Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:11]([O:9][C:5]1[CH:4]=[C:3]([CH3:10])[C:2]([Br:1])=[C:7]([CH3:8])[CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(C)c1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (8.00 g, 39.8 mmol) and benzyl bromide (5.80 mL, 47.7 mmol) in N,N-dimethylformamide (130 mL) was added potassium carbonate (8.25 g, 59.7 mmol), and the mixture was stirred at 80° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=97/3) to give the title compound (9.97 g, yield 86%) as a colorless oil.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:2][CH2:1][CH:3]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(C#N)=C/c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CN)Cc1ccccc1
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a solution of ethyl (2E)-2-cyano-3-phenylacrylate (1.2 g) in ethanol (30 mL) was added 10% Palladium hydroxide (0.3 g) and the mixture was hydrogenated at 3 atms. for 2 hours. After removing the catalysts by filtration on celite pad, the filtrate was evaporated in vacuo. The residue was dissolved in 1N HCl (2 mL) and washed with chloroform. The separated aqueous layer was adjusted to pH=7 by addition of saturated sodium bicarbonate solution and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to afford ethyl 3-amino-2-benzylpropanoate (388 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)[C:3]=1[OH:13].[OH-].[K+]>O1CCOCC1>[F:1][C:2]1[C:3]2[O:13][C@@H:10]([CH2:12][OH:11])[CH2:9][O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(F)cccc1OCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: OC[C@H]1COc2cccc(F)c2O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Preparation according to Preparation 20 using 2-fluoro-6-(oxiran-2-ylmethoxy)phenol (3.9 g, 21.2 mmol), dioxane (20 ml) and KOH (10%, 10 ml). The mixture stirred at RT for 1.5 h. Yield 3.8 g. MS m/z (rel. intensity, 70 eV) 338 (50), 166 (bp), 165 (42), 139 (24), 91 (51).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[S:3][CH2:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:4]3[S:3][CH2:2][S:1][CH:5]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)C1=CSCS1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1=CSCS1
Yield: 38.7 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 1,3-dithiole-4-carboxylic acid (4.6 g), N,N'-carbonyldiimidazole (7.5 g) and 2-amino-7-chloro-1,8-naphthyridine (4.2 g). The product obtained by precipitation in water (4.8 g) is taken up with boiling acetonitrile (300 cc), the insoluble material is removed by filtration, and the filtrate is poured into water (500 cc). The precipitate obtained is purified by recrystallization in an acetonitrile/water (5:2 by volume) mixture (650 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)- 1,3-dithiole-4-carboxamide (2.8 g), m.p. 235° C., is thereby obtained.
Reaction SMILES: C[O-].[Na+].Cl[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[OH:15])=[O:7].Cl>CO>[OH:14][C:11]1[CH:12]=[CH:13][C:8]2[C:6](=[O:7])[CH2:5][O:15][C:9]=2[CH:10]=1
Reactant: O=C(CCl)c1ccc(O)cc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1COc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Solid NaOMe (6134 g) was added to a 0° C. solution of the chloroketone 2 (7062 g) in 49 L of methanol (MeOH) in portions over 2 h while maintaining the temperature at <20° C. The slurry was aged at room temperature for 1 h, at which time cyclization was determined to be complete by HPLC. The mixture was cooled to 0° C., and 2N HCl (49 L) was added while maintaining the temperature at <20° C. The slurry was cooled to 5-10° C., filtered, and washed first with cold 1:1 MeOH/water (5 L), and then with water (16 L). The wet filter cake was slurry washed with isopropyl alcohol (IPA) (18 L), and then was finally washed with heptane. The filter cake was then dried under a fast stream of nitrogen. Ketone 3 was isolated as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][S:12]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li][CH2:23]CCC.ClCI>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:23])(=[O:14])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)OCCNS(=O)(=O)Cc1ccccc1
Agent: ClCI
Solvent: C1CCOC1
