Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50][F:51])[CH2:11][O:12]2)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.O1CCCC1.[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:50][F:51])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CF)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CF)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
To a solution of {(1S,2S,3S,4R,5S)-2,3,4-Tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-1-yl}-methanol (616 mg, 0.871 mmol) in dichloromethane (3 mL) at 0 degrees Celsius was added diethylaminosulfur trifluoride (170 microL, 1.3 mmol) and the resulting mixture was slowly warmed to room temperature and stirred at this temperature for 16 hours. The mixture was diluted with dichlorometane and washed with a saturated solution of aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a 40 g redisep silica cartridge (eluting with a gradient of 0 to 20% ethyl acetate in heptane) to afford (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane as a colorless oil (40 mg, 7% yield). (LCMS) 753.4 (M+HCOO−: negative mode). To a suspension of (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane (40 mg, 0.06 mmol) and palladium black (40 mg, 0.38 mmol, Aldrich® high surface area) in ethanol (0.5 mL) and tetrahydrofuran (0.1 mL) was added fomic acid (0.085 mL, 2.24 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added and the mixture was filtered through a short pad of Celite® and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using a 4 g redisep silica cartridge (eluting with a gradient of 50 to 100% ethyl acetate in heptane) to afford the title compound as a solid (15.6 mg, 63% yield). (LCMS) 483.0 (M+HCOO−: negative mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 7.44 (s, 1H), 7.38 (s, 1H), 7.37 (s, 1H), 7.09-7.12 (m, 2H), 6.80-6.83 (m, 2H), 4.71 (dd, J=46.59, 10.49 Hz, 1H), 4.50 (dd, J=48.30, 10.73 Hz, 1H), 4.19 (dd, J=7.56, 0.98 Hz, 1H), 4.04 (d, J=0.98 Hz, 2H), 4.00 (q, J=6.99 Hz, 2H), 3.80 (dd, J=8.29, 0.98 Hz, 1H), 3.67 (t, J=8.17 Hz, 1H), 3.54-3.57 (m, 2H), 1.37 (t, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Cl-].Cl[CH2:17][C:18]1[S:19][CH:20]=[CH:21][NH+:22]=1>CN(C=O)C.CCN(C(C)C)C(C)C.O>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[CH2:17][O:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: ClCc1[nH+]ccs1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCc2nccs2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a solution of N-Boc-azetidin-3-ol (260 mg, 1.5 mmol) in DMF (3.5 mL) at 0° C. under nitrogen was added NaH (60% in oil, 126 mg, 3.15 mmol). The suspension was stirred for 0.5 h at 0° C. then treated with 2-(chloromethyl)-1,3-thiazol-3-ium chloride (510 mg, 3.0 mmol; which may be prepared as described in Step 1) dissolved in DMF (1 mL) and DIPEA (1.05 mL). The mixture was allowed to warm to room temperature then heated to 80° C. overnight. The reaction mixture was cooled, water (20 drops) was added and the mixture concentrated under reduced pressure. The crude material was purified on column chromatography (eluent: Pentane/EtOAc, 90/10 to 50/50) to give the product (193 mg, 48%) as a brown oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9][N:8]=1.Br.O>C(O)(=O)C>[C:17]1([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH2:6])=[N:8][N:9]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(CNc2nnc(-c3ccccc3)c3ccccc23)c(OC)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Nc1nnc(-c2ccccc2)c2ccccc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In a 150 mL sealed tube, dissolved N-(2,4-dimethoxybenzyl)-4-phenylphthalazin-1-amine (3.00 g, 8.1 mmol) in acetic acid (40 mL). Hydrobromic acid (48% aqueous) (2.6 mL, 24 mmol) was added and the tube was stirred at 90° C. for 3 h. The solution was cooled to RT, and slowly poured into water, which caused a pink solid to crash out. The solid was filtered and rinsed with water. The product containing filtrate was slowly poured into saturated sodium carbonate. The aqueous phase was extracted with DCM, washed twice with water, dried with Na2SO4, filtered through fritted funnel, and concentrated to yield 4-phenylphthalazin-1-amine as light yellow solid. MS [M+H]=222; Calc'd 221.3 for C14H11N3.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[C:6]([OH:11])(=[O:10])/[CH:7]=[CH:8]/[CH3:9].[Cl:12][C:13]([Cl:17])([Cl:16])[CH2:14]O.S(=O)(=O)(O)O>O>[Cl:12][C:13]([Cl:17])([Cl:16])[CH2:14][O:10][C:6](=[O:11])/[CH:7]=[CH:8]/[CH3:9]
Reactant: C/C=C/C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: C/C=C/C(=O)OCC(Cl)(Cl)Cl
Yield: 95 %

