Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7](O)[CH2:8][O:9][CH2:10][CH2:11]O.P(=O)(O)(O)O.[OH-].[Na+]>CS(C)=O.C1(C)C=CC=CC=1>[O:9]([CH2:10][CH2:11][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[CH2:8][CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: OCCOCCO
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1nccn1CCOCCn1ccnc1C
Reaction time: 16 h

Procedure:
2-Methyl imidazole (279 g; 3.4 moles), diethylene glycol (159 g; 1.5 mole), toluene (30 g), and 85% phosphoric acid (20 g; 0.17 mole) were charged in a flask equipped with a stirrer, a thermometer, and a distillation column, and the mixture was stirred at 240°~250° C. for 16 hours. Water produced during that time was distilled out by azeotropic distillation with toluene, and after fractionation the toluene was reflexed. The resulting product was incorporated with an aqueous solution of 48% sodium hydroxide (28.8 g; 0.35 mole) and subjected to distillation under reduced pressure of 1 mm Hg at 210°~215° C. to give a fraction of 239 g (yield, 68% based on diethylene glycol). Total amine value: 465 (theoretical value: 479). 'H--NMR (DMSO--d6, δppm)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCOCC1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (400 mg, 0.99 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amine (8j) (513 mg, 1.98 mmol) in dimethylformamide (6 mL) were added N,N-diisopropylethylamine (0.5 mL, 2.97 mmol) and HATU (564 mg, 1.48 mmol). Stirring was continued at room temperature for 1 h. Water (75 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amide (308) (540 mg, 84.53%) as a colorless sticky solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:3]=1)=[N+:19]=[N-:20]
Reactant: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Oc2ccc3[nH]ccc3c2)ncn1

Procedure:
490 mg (2.0 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-indole (WO 03/099771; Stage 163.1) and 260 mg (4.0 mMol) NaN3 in 3 ml DMF are stirred for 3 h at 90° C. Then the reaction mixture is poured into water and extracted three times with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: MS: [M+1]+=253.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1.[C:19](Cl)(=[O:21])[CH3:20]>CN(C)C=O>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cn2c(n1)COc1ccc(N)cc1-2
Solvent: CN(C)C=O
Product: COC(=O)c1cn2c(n1)COc1ccc(NC(C)=O)cc1-2
Yield: 72 %

Procedure:
By the procedure of Step C in Example 1, methyl 8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine-2-carboxylate and acetyl chloride were reacted in dimethylformamide as solvent to obtain a 72% yield of methyl 8-acetamido-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 216-9° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH:11]([CH3:16])[C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH2:8][CH2:9][NH:10][CH:11]([CH3:16])[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)NCCC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(NCCC(=O)OC(C)(C)C)C(=O)O
Reaction time: 12 h
Yield: 73.6 %

Procedure:
Methyl 2-(tert-butoxycarbonylethylamino)propionate (1.27 g; 5.5 mmol) is dissolved in 5 ml of methanol, and potassium hydroxide (1.2 eq.; 6.6 mmol; 0.37 g) dissolved in 1.6 ml of water is then added. The reaction medium is left at room temperature for 12 hours and then evaporated to dryness, taken up in water and washed with ether. The aqueous phase is acidified by adding 1N hydrochloric acid and extracted three times with ether. The organic phases are combined, dried over sodium sulfate and evaporated to dryness to give 0.88 g of a white solid.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52]5=[N:62][N:63]=[CH:64][N:51]5[CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[C:56]1([C:55]2[C:46]([C:43]3[CH:42]=[CH:41][C:40]([C:36]4([NH2:35])[CH2:39][CH2:38][CH2:37]4)=[CH:45][CH:44]=3)=[N:47][C:48]3[CH2:49][CH2:50][N:51]4[CH:64]=[N:63][N:62]=[C:52]4[C:53]=3[CH:54]=2)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3nncn3CC4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3nncn3CC4)cc2)CCC1
Yield: 127.1 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(9-phenyl-5,6-dihydro-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)phenyl)cyclobutyl)carbamate (9 mg, 0.02 mmol) was reacted to afford the title compound (10 mg, quantitative). LCMS (Method A): RT=3.53 min, M-NH2=377. 1H NMR (500 MHz, MeOD) 8.70 (1H, s), 8.41 (1H, s), 7.52 (2H, d), 7.43 (2H, d), 7.33-7.31 (3H, m), 7.29-7.27 (2H, m), 4.57 (2H, t), 3.51 (2H, t), 2.79-2.73 (2H, m), 2.60-2.54 (2H, m), 2.27-2.20 (1H, m), 1.99-1.92 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:42][C:43]([F:52])([F:51])[C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47]>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([C:43]([F:42])([F:51])[F:52])[CH:45]=2)=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccn1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 75.7 %

