Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:8][CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
NaH (60% in mineral oil, 1.2 g, 30 mmol) was added to an ice-cooled solution of (4-hydroxy-phenyl)-phenyl-methanone (5 g, 25.2 mmol) in DMF (25 mL). Stirred for 20 minutes at room temperature. Benzyl bromide (6.1 ml, 50 mmol) was added at 0° C. The reaction temperature was raised to room temperature after 1 h. Stirred 2 h. Water (20 mL) was added and aqueous phase was extracted dichloromethane (2×30 mL). The combined organic phase was concentrated and purified by flash chromatography (eluent: dichloromethane). 1H nmr revealed the product was pure. Yield: 7.0 g, 96%
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Brc1ccccn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccccn4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-bromopyridine [CAS109-04-6; commercially available] (237 mg, 1.5 mmol) according to general procedure II. Obtained as a yellow solid (345 mg, 80%). MS (ISP) 433.2 [(M+H)+]; mp 158-159° C.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[CH3:4][S:1]([O:20][CH:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH2:6])=[CH:10][CH:11]=2)[CH2:16]1)(=[O:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(c2ccc(N)cc2)C1
Yield: 106.3 %

Procedure:
40 ml (0.516 mol) of mesyl chloride was added dropwise at 5° C. to 83.3 g (0.4 mol) of N-(4-nitrophenly)-3-hydroxypyrrolidine (1) dissolved in 625 ml of anhydrous THF and 72.7 ml (0.6 mol) of triethylamine. The mixture was allowed to return to room temperature and was then poured onto ice. After filtering off the precipitate by suction and drying, 109 g of yellow powder (2) was obtained.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54]([O:58][C:59]([NH:61][C:62]1[S:63][CH:64]=[C:65]([CH2:67][C:68](O)=[O:69])[N:66]=1)=[O:60])([CH3:57])([CH3:56])[CH3:55].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:68](=[O:69])[CH2:67][C:65]4[N:66]=[C:62]([NH:61][C:59]([O:58][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:60])[S:63][CH:64]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Temperature: -30 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethyl-thio)-3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg: 1.06 mMol.) and 2-(2-t-butoxycarbonylaminothiazol-4-yl)acetic acid (287 mg: 1.11 mMol.) in dichloromethane (8 ml) cooling at -30° C. are added N-methylmorpholine (0.27 ml: 2.46 mMol.) and phenyl dichlorophosphate (0.19 ml: 1.27 mMol.), and the mixture is stirred at -30° C. for 40 minutes. The reaction mixture is quenched with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=3:1) to give 7β-[2-(2-t-butoxycarbonylaminothiazol-4-yl)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (812 mg) as pale yellow foam. Yield: 77%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[C:28]([N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:34]([O:36][CH3:37])=[O:35])[CH:25]=2)[N:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:19]2[C:28]([N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[N:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:34]([O:36][CH3:37])=[O:35])[CH:25]=3)[N:20]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(NC(=O)OC(C)(C)C)nc3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 6-(tert-butoxycarbonylamino)pyridin-3-ylboronic acid (316.0 mg, 1.33 mmol) in dioxane (5 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (130.0 mg, 0.44 mmol), K3PO4 (280.0 mg, 1.33 mmol) and Pd(PPh3)4 (25.6 mg, 0.02 mmol) and three drops water. The reaction mixture was stirred for 1 h at 90° C. in an oil bath with an inert atmosphere of nitrogen and concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (160 mg, 80%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BrH:12].[Br:13]CC(C1C=C(C)C=CN=1)=O>>[BrH:13].[Br:12][CH2:2][C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: COc1ccnc(C(C)=O)c1
Reactant: Cc1ccnc(C(=O)CBr)c1
Agent: Br
Product: COc1ccnc(C(=O)CBr)c1

Procedure:
* 2-Bromoacetyl-4-methoxypyridine hydrobromide was prepared from 2-acetyl-4-methoxypyridine (B. Case et al., J. Org. Chem., 1961, 26, 4415) according to the procedure for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.C(N(CC)CC)C.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1>C(Cl)Cl>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[C:13]=1[C:4]1[N:3]=[C:2]([N:28]2[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (700 mg, 2.42 mmol) in 10 ml CH2Cl2 at 0° C. was added triethylamine (0.67 mL, 4.8 mmol) followed by the addition of tert-butyl piperidin-4-ylcarbamate (630 mg, 3.14 mmol) under an N2 atmosphere. The reaction was gradually warmed to room temperature and stirred overnight. The reaction mixture was then quenched with water, and the layers were separated. The aqueous layer was extracted twice with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to obtain tert-butyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate (1.05 g, 96%) LC/MS: m/z 453.3 (M+H)+ at 2.60 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].FC(F)(F)C(O)=O.O.O.O.C([O-])(=O)C.[Na+]>ClCCl>[CH3:1][C:2]([CH3:30])([CH3:29])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Oc3ccccc3)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Oc3ccccc3)nc12
Reaction time: 2 h

