Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].CS[C:5](=[S:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][CH:16]([CH3:20])[C:17](=[O:19])[CH3:18].Cl>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:5](=[S:14])[CH2:18][C:17](=[O:19])[CH:16]([CH3:20])[CH3:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CSC(=S)OCc1ccccc1
Reactant: CC(=O)C(C)C
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)C(=O)CC(=S)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a suspension of sodium amide (3.9 g) in toluene (150 mL) was added a mixture of dithiocarbonic acid O-benzyl ester S-methyl ester (9.9 g) and 3-methyl-2-butanone (4.3 g) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a hydrochloric acid aqueous solution (1 mol/L, 500 mL), and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane-hexane/ethyl acetate=20/1) to give the title compound (4.6 g).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:33])[C@@H:12]([NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][S:14]CC1C=CC(OC)=CC=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(OC)C=CC=CC=1.S>FC(F)(F)C(O)=O.CN(C)C=O>[CH3:9][C:2]([NH:10][C:11](=[O:33])[C@@H:12]([NH:24][C:25](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:13][SH:14])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(CSC[C@H](NC(=O)c2ccccc2)C(=O)NC(C)(C)c2ccccc2)cc1
Agent: S
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)[C@H](CS)NC(=O)c1ccccc1)c1ccccc1
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
1.010 g of (2R)-N-(α,α-dimethylbenzyl)-2-benzoylamino-3-(p-methoxybenzylthio)propionamide [prepared as described in step (a) above] was dissolved in 10 ml of trifluoroacetic acid. To this solution was added 1.0 ml of anisole and, whilst ice-cooling, this was followed by the addition of 793 mg of mercuric acetate under a nitrogen stream, and then the mixture was stirred. After stirring for 1.5 hours, the solvent was distilled off at room temperature. Diethyl ether was added to the residue and the material which separated out was filtered off. This material obtained by filtration (the mercuric salt) was dissolved in 50 ml of dimethylformamide, and, whilst ice-cooling, hydrogen sulfide gas was passed through this solution. After 1.5 hours, the mercuric sulfide which separated out was filtered off with Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure at room temperature to give 702 mg of the title compound as crystals melting at 169°-173° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1>>[CH3:23][O:24][CH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: COC[C@H]1CCCNC1
Product: COC[C@@H]1CCCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and (S)-3-(methoxymethyl)piperidine to give 223. MS: (ESI+)=425.1
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C(Cl)Cl>[CH3:15][S:16]([O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: OCc1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCc1cccs1
Reaction time: 2 h
Yield: 37.8 %

Procedure:
To a 0° C. mixture of 2-thiophenemethanol (2.80 g, 24.5 mmol) and triethylamine (5.10 mL, 36.8 mmol) in CH2Cl2 (25 mL) was added methanesulfonyl chloride (2.09 mL, 27.0 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into H2O and the layers were separated. The organic phase was washed with cold 1N HCl (3×), saturated aqueous NaHCO3, and brine, dried over MgSO4, filtered. and concentrated in vacuo. 2-thienylmethyl methanesulfonate (1.78 g, 38%) was obtained by chromatography on silica gel (20% ethyl acetate/hexane).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)(O)[O-].[Na+]>ClCCl>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]2)=[O:28])=[CH:30][CH:31]=1)([O-:22])=[O:21]
Reactant: O=C1CCCNc2ccccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21

Procedure:
A 3.32 g portion of 2,3,4,5-tetrahydro-1H-1-benzazepin-5-one and 4.31 ml of triethylamine were dissolved in 33 ml of dichloromethane and, with stirring on an ice bath, 4.59 g of p-nitrobenzoyl chloride was added to the resulting solution. The reaction solution was stirred at room temperature for additional 60 minutes. The reaction solution was then mixed with a saturated sodium bicarbonate aqueous solution and subjected to phase separation. The dichloromethane layer was separated and washed with a 1N hydrochloric acid aqueous solution and a saturated sodium chloride aqueous solution once for each. The thus washed layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The thus obtained residue was recrystallized from methyl alcohol to obtain 5.68 g of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: CC(C)([O-])C.[K+].CS(C)=O.[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[C:31]12[O:42][CH2:41][CH2:40][CH2:39][O:38]1)(=[O:27])=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[CH2:44][C:45]([CH3:49])([CH3:48])[C:46]#[N:47]>O>[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:44][C:45]([CH3:49])([CH3:48])[C:46]#[N:47])[C:32](=[O:37])[C:31]12[O:38][CH2:39][CH2:40][CH2:41][O:42]1)(=[O:26])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COCc3ccccc3)cc2C12OCCCO2
