.4, 129.1, 128.8, 128.6, 128.0, 127.4, 126.5, 123.9, 123.5, 120.2, 120.0, 119.0, 109.4, 93.3, 80.8, 72.4, 65.9, 57.9, 52.3, 42.4, 29.1, 15.3; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:37])=[C:15]([C@:17]23[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]2[C:21](=[O:27])[N:20]([CH3:28])[C:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:18]3)[CH:16]=1.[CH3:38][O:39][C:40]1[N:41]=[CH:42][C:43]([C:46](O)=[O:47])=[N:44][CH:45]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:37][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:46]([C:43]2[CH:42]=[N:41][C:40]([O:39][CH3:38])=[CH:45][N:44]=2)=[O:47])=[CH:16][C:15]=1[C@:17]12[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]1[C:21](=[O:27])[N:20]([CH3:28])[C:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[N:18]2
Reactant: C[C@H]1OC[C@]2(c3cc(N)ccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Reactant: COc1cnc(C(=O)O)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C)[C@H]3C(=O)N(C)C(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
N-Ethyl-N-(propan-2-yl)propan-2-amine (0.33 mL, 1.9 mmol) was added to a stirred mixture of tert-butyl ((4aS,5R,7aS)-7a-(5-amino-2-fluorophenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (150 mg, 0.38 mmol), 5-methoxypyrazine-2-carboxylic acid (89 mg, 0.57 mmol) and (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (300 mg, 0.57 mmol) in dry DCM (2 mL). The mixture was stirred at RT overnight. The reaction mixture was partitioned between DCM and NaHCO3 (aq). The aqueous layer was extracted with DCM (×2). The combined extracts were dried by passing through a hydrophobic frit and then evaporated. The residue was purified by column chromatography (normal phase, 10 g, Biotage SNAP cartridge KP-Sil, 12 mL per min, gradient 5% to 30% EtOAc in n-hexane) to give the title compound (213 mg, foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.52 (d, J=6.06 Hz, 3H) 1.56 (s, 9H) 3.31 (s, 3H) 3.44 (dd, J=9.09, 1.77 Hz, 1H) 4.08 (s, 3H) 4.31 (d, J=9.85 Hz, 1H) 4.37-4.47 (m, 2H) 7.16 (dd, J=10.74, 8.97 Hz, 1H) 7.54 (dd, J=6.82, 2.53 Hz, 1H) 7.84 (ddd, J=8.78, 4.23, 2.65 Hz, 1H) 8.15 (d, J=1.26 Hz, 1H) 9.01 (d, J=1.26 Hz, 1H) 9.49 (s, 1H) 10.60 (s, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[N:10]=1.C(Cl)(=O)C>>[C:5]([NH:8][C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[N:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CC(=O)Cl
Product: CC(=O)Nc1nc(Cl)cc(Cl)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 250 ml. three necked flask was fitted with a mechanical stirrer and a reflux condenser with drying tube. The flask is charged with 50 ml. of acetic anhydride and 3.85 g of 2-amino-4,6-dichloropyrimidine (0.025 mole). Then, 10 ml. of acetyl chloride was added slowly and the mixture was heated to 110° C for 8 hours. The mixture was allowed to stand overnight at room temperature. The crystalline solid product which formed was filtered and washed with water and sodium bicarbonate solution. It was then recrystallized from 50% alcohol. There was obtained 3.8 g of 2-acetamido-4,6-dichloropyrimidine (PY-25) in the form of white crystals, melting point, 198°-200° C, yield, 74.5%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.N1C=CC=C[CH:32]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Na+]>CN(C)C=O.O>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[CH:3]=[C:2]4[N:1]=[CH:32][N:12]([CH2:13][CH3:14])[C:11]4=[CH:10][C:9]=3[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cnc2cc3c(N4CCN(C(=S)NCc5ccccc5)CC4)ncnc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 504.4 mg (1.20 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 10 ml of dimethylformamide were added 0.29 ml (3.60 mmol) of pyridine and 0.13 ml (1.49 mmol) of oxalyl chloride under ice-cooling, followed by overnight stirring at room temperature in an atmosphere of argon. Then, the resulting mixture was heated at 80° C. with stirring for 5 hours. The reaction mixture was allowed to cool to room temperature and then poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:8]=1>C1COCC1>[CH2:1]([NH:5][S:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:15])=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCCCNS(=O)(=O)Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
n-Butylamine (3.25 g, 44.43 mmol) was dissolved in THF (25 mL) and it was then cooled in an ice-bath. ((4-Chlorophenyl)methyl)sulfonyl chloride (5.0 g, 22.21 mmol) in THF (25 mL) was dropped in. The cooling-bath was removed after the addition. The mixture was stirred for 2 h and then evaporated to dryness. DCM (50 mL) was added to the residue. It was washed with HCl (5%, 10 mL), water (30 mL×3) and brine (20 mL), dried (MgSO4) and evaporated to give the title compound (5.43 g, 93%) as a solid; 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 2H), 7.32 (d, 2H), 4.19 (s, 2H), 4.11 (bt, 1H), 2.99 (dd, 2H), 1.50-1.43 (m, 2H), 1.36-1.26 (m, 2H), 0.90 (t, 3H); Mass Spectrum: M−H+ 260.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][C:20]=1[F:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[CH:19][C:20]([F:21])=[C:15]([F:14])[CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)Cc2ccc(F)c(F)c2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine and 3,4-difluorophenylacetic acid.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][CH:9]1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1.C(O)(=O)C.[H][H]>[Pd].O1CCCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][NH:8]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC1CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCN1
Yield: 92.4 %