Procedure:
In 200 ml. carbon tetrachloride are dissolved 0.5 mole (43.07 g.) crotonic acid and the equimolar amount of 2,2,2-trichloroethanol, 1 ml. concentrated sulphuric acid is added thereto and the reaction mixture is heated under reflux on a water separator until the theoretical amount of water (9 ml.) has separated off. Subsequently, the organic phase is shaken out twice with, in each case, 100 ml. aqueous 2N sodium hydrogen carbonate solution and twice with, in each case, 50 ml. of water, the organic phase is then dried with anhydrous magnesium sulphate and the solvent is distilled off in a vacuum. There is finally obtained the desired product (i) in the form of a bright yellow oil in a yield of 95% of theory. C6H7O2Cl3 (217.4791)
Reaction SMILES: [ClH:1].[CH3:2][NH2:3].[CH2:4]=O.[C:6](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[NH2:7]>C(O)C>[ClH:1].[CH3:2][NH:3][CH2:4][NH:7][C:6](=[O:12])[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: C=O
Reactant: CN
Reactant: CC(C)OC(N)=O
Agent: Cl
Solvent: CCO
Product: CNCNC(=O)OC(C)C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To 50 ml of ethanol, 20.3 g (0.3 mole) of methylamine hydrochloride and 30.9 g (0.36 mole) of 37% formaldehyde aqueous solution were added and the mixture was warmed to 35°-40° C. Then, a solution prepared by dissolving 30.9 g (0.3 mole) of isopropyl carbamate in 150 ml of ethanol was added dropwise to the mixture with stirring maintaining the said temperature. After the dropwise addition of the solution, stirring was continued for 1 hour with heating and then the solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethanol to give 42.7 g of isopropyl N-(methylaminomethyl)carbamate hydrochloride having a melting point of 163°-164° C. in yield of 77.8%. ##STR5##
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.O>[OH:7][CH:8]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([O:11][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)CC(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CC(C)(C)CC(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
743 mg (2.28 mmol) of caesium carbonate were added to a solution of 667 mg (4.56 mmol) of 2-hydroxy-4,4-dimethylpentanoic acid (racemate) in 8.7 ml of methanol and 1.7 ml of water The reaction mixture was stirred at RT for 60 min and the solvent was then removed under reduced pressure. The residue was dried under high vacuum (4 h) and then taken up in 10 ml of dimethylformamide. At 0° C., 516 μl (4.33 mmol) of benzyl bromide were slowly added dropwise. The reaction mixture was stirred at RT for 12 h, the reaction was terminated by addition of 25 ml of water and the reaction mixture was extracted three times with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (40 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 584 mg (54% of theory)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1O[CH2:8]1)[CH:2]1[O:4][CH2:3]1.OC1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=CC=1>>[CH3:19][C:17]([C:14]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH:2]2[O:4][CH2:3]2)=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:1][CH:2]2[O:4][CH2:3]2)=[CH:24][CH:25]=1)[CH3:18]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C(OCC1CO1)C1CO1
Product: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1

Procedure:
By use of the Dienoxy A copolymer described above, a 1,2-polybutadiene epoxy copolymer composition of approximately 33/67 composition was prepared and both the epoxy constituent and the polybutadiene constituent were cured. It should be noted that the blend of Dienoxy A copolymer with the additional diglycidylether of bisphenol A (DGEBA) and the anhydride curative system formed a stable dispersion while a blend of 1,2-polybutadiene with DGEBA and the anhydride curative system rapidly separated into two phases.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][CH3:22].O.[NH2:31][NH2:32].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:31][N:32]=[C:19]([CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][CH3:22])[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: CCC(C(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(c1ccccc1)c1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-(2-phenylbutyryl)-1,8-naphthyridin-2(1H)-one (98 mg, 0.25 mmol) produced in Synthesis Example 39 in DMF (2 mL) was added hydrazine monohydrate (purity of 80%, 40 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration and washed with water. The precipitate was recrystallized from ethanol and diisopropyl ether to give 5-phenyl-3-(1-phenylpropyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (51 mg, yield 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:6].[H-].[Na+].I[CH3:23]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH3:23])=[O:6]
Reactant: COc1ccccc1NC(=O)c1ccc(Cl)c(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
To 3-bromo-4-chloro-N-(2-methoxy-phenyl)-benzamide (13.5 g, 39 mmol) in DMF (100 mL) at 0-5° C., was added NaH (1.9 g, 46.8 mmol, 60% in mineral oil) in several portions, followed by addition of iodomethane (3.15 mL, 50.7 mmol). The mixture was stirred at room temperature for 4 hrs and was partitioned between ethyl acetate and water. The organic layer was then washed with 1N HCl, saturated NaHCO3, brine and dried over MgSO4. Filtration over a silica gel pad followed by concentration and crystallization from ether/hexane yielded 3-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide (10.9 g) as a white solid. MS (M+H)+: 353.9, tR=2.812 min (method 1); NMR (CDCl3), 6, 7.62 (1H, d, J=1.5 Hz), 7.23-7.09 (3H, m), 7.06-7.00 (1H, m), 6.88-6.78 (2H, m), 3.75 (3H, s), 3.34 (3H, s)
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:27][CH2:26][C:25]([F:29])([F:28])[F:24])=[O:18])=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(F)(F)F
Agent: Cl
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 18 %

