Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[C:23]([C:19]1[CH:18]=[C:17]([N:14]2[CH2:13][CH2:12][N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:25])=[O:2])[CH2:16][CH2:15]2)[CH:22]=[CH:21][CH:20]=1)#[N:24]
Reactant: COC(=O)c1cccc(CN2CCN(c3cccc(C#N)c3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(N2CCN(Cc3cccc(C(=O)O)c3)CC2)c1
Reaction time: 8 h

Procedure:
Dissolve 3-[4-(3-cyano-phenyl)-piperazin-1-ylmethyl]-benzoic acid methyl ester into 10 mL of 1:1 THF/MeOH and add 2 mL of 15% NaOH. Stir the mixture overnight and concentrate to dryness. Dissolve the residue in 5% HCl and apply to Dowex column. Rinse the resin with 2×20 mL H2O, 2×20 mL MeOH and 2×20 mL of dichloromethane. Liberate the basic residues by washing the resin with 3×20 mL of 10% NH3/MeOH to give 0.26 g 3-[4-(3-cyano-phenyl)-piperazin-1-ylmethyl]-benzoic acid as a white solid. 1H NMR indicates some contamination with starting amine. The crude intermediate is carried on without further purification.
Reaction SMILES: ClC1C(Cl)=C(O)C=C2C=1C1C(CC)(C2)CCC(=O)C=1.BrCC(OCC)=O.[Cl:27][C:28]1[C:40]([Cl:41])=[C:39]([OH:42])[CH:38]=[C:37]2[C:29]=1[C:30]1[C:35]([CH3:43])([CH2:36]2)[CH2:34][CH2:33][C:32](=[O:44])[CH:31]=1.Br[C:46]1([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47]1>>[Cl:27][C:28]1[C:40]([Cl:41])=[C:39]([O:42][C:46]2([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:38]=[C:37]2[C:29]=1[C:30]1[C:35]([CH3:43])([CH2:36]2)[CH2:34][CH2:33][C:32](=[O:44])[CH:31]=1
Reactant: CCOC(=O)C1(Br)CCCC1
Reactant: CC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Agent: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Agent: CCOC(=O)CBr
Product: CCOC(=O)C1(Oc2cc3c(c(Cl)c2Cl)C2=CC(=O)CCC2(C)C3)CCCC1

Procedure:
Carrying out a reaction as described in Example 1, Step D, except that the 5,6-dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one and ethyl bromoacetate are replaced by equimolar quantities of 5,6-dichloro-7-hydroxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one and ethyl 1-bromocyclopentane-1-carboxylate, there is obtained ethyl 1-[(5,6-dichloro-9a-methyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]cyclopentane-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[S:17](Cl)(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:9][S:17][N:8]=2
Reactant: Nc1ccc(F)cc1N
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Fc1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
4-Fluoro-benzene-1,2-diamine (2.5 g, 19.8 mmol) was added into a 50-mL Schlenk flask. The system was flushed with argon before 200 mL of chloroform was added and followed by addition of triethylamine (11.05 mL, 79.3 mmol). A clear solution was observed after stirring at room temperature for 10 minutes. Thionyl chloride (5.18 g, 43.6 mmol) was added dropwise. The mixture was heated to reflux for 5 hours before being cooled down to room temperature. The organic layer was washed with brine (100 mL) and further dried over anhydrous MgSO4. After removal of the solvent, the product was purified by silica gel column with hexane/dichloromethane (v/v, 1/2) as the eluent. Removal of the solvent offered a colorless oil (1.35 g, 44.3% yield) after being dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ 7.93 (d×d, 1H, J=9.0 Hz×5.0 Hz), δ 7.56 (d×d, 1H, J=9 Hz×2.5 Hz), δ 7.38 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH2:16]2)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:19][CH2:20]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(C[C@@H]2CCCNC2)CC1
Yield: 106.2 %

Procedure:
Benzyl 4-{[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]methyl}piperazine-1-carboxylate (4.46 g) was stirred in a mixture of trifluoroacetic acid (20 ml) and dichloromethane (200 ml) for two hours at room temperature. The reaction mixture was concentrated in vacuo and the resulting oil separated between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate solution (500 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo to give the title compound (3.6 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.Cl.O1CCOCC1>C(O)(C)C>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@H]2CCC[C@@H](N3CCOCC3)C2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCOCC3)C2)ccc2[nH]ncc12
Yield: 87.2 %

