Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].C(O)(C)C.[ClH:16].CCOCC>C1COCC1.[Pt](=O)=O>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
3-cyanobenzoic acid (5.88 g, 40 mmol) was suspended in 50 mL THF and the mixture was warmed up with stirring. After all solid went into solution, 50 mL isopropanol was added and the solution was allowed to cool to room temperature. To it was added 4.2 mL precooled concentrated HCl followed by 300 mg platinum(IV) oxide. The mixture was hydrogenated at 55 psi overnight. Ether (50 mL) was added, and the precipitate was filtered, washed with ether and dissolved in methanol. The catalyst was filtered off and the solvent was removed under reduced pressure to give 6.2 g (82%) product. 1H-NMR (DMSO-d6): δ=4.08 (d, 2H); 7.53 (t, 1H); 7.80 (d, 1H); 7.94 (d, 1H); 8.10 (s, 1H); 8.65 (s, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([Li])CCC.CCC(CC(Br)[Br:18])=O.P([O-])(O)(O)=O.[K+].[O:26]1C[CH2:29][CH2:28][CH2:27]1>CCCCCC>[Br:18][CH:28]([CH3:29])[C:27]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])=[O:26]
Reactant: C1CCOC1
Reactant: O=C1NCCO1
Reactant: CCC(=O)CC(Br)Br
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(Br)C(=O)N1CCOC1=O
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of oxazolidin-2-one (4.00 g; 45.9 mmol) in dry tetrahydrofuran (70 ml), a solution of n-butyl lithium in hexane (1.60 N; 30 ml) was added at 0° C., and then 1-bromopropionyl bromide (5.83 ml, 45.9 mmol) was added at the same temperature. After 1 hour, an aqueous solution of saturated potassium dihydrogen phosphate (5 ml) was added to decompose the excess reaction agent. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (n-hexane:dichloromethane=1:1) to give 3-(2'-bromopropionyl)oxazolidin-2-one (8.68 g, yield, 84%) as a colorless solid. The sample for analysis was obtained by recrystallization from diethyl ether. M.P., 41° C.
Reaction SMILES: [CH:1](O)=[O:2].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[F:28][C:29]1[C:41]([F:42])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:30]=1[O:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>C(OCC)C.O>[CH:1]([N:35]1[CH2:36][CH2:37][CH:32]([O:31][C:30]2[C:38]([F:45])=[C:39]([F:44])[C:40]([F:43])=[C:41]([F:42])[C:29]=2[F:28])[CH2:33][CH2:34]1)=[O:2]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: O=CO
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 1.5 ml of formic acid and 3.5 ml of acetic anydride was stirred at 55° C. for one hour, cooled, and treated with a solution of 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 50 ml of diethyl ether. The reaction mixture was then stirred at ambient temperature for three hours. Thereafter, the mixture was poured into 100 ml of water, adjusted to pH 10 by the addition of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated solution of chloride and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvent afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to yield 4.0 g (91%) of 1-formyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 32°-34° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][CH2:35][C@H:36]([OH:37])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: NC[C@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)NC[C@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (1R)-2-amino-1-phenylethanol, the title compound was obtained in 84% purity by HPLC. MS(ESI+): m/z=458.
Reaction SMILES: O=S(Cl)Cl.[C:5]1([C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])[OH:6].[CH3:13][O:14][CH:15](OC(OC)C)[CH3:16].C1(C(=CC=CC=1)O)O.[OH-].[Na+]>>[CH3:13][O:14][CH:15]([O:6][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[OH:8])[CH3:16]
Reactant: Oc1ccccc1O
Reactant: COC(C)OC(C)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COC(C)Oc1ccccc1O

