Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:14](Cl)=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[S:13]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:14]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:15]
Reactant: O=C(Cl)c1cccs1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 2-thenoyl chloride (1.466 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 8 hours. The reaction mixture was treated in the same manner as described in Example 35 to obtain 965 mg of the title compound (yield: 44%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])=[CH:3]1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: NS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1cc(CNS(N)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methylindole-3-carboxaldehyde (1.66 g, 10.4 mmol) was dissolved in anhydrous ethanol (50 mL). Sulfamide (4.5 g, 47 mmol) was added and the mixture was heated to reflux for 16 hours. Additional sulfamide (1.0 g, 10.4 mmol) was added and the mixture was heated to reflux for 24 hours. The mixture was cooled to room temperature. Sodium borohydride (0.722 g, 12.5 mmol) was added and the mixture was stirred at room temperature for one hour. The reaction was diluted with water (50 mL) and extracted with DCM (3×75 mL). The extracts were concentrated and about 1 mL of methanol was added to create a slurry which was filtered to yield the title compound as a white powder.
Reaction SMILES: [OH-].[Na+].[CH:3]([C:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([CH3:5])[CH3:4].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.Cl>O.CO>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:8]2[CH2:9][CH2:10][C:6]([CH:3]([CH3:5])[CH3:4])([C:12]([O:14][CH3:15])=[O:13])[C:7]2=[O:11])=[CH:19][CH:18]=1
Reactant: COC(=O)C1(C(C)C)CCCC1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1(C(C)C)CCC(=Cc2ccc(Cl)cc2)C1=O

Procedure:
To a solution of 4 g of sodium hydroxide in 1000 ml of water were added 21 g of methyl 1-isopropyl-2-oxocylopentanecarboxylate (prepared in Reference Example 2 hereinafter) and a solution of 16 g of 4-chlorobenzaldehyde in 1000 ml of methanol, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was neutralized with diluted hydrochloric acid and the precipitate was collected by filtration. Product 33.6 g (yield, 96.2%)
Reaction SMILES: [CH2:1]([C@:8]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]([O:19]C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29].COC(C)(C)C>CO>[CH2:1]([C@:8]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]([NH2:29])=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CS[C@H]2C[C@@](Cc3ccccc3)(NC(=O)OC(C)(C)C)C(=O)N21
Reactant: N
Solvent: CO
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C(N)=O)N2C1=O
Reaction time: 8 h

Procedure:
A mixture of 170 mg of methyl (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylate and 10 ml of a 7N NH3 solution in methanol is left to stand at room temperature overnight. The volatile constituents are stripped off in vacuo, and the residue is stirred with tert-butyl methyl ether, and the solid is filtered off with suction and dried in vacuo at 40° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[NH:10][C:11]=1[C:12]([O:14][CH3:15])=[O:13])([O:5][CH3:6])=[O:4].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1>CN(C=O)C>[C:12]([C:11]1[N:10]=[C:9]([CH2:16][CH2:17][CH3:18])[N:8]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:7]=1[C:3]([O:5][CH3:6])=[O:4])([O:14][CH3:15])=[O:13]
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
Sodium hydride (1.06 g, 44.2 mmol, 1 eq) was added to a solution of 4,5-dicarbomethoxy-2-n-propylimidazole (10.00 g, 44.2 mmol, 1 eq) in DMF at room temperature. Foaming and gas evolution occurred. The temperature was increased to 60° C. for 15 minutes to dissolve all of the sodium hydride. Gas evolution ceased and the mixture was cooled to room temperature. To this mixture was added a DMF solution of 4-bromomethyl-2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl (24.64 g, 44.2 mmol, 1 eq). After 24 h, the solvent was removed in vacuo, and the residue was flash chromatographed in 75:25 hexane/ethyl acetate to 100% ethyl acetate over silica gel to yield 15.78 g (51%) of a white glass which was suitable for further transformation. Recrystallization from ethanol yielded an analytical sample (white crystals); top: 124.0°-125.5° C. NMR (CDCl3) δ 7.91 (d of d,1H,J=3,9 Hz); 7.59-7.20 (m12H); 7.09 (d,2H,J=9Hz); 6.94 (m, 6H); 6.76 (d,2H,J=9Hz); 5.30 (s,2H); 3.89 (s,3H); 2.50 (t,2H,J=7Hz); 1.67 (t of t, 2H,J=7,7Hz); 0.85 (t,3H,J=7Hz). IR (neat) 1718 cm-1. Anal. calcd. for C43H38N6O4 : C, 73.49; H, 5.45; N, 11.96. Found: C, 73.23; H, 5.48; N, 12.22. ##STR78##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][C:6]2([CH3:14])[CH3:13].S(=O)(=O)(O)O.[N-:20]=[N+]=[N-].[Na+]>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:20][CH2:7][C:6]2([CH3:14])[CH3:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)C(C)(C)CC2=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(C)(C)CNC2=O
Temperature: 60 °C
Yield: 98 %

