Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC=CC=1/C=[N:5]\[C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10]([CH:27]=[CH2:28])=[C:11]2[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16].O.CS(O[C:39](=[O:57])/[C:40](/[C:51]1[N:52]=[C:53]([NH2:56])[S:54][CH:55]=1)=[N:41]\[O:42][CH2:43][C:44]([O:46]C(C)(C)C)=[O:45])(=O)=O.ClCCl>C(OC)(C)(C)C>[NH2:56][C:53]1[S:54][CH:55]=[C:51](/[C:40](=[N:41]/[O:42][CH2:43][C:44]([OH:46])=[O:45])/[C:39]([NH:5][C@@H:6]2[C:13](=[O:14])[N:12]3[C@@H:7]2[S:8][CH2:9][C:10]([CH:27]=[CH2:28])=[C:11]3[C:15]([OH:17])=[O:16])=[O:57])[N:52]=1
Reactant: C=CC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](/N=C\c3ccccc3O)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)OS(C)(=O)=O)c1csc(N)n1
Solvent: ClCCl
Solvent: O
Solvent: COC(C)(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor is charged with (6R,7R)-4-methoxybenzyl 7-((Z)-(2-hydroxybenzylidene)amino)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1 eq), water (6-9 weight % relative to the Schiff base), (Z)-2-(2-aminothiazol-4-yl)-2-((2-(tert-butoxy)-2-oxoethoxy)imino)acetic methanesulfonic anhydride (2.5 eq) and dichloromethane (1.75 mL per gram of Schiff base). The mixture is stirred for three hours at room temperature, then added to methyl tertiary butyl ether over the course of 2-3 hours, resulting in the formation of a solid. The solid is filtered and the filter cake was washed with additional methyl tertiary butyl ether. The filtered solid is deprotected using conventional methods and dried under vacuum to yield the title compound.
Reaction SMILES: C1O[C:4]2([CH2:21][CH2:20][C@@:19]3([CH3:22])[C:6](=[CH:7][CH2:8][C@@H:9]4[C:18]3=[CH:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][C@@H:12]([CH3:35])[C@@H:13]3[C:23](=[O:34])[CH2:24][CH2:25][CH2:26][O:27]C3CCOCC3)[CH2:5]2)[O:3]C1.Cl.C(=O)(O)[O-].[K+]>CC(C)=O>[CH3:35][C@@H:12]1[CH2:11][C@H:10]2[C@H:9]3[C:18](=[CH:17][CH2:16][C@:14]2([CH3:15])[C@H:13]1[C:23](=[O:34])[CH2:24][CH2:25][CH2:26][OH:27])[C@:19]1([CH3:22])[C:6](=[CH:5][C:4](=[O:3])[CH2:21][CH2:20]1)[CH2:7][CH2:8]3
Reactant: C[C@@H]1C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CCCOC1CCOCC1)OCCO5
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CCCO

