Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[C:11]2[O:10][CH:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1>CO.C(Cl)Cl>[Br:25][C:5]1[CH:4]=[C:3]([F:2])[C:11]2[O:10][CH:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:6]=1
Reactant: Fc1cccc2c1OC(C1CCNCC1)C2
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Fc1cc(Br)cc2c1OC(C1CCNCC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 4-(7-fluoro-2,3-dihydrobenzofuran-2-yl)piperidine hydrochloride (1.18 g, 4.58 mmol) in MeOH (36.6 mL) at 0° C. was added NBS (0.815 g, 4.58 mmol) in one portion. Upon completion of addition, the reaction mixture was immediately warmed to room temperature, where it stirred for 3 hours. At the conclusion of this period, the reaction mixture was quenched with aqueous Na2H2S2O5 (5%, 5 mL). The solvent was removed under reduced pressure to yield a residue. The residue was diluted with CH2Cl2 (5 mL), washed with NaHCO3 (aq, sat, 3 mL) and brine (3 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to afford Compound 3E as a colorless oil (1.3 g, 95% yield). LC/MS (m/z)=301 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[S:8]1[CH:9]=[CH:10][C:6]([C:3](=[O:5])[CH2:4][C:15]([O:16][CH3:17])=[O:18])=[CH:7]1
Reactant: CC(=O)c1ccsc1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(=O)c1ccsc1
Yield: 46 %

Procedure:
24 g (0.6 mmol) of sodium hydride (60%) are added in portions at 0° C., over a period of 10 minutes, to 25.2 g (0.2 mmol) of 3-acetylthiophene in 600 ml of dimethyl carbonate, and then the whole is heated at reflux for 30 minutes, allowed to cool and poured into 1 liter of a water/ice mixture containing 53 ml of acetic acid. Extraction is carried out 3 times with 250 ml of ether each time. The combined organic phases are dried over magnesium sulphate. After evaporation, the residue is chromatographed on silica (eluant: dichloromethane) to yield 17 g of the desired compound (yield: 46%).
Reaction SMILES: ClC1C=CC=CC=1O[C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1.[Na].[C:18](O)(=[O:20])C>C[O-].[Na+].CO>[N:10]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[C:11](=[NH:12])[O:20][CH3:18]
Reactant: N#Cc1cccc(Oc2ccccc2Cl)n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 8 h

Procedure:
6-o-Chlorophenoxy-2-cyanopyridine (10 g) was dissolved in a solution of sodium methoxide in methanol prepared from methanol (150 ml) and metallic sodium (0.50 g). After the solution was left to stand overnight, acetic acid (1.3 g) was added thereto, followed by concentration under reduced pressure. The resulting residue was dissolved in ether (200 ml) and insoluble materials were filtered out. The filtrate was concentrated under reduced pressure to obtain methyl 2-picoline imidate derivative.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>C(O)C>[CH3:1][N:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[C:5](=[O:7])[N:14]2[CH2:21][CH2:20][CH2:19][CH:15]2[C:8]1=[O:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: CCO
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 17.7 g. of N-methyl isatoic anhydride, 11.5 g. of L-proline and 250 ml. of ethanol is heated on a steam bath for three hours and then concentrated to remove the ethanol. The residue is mixed with benzene and a small portion of water and the layers are separated. The benzene layer is washed twice with water and concentrated to remove the solvent. The residue is triturated with ether. The crystals which form are collected by filtration and recrystallized from ethyl acetate yielding the pure dextrorotatory isomer, melting point 120°-122° C., [α]D25 + 486° (1%, methanol).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[O:34]=[C:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH2:41][CH2:42][NH2:43]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:43][CH2:42][CH2:41][CH2:40][N:36]1[CH2:37][CH2:38][CH2:39][C:35]1=[O:34])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NCCCN1CCCC1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 29.7 %