Procedure:
A suspension of 18.8 g (68.0 mmol) of 1-benzyl2-[(t-butoxycarbonylamino)methyl]azetidine, 8.2 g (137 mmol) of acetic acid, 1.0 g of 20% palladium on carbon and 200 ml of tetrahydrofuran was shaken in a hydrogen atmosphere at pressures of 48.3-51.7 psi and temperatures of 21.5°-27° for 16 hours. The catalyst was removed by filtration and the solvent was removed. in vacuo to give 11.7 g (92%) of the title compound as a colorless viscous oil which was used without further purification.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@H:5]([OH:30])[CH2:4]1)[CH3:2].[C:31](Cl)(=[O:42])[O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)O[C@H]1C[C@H](C2N3C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=CC3=NN=2)[C@H](CC)C1>[C:31](=[O:42])([O:32][C:33]1[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=1)[O:30][CH:5]1[CH2:6][CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: CC[C@@H]1C[C@@H](O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CC[C@@H]1C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCC1CC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (1.20 g, 2.82 mmol) in pyridine (10 mL) was added DMAP (0.103 g, 0.846 mmol) and 4-nitrophenyl carbonochloridate (0.853 g, 4.23 mmol). The resulting mixture was stirred at ambient temperature for about 1 h. The reaction mixture was purified using silica gel chromatography eluting with 0-30% EtOAc in DCM to give a scalemic mixture enriched in (1R,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl 4-nitrophenyl carbonate (0.72 g. 43%): LC/MS (Table 1, Method b) Rt=2.64 min; MS m/z: 591 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([CH2:16][CH2:17][CH3:18])[N:6]=[N:5]1)[CH2:2][CH3:3].[H][H]>C(O)(C)(C)C.[Rh]>[NH2:5][CH:4]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([NH2:6])[CH2:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCC1CC=CCCC=CCC(CCC)N=N1
Agent: [Rh]
Solvent: CC(C)(C)O
Product: CCCC(N)CCCCCCCCC(N)CCC
Yield: 47.5 %