Procedure:
16α-Methyl-17β-(1-oxo-[4-tetrahydropyranyloxy]butyl)-androsta-5,9(11)-dien-3-one 3-ethylene ketal, step (D), is dissolved in acetone (90 ml) and hydrochloric acid (1N, 10 ml) and allowed to stand at 20°-25° for several hours. Following addition of potassium bicarbonate (1N, 25 ml), the mixture is concentrated and extracted with ethyl acetate. The concentrate is chromatographed on silica gel eluting with acetone/methylene chloride. The appropriate fractions are pooled and concentrated to give 16α-methyl-17β(1-oxo-[4-hydroxy]butyl)androsta-4,9(11)-dien-3-one.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])=O.[NH3:14].CO>>[NH:14]=[C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])[CH3:1]
Reactant: N
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1O
Solvent: CO
Product: CC(=N)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 2-hydroxy-5-nitroacetophenone (2.96 g, 16.34 mmol) and ammonia in MeOH (11.67 mL, 82 mmol) was stirred for 1 hr at rt. The reaction mixture was concentrated to afford the crude title product (2.94 g, 16.32 mmol, 100% yield) as a yellow solid. tR: 0.53 min (LC-MS 2); ESI-MS: 181 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([CH2:30][OH:31])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]I.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH:19]([CH2:30][O:31][CH3:32])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:25])[CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCCC(CO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
1.37 g (3.04 mmol) of the above prepared (rac)-4-[3-(tert-butyl-dimethyl-silanyloxy)-1-hydroxymethyl-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and 0.95 ml (15.20 mmol) of methyl iodide were dissolved in 4.8 ml of N,N-dimethylformamide. After cooling (0° C.), 0.16 g (3.65 mmol) of NaH (55% in oil) was added. The reaction was stirred for 3 h at this temperature, then poured onto crushed ice/10% aq. potassium hydrogensulfate solution and extracted with diethyl ether (3×). The organic layers were washed with 10% aq. potassium hydrogensulfate solution and 10% aq. sodium chloride solution, dried over Na2SO4 and evaporated to dryness to yield 1.36 g (96%) of the title compound as light yellow oil. MS: 465.3 (MH+).
Reaction SMILES: [CH2:1]([N:5]([CH:8]=[CH2:9])[CH:6]=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:11][CH2:12]CCCC.[Na+].[Cl-]>>[CH2:1]([N:5]([CH:8]=[CH2:9])[CH:6]=[O:7])[CH2:2][CH2:3][CH2:4][CH2:11][CH3:12]
Reactant: CCCCCCBr
Reactant: C=CN(C=O)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: C=CN(C=O)CCCCCC
Yield: 63 %

Procedure:
The synthetic procedure was identical to that described for the preparation of 1a, where 1-bromohexane is used in place of 1-bromobutane. Yield: 63%; IR (NaCl, v: cm−1): 1698 (—NHC(═O)H); 1630 (C═C); 1H-NMR (CDCl3, δ: ppm): 8.31, 8.14 (2s, 1H, —C(═O)H); 7.25–7.16, 6.61–6.52 (m, 1H, H2C═CH—); 4.65–4.54 (m, 1H, HaHbC═CH—); 4.45–4.42 (s, 1H, HaHbC═CH—); 3.60–3.44 (t, 2H, —NCH2CH2—); 1.65–1.56 (m, 2H, —CH2CH2CH2—); 1.31 (m, 6H, —CH2(CH2)3CH3); 0.90–0.88 (t, 3H, —NCH2CH2(CH2)3CH3).
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:7]([O:9]C)=[O:8])(=[O:3])[NH2:2]>Cl>[C:1]([CH2:4][C@@H:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[NH2:2]
Reactant: COC(=O)C[C@@H](CC(N)=O)CC(C)C
Agent: Cl
Product: CC(C)C[C@H](CC(N)=O)CC(=O)O
Reaction time: 5.5 h

Procedure:
A flask is equipped with a magnetic stirrer and is charged with 3N HCl (100 ml) and (R)-methyl 3-(carbamoylmethyl)-5-methylhexanoate (20 g). The mixture is stirred for 1-10 hours at a temperature of 20° C. to 25° C., followed by quenching with 47% NaOH to pH 3. The resulting slurry is filtered, washed with water, and dried to obtain a white solid of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[C:15]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)(=[O:17])[CH3:16].C(=O)([O-])O.[Na+]>C(OCC)C>[S:9]1[C:10]([C:15]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)([OH:17])[CH3:16])=[CH:11][N:12]=[CH:8]1
Reactant: C[Si](C)(C)c1nccs1
Reactant: CC(=O)c1ccsc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(O)(c1ccsc1)c1cncs1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 5.6 ml) in diethylether (25 ml) was stirred at -70° C. under a nitrogen atmosphere and 2-trimethylsilylthiazole (2 g) in diethylether (25 ml) was added dropwise. After 30 minutes 3-acetylthiophene (1.93 g) in diethylether (25 ml) was added dropwise. After a further 45 minutes the mixture was allowed to warm to room temperature and then left to stir for a further 1 hour. Saturated aqueous sodium hydrogen carbonate was added and the organic layer was separated. The aqueous layer was extracted with diethylether. The organic layers were combined, washed, dried and evaporated and the residue was purified by flash chromatography to give the title compound as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:42])([F:41])[CH2:16][N:17]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1>>[F:40][C:37]([F:38])([F:39])[CH2:36][N:17]([CH2:16][C:15]([F:14])([F:41])[F:42])[C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:29]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:30])=[CH:32][CH:33]=3)=[N:24][C:20]=2[CH:19]=1
Reactant: O=C([O-])c1ccc(-c2nc3cc(N(CC(F)(F)F)CC(F)(F)F)ccc3[nH]2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(N(CC(F)(F)F)CC(F)(F)F)ccc3[nH]2)cc1