Procedure:
To a suspension of 4-bromo-pyridine-2-carboxylic acid (1.00 g, 5.00 mmol) in dimethylformamide (5 mL) was added 1-methylmorpholine (1.1 mL, 10 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HATU) (2.37 g, 6.23 mmol). The mixture became an orange solution after 10 minutes. 3-Trifluoromethylaniline (0.5 mL, 5.5 mmol) was added and the solution was stirred at room temperature for 21 hours. The dimethylformamide was evaporated in vacuo and the residue was triturated with water. The resulting solid was filtered and washed twice with water and then vacuum dried at 40° C. to give a crude residue. Chromatography on silica gel (40 g), sample applied in dichloromethane and eluted with hexanes:ethyl acetate (1:1) gave the title compound (1.306 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[NH:26][C:27]4[C:32]([CH:33]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[C:25]1[C:23]1[N:16]2[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[N:15]2)=[C:20]([CH3:21])[N:22]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cc4ccccc4[nH]3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cc5ccccc5[nH]4)n3n2)cc(OC)c1OC
Yield: 60.6 %

Procedure:
In a similar manner as described for Example 9, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-2-carboxamide (Intermediate 33) (219 mg, 0.491 mmol), and 1,2,4-triazole (210 mg, 3.0 mmol) in pyridine (10 mL) and phosphorous oxychloride (0.14 mL, 1.5 mmol) gave 7-(1H-indol-2-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (128 mg, 61%) as a yellow solid: 1H NMR (DMSO-d6): δ11.85 (s, 1H), 9.67 (s, 1H), 9.26 (s, 1H) 7.55 (s, 1H), 7.52 (d, J=8.24 Hz, 1H), 7.46 (d, J=8.24 Hz, 1H), 7.21 (s, 2H), 7.15 (t, J=7.51, 1H), 7.04 (t, J=7.51 Hz, 1H), 3.82 (s, 6H), 3.68 (s, 3H), 2.58 (s, 3H). MS m/z 430 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[N:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccccc2N)nc1
Yield: 94.8 %

Procedure:
To a stirring solution of N-(5-methylpyridin-2-yl)-2-nitrobenzamide (1.5 g, 5.8 mmol) and Ni(OAc)2.4H2O (2.9 g, 11.7 mmol) in THF (20 mL) and methanol (40 mL) at 0° C. was added, in small portions, sodium borohydride (0.88 g, 23.2 mmol). After complete addition and an additional 5 min, the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and 50% conc NH4OH (206 mL). The organic phase was separated and washed again with 50% conc NH4OH, followed by brine, then dried with MgSO4, filtered and concentrated in vacuo to give 1.25 g (95%) of a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14](=[O:26])[C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:16])=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C1C(=O)N([Cl:34])C(=O)C1>CN(C=O)C>[ClH:34].[NH2:1][C:2]1[C:10]([Cl:34])=[C:9]2[C:5]([C:6]([C:14](=[O:26])[C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[O:16])=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[NH2:1][C:2]1[C:10]([Cl:34])=[C:9]2[C:5]([C:6]([C:14](=[O:26])[C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[O:16])=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)n1cc(C(=O)C(=O)NCCN2CCCCC2)c2ccc(N)cc21
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(=O)NCCN2CCCCC2)c2ccc(N)c(Cl)c21
Product: Cl