Procedure:
A solution of 5-methoxy-3,3-dimethyl-indane-1-one (Intermediate 16, 3.3 g, 17.4 mmol) in benzene (50 mL) was treated with concentrated sulfuric acid (10 mL) and heated to 60° C. Sodium azide (1.95 g, 30 mmol) was added in small portions and after the addition was complete, the reaction mixture was heated further for 4 h. It was then cooled, diluted with water and extracted with chloroform (×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown solid (3.5 g, quantitative by weight).
Reaction SMILES: [NH2:1][C:2]([CH2:5][OH:6])([CH3:4])[CH3:3].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9]>C(Cl)(Cl)Cl>[CH2:9]=[CH:8][C:7]([NH:1][C:2]([CH2:5][OH:6])([CH3:4])[CH3:3])=[O:10]
Reactant: CC(C)(N)CO
Reactant: C=CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: C=CC(=O)NC(C)(C)CO
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a stirred solution of H2NC(CH3)2CH2OH (16.8 g, 188 mmol) in CHCl3 (150 mL),under nitrogen at 0° C., acryloyl chloride (8.5 g, 94 mmol) (filtered over basic alumna) was added drop-wise via an addition funnel in such a way that the temperature did not exceed 5° C. (˜1.5 h). After complete addition, the reaction mixture was stirred for ˜2 h at 0-5° C., brought to room temperature, filtered and the filtrate concentrated by rotary evaporation. The residue was treated with 75 ml CHCl3 and ˜20 g basic alumina. This mixture was stirred for 0.5 h at room temperature (20-25° C.) and filtered. The alumina was washed with 2×10 mL CHCl3 and the combined filtrate was concentrated at reduced pressure to afford CH2═CHC(O)NHC(CH3)2CH2OH (13.5 g ) as a semisolid material. This material was used in the next step without further purification. 1H NMR (CDCl3) spectral data is consistent with the structure; δ 6.27 (br s, overlaps, 1H), 6.24 (dd, 1H), 6.14 (dd, 1H), 5.63 (dd, 1H), 4.88 (brs, 1H), 3.59 (s, 2H), 1.3 1 (s, 6H) ppm.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8])([O-:3])=[O:2].[Br:10]Br.O>CO>[Br:10][CH2:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: BrBr
Reactant: CC(=O)CCC[N+](=O)[O-]
Solvent: CO
Solvent: O
Product: O=C(CBr)CCC[N+](=O)[O-]
Reaction time: 2 h
Yield: 55 %

Procedure:
80.0 g (0.61 mole) of 1-nitro-pentane-4-one are dissolved in 250 ml of anhydrous methanol, whereupon 31.5 ml (0.61 mole) of bromine are quickly added under cooling with ice. The reaction mixture is stirred for a further 2 hours at a rate that the internal temperature should not exceed 40° C. To the reaction mixture 250 ml of water are added, the reaction mixture is stirred at room temperature overnight. Next morning the solution is extracted three times with 300 ml of ether each, the etheral solution is washed with a 10 % sodium carbonate solution free of acid, whereupon it is washed three times with 200 ml of water each and 200 ml of a saturated sodium chloride solution, dried over calcium chloride and evaporated. The dry residue is subjected to chromatogaphy on a silica column and eluted with a 3:1 mixture of n-hexane and ethyl acetate. Thus 70.4 g of the desired compound are obtained in the form of a faint yellow liquid, yield 55%. Rf =0.30. IR(film) :2950, 1720, 640 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1)=[O:4]
Reactant: Nc1ccccc1C1Cc2ccccc2N1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Temperature: 25 °C

Procedure:
Trimethylacetyl chloride (3.6 ml) was added dropwise to a solution of 5.8 g 2-(2-aminophenyl)-2,3-dihydro-1H-indole and 4.3 ml Et3N in 75 ml CH2Cl2 with ice bath cooling. The resulting mixture was stirred at room temperature for thirty minutes and then quenched with water. The organic extract was washed with water, saturated NaHCO3 solution and saturated NaCl solution and dried (MgSO4). Concentration gave 7.7 g crude product which was flash chromatographed using CH2Cl2 as eluent to give 4.9 g solid, m.p. 175°-178° C.
Reaction SMILES: CON(C)[C:4](=[O:18])[CH:5]([O:16][CH3:17])[C:6]1[CH:15]=[CH:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[CH:7]=1.[Br:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:22]=1[O:34][CH3:35]>>[Br:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]([C:29]2[O:30][C:31]([C:4](=[O:18])[CH:5]([O:16][CH3:17])[C:6]3[CH:15]=[CH:14][C:9]4[N:10]([CH3:13])[N:11]=[N:12][C:8]=4[CH:7]=3)=[CH:32][CH:33]=2)=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COC(C(=O)N(C)OC)c1ccc2c(c1)nnn2C
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc4c(c3)nnn4C)o2)cc(OC)c1Br
Yield: 34 %