Procedure:
Compound 456 was prepared from 4-morpholinoaniline and 4-(5-bis(2,2,2-trifluoroethyl)amino-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C28H25F6N5O2: 578.19; found: 578.04.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18](=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27](=O)[CH2:28][C:29](=[O:31])[CH3:30]>C(O)(=O)C.S(=O)(=O)(O)O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[S:16][C:15]3[N:17]=[C:27]([CH3:26])[C:28]([C:29](=[O:31])[CH3:30])=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]=3[C:11]=2[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C(=O)c2ccccc2)C1
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCN(C(=O)OC(C)(C)C)C3
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 11.9 %

Procedure:
To a stirred solution of 0.50 g (1.39 mmol) 2-amino-3-benzoyl-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester in 6 ml acetic acid was added 0.19 ml (1.89 mmol) of pentane-2,4-dione and two drops of sulfuric acid. The mixture was then stirred at 100° C. for 25 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 4:1) afforded 70 mg (12%) 3-acetyl-2-methyl-4-phenyl-5,8-dihydro-6H-9-thia-1,7-diaza-fluorene-7-carboxylic acid tert-butyl ester as a yellow oil. ES-MS m/e (%): 423 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1([CH3:22])[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:31])[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: CC1(C)CN(Cc2ccccn2)c2cc([N+](=O)[O-])ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CN(Cc2cccc[n+]2[O-])c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 4 ml of methylene chloride was dissolved 0.33 g of 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridylmethyl)-2H-1,4-benzoxazine followed by addition of 0.26 g of m-chloroperbenzoic acid, and the mixture was stirred at room temperature overnight. This reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude crystals of 2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)methylpyridine N-oxide. Recrystallization from ethanol-chloroform gave 0.2 g of the object compound. This compound was found to have the following physicochemical properties.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH2:7][O:6]1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>CN(C)C=O>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]([C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1)([OH:6])[CH2:7][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: N#CC1(C2(Cc3ccccc3F)CO2)CC1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Product: N#CC1(C(O)(Cc2ccccc2F)Cn2cncn2)CC1
Reaction time: 4 h
Yield: 46 %

Procedure:
2.26 g (10.4mmol) of 2-(2-fluorobenzyl)-2-(1-cyanocyclo-propyl)-oxirane in 10 ml of dimethylformamide are added dropwise at 80° C. with stirring to a solution of 0.23 g (2.1 mmol) of potassium tert.-butylate and 2.15 g (31.2 mmol) of 1,2,4-triazole in 10 ml of dimethylformamide. When the addition has ended, stirring of the reaction mixture is continued for 4 hours at 80° C. The mixture is subsequently concentrated under reduced pressure, and the residue is taken up in ethyl acetate/water. The aqueous phase is extracted three times using ethyl acetate. The combined organic extracts are dried over sodium sulphate, concentrated under reduced pressure and chromatographed on silica gel using the eluent cyclohexane/ethyl acetate =1:1. 1.37 g (46% of theory) of 1-(2-fluorophenyl)-2-(1-cyanocyclopropyl)-3-(1,2,4-triazol-1-yl)-propan -2-ol are isolated.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[CH3:15][NH2:16]>C(Cl)Cl.CN(C=O)C.N1C=CC=C1C(Cl)=O.C(OCC)(=O)C>[CH3:15][NH:16][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CN
Reactant: O=C(O)c1ccc[nH]1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1H-pyrrole-2-carboxylic acid (1 g, 9 mmol) (Aldrich, Milwaukee, Wis.) in DCM (15 mL) was added oxalyl chloride (1.1 mL) and DMF (3 drops). The mixture was stirred at room temperature resulting in 1H-pyrrole-2-carbonyl chloride. Methylamine (30 mmol) was then added to the acid chloride and the mixture was stirred at room temperature. The reaction was diluted with ethyl acetate, washed with brine (2×), NaHCO3, dried and concentrated to give 1H-pyrrole-2-carboxylic acid methylamide.
Reaction SMILES: C1(=O)C2C(=CC=CC=2)CC1.CO[C:13]1[CH:21]=[CH:20][C:19]2[NH:18][C:17]3[C:22]4[C:27]([CH2:28][C:16]=3[C:15]=2[CH:14]=1)=[CH:26][CH:25]=[CH:24][CH:23]=4.C(Cl)(Cl)[Cl:30]>>[Cl:30][C:20]1[C:19]2[NH:18][C:17]3[C:22]4[C:27]([CH2:28][C:16]=3[C:15]=2[CH:14]=[CH:13][CH:21]=1)=[CH:26][CH:25]=[CH:24][CH:23]=4
Reactant: ClC(Cl)Cl
Reactant: COc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Agent: O=C1CCc2ccccc21
Product: Clc1cccc2c3c([nH]c12)-c1ccccc1C3
Reaction time: 1 h