Product: C=C(c1ccccc1)S(=O)(=O)NCCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To a solution of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1-phenyl-methanesulfonamide (33 g, 100.2 mmol) in tetrahydrofuran (334 mL) at −78° C. was slowly added n-BuLi (2.5 M in hexanes) (100 mL, 250 mmol) via cannula and the reaction was stirred at −78° C. was 2 hours. Chloroiodomethane (8.3 mL, 110 mmol) was then slowly added and the reaction was stirred at −78° C. for one hour, then allowed to warm to room temperature and aged for 16 hours. The reaction was then quenched with saturated NH4Cl and extracted with dichloromethane, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-60% EtOAc in heptane) to give N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1-phenyl-ethenesulfonamide (24 g, 70% yield). LCMS (ESI), m/z, 342. [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:8]=[C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][C:12]([F:11])([F:23])[F:24])[CH:15]=2)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Nc1c(F)cc(-c2cccc(OC(F)(F)F)c2)cc1F
Yield: 58.5 %

Procedure:
The title compound (0.812 g) was prepared from 2,6-difluoro-4-bromo aniline (1 g, 4.8 mmol) and 3-(trifluoromethoxy)phenylboronic acid (1.28 g, 6.24 mmol) as a colourless liquid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=34)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O.[Pt](=O)=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=34)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4ccccc34)nc12
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3ncn4c3CCCC4)nc12
Reaction time: 6 h
Yield: 25.6 %

Procedure:
To a solution of 2-imidazo[1,5-a]pyridin-1-yl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (70 mg, 0.15 mmol) in TFA (2 mL) was added platinum(IV) oxide (7 mg, 0.03 mmol). The reaction mixture was stirred under hydrogen (balloon) for 6 h then filtered over Celite, rinsing with CH2Cl2. The filtrate was concentrated. The residue was dissolved in CH2Cl2 (3 mL) and treated with ethylenediamine (0.4 mL). The reaction mixture was stirred for 1 h then quenched with water and extracted with CH2Cl2 (2×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 0% to 3% MeOH/CH2Cl2 (0.5% NH4OH). The appropriate fractions were combined and concentrated to afford a yellow solid which was triturated with Et2O to obtain 13 mg (26%) of 2-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a pale yellow solid. MS: (M+H)+=339; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.50 (br. s., 1H), 8.96 (s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 4.06 (t, J=5.9 Hz, 2H), 3.21 (t, J=6.2 Hz, 2H), 1.76-1.98 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][O:22]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])=[C:27]([F:42])[CH:26]=1)#[N:8]>O1CCCC1>[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]([OH:22])[CH2:23][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[O:33])=[C:27]([F:42])[CH:26]=1)#[N:8]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CO1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC(O)CN1CCOCC1
Temperature: 50 °C

Procedure:
After adding tetrahydrofuran (1 ml) and morpholine (0.1 ml) to N-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea (100 mg), the mixture was heated at 50° C. for 30 minutes. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (32 mg) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:17]=[CH:16][O:15][C:14]=1[C:18](Cl)=O>>[Br:12][C:13]1[CH:17]=[CH:16][O:15][C:14]=1[C:18]1[O:9][N:8]=[C:6]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:7]=1
Reactant: O=C(Cl)c1occc1Br
Reactant: NC(=NO)c1ccc(Cl)cc1
Product: Clc1ccc(-c2noc(-c3occc3Br)n2)cc1

Procedure:
The title compound was prepared from 4-chlorobenzamidoxime (479 mg, 2.29 mmol) and 3-bromo-furan-2-carbonyl chloride (390 mg, 2.29 mmol) similar to Example 16, and yielded 570 mg (81%) of white solid. 1H NMR (CDCl3): 8.13 (dd, J=8.80, 2.20 Hz, 2H), 7.67 (d, J=1.92 Hz, 1H), 7.49 (dd, J=8.79, 2.20 Hz, 2H), 6.75 (d, J=1.92 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[N:25]1([CH:32]=[O:33])[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C=O)C.CS(C)=O.CO>[CH:32]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:27][CH2:26]1)=[O:33]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: O=CN1CCCNCC1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCN(C=O)CC3)n2n1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 1,4-diazepane-1-carbaldehyde (97 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (84.4 mg, 77%). 