Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][N:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[CH:11][CH:10]([CH3:23])[CH2:9][C:8]1=[O:24])=[O:5])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([NH:6][N:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[CH:11][C:10]([CH3:23])=[CH:9][C:8]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)NN1C(=O)CC(C)C=C1c1cccc(C(F)(F)F)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)Nn1c(-c2cccc(C(F)(F)F)c2)cc(C)cc1=O

Procedure:
A solution of 2.6 g (8 mmol) of 1-(ethoxycarbonyl)amino-3,4-dihydro-4-methyl-6-(3'-trifluoromethylphenyl)-2-(1H)-pyridone in 75 ml of toluene is treated with 2.3 g (10 mmol) of DDQ and the mixture is refluxed for 6 hours. After cooling, the reaction solution is filtered off by suction through Alox n and the filtrated is evaporated on a rotary evaporator. The oil which remains is purified by column chromatography on Alox n (eluent: ethyl acetate:methanol=95:5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][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+]>CC(C)=O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][CH3:10])[CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-bromo-3-methoxyphenol (21 g), benzyl bromide (13.5 ml), potassium carbonate (21.4 g) and acetone (200 ml) was stirred at room temperature for 24 h. The insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate 20:1) to give 4-benzyloxy-2-methoxybromobenzene (25 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH:9]([CH3:12])[CH2:10][OH:11])[CH:5]=[C:4]([Cl:14])[N:3]=1.[Li+].[OH-:16].OO>O>[Cl:14][C:4]1[CH:5]=[C:6]([N:8]([CH:9]([CH3:12])[CH2:10][OH:11])[CH3:13])[NH:7][C:2](=[O:16])[N:3]=1
Reactant: CC(CO)N(C)c1cc(Cl)nc(Cl)n1
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: O
Product: CC(CO)N(C)c1cc(Cl)nc(=O)[nH]1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-((2,6-dichloropyrimidin-4-yl)(methyl)amino)propan-1-ol (3.0 g, 13 mmol) and LiOH one hydrate (1.60 g, 38 mmol) in water (2 mL) was added H2O2 (0.78 mL, 25 mmol). The reaction mixture was stirred at 45° C. for 3 h, then quenched with Na2S3O3 solution (2 mL) and concentrated. Purification via Biotage Spla HPFC system (C18, mobile phase: 0.01% NH4HCO3 in H2O/CH3CN, 10˜95%, 9.5 min, 30 mL/min) afforded the title product as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(OC(=O)[NH:17][C@@H:18]1[CH2:22][CH2:21][N:20](C2C(C(F)(F)F)=CC=CN=2)[CH2:19]1)(C)(C)C.FC(F)(F)C1C(N2CC[C@@H](N)C2)=NC=CC=1>>[F:8][C:7]([F:10])([F:9])[C:5]1[N:6]=[C:2]([N:20]2[CH2:21][CH2:22][C@@H:18]([NH2:17])[CH2:19]2)[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Reactant: FC(F)(F)c1csc(Br)n1
Agent: N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Product: N[C@@H]1CCN(c2nc(C(F)(F)F)cs2)C1

Procedure:
Prepared from 2-bromo4-trifluoromethylthiazole (J. A. Edwards Ger. Offen., 2252070, 1973) in a manner similar to that described in D1 and D2.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][C:10]=1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(C2CCCC2)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a 100 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet were added 2.58 g of methyl 4-((tert-butyldimethylsilyl)oxy)-3-cyclopentylbenzoate and 15 mL of anhydrous toluene. The solution was cooled in an ice water bath and was treated with 19.3 mL of 1M diisobutylaluninum hydride in toluene (Aldrich). The solution was stirred at 0° C. for 30 min and was allowed to warm to RT. After 2 h at RT the solution was poured into 130 mL of saturated aqueous potassium sodium tartrate and the resulting mixture was stirred for 20 min. The mixture was then extracted with ethyl ether (3×70 mL). The combined ether extracts were washed with water (3×70 mL), dried over anhydrous MgSO4, and concentrated to give a cloudy oil. The crude product was purified by flash chromatography on silica gel (8:2 hexane:EtOAc) to afford 1.94 g (82%) of 4-((tert-butyldimethylsilyl)oxy)-3-cyclopentylbenzyl alcohol as a clear liquid.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:21])[N:4]=1.CN(C=O)C.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>>[Cl:21][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:3]([CH2:2][N:31]1[C:27](=[O:37])[C:28]3[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30]1=[O:32])=[N:4]2
Reactant: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 100 °C

