Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[CH3:44][C:45]([O:47][CH2:48][C:49]1[CH2:58][S:57][C@@H:52]2[C@H:53]([NH2:56])[C:54](=[O:55])[N:51]2[C:50]=1[C:59]([OH:61])=[O:60])=[O:46].Cl>C(Cl)CCl.C(N(CC)CC)C.O.C(O)(=O)C.CN(C)C=O>[C:45]([O:47][CH2:48][C:49]1[CH2:58][S:57][C@@H:52]2[CH:53]([NH:56][C:27](=[O:29])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[S:22][CH:23]=3)=[N:30][O:31][CH3:32])[C:54](=[O:55])[N:51]2[C:50]=1[C:59]([OH:61])=[O:60])(=[O:46])[CH3:44]
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h

Procedure:
576.5 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid were added at 0° C. to a solution of 247.8 g of tosyl chloride in 780 m. of dimethylformamide and then 196 ml of triethylamine were added thereto. The mixture was held at 0° C. while adding thereto a solution of 272 g of 7-amino-cephalosporanic acid in 3 liters of ethylene chloride and 450.7 ml of triethylamine cooled to -70° to -75° C. and the mixture was held at -20° C. for 30 minutes. Then 270 ml of acetic acid followed by 540 ml of demineralized water were added thereto and the temperature rose to -15° to -20° C. 11 liters of demineralized water were added thereto and the pH was adjusted to 1 to 1.2 by addition of 0.1N hydrochloric acid. The decanted organic phase was washed 3 times with 2700 ml of demineralized water and was concentrated under reduced pressure in a bath at 8° to 30° C. to a volume of 1350 ml to obtain a solution of syn isomer of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(N(CC)CC)C.CN(C)C=O>O>[CH3:21][C:22]1[N:23]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=[CH:25][N:26]=1
Reactant: Cc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Triphenylmethyl chloride (16.0 g, 57.5 mmol) was added portionwise to a solution of 2-methylimidazole (4.10 g, 50.0 mmol) and Triethylamine (9.02 mL, 64.7 mmol) in20 ml of N,N-dimethylformamide. The mixture was stirred for 18 hours, mixed with 300 ml of water and extracted with 1000 ml of ethyl acetate. The organic extract was washed with 1 L of water, brine, dried over MgSO4 and concentrate in vacuum to 50 ml volume. A precipitate was collected, washed with ethyl acetate and dried in high vacuum for 18 hours. Weight 15.0 g (92.5%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.29 (m, 9H), 7.16-7.11 (m, 6H), 6.90 (d, J=1.5, 1H), 6.71 (d, J=1.5, 1H), 1.65 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>C1COCC1>[N:17]1[C:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:2][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccccn1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cn2ccccc2n1
Yield: 26.9 %

Procedure:
A mixture of ethyl 4-chloro-3-oxobutanoate (15 g, 91 mmol) and pyridin-2-amine (8.58 g, 91 mmol) in THF (80 mL) was refluxed overnight. Then, the reaction mixture was concentrated and the residue purified by silica gel chromatography (PE:EA=1:1) to afford ethyl 2-(imidazo[1,2-a]pyridine-2-yl)acetate (5 g, yield 26.9%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14])(=[O:17])[CH3:16]
Reactant: COc1cc2c(=O)[nH]cnc2cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Pyridine (20 ml) was added to a suspension of 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.5 g, 107 mmol) in acetic anhydride (150 ml, 1.6 mol). The reaction mixture was heated to 120° C. for three hours, during which time the solid dissolved. The reaction mixture was allowed to cool then poured into ice-water (900 ml). The reaction mixture was stirred for one hour then the solid was removed by filtration and dried over phosphorus pentoxide yielding 7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one as a white solid (20.98 g, 84%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClCCl.CN(C)C1C=CN=CC=1>[O:7]([CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: C#CCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 5-hexyn-1-ol (9.81 g) in dichloromethane (50 ml) was added, at 0° C., triethylamine (10 ml), t-butyldimethylsilylchloride (17 g) and 4-dimethylaminopyridine (100 mg) and the mixture was stirred 16 hrs. while warming to room temperature. Dichloromethane (100 ml) was added and the organic layer was washed with 1N HCl (2×50 ml), brine and dried with Na2SO4. Solvents were removed and residue distilled under vacuum to yield the title compound as an oil (19 g, 89%).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:11]Br>C(Cl)Cl.[Fe]>[Br:11][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[C:2]([CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccccc1C(=O)O
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Product: Cc1ccc(Br)cc1C(=O)O
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A mixture of o-toluic acid (28 g, 206 mmol), iron powder (0.74 g, 13 mmol), and Br2 (42 g, 260 mmol) were stirred at 0° for 2 hr. At this point the reaction, which had proceeded ˜40%, was diluted with 25 mL of CH2Cl2 to facilitate stirring. The reaction was then heated at 45° for 16 hr to drive to completion. Upon cooling, the reaction was diluted with CH2Cl2, washed 2× with 10% NaHSO3, 1× with brine prior to drying over Na2SO4. After removal of the volatiles, the residue comprising a 2:1 mixture of 5-bromo to 3-bromotoluic acid was recrystallized from 95% EtOH to yield 14.4 g of 5-bromo-2-methylbenzoic acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15](=[O:23])[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].N([O-])=O.[Na+].Cl>CN(C)C=O.[Fe](Cl)(Cl)Cl.O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:15]([C:16]1[NH:3][N:2]=[N:1][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C=CC(=O)c1ccc(OC)c(OC)c1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn[nH]c1C(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 175.9 %