Procedure:
In 100 ml of THF was dissolved 9.97 g of compound (29) and after adding slowly thereto 4.45 g of triethylamine and then 6.01 g of isobutyl chloroformate under ice-cooling, the reaction was performed under ice-cooling. To the reaction mixture was slowly added 11.37 g of 3-(2-oxo-1-pyrrolidinyl)-propylamine and then the reaction was performed for one hour under ice-cooling. Precipitates were filtered off, the filtrate was concentrated, and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with ethyl acetatemethanol (4:1), 4.43 g of (S)-1-benzyloxycarbonyl-N-[3-(2-oxo-pyrrolidinyl)propyl]-2-pyrrolidine carboxamide (99) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2COCCOC
Reaction time: 66 h
Yield: 24 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (6 g, 26.5 mmol) in anhydrous DMF (30 ml) was added sodium carbonate (3.09 g, 29.15 mmol). After 10 minutes stirring at room temperature methoxyethoxymethylchloride (3.03 ml, 26.5 mmol) was added and stirring continued under nitrogen at room temperature for 66 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (100 ml) and washed with brine (100 ml), the aqueous extract was extracted with DCM (100 ml) and the organic extracts dried (MgSO4) combined and concentrated in vacuo. The residue was triturated with EtOAc and the solid filtered off. Concentration of the filtrate afforded a light brown oil that was absorbed onto silica and purified by SPE (Si, 50 g) eluting with a gradient of 1:1 EtOAc/cyclohexane-EtOAc to afford the title compound as a white solid (2 g, 24%), m/z 315.2[MH+].
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[CH:20]=[CH:21][C:22]([NH:24][NH2:25])=[O:23])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:31][C:30]([C:27]1[CH:26]=[C:19]([CH:20]=[CH:21][C:22]2[O:23][C:1](=[O:2])[NH:25][N:24]=2)[CH:18]=[C:17]([C:14]([CH3:13])([CH3:15])[CH3:16])[C:28]=1[OH:29])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C=Cc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.4 %

Procedure:
Carbonyl diimidazole (0.7 g, 0.004 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-cinnamic acid hydrazide (1.0 g, 0.003 mole) and triethylamine (0.4 g, 0.004 mole) in tetrahydrofuran (12 ml). The mixture is stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stir 45 minutes. The solution is concentrated and the residue dissolved in ether (50 ml) and washed with aqueous 2M HCl. The product is extracted from the organic layer by treatment with aqueous 1M NaOH (20 ml). The aqueous extract is made acidic by treatment with cold aqueous 2M HCl and the product is extracted with ether. The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provided a solid which was recrystallized from ethyl acetate/hexane to give 1.0 g (1.1 g theor., 94%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-oxadiazole-2(3H)-one, mp >260° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[CH3:19][C:20](=[CH2:22])[CH3:21]>ClCCl>[C:20]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 71 %

Procedure:
A mixture of 4-bromobenzoic acid (100 g, 0.5 mol), trifluoromethane sulphonic acid (2.6 mL, 0.03 mol) and isobutylene (1.5 L) in dichloromethane (1.5 L) was stirred at RT in a closed autoclave for 5 days. The organic layer was washed with an aqueous solution of NaHCO3 (10%), water, brine, dried and concentrated to give tert-butyl-4-bromobenzoate (90 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[CH3:20]>>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)=[CH:13][C:12]=1[CH3:20]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: Fc1cccc(CBr)c1
Product: Cc1cc(C(=O)Cc2cccc(F)c2)ccc1Br