Procedure:
0.5 parts of SOCl2 is added to 113 parts by weight of pyrocatechol-bis-[(1-methoxy)-ethyl]-ether and 55 parts by weight of pyrocatechol at 40° C. and the whole is stirred at this temperature for half an hour. It is then allowed to cool and 2 parts by volume of 25% by weight aqueous caustic soda solution is added. The product is separated and dried over sodium sulfate and the solvent is evaporated. There remains 168 parts of the abovementioned compound having a boiling point of 85° to 90° C. at 0.5 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC(C(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 2-(3,4-dichlorophenyl)pent-4-enoate (2.47 g, 9.53 mmol) in tetrahydrofuran (15.0 mL) was added a solution of lithium hydroxide monohydrate (2.00 g, 47.6 mmol) in water (15.0 mL). The mixture was vigorously stirred at rt for 12 hrs. The resulting mixture was acidified by addition of 12.0 M of hydrochloric acid in water (3.97 mL, 47.6 mmol) at 0° C., and extracted with EtOAc (×3). The combined organic layer was dried and concentrated to provide 2-(3,4-dichlorophenyl)pent-4-enoic acid as a yellow syrup (2.65 g, quantative). 1H NMR (400 MHz, CDCl3) δ 7.45-7.35 (m, 2H), 7.21-7.11 (dd, J=8.3, 2.1 Hz, 1H), 5.76-5.59 (ddt, J=17.0, 10.2, 6.8 Hz, 1H), 5.14-4.99 (m, 2H), 3.65-3.56 (t, J=7.7 Hz, 1H), 2.88-2.74 (dt, J=14.8, 7.5 Hz, 1H), 2.58-2.43 (dt, J=14.3, 6.9 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sccc1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of 2.0 g (6.116 mmol) of the product of Example 1 in 25 mL of DMF was added 0.257 g (6.422 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperature and then 0.76 mL (6.422 mmol) of benzyl bromide was added. This reaction mixture was stirred overnight at room temperature, poured into water and then extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexanes (1:3) to provide 1.62 g (65%) of the desired product as white crystals. CI Mass Spec: 418 (M+H).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][C:10]([F:24])([F:23])[S:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:13])=[O:12]>CCOCC>[F:9][C:10]([F:24])([F:23])[S:11]([O-:14])(=[O:13])=[O:12].[CH2:15]([N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOS(=O)(=O)C(F)(F)F
Reactant: Clc1nsc(Cl)c1Cl
Solvent: CCOCC
Product: CCCCCCCC[n+]1sc(Cl)c(Cl)c1Cl
Product: O=S(=O)([O-])C(F)(F)F
Yield: 31 %

Procedure:
Trichloroisothiazole (6.6 g, 0.035 mol) and n-octyl trifluoromethane sulfonate (7.5 g, 0.0286 ml) were heated at 110° for 2 hrs. After cooling, 150 ml of ether was added and solution cooled in a dry ice/acetone bath. The ether was decanted and the brown oil dried to yield 4.0 g (31%) of product. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=O)[CH3:11].[NH2:13][OH:14].Cl.[Li+].[OH-]>C(O)C.O>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=[N:13][OH:14])[CH3:11]
Reactant: CC(=O)c1cc2ccncc2[nH]1
Reactant: NO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1cc2ccncc2[nH]1
Yield: 47 %

Procedure:
To a solution of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone (Example 70) (0.39 g, 2.42 mmol) and hydroxylamine.HCl (0.34 g, 4.84 mmol) in ethanol (12.1 mL) and water (3.4 mL) was added LiOH (0.31 g, 7.26 mmol). The reaction mixture was refluxed for 1.0 h, and then the heat was removed. After concentration under reduced pressure, the residue was triturated with water. The solid was collected by filtration, rinsed with water and Et2O, and dried under vacuum at 45° C. to give 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone oxime (0.20 g, 47%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ2.26 (3H, s), 6.78 (1H, s), 7.54-7.57 (1H, m), 8.03 (1H, d, J=5.6 Hz), 8.64 (1H, s); ESI MS m/z 176 [C9H9N3O+H]+; HPLC (Method A) >99% (AUC, isomeric ratio=89.3:10.7), tR=12.47 (major) and 12.25 (minor).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([OH:22])=O)=[O:14])[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:63][CH2:64][CH2:65][NH2:66]>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:22])[NH:66][CH2:65][CH2:64][F:63])=[O:14])[N:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)O)n(-c2ccccc2)n1
Reactant: NCCF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reaction time: 12 h