Procedure:
Iron(III) chloride (309 mg, 1.90 mmol) was added at room temperature to a solution (37.5 mL) of sodium azide (1.84 g, 28.3 mmol) in N,N-dimethylformamide. A solution (25 mL) of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (2.50 g, 9.46 mmol) in N,N-dimethylformamide was then added to the mixture at 5° C. under an oxygen atmosphere. The temperature of the reaction solution was raised to room temperature before the reaction solution was stirred for 3 hr. Thereafter, ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (2.50 g, 9.46 mmol) was added to the reaction solution at room temperature, and the mixture was stirred for additional 4 hr. After the completion of the reaction, the reaction solution was poured into iced water, and sodium nitrite (636 mg, 9.22 mmol) was added thereto. The mixture was adjusted to pH 2 by the addition of 1 N hydrochloric acid and was extracted with ethyl acetate, and 5 wt % brine was then added. The mixture was adjusted to pH 2.0 by the addition of 1 N hydrochloric acid, followed by separation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. Toluene was added to the residue, and toluene was removed by evaporation under the reduced pressure. The resultant crystal was collected by filtration, was washed with toluene, and was then dried under the reduced pressure to give ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (5.08 g, 88%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:5]=1.[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCOC(C)=O.CCCCCC>C(#N)C>[F:20][CH:9]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]1
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate, 2.2 (300 g, 1.102 mol) was dissolved in dry Acetonitrile (300 mL) and cooled to 0° C. and Selectfluor (430 g, 1.21 mol) was added in portion wise over a period of 45 min. under N2 atmosphere. After addition completed, the reaction mixture was allowed to room temperature and stirred for 2 h. The reaction was monitored by TLC (50% EtOAc/hexane). After completion of reaction by TLC the reaction mixture poured into ice cold saturated brine solution (300 mL) and extracted with EtOAc (2×200 mL). The combined EtOAc layers were washed with brine solution, water, dried over Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography on silica gel (10-40% EtOAc-Hexane) to afford tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate 2.3 (170 g; 70.7%). 1HNMR (CDCl3, 400 MHz): δ 4.88 (dd, 0.5H), 4.77 (dd, 0.5H), 4.47 (brs, 1H), 4.17 (ddd, 1H), 3.25 (brs, 1H), 3.23 (ddd, 1H), 2.58 (m, 1H), 2.51 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[C:15](OCC)(=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[O-]CC.[Na+].Cl>C(O)C.O>[NH2:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1](=[O:3])[CH:2]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c2ccc(N)cc2o1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of N-(4-acetyl-3-hydroxyphenyl)acetamide (4.00 g., 21 mmol) and diethyl oxalate (7.3 mL, 54 mmol) in absolute ethanol is added dropwise to a solution of sodium ethoxide (0.1 mol) in absolute ethanol. The mixture is heated at reflux temperature for 1.5 h, cooled to ambient temperature, poured into water, acidified to pH 3 with 6N HCl and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford an oily residue. The residue is dissolved in ethanol, treated with concentrated HCl heated at reflux temperature overnight, cooled to 0° C. for several hours and filtered. The filtercake is dried to afford the title compound as an orange solid, 2.95 g (61% yield), mp 195°-198° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [OH-].[K+:2].[C:3]([OH:14])(=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O>[C:3]([O-:14])(=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[K+:2]
Reactant: CCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCC(=O)[O-]