Procedure:
The title compound was prepared according to the procedure of step 3 in the Example 169 using 3-fluorobenzyl bromide and 4-bromo-3-methylbenzoyl chloride (Cignarella; G.; Curzu, M. M.; Grella, G.; Loriga, M.; Anania, V.; Desole, M. S.; J. Farmaco. Ed. Sci., 1983, 38, 187-198.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.C1COCC1.[Cl:21]N1C(=O)CCC1=O>O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[C:11]([Cl:21])[C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a mixture of methyl((3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (10.4 g) and THF (20 mL) was added N-chlorosuccinimide (6.67 g). The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (8.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][C:8]2=[CH:13]/[C:14](/[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)=[N:15]/[H].C[O:26][C:27]1C=CC=C2[C:28]=1CCN=C2C.[Li+].CC([N-]C(C)C)C.COC1C=C(C=CC=1)C#N>CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:27](=[O:26])[CH2:28][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH:13]=[C:8]12
Reactant: [H]/N=C(/C=C1NCCc2c(OC)cccc21)c1cccc(OC)c1
Reactant: COc1cccc2c1CCN=C2C
Agent: CC(C)[N-]C(C)C
Agent: COc1cccc(C#N)c1
Agent: [Li+]
Solvent: CCOCC
Product: COc1cccc(C2=NCC(=O)N3CCc4c(OC)cccc4C3=C2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
(Z)-2-(5-methoxy-3,4-dihydroisoquinolin-1(2H)-ylidene)-1-(3-methoxyphenyl)ethanimine. 1-1. A flask was charged with 5-methoxy-1-methyl-3,4-dihydroisoquinoline (3.0 g, 17.1 mmol) and Et2O (100 mL) under N2 and cooled to −30° C. A 2M solution of LDA (8.56 mL, 17.1 mmol) was added dropwise. The resulting brown suspension was stirred for 30 min at this temperature, and then cooled to −78° C. A solution of 3-methoxybenzonitrile (2.28 g, 17.1 mmol) in Et2O (25 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h, and then allowed to warm to RT and stirred for another 18 h. the mixture was then poured onto H2O and extracted with AcOEt. The org. layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (5.9 g) as a brown oil that was used as it is in the next step. UPLC-MS: MS 309.3 (M+H+); UPLC rt 0.73 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH3:14])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:17][C:18](=[O:20])[CH3:19])[CH3:14]
Reactant: CC(=O)CCl
Reactant: COC(=O)[C@H](C)NCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H](C)N(CC(C)=O)Cc1ccccc1
Temperature: 70 °C
Yield: 49.8 %

Procedure:
A mixture of N-benzylalanine methyl ester hydrochloride (1.00 g, 4.35 mmol), chloroacetone (1.21 g, 13.1 mmol), and sodium hydrogencarbonate (951 mg, 11.3 mmol) in 1,4-dioxane (11 mL) and water (1 mL) was heated at 70° C. for 2 days, then partitioned between EtOAc and 2 M aq. sodium carbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-EtOAc gradient) produced the title compound (540 mg, 50%). Colourless oil, MS: 250.1 (M+H)+.
Reaction SMILES: ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([F:28])=[CH:23][N:22]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]2[O:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=2[N:39]=1>>[Cl:20][C:21]1[N:26]=[C:25]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[O:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=3[N:39]=2)[C:24]([F:28])=[CH:23][N:22]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(n1)NC(=O)CO2
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: O=C1COc2ccc(Nc3nc(Cl)ncc3F)nc2N1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one were reacted to yield 2-chloro-5-fluoro-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 4.63 (s, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 8.33 (d, J=3.3 Hz, 1H), 10.14 (s, 1H, NH), 11.19 (s, 1H, NH); 19F NMR (282 MHz, DMSO-d6): δ−152.35; LCMS: ret. time: 26.74 min.; purity: 85.90%; MS (m/e): 296.13 (MH+).
Reaction SMILES: [CH2:1]=[O:2].[C:3]1([N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][S:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[C:11](=[O:25])[N:10]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:26]1([N:10]2[C:11](=[O:25])[C:12]([CH2:15][CH2:16][S:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:18])([CH2:1][OH:2])[C:13](=[O:14])[N:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=O
Reactant: O=C1C(CCS(=O)c2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1
Solvent: CO
Product: O=C1N(c2ccccc2)N(c2ccccc2)C(=O)C1(CO)CCS(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
40% Formaline (25 ml) is added to a solution of 20 grams of 1,2-diphenyl-4-[2-(phenylsulfinyl)-ethyl]-pyrazolidine-3,5-dione in 120 ml of methanol. The solution, under magnetic stirring, is heated up to 50° C. for one hour and kept, always under a magnetic stirring, at room temperature for 12 hours. At the end the solvent is evaporated under reduced pressure, the residue is washed with water and extracted with dichloromethane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH2:12][CH2:13][CH2:14][OH:15])[CH:9]([OH:16])[CH2:8][CH2:7]2.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH2:12][CH2:13][CH2:14][O:15][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:9]([OH:16])[CH2:8][CH2:7]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCC1c2c(Br)cccc2CCC1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCC1c2c(Br)cccc2CCC1O
Temperature: 25 °C
Yield: 107.1 %