Procedure:
Under nitrogen, the 4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (80 mg, 0.200 mmol) obtained in Example 727 was dissolved in isopropyl alcohol (3 ml), followed by adding thereto 4N-hydrochloric acid/1,4-dioxane (3 ml), and the resulting mixture was stirred at room temperature for 19 hours. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/1, 100/2) to obtain 4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1H-indazole (55 mg, yield 87.1%) as a white amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][N:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[F:21][C:18]1[CH:19]=[CH:20][C:13]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=2)=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(F)ccc1F
Reactant: Cc1noc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1noc2cc(Oc3ccc(F)cc3C#N)ccc12
Temperature: 100 °C
Yield: 58 %

Procedure:
3-Methyl-benzo[d]isoxazol-6-ol (1v) (reference for synthesis, see Indian J. Chem. Sect.B; 19:571-575 (1980)) (1.58 g, 10.6 mmol) and 2,5-difluoro-benzonitrile (2v) (1.47 g, 10.6 mmol) were combined with potassium carbonate (1.46 g. 10.6 mmol) in 15 mL of dry DMA. The reaction was heated in a 100° C. bath for 6 hours. The reaction was cooled and diluted with EtOAc (200 mL) and washed three times with water, NH4Cl, NaHCO3, and brine. The organic solution was dried over MgSO4 and concentrated. The crude residue was purified by column chromatography (silica, 70-80% CH2Cl2/hexane) to provide compound (3v) (1.65 g, 58% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[K+].CCOCC.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[CH2:21]([O:20][C:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(S)[C@H](N)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Yield: 71 %

Procedure:
To L-penicillamine (15.75 g; 105.8 mmol) was added a solution of KOH (12.4 g; 222.2 mmol) in water (250 ml). When the solution was complete, Et2O (100 ml) was added and the solution cooled to 0° C. Benzyl chloroformate (14.9 ml; 105.8 mmol) was added dropwise and the stirred reaction mixture allowed to warm to RT. The layers were separated, the aqueous layer acidified to pH 1-1.5 with 1N hydrochloric acid, extracted with CH2Cl2 (×3) and dried (MgSO4). The solvent was removed in vacuo to yield N-benzyloxycarbonyl-L-penicillamine (21.27 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7]I.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][NH:16][C:12]=2[N:13]=[CH:14][N:15]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([CH3:7])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
According to Scheme 5, cesium carbonate (968 mg, 3 mmol) followed by methyl iodide (1 g, 7.1 mmol) was added to a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (121 mg, 0.79 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 6 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated and column chromatographed to give 116 mg (88%) of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a white solid. 1H NMR (360 MHz, DMSO-d6) 8.62 (s, 1H), 7.71 (s, 1H), 6.62 (s, 1H), 3.84 (s, 3H, CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](NC)=[S:22])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.FC1C=C(N2C[C@H](CNC(=S)C)OC2=O)C=CC=1N1CCOCC1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][CH:21]=[S:22])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CNC(=S)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: CC(=S)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: O=C1O[C@@H](CNC=S)CN1c1ccc(N2CCOCC2)c(F)c1
Reaction time: 1.5 h
Yield: 28.5 %

Procedure:
A stirred mixture of 6 (0.38 g, 0.00118 mol) in dioxane (20 mL), under nitrogen was treated with 4 (0.51 g, 0.00126 mol), warmed to reflux during 30 min and kept at this temperature for 90 min. It was then evaporated under a stream of nitrogen. The residue was chromatographed on silica gel with 1.25% MeOH—CH2Cl2 and the slightly impure product was rechromatographed on silica gel with 25% EtOAc-CH2Cl2. The resulting product was crystallized from EtOAc-methyl tert-butyl ether to give 0.114 g of 7: mp 150-155° C. (dec.); IR (DRIFT) 3322, 1752 cm−1; MS(ES) m/z 340 (M+H+), 362 (M+Na+); 1HNMR [300 MHz, (CD3)2SO] d 2.94 (m, 4H), 3.72 (m, 4H), 3.77 (d,d, 1H), 3.94 (t, 2H), 4,12 (t, 1H), 4.93 (m, 1H), 7.05 (t, 1), 7.16 (d,d, 1H), 7.47 (d,d, 1H), 9.33 (d, 1H), 10.59 (s, 1H), Anal. cald for C15H18FN3O3S: C, 53.08; H, 5,35; N, 12.38. Found: C, 53.02; H, 5.44; N, 12.36.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1.[Cl:50][C:51]1[CH:52]=[C:53]([OH:57])[CH:54]=[CH:55][CH:56]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.O>[Cl:50][C:51]1[CH:52]=[C:53]([CH:54]=[CH:55][CH:56]=1)[O:57][C:7]1[N:6]=[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)[N:10]2[N:11]=[CH:12][C:13](/[CH:14]=[C:15]3/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/3)=[C:9]2[N:8]=1
Reactant: Oc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(Oc4cccc(Cl)c4)nc23)N1
Temperature: 90 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (1.0 eq, 25 mg, 0.0704 mmol) was combined in a vial with 3-chlorophenol (5.0 eq, 45 mg, 0.35 mmol) and K2CO3 (5.0 eq, 48 mg, 0.347 mmol) in NMP (0.2 ml). The mixture was stirred at 90° C. for 1 hour. Water was added and the resulting solid was filtered and dried. Trituration in a mixture of ethyl acetate and hexanes followed by filtration provided (Z)-5-((2-(3-chlorophenoxy)-4-(cyclopropylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione as a tan solid (20 mg, 69%). LCMS (ES): >95% pure, m/z 412 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.NC1C=CC=C2C(N(O)C(=O)C=12)=[O:15]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:15])=[CH:3][CH:4]=1
Reactant: COc1ccc(C)cc1
Reactant: Nc1cccc2c1C(=O)N(O)C2=O
Product: COc1ccc(C=O)cc1
Yield: 61 %