Procedure:
A solution of KOH (2.6 g, 46.4 mmol) in water (50 ml) was added dropwise to a suspension of decanoic acid (8.0 g, 46.4 mmol) in water (300 ml) at 60 ° C. until pH 7. Water was removed by lyophilization.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].[I:14]I>O1CCOCC1.O>[I:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1H-indazole-5-carboxaldehyde (3.75 g, 25.7 mmol) in dioxane (120 mL) was added a solution of NaOH (15.48 g, 384.9 mmol) in water (120 mL). To this solution, iodine (8.2 g, 32 mmol) was added. After 1 hr at rt, more iodine (8.2 g, 32 mmol) was added, and the reaction mixture was stirred for an additional 1 hr at rt. After removal of most of the dioxane in vacuo, the reaction mixture was extracted with EtOAc, washed with brine, dried, and concentrated. The crude product was purified by flash chromatography to afford 3-iodo-1H-indazole-5-carboxaldehyde (4.5 g, 64.5%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:26]2[C:27]([O:32][C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)=[N:28][CH:29]=[CH:30][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][C:27]2[C:26]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[CH:10][C:3]=34)=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2cccnc2Oc2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)ccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cccnc3Oc3ccc(N)cc3)ccnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In an argon-purged sealed tube, tert-butyl 4-chloro-1-H-pyrrolo[2,3-b]pyridine-1-carboxylate (2.77 g, 11.0 mmol), 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine (5.14 g, 16.5 mmol), sodium carbonate (3.49 g, 32.9 mmol), 1,4-dioxane (32.3 mL), water (11.7 mL) were added. The reaction was stirred at rt for 5 min. Then palladium acetate (0.246 g, 1.10 mmol) and tri-t-butylphosphonium tetrafluroroborate (0.637 g, 2.19 mmol) were added. The tube was sealed and heated to 100° C. After 1 h 45 min, the reaction was monitored and found to be complete. The reaction mixture was cooled to rt and passed through a pad of celite, washing with EtOAc. The filtrate was dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on 120 g silica gel column using DCM and 95:05 DCM:(90:10:1 DCM:MeOH:NH4OH) to flush out the nonpolar spots, then 80:20 DCM:(90:10:1 DCM:MeOH:NH4OH) to collect the Boc-product. A viscous brown oil was obtained. After setting the oil at rt for several hours, small amounts of crystaline colonies were formed. The oil was cooled to 0° C. and light yellow solid precipitated out after adding small amounts of hexanes and a little bit of ether in addition to scratching the wall of the flash with a spatula. The light yellow solid was filtered, washed with cold hexanes, and dried under vacuum. This solid, tert-butyl 4-(2-(4-aminophenoxy)pyridin-3-yl)-1-H-pyrrolo[2,3-b]pyridine-1-carboxylate was obtained. MS m/z=403 [M+1]+. Calcd for C23H22N4O3: 402.17.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8](O)=O)[CH2:3][C:4](O)=O.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>C(O)CO.O>[NH:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:18]=[C:4]1[CH2:3][N:2]([CH2:7][C:8]1[NH:18][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]=1)[CH3:1]
Reactant: CN(CC(=O)O)CC(=O)O
Reactant: Nc1ccccc1N
Solvent: OCCO
Solvent: O
Product: CN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1
Temperature: 190 °C
Reaction time: 4 h

Procedure:
A mixture of 4.00 g (27.2 mmol) N-methyliminodiacetic acid and 5.99 g (54.4 mmol) o-phenylene diamine in 30 ml ethylene glycol was stirred at 190° C. for 4 hours. The water produced during was distilled off continuously. At the end of the reaction, the reaction mixture was allowed to cool down to room temperature and then poured in 150 ml water. The obtained slurry was triturated for 30 min, filtered, washed with water (3×30 ml) and dried at 60° C. under reduced pressure for 48 hours. Yield 6.88 g (87.0%). 1H NMR (250 MHz, DMSO-d6), δ 2.25 (s, 3H), 3.90 (s, 4H), 7.15 (m, 4H), 7.47–4.58 (m, 4H), 12.33 (br. s, 2E). Microanalysis, %: Calculated for C17H17N5: C, 70.10; H, 5.84; N, 24.05. Found: C, 70.22; H, 6.05; N, 23.76. +CI MS (m/z): [292]. (+CI-MS is Positive Chemical Ionisation Mass Spectroscopy).
Reaction SMILES: Cl.[CH2:2]([N:9]([CH3:13])[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:14][C:15]1([CH3:36])[CH:24]=[C:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([OH:35])=[CH:20][CH:21]=2)[O:16]1.CC1(C)CC(C2C=CC(C(F)(F)F)=CC=2)C2C(=CC(OCCN(C)C)=CC=2)O1>>[CH2:2]([N:9]([CH2:10][CH2:11][O:35][C:19]1[CH:18]=[C:17]2[C:22]([C:23]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:24][C:15]([CH3:36])([CH3:14])[O:16]2)=[CH:21][CH:20]=1)[CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Reactant: CN(CCCl)Cc1ccccc1
Agent: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CN(CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc2ccccc2c1)Cc1ccccc1
Yield: 49 %