Procedure:
To a solution of 1.3 g 5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 20 ml DMF were added 1.28 g HATU and 0.56 ml DIPEA. After 10 minutes 334 mg 2-fluoroethylamine hydrochloride were added. Additional 100 mg 2-fluoroethylamine hydrochloride and 400 mg HATU were added after 2 h. The reaction mixture was allowed to stir for further 12 h before being diluted with dichloromethane and extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using ethyl acetate/heptane 80:20 to ethyl acetate/heptane 100:0 as eluent. Yield: 1.5 g colorless oil.
Reaction SMILES: Cl[C:2](Cl)(Cl)C(OC(=O)C(Cl)(Cl)Cl)=O.[NH2:14][C:15]1[N:20]=[C:19]([N:21]([CH2:28][CH2:29][O:30][CH3:31])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=[C:17]([C:32](=[N:34][OH:35])[NH2:33])[N:16]=1.Cl.[O:37]([CH:44]1[CH2:47][NH:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:31][O:30][CH2:29][CH2:28][N:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]1[N:20]=[C:15]([NH2:14])[N:16]=[C:17]([C:32]2[N:33]=[C:2]([N:46]3[CH2:47][CH:44]([O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:45]3)[O:35][N:34]=2)[N:18]=1
Reactant: c1ccc(OC2CNC2)cc1
Reactant: COCCN(c1ccccc1)c1nc(N)nc(C(N)=NO)n1
Reactant: O=C(OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(N3CC(Oc4ccccc4)C3)n2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.8 %

Procedure:
Trichloroacetic anhydride (0.181 mL, 0.989 mmol) was added to 4-amino-N′-hydroxy-6-[(2 methoxyethyl)(phenyl)amino]-1,3,5-triazine-2-carboximidamide (Intermediate 160, 0.250 g, 0.824 mmol) in toluene (10 mL) and stirred at room temperature for 5 min. Pyridine (3 mL) was added and the mixture was heated to 85 C for 1 h. The mixture was concentrated under vacuum and the residue dissolved in EtOAc. This was washed with water, saturated aq. sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in DMF (2 mL) and 3-phenoxyazetidine hydrochloride (0.13 g, 0.685 mmol) and DIPEA (0.499 mL, 1.370 mmol) were added. The mixture was stirred at room temperature for 13 h and was then concentrated under vacuum. The mixture was extracted with EtOAc (30 mL), washed with water, saturated aq. sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 0-2% MeOH in DCM. The crude material was further purified by FCC, eluting with 50% EtOAc in heptane then 0-2% MeOH in DCM to afford the title compound (0.091 g, 29%).
Reaction SMILES: C(O)(=O)C.C1COCC1.[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])=[CH:13][C:12]=1[NH:28][C:29]([N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:30]>O>[Br:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH:18]([OH:20])[CH3:19])=[CH:13][C:12]=1[NH:28][C:29]([N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]1[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1)=[O:30]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1cc(NC(=O)N2C=CC(=O)CC2c2ccc(F)cc2)c(Br)cc1Cl
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cc(NC(=O)N2C=CC(=O)CC2c2ccc(F)cc2)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of acetic acid (4.5 ml), water (1.5 ml) and THF (1.5 ml) was added to a flask containing 2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid {2-bromo-5-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-chloro-phenyl}-amide (0.144 g, 0.247 mmol). The mixture was stirred at room temperature for 16 hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification by flash chromatography (EtOAc) gave 2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [2-bromo-4-chloro-5-(1-hydroxy-ethyl)-phenyl]-amide (0.082 g, 71%) as a white foam. MS (M+H) 468.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[CH:5]=[CH:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.C[N:20](C=O)C.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:20])=[O:10])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)c1cccc(-n2cccn2)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)c1cccc(-n2cccn2)c1
Yield: 80 %

