Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12](OC)=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1>C1COCC1>[OH:13][CH2:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]2[S:5][CH2:6][C:7](=[O:16])[NH:8][C:9]=2[N:10]=1
Reactant: COC(=O)c1nc2c(cc1C)SCC(=O)N2
Solvent: C1CCOC1
Product: Cc1cc2c(nc1CO)NC(=O)CS2
Temperature: -10 °C

Procedure:
Methyl 7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (54 mg, 0.195 mmol) was dissolved in THF (5 mL), cooled to −10° C. and treated with 1.0M LiH3BNMe2 (0.42 mL, 0.42 mmol). The reaction was maintained at −10° C. for 1 h and then quenched with 6N HCl. The reaction solution was diluted with EtOAc and water and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered and concentrated. The crude product (30.3 mg) was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)[C:13]([F:27])=[CH:12][N:11]=1>>[F:27][C:13]1[C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[N:15][C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2ncccc2c1
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4ncccc4c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-5-fluoro-N4-(quinolin-6-yl)-4-pyrimidineamine gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.50 (s, 1H), 10.14 (s, 1H), 8.29 (d, 1H, J=4.8 Hz), 8.14 (d, 1H, J=1.8 Hz), 7.96 (d, 1H, J=9.3 Hz), 7.83 (dd, 1H, J=2.4 and 9.0 Hz), 7.40 (d, 1H, J=8.7 Hz), 7.04 (t, 1H, J=8.1 Hz), 6.93 (m, 2H), 6.52 (m, 2H); LCMS: purity: 93%; MS (m/e): 365 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:22][PH:23]([O-])([O-:27])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@:10]([NH:9][C@@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:23]([CH3:22])(=[O:27])[O:24][CH2:25][CH3:26])=[CH:3][CH:4]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)[S@](=O)N[C@H](c1ccccc1)c1ccc(Br)cc1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@](=O)C(C)(C)C)c2ccccc2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To (S)—N—((R)-(4-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 22-a, (16 g, 43.83 mmol), ethyl methylphosphite (9.47 g, 87.67 mmol) and Et3N (13.3 g, 132 mmol) in THF (200 ml) was added PdCl2(dppf) (1.6 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1/1) to provide the crude product, 22-b, (9.5 g, 55%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[Si:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 3-hydroxybenzaldehyde (12.21 g, 100 mmol) in 600 mL THF was added tert-butyldimethylsilyl chloride (TBDMSCl, 18.84 g, 125 mmol). The solution was cooled to 0° C. and triethylamine (12.65 g, 17.4 mL, 125 mmol) was added dropwise. The reaction mixture was brought to room temperature and stirred 5 h. The mixture was filtered and the THF removed under reduced pressure. The oil was repeatedly dissolved in 200 mL portions of THF and evaporated, until no more triethylamine hydrochloride precipitated. The oil was then dissolved in 150 mL diethyl ether, filtered through a plug of neutral alumina and activated charcoal to remove the salt and the yellow color, and evaporated. The colorless, mobile oil was dried in vacuo overnight. Yield: 21.43 g (91%). IR: 1703, 1583, 1482, 1278, 1145, 840 cm-1. 1H NMR (CDCl3, TMS) δ 9.927 (s, 1H), 7.447 (d, J) 7.50 Hz, 1H), 7.379-7-335 (m, 2H), 7.096-7.074 (m, 1H), 0.994 (s, 9H), 0.215 (s, 6H). 13C NMR (CDCl3, TMS) δ 191.60, 156.34, 138.03, 130.03, 126.34, 123.46, 119.70, 25, 59, 18.12, −4.52. Anal. Calcd. for Cl3H20O2Si: C, 66.05; H, 8.53. Found: C, 66.13; H, 8.53.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:29])[CH:20](O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)C>[CH3:17][O:18][C:19](=[O:29])[CH:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)C(Cc1ccccc1)Oc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 4′-hydroxy-4-nitro-biphenyl (4.12 g, 19.1 mmol), prepared in step 2 of Example 16, 2-hydroxy-3-phenyl-propionic acid methyl ester (3.35 g, 18.5 mmol) and triphenylphosphine (4.12 g, 19.1 mmol) in diethyl ether was cooled under nitrogen to 0° C. Diisopropyl azodicarboxylate (6.09 mL, 30.96 mmol) was then added and the reaction allowed to come to room temperature and then stirred overnight at room temperature. The reaction was concentrated under reduced pressure. Purification of the residue on silica gel using 15% ethyl acetate hexanes as the eluent gave 2-(4′-nitro-biphenyl-4-yloxy)-3-phenyl-propionic acid methyl ester.
Reaction SMILES: C(O[C:5]([C:7]1[C:12]([CH2:13]O)=[CH:11][C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][N:8]=1)=[O:6])(C)C.[CH3:23][O:24][C:25](=[O:38])[CH2:26][NH:27]S(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>>[CH3:23][O:24][C:25]([C:26]1[C:5]([OH:6])=[C:7]2[C:12]([CH:11]=[C:10]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:9]=[N:8]2)=[CH:13][N:27]=1)=[O:38]
Reactant: CC(C)OC(=O)c1ncc(Cc2ccc(F)cc2)cc1CO
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)c1ncc2cc(Cc3ccc(F)cc3)cnc2c1O
Yield: 83 %