1H NMR (DMSO-d6) δ: 10.86 (s, 1H), [1:1 ratio of rotamers: 8.09 (s, 1H); 7.93 (s, 1H)], 7.98 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.14 (d, J=2.8 Hz, 1H), 6.16 (s, 1H), 4.25-4.39 (m, 3H), 3.55-3.71 (m, 4H), 3.46-3.54 (m, 1H), 2.37 (s, 3H), 1.97-2.09 (m, 1H), 1.86-1.97 (m, 1H), 1.45 (s, 6H); ESI-MS: m/z 437.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCOC[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCC(=O)O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Methyl 3-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethoxy)propionate (2.84 g, 9.30 mmol) was dissolved in THF (40 ml). To the resulting solution was added 0.25N NaOH (40 ml) and the mixture was stirred at room temperature for 19 hours. The solvent was distilled off under reduced pressure. After the residue was acidified with 1N HCl, extraction was conducted with ethyl acetate. The extract was washed with ice water and brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (2.48 g, 92%) was obtained as a colorless oil (this compound was provided for the subsequent reaction without further purification).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[N:12]([S:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cnc2c(C3CCN4CCCC4C3)c[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccccc2c1)n1cc(C2CCN3CCCC3C2)c2ncccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (10 mg, 0.0415 mmol), 2-naphthalenesulfonyl chloride (17.3 mg, 0.083 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35]([C:37](=[N:41][O:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38](O)=[O:39])[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)=O.Cl.[F:67][CH2:68][CH:69]1[NH:72][C:71](=[O:73])[CH:70]1[NH2:74]>C(Cl)Cl.C(N(CC)CC)C>[F:67][CH2:68][C@H:69]1[NH:72][C:71](=[O:73])[C@H:70]1[NH:74][C:38](=[O:39])[C:37]([C:35]1[N:36]=[C:32]([NH:31][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:33][CH:34]=1)=[N:41][O:42][C:43]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: NC1C(=O)NC1CF
Reactant: O=C(O)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CF)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h

Procedure:
0.228 g of tosyl chloride were added to a mixture of 0.806 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetic acid, 5 ml of acetone and 0.17 ml of triethylamine and the mixture was stirred for one hour. A solution of 0.155 g of 4-fluoromethyl-3-amino-2-oxo-azetidine hydrochloride in 5 ml of methylene chloride and 0.31 ml of triethylamine was added to the mixture which was stirred for 20 minutes and added to methylene chloride. The mixture was stirred for 90 minutes and was evaporated to dryness. The residue was added to methylene chloride and water with stirring and the decanted organic phase was dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with ether to obtain 0.598 g of racemate of the syn isomer of cis 4-fluoromethyl-3-[2-(2-tritylamino-4-thiazolyl)-2-trityloxyimino-acetamido]-2-oxo-azetidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:39][C:40]1[C:49](O)=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C1(C)C=CC=CC=1>[CH3:45][O:44][C:42]([C:41]1[CH:46]=[CH:47][CH:48]=[C:49]2[O:16][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:39][C:40]=12)=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: COC(=O)c1cccc(O)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cccc2oc(C3CCNCC3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)piperidin-4-carboxylic acid (2.47 g, 10.78 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.43 g, 17.96 mmol), 1-hydroxybenzotriazole (2.42 g, 17.96 mmol) and methyl 2-amino-3-hydroxybenzoate (1.50 g, 8.98 mmol) in dichloromethane (25 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (1.47 mL, 10.6 mmol) was added. The resulting reaction mixture was stirred at room temperature for 5 h, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate (15 mL), and then extracted with dichloromethane (2×150 mL). The combined organic phase was washed with water (2×100 mL), brine (2×100 mL), and dried (Na2SO4), filtered and concentrated to afford a