Procedure:
A solution of impure 2,2-dimethyl-1-[2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one, prepared according to general procedures as described in these Examples, (0.032 g, “0.075 mmol”) in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 13 h, then concentrated to a yellow-green oil, which was partitioned between 5 mL of a sat. aq. NaHCO3 solution and 5 mL of dichloromethane. The aqueous layer was extracted with 5 mL of dichloromethane, and the combined organic layers were dried over MgSO4, filtered and concentrated to a pale yellow oil. The oil was dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.103 g, 0.756 mmol). The mixture was stirred for 2 h, then concentrated. The residue was partitioned between 5 mL of water and 5 mL of dichloromethane. The aqueous layer was extracted with 5 mL of dichloromethane, and the combined organic layers were dried over MgSO4, filtered and concentrated to a pale yellow oil. The oil was again dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.101 g, 0.745 mmol). The mixture was stirred for 4 h, then concentrated. The residue was partitioned between 5 mL of water and 5 mL of dichloromethane. The aqueous layer was extracted with 5 mL of dichloromethane, and the combined organic layers were dried over MgSO4, filtered and concentrated to an off-white solid. Column chromatography (0→33% EtOAc/hexanes) afforded 0.014 g (65% from impure; 40% 2-step) of 2,2-dimethyl-1-(2-phenoxy-5H-pyrrolo[2,3-b]pyrazin-7-yl)-propan-1-one as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:13](=[O:14])[O:12][C:9]([CH3:10])([CH3:11])[C:3]=2[CH:4]=1
Reactant: CC(C)(O)c1cc(Br)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2ccc(Br)cc21
Temperature: 50 °C

Procedure:
To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18g, 78 mmol) in dry THF (150 mL) was added 1,1′-carbonyldiimidazole (15.5 g, 94 mmol) under nitrogen. The reaction solution was heated at 50° C. overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with 1N aqueous hydrochloride solution (2×40 mL), brine (20 mL), and dried with MgSO4. After removal of the solvent in vacuo, 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was obtained as a white solid (20 g, 100%): mp 199–200° C.; 1H-NMR (DMSO-d6) δ 10.32 (s, 1H, D2O exchangeable), 7.48 (d, 1H J=2.1 Hz), 7.43 (dd, 1H, J=8.5, 2.1 Hz), 6.84 (d, 1H, J=8.4 Hz), 1.61 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].N12CCCN=C1CCCCC2.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>C(#N)C.[Cu]>[CH3:25][C:22]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:26])[C:23]#[CH:24]
Reactant: C#CC(C)(C)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: [Cu]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Temperature: 12.600000381469727 °C

Procedure:
To a solution of 4-cyanophenol (9.0 g, 75.55 mmol, commercially available) and anhydrous acetonitrile (120 mL) at ~0° C. under argon was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 14.0 mL, 93.61 mmol, 1.24 eq based on the input of 4-cyanophenol). A temperature increase to 12.6° C. was observed. After the solution had cooled to 0° C., copper bronze (cooper powder, 49.8 mg, 0.783 mmol, 0.0104 eq, 1.04 mol %) was added followed by the addition of a portion of the cuprous chloride in acetonitrile solution prepared above (600 μL, 15.49 μmole, 0.000205 eq., 0.0205 mol %). To the resulting mixture was added, dropwise over 12 minutes, 3-chloro-3-methyl-1-butyne (7.03 g, 68.54 mmol, 0.907 eq. based on the input of 4-cyanophenol). The resulting mixture was allowed to stir at 0° C. under argon. After stirring for 10 hours, the reaction mixture was filtered through a small pad of Celite (to remove the remaining copper bronze) using additional acetonitrile to complete the transfer and to wash the filter bed. The filtrate was concentrated at reduced pressure (bath temperature 40° C.) and the residue was partitioned between 1N HCl (100 mL) and toluene (400 mL). The organic fraction was washed with 1N HCl (2×60 mL), 1N NaOH (2×60 mL), and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil (10.68 g). Distillation of the crude material (bulb-to-bulb, ~70°-90° C., ~15 mm Hg) afforded the title compound as a colorless, low melting (mp 28°-29° C.) solid (10.40 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][OH:12].C(Cl)[Cl:14]>>[ClH:14].[F:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[O:12][CH3:11])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CO
Reactant: ClCCl
Agent: Cl
Product: COC(=N)c1ccc(F)cc1
Reaction time: 48 h
Yield: 36 %

Procedure:
Dry HCl (g) was bubbled through a solution of 4-fluorobenzonitrile (5.0 g, 0.041 mol) in dry MeOH—CH2Cl2 (20 mL, 1:1 v/v) until saturation. The clear solution was kept at 0° C. for 2 days to crystallize methyl 4-fluorobenzimidate as hydrochloride salt, which was isolated by filtration (2.8 g, yield 36%). 1H NMR (400 MHz, DMSO-d6) δ 7.95-7.92 (m, 2H), 7.38 (br s, 1H), 7.29-7.25 (m, 2H), 3.06 (s, 3H). MS (ESI) m/z: Calculated for C8H8FNO: 153.06. found: 154.2 (M+H)+.
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.[C:12](=S)=[S:13].C(N(CC)CC)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:12]([SH:13])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: S=C=S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Sc1nc(-c2ccc(Cl)cc2)no1
Temperature: 70 °C
Yield: 61 %

