Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.Br[CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.C([O-])(=O)C.[NH4+:34]>C(O)C.OS(O)(=O)=O.C(O)(=O)C.O>[C:18]1([C:16]2[N:34]=[C:11]([CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)[O:13][C:15]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Reactant: [NH4+]
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1ccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Reaction time: 1.67 h
Yield: 65.1 %

Procedure:
Sodium metal (1.00 g, 43 mg atom) was dissolved in ethanol (125 mL) and 3-(4-hydroxyphenyl)propionic acid (6.04 g, 36 mmol) added to give a white precipitate. The mixture was warmed briefly with stirring and concentrated H2SO4 (3 drops) added followed by 2-bromo-2-phenylacetophenone (1.00 g, 36 mmol). The mixture was heated at reflux for 2 hours, cooled, concentrated and diluted with water. The mixture was extracted with CH2Cl2, the combined extracts dried over sodium sulfate and concentrated to give an oil which was dissolved in acetic acid (250 mL). Ammonium acetate (14.00 g, 180 mmol) was added and the mixture heated to reflux. After 100 minutes, the solution was cooled, diluted with water and extracted with CH2Cl2. The combined extracts were dried over sodium sulfate and the solvent evaporated to leave a solid that was triturated with a mixture of hexanes and diethyl ether and filtered to give 4-[2 -(4,5-diphenyl-2-oxazolyl)ethyl]phenol (8.00 g, 64%). An analytical sample was prepared by recrystallizing 1.5 g from a mixture of hexanes and CH2Cl2 to give 1.20 g of pure material, m.p. 142°-144° C.
Reaction SMILES: [C:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:19]I.[Mg].Cl>CCOCC>[C:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([CH3:19])=[CH2:2]
Reactant: CC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Reactant: CI
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: C=C(C)c1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Acetylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.8 g) was suspended in ether (15 ml) and 20 equivalent amounts of magnesium methyl iodide was added under ice-cooling. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 1M hydrochloric acid under ice-cooling and insoluble matter was filtered off. The resulting mixture was extracted twice with chloroform. The chloroform layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was suspended in toluene and a catalytic amount of p-toluenesulfonic acid was added. The mixture was stirred under reflux with heating for 20 minutes. The reaction system was cooled to room temperature and the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue. The precipitated crystals were collected by filtration to give 2-isopropenylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (800 mg).
Reaction SMILES: [C:1](O)(=O)[CH3:2].[C:5]([C:7]1[C:8]([F:27])=[C:9]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[C:10]([C:12](=[CH:18][N:19]([CH3:21])C)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11])#[N:6].C1(N)CC1.O>C1(C)C=CC=CC=1>[C:5]([C:7]1[C:8]([F:27])=[C:9]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[C:10]([C:12](=[CH:18][NH:19][CH:21]1[CH2:2][CH2:1]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11])#[N:6]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(C#N)c1F
Agent: NC1CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(C#N)c1F
Temperature: 30 °C
Reaction time: 1 h

Procedure:
30 g of glacial acetic acid are added dropwise to the crude product from step e at 20° C. Then a solution of 15,75 g of cyclopropylamine in 30 ml of toluene is added dropwise. The reaction mixture is stirred at 30° C. for 1 hour. After the addition of 200 ml of water the mixture is stirred for 15 minutes. The organic phase is separated, extracted with 100 ml of water, dried with Na2CO3 and concentrated in vacuo. The crude product is used for the next step without further purification.