Procedure:
195 mg (1.60 mmol) of 4-methylanisole were reacted analogously to Example 1 in the presence of 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide. After a reaction time of 22 hours, the reaction solution was extracted with chloroform and examined by NMR spectroscopy and gas chromatography. Yield 61% of 4-methoxybenzaldehyde (approx. 90%, based on conversion).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:28])[C:25]([OH:27])=O)[C:4]=12.[Cl-].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[C:40]([N:41]2[CH2:46][CH2:45][NH2+:44][CH2:43][CH2:42]2)=[N:39][N:38]=[N:37]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:28])[C:25](=[O:27])[N:44]3[CH2:43][CH2:42][N:41]([C:40]4[N:36]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=5)[N:37]=[N:38][N:39]=4)[CH2:46][CH2:45]3)[C:4]=12
Reactant: c1ccc(-n2nnnc2N2CC[NH2+]CC2)nc1
Reactant: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A mixture of 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (15 mg, 0.039 mmol), 4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-ium chloride (11.43 mg, 0.043 mmol), 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (13.71 mg, 0.043 mmol) and N,N-diisopropyl ethylamine (0.022 ml, 0.124 mmol) in DMF (1 ml) was stirred overnight at room temperature. The reaction mixture was filtered through a silica gel pad and concentrated under reduced pressure. The resulting crude was purified by prep HPLC to give N-(1-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide (10 mg, 43%) as white solid. LCMS: m/e 600.47 (M+H)+, ret time 2.67 min (method 4). 1H NMR (500 MHz, DMSO-D6) δ ppm 1.22 (s, 9H) 3.23-3.29 (m, 2H) 3.39-3.49 (m, 4H) 3.68-3.74 (m, 2H) 3.99 (s, 3H) 7.64 (dd, J=7.63, 4.88 Hz, 1H) 7.85 (d, J=8.24 Hz, 1H) 7.88 (s, 1H) 8.13-8.18 (m, 1H) 8.21 (s, 1H) 8.23 (d, J=3.66 Hz, 1H) 8.64-8.69 (m, 1H) 11.36 (s, 1H) 12.59 (d, J=3.36 Hz, 1H)
Reaction SMILES: C([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[N:13][C:14](C)=[N:15][C:16]=32)[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.C(N)=[NH:26]>>[CH:17]12[CH2:19][CH:10]([CH2:9][NH:8][CH2:18]1)[C:11]1[CH:12]=[N:13][C:14]([NH2:26])=[N:15][C:16]2=1
Reactant: N=CN
Reactant: Cc1ncc2c(n1)C1CC2CN(Cc2ccccc2)C1
Solvent: CC(=O)O
Product: Nc1ncc2c(n1)C1CNCC2C1