Reactant: CC(C)(C#N)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCC[C@H]3COCc3ccccc3)ccc21
Temperature: 132 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of potassium t-butoxide (3.58 g, 31.9 mmol, 1.2 eq) in anhyd DMSO (72 mL) was added 5′-({(2S)-2-[(benzyloxy)methyl]pyrrolidin-1-yl}sulfonyl)spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (12.20 g, 26.6 mmol ) all at one time under a dry N2 atmosphere. After stirring 20 minutes, 3-chloro-2,2-dimethylpropionitrile (9.38 g, 79.8 mmol, 3 eq) was added drop-wise and the reaction was heated at 132° C. for 21 hr. After cooling in an ice bath, the reaction mixture was poured into H2O and extracted with Et2O. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel using a step gradient of CH2Cl2/CH3OH/NH4OH (99.25/0.5/0.25 to 96/2/1) to give the title compound as a yellow solid (9.48 g, 66% yield). NMR (400 MHz, DMSO-d6): consistent.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[CH:19]=[N:20][NH:21][C:22]=2[CH3:23])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>O.C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[C:22]([CH3:23])=[N:21][N:20]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:19]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]ncc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)c(C)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
N-(3-Cyano-4-neopentyloxyphenyl)-5-methylpyrazole-4-carboxamide (2.4 g), potassium carbonate (1.1 g), potassium iodide (1.4 g) and ethyl bromoacetate (1.4 g) were added to a mixed solvent of dimethylformamide (24 ml) and toluene (24 ml) and the mixture was stirred at 60° C. for 4 h. The reaction mixture was added into water, washed with dilute hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform). Methylene chloride was added to the obtained oily substance to allow crystallization. The crystals were recrystallized from a mixed solvent of methylene chloride-n-hexane to give the title compound (0.7 g), melting point: 240° C.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][C:17]([CH3:32])([CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])[CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([O:19][CH2:18][C:17]([OH:16])([CH3:32])[CH2:27][NH:28][CH:29]([CH3:30])[CH3:31])=[CH:21][CH:22]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NCC(C)(O)COc1ccc(N)cc1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Product: CC(C)NCC(C)(O)COc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous method to that described in Example 1, but starting from 4-anilino-5-bromo-2-chloropyrimidine (Method 13) and 4-[2-hydroxy-2-methyl-3-(isopropyl amino)propoxy]aniline (Method 118), the product was obtained. MS (MH+): 486, 488; HPLC (RT): 4.26.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:31]2[N:36]=[C:35]([NH:37]C=O)[CH:34]=[CH:33][N:32]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([O-:28])=[O:27])=[C:16]([CH2:19][N+:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(=O)(O)[O-].[Na+]>[CH:1]1([O:6][N:7]=[C:8]([C:31]2[N:36]=[C:35]([NH2:37])[CH:34]=[CH:33][N:32]=2)[C:9]([NH:11][CH:12]2[C:29](=[O:30])[N:14]3[C:15]([C:26]([O-:28])=[O:27])=[C:16]([CH2:19][N+:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CNc1ccnc(C(=NOC2CCCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccnc(C(=NOC2CCCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
This solution was added to the activated acid solution prepared above, and the mixture was stirred at -20° to -12° C. for 45 minutes and at ambient temperature for additional an hour. The reaction mixture was poured into an aqueous solution (100 ml) of sodium bicarbonate (8.47 g). The aqueous layer containing 7-[2-cyclopentyloxyimino-2-(4-formamidopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) was separated out, adjusted to pH 1 with 6 N hydrochloric acid and washed with ethyl acetate, followed by standing at 5° C. for 15 hours. This aqueous solution was subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (Trade mark, manufactured by Mitsubishi Chemical Industries) (100 ml). After the column was washed with water, elution was carried out with 7.5% aqueous isopropyl alcohol. The eluates containing a desired compound were collected, evaporated to remove isopropyl alcohol under reduced pressure. The resultant solution was lyophilized to give pale-yellow powder of 7-[2-cyclopentyloxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.67 g), mp 165°-180° C. (dec.).