Procedure:
After subjecting the above Compound 5 (59.0 g, 195 mmol) to Mitsunobu reaction with N-tosylglycine methyl ester according to the method described in Document (WO02/30930), ring-closure was caused with 1M sodium methoxide, to give 3-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester 6 (50.3 g) in 83% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3](S(O)(=O)=O)=[CH:4][CH:5]=[C:6](S(O)(=O)=O)[CH:7]=1.[C:16](#[N:18])[CH3:17]>O>[C:2](#[N:1])[C:7]1[C:17](=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]#[N:18]
Reactant: CC#N
Reactant: Nc1cc(S(=O)(=O)O)ccc1S(=O)(=O)O
Solvent: O
Product: N#Cc1ccccc1C#N
Temperature: 40 °C

Procedure:
A solution of aniline 2,5 disulphonic acid (27.5 g) in water (250 ml) was added to intermediate E (63.2 g) in acetonitrile (800 ml) and heated at 40° C. and at pH 5 to 7 overnight. The reaction solvent was removed under reduced pressure, water (50 ml) was added and then brine (60 ml) the solid which precipitated of filtered off, washed with 10% brine and dried to give product (91.1% strength, 22 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:16]=[CH:15][C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][CH:8]=1)[CH3:6].O>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:1]([C:9]1[CH:8]=[C:7]([CH2:5][CH3:6])[CH:16]=[CH:15][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(NC(C)=O)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
A mixture of fuming nitric acid (1.4 ml.) and acetic acid (2 ml.) was addedportionwise to a stirred 0° C. solution of p-ethylacetanilide (4.0 grams) in acetic anhydride (4.2 ml.) and acetic acid (4.4 ml.). The temperature was allowed to rise slowly to 25° C. Subsequently the reaction mixture was poured into 100 ml. of water. An oil settled but did not crystallize. The mixture was extracted with ether and evaporated, leaving the 2' -nitro-4'-ethylacetanilide as a dark oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.[Pb](=O)=[O:17]>[Ti].[Ni].S(=O)(=O)(O)O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Pb]=O
Reactant: Cc1ccc(C(C)(C)C)cc1
Agent: [Ni]
Agent: [Ti]
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(C=O)cc1

Procedure:
2.5 ml of p-tert.butyltoluene, 10 ml of dichloroethane and 110 ml of 10N sulphuric acid are emulsified while stirring magnetically in a glass vessel provided with a cover. Expanded titanium metal (5×5 cm) coated with lead dioxide [lead dioxide-titanium composite electrode described in "Zeitschrift fur Naturforschung" 31 b, 39-50 (1976)] is used as the anode and the cathode is a nickel wire at a distance of 3 cm from the anode. A voltage of 3.4 volt is applied between the electrodes, whereupon a current of 50 mA is set. The temperature is held at 25° C. by external cooling. After the throughput of 1.55 aH, corresponding to 100% of the theoretically required current, the electrolysis is discontinued. The solution is extracted three times with 60 ml of chloroform each time and the combined extracts are analysed quantitatively by gas chromatography. With a conversion of 83% there is obtained a yield of p-tert.butylbenzaldehyde which amounts to 77% of theory.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1)[CH3:2]>Cl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Yield: 62.3 %