Procedure:
942 g (3.79 moles) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomer mixture) are dissolved in a stirred autoclave in 3800 ml of tert-butanol. After addition of 90 g of a rhodium/alumina catalyst (5% by weight), hydrogen is introduced up to a pressure of 130-150 bar and hydrogenation is effected at 150°-180° C. until the uptake of hydrogen is complete. After cooling, excess hydrogen is blown off, the suspension is sucked from the autoclave and the catalyst is collected by suction over a small amount of hyflo (filter aid). The filtrate is concentrated by rotary evaporation and the product is purified by distillation, yielding as main fraction 462 g (48% of theory) of 4,13-diaminohexadecane as a colourless oil [b.p. 132°-135° C./0.01 torr; nD20. 1.4590; IR spectrum (liquid) includes bands at 3278 and 1613 cm-1 ].
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1[NH2:25].Cl.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)=[C:3]([NH2:25])[N:4]=2)=[N:9]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1-c1ccncc1
Reaction time: 0.17 h
Yield: 35.3 %

Procedure:
Under an argon atmosphere, 140 mg (purity 65%, 0.256 mmol) of 6-chloro-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5-amine were suspended in 5 ml of absolute dioxane. 122 mg (0.767 mmol) of pyridin-4-ylboronic acid hydrochloride, 1.023 ml (1.023 mmol) of 1N aqueous potassium carbonate solution and 14 mg (0.051 mmol) of tricyclohexylphosphine were added and argon was passed through the suspension for 10 min with stirring. Then, 28 mg (0.038 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 30 min in the microwave at 140° C. The reaction mixture was again stirred for 60 min in the microwave at 140° C. After cooling, the mixture was filtered over an Extrelut cartridge and after-washed with a mixture of dichloromethane/methanol (v/v=20:1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). 36 mg of the target compound were obtained (33% of theory).
Reaction SMILES: [CH3:1][C:2]([C:4](=[O:12])[CH:5]=[C:6]([CH3:11])[CH2:7][CH:8]([CH3:10])[CH3:9])=[CH2:3].CC(CC(C)(O)C#CC(C)=C)C>[V]>[CH3:3][CH:2]([C:4](=[O:12])[CH2:5][CH:6]([CH3:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:1]
Reactant: C=C(C)C(=O)C=C(C)CC(C)C
Agent: [V]
Agent: C=C(C)C#CC(C)(O)CC(C)C
Product: CC(C)CC(C)CC(=O)C(C)C

Procedure:
2,5,7-Trimethyl-1,4-octadien-3-one can be prepared, for example, from 2,4,7-trimethyl-7-octen-5-yn-4-ol by propargylic rearrangement in a manner known per se with the aid of a vanadium catalyst. By catalytically hydrogenating the resulting dienone at room temperature, as described hereinbefore, there is obtained 2,5,7-trimethyl-3-octanone. 6,8-Dimethyl-3-nonen-2-one can be prepared, for example, by aldol condensation of 3,5-dimethyl-hexanal with acetone.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[N:16]=[C:15]2[N:17]=[C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:20][C:14]2=[N:13][CH:12]=1.[Cl-].[NH4+]>C1COCC1.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:2]([C:11]1[N:16]=[C:15]2[N:17]=[C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:20][C:14]2=[N:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc2ncc(Cc3ccccc3)nc2n1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
2.4 ml of a 0.5 M solution of benzylzinc bromide (1.20 mmol) in THF and 24.7 mg of tetrakis(triphenylphosphine)palladium(0) (0.02 mmol) were initially charged in 1 ml of dioxane under nitrogen. Subsequently, 102.4 mg of 1-(3-chloropyrido[2,3-b]pyrazin-6-yl)-3-ethylurea (0.41 mmol) and 1 ml of dioxane were added in portions. The mixture was then heated to 100° C. After 7 h, the reaction mixture was allowed to cool and then saturated ammonium chloride solution was added. The aqueous phase was extracted repeatedly with dichloromethane and the collected organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and freed from the solvent under reduced pressure. Column chromatography purification on silica gel (dichloromethane/methanol eluent) afforded a yellow solid.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C[O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH-].[Li+:36]>C(#N)C.O>[Li+:36].[C:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:24][CH2:23][CH2:22][C:21]([O-:26])=[O:20])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)CCCBr
Reactant: CC(C)(C)c1ccc(N2CCCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(N2CCCN(CCCC(=O)[O-])CC2)cc1
Temperature: 100 °C
Yield: 193.2 %