Procedure:
N,2-Dimethoxy-N-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)acetamide was coupled with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to the procedure for the synthesis of Example 13. Purification by chromatography provided 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)ethanone as a light yellow foam (0.153 g, 34% yield). MS: m/z 486.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14].[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O[Li].O.Cl>ClCCl>[CH2:16]([O:23][C:7]1[C:2]([F:1])=[C:3]([CH2:12][C:13](=[O:15])[CH3:14])[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (2.5 g, 82% purity by HPLC analysis, 9.54 mmol) were added benzyl alcohol (2.5 mL) and LiOH.H2O (1.07 g, 25.58 mmol). The reaction mixture was then heated to 100-110° C. and stirred for 4 hours until HPLC analysis indicated complete reaction. After cooling to RT, the reaction mixture was diluted with dichloromethane (18 mL) and neutralized to pH 6-7 with 1 N HCl. The layers were separated and the organic phase was washed with brine and collected. With stirring, heptane (30-25 mL) was added to the organic solution whereupon crystallization was initiated. The resulting slurry was cooled to 0-5° C. and stirred for an additional 1 h. The slurry was then filtered and the filter cake was washed with heptane. The yellow-brown solids were then dried in vacuo at 50° C. for 12-15 h to afford 1.6 g of the desired compound which was 95% pure by HPLC analysis. HPLC method: Column: YMC Pack Cyano 3 um 4.6×50 mm Solvent A: 0.05% TFA in MeOH:Water (20:80), Solvent B: 0.05% TFA in MeOH:water (20:80), Wavelength: 254 nm Flow Rate: 3 mL/min. Gradient Time: 3 min. Final % B: 100 Initial Hold: 0.5 min. Start % B: 0. Typical Retention Times: SM, 1.2 min; Product 2.2-2.3 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[CH:7]=1.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:44])=[C:22]([S:24]([N:27]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])[CH:23]=1.[Cl-].[Na+]>>[Cl:17][C:18]1[C:19]([O:16][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:20][C:21]([F:44])=[C:22]([S:24]([N:27]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:25])=[O:26])[CH:23]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: N#Cc1cc(-c2cc(Cl)ccc2O)ccn1
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(Cl)cc3-c3ccnc(C#N)c3)cc2F)c(OC)c1
Yield: 100 %

Procedure:
Prepared according to Preparation 255 using 4-(5-chloro-2-hydroxyphenyl)pyridine-2-carbonitrile (Preparation 339, 0.23 g, 0.001 mol) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 333, 461 mg, 0.998 mmol). Saturated aqueous sodium chloride solution (20.0 mL) was added to the reaction resulting in the formation of a white precipitate. This was filtered and washed with water (20.0 mL) and heptane (20.0 mL) before being dried in vacuo for 2 hours to afford the title compound as a white solid, 0.67 g, 100% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>CCOC(C)=O>[CH:15]1([C:18]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=2)=[O:19])[CH2:17][CH2:16]1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(S)cc1)C1CC1
Reaction time: 8 h
Yield: 88 %