Procedure:
A solution of 8-bromo-1,2,3,4-tetrahydro-1-(3-hydroxypropyl)-2-hydroxynaphthalene (B-3, 29.15 g, 0.10 mol) and imidazole (17.02 g, 0.25 mol) in dimethylformamide (70 mls) was cooled in ice, and t-butyldimethylsilyl chloride (17.3 g, 0.115 mol) was added with stirring. The mixture was allowed to warm to room temperature slowly. After stirring for a total of 18 hours, crushed ice (30 mls) was added, and the mixture was stirred at ambient temperature for 0.5 hour. The mixture was diluted with water (300 mls) and extracted twice with 1:1 diethylether/hexane. The extracts were washed twice with water and once with brine. The solution was dried (MgSO4), and the solvent was removed under vacuum to leave the title compound as an oil (B-4, 42.78 g, 100%). NMR (CDCl3, TMS)δ0.083, 0.099 (twos,6H,Si-CH3), 0.91 (s,9H,Si-tBu), 1.50-1.60(m, 1H), 1.8-2.0(m,5H), 2.8-3.0(m,2H), 3.19 (d,J=4.3 Hz, 1H), 3.48(m,5 lines, 1H), 3.65-3.85 (m,2H), 4.0-4.13 (m,1H), 6.86(t,J=7.6 Hz, 1H), 6.93 (br. d,J=7.6 Hz, 1H), 7.30 (br. d,J=7.5 Hz,1H). IR (Major peaks)3411, 3057, 1592, 1559, 1472, 1463, 1438, 1256, 1100, 1067, 835, 774. CI Mass spec. m+at m/z 399,401.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:3]=1[F:17].O.[NH2:19][NH2:20]>CS(C)=O>[F:17][C:3]1[C:2](=[N:19][NH2:20])[N:7]=[C:6]([S:8][CH3:9])[NH:5][C:4]=1[NH:10][CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: CSc1nc(Cl)c(F)c(NCc2nccs2)n1
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(=NN)c(F)c(NCc2nccs2)[nH]1
Temperature: 80 °C
Yield: 29.3 %

Procedure:
6-Chloro-5-fluoro-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (0.6773 g, 2.336 mmol) was dissolved in DMSO (7 mL) and hydrazine monohydrate (0.91 mL, 18.72 mmol). The reaction vessel was pressure sealed and heated to 80° C. for 2 hours. The reaction mixture was purified by RP-HPLC to provide 5-fluoro-2-(methylthio)-6-[(1,3-thiazol-2-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone as an orange solid (0.1958 g, 29%). LCMS: (M+H)+=287.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22]>C(Cl)Cl>[C:21](=[O:22])([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[O:11][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)OC(=O)CNC(=O)OC(C)(C)C