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)C.[Li+].[CH2:9]([S:11]SCC)[CH3:10].CC[CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH2:9]([S:11][C:18]([CH3:17])([CH2:19][CH3:20])[C:1]#[N:4])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: CCSSCC
Reactant: CCCCCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCSC(C)(C#N)CC
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
In 300 ml of tetrahydrofuran under nitrogen was placed 81 ml of 10% lithium diisopropylamide in hexane. The mixture was then cooled to -70° C. and 6.7 g of 2-methylbutaneitrile was added. The reaction mixture was stirred and maintained at this temperature for 1 hour and then 9.9 g of diethyl disulfide was slowly added. After 30 minutes, the reaction mixture was allowed to warm to room temperature. A solid was filtered through celite and the filtrate was evaporated. The resulting residue was dissolved in methylene chloride, washed with water, and dried over NaSO4. Solvent removal gave 6.9 g of the desired product, b.p. 62°-65° C. (0.85 mm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([NH:13][C@H:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[CH3:15])=[O:12].O[Li:30].O>>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([NH:13][C@H:14]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([O-:22])=[O:21])=[CH:24][CH:25]=1)[CH3:15])=[O:12].[Li+:30]
Reactant: [Li]O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2cccc(F)c2)cc1
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CCCN1Cc1cccc(F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E14) (48 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((S)-1-((R)-1-(3-fluorobenzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D31) (53 mg). (LiOH H2O: 1.5 eq; reaction time: 24 hrs)
Reaction SMILES: BrC1C=C(C[N:11]([CH2:20][C:21]2[C:22]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:23]3[CH:31]=[N:30][N:29]([CH2:32][CH3:33])[C:24]3=[N:25][C:26]=2[CH2:27][CH3:28])[C:12]([C:14]2([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15]2)=[O:13])C=CC=1OC.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[C:51]([CH2:55][CH:56]3[CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]3)[CH:52]=[CH:53][CH:54]=2)O1.[C:70](=[O:73])([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:32]([N:29]1[C:24]2=[N:25][C:26]([CH2:27][CH3:28])=[C:21]([CH2:20][NH:11][C:12]([C:14]3([C:17]([NH:19][CH2:55][C:51]4[CH:50]=[CH:49][C:54]([O:73][CH3:70])=[C:53]([C:49]5[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][CH:56]6[CH2:57][CH2:58][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:60][CH2:61]6)[CH:50]=5)[CH:52]=4)=[O:18])[CH2:15][CH2:16]3)=[O:13])[C:22]([NH:34][CH:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[C:23]2[CH:31]=[N:30]1)[CH3:33]
Reactant: O=C([O-])[O-]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(OC)c(Br)c1)C(=O)C1(C(N)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)NCc2ccc(OC)c(-c3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)CC1
Temperature: 100 °C
Yield: 247.5 %

Procedure:
To N1-{[3-bromo-4-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (6.75 g, 11.00 mmol) in 1,4-dioxane (120 mL) was added 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (4.42 g, 11.00 mmol). Then potassium carbonate (4.56 g, 33.0 mmol), water (40.0 mL) and tetrakis(triphenylphosphine)palladium(0) (0.636 g, 0.550 mmol) was added and the reaction was heated at 100° C. for 1 h. HPLC showed a small amount of starting material present therefore the reaction was left for a further hour. HPLC showed no change so the reaction was worked up. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was washed with EtOAc and the combined organic layers were rinsed with brine, dried over MgSO4, filtered and evaporated to give a light brown foam (˜11 g). The foam was dissolved in DCM and passed through a celite column before combining with a batch from a similar preparation (0.85 g). The combined brown solutions were concentrated and applied to a 330 g silica column using 15-100% EtOAc-DCM over 10 column volumes as the gradient. Product fractions were combined and evaporated to yield a white foam 7.42 g (83%). A second peak containing the product was combined and evaporated to yield as a pale yellow oil, 0.69 g (7%) HPLC 2.61 min (ret time) 96.6%; LC-MS m/z 808 (M+H)+, 3.78 min (ret time).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[N:18][C:19]([CH3:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.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.[CH3:59][S:60]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)(=[O:62])=[O:61]>CN(C=O)C>[CH3:59][S:60]([N:63]1[CH2:68][CH2:67][N:66]([C:21]([C:20]2[C:19]([CH3:25])=[N:18][CH:17]=[C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][N:11]=3)[CH:24]=2)=[O:22])[CH2:65][CH2:64]1)(=[O:62])=[O:61]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(C(=O)O)c3)nc2)cc1
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: CN(C)C=O
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(C(=O)N4CCN(S(C)(=O)=O)CC4)c3)nc2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid 10 (0.05 mmol) in DMF (1 mL) is added HATU (0.06 mmol) and DIEA (0.14 mmol) at rt. The resulting mixture is stirred for 2 min then 1-methanesulfonyl-piperazine (0.05 mmol) is added. The reaction mixture is stirred at rt for 4 h and then directly purified by preparative LCMS to give (4-methanesulfonyl-piperazin-1-yl)-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-yl}-methanone B1. 1H NMR (400 MHz, d4-CH3OH) δ 9.30 (d, J=4.0 Hz, 1H), 8.81 (s, 2H), 8.50 (d, J=4.0 Hz, 1H), 7.60-7.758 (m, 2H), 7.07-7.05 (m, 2H), 3.96-3.94 (m, 2H), 3.85 (s, 3H), 3.54-352 (m, 2H), 3.42-3.39 (m, 2H), 3.27 (bs, 2H), 2.91 (s, 3H), 2.62 (s, 3H). MS (m/z) (M+1)+: 483.1.