Procedure:
As described in example 53g, 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (49 mg, 0.16 mmol) was converted, using 2,2,2-trifluoroethylamine hydrochloride instead of cyclobutylamine, to the title compound (11 mg, 18%) which was obtained as a colorless oil. MS: m/e=388.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:6][C:5]=12.[ClH:15]>>[ClH:15].[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][C:5]=12
Reactant: CCOC(=O)C1CCn2ccnc2C1
Agent: Cl
Product: O=C(O)C1CCn2ccnc2C1

Procedure:
A solution of 0.18 g ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate in 10 ml of 3N-HCl was heated overnight under reflux, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was dried, thus giving 0.18 g of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic acid.hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22].F[C:24]1C=C(C(O)C)C=C(F)C=1C1N=C(C(O)=O)C=CC=1F.[H-].[Na+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][CH3:24])[CH3:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)O)cc2F)n1
Reactant: CC(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C(C)OC)cc2F)n1
Reaction time: 0.03 h
Yield: 63 %

Procedure:
To a solution of methyl 6-[2,6-difluoro-4-(1-hydroxyethyl)phenyl]-5-fluoro-pyridine-2-carboxylate (1.21 mmol, 376 mg; penultimate intermediate en route to Intermediate 136) in N,N-dimethylformamide (50 mL) at 0° C. was added sodium hydride (60 mass % in mineral oil, 1.5 equiv., 1.81 mmol, 72.5 mg). The mixture was stirred for 2 minutes, then iodomethane (3.0 equiv., 3.62 mmol, 0.226 mL) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica eluted with 0 to 50% EtOAc in Heptane to provide methyl 6-(2,6-difluoro-4-(1-methoxyethyl)phenyl)-5-fluoropicolinate (392 mg, 63%). This ester was diluted with MeOH (15 mL) and water (5 mL) and lithium hydroxide (60 mg) was added. The mixture was stirred overnight at rt. The reaction was quenched by the addition of 1 N HCl(aq), then the mixture was diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (quant) which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C[N:26]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][N:26]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ncccc1N)C(=O)O

Procedure:
(2S)2-tert-Butoxycarbonylamino-3-(3-aminopyridin-2-ylamino)propionic acid was prepared by a similar method to (2S)2-tert-Butoxycarbonylamino-3-(2-aminophenylamino)-propionic acid in Step B of the synthesis of 600a/103 to give 3.68 g (quant.) as a dark solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[C:8](=O)[CH:9]=[CH:10][N:11]([CH3:13])C)=[CH:4][CH:3]=1.NC1[N:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:8]2[N:20]3[N:21]=[C:22]([CH3:24])[N:23]=[C:13]3[N:11]=[CH:10][CH:9]=2)[CH3:15])=[CH:16][CH:17]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)C=CN(C)C
Solvent: CC(=O)O
Product: Cc1nc2nccc(C(C)Oc3ccc(Cl)cc3)n2n1
Temperature: 25 °C