Procedure:
To a heterogeneous mixture of 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluoro-phenyl)quinoxaline (0.1815 g, 0.4702 mmol) in DMF (3.444 mL, 0.4702 mmol) was added potassium phthalimide (0.2177 g, 1.175 mmol) and the heterogeneous mixture was stirred at 100° C. After stirring at 100° C. for 30 min, the mixture was concentrated under reduced pressure and triturated with water (30 mL). The precipitate was collected by filtration. The resulting solid was filtered and washed with 2 N NaOH (30 mL) and then with water (100 mL), and air-dried to give 2-((5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)methyl)isoindoline-1,3-dione as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1 H, dd, J=7.6, 1.4 Hz), 7.95-8.01 (1 H, m), 7.82-7.91 (5 H, m), 7.65-7.75 (2 H, m), 7.43-7.52 (1 H, m), 4.99 (2 H, br. s.); LC-MS (ESI) m/z 452.0 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:27]1([CH:33]([NH2:41])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:41][CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: NC(Cc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NC(Cc3ccccc3)c3ccccc3)ncc2[N+](=O)[O-])CC1
Reaction time: 18 h
Yield: 77.4 %

Procedure:
trans-{4-[(2-Chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) was dissolved in DCM (5 mL). 1,2-Diphenylethylamine (154 mg, 0.78 mmol) was added in one portion. After 18 h, the solution was partitioned between DCM (15 mL) and 2% AcOH (aq; 10 mL). The layers were separated and the aqueous layer was extracted with DCM (20 mL). The combined organic fraction were washed with saturated sodium carbonate (10 mL) and water, dried over MgSO4, filtered and concentrated to yield a pale yellow solid. Chromatography (silica, 10%-50% Hex/EtOAc) yielded 110 mg of (4-{[2-(1,2-diphenyl-ethylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester as a pale yellow solid, m/z 547.4 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([CH2:13]O)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.O=S(Cl)[Cl:18]>ClCCl>[Cl:18][CH2:13][C:4]1[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=[C:2]([F:1])[C:3]=1[F:15]
Reactant: CC1(C)Cc2cc(F)c(F)c(CO)c2O1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(F)c(F)c(CCl)c2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (5,6-difluoro-2,2-dimethyl-3H-benzofuran-7-yl)methanol (736) (0.18 g, 0.84 mmol) in anhydrous dichloromethane (5 mL) was added SOCl2 dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (30 mL), dried over anhydrous sodium sulfate, and evaporated in vacuo to give a solid 7-(chloromethyl)-5,6-difluoro-2,2-dimethyl-2,3-dihydrobenzofuran (737) (0.194 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15]/[CH:16]=[C:17](/[C:28]1[N:33]=[C:32]([O:34][CH3:35])[C:31]([Cl:36])=[CH:30][CH:29]=1)\[C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.O>C(#N)C>[C:24]([C:21]1[CH:22]=[CH:23][C:18](/[C:17](/[C:28]2[CH:29]=[CH:30][C:31]([Cl:36])=[C:32]([O:34][CH3:35])[N:33]=2)=[CH:16]\[CH2:15][N:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:7])=[CH:19][CH:20]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CN1CCNC1=O
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1nc(/C(=C/CN2CCN(C)C2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 84 h
Yield: 10.1 %