Reaction SMILES: [F:1][C@@:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[S:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C@:2]([F:1])([CH3:6])[C:3]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:4])=[CH:8][CH:9]=1)(=[O:16])=[O:15]
Reactant: CS(N)(=O)=O
Reactant: C[C@](F)(C(=O)O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@](F)(C(=O)NS(C)(=O)=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 3 (0.5 g, 1.6 mmol) in dry CH2Cl2 (10 ml), N,N-carbonyldiimidazole (0.33 g, 2.0 mmol) was added under vigorous stirring. After 1 h methanesulfonamide (0.19 g, 2 mmol) and triethylamine (0.28 mL, 2 mmol) were added and the resulting mixture was left stirring overnight at room temperature. The organic mixture was washed with a saturated solution of NaHCO3 (2×10 mL) and brine (3×10 mL), dried over Na2SO4 and evaporated under vacuum to give pure 17 as a colourless oil (0.60 g, yield 95%). [α]b=+9 (c=1; CH3OH). 1H-NMR (DMSO-d6) δ 7.70 (d, 2H, J=7 Hz), 7.55 (d, 2H, J=7 Hz), 3.05 (s, 3H), 1.85 (d, 3H, J=23 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>ClCCl>[C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:23][CH2:22][CH:19]2[CH2:21][CH2:20]2)[CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC1CC1
Reactant: CC(C)(C)OC(=O)NNc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNc1cccc(C(=O)NCC2CC2)c1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
The 4.40 g of unpurified 3-(2-tert-butoxycarbonylhydrazino)benzoic acid was dissolved in 80 ml of dichloromethane. To this mixture, 1.78 g of cyclopropylmethylamine and 3.45 g of 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloric acid salt were added and the resulting mixture was heated at reflux for 2 hours. After leaving the reaction mixture to cool to room temperature, the mixture was sequentially washed with 50 ml of water, 50 ml of 1N hydrochloric acid and then 50 ml of aqueous saturated sodium hydrogen carbonate solution, dried and concentrated to obtain 3.42 g of crude crystals. The crude crystals were recrystallized twice from ethyl acetate-hexane to obtain 1.29 g (yield 40%, three steps) of the captioned compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].C(N(CC)CC)C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(#N)C>[CH3:8][Si:9]([CH3:11])([CH3:10])[C:12]#[C:13][C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)cs1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)cs1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-bromo-2-methylthiophene (1.00 g), trimethylsilyl acetylene (1.17 mL), bis(triphenylphosphine) palladium(II) dichloride (119 mg), copper(I) iodide (65 mg), triethylamine (1.57 mL), and acetonitrile (15 mL) was stirred at 80° C. for 4 hours under an argon atmosphere. The reaction mixture was left to be cooled and filtrated through a Celite (registered trademark) pad. To the filtrate was added saturated brine, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (605 mg). 1H-NMR (CDCl3) δ ppm: 0.23 (9H, s), 2.44 (3H, d, J=1.0 Hz), 6.75-6.80 (1H, m), 7.21-7.25 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:14]1([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH:18]=[CH:17][N:16]=[CH:15]1.Cl.O.[S-2].[Na+].[Na+]>CO.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(=O)C>[N:14]1([C:19]2[CH:26]=[CH:25][C:22]([C:23]3[NH:1][C:2]4[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=4[N:13]=3)=[CH:21][CH:20]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)c1cccc(N)c1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2nc(-c3ccc(-n4ccnc4)cc3)[nH]c12
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
1 g (5.5 mmol) of ethyl 2,3-diaminobenzoate and 0.7 ml of concentrated acetic acid were dissolved in 13 ml of methanol. 1.24 g (7.2 mmol) of 4-imidazol-1-ylbenzaldehyde, dissolved in 25 ml of methanol, were then added dropwise over a period of 30 minutes. 1.4 g (7.2 mmol) of copper(II) acetate, dissolved in 19 ml of warm water, were then rapidly added dropwise, and the entire mixture was subsequently refluxed for 20 minutes. The reaction solution was cooled to 50° C. and 2.25 ml of 32% strength hydrochloric acid were added. This was followed by careful dropwise addition of a solution of 2.13 g of sodium sulfide hydrate in 15 ml of water, and the entire mixture was stirred for another 15 minutes. The reaction solution was poured into ice-water and the resulting precipitate was filtered off with suction. The filtrate was made alkaline using aqueous sodium bicarbonate solution and extracted repeatedly with ethyl acetate. The ethyl acetate phase was separated off, dried and concentrated under reduced pressure. This gave 1.7 g of the intermediate.
