Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:22])[NH:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[C:9]1(O)[CH2:12][CH2:11][CH2:10]1)(C)(C)C.[H-].[Na+].O>C1COCC1>[F:21][C:16]1[CH:15]=[C:14]([CH:8]2[C:9]3([CH2:10][CH2:11][CH2:12]3)[O:22][C:6](=[O:5])[NH:7]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CC(C)(C)OC(=O)NC(c1ccc(F)c(F)c1)C1(O)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(c2ccc(F)c(F)c2)C2(CCC2)O1
Temperature: 35 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To a well stirred solution of [(3,4-difluorophenyl)-(1-hydroxy-cyclobutyl)-methyl]-carbamic acid-tert-butyl ester (1.0 g, 3.2 mmol) in THF (20 mL) was added 95% NaH (0.2 g, 8.3 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo to yield 8-(3,4-difluorophenyl)-5-oxa-7-aza-spiro[3.4]octan-6-one in racemic form as a white solid.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH:25]1([CH2:28][NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][NH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[C:35]([C:2]3[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH2:15][N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[O:7])=[CH:4][N:3]=3)[CH:36]=2)=[O:47])[CH2:27][CH2:26]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.46 min, MH+ 498. NMR: δH [2H6]-DMSO 11.67, (1H, b), 9.24, (1H, s), 8.63, (1H, t), 8.39, (1H, d), 8.32, (1H, d), 7.97, (1H, s), 7.88-7.83, (2H, m), 7.45, (1H, d), 7.36, (1H, t), 7.30, (1H, d), 7.11, (1H, t), 3.77, (2H, s), 3.15, (2H, t), 2.70-2.21, (11H, m), 1.04, (1H, m), 0.43, (2H, m), 0.23, (2H, m).
Reaction SMILES: [CH:1]1(S)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OO)(=O)C.[S:12](=[O:15])([OH:14])[O-:13].[Na+].Cl>O.C(Cl)Cl>[CH:1]1([S:12]([OH:14])(=[O:13])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCC1
Reactant: O=S([O-])O
Agent: CC(=O)OO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(O)C1CCCC1
Temperature: 15 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A one liter three-neck flask was charged with 300 mL of methylene chloride and 25 grams (245 mmole) of cyclopentyl mercaptan to produce a reaction solution. The reaction solution was chilled to 15° C. in an ice-water bath and followed by the addition of 190 mL of 35% peroxy acetic acid. Said peroxy acetic acid was added over a period of about 3 hours and the reaction solution was maintained at a temperature of about 18°-26° C. After the reaction solution was stirred overnight at room temperature, 100 mL of water and 25 grams of sodium bisulfite were added followed by 2 additional hours of stirring. The reaction solution was then reduced on a rotovap and the pH was adjusted with dilute hydrochloric acid until a white solid precipitate formed. Said precipitate was isolated via filtration and dried in vacuo (50% yield of cyclopentane sulfonic acid).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(Cl)Cl.[O:8](S(C(F)(F)F)(=O)=O)[S:9]([C:12]([F:15])([F:14])[F:13])(=O)=[O:10]>O>[S:9]([N:1]=[N+:2]=[N-:3])([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)C(F)(F)F

Procedure:
To a solution of NaN3 (3445 mg, 53 mmol) in H2O (12 mL) was added CH2Cl2 (18 mL). The resulting biphasic mixture was cooled in an ice bath and stirred vigorously and treated with Tf2O (3000 mg, 106 mmol) over a period of 60 min. The reaction mixture was stirred in an ice bath for 4 h. The organic phase was separated and the aqueous phase was extracted once with CH2Cl2 (20 mL). The organic extracts were washed with saturated Na2CO3 solution and used without further purification.
Reaction SMILES: [N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])=[N+:2]=[N-:3].[CH:9]#[C:10][CH2:11][CH2:12][CH3:13].O[C@H]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+].O>S([O-])([O-])(=O)=O.[Cu+2].C(O)CCC>[CH2:11]([C:10]1[N:3]=[N:2][N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:9]=1)[CH2:12][CH3:13]
Reactant: C#CCCC
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCCCO
Product: CCCc1cn(C[Si](C)(C)C)nn1
Reaction time: 96 h