light yellow solid. The crude solid was dissolved in toluene (20 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (2.08 g, 10.9 mmol). The reaction mixture was then heated to reflux under nitrogen for 4 h. The reaction was cooled to room temperature and concentrated. The crude product was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford 2-(piperidin-4-yl)benzoxazole-4-carboxylate methyl ester (1.64 mg, 70%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.99 (dd, J=7.8, 0.9 Hz, 1H), 7.78 (dd, J=7.8, 0.9 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 4.00 (s, 3H), 3.52-3.45 (m, 2H), 3.36-3.30 (m, 1H), 3.10-3.03 (m, 2H), 2.33-2.20 (m, 4H); MS (ESI+) m/z 261 (M+H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20].[CH3:21][Mg]Br.O>C1COCC1.C(OCC)(=O)C>[CH3:21][C@@:3]1([OH:20])[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([CH2:18][CH2:19][C@:2]12[CH3:1])[C@:15]1([CH3:16])[CH:10]([CH2:11][CH:12]=[CH:13][CH2:14]1)[CH2:9][CH2:8]3
Reactant: C[Mg]Br
Reactant: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC=CCC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of compound 2 (300 mg, 1.10 mmol) in anhydrous THF (15 mL) under an atmosphere of argon at 0° C. was added methyl magnesium bromide (1.4 M in THF; 945 μL, 1.32 mmol). The solution was allowed to return to room temperature and was subsequently stirred overnight. The solution was then diluted with ethyl acetate and poured into water. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by high performance flash chromatography (Biotage) using Hexanes/EtOAc (95:5) as eluant to yield compound 27 (123 mg, 39%). 1H NMR (CDCl3) δ: 0.78 (s, 18-CH3), 0.86 (s, 19-CH3), 1.21 (s, 17α-CH3), 0.65-2.05 (residual CH and CH2), 5.59 (m, 2×CH of alkene).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([NH:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 29.6 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 4-aminotetrahydropyran (173 mg, 1.71 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 73 mg, 30%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][C:12](OCC)=[O:13])=O)=[CH:7][CH:6]=1.C(O)(=O)C.CCOCC>O>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]2[CH2:11][C:12](=[O:13])[N:2]([CH3:1])[N:3]=2)=[CH:7][CH:6]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CN1N=C(c2ccc(Cl)cc2)CC1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
71.2 g (1.55 mol) of methylhydrazine were added dropwise over the course of40 minutes to a suspension of 267 g (1.19 mol) of ethyl 4-chlorobenzoylacetate in 1.5 1 of acetic acid, the temperature rising to 50° C. The reaction solution was stirred at 100° C. for 2 hours and cooled, and then about 1.5 1 each of ether and water were added.The precipitate formed (66.5 g) was filtered off and washed with petroleum ether/ether (1:1). The organic phase was washed four times with saturated sodium hydrogen carbonate solution and concentrated, and the residue was taken up in water. Once again the precipitate formed was filtered off and washed with petroleum ether/ether (1:1). Overall yield: 171 g; m.p. 189° C.
Reaction SMILES: [CH3:1][CH:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=2[CH3:12])[C:3]1=O.[OH-].[K+].C(OC1C2C(=C(C)C(CCOC)=C(C)C=2)C(=O)C1C)(=O)C>O1CCCC1.[Zn]>[CH3:1][C:2]1[C:10](=[O:11])[C:9]2[C:4]([CH:3]=1)=[CH:5][C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=2[CH3:12]
Reactant: Cc1cc2c(c(C)c1C)C(=O)C(C)C2=O
Agent: COCCc1c(C)cc2c(c1C)C(=O)C(C)C2OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=Cc2cc(C)c(C)c(C)c2C1=O

Procedure:
The 2,5,6,7-tetramethyl-l-indenone was prepared by reducing 2,4,5,6-tetramethyl-1,3-indandione with zinc dust at 50° C. Product was purified by chromatography with 1% ethyl acetate in benzene to yield two isomers. The major isomer was treated with 10% potassium hydroxide, then purified by sublimation. The compound has the structure: ##STR11## Dehydropterosin O synthesis: 3-acetoxy-6-(beta-methoxy)ethyl-2,5,7-trimethyl-1-indanone was dissolved in tetrahydrofuran and 10% potassium hydroxide and refluxed for two hours. The solution was then extracted three times with ether and the combined extracts chromatographed with 2% ethylacetate in benzene to yield the Dehydropterosin O compound. The compound has the structure: ##STR12##