Procedure:
A mixture of 1-(4-tert-butyl-phenyl)-[1,4]diazepane hydrochloride (220 mg; 0.82 mmol, prepared in accordance with Example 161), 4-bromo-butyric acid methyl ester (160 mg; 0.82 mmol), potassium carbonate (113 mg; 0.82 mmol) and potassium iodide (136 mg; 0.82 mmol) in acetonitrile (5 mL) is heated to 100° C. for 3 hours. The reaction mixture is allowed to attain room temperature and filtered. The filtrate is diluted with a solution of lithium hydroxide (59 mg; 2.46 mmol) in water (2 mL) and the resulting mixture is stirred at room temperature over night. All volatiles are then removed under high vacuum and more lithium hydroxide solution is added to drive the reaction to completion. Acetonitrile is added and the precipitate formed is then filtered and dried under high vacuum to afford the desired product (514 mg) which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([C:17]([O:19]CC)=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([C:17]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)c2ccccc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 0.7 g of ethyl 1-(tert-butoxycarbonyl)indoline-3(R,S)-carboxylate (Example 97d) in 18 ml of methanol/water (1:1) and 2.9 ml of a 1N sodium hydroxide solution is stirred at 50° C. for 3 h. After the methanol has been removed in vacuo, the aqueous phase is brought to pH 2 and extracted with ethyl acetate. Customary further working up gives the title compound as a white solid: Rf (hexane/ethyl acetate/glacial acetic acid (75:25:1))=0.23.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[CH:14][N:15]=[C:16]([CH2:17][CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[N:8]3[C:7]=2[N:6]=[C:5]([N:25]2[CH:29]=[CH:28][N:27]=[C:26]2CCC2CCCCC2)[N:4]=1)[CH3:2].N1C=CN=C1>>[CH2:1]([C:3]1[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[CH:14][N:15]=[C:16]([CH2:17][CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[N:8]3[C:7]=2[N:6]=[C:5]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[N:4]=1)[CH3:2]
Reactant: CCc1nc(-n2ccnc2CCC2CCCCC2)nc2c1[nH]c(=O)c1cnc(CCC3CCCCC3)n12
Agent: c1c[nH]cn1
Product: CCc1nc(-n2ccnc2)nc2c1[nH]c(=O)c1cnc(CCC3CCCCC3)n12

Procedure:
Prepared by treatment of the product of Example 9c with excess imidazole at 200° C.
Reaction SMILES: [Na].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[C:7]=1[OH:14])([CH3:5])([CH3:4])[CH3:3].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C(O)(=O)C>C1(C)C=CC=CC=1>[C:2]([C:6]1[C:7]([OH:14])=[C:8]([CH3:13])[C:9]([CH3:12])=[C:10]([CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18])[CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: C=CC(=O)OC
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C
Agent: [Na]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Reaction time: 2 h

Procedure:
1.53 grams of sodium metal was added in small pieces to 240.6 grams of 2-tert.-butyl-5,6-dimethylphenol warmed at 60°. The reaction mixture was then heated at 120° with stirring for 2 hours, during which time the sodium metal was completely reacted. 174 grams of methyl acrylate was then added gradually over a period of 1 hour so that the temperature was maintained at 120°. The reaction mixture was then heated at 120° to 130° for an additional 4 hours. 3.9 ml. of acetic acid was then added. The reaction mixture was diluted with 600 ml. of toluene and warmed to dissolve a precipitate. The toluene solution was washed successively with 2N sodium carbonate, saturated sodium chloride, water, dilute aqueous hydrochloric acid and finally with water until the water washings were almost neutral. After drying over sodium sulfate, the clear toluene solution was evaporated at 20 mm Hg. pressure and finally at 1 mm. Hg. pressure for 2 hours. The crude residual product was crystallized from a mixture of 450 ml. of isopropanol and 200 ml. water and kept at about 15°C overnight. The thick crystalline slurry was filtered, the filter cake being washed with a little cold isopropanol-water mixture. After drying and recrystallization, the desired product was obtained as white crystals melting at 74° to 76°C (Compound 1).