Procedure:
(Azidomethyl)trimethylsilane, pent-1-yne, copper (II) sulfate and sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate) were added to a 1:2 solution of water:butan-1-ol. The reaction was stirred for about 4 days and t-butanol and water were removed, producing a 4-propyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole solid.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:30][CH2:31][OH:32])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:16][N:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][S:1]([O:32][CH2:31][CH2:30][N:22]1[C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:19]([C:17]2[O:16][N:15]=[C:14]([C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[F:6])[N:18]=2)[CH:20]=[N:21]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: OCCn1ncc(-c2nc(-c3cc(F)ccc3F)no2)c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1ncc(-c2nc(-c3cc(F)ccc3F)no2)c1-c1ccccc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Mesyl chloride (280 μL; 3.6 mmol) was added to a solution of 2-(4-(3-(2,5-difluorophenyl)-1,2,4-oxadiazol-5-yl)-5-phenyl-1H-pyrazol-1-yl)ethanol (663 mg; 1.8 mmol), obtained from step 1, and triethylamine (502 μL; 3.6 mmol) in dry DCM (5 mL) at 0° C. The tube was sealed and allowed to warm to room temperature overnight. The mixture was washed with saturated aqueous sodium hydrogen carbonate and the organic fraction passed through a hydrophobic frit and the solvent removed in vacuo to give the title compound as a pale yellow solid (785 mg; 97%). 1H NMR (CDCl3, 400 MHz) δ 8.31 (1 H, s), 7.69-7.64 (1 H, m), 7.59-7.81 (3 H, m), 7.50-7.45 (2H, m), 7.21-7.10 (2 H, m), 4.64 (2 H, t, J=5.2 Hz), 4.38 (2 H, t, J=5.2 Hz), 2.90 (3 H, s). LC/MS: 447 (M+H)+. HPLC (Method A) Rt=3.69 min (Purity: 99.4%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:33][C:11]2[N:12]=[C:13]([NH2:32])[N:14]=[C:15]([C:16]3[CH:21]=[C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:19]([Cl:30])=[CH:18][C:17]=3[Cl:31])[C:10]=2[CH:9]=1)=[O:7])C.C(O)C>O>[NH2:32][C:13]1[N:14]=[C:15]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]([Cl:30])=[CH:18][C:17]=2[Cl:31])[C:10]2[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[S:33][C:11]=2[N:12]=1
Reactant: CCOC(=O)c1cc2c(-c3cc(OCc4ccccc4)c(Cl)cc3Cl)nc(N)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2cc(OCc3ccccc3)c(Cl)cc2Cl)c2cc(C(=O)O)sc2n1

Procedure:
Sodium hydroxide (0.190 g; 4.75 mmol) was added to 2-Amino-4-(5-benzyloxy-2,4-dichloro-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (step 4 example 235). Ethanol (25 ml) was added followed by water (2.5 ml) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool and solvents were removed in vacuo. The resulting residue was dissolved in water and stirred in ice-water bath and the neutralised by the drop-wise addition of 37% (aq) hydrochloric acid solution. The reaction mixture was freeze dried to afford product as a yellow powder (containing 2 equivalents of NaCl) 1.33 g; 100%.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]2[C@@:8]3([CH3:43])[C@@H:18]([O:19][C:20]([CH3:22])=[O:21])[C@@H:17]([O:23][C:24]([CH3:26])=[O:25])[C@@H:16]4[C@@:27]5([CH3:42])[C@@H:32]([O:33][C:34]([CH3:36])=[O:35])[C@H:31]6[O:37][C@H:30]6[CH2:29][C@@H:28]5[C:38]([C@H:40]([OH:41])[C@H:15]4[C@@H:9]3[C@@H:10]([O:11]C(C)=O)[C@H:6]2[C@@:5]2([CH3:50])[C@@:44]([OH:49])([CH3:48])[C:45]([O:47][C:4]2=[CH:3]1)=[O:46])=[O:39]>CO.C(=O)(O)[O-].[Na+]>[CH3:1][C@H:2]1[C@@H:7]2[C@@:8]3([CH3:43])[C@@H:18]([O:19][C:20]([CH3:22])=[O:21])[C@@H:17]([O:23][C:24]([CH3:26])=[O:25])[C@@H:16]4[C@@:27]5([CH3:42])[C@@H:32]([O:33][C:34]([CH3:36])=[O:35])[C@H:31]6[O:37][C@H:30]6[CH2:29][C@@H:28]5[C:38]([C@H:40]([OH:41])[C@H:15]4[C@@H:9]3[C@@H:10]([OH:11])[C@H:6]2[C@@:5]2([CH3:50])[C@@:44]([OH:49])([CH3:48])[C:45]([O:47][C:4]2=[CH:3]1)=[O:46])=[O:39]
Reactant: CC(=O)O[C@@H]1[C@H]2[C@H]3[C@H]([C@H](OC(C)=O)[C@H](OC(C)=O)[C@]2(C)[C@@H]2[C@@H]1[C@]1(C)C(=C[C@H]2C)OC(=O)[C@@]1(C)O)[C@]1(C)[C@H](C[C@@H]2O[C@@H]2[C@@H]1OC(C)=O)C(=O)[C@@H]3O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)O[C@H]1[C@H]2[C@H]([C@@H]3[C@@H](O)[C@@H]4[C@H]([C@H](C)C=C5OC(=O)[C@@](C)(O)[C@@]54C)[C@@]3(C)[C@H]1OC(C)=O)[C@@H](O)C(=O)[C@H]1C[C@@H]3O[C@@H]3[C@H](OC(C)=O)[C@]21C
Temperature: 25 °C
Reaction time: 44 h
Yield: 68.6 %