Procedure:
A mixture of 17.7 g of the above ester was refluxed in 150 ml of 37% hydrochloric acid for 2 hours, giving 10 g of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, mp 240° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].F[C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[C:13]#[N:14].O>CN1CCCC1=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:10]2[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[C:12]([CH:11]=2)[C:13]#[N:14])[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2cc(C#N)cc(C(F)(F)F)c2)cn1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A solution of 4-methyl-1H-imidazole (1.98 g, 24.11 mmol) in N-methylpyrrolidinone (NMP) (18 mL) is added to a solution of sodium hydride (0.82 g, 60%, 20.5 mmol) in NMP (18 mL) at 20-25° C. under an atmosphere of nitrogen. The mixture is stirred for 1 hour, before a solution of 3-fluoro-5-trifluoromethyl benzonitrile (XXI) (3.2 g, 16.4 mmol) in NMP (8 mL) is added. The reaction mixture is stirred for 2 hours at 20-25° C. and then water (120 mL) is added within 20 minutes and the resulting suspension is stirred for 16 hours.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[CH:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=1.[H-].[Na+]>CN(C)C=O.C(O)(=O)C>[N+:20]([C:19]1[CH:14]=[CH:15][C:16]([O:23][CH2:2][N:3]2[C:7](=[O:8])[C:6]3=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]3[C:4]2=[O:13])=[CH:17][CH:18]=1)([O-:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(Chloromethyl)phthalimide (4.2 g) and the yellow dye, p-nitrophenol (3.0 g) were dissolved sequentially in 100 ml of dimethylformamide (DMF). Sodium hydride (2.0 g of a 50% oil dispersion) was added and the solution stirred for three days at room temperature. The mixture was diluted with 500 ml 1% aqueous acetic acid to precipitate out the desired product: 5.6 g, m.p. 145°-148° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CC(O)(C)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])=[CH:21][CH:20]=1.CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])=[CH:21][CH:20]=2)[N:7]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
ZnCl2 (1.0 M in Et2O; 3.27 mL, 3.27 mmol) was added to a stirred solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (620 mg, 2.86 mmol) in a 1:1 t-BuOH:DCE mixture (120 mL) at room temperature. After stirring for 20 minutes tert-butyl 1-(4-aminophenyl)ethylcarbamate (0.643 g, 2.72 mmol) (prepared according to Bioorganic and Medicinal Chemistry Letters, 14(7), 1751-1755; 2004) followed by Et3N (455 μL, 3.27 mmol) was added and the resulting mixture stirred at room temperature overnight. The volatiles were evaporated to dryness and the resulting residue purified by silica gel column chromatography (CombiFlash Rf, SiO2 cartridge, 0-10% EtOAc in cyclohexane) to give the title compound A63 (480 mg, 42%); 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 7.56 (m, 1H), 7.56 (d, J=8.61 Hz, 2H), 7.33 (d, J=8.61 Hz, 2H), 4.81 (m, 2H), 1.46 (m, 12H). LCMS-B: rt 8.47 min; m/z 417 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.Cl.Cl[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:3][S:4][C:5]1[N:9]=[C:8]([N:10]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1
Reactant: ClCCNCCCl
Reactant: CSc1nc(N)n(-c2ccccc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N2CCNCC2)n(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (4.7 g) was taken in dry DMF (100 ml) and a solution of compound 3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-amine (4 g in 10 ml of DMF) was added slowly at 0° C. The reaction mixture was stirred for 30 min at 0° C. and a solution of bis (2-chloroethyl) amine hydrochloride (4.15 g) in dry DMF (20 ml) was added very slowly. The reaction mixture was allowed to stir over night at room temperature. The reaction mixture was quenched with cold water (5 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of solvent under reduced pressure gave crude product, which, was purified by column chromatography using methanol\dichloromethane (1:9) as eluent to afford 1-(3-(methylthio)-1-phenyl-1H-1,2,4-triazol-5-yl)piperazine, G-26-In, as brown oil.
Reaction SMILES: [CH:1]1([NH:11][C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br.C(C(C)=[O:19])C.O=O>C(O)(=O)C.O>[O:19]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][C:12]([NH2:14])=[O:13])[CH2:2][CH2:3]1
Reactant: NC(=O)NC1CCCc2ccccc21
Reactant: CCC(C)=O
Agent: Br
Agent: O=O
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
A mixture of 1,2,3,4-tetrahydro-1-naphthylurea (1.9 g), cobaltous acetate tetrahydrate (1.08 g), 30% hydrobromic acid in acetic acid (0.9 ml) and a 1:1 mixture of methyl ethyl ketone: acetic acid (30 ml) is shaken in a pressure vessel under 31 psig of oxygen for 7.5 hours. The vessel is then vented, the contents are mixed with an equal volume of water and extracted with chloroform (2×25 ml). The combined chloroform extracts are dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo to afford 2.34 g solid. The solid is washed with cold methanol (30 ml) to afford 0.75 g of title compound, m.p. 210° C. to 214° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([C:16](=[C:33](OS(F)(=O)=O)[CH3:34])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:40])[C@H:13]1[NH:41][C:42](=[O:51])[CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C.C(#N)C.O>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([C:16](=[C:33]=[CH2:34])[C:17]([O:19][CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:18])[C:14](=[O:40])[C@H:13]1[NH:41][C:42](=[O:51])[CH2:43][O:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(OS(=O)(=O)F)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C=C=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 80 %