Procedure:
To a suspension of 3-(1H-pyrazol-1-yl)-benzoic acid [see WO 00/21951] (104 g, 0.55 mol) in anhydrous benzene (500 ml) was added thionyl chloride (85 g, 0.715 mol) and DMF (0.5 ml). The mixture was heated at reflux for 3 hours, then evaporated under reduced pressure. The residue was dissolved in anhydrous THF (100 ml) and evaporated. The residue was dissolved in anhydrous acetone (600 ml), and treated with ammonium acetate (77 g, 1 mol). The mixture was heated at reflux for 12 hours, solvent was evaporated and the residue treated with cold water (2000 ml). The resulting precipitate was filtered, washed with cold water (200 ml) and recrystallised from absolute ethanol (600 ml) to give 3-(1H-pyrazol-1-yl)benzamide (82 g, 80%). A solution of this material (82 g, 0.44 mol) in THF was added dropwise to a solution of LiAlH4 (25 g, 0.66 mol) in anhydrous THF (800 ml). The mixture was heated at reflux for 4 hours, cooled and quenched by the sequential addition of water (25 ml), 15% aqueous NaOH (25 ml), and water (50 ml). The inorganic by-products were filtered off and washed several times with diethyl ether (overall volume 1000 ml). The combined filtrates were dried over Na2SO4, filtered and evaporated. The residue was dissolved in methanol (400 ml), the solution was treated with activated carbon (10 g), and the mixture was refluxed for 40 minutes, then filtered and evaporated. The residue was treated with 1N HCl in ether (1000 ml), and the precipitate formed was filtered, washed with ether and dried to give the title compound (53 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@H:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([Cl:22])[N:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[N:6]=1>CO>[ClH:22].[N:19]1[CH:20]=[CH:21][C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][C@H:5]3[CH2:4][O:3][C:2]([NH2:1])=[N:6]3)=[CH:14][CH:13]=2)=[N:17][CH:18]=1
Reactant: NC1=N[C@@H](CCc2ccc(Nc3cc(Cl)ncn3)cc2)CO1
Solvent: CO
Product: Cl
Product: NC1=N[C@@H](CCc2ccc(Nc3ccncn3)cc2)CO1
Yield: 86.9 %

Procedure:
{4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-(6-chloro-pyrimidin-4-yl)-amine (16 mg, Example 32) was dissolved in methanol to give a colourless solution. The mixture was degassed by bubbling through argon for several minutes. 10% Palladium on charcoal (11 mg) was added and the reaction mixture was stirred under a hydrogen-filled balloon at room temperature for 2 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford (S)-4-(4-(pyrimidin-4-ylamino)phenethyl)-4,5-dihydrooxazol-2-amine hydrochloride (14 mg, 87%) as a white solid. MS (ISP): 284.2 ([M+H]+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB(/[CH:31]=[CH:32]/[C:33]2[CH:34]=[CH:35][C:36]3[O:42][CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C:37]=3[CH:50]=2)O1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[O:42]1[C:36]2[CH:35]=[CH:34][C:33](/[CH:32]=[CH:31]/[C:2]3[C:10]4[C:5](=[CH:6][C:7]([C@H:11]5[C@@:13]6([C:21]7[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=7)[NH:15][C:14]6=[O:22])[CH2:12]5)=[CH:8][CH:9]=4)[NH:4][N:3]=3)=[CH:50][C:37]=2[CH2:38][NH:39][CH2:40][CH2:41]1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(/C=C/B3OC(C)(C)C(C)(C)O3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(/C=C/c3ccc4c(c3)CNCCO4)n[nH]c2c1
Reaction time: 1 h
Yield: 30 %