Procedure:
To 4-aminothiophenol (9.4 g, 75.0 mmol, 1.5 equiv) and pyridine (8.09 mL, 100.0 mmol, 2 equiv) at 0° C. was added cyclopropanecarbonyl chloride (4.58 mL, 50.0 mmol, 1 equiv) drop wise. The reaction was stirred from 0° C. to room temperature for overnight, diluted with EtOAc (200 mL), washed with 1 N HCl (50 mL×4), dried over Na2SO4, concentrated, and dried under vacuum to yield the compound 5 as a off-white solid (8.5 g, 88%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]([OH:17])[CH3:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:17][C@@H:15]([CH:12]1[CH2:13][CH2:14][N:9]([C:7]2[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=2)[CH2:10][CH2:11]1)[CH3:16])(=[O:28])=[O:27]
Reactant: CC(C)c1noc(N2CCC([C@@H](C)O)CC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC([C@@H](C)OS(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol (1.68 g, 7.0 mmol) in dichloromethane (100 mL) at 0° C. was treated with Et3N (1.98 mL, 14.0 mmol) followed by methanesulfonyl chloride (0.66 mL, 8.4 mmol). The mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. The mixture was diluted with dichloromethane (50 mL), washed with 1M NaH2PO4 (75 mL×2) and brine, and dried over Na2SO4 and concentrated to give (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (2.23 g, 7.0 mmol, 100% yield) as a brown oil, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]OCCl>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:20])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 300 g of 3-benzyloxy-4-hydroxybenzaldeyde (obtained as described in example 62) in 600 ml of dimethylformamide was added to a suspension of 34.6 g of sodium hydride in 346 ml of dimethylformamide under stirring in nitrogen atmosphere. After complete dissolution of sodium hydride 116 g of chloromethyl methyl ether were added; stirring was continued for 30 minutes. The mixture was then diluted with water and extracted with ethyl ether. The combined organic phase was dried over sodium sulfate, filtered and evaporated. The residue was distilled (b.p. 178°-183° C./0.1 mm Hg) to give 3-benzyloxy-4-methoxybenzaldehyde, m.p. 30° C. (from petroleum ether, b.p. 30°-70° C.).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.[CH3:21][C:22]1([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:24]3[CH2:25][C:22]([CH3:21])([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:23]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)(NC(=O)C(F)(F)F)C3)c(F)c21
Yield: 37.5 %

Procedure:
A solution of 1.1 g (4 mmoles) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.32 g (6 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 0.8 g (8 mmoles) of triethylamine in 10 ml of pyridine is heated under reflux for 3 hours. Cooling, filtering and washing with water acidified with a little acetic acid yields 0.65 g (37%) of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-3-trifluoroacetamido-1-azetidinyl)-3-quinolinecarboxylic acid, melting at 196°-210° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C[Si]([N:14]=[N+:15]=[N-:16])(C)C.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:14]=[N:15][NH:16][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Brc1ccc(-c2c[nH]nn2)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
1-Bromo-4-ethynylbenzene (650 mg, 3.59 mmol) and trimethylsilyl azide (3.57 mL, 26.9 mmol) were combined in t-BuOH (5.0 mL) and water (3.0 mL) CuSO4.5H2O (90 mg, 0.36 mmol) in water (1.0 mL) and sodium ascorbate (285 mg, 1.44 mmol) in water (1.0 mL) were added, and the sealed reaction mixture was stirred at 100° C. for 48 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (dry load, 0-50% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[F:16][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][NH:1][C:24](=[O:26])[CH3:25])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[I:15]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A suspension of (5S)-5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 16.0 g, 47.6 mmol) in CH2Cl2 (150 mL) was treated with triethylamine (TEA, 9.62 g, 13.2 mL, 95.2 mmol, 2.0 equiv) at 25° C., and the resulting reaction mixture was cooled down to 0-5° C. before being treated with acetic anhydride (Ac2O, 7.29 g, 6.75 mL, 71.4 mmol, 1.5 equiv) and 4-N,N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01 equiv) at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed that the reaction was complete, the reaction mixture was quenched with H2O (100 mL). The two layers were separated, and the aqueous layer was then extracted with CH2Cl2 (2×50 mL), and the combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1010, 17.36 g, 17.99 g theoretical, 96.5%) as white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1010: 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H, NHCOCH3), 3.25 (t, 2H, J=5.4 Hz), 3.56 (dd, 1H, J=6.4, 9.2 Hz), 3.95 (t, 1H, J=9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H, J=5.7 Hz, OH), 7.02 (dd, 1H, J=2.4, 8.2 Hz), 7.38 (dd, 1H, J=2.4, 10.8 Hz), 7.66 (t, 1H, J=7.5, 8.4 Hz), 8.08 (t, 1H, J=5.8 Hz, NHCOCH3); C12H12FIN2O3, LCMS (EI) m/e 379 (M++H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=[O:10])=[N+:2]=[N-:3].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>>[CH3:15][Si:16]([CH3:18])([CH3:17])[C:19]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=2)[O:7][CH2:8][C:9]([OH:11])=[O:10])[CH:20]=1
Reactant: C#C[Si](C)(C)C
Reactant: [N-]=[N+]=Nc1cccc(OCC(=O)O)c1
Product: C[Si](C)(C)c1cn(-c2cccc(OCC(=O)O)c2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a 15 mL sealed tube was added (3-azidophenoxy)-acetic acid 5 (527 mg, 2.73 mmol, 1.0 eq.) and trimethylsilylacetylene (10 mL) and a stirbar. The tube was sealed and reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and solid was washed with ethyl ether to yield a dark gray solid (483 mg, 61%). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 13.11 (bs, 1H), 8.86 (s, 1H), 7.52-7.46 (m, 3H), 7.03-7.00 (m, 1H), 4.80 (d, 2H), 0.31 (s, 9H) ppm.