Procedure:
Taccalonolide A (40 mg) was dissolved in 4 mL of methanol and to this solution 8 mL of 0.05 M sodium bicarbonate was added. The solution was stirred at room temperature for 44 hours. The reaction solution was extracted with EtOAc and purified on HPLC to yield 25.8 mg of taccalonolide B. Taccalonolides N and AB were produced by hydrolysis of taccalonolides E and Z, respectively, using the same method. Taccalonolide AB was obtained as white powder. The LC/MS showed pseudomolecular ions at 677 [M+H]+, 694 [M+NH4]+, and 699 [M+Na]+, indicating the loss of an acetyl group from taccalonolide Z. The proton NMR showed the chemical shift of H-15 of taccalonolide AB at δ 4.75 (ddd, J=3.5, 9.0, 11.6 Hz), which is shifted 0.78 ppm up-field than that of taccalonolide Z, suggesting the loss of acetyl group at 15-OH. The HMBC correlation between 15-OH (δ 4.94) and C-15 (δ 71.5) confirmed the assignment.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[OH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)c1ccnc(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(CO)ccn1
Temperature: 5 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A solution of methyl 2-methyl-pyridine-4-carboxylate (800 mg, 6 mmol) in ether (5 ml) was added to lithium aluminium hydride (340 mg, 9 mmol) in ether (10 ml) cooled to 5° C. and the mixture stirred for 2 hours. Water was added, the mixture was filtered through diatomaceous earth and the pad was washed through with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 4-hydroxymethyl-2-methylpyridine (240 mg, 38%) as a yellow oil. 1H NMR Spectrum: (CDCl3)2.48(s, 3H); 5.44(s, 2H); 7.00(d, 1H); 7.10(s, 1H); 8.40(d, 1H) MS-ESI: 124 [MH]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:15])([F:16])[F:14]
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)c(Br)c1
Solvent: CCOC(C)=O
Product: Nc1ccc(OCC(F)(F)F)c(Br)c1
Reaction time: 8 h

Procedure:
2-Bromo-4-nitro-1-(2,2,2-trifluoro-ethoxy)-benzene was dissolved in EtOAc, purged with nitrogen, and a catalytic amount of Pd on Carbon added. The solution is purged a number of times, then left to stir overnight under an atmosphere of nitrogen. The solution is filtered through Celite and concentrated yielding the desired product in quantitative yield. LC Rt=1.852 min. MH+=270.0
Reaction SMILES: [CH3:1][C:2]1[C@@H:3]([OH:11])[CH2:4][C:5](=[O:10])[C:6]=1[CH2:7][C:8]#[CH:9].[CH2:12](N(CC)CC)[CH3:13].C(Br)=C.Cl>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[C@@H:3]([OH:11])[CH2:4][C:5](=[O:10])[C:6]=1[CH2:7][C:8]#[C:9][CH:12]=[CH2:13]
Reactant: CCN(CC)CC
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CBr
Agent: Cl
Solvent: c1ccccc1
Product: C=CC#CCC1=C(C)[C@@H](O)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 Grams of (+)-(S)-2-methyl-3-propargylcyclopent-2-en-4-one-1-ol was dissolved in 100 ml of benzene. Thereto were added successively 3.85 g of tetrakis(triphenylphosphine)palladium, 1.27 g of cuprous iodide and 13.5 g of triethylamine. 150 Grams of vinyl bromide was promptly added to the resultant mixture. The mixture was stirred under nitrogen atmosphere at room temperature overnight. Thereafter, the mixture was poured on dilute hydrochloric acid. A benzene layer was recovered from the mixture, and the water layer was further extracted with benzene. The benzene layers were mixed, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Methanol was added to the residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=3:1) to obtain 7.5 g of (+)-(S)-2-methyl-3-(pent-4-en-2-ynyl)-cyclopent-2-en-4-one-1-ol.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:5][C:6](=[O:8])[CH:7]=1.O.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:5][C:6](=[O:8])[C:7]=1[N:16]=[O:17]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(C2CCCCC2)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(C2CCCCC2)[nH]c(=O)c1N=O
Temperature: 70 °C