Procedure:
The title compound was prepared according to the following procedure: a solution of 2-(6-amino-1-isopropyl-1H-indol-3-yl)-2-oxo-N-(2-(piperidin-1-yl)ethyl)acetamide (150 mg, 0.42 mmol) and NCS (56 mg, 0.42 mmol) in DMF was stirred at RT overnight. The crude mixture was purified on silica gel (Biotage, 0-10% MeOH/DCM, 30 min.) to provide 2-(6-amino-7-chloro-1-isopropyl-1H-indol-3-yl)-2-oxo-N-(2-(piperidin-1-yl)ethyl)acetamide. This free amine was dissolved in DCM (2 mL) and 1M HCl in Et2O (2 mL) was added. The mixture was stirred at RT for 2 hr and additional 5 mL of Et2O was added. The light yellow solid was filtered and washed with Et2O to yield the title compound (32 mg, 18% yield): 1H NMR (400 MHz, DMSO-d6): δ 10.10 (NH+, br s, 1H), 9.04 (t, 1H), 8.79 (s, 1H), 8.07 (d, 1H), 7.09 (d, 1H), 5.56 (m, 1H), 4.18 (br s, NH2), 3.61 (q, 2H), 3.48 (d, 2H), 3.19 (d, 2H), 2.87 (m, 2H), 1.76 (m, 4H), 1.68 (d, 1H), 1.51 (d, 6H), 1.37 (m, 1H); MS (ESI) m/z: Calculated for C20H27ClN4O2: 390.2. Found: 391.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:8](=[O:10])[CH2:7][CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CC3CCOCC3)nc12

Procedure:
From tetrahydropyran-4-yl-acetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.1° (c=1.07, CHCl3), ES-MS m/e (%): 393 (M+H+, 100).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](O)(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].P(Cl)(Cl)(Cl)(Cl)[Cl:21]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:21])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)O)ccc1F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 25 °C
Yield: 81.7 %

Procedure:
To 2-fluoronitrobenzene (2.33 g) was added fuming sulfuric acid (20 mL), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice and potassium chloride (10 g), and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g). To phosphoryl chloride (85 mL) were added 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g) and phosphorus pentachloride (2.82 g) under ice-cooling, and the mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue was added ice water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/1) to give the title compound (2.65 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([Si:15]([CH3:30])([CH3:29])[O:16][CH2:17][CH:18]([OH:28])[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:15]([O:16][CH2:17][C:18](=[O:28])[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(O)CO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a stirring solution of oxalyl chloride (13.6 mL, 0.16 mol) in dry CH2Cl2 (150 mL) at −78° C. under N2 was added DMSO (15.2 mL, 0.21 mol) dropwise over 30 min. After complete addition the resulting solution was stirred at −78° C. for 1 h. A solution of tert-butyl 3-(tert-butyldimethyl-silyloxy)-2-hydroxypropylcarbamate (32.6 g, 0.11 mol) in CH2Cl2 (50 mL) was then added dropwise over 20 min. Stirring was continued for a further 1 hour at which time triethylamine (59.6 mL, 0.43 mol) was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was partitioned between water (100 mL) and CH2Cl2 (70 mL) and the aqueous layer was extracted with further CH2Cl2 (2×70 mL); the combined organics were dried over Na2SO4 and concentrated under a stream of nitrogen gas. The crude residue was purified over silica gel eluting with 5% ethylacetate in n-hexane to give tert-butyl 3-(tert-butyldimethylsilyloxy)-2-oxopropylcarbamate (29.8 g, 92%) as a pale yellow oil. 1H-NMR (300 MHz; CDCl3) δ ppm: 0.11 (6H, s), 0.94 (9H, s), 1.47 (9H, s), 3.92 (2H, s), 4.26 (2H, d, J 4.6 Hz), 5.22 (1H, br s).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:26])[CH2:17][C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]([Cl:25])[CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([CH:16]([OH:26])[CH2:17][C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]([Cl:25])[CH:19]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (240 mg) is added to an ice-cooled solution of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylic acid tert-butyl ester (1.65 g) in a mixture of tetrahydrofuran (40 mL) and water (10 mL). The resulting mixture stirred for 0.5 h. 2 N Citric acid is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 65:35) to give the title compound. LC (method 5): tR=1.48 min; Mass spectrum (ESI+): m/z=419, 421 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]3[CH:22]=[CH:23][N:24]=[CH:25][C:17]2=3)=[O:15])[O:11][N:10]=1)C1C=CC=CC=1.O.C(=O)([O-])O.[Na+]>Br.C(O)(=O)C>[O:19]1[CH2:20][CH2:21][N:16]([C:14]([C:12]2[O:11][N:10]=[C:9]([OH:8])[CH:13]=2)=[O:15])[C:17]2[CH:25]=[N:24][CH:23]=[CH:22][C:18]1=2
Reactant: O=C(c1cc(OCc2ccccc2)no1)N1CCOc2ccncc21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1cc(O)no1)N1CCOc2ccncc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 3 ml of 33% hydrobromic acid in acetic acid solution, (3-benzyloxy -isoxazol-5-yl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (45 mg, 0.13 mmol) was dissolved and then stirred at room temperature for 24 hours. After completion of the reaction by adding water dropwise, the mixture was adjusted to weak acidic condition (pH=6) by using saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The aqueous layer was evaporated under reduced pressure and the residue was purified by using preparative TLC plate to obtain the target compound 44, i.e., (2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-(3-hydroxy-isoxazol-5-yl)-methanone, as white solid (8 mg, 24%).
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:8]/[C:9](/[CH3:18])=[CH:10]\[C:11]([O:13][CH2:14][CH2:15][C:16]#[N:17])=[O:12].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20]>C(O)(C)C>[C:16]([CH2:15][CH2:14][O:13][C:11]([C:10]1[CH:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:2]([C:1]([OH:7])=[O:6])=[C:3]([CH3:5])[NH:8][C:9]=1[CH3:18])=[O:12])#[N:17]
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)[O-]
Solvent: CC(C)O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCC#N)=C(C)N1
Yield: 88.4 %