Reaction SMILES: O=[O+][O-].[CH3:4][C@H:5]([CH2:18][CH2:19][CH:20]=C(C)C)[CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>O=O.C(Cl)Cl.CC(C)=O>[CH3:4][C@H:5]1[CH2:6][N:7]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[C:20](=[O:26])[CH2:19][CH2:18]1
Reactant: CC(C)=CCC[C@@H](C)CNC(=O)OCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@@H]1CCC(=O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ozone in oxygen (4%) was passed through a solution of 2-(R),6-dimethyl-1-benzyloxycarbonylamino-5-heptene (9.8 g) in 150 mL of methylene chloride at -78° C. until the blue color persisted. Nitrogen was then bubbled for 15 mins. 16 mL of dimethyl sulfide was added and the mixture was stirred 1 hr as it warmed to room temperature and then concentrated to give a residual oil. This was taken up in 100 mL of acetone and cooled in ice bath. Jones reagent was added dropwise until orange color was sustained. After stirring 30 mis, 4 mL of isoprpopyl alcohol was added and the mixture was stirred for an additional 15 mins. Solvent was then removed in vacuo and the residue was stirred with water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The resulting residue was purified on silica gel using first 10% ethyl acetate in hexane as solvent to give 2.0 g of 5(R)-methyl-1-benzyloxycarbonyl-2-piperidone as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C=O)C>CCOCC>[CH3:13][Si:12]([CH3:14])([C:15]([CH3:18])([CH3:17])[CH3:16])[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To 4-amino-3-nitrophenol (20 g, 128.9 mmol) was added tert-butyldimethylsilyl chloride (21.5 g, 142.9 mmol), imidazole (13.3 g, 194.8 mmol), and DMF (100 mL). The mixture was stirred at room temperature for 3 h and then diluted with Et2O and washed with H2O. The organics were concentrated under reduced pressure and the resulting solid recrystallized from Et2O—H2O; yielding 26.5 g (76%) product.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:4]1[S:3][C:2]([CH3:1])=[N:6][CH:5]=1)[CH3:10]
Reactant: CCN
Reactant: Cc1ncc(C=O)s1
Solvent: C1CCOC1
Product: CCNCc1cnc(C)s1

Procedure:
prepared by reaction of 2-methyl-thiazole-5-carbaldehyde (Khanna I. K. et al J. Med. Chem. 2000, 43, 16, 3168-3185) with 2M ethylamine in THF.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:31])([CH3:30])[CH:4]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:18][CH:17]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1.[C:32]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]O)[CH2:41][CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(N1CCC(C=O)CC1)(OC(C)(C)C)=O>CCO.C(Cl)Cl>[C:35]([O:34][C:32]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][N:14]2[N:13]=[N:12][C:11]([C:8]3[CH:7]=[CH:6][C:5]([CH:4]([C:16]4[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[C:3]([CH3:31])([CH3:30])[CH3:2])=[CH:10][CH:9]=3)=[N:15]2)[CH2:41][CH2:40]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)C(c1ccc(OCc2ccccn2)cc1)c1ccc(-c2nnn[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cn2nnc(-c3ccc(C(c4ccc(OCc5ccccn5)cc4)C(C)(C)C)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HCl (1M solution in ethanol; slight excess) was added to a solution of 2d (42.0 mg, 0.102 mmol) in EtOH (1.0 mL) at room temperature. After ˜10 min, the resulting mixture was concentrated in vacuo to afford crude g. The residue was dissolved in DCM (1.5 mL), and to this solution was added N-Boc-4-piperidinemethanol (68.0 mg, 0.315 mmol), triphenylphosphine (132 mg, 0.505 mmol), and diethyl azodicarboxylate (80.0 μl, 0.511 mmol). After maintaining the reaction mixture at room temperature for 17 h, second portions of N-Boc-4-piperidinemethanal (68.0 mg, 0.315 mmol), triphenylphosphine (132 mg, 0.505 mmol), and diethyl azodicarboxylate (80.0 μl, 0.511 mmol) were added. The resulting solution was aged for another 5.5 μl, and then purified directly by flash chromatography on silica gel (gradient elution; 0%-50% EtOAc/hexanes as eluent) to afford 2h.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: OB(O)c1cccnc1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccnc2)cn1
Yield: 19 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3-pyridylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (18 mg, 19%) which was obtained as an off-white solid. MS: m/e=321.4 [M+H]+.