Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=1)[O:9][C:8]([CH3:20])([CH3:19])[CH2:7][C:6]2([CH3:22])[CH3:21])#[CH:2].[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][C:28]=1[F:34].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=2)[O:9][C:8]([CH3:20])([CH3:19])[CH2:7][C:6]3([CH3:22])[CH3:21])=[CH:29][C:28]=1[F:34]
Reactant: COC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1cc(C#C[Si](C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(C#C[Si](C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure J and using 6-ethynyl-8-trimethylsilanylethylnyl-2,2,4,4-tetramethyl chroman (Compound 37, 0.1 g, 0.32 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (see U.S. Pat. No. 6,252,090, 0.095 g, 0.32 mmol), triethyl amine, copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.071 g, 0.1 mmol), followed by flash column chromatography over silica gel (230-400 mesh) using 4-10% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.11 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][S:26]([C:24]2[S:25][C:21]([Cl:20])=[CH:22][CH:23]=2)(=[O:28])=[O:27])[C:3]([C:9](=[O:10])[C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])=[N:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COc1cccc(F)c1C(=O)c1ncc(Cl)cc1N
Product: COc1cccc(F)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)s1

Procedure:
(3-Amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanone (50 mg, 0.178 mmol) and 5-chloro-thiophene-2-sulfonyl chloride (85 mg, 0.392 mmol) were reacted according to the procedure described in example 94. The crude product was purified by flash chromatography on silica gel using Combi-flash and pure product fractions were dried under reduced pressure to provide 5-chloro-thiophene-2-sulfonic acid [5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-amide. MS m/z: 460.9 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH-].[Na+].Cl[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>CN(C)P(N(C)C)(N(C)C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: Fc1ccccc1S
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1ccccc1Sc1ccccc1F
Yield: 76.8 %

Procedure:
A solution of 43.8 g 2-fluorothiophenol (I. Cervena et al., Collect. Czech. Chem. Commun. 44, 2139, 1979) in 85 ml of hexamethylphosphoramide is treated in a nitrogen atmosphere first with a solution of 13.6 g sodium hydroxide in 26 ml of water and then with 45.0 g of 2-chlorobenzaldehyde. Then the mixture is heated for 3.5 hours to 100° C. It is next poured into 500 ml of water and the product extracted with benzene. The extract is dried with magnesium sulfate and evaporated. The residue crystallizes after mixing with 120 ml of petroleum ether. There are obtained 57.1 g (77%) 2-(2-fluorophenylthio)benzaldehyde, crystallizing from benzene and melting in pure state at 56°-57° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1F
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred solution of 2-fluoroanisole (33.7 mL, 301 mmol) in chloroform (250 mL) was cooled to 0° C. and treated drop-wise with chlorosulfonic acid (50.0 mL, 752 mmol). After stirring at room temperature for 14 hours, the reaction mixture was poured into ice-water (700 mL) and the separated, aqueous phase extracted with chloroform (2×200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 3-fluoro-4-methoxybenzenesulfonyl chloride as a fine, white solid (58.6 g, 87%), m.p. 80° C.;
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CCCCCCC(C)OC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)OC(=O)c1ccc(O)cc1