Procedure:
1-Methyl-2-imidazolidinone (80 mg) and potassium carbonate (135 mg) were added to a solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine (123 mg) in acetonitrile (2 mL), and the mixture was stirred at room temperature for 3.5 days. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:10) to give 1-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-3-methylimidazolidin-2-one as a yellow oil (13 mg, 10%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[CH3:22][C:23]1([CH3:32])[O:27][C@@H:26]([CH2:28][CH2:29][O:30][NH2:31])[CH2:25][O:24]1>[Hg](OC(C)=O)OC(C)=O.C1(C)C=CC=CC=1>[CH3:22][C:23]1([CH3:32])[O:27][C@@H:26]([CH2:28][CH2:29][O:30]/[N:31]=[C:11]2\[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:21])[C:5]\2=3)[CH2:25][O:24]1
Reactant: CC1(C)OC[C@H](CCON)O1
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(N)nc2c1/C(=N/OCC[C@H]1COC(C)(C)O1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 100 °C
Yield: 58.7 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (311,100 mg, 0.3 mmol), (S)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (194 mg, 1.2 mmol), Hg(OAc)2 (192 mg, 0.6 mmol) and anhydrous toluene (2 mL) was heated at 100° C. for 1 h. LCMS shows completion of the reaction. The mixture was cooled, filtered through celite and washed with ethyl acetate. Filtrate concentrated and the resulting oily residue was purified by preparative LCMS to afford (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (35A, 87 mg, 65%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.35 (s, 3H) 1.40 (s, 3H) 2.01 (qd, J=6.32, 3.03 Hz, 2H) 2.76 (s, 3H) 2.95 (dd, J=16.42, 8.84 Hz, 1H) 3.18 (dd, J=17.18, 5.05 Hz, 1H) 3.56-3.62 (m, 1H) 4.09 (dd, J=7.96, 5.94 Hz, 1H) 4.16-4.28 (m, 2H) 4.98 (ddd, J=8.78, 4.61, 1.52 Hz, 1H) 7.07 (td, J=8.21, 2.53 Hz, 1H) 7.34 (dd, J=8.08, 2.53 Hz, 1H) 7.68 (dd, J=12.00, 6.95 Hz, 1H). MS (ES) [M+H] calculated for C2iH26BrFN5O3, 494.11; found 494.00.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([C:14](O)=[O:15])[N:13]=1.O.OC1C2N=N[NH:31]C=2C=CC=1.CN(C)CCCN=C=NCC.N.O1CCOCC1>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([C:14]([NH2:31])=[O:15])[N:13]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1nc(-c2c(F)cccc2F)oc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylic acid (0.030 g, 0.095 mmol) in DCM (3 mL) was added hydroxybenzotriazole monohydrate (0.015 g, 0.098 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.020 g, 0.10 mmol) and 0.5M ammonia in dioxane (0.9 mL, 0.45 mmol). The reaction mixture was stirred at room temperature overnight. Further 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.007 g, 0.038 mmol) and ammonia in dioxane (0.57 mL, 0.29 mmol) were added and the reaction stirred for 3 hours at room temperature. The solvent was evaporated in vacuo and the residue purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxamide (0.006 g, 0.019 mmol, 20%) as a white solid. 1H NMR (DMSO) δ 7.03 (1H, dd), 7.35 (4H, m), 7.38 (2H, br. s), 7.43 (2H, m), 7.64 (1H, m), 9.34 (1H, br. s). LCMS (2) Rt 2.87 min; m/z (ES+) 338 (M+Na), 299 (M-NH2).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].Cl.[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>>[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]3[C:8]([OH:10])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Yield: 24.8 %