Procedure:
Embodiment a: To a solution of 200 mg (0.261 mmol) of diphenylmethyl 2-[(3R, 4R)-4-[(benzothiazol-2yl)dithio]-3-phenoxyacetamido-2-oxo-azetidin-1-yl]3-fluorosulfonyloxy-2-butenoate (XXd) in 2.0 mL of dry dichloromethane at room temperature was added, dropwise, 38.26 μL (0.274 mmol) of triethylamine. The solution was stirred at ambient temperature for 25 min. HPLC indicated disappearance of the starting material and formation of the product (retention time=4.74 min, 2.0 mL/min, 70% acetonitrile: 30% water, reversed phase C-18 column). The resultant solution was poured into water. The organic layer was separated and further washed with brine (10 mL) and 5% HCl solution (10 mL). It was subsequently dried (magnesium sulfate) and concentrated to give 139.09 mg (81%) of the title product as a light brown foam, which was further purified by recrystallization from isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:32][CH2:33][C:34](Cl)=[O:35])(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@@H:19]([NH:21][C:33](=[O:32])[CH2:34][OH:35])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CC(=O)OCC(=O)Cl
Product: C[C@H](NC(=O)CO)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 64 using (2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-amine (60 mg, 0.16 mmol) and acetoxyacetyl chloride (0.069 mL, 0.64 mmol). Yield 60 mg (87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][N:13]=1>>[F:11][C:12]1[N:13]=[CH:14][C:15]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Reactant: CC(=O)c1ccc(Br)cc1
Product: CC(=O)c1ccc(-c2ccc(F)nc2)cc1

Procedure:
1-(4-(6-Fluoropyridin-3-yl)phenyl)ethanone T405 was prepared using general procedure A from 1-(4-bromophenyl)ethanone (117 mg, 0.5 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 mg, 0.5 mmol). T405 was obtained as a yellow solid (64 mg, 59%). 1H NMR (400 MHz, CDCl3): δ 8.47 (m, 1H), 8.06 9m, 2H), 8.04-7.99 (m, 1H), 7.65 (m, 2H), 7.05 (ddd, J=8.4, 3.2, 0.8 Hz, 1H), 2.65 (s, 3H); MS (ESI): 216 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH3:9])[CH3:18]
Reactant: CC(=O)c1cccc(C)c1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3′-methylacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) was heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract was concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, was isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether. The purified oil solidified on standing at room tempera-ture.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCBr)C1c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A suspension comprising 9.96 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, 5.4 ml of 1,4-dibromobutane and 2.07 g of potassium carbonate in 60 ml of dimethylformamide was heated at 50° C. under stirring for 2.5 hours. The mixture was then cooled to room temperature, poured into 400 ml of water and extracted with diethyl ether. The ethereal extracts were then dried on anhydrous sodium sulfate and evaporated to dryness to give an oil which was purified by flash chromatography on silica gel columns, employing first chloroform and then chloroform:ethyl acetate 97:3 by volume as eluent.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10]C)=[O:9])[N:7]=1.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: COC(=O)c1coc(CCl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1coc(CCl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (1.0 g, 5.70 mmol) was dissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (11.39 ml, 11.39 mmol) was added slowly. The reaction mixture was stirred at RT for 1 h, diluted with water and pH was adjusted to 2. The reaction mixture was extracted three times with ethyl acetate. Ethyl acetate phases were combined, dried and evaporated to dryness to yield the title compound (94%). 1H-NMR (400 MHz; DMSO3): δ 4.93 (s, 2H), 8.80 (s, 1H), 13.20 (bs, 1H).