Procedure:
The compound obtained in (1) above was dissolved in 15 ml of ethanol, and 0.36 g of 10 % palladium-on-carbon was added to the solution to conduct hydrogenation in a hydrogen atmosphere to obtain 1.29 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]([OH:12])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[NH:46][CH2:45][CH2:44][CH2:43]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]([N:46]2[C:47]3[C:42](=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:37])[CH2:43][CH2:44][CH2:45]2)=[O:12])=[N:6][CH:7]=1
Reactant: Cc1cccc2c1NCCC2
Reactant: O=C(O)CSc1ccc(Cl)cn1
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
Solvent: ClCCl
Product: Cc1cccc2c1N(C(=O)CSc1ccc(Cl)cn1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of (5-chloro-pyridin-2-ylsulfanyl)-acetic acid (15, 0.27 g, 1.3 mmol) in dry CH2Cl2 (10 mL) and DMF (2 mL) at 0° C. was added HATU (0.5 g, 1.3 mmol) and reaction mixture was stirred for 30 min at ambient temperature. Then the reaction mixture was cooled to 0° C. and neat 8-methyl-1,2,3,4-tetrahydroquinolin (0.20 g, 1.3 mmol) was added via syringe followed by addition of DIPEA, (0.69 mL, 3.9 mmol). The reaction mixture was allowed to warm to room temperature over 18 h. The reaction mixture was diluted with 50 mL of CH2Cl2, washed with H2O, 10% citric acid, NaHCO3 (saturated), brine, dried over Na2SO4 and concentrated. The crude was purified by column chromatography (hexanes/EtOAc) to give 90 mg of the target 16 as a white solid in 20% yield. MS (APCI) m/z: 333.1 (100%, [M+H]+, 186.0 (20%, [M−147+H]+; HPLC purity: 100%; Anal. Calcd. for C17H17ClN2OS: C, 61.34; H, 5.15; N, 8.42; Cl, 10.65; S, 9.63. Found: C, 61.33; H, 5.06; N, 8.36; Cl. 10.67; S, 9.56.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.Cl>>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:37])([F:38])[C:26](=[O:36])[NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21])[C:15]([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCC(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(N)c1=O)C(=O)C(F)(F)C(=O)NCC(=O)OC(C)(C)C

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-N-[3,3-difluoro-1-isopropyl-2-oxo-3-[N-(tert-butoxycarbonylmethyl)carbamoyl]propyl]acetamide. The procedure was similar to Example 1 except that a 10% hydrochloric acid wash was done. Chromatography solvent: chloroform:methanol (40:1); TLC: Rf =0.5, chloroform:methanol (40:1); MS: m/z=688(M+1). This product is also a Compound of the invention.
Reaction SMILES: [I:1]I.[C:3]1([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)C>[I:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: II
Reactant: c1ccc(N2CCCC2)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Ic1ccc(N2CCCC2)cc1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
Iodine (6.09 g) was added slowly to a stirred solution of phenylpyrrolidine (3.21 g) and sodium bicarbonate (2.75 g) in water (30 ml). The reaction was stirred for 1 h and then left to stand overnight. The solid was isolated by filtration, dissolved in ethanol (506 ml) and discoloured with aqueous sodium thiosulfate. The product was then isolated by filtration and recrystalised from ethanol to give the desired product as a brown/red powder (1.17 g).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:18]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClC1C=CC=CC=1Cl>[CH2:18]([S:26]([NH:29][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:27])=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Reactant: CCCCCCCCS(N)(=O)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
A 100ml round bottom flask, equipped with a magnetic stirrer and cooling condenser, was charged with 1-chloroanthraquinone (2.0g), n-octylsulfonamide (3.0g), copper acetate (0.8g), potassium carbonate (0.8g) and o-dichlorobenzene (25ml). This mixture was slowly heated to reflux. After 2.5 hours the reaction mixture was cooled and filtered. Methanol was then added to induce precipitation, and after filtration the solid was recrystallized from a mixture of dichloromethane and methanol to give a yellow product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH:7]([CH3:11])[C:8](Cl)=[O:9].Cl.[CH2:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[Cl:5][CH2:6][CH:7]([CH3:11])[C:8]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:15][CH:16]=1)=[O:9]
Reactant: CC(CCl)C(=O)Cl
Reactant: c1ccc(Cc2cccnc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(CCl)C(=O)c1ccc(Cc2cccnc2)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
In 25 ml of methylene chloride was suspended 13.3 g of anhydrous aluminum chloride, and 7.3 g of 3-chloro-2-methylpropionyl chloride was added to the suspension with ice-cooling, after which 8.2 g of 3-benzylpyridine hydrochloride was added in small portions to the suspension. The resulting mixture was subjected to reaction with ice-cooling for 2 hours and then at room temperature for one hour. The reaction mixture was added in small portions to a mixture of 246 ml of iced water and 49 ml of methylene chloride, and the organic layer was separated, while the aqueous layer was extracted with 40 ml of methylene chloride. The organic layers were combined and then 80 ml of water was added thereto after which the resulting mixture was neutralized with sodium hydrogencarbonate. The organic layer was separated, washed with 50 ml of water, and thereafter dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform:ethyl acetate (1:1 by volume)] to obtain 10.53 g (yield 96.0%) of colorless, oily 3-[p-(3-chloro-2-methylpropionyl)benzyl]pyridine.
Reaction SMILES: [BH4-].[Na+].II.[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:7]=1[C:8](O)=[O:9].CC(=O)OCC>C1COCC1>[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:7]=1[CH2:8][OH:9]
Reactant: O=C(O)c1cc(I)ccc1Cl
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc(I)ccc1Cl
Temperature: 0 °C