Procedure:
Following the method described in Example 13, 10-benzyl-4-methyl-3,5,10-triaza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene and formamidine acetate were converted to the title compound in 18% overall yield. APCl MS m/z 177.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([O:7][C:8]1[C:9](Cl)=[N:10][C:11]([Cl:15])=[N:12][C:13]=1[Cl:14])[CH3:6])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:17])[C@H:5]([O:7][C:8]1[C:13]([Cl:14])=[N:12][C:11]([Cl:15])=[N:10][C:9]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1Cl
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
A mixture of (R)-2-(2,4,6-trichloro-pyrimidin-5-yloxy)-propionic acid ethyl ester (522 mg, 1.74 mmol), morpholine (152 μL, 1.74 mmol) and triethylamine (484 μL, 3.48 mmol) in ethanol (15 mL) was stirred at RT for 18 hours then partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo affording (R)-2-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propionic acid ethyl ester (490 mg, 80%). LCMS: RT=3.57 min, [M+H]+=350/352.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Cl:11][CH:12]([CH2:16][CH3:17])[C:13](O)=[O:14]>>[Cl:11][CH:12]([CH2:16][CH3:17])[C:13]([C:7]1[CH:8]=[CH:9][C:4]2[NH:3][C:2](=[O:10])[O:1][C:5]=2[CH:6]=1)=[O:14]
Reactant: CCC(Cl)C(=O)O
Reactant: O=c1[nH]c2ccccc2o1
Product: CCC(Cl)C(=O)c1ccc2[nH]c(=O)oc2c1
Temperature: 125 °C
Reaction time: 3 h

Procedure:
81.70 g (604.65 mmol) 2-benzoxazolinone are stirred together with 720.00 g polyphosphoric acid at 80° C. 63 mL (607.64 mmol) 2-chlorobutyric acid are added and the mixture is stirred for 3 h at 125° C. The reaction mixture is then poured onto ice water and extracted with DCM. The org. phase is concentrated by rotary evaporation i. V. and the residue is separated on silica gel (eluant cyclohexane/EA). The suitable fractions are concentrated by rotary evaporation i. V. and the residue is crystallised with diethyl ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH2:11])[CH2:8][CH2:9][CH3:10])[CH:2]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C(O)C>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:11][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:9][CH3:10])[CH:18]=1
Reactant: CCCC(N)c1cccnc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(Nc1cc(Cl)ncn1)c1cccnc1
Reaction time: 72 h

Procedure:
To a solution of 1-pyridin-3-ylbutan-1-amine (100 mg, 0.67 mmol) in ethanol (4 mL) was added 4,6-dichloropyrimidine (109 mg, 0.73 mmol) and diisopropylethylamine (232 μL, 1.33 mmol). The solution was stirred for 3 days after which time the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and washed with H2O (3×15 mL), brine (15 mL) and dried (Na2SO4). The residue remaining after concentration in vacuo was chromatographed using ethyl acetate-hexanes (4:6-9:1) as eluant to separate the desired product (28 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26].[CH:27](O)=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][CH:27]=[O:28])[CH2:23][CH2:24]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:26]
Reactant: O=C1Nc2nc(N[C@H]3CC[C@H](O)CC3)ncc2CN1c1ccccc1Cl
Reactant: O=CO
Product: O=CO[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(2-chlorophenyl)-7-(trans-4-hydroxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (300 mg, 0.8 mal) (prepared as described in Example 73) and 96% formic acid (2 mL) was stirred at 60° C. for 3 hours, then concentrated under reduced pressure. The residue was triturated in ether, filtered and dried to give 250 mg of 3-(2-chlorophenyl)-7-(trans-4-formyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-])=O)=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[C:24](OCC)=[O:25]>C(OCC)(=O)C>[NH2:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([OH:10])=[C:12]([C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:25])[CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1O
Solvent: CCOC(C)=O
Product: Nc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2c1
Temperature: 180 °C

Procedure:
A suspension of 0.60 mL of 4-chlorobenzylamine and 0.200 g of ethyl 4-hydroxy-7-nitro-3-quinoline carboxylate is heated to 180° C. for 1 h. The reaction is cooled to room temperature. Ethyl acetate is added and the resulting solid is collected and washed with ethyl acetate to yield 0.071 g of the title compound as a tan solid.
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(I)ccc21
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2ccc3c(c2)C(c2cccc(C#N)c2)=NCC(=O)N3C)cc1OC
Yield: 72 %

Procedure:
Prepared from 3-(7-iodo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 11 using the same conditions used to prepare Example 1 but using 3,4-dimethoxyphenyl boronic acid instead of benzene boronic acid. The title compound (110 mg) was obtained as a beige solid, (yield=72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Br[C:25]([CH3:30])([CH3:29])[C:26](Br)=[O:27]>O>[CH3:29][C:25]1([CH3:30])[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OC(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (9.8 g) in a mixed solvent of ethyl acetate (200 ml) and water (200 ml) were added sodium hydrogen carbonate (7.3 g) and 2-bromoisobutyryl bromide (13.7 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (500 ml), to the solution was added potassium carbonate (8.9 g) and the mixture was stirred at room temperature for a day. The reaction solution was poured into water to give precipitates, which were taken by filtration and dried to give 2,2-dimethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (10.8 g).