Procedure:
The title compound was synthesized according to the method of Example A51B, by using (1R,2S)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (105 mg, 0.27 mmol) and (E)-tert-butyl 7-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (130 mg, 0.32 mmol). The residue from the reaction was dissolved into CH2Cl2 (5 mL) and TFA (0.2 mL) was added and the mixture was stirred for 1 h and concentrated to dryness. Purification by preparative HPLC gave the title compound as a cream solid (40 mg, 30%). 1H NMR (400 MHz, CD3OD) δ 7.97 (d, J=8.2 Hz, 1H), 7.68-7.64 (m, 2H), 7.50-7.39 (m, 3H), 7.16 (d, J=8.2 Hz, 1H), 7.07-7.01 (m, 2H), 6.94 (d, J=7.8 Hz, 1H), 6.57 (t, J=7.6 Hz, 1H), 5.98 (d, J=7.4 Hz, 1H), 4.45 (s, 2H), 4.39 (br. s, 2H), 3.68 (br. s, 2H), 3.39-3.33 (m, 1H) 2.25-2.16 (m, 2H); MS ESI 449.3 [M+H]+, calcd for [C28H24N4O2+1-1]+ 449.2.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]([F:16])([F:15])[F:14])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:17][O:18][CH2:19][CH2:20]Br>CCCCC.CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]([F:14])([F:15])[F:16])=[C:8]([CH2:10][O:11][CH2:20][CH2:19][O:18][CH3:17])[CH:9]=1
Reactant: COCCBr
Reactant: OCc1cc(Br)ccc1OC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: COCCOCc1cc(Br)ccc1OC(F)(F)F
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
In a 3-neck flask under argon, a 55-65% dispersion of NaH in oil (0.097 g, 2.44 mmol) is washed with n-pentane, the organics are removed and DMF (10 mL) is added. The mixture is cooled to 0-5° C., and a solution of (5-bromo-2-trifluoromethoxy-phenyl)-methanol (0.60 g, 2.21 mmol) in DMF (3.0 mL) is added dropwise. After warming to room temperature, stirring is continued for 1 h before this mixture is added to a solution of 2-bromoethyl methyl ether (0.312 mL, 3.32 mmol) in DMF (3mL). After 4 hrs at room temperature, the reaction is still incomplete by TLC. Another aliquot of NaH (1 equiv; oil dispersion washed with pentane) and 2-bromoethyl methyl ether (0.312 mL, 3.32 mmol) are added, followed by stirring for 18 hrs at room temperature. The mixture is poured into ice-water and extracted with AcOEt, the combined organics are dried (Na2SO4) and evaporated to dryness to give the title compound as yellowish oil. MS: 346.0/348.0 [M+H2l O]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.80 min. 1H-NMR (CDCl3): δ 3.49 (s, 3H), 3.64 (m, 2H), 3.72 (m, 2H), 4.69 (s, 2H), 7.13 (dd, 1H), 7.46 (dd, 1H), 7.77 (d, 1H) ppm.
Reaction SMILES: I.[CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[NH:12])[NH2:11])[CH2:6][CH2:5]1)=[O:3].[O-]CC.[Na+].[NH2:17]N.[CH:19]1[CH:24]=[C:23]([C:25]([C:27]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=O)=O)[N:22]=[CH:21][CH:20]=1>C(O)C>[CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[N:17][C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:34]=3)=[C:25]([C:23]3[CH:24]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=2)[CH2:6][CH2:5]1)=[O:3]
Reactant: N=C(N)N1CCN(C=O)CC1
Reactant: NN
Reactant: O=C(C(=O)c1ccccn1)c1ccccn1
Agent: CC[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: O=CN1CCN(c2nnc(-c3ccccn3)c(-c3ccccn3)n2)CC1
Reaction time: 0.25 h

Procedure:
A mixture of 4-formyl-piperazinecarboximidamide hydroiodide (prepared according to U.S. Pat. No. 4,351,832) in ethanol (4 ml) and ethanolic sodium ethoxide (1.4N, 6.8 ml) is stirred for 15 min and then anhydrous hydrazine (0.32 g) in ethanol (3 ml) is added. The mixture is stirred an additional 15 min, then 2,2'-pyridil (2.12 g) is added. The mixture is stirred for 12 hours at 25° and concentrated. The residue is chromatographed on silica gel eluting with a methylene chloride/methanol mixture. The appropriate fractions are pooled and concentrated to give 1-formyl 4-[5,6-bis(2-pyridinyl)-1,2,4-triazin-3-yl]-piperazine. Hydrolysis of the formamide in the usual way (PREPARATION A-14) give the title compound.