Reaction SMILES: C([C:3](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4]([C@@H:6]([NH:11][C:12](=[O:28])[O:13][C:14]1([C:19]2[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#N.[O:48]=[O+][O-].N#N.[NH2:53][C:54]1[CH:58]=[CH:57][NH:56][N:55]=1>ClCCl.O1CCCC1>[O:48]=[C:3]([NH:53][C:54]1[CH:58]=[CH:57][NH:56][N:55]=1)[C:4]([C@@H:6]([NH:11][C:12](=[O:28])[O:13][C:14]1([C:19]2[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:8][CH2:9][CH3:10])=[O:5]
Reactant: CCCC[C@H](NC(=O)OC1(c2nc3ccccc3s2)CCCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Reactant: Nc1cc[nH]n1
Agent: N#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC1(c2nc3ccccc3s2)CCCC1)C(=O)C(=O)Nc1cc[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
660 mg (1 mmol) of 1-(1,3-benzothiazol-2-yl)cyclopentyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate was dissolved in 25 mL of dichloromethane and ozone was passed through the solution at −78° C. for 15 min. The reaction was quenched with N2 for 5 min before 79 mg (0.95 mmol) of 3-aminopyrazole in 4 mL of tetrahydrofuran was added. The reaction was allowed to warm to room temperature over 1 h. Solvent was removed and the residue was redissolved in 5 mL of tetrahydrofuran. 1 mL of 1 M silver nitrate in water was added and the reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with ether (4×). The ether layer was washed with brine (3×) and dried over magnesium sulfate. After removal of solvent, purification by silica gel column chromatography eluting with hexane:ethyl acetate (1:2) gave 150 mg (32%) of 1-(1,3-benzothiazol-2-yl)cyclopentyl(1S)-1-[oxo(1H-pyrazol-3-ylamino)acetyl]pentylcarbamate as a solid. 1H-NMR (400 MHz CDCl3) δ 7.87 (d, J=8 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.42 (s, 1H), 7.36 (t, J=8 Hz, 1H), 7.22 (m, 2H), 6.78 (s, 1H), 4.96 (br, 1H), 2.45 (m, 4H), 1.86 (m, 4H), 1.30 (m, 6H), 0.88 (t, J=8 Hz, 3H). ES-LCMS m/z 469 (M+H). C23H27N3O4S: 0.34 EtOAc: 0.13 H2O: Anal C 58.3%, H 5.93%, N 13.95%; Calcd C, 58.3%, H, 6.02%, N, 13.95%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2
Reactant: Cc1cc(Br)c2c(=O)[nH]cnc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(Br)c2c(=O)[nH]cnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.9 %

Procedure:
To a solution of 5-bromo-7-methylquinazolin-4(3H)-one (700 mg, 2.94 mmol) in cone. H2SO4 (10 mL) was added fuming HNO3 (185 μL, 2.94 mmol) at 0° C. and then the reaction mixture was stirred at rt for 12 h. Then the reaction mixture was quenched with water and the precipitate obtained was filtered and dried to afford 500 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.80 (br s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 2.41 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([NH2:11])=[O:10].[OH:14]O>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:8]=[CH:7][N+:6]([O-:14])=[CH:5][C:4]=1[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)c1cnccc1C(F)(F)F
Reactant: OO
Solvent: CC(=O)O
Product: NC(=O)c1c[n+]([O-])ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
0.8 g of 4-trifluoromethyl-3-pyridine carboxamide was dissolved in 7 ml of acetic acid. Then, 0.72 g of a 30% hydrogen peroxide aqueous solution was gradually dropwise added thereto. After completion of the dropwise addition, the reaction solution was heated to 70° C. and stirred for 8 hours at this temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue thereby obtained was washed with n-hexane to obtain 0.6 g of 4-trifluoromethyl-3-pyridine carboxamide 1-oxide (melting point: 198.8° C.) as the desired product.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6]CC)=O.[CH2:13]([O:15][CH2:16][CH2:17]Br)[CH3:14].[NH2:19][C:20]([NH2:22])=[O:21].Cl>C(O)C>[CH2:13]([O:15][CH2:16][CH2:17][CH:3]1[C:2](=[O:10])[NH:22][C:20](=[O:21])[NH:19][C:4]1=[O:6])[CH3:14]