Procedure:
10.3 g of 3-nitratopropyl acetoacetate, 7.7 g of 2-cyanoethyl 3-aminocrotonate and 7.6 g of 3-nitrobenzaldehyde in 76 ml of isopropyl alcohol were heated at reflux for 6.5 hours, and cooled on ice. The crystals which precipitated were collected by filtration, dried, applied to a silica gel column chromatography (eluent: dichloromethane) and recrystallized from ethanol to give 16.4 g of 2,6-dimethyl-4-(3-nitrophenyl)1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester 5-(3-nitratopropyl) ester.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][CH2:9][C@H:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][O:12][CH2:11]1
Reactant: CN1C(=O)COC[C@H]1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)COC[C@H]1CO
Yield: 96.1 %

Procedure:
Prepare a slurry containing 10% Pd/C (137 mg) in MeOH (50 mL). Add a solution of (R)-5-benzyloxymethyl-4-methyl-morpholin-3-one (1.3 g, 5.5 mmol) in MeOH (100 mL). Pressurize with hydrogen gas (50 psi) and stir for 2 h. Filter the reaction through Celite® and elute with MeOH. Concentrate the filtrate to give 767 mg (96%) of the title compound. MS/ES m/z 146.1 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([N:36]1[CH2:40][C:39]([C:41]2([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:42]2)=[C:38]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[CH2:29]([N:36]1[CH2:40][C@H:39]([C:41]2([NH:44][C:45]([O:47][C:48]([CH3:50])([CH3:51])[CH3:49])=[O:46])[CH2:42][CH2:43]2)[C@H:38]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1=C(C2(NC(=O)OC(C)(C)C)CC2)CN(Cc2ccccc2)C1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
Under a nitrogen gas stream, bis(bicyclo[2.2.1]hepta-2,5-diene)rhodium (I) perchlorate (54.5 mg, 0.14 mmol) and 1,2-bis(diphenylphosphino)ethane (67.4 mg, 0.17 mmol) were dissolved in degassed methanol (25 ml) and stirred at room temperature for 10 minutes. To this catalyst solution was added a solution of ethyl 1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-pyrroline-3-carboxylate (1.090 g, 2.820 mmol) in dry and degassed methanol (15 ml). The thus obtained liquid reaction mixture was then stirred under a hydrogen atmosphere (1 kg/cm2) at room temperature for 2.5 hours. After adding active carbon (1 g), the liquid reaction mixture was allowed to stand at room temperature for 30 minutes and then filtered.through celite (washed with methanol). The filtrate was concentrated under reduced pressure and the residue was subjected to flash silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1) to obtain 1.071 g (97.8%) of the title compound as colorless crystals.