Procedure:
The o-chlorophenylhydrazone of 1-indanone (650 mg, 2.5 mmol) was boiled in a chloroform solution of polyphosphonate ester (see the preparation of 5,10-dihydro-8-methoxyindeno[1,2-b]indole) for 30 minutes. The solvent was removed, and the residue stirred in water (75 cm3) for 1 hour. Extraction into diethylether gave a green solution which was washed with water, dried (MgSO4), and evaporated. Purification by column chromatography (Rf [5% EtOAc/petrol (60°-80° C.)]0.5), gave the title compound as a colourless solid. Yield 500 mg, (82%). M.p. 139° C. 1H NMR (CDCl3) δ: 3.72 (2H,s,), 7.0-7.6 (7H, m,), 8.5 (1H, br,).
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: COc1ccc(OCCCCCCCCI)c(Cl)c1
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 25 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)8, R is C2H5, R' is CH3CO] was prepared from 0.38 g of lithium hydride, 9.5 g of diethyl acetonylphosphonate and 19.4 g of 8-(2-chloro-4-methoxyphenoxy)octyl iodide according to the procedure of Example 12(b). The product was chromatographed on Florisil to give 5.67 g of diethyl [1-acetyl-9-(2-chloro-4-methoxyphenoxy)nonyl]phosphonate as a light yellow oil; MIC vs. herpes simplex type 2=12 mcg/ml. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:15][S:16](O)(=[O:18])=[O:17])=[CH:5][C:4]1([CH3:21])[CH3:20])C.CN1C2C(=CC=C(OC)C=2)C(CS(O)(=O)=O)CC1(C)C.P(Cl)(Cl)(Cl)(Cl)[Cl:43]>>[CH3:1][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]([CH2:15][S:16]([Cl:43])(=[O:18])=[O:17])[CH2:5][C:4]1([CH3:21])[CH3:20]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCN1c2cc(OC)ccc2C(CS(=O)(=O)O)=CC1(C)C
Agent: COc1ccc2c(c1)N(C)C(C)(C)CC2CS(=O)(=O)O
Product: COc1ccc2c(c1)N(C)C(C)(C)CC2CS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
(1-Methyl-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydroquinol-4-yl)-methane-sulfonic acid chloride (19) is prepared similarly to compound (16) using compound (3) and phosphorus pentachloride except that it is stirred for 18 hours at room temperature.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19].[NH2:22]/[C:23](/[CH3:31])=[CH:24]\[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26].C(O)(=O)C>CC(O)C>[C:18]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])=[C:23]([CH3:31])[NH:22][C:16]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: C/C(N)=C/C(=O)OC(C)C
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(C)=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 93.1 mg (0.93 mmol) of 2,4-pentanedione, 76.1 mg (0.53 mmol) of isopropyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 62 mg (29% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[C:15]([Cl:16])=[C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([O:27][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:26])[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[C:15]([Cl:16])[C:10]=1[Cl:9])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccc(C(=O)c2ccc(O)c(Cl)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(C(=O)c2ccc(OC)cc2)c(Cl)c1Cl

Procedure:
A solution of 9.96 (0.055 mole) of ethyl 2-bromopropionate in 12 ml. of acetone was added over a period of 2 hours to a stirred, refluxing mixture of 14.85 g. (0.05 mole) of 2,3-dichloro-4-(4'-methoxybenzoyl)phenol and 7.60 g. (0.055 mole) of powdered anhydrous potassium carbonate in 200 ml. of acetone. After the addition, the mixture was refluxed for 20 hours and the hot mixture was filtered. The filtrate was evaporated in vacuo and the residue was taken up in 250 ml. of chloroform. The chloroform solution was washed with 10% aqueous potassium carbonate, water, dried over anhydrous sodium carbonate and evaporated in vacuo to give the product.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([N:20]3[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[N:21]3)[CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[F:26][C:25]([F:28])([F:27])[C:24]1[N:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][CH2:6][C:5]3[CH:34]=[CH:35][C:2]([C:41]4[CH:42]=[CH:43][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=4)=[CH:3][CH:4]=3)[N:19]=2)[N:21]=[CH:22][C:23]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a flask containing the title compound from Example 2 Step A (40.0 mg, 0.073 mmol) were added 4-trifluoromethylphenyl boronic acid (21.0 mg, 0.110 mmol) and dichlorobis(triphenylphosphine)palladium(II) (2.6 mg, 0.004 mmol). Degassed acetonitrile (0.5 mL) and sodium carbonate (0.183 mL, 1.0 M aqueous, 0.183 mmol) were added, and the reaction mixture was stirred at 70° C. After 1.5 h, the reaction mixture was allowed to cool to ambient temperature, then was filtered through a short plug of silica gel, eluting with DCM. The Suzuki product was used in the subsequent step without further purification: LCMS m/z 612.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1.[CH3:28][C@H:29](O)[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:28][C@H:29]([O:26][C:25]([C:22]1([C:20]2[N:21]=[C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[C:14](=[O:18])[O:13][CH2:12]5)[N:5]3[N:19]=2)[CH2:23][CH2:24]1)=[O:27])[CH2:30][CH3:31]
Reactant: CC[C@H](C)O
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)OC(=O)C1(c2nc3c(OC)ccc(-c4ccc5c(c4)COC5=O)n3n2)CC1
Temperature: 50 °C

Procedure:
A mixture of 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (10 mg, 27 μmol), (1S)-1-methylpropanol (10 μL, 108 μmol), DMAP (6.7 mg, 54 μmol) and EDCI.HCl (10.5 mg, 54 μmol) in DCM (0.5 mL) was stirred in a sealed vial at RT overnight before more (1S)-1-methylpropanol (10 μL, 108 μmol) and DMAP (6.7 mg, 54 μmol) was added and the mixture was heated to 50° C. for 3 hours. Evaporated to dryness and acidic prepHPLC purification afforded the title compound. HPLC-Retention time (XE Metode 7 CM): 2.35 minutes. Detected “M+1”-mass: 422.16. Calculated “M+1”-mass: 422.17. 1H NMR (DMSO, 600 MHz): δ=8.25-8.21 (m, 1H), 8.14 (dd, 1H, J=8.0, 1.2 Hz), 8.01-7.97 (m, 1H), 7.41 (d, 1H, J=8.2 Hz), 7.23 (d, 1H, J=8.2 Hz), 5.51 (s, 2H), 4.78 (h, 1H, J=6.3 Hz), 4.04 (s, 3H), 1.61-1.40 (m, 6H), 1.13 (d, 3H, J=6.2 Hz), 0.78 (t, 3H, J=7.4 Hz) ppm.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[CH3:30][NH2:31]>O1CCCC1>[CH3:30][NH:31][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Into a 250-mL sealed bottle was placed a solution of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (14 g, 32.41 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) followed by CH3NH2 (66.9 g, 712.16 mmol, 21.98 equiv, 33% in ethanol) and the resulting solution was stirred overnight at 50° C. The resulting mixture was concentrated under vacuum, dissolved in 150 mL of dichloromethane and then washed with 2×150 mL of water and 1×150 mL of brine. The organic layer was dried over sodium sulfate and concentrated under vacuum to afford 8.2 g (87%) of tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)propanoate as yellow oil.