Procedure:
A mixture of p-chlorobenzamidoxime (170 parts), carbon disulphide (76 parts), triethylamine (101 parts) and pyridine (170 parts) was heated at 70° C. for three days. The solution was evaporated to dryness and the residue washed with 3-normal hydrochloric acid and recrystallised from benzene to give 3-(p-chlorophenyl)-5-mercapto-1,2,4-oxadiazole (130 parts, 61% yield), melting point 145°-147° C.
Reaction SMILES: [ClH:1].[O:2]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2([C:28]([OH:30])=O)[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[CH:27])[CH2:21][CH2:20]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[NH2:50][OH:51]>CN(C=O)C.O>[ClH:1].[OH:51][NH:50][C:28]([C:19]1([CH2:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([O:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:10][CH:11]=2)(=[O:16])=[O:17])[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[CH:27])[CH2:21][CH2:20]1)=[O:30]
Reactant: C#CCN1CCC(CS(=O)(=O)c2ccc(Oc3ccccc3)cc2)(C(=O)O)CC1
Reactant: NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: C#CCN1CCC(CS(=O)(=O)c2ccc(Oc3ccccc3)cc2)(C(=O)NO)CC1
Reaction time: 48 h

Procedure:
Part H: To a solution of the carboxylic acid of Part G (460 mg, 1.1 mmol) in DMF (10 mL) was added N-hydroxbenzotriazole.H2O (180 mg, 1.33 mmol) and after 5 minutes of stirring was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (299 mg, 1.56 mmol). After 10 additional minutes 4-methylmorpholine (0.49 mL, 4.45 mmol) and 50% aqueous hydroxylamine (0.22 mL, 3.34 mmol) and the solution stirred for 24 hours. An additional aliquot of each reagent was added and the solution stirred for an additional 48 hours. The solution was diluted with H2O, extracted with chloroform, washed with satd. NaCl and dried over MgSO4. Reverse phase HPLC (acetonitrile/H2O) provided the hydroxamate compound as a white solid (N-hydroxy-4-[[(4-phenoxyphenyl)-sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride; 200 mg, 42%). HRMS calc'd for C22H24N2O5S: 429.1489, found 429.1480. Anal. calc'd for C22H24N2O5S: C, 61.66; H, 5.64; N, 6.54; S, 7.48. Found: C, 61.33; H, 5.68; N, 6.36; S, 7.35.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:31]C(OC(Cl)C)=O>ClCCl>[ClH:31].[C:22]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:24][C:19]([O:18][CH:16]2[CH2:17][NH:14][CH2:15]2)=[CH:20][CH:21]=1
Reactant: c1ccc(-c2ccc(OC3CN(C(c4ccccc4)c4ccccc4)C3)cc2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cl
Product: c1ccc(-c2ccc(OC3CNC3)cc2)cc1
Reaction time: 25.5 h
Yield: 72 %

Procedure:
1-Benzhydryl-3-(biphenyl-4-yloxy)azetidine (15.40 g, 39.34 mmol) was dissolved in dichloromethane (400 mL), stirred, and cooled in an ice-water bath. 1-Chloroethyl chloroformate (8.49 mL, 11.25 g, 78.69 mmol) was added in 1 mL portions over 10 minutes, and the mixture stirred for a further 30 minutes at 0° C., then at rt for 25.5 hours. Further 1-chloroethyl chloroformate (4.25 mL, 5.63 g, 39.35 mmol) was added and the mixture stirred for 3 days. The solvents were evaporated in vacuo and methanol (300 mL) added to the resulting white solid. The mixture was heated gently to dissolve, and then allowed to cool whilst stirring vigorously, whereupon a white precipitate formed. After a further 2 hours stirring at room temperature, the solids where collected by filtration to give the amine (7.41 g, 72%) as a white solid; mp>195° C.; LCMS retention time 1.64 mins, m/z 226.1 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ 9.26 (br s, 2H), 7.64-7.60, (m, 4H), 7.47-7.41 (m, 2H), 7.33 (ft, 1H, J=7.3 and 1.2 Hz), 6.96 (d, 2H, J=8.8 Hz), 5.13 (tt, 1H, J=6.8 and 4.8 Hz), 4:46 (dd, 2H, J=12.4 and 6.8 Hz) and 4.01 (dd, 2H, J=12.4 and 4.8 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:12])=[O:13])=[C:7]([C:24]2[CH:29]=[N:28][CH:27]=[N:26][CH:25]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1-c1cncnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(-c2cncnc2)c1
Temperature: 77.5 °C
Yield: 116.3 %

Procedure:
To a solution of 18 (62.0 mg; 0.14 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added aqueous sodium hydroxide (2 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a white oil (68.0 mg).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1nccnc1C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyrazine (1.1147 g, 6.12 mmol), 4-aminophenol (0.801 g, 7.34 mmol), and cesium carbonate (5.98 g, 18.35 mmol) in DMSO (20.39 mL) in DMSO at 110° C. to stir overnight. The reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with 50% sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in DCM, to provide 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline. [M+H]=272.1.