Procedure:
A 250 mL of 4-necked flask equipped with thermometer and mechanical stirring was charged with NaBH4 (4.16 g, 0.11 mol) and THF (60 mL) under argon. After cooling to 0˜5° C. with stirring, a solution of iodine in THF (12.7 g I2 in 25 mL THF) was added slowly dropwise over 30 min and the reaction temperature was maintained below 10° C. After the addition was completed, a solution of 2-chloro-5-iodobenzoic acid (15.0 g, 50 mmol) in THF (20 mL) was added dropwise over 30 min and kept the reaction temperature below 10° C. After stirring for another 3 h at 20˜25° C., the reaction mixture was heated to reflux for additional 16 h and monitored by TLC (PE/EA=1:1, Rf=0.2). The mixture was cooled to 20˜25° C. and poured into ice water (100 mL), extracted with ethyl acetate (2×100 mL), washed with water (2×100 mL), brine (100 mL), concentrated and the residue was purified by flash chromatography (PE:EA=20:1 as eluant, 200 mL) to give an off-white solid. Yield: 10.0 g (70%) MS ESI (m/z): 269 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]O)=[CH:17][CH:16]=2)=[C:10]([F:25])[CH:9]=1)=[O:6].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:31][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:2]([Cl:1])[CH:3]=3)=[CH:9][C:10]=2[F:25])=[CH:16][CH:17]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(Nc1ccc(Oc2ccc(CCCO)cc2)c(F)c1)c1ccc(Cl)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccc(CCCBr)cc2)c(F)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 3,4-dichloro-3′-fluoro-4′-[4-(3-hydroxypropyl)phenoxy]benzanilide (2.32 g, 5.34 mmol) in dichloromethane (46 mL) were added carbon tetrabromide (2.13 g, 6.41 mmol) and triphenylphosphine (1.54 g, 5.88 mmol), and the resulting solution was stirred for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 2.41 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:22]/[OH:23])/[C:8]([O:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[O:9])[N:6]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:22]/[O:23][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:8]([O:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1nc(/C(=N/O)C(=O)OCCS(=O)(=O)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)OCCS(=O)(=O)c1ccccc1)c1csc(N)n1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
In 100 ml of acetone was suspended 5 g (0.0141 mole) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 11. After a serial addition of 4.0 g (0.0205 mole) of t-butyl bromoacetate, 0.3 ml of water and 7.7 g of anhydrous potassium carbonate, the mixture was stirred at 40° C. for 1.5 hours. After completion of the reaction, the insoluble matter was filtered off and 100 ml of water and 100 ml of ethyl acetate were added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined, washed twice with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and ethyl acetate-isopropyl ether (1:5, v/v) was added to the residue, whereupon white crystals separated out. After cooling, the crystals were collected by filtration to give 4.1 g (yield, 62%) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][N:4]=1.[F:21][C:22]([C:25]1[NH:29][N:28]=[N:27][N:26]=1)([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][N:4]=[C:3]([CH2:2][N:27]2[N:28]=[N:29][C:25]([C:22]([F:24])([F:23])[F:21])=[N:26]2)[N:8]=1
Reactant: CCOC(=O)c1cnc(CBr)nc1-c1ccccc1Cl
Reactant: FC(F)(F)c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 6 h

Procedure:
An amount of 345 mg (0.97 mmol) of ethyl 2-(bromomethyl)-4-(2-chlorophenyl)pyrimidine-5-carboxylate was added to a solution of 200 mg (1.45 mmol) of trifluoromethyltetrazole in 10 ml of acetonitrile. Then 174 mg (1.26 mmol) of potassium carbonate were added to the reaction solution, which was stirred at 60° C. for 6 hours. After cooling to room temperature, the reaction solution was filtered and the mother liquor was freed from the solvent under reduced pressure. The residue was admixed with 10 ml of water and extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by chromatography.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[C:15]([O:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:31][C:32]([O-:34])=[O:33].[K+].Cl.[OH-].[Na+:38]>C(O)(C)(C)C.O.CC(C)=O>[C:7]1([C:13]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:16]=[C:15]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:31][C:32]([O-:34])=[O:33])[CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[Na+:38]
Reactant: OCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Reactant: O=C([O-])CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])COCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To potassium tert-butylate (5.52 g) in tert-butanol (60 cc) heated to 100° C. is added, in the form of a homogeneous solid, a mixture of 3-[(4,6-di-phenyl-2-pyridyl)oxy]-1-propanol (5 g) and potassium 2-bromoacetate (4.35 g). The addition is carded out in 1 hour. The reaction mixture is then heated for 48 hours at 100° C. and then poured in iced water (100 g). The pH of the aqueous phase is brought to 5 by addition of 1N hydrochloric acid. The mixture is then extracted with dichloromethane (3×50 cc) after saturating the aqueous phase with sodium chloride. The combined organic phases are dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The oily residue obtained is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-diethyl ether 65-35 and then 40-60 and then diethyl ether-methanol; 9-1). The white solid obtained, taken up in acetone (5 cc), is treated with sodium hydroxide pellets (0.19 g) and distilled water (1. cc). The mixture is stirred for 60 hours at room temperature. The precipitate obtained is filtered, washed with ethyl ether and dried at 40° C. under reduced pressure. (white solid; m.p.=285°-288° C.)
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@H:6]1[C@@H:9]([N:10]=[N+:11]=[N-:12])[C:8](=[O:13])[NH:7]1)(=O)=O.[Na+].[I-:22]>CC(C)=O>[N:10]([C@H:9]1[C:8](=[O:13])[NH:7][C@H:6]1[CH2:5][I:22])=[N+:11]=[N-:12]
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2N=[N+]=[N-])cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@H]1CI

Procedure:
A degassed solution of cis-3-azido-4-oxo-2-azetidinylmethyl tosylate (2.36 g) in acetone (80 ml) was refluxed with NaI (5.85 g) overnight. Reaction was cooled and the acetone was removed in vacuo. The reaction mixture was partitioned between ethyl acetate and aqueous sodium thiosulfate solution. Phases were separated and the organic layer was extracted with thiosulfate solution. The combined aqueous extracts were extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried and evaporated to give an off-white solid. The product was recrystallized from ethyl acetate-hexane, melting point 130°-2° (dec.), 1.5 g (75%).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)(=O)=O.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1O)[CH:29]=[O:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)[CH:29]=[O:30]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4Cl)C3)o2)cc1
Yield: 15 %

Procedure:
Using a similar protocol as described in Example 71A employing 73B and 3-chloro-4-hydroxybenzaldehyde as starting materials afforded 80 mg (15%) of 79A as a solid. 1H NMR (500 MHz, CDCl3): δ 3.89 (s, 3H), 4.43 (m, 1H), 4.74 (m, 1H), 4.85 (m, 1H), 5.21 (m, 2H), 6.75 (s, 1H), 7.02 (d, 2H), 7.79 (d, 1H), 7.97 (s, 1H), 8.11 (d, 2H), 9.89 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[C:21]1([C:31](Cl)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:31]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:32])[CH2:2][CH2:3]2)[N:14]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4cccc5ccccc45)CC3)cccc2n1
Yield: 96 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using 1-naphthoyl chloride (70.5 mg; 0.37 mmol) via Method AA to yield 152 mg. (96% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.99 (m, 2H), 7.82 (m, 1H), 7.56 (m, 2H), 7.41 (m, 1H), 7.34 (m, 2H), 7.12 (br s, 2H), 6.76 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.74 (t, J=12.0 Hz, 1H), 4.04 (d, J=6.0 Hz, 2H), 3.25 (br d, J=12.4 Hz, 1H), 3.00 (m, 2H), 2.22 (s, 1H), 1.97 (m, 1H), 1.63 (m, 1H), 1.44 (m, 1H), 1.3 (m, 1H). MS m/z (ESI) 428 (M+H)+.