Procedure:
According to the procedure of Example 10, Step 1, the reaction of 486.8 mg (3.4 mmol) of trans-2-amino-1-cyclohexane-carboxylic acid with 1.31 g of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesufonyl chloride hydrochloride provided 382.7 mg of trans-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylic acid in 25% yield. MS: 455.1 (M+H)+
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:15](N(OC)C)=[O:16])=[CH:9][CH:8]=1>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:15](=[O:16])[CH2:1][CH2:2][CH3:3])=[CH:11][CH:12]=1
Reactant: CCC[Mg]Br
Reactant: CON(C)C(=O)C(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
A solution of propylmagnesium bromide (29.7 g, 201.6 mmol, 3.0 equiv) in THF (200 mL) was added dropwise with stirring at 0° C. to a solution of the carbamate (26 g, 66.5 mmol, 1.0 equiv) in THF (200 mL). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of aqueous NH4Cl (200 mL). The resulting solution was extracted with EtOAc and the organic layers combined. The resulting mixture was washed with saturated NaHCO3 (200 mL) and saturated aqueous NaCl (200 mL), then dried over anhydrous MgSO4. The residue was applied onto a silica gel column with petroleum ether/EtOAc (5:1) to yield t-butyl 1-(4-bromophenyl)-3-oxohexan-2-ylcarbamate (14 g) as a white solid.
Reaction SMILES: Cl.N1(S([N:10]=[N+:11]=[N-])(=O)=O)C=CN=C1.[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CO>[N:13]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=NS(=O)(=O)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
Imidazole-1-sulfonyl azide hydrochloride (1.03 g, 6.0 mmol) was added to (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.0 g, 5.0 mmol), K2CO3 (1.33 g, 10.0 mmol) and CuSO4.5H2O (0.012 g, 0.05 mmol) in MeOH (30 mL) and the mixture was stirred at room temperature for 12 h. The mixture was concentrated, diluted with H2O (50 mL), extracted with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give (R)-tert-butyl 3-azidopiperidine-1-carboxylate (0.65 g).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6](C(OC(C)(C)C)=O)[CH:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.O1CCOCC1>Cl>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[NH:6][CH:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1COc2cc(Br)ccc2N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC1COc2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
tert-Butyl 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate (Intermediate 24, 556 mg, 1.39 mmol) was dissolved in hydrogen chloride in dioxane (5.0 mL, 162.8 mmol) and the mixture stirred for 2 h at rt. The solvent was evaporated and the residue dissolved in EtOAc (50 mL), washed with sat. aq. Na2CO3 (30 mL) and brine (20 mL), dried over Na2SO4 and evaporated after filtration to give the title compound (399 mg, 96%) as an oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:27]([C:29]([OH:31])=O)[N:28]=1.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([CH2:45][NH:46][C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[NH:40]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH2:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:27]([C:29]([N:40]2[C@H:41]([CH2:45][NH:46][C:47](=[O:52])[C:48]([F:50])([F:51])[F:49])[CH2:42][C@H:43]3[C@@H:39]2[CH2:44]3)=[O:31])[N:28]=1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
TBTU (3.22 mmol, 1.05 eq) is added to a solution of 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid (3.07 mmol, 1.0 eq), N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide (3.07 mmol, 1.0 eq) and DIPEA (9.20 mmol, 3.0 eq) in DCM (15 mL) and DMF (3.0 mL). After 2 h the mixture is washed twice with water, once with sat. aqueous NaHCO3 solution, once with hydrochloric acid (0.2 M) and three times with water. The organic layer is dried over Na2SO4, the solvents are removed in vacuo and the residue is purified by preparative TLC (DCM/MeOH 9/1) to give the desired product as an orange foam. LC-MS (acidic): tR=0.87 min; [M+H]+=429.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[OH-].[Na+].[Br-].C([NH3+])(C)(C)C.[CH3:15][CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18]>CCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:20][CH:16]([CH3:15])[CH:17]([CH3:19])[CH3:18]
Reactant: BrCCCCBr
Reactant: CC(C)C(C)O
Agent: CC(C)(C)[NH3+]
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(C)C(C)OCCCCBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,4-dibromo-n-butane (119.20 g, 0.0903 mol) in hexane (80 ml) was cooled at 0° C. with a sodium hydroxide aqueous solution (150 ml of solution prepared by mixing 75 g of sodium hydroxide and 150 ml of water) and tert-butylammonium bromide (4.4 mol %, 0.68 g, used as phase transfer catalyst), and a solution of 1,2-dimethylpropan-1-ol (1.27 g, 0.022 mol) in hexane (70 ml) was added dropwise over 1 h with vigorous mechanical stirring. The reaction mixture was allowed to warm to room temperature and left stirring for 2 h, the reaction mixture was then heated under reflux for 4 h. The organic layer was collected and dried (MgSO4) and the solvent was removed in vacuo. The crude oil was purified by column chromatography [DCM-petroleum fraction (bp 40-60° C.), 1:51] to give a colourless oil.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][N:12]=[N+:13]=[N-:14])[CH2:5][CH2:4]1)=O.C(Cl)(=O)C(Cl)=O.[NH2:21][CH:22]1[C:41](=[O:42])[N:24]2[C:25]([C:30]([O:32][CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:31])=[C:26]([CH3:29])[CH2:27][S:28][C@H:23]12>C(N(CC)CC)C>[N:12]([CH2:11][CH2:10][CH2:9][CH:6]1[CH2:7][CH2:8][N:3]([CH:1]=[N:21][CH:22]2[C:41](=[O:42])[N:24]3[C:25]([C:30]([O:32][CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:37])([CH3:38])[CH3:39])=[O:31])=[C:26]([CH3:29])[CH2:27][S:28][C@H:23]23)[CH2:4][CH2:5]1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=NCCCC1CCN(C=O)CC1
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N=CN3CCC(CCCN=[N+]=[N-])CC3)[C@H]2SC1
Temperature: -10 °C

Procedure:
A solution of N-formyl-4-(3-azidopropyl)-piperidine (1.13 g) in alcohol-free chloroform (2.5 ml) was cooled to -20° C. and oxalyl chloride (0.44 ml) in alcohol-free chloroform (2.5 ml) was added dropwise. After 1 hour at -20° C. the solution was added dropwise at -60° C. to -70° C. to a stirred solution of pivaloyloxymethyl 7-amino-3-methyl-3-cephem-4-carboxylate (1.72 g) in alcohol-free chloroform (12 ml). Triethylamine (1.46 ml) was added and within the next hour the temperature was gradually raised to -10° C. The solvent was evaporated and the residue was extracted with ether. The ether extract was evaporated to leave an oil, which was purified by column chromatography on Sephadex to yield the desired compound as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]3([C:24]([NH:26][C:27]4[CH:28]=[N:29][C:30]([CH3:34])=[C:31](Br)[CH:32]=4)=[O:25])[CH2:23][CH2:22]3)=[CH:20][C:15]=2[O:14][CH2:13]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]3([C:24]([NH:26][C:27]4[CH:28]=[N:29][C:30]([CH3:34])=[C:31]([C:6]5[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=5)[CH:32]=4)=[O:25])[CH2:23][CH2:22]3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CO)cc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(4-(hydroxymethyl)phenyl)-6-methylpyridin-3-yl)cyclopropanecarboxamide was prepared from 4-(hydroxymethyl)phenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.