Procedure:
A solution of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one (1.58 g, prepared in a similar manner to that described in Example 2 above) in glacial acetic acid (5 ml) was added to a stirred solution of 3-amino-5-methyl-1,2,4-triazole (0.62 g) in glacial acetic acid (10 ml). The mixture was heated under reflux for 2 hours and 30 minutes and then cooled to room temperature. The mixture was then poured into ice-water (50 ml) and extracted with toluene. The toluene extracts were washed with a 10% aqueous solution of sodium hydrogen carbonate followed by water, then dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was triturated with cold diethyl ether and the solid was collected by filtration, followed by recrystallisation from a mixture of ethyl acetate and petroleum ether (b.p. 40°-60° C.), to give 7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo [1,5-a]pyrimidine. Yield 1.13 g, (mp 138° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.CO.[ClH:12].[N:13]#[C:14][NH2:15].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:2]1[N:7]=[C:6]([C:8](=[NH:9])[NH:15][C:14]#[N:13])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(Cl)n1
Reactant: N#CN
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CNC(=N)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of 2-chloro-4-pyrimidinecarbonitrile (23 g, 0.16 mol) in toluene (500 mL) was added methanol (7.5 mL, 0.18 mol), followed by treatment with gaseous hydrogen chloride for 2 h. The HCl-saturated solution was sealed and stirred overnight at room temperature, and then the white solid was collected by filtration and washed with diethyl ether (200 mL) and ethyl acetate (200 mL). The solid was then dissolved in methanol (400 mL) and treated with ammonia solution (100 mL, 7 M in MeOH) at room temperature. After stirring 4 h, the solution was concentrated in vacuo and the residue washed with ethyl acetate (200 mL). The resulting crude solid was dissolved in a mixture of water (150 mL) and isopropanol (50 mL), and to this solution was added cyanamide (8.5 g, 0.2 mol), and sodium bicarbonate (9 g, 0.1 mol). The mixture was stirred at room temperature for 5 h, cooled to 0° C. and stirred for an additional 5 h. The resulting grey mixture was filtered, rinsed with water, and dried in vacuo for 24 h to give 13 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7][CH2:6]2.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][Cl:33])[CH2:26]1>>[ClH:33].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:15])[CH2:26]1
Reactant: COc1ccc(OCCCN2CCCCC(CCl)C2)cc1OC
Reactant: COc1cc2c(cc1OC)C(=O)NCC2
Product: COc1ccc(OCCCN2CCCCC(CN3CCc4cc(OC)c(OC)cc4C3=O)C2)cc1OC
Product: Cl

Procedure:
Prepared from 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and N-[3-(3,4-dimethoxy-phenoxy)-propyl]-3-chloromethylhexahydro-azepine analogously to Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(#N)C.[NH2:23][C:24]1[C:32]([CH3:33])=[CH:31][C:30]([Cl:34])=[CH:29][C:25]=1[C:26](O)=[O:27].CS(Cl)(=O)=O>C(N(CC)CC)C>[Cl:34][C:30]1[CH:31]=[C:32]([CH3:33])[C:24]2[N:23]=[C:13]([C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:26](=[O:27])[C:25]=2[CH:29]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
To a mixture of 1.0 g of 1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride and 10 ml of acetonitrile was added 0.60 g of 2-amino-5-chloro-3-methylbenzoic acid, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture, 0.46 ml of triethylamine was added. After the mixture was stirred at room temperature for 20 minutes, 0.92 ml of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 0.28 ml of methanesulfonyl chloride was added thereto and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.98 g of 6-chloro-2-[1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[C@H:3]([C:8]1[CH:23]=[CH:22][C:11]([C:12]([NH:14][O:15]C2CCCCO2)=[O:13])=[CH:10][CH:9]=1)[NH:4][C:5]([NH2:7])=[S:6].Br[CH2:26][C:27]([C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=1)=O.Cl>O1CCOCC1.C(Cl)Cl>[OH:15][NH:14][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([C@H:3]([NH:4][C:5]2[S:6][CH:26]=[C:27]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:30]=3)[N:7]=2)[CH:2]([CH3:1])[CH3:24])=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1cc(-c2ccccc2)no1
Reactant: CC(C)[C@@H](NC(N)=S)c1ccc(C(=O)NOC2CCCCO2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)[C@@H](Nc1nc(-c2cc(-c3ccccc3)no2)cs1)c1ccc(C(=O)NO)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
A mixture of 4-((R)-2-methyl-1-thioureidopropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide (0.0252 g, 0.0717 mmol) and 5-(bromoacetyl)-3-phenylisoxazole (0.0191 g, 0.0717 mmol) in 1,4-dioxane (0.50 mL) was heated at 40° C. for 1 h. The solution was diluted with DCM (0.50 mL) and hydrochloric acid (0.20 mL, 0.80 mmol, 4.00 M of in 1,4-dioxane) was added. The reaction was stirred at rt for 3 h. The mixture was evaporated to dryness, the residue dissolved in DMSO and the solution purified on prep-HPLC to give (R)—N-hydroxy-4-(2-methyl-1-(4-(3-phenylisoxazol-5-yl)thiazol-2-ylamino)propyl)benzamide as a white solid (0.0173 g, 56%). LC-MS: (FA) ES+ 435. 1H NMR (dmso-d6, 400 MHz) δ11.13 (s, 1H), 9.00 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 7.90 (m, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.51 (dd, J=5.1, 1.9 Hz, 3H), 7.44 (d, J=8.3 Hz, 2H), 7.26 (s, 1H), 7.09 (s, 1H), 4.48 (t, J=8.1 Hz, 1H), 2.10 (m, 1H), 1.00 (d, J=6.6 Hz, 3H), 0.78 (d, J=6.7 Hz, 3H).