Reactant: CCOCCBr
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOCCC1C(=O)NC(=O)NC1=O
Temperature: 25 °C

Procedure:
Sodium metal (8.6 g, 0.38 mol) was added to ethanol (375 mL), and the mixture was stirred at ambient temperature until homogeneous. Diethyl malonate (60 g, 0.38 mol) was added, followed by bromoethyl ethyl ether (57.4 g, 0.38 mol). After stirring at reflux for 3 hours, the mixture was cooled to ambient temperature and concentrated in vacuo. The resulting material was added to a mixture of sodium ethoxide and ethanol (prepared by the reaction of 17.2 g of sodium metal with 600 mL of methanol). Urea (249) was added, and the resulting mixture was refluxed for 2.5 hours. After cooling to ambient temperature, the mixture was stirred for 12 hours, acidified with 1M hydrochloric acid solution, extracted three times with ethyl acetate, and the combined organic layers were dried over sodium sulfate (Na2SO4), filtered and concentrated in vacuo, affording 5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione as a colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[S:44])=[CH:38][CH:37]=1>ClCCl>[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][N:15]([C:43](=[S:44])[NH:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:41][CH:40]=3)[CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=S)N2CCn3c(c(C(N)=O)c(Cl)c3-c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (50 mg, Reference Example 1) in dry dichloromethane (5 mL) was treated with dry triethylamine (54 μL), then with a solution of 4-methoxyphenyl isothiocyanate (18 μL) in dry dichloromethane (5 mL). After stirring at room temperature for a further 3 hours the reaction mixture was further treated with dichloromethane (10 mL) and then washed three times with water (5 mL). The organic phase was dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of pentane and ethyl acetate (1:1, v/v) to give 7-chloro-2-(4-methoxyphenylthiocarbamoyl)-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (40 mg) as a white solid, m.p. 176–178° C. MS: 443 [MH]+, 441 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[N:3]=1)[N:10]=[C:9]([CH3:14])[CH:8]=[C:7]3O.O=P(Cl)(Cl)[Cl:19].[NH4+].[OH-]>CN(C)C=O>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]3[N:3]=[C:2]([CH3:1])[NH:16][C:5]3=2)[N:10]=[C:9]([CH3:14])[CH:8]=1
Reactant: Cc1cc(O)c2c(ccc3nc(C)[nH]c32)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c2c(ccc3nc(C)[nH]c32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 31 g. (0.146 m.) of 2,7-dimethyl-1H-imidazo[4,5-f]quinoline-9-ol and 1336 ml. (223 g. 1455 m.) of POCl3 is added dropwise 267.2 ml. of dimethylformamide. The mixture is stirred overnight at room temperature, then poured into 1000 ml. of ice. The solution is basified to pH 8.0 using conc. NH4OH, keeping the temperature below 20° C. It is then filtered, washed with H2O and air-dried. The crude product is recrystallized from 2000 ml. of MeOH, and concentrated in vacuo to yield 338 g. m.p. 314°-330° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11]C1N=CC=CN=1>>[NH2:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1ncccn1
Product: Nc1ccc([N+](=O)[O-])cn1
Product: Nc1ccccn1

Procedure:
Alternatively, 2-chloro-5-nitropyridine can be prepared using the procedure described in the Journal Chemical Society 9 (1941), starting with 2-aminopyrimidine. Nitration of 2-aminopyridine gives 2-amino-5-nitropyridine, which can be converted into 2-hydroxy-5-nitropyridine by a diazonium reaction. Subsequent heating of 2-hydroxy-5-nitropyridine in a phosphorous pentachloride/phosphorous oxychloride mixture yields 2-chloro-5-nitropyridine. The synthesis is summarized below: ##STR13##