Procedure:
One millimole of t-butoxycarbonyl-glycine in 10 ml methylene chloride at 0° is treated successively with one millimole each of triethylamine and isobutyl chloroformate, forming N-(t-butoxycarbonyl)glycyl i-butyl carbonate. To this solution at -78° is added p-nitrobenzyl 5-methoxymethyl 6H-1,3-thiazine-4-carboxylate and then a second millimole of triethylamine. The reaction mixture is allowed to warm to room temperature over one hour, and kept at 25° one hour. The mixture is then washed successively with aqueous pH 2 buffer, water, and aqueous bicarbonate, dried with MgSO4, filtered and evaporated, affording p-nitrobenzyl 7-t-butoxycarbonylamino-3-methoxymethyl decephalosporanate, which may be purified if desired by chromatography on silica gel, eluting with 4:1 chloroform-ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[Li].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:8]1[C:7](=[O:12])[CH:6]2[CH2:13][O:14][CH2:15][CH2:16][N:5]2[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: BrCc1ccccc1
Agent: [Li]
Solvent: CN(C)C=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x38 using 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x1, 500 mg, 2.078 mmol), 1M lithium bis(trimethylsiylyamide) in hexanes (2.493 mL, 2.493 mmol) and (bromomethyl)benzene (0.271 mL, 2.286 mmol) in DMF (10 mL) at 0° C. for 18 hours. 1H NMR (400 MHz, DMSO-d6) δ 2.94-3.06 (m, 1 H), 3.50-3.61 (m, 1 H), 3.62-3.72 (m, 1 H), 3.90-3.99 (m, 1 H), 4.17-4.32 (m, 2 H), 4.56-4.67 (m, 1 H), 5.02-5.22 (m, 2 H), 7.29 (s, 5 H), 7.72 (s, 1 H). ESI-MS m/z [M+H]+ calc'd for C16H15ClN4O2, 331.09; found 331.2.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O>[CH:24]1([O:10][C:5]2[CH:6]=[C:7]([C:2]([F:1])=[CH:3][C:4]=2[O:11][CH3:12])[CH:8]=[O:9])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrC1CCCC1
Reactant: COc1cc(F)c(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(C=O)cc1OC1CCCC1

Procedure:
A mixture of 6-fluoro-3-hydroxy-4-methoxybenzaldehyde (2 g), potassium carbonate (1.66 g) and anhydrous dimethylformamide (20 mL) is treated with cyclopentyl bromide (1.62 mL) and heated on a steam bath for 43 hours. The mixture is cooled, poured into water (200 mL) and extracted with diethyl ether (3×100 mL). The combined ethereal extracts are washed with sodium hydroxide solution (2×50 mL; 2 N), and brine (2×50 mL), dried over magnesium sulphate and concentrated. The residual brown oil is subjected to flash chromatography [a solvent gradient of 9:1 to 4:1 v/v petroleum ether (b.p. 60-80° C.) and ethyl acetate is used as eluent on a silica gel column] to give 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.42 g) in the form of a yellow oil. [NMR (CDCl3):—10.22 (s, 1H), 7.27 (d, 1H, J=8 Hz), 6.63 (d, 1H, J=16 Hz), 4.81-4.76 (m, 1H), 3.91 (s, 3H), 2.01-1.57 (m, 8H)].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=[O:18])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[C:17]([C:14]1[C:15]([O:16][C:27](=[O:29])[CH3:28])=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=2)[S:12][CH:13]=1)(=[O:18])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C(C)=O)csc1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 2-(4-tert-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (137 mg, 0.5 mmol) in THF (2 mL) were added triethylamine (105 μL, 0.75 mmol) and acetyl chloride (53.3 μL, 0.75 mmol). The reaction mixture was stirred at room temperature for 0.5 h. After removing solvent, the residue was diluted with AcOEt, washed with a saturated aqueous NH4Cl solution, dried over MgSO4 and concentrated to give product as a brown oil (146 mg, yield 92%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[N:10]([CH3:20])[CH2:11][CH2:12][NH:13]C(=O)C(F)(F)F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH2:1]([O:8][C:9](=[O:21])[N:10]([CH2:11][CH2:12][NH2:13])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a solution of compound Y (103.0 g, 340.7 mmol) in MeOH (1200 mL) was added a solution of LiOH (16.4 g, 681.4 mmol) in water (120 mL). The reaction mixture was stirred at room temperature for 3 h. Solvents were evaporated to ¾ of initial volume followed by dilution with water (400 mL). Solution was extracted with EtOAc (2×300 mL). The organic layer was washed with brine (200 mL), dried over MgSO4 and evaporated in vacuo. The resultant residue was dissolved in ether (300 mL) and treated with 2 N HCl/ether (200 mL). The formed precipitate was filtered, washed with ether and dried in vacuo to provide hydrochloric salt of compound Z (54.5 g, 261.2 mmol) as white solid. LC-MS [M+H] 209.5 (C11H16N2O2+H, calc: 209.3).