Procedure:
Reaction of N-benzyl-N-(2-chloroethyl)methylamine hydrochloride with 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7-ol by an analogous method to that described in Preparation 18 (c) gave the title compound (49%) as a colourless oil, The hydrochloride salt had m.p. 112°-115° C decomposed.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[CH2:6][CH2:7][C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15]([N:9]1[C@@H:8]([CH2:7][CH2:6][C:5]([OH:22])=[O:4])[CH2:12][O:11][C:10]1([CH3:14])[CH3:13])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1[C@@H](CCC(=O)O)COC1(C)C
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
An aqueous solution of sodium hydroxide (195 mL, 4.0 M in H2O, 0.261 mol, 3.0 eq) was added to a solution of (S)-tert-butyl 4-(3-methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (25.1 g, 0.087 mol), and the resulting cloudy reaction mixture was stirred at 23° C. for 3.5 hr. The mixture was concentrated under reduced pressure to 50 mL volume and then was partitioned between 0.5 M HCl (360 ml) and EtOAc (2×360 ml). The combined organic layers were dried over Na2SO4 and were filtered. The filtrate was concentrated under reduced pressure to give (s)-3-(3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)propanoic acid (21.6 g, 91%), which was used without further purification.
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][NH:6][OH:7].[Cl-].[Na+].[CH3:10][C:11](=[CH2:22])[CH2:12][N:13]([CH2:19][CH:20]=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CO.C1(C)C=CC=CC=1.O>[CH3:5][N:6]1[O:7][CH2:10][C:11]2([CH3:22])[CH:20]1[CH2:19][N:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12]2
Reactant: CNO
Reactant: C=C(C)CN(CC=O)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2N(C)OCC2(C)C1

Procedure:
21.7 g of 30% strength sodium methylate solution are added dropwise to 10 g (0.12 mol) of N-methylhydroxylamine hydrochloride in 26 ml of methanol The sodium chloride is filtered off with suction and washed with 8 ml of methanol and 80 ml of toluene. This solution is added dropwise to 19.2 g (0.11 mol) of N-(2-methyl-prop-2-enyl)-N-(2-oxoethyl)-urethane, which is heated under reflux in 160 ml of toluene using a water separator. The mixture is heated under reflux overnight, the product is extracted with 160 ml of 10% strength hydrochloric acid and the hydrochloric acid solution is rendered alkaline with potassium carbonate and extracted with six portions of 200 ml of CHCl3. The extracts are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5].[OH-].[Li+:33]>CO>[NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:18]([F:21])([F:19])[F:20])=[N:13][C:14]([C:15]([O-:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5].[Li+:33]
Reactant: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)[O-])c2C1)Cc1cc(F)c(F)cc1F
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
(R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 3 (100 mg, 0.22 mmol) was dissolved in 5 mL of methanol followed by addition of aqueous lithium hydroxide solution (0.44 mL, 0.22 mmol). The reaction was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound lithium (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate 5 (48 mg, 98.6%) as a white solid. HPLC: 99.66%. MS m/z (ESI): 451.2 [M+1]. 1H NMR (400 MHz, CD3OD, ppm): δ 7.31-7.38 (m, 1H), 7.13-7.22 (m, 1H), 5.07-5.27 (m, 2H), 4.26-4.36 (m, 2H), 4.01-4.15 (m, 2H), 3.53-3.60 (m, 1H), 2.80-2.91 (m, 2H), 2.59-2.72 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cn2)CC1
Yield: 107.2 %

Procedure:
A solution of 226 mg (0.740 mmol) 5-nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (as prepared in the previous step) in 15 mL MeOH was treated with 110 mg 10% Pd/C (Degussa type E101-NE/W, Aldrich, 50% by weight water) and 1 atm H2 at room temperature for 18 h. The mixture was filtered through Celite, and the filter cake was washed with MeOH. Concentration afforded 220 mg (107%) of the title compound as a colorless glassy solid. Mass spectrum (ESI, m/z): Calcd. for C15H23N3O2, 278.2 (M+H). found 278.0.