Procedure:
A mixture of 4-amino-2-cyclohexylpyrimid-6-one (18 g.) and water (150 ml.) was stirred and heated to 70° C, and treated slowly with sodium nitrite (8 g.), followed by an excess of glacial acetic acid. The mixture was stirred for a further 1 hour and the blue solid (25 g.) filtered off and used directly for the next stage. A sample recrystallised from glacial acetic acid gave pure 4-amino-2-cyclohexyl-5-nitrosopyrimid-6-one, m.p. 233°-234° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.C(OC([NH:40][CH2:41][CH2:42][C:43](O)=[O:44])=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[NH2:40][CH2:41][CH2:42][C:43]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:44]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 117.1 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), N-(tert-butoxycarbonyl)-β-alanine (0.27 g, 1.43 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride 0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 1% to methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with hexane:dichloromethane (5:1) yielded the tert-butoxycarbonyl derivative of the title compound as a waxy off-white solid (0.34 g). This protected derivative was dissolved in methylene chloride (5 ml) and trifluoroacetic acid (10 ml) was added. The resulting light yellow solution was stirred at room temp. for 1 hour, then concentrated in vacuo. The residue was suspended in dioxane (20 ml), and treated with 4M HCl in dioxane (2 ml). The resulting thick suspension was stirred for 10 minutes, diluted with ether, and filtered to yield the hydrochloride salt of the title compound as a hygroscopic yellow solid (0.30 g), mp68–75° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[SH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1>C(O)C>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][S:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(SCC(=O)c2ccccc2)cc1

Procedure:
To bromoacetophenone (322.8 mg, 1.62 mmole) and anhydrous K2CO3 (896 mg, 6.48 mmole) in ethanol (20 ml), 250 mg (1.62 mmole) 4-mercaptobenzoic acid was added and the mixture refluxed overnight. The solvent was evaporated and water added to the solid residue. The basic aqueous solution was extracted with ethyl acetate to remove unreacted bromoacetophenone. The aqueous layer was acidified to yield a precipitate which was filtered and dried (356 mg). m/z 271 (M−1)+1H NMR (DMSO) δ 4.75 (2H, s, —CH2-), 7.35-7.72 (5H, m, 5×ArH), 7.82 (2H, d, 2×ArH), 8.05 (2H, d, 2×ArH).
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:4][C:3](=[O:5])[C:2]([NH2:1])([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH3:6])[CH3:16]
Reactant: CCO
Reactant: CC(N)(C(=O)O)c1ccc(Br)cc1
Agent: Cl
Product: CCOC(=O)C(C)(N)c1ccc(Br)cc1
Reaction time: 24 h
Yield: 72 %

Procedure:
To a solution of 2-amino-2-(4-bromo-phenyl)-propionic acid (1.0 g, 4.1 mmol) in ethanol (20 mL) was bubbled through HCl gas for five minutes. The mixture was stirred at ambient for 24 hours, then refluxed for 18 hours. The volatile component was removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL), washed with NaHCO3 solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (800 mg, 72%). m/z 271.7, 273.7 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(COc2cccnc2N)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (1.80 g, 0.0078 mol), 4chlorophenyl isothiocyanate (1.58 g, 0.0094 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.2 g (70.5%), m.p. 136°-138 ° C.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][C:33](Br)=[CH:34][CH:35]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:24]4[N:29]=[CH:28][C:27]([C:30]5[CH:31]=[N:32][C:33]([C:16]6[CH:17]=[CH:18][C:19]7[N:7]([C:1]8[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=8)[C:8]8[C:13]([C:14]=7[CH:15]=6)=[CH:12][CH:11]=[CH:10][CH:9]=8)=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: Brc1ccc(-c2ccc(Br)nc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc(-c5ccc(-c6ccc7c(c6)c6ccccc6n7-c6ccccc6)nc5)cn4)ccc32)cc1
Temperature: 85 °C
Yield: 64.2 %

Procedure:
A mixture of (9-phenyl-9H-carbazol-3-yl)boronic acid (1.41 g, 4.92 mmol), 6,6′-dibromo-3,3′-bipyridine (0.750 g, 2.39 mmol), tetrakis(triphenylphosphine)palladium(0) (0.166 g, 0.143 mmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) was degassed with argon for about 25 min while stirring. The reaction mixture was then maintained at about 85° C. under argon. Upon confirming consumption of the starting material by thin layer chromatography (TLC) (SiO2, dichloromethane), the reaction was cooled to RT and poured over CH2Cl2 (ca. 350 mL). The organics were then washed with saturated NaHCO3, H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude via flash chromatography (SiO2, 100% CH2Cl2 to 29:1 CH2Cl2-acetone) afforded Compound 22 (0.98 g, 64%) as an off-white solid. MS (ES+) m/z: 639 (C46H30N4 requires 639).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH2:19][CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:16][C:17]1([CH2:18][CH2:19][CH3:20])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1
Reactant: CCCC(C)=O
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 70 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-pentanone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 2 h at 70° C. then for 3 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 150 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was triturated with dichloromethane, and the precipitate was collected by filtration to afford the title compound (0.0632 g, 44%) as a yellow solid: