Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH2:10][S:11][CH2:12][CH2:13][NH2:14])[CH3:5].[OH-].[Na+].[N+](N[C:24]1[NH:29][C:28](=[O:30])[C:27]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][N:25]=1)([O-])=O>O.C(O)C>[CH3:5][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH2:10][S:11][CH2:12][CH2:13][NH:14][C:24]1[NH:29][C:28](=[O:30])[C:27]([CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][N:25]=1)[CH3:3]
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Reactant: CN(C)Cc1cccc(CSCCN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1cccc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)c1

Procedure:
2-[3-(Dimethylaminomethyl)benzylthio]ethylamine dihydrochloride (4.2 g) was dissolved in water and the solution was made alkaline with aqueous sodium hydroxide and extracted with chloroform. The chloroform extract was evaporated to give the free base. 2-Nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (3.16 g) was added to the residue and the mixture was heated under reflux in ethanol (20 ml) for 35 hours and evaporated to dryness. Water (30 ml) was added to the residue and the mixture was adjusted to pH 13 with aqueous sodium hydroxide and extracted with chloroform. The latter chloroform extracts were evaporated and the residue was recrystallised from acetonitrile to give 2-[2-(3-(dimethylaminomethyl)-benzylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 143°-145°. Treatment with hydrogen chloride in ethanol gives the trihydrochloride salt and treatment with hydrogen bromide in ethanol gives the trihydrobromide salt.
Reaction SMILES: [F:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([F:13])[C:7]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([F:13])[C:7]=1[C:14]1[C:23](=[O:24])[N:22]([CH2:3][CH2:2][F:1])[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: FCCBr
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2nccnc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)n(CCF)c2nccnc12
Temperature: 120 °C

Procedure:
2-Fluoroethyl bromide was added to a mixture of 2,2-dimethyl-propionic acid 7-(2-chloro-3,6-difluoro-phenyl)-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazin-8-yl ester (Example 1.3) (0.20 g), potassium carbonate (0.207 g) and potassium iodide (catalytic amount) in N,N-dimethylformamide (10 ml). The reaction mixture was heated in the microwave for 20 minutes at 120° C. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:1) to give Compound No. C9 of Table C as a yellow solid (0.103 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6](Cl)=[O:7])=[C:2]=[O:3].C[Si](C)(C)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][Si](C)(C)C)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[N:1]([CH2:4][CH2:5][C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:6](=[O:7])[CH2:5][CH2:4][N:1]=[C:2]=[O:3])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])=[C:2]=[O:3]
Reactant: O=C=NCCC(=O)Cl
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(O[Si](C)(C)C)cc2)cc1
Product: O=C=NCCC(=O)Oc1ccc(-c2ccc(OC(=O)CCN=C=O)cc2)cc1

Procedure:
From 35 g (0.26 mol) of 3-isocyanatopropanoic acid chloride and 30 g (0.09 mol) of 4,4'-bis(trimethylsiloxy)biphenyl.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5]O.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.O>O1CCOCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH2:5][C:15]1[NH:14][CH:18]=[CH:17][CH:16]=1
Reactant: c1cc[nH]c1
Reactant: O=[N+]([O-])c1cc(CO)cc(O)c1O
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cc(Cc2ccc[nH]2)cc(O)c1O
Temperature: 100 °C

Procedure:
A solution containing 1.0 g of 3,4-dihydroxy-5-nitrobenzylalcohol and 5.0 ml of pyrrole in 3.0 ml of dioxane was heated for 5 h at 100° C. Water was added and the solution was extracted with dichloromethane. The solvent was evaporated and the residue was purified in a silicagel column using toluene-acetic acid-dioxane (18:1:1) mixture as an eluent. Yield 0.42 g (33%), m.p. 115°-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>>[C:19]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23]([C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26]([OH:28])=[O:27])=[O:33])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(-c2ccc(NC(=O)c3ccccc3C(=O)O)cc2)cc(C(C)(C)C)c1O
Reaction time: 16 h
Yield: 53.9 %

Procedure:
To a solution of 2.97 g (0.01 mole) of 4'-amino-3,5-di-t-butyl-4-hydroxy biphenyl in 200 ml of diethyl ester was added a solution of 1.48 g (0.01 mole) of phthalic anhydride, and the resulting solution was stirred for about 16 hours. The solvents were removed under vacuum and the residual solid was recrystallized from a mixture of ethyl acetate and hexane to give 2.4 g of 2-{N-[4-(3,5-di-t-butyl-4-hydroxyphenyl)phenyl]carbamoyl}benzoic acid, m.p. 196°-198° C. Analysis: Calculated for C28H31NO4 : % C, 75.5; % H, 7.0; % N, 3.1; Found: % C, 75.5; % H, 7.1; % N, 3.0.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][CH2:20][S:21][CH3:22])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Cl
Solvent: Cc1ccccc1
Product: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1C
Temperature: 55 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(3-methylthiopropoxy)quinoline (0.95 g, 2.97 mmol) and 2-methylaniline (1.27 g, 11.8 mmol) in toluene was heated to 55° C. and stirred overnight. The solvent was evaporated and the residue was partioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographed (SiO2 ; CH2Cl2MeOH 95:5) yielding 0.98 g (80.9%) of the desired product.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([CH2:13][N:14]4[CH:18]=[CH:17][CH:16]=[N:15]4)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:19]1(C)C=CC=CC=1.C([Li])CCC.CI>O1CCCC1>[CH3:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([CH3:1])([CH2:3][C:4]([CH2:13][N:14]4[C:18]([CH3:19])=[CH:17][CH:16]=[N:15]4)([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: CC12CC3CC(C)(C1)CC(Cn1cccn1)(C3)C2
Reactant: Cc1ccccc1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccnn1CC12CC3CC(C)(CC(C)(C3)C1)C2
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 32A (2.44 g) in tetrahydrofuran (25 mL)/toluene (25 mL) was added n-butyllithium (7.49 mL) at −40° C. The reaction mixture was stirred for 60 minutes when CH3I (1.873 mL) was added and the stirring was continued for 2 hours at −40° C. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated and purified by flash chromotography (silica gel, 0%-15% ethyl acetate/hexanes).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][CH:16]1[CH:21]([OH:22])[CH2:20][CH2:19][CH2:18][CH:17]1[OH:23])=[O:14])=O)C1C=CC=CC=1>C(O)C.Cl>[OH:22][CH:21]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:23])[CH:16]1[NH:15][C:13](=[O:14])[CH2:12][NH2:11]
Reactant: O=C(CNC(=O)OCc1ccccc1)NC1C(O)CCCC1O
Agent: Cl
Solvent: CCO
Product: NCC(=O)NC1C(O)CCCC1O

Procedure:
N-protected benzyloxycarbonyl N-(2,6-dihydroxycyclohexyl) glycinamide (3 g, 0.093 mol) was dissolved in 100 ml of absolute ethanol with a molar equivalent of 10% HCl. Hydrogenolysis with 5% Pd/C at 30 psi, removal of the catalyst over celite, and subsequent evaporation of solvents in vacuo yielded a pale brownish solid which was triturated with ether and recrystallized from ethyl acetate and ether, m.p. 207°-210° C. NMR (D2O) δ, 3.65 (t, 3H, C1H of cyclohexane ring); 3.55 (m, 2H, C2H and C6H of cyclohexane); 3.4 (s, 2H, --CO--CH2 --NH2); 2.05, 1.80, and 1.38 (m,m,m, 2 to 1 to 3H, hydrogens of C3, C4 and C5 of cyclohexane).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([C:8]2[C:9](=[O:15])[NH:10][CH:11]=[CH:12][C:13]=2[I:14])=[N:5][C:4]=1[CH3:16].[CH3:17]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>ClCCl>[I:14][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([O:15][CH3:17])[C:8]=1[C:6]1[NH:7][C:3]([CH:2]=[O:1])=[C:4]([CH3:16])[N:5]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: Cc1nc(-c2c(I)cc[nH]c2=O)[nH]c1CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1nccc(I)c1-c1nc(C)c(C=O)[nH]1
Reaction time: 0.08 h
Yield: 45.3 %

Procedure:
To a stirred suspension of 3-(5-(hydroxymethyl)-4-methyl-1H-imidazol-2-yl)-4-iodopyridin-2(1H)-one (0.020 g, 0.0579 mmol) in dichloromethane (2 mL) was added the Dess-Martin reagent (0.049 g, 0.1158 mmol) at room temperature. The reaction became clear after 5 minutes of stirring. Ethyl acetate was added and the reaction was washed with 5% aqueous Na2S2O3.5H2O, saturated aqueous sodium bicarbonate and brine. The organic layer was driede over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel chromatography (ethyl acetate) to give the title material (0.009 g, 45%). 1H NMR (400 MHz, Acetone-d6) δ (ppm): 2.47 (s, 3H) 3.72 (s, 3H) 7.42-7.50 (m, 1H) 7.78 (s, 1H) 9.81 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:34][CH2:35][CH2:36]O)[CH:31]([CH3:33])[CH3:32].Cl>>[CH2:30]([O:34][CH2:35][CH2:36][O:24][C:23]([C:18]1([C:20]([O:22][CH2:36][CH2:35][O:34][CH2:30][CH:31]([CH3:32])[CH3:33])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC(C)COCCO
Agent: Cl
Product: CC(C)COCCOC(=O)C1(C(=O)OCCOCC(C)C)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-isobutoxyethanol according to the procedure of Example 1 as a colorless oil; 1H NMR (300 MHz, CDCl3): δ 0.70-0.95 (m, 12H), 1.10-2.0 (complexm, 11H), 3.09-3.29 (m, 4H), 3.51-3.58 (m, 1H), 3.60-3.72 (m, 4H), 4.31-4.48 (m, 2H), 6.70-7.00 (m, 4H), 7.15-7.50 (m, 4H); MS (ES) m/z (relative intensity): 622 (M+ -HCl, 100).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC1(c2ccc(F)c(Cl)c2)CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(c2ccc(F)c(Cl)c2)CCNC1
Yield: 87.9 %

Procedure:
Preparation according to Preparation 15. Tert-butyl-3-(3-chloro-4-fluorophenyl)-3-methoxypyrrolidin-1-carboxylate (1.81 g, 5.5 mmol), methylene chloride (20 mL) and trifluoroacetic acid (5 mL). Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (1.11 g, 88%). MS m/z (rel. intensity, 70 eV) 214 (38), 199 (73), 187 (bp), 157 (40), 133 (39).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH2:18][CH:19]=O>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:9]=[C:19]([CH2:18][C:12]1[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:17])[NH:8]2
Reactant: Nc1ncnc(Cl)c1N
Reactant: O=CCc1c(Cl)cccc1Cl
Solvent: C1COCCO1
Product: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2[nH]1
Temperature: 100 °C
Reaction time: 24 h
Yield: 11.5 %

Procedure:
To a mixture of 6-chloro-pyrimidine-4,5-diamine (100 mg, 0.694 mmol), (2,6-dichloro-phenyl)-acetaldehyde (260 mg, 1.38 mmol) and 1,4-dioxane (7 mL) was added 5% FeCl3.SiO2 (150 mg). The resulting mixture was heated to 100° C. in a sealed tube. After 24 h, the mixture was cooled to rt and filtered through a pad of diatomaceous earth, washing with EtOAc (3×10 mL). The filtrate was concentrated and the residue was purified by preparative reverse-phase HPLC to afford the title compound as a white solid (25 mg, 36%). MS (ESI): mass calcd. for C12H7Cl3N4, 311.9; m/z found, 313.0 [M+H]+. 1H NMR (CDCl3): 8.65 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.34-7.29 (m, 1H), 4.78 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1>O>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: C1CNCCN1
Reactant: Clc1cnc(Cl)c(Cl)c1
Solvent: O
Product: Clc1cnc(N2CCNCC2)c(Cl)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Piperazine (24.0 g) was melted by heating at 140° C. and 2,3,5-trichloropyridine (5.00 g) was added thereto. The mixture was stirred at 120° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3,5-dichloro-2-pyridyl)piperazine (6.43 g) as a brown solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCOc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc(OCCOc2ccccc2)cc1
Yield: 85 %

Procedure:
To 100 ml of water were added 40 g of hydroquinone, 20 g of β-bromophenetole and 6 g of potassium hydroxide and the mixture was subjected to reaction at 80° C. for about 2 hours. The solid precipitated was filtered and washed with warm water. The unreacted materials were extracted with alkali for removal. The remaining insoluble solids were removed by filtration and the filtrate was neutralized with hydrochloric acid. The solid precipited was filtered, washed with water and recrystallized from ethyl alcohol, giving 1-(4-hydroxyphenoxy)-2-phenoxy ethane in a yield of 85%. M.p. 156° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](O)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[N:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cn(C2CC2)c2nc(O)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 0.19 g (0.72 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid in 2 ml of phosphorus oxychloride was heated at reflux for one-half hour. The resulting solution was cooled to room temperature and the solvent was removed in vacuo. The residue was triturated with ice water and the resulting solid was removed by filtration, washed with water, then ether, and dried in vacuo to give 0.11 g of the title compound, mp 209-212° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[NH:16][N:15]=[N:14][N:13]=1>S(Cl)(Cl)=O>[NH:13]1[C:12]([NH:11][C:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:10])=[N:16][N:15]=[N:14]1
Reactant: O=C(O)c1ncccc1Cl
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nnn[nH]1)c1ncccc1Cl
Yield: 39.3 %

Procedure:
0.53 g of 3-chloro-2-pyridinecarboxylic acid, 10 ml of thionyl chloride and 0.27 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.28 g of N-(5-tetrazolyl)-3-chloro-2-pyridinecarboxamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])[S:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+].O>COCCOC>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(O)CCSC(SCCC(=O)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl ester (Step 2) (1.7 g) in 1,2-dimethoxyethane (60 ml) was added lithium hydroxide (10 ml of 2N). The reaction mixture was stirred overnight at room temperature. H2O (100 ml) was added and the 1,2-dimethoxyethane was removed under vacuo. The solution was extracted with ethylacetate (300 ml). The aqueous phase was acidified to pH 3, extracted with ethylacetate (200 ml), dried and evaporated. Flash chromatography of the residue using 5% EtOH in CH2Cl2 with 1% of acetic acid afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH2:20][CH2:21]Cl)[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1C=CC=CC=1.CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@H:14]([CH:20]=[CH2:21])[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H]1[C@H](CCCl)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: C=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C
Yield: 98.7 %

Procedure:
610 mg of (4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-5-(2-chloroethyl)-4-isobutyloxazolidine was dissolved in 3.6 ml of dry benzene, and a solution prepared by dissolving 390 mg of potassium tert-butoxide in 3.6 ml of dimethyl sulfoxide, was added thereto. The mixture was reacted at room temperature for 10 minutes. The reaction solution thus obtained was purified by silica gel column chromatography (packed with 36 g of silica gel, developer: benzene/ethyl acetate (30/1)), and the fraction containing the desired compound was collected and concentrated. The residue thus obtained was dried under reduced pressure to obtain 540 mg (yield: 99%) of (4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-5-ethenyl-4-isobutyloxazolidine as a colorless transparent syrup having the following physical properties.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[N:6]1[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108.9 %

Procedure:
To a solution of 5 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 100 ml of tetrahydrofuran are dropwise added 1.82 ml of pyridine and a solution of 2.86 g of benzoyl chloride in 20 ml of tetrahydrofuran at 0° C. under nitrogen atmosphere. After 20 minutes, the reaction mixture is warmed up to room temperature. After additional 2 hours, the mixture is diluted with ice water and extracted with ethyl acetate. The extract is washed with an aqueous sodium sulfate and condensed under reduced pressure to yield 7.02 g of benzyl α-(3ξ-carbomethoxy-2-benzoyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.C(OCC)(=O)C.[H][H]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)nc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)nc1
Yield: 94 %

Procedure:
2-[(E)-2-(2,4-difluorophenyl)vinyl]-5-(phenylsulfonyl)pyridine (Example 26, 0.52 g, 1.45 mmol) and palladium hydroxide (20% wt. Pd on carbon, 100 mg, 0.14 mmol) were stirred in acetic acid (10 mL) and ethyl acetate (5 mL) under a balloon of hydrogen for 3 hours. The catalyst was removed by filtration and the filtrate washed with 4N sodium hydroxide solution (×2). The aqueous layers were extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 2-[2-(2,4-difluorophenyl)ethyl]-5-(phenylsulfonyl)pyridine as a pale yellow solid (0.49 g, 94%). δH (500 MHz, d6 DMSO): 9.02 (1H, s), 8.23 (1H, dd, J=2.2, 8.2 Hz), 7.99 (2H, d, J=7.4 Hz), 7.70 (1H, t, J=7.4 Hz), 7.63 (2H, t, J=7.7 Hz), 7.48 (1H, d, J=8.2 Hz), 7.27 (1H, q, J=8.0 Hz), 7.11 (1H, td, J=2.0, 9.9 Hz), 6.94 (1H, td, J=1.9, 8.6 Hz), 3.07 (2H, t, J=7.7 Hz), 2.97 (2H, t, J=7.7 Hz); m/z (ES+) 360 [MH+].
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(O)nc1C
Product: CCOC(=O)c1cnc(Cl)nc1C
Yield: 27 %

Procedure:
A solution of ethyl 2-hydroxy-4-methylpyrimidine-5-carboxylate (5 g, 27.5 mmol) and POCl3 (84 g, 550 mmol) was heated at reflux under N2 for 1 h. The reaction was cooled and concentrated. The residue was partitioned between CHCl3 and H2O and the organic layer was dried (Na2SO4), filtered, and concentrated to yield the title compound in a yield of 27% (1.5 g); 1HNMR (CDCl3) δ 9.04 (s, 1H), 4.42 (q, 2H), 2.85 (s, 3H), 1.43 (t, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[I:12][C:9]1[CH:8]=[C:4]([C:5](=[O:7])[NH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=[C:2]([I:1])[C:10]=1[OH:11]
Reactant: NCCCCCCCCc1ccccc1
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(I)c(O)c(I)c1

Procedure:
The title compound was prepared as a solid (0.718 g, 66%) from 3,5-diiodo-4-hydroxybenzoic acid using 8-phenyloctylamine and a procedure similar to step 2 of Example 93; 1H NMR (DMSO-d6) δ1.17-1.36 (m, 8H), 1.41-1.61 (m, 4H), 2.48-2.60 (m, 2H), 3.20 (dd, J=5.9, 8.8 Hz, 2H), 7.10-7.21 (m, 3H), 7.21-7.30 (m, 2H), 8.21 (s, 2H), 8.40 (t, J=4.4 Hz, 1H), 10.06 (s, 1H); mass spectrum [(+) ESI], m/z 578 (M +H)+.