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:22]([O:23][C@@H:24]2[O:53][C@@H:52]([CH3:54])[C@@H:43]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:34]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:25]2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:21]([O:55][C@@H:56]2[O:72][C@H:71]([CH2:73][O:74][C:75](=[O:82])[C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)[C@H:69]([OH:70])[C@H:67]([OH:68])[C@H:57]2[O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:20]([CH2:83][O:84][C:85](=[O:92])[C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)[O:19][C@H:11]1[O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=[O:100])=CC=1.[CH:104]1[CH:109]=CC=CC=1>C(OCC)(OCC)(OCC)C.C(N(CC)CC)C>[C:1]([O:9][C@@H:10]1[C@@H:22]([O:23][C@@H:24]2[O:53][C@@H:52]([CH3:54])[C@@H:43]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:34]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C@@H:25]2[O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:21]([O:55][C@@H:56]2[O:72][C@H:71]([CH2:73][O:74][C:75](=[O:82])[C:76]3[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=3)[C@H:69]([O:70][C:109](=[O:100])[CH3:104])[C@H:67]([OH:68])[C@H:57]2[O:58][C:59](=[O:66])[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@@H:20]([CH2:83][O:84][C:85](=[O:92])[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)[O:19][C@H:11]1[O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccccc1
Reactant: C[C@@H]1O[C@@H](O[C@@H]2[C@@H](OC(=O)c3ccccc3)[C@H](OCC[Si](C)(C)C)O[C@H](COC(=O)c3ccccc3)[C@H]2O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@H](O)[C@H](O)[C@H]2OC(=O)c2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(C)(OCC)OCC
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1[C@H](O)[C@@H](OC(=O)c2ccccc2)[C@H](O[C@@H]2[C@H](O[C@@H]3O[C@@H](C)[C@@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OCC[Si](C)(C)C)O[C@@H]2COC(=O)c2ccccc2)O[C@@H]1COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of compound 10a (1.87 g), in a mixture of benzene (50 mL) and triethyl orthoacetate (50 mL), containing 4-toluenesulfonic acid (0.25 g) was stirred for 1 h at room temperature. The acid was then neutralized with a few drops of triethylamine, and the mixture evaporated to dryness. The residue was mixed with 80% aqueous acetic acid (100 mL) and the mixture stirred for 40 min at room temperature. Processing as described for 10b (to give 11b), gave the title compound 11a (1.86 g,89%); a white amorphous solid; [α]D -2.7° (c, 1.1, chloroform). 13C NMR (CDCl3): δ171.03 (CH3CO), 166.78, 166.35, 166.18, 165.02 (4×PhCO), 101.27, 101.09 (C-1, C-1'), 98.17 (C-1 fuc), 80.10, 78.20 (C-3, C-4), 74.67, 73.54, 73.30 (3×PhCH2), 67.86 (OCH2CH2Si), 63.31, 61.42 (C-6, C-6'), 21.21 (CH3 CO), 18.47 (OCH2CH2Si), and 17.53 (C-6 fuc); negative ion LSIMS: 1470.8 (M+mNBA)-, 1363.7 (M+NO2)-.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([O:15][C:16](OC1CC(=O)NC1=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[C:16]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: OCCNCCO
Reactant: O=C1CC(OC(=O)OCc2ccccc2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N(CCO)CCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a 0° C. solution of diethanolamine (1.9 ml, 20 mmol) in 50 ml of THF was added benzyloxycarbonyloxysuccinimide (5.0 g, 20 mmol) followed by the slow addition of a solution of sodium carbonate (3.2 g, 30 mmol) in 50 ml of water. The reaction was stirred at 0° C. for 2 hours, diluted with 50 ml of water, and the majority of the THF was removed under vacuum. The reaction mixture was extracted with ethyl acetate (2×75 ml), washed with brine and dried over sodium sulfate. The solvent was concentrated and the residue was purified by SiO2 chromatography (250 g SiO2, 8% MeOH/methylene chloride) to give N-Cbz-diethanolamine (4.25 g) as a clear oil.