Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][OH:38]>C(#N)C>[CH:1]1([C:4]2[C:12]([N:13]([CH2:36][CH2:37][OH:38])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: OCCBr
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCO)S(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of Compound (1) (300 mg, 0.75 mmol) in ACN (6 mL) was added potassium carbonate (311 mg, 2.25 mmol) followed by 2-bromoethanol (91.8 μL, 1.30 mmol). The mixture was heated at 85° C. (a thick precipitate was observed after 10 min) and stirred overnight. More potassium carbonate (300 mg, 2.17 mmol) and 2-bromoethanol (90 μL, 1.27 mmol) were added and the mixture was stirred at 90° C. for another 24 hr. The mixture was cooled to RT and the volatiles were removed in vacuo. The residue was suspended in EtOAc (10 mL) and the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed in vacuo and approximately one sixth of the residue was subjected to column chromatography on silica gel eluting with MeOH:DCM (gradient elution, 0% to 10%) to give partially purified material (50 mg). This material was purified further by column chromatography using C18-reverse phase preparative LCMS eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 100% v/v) to give Compound (2) (7.23 mg). ESI-MS m/z calculated for [M+H]+: 444.2. found: 444.2. 1H NMR (400 MHz, CDCl3) δ 8.51-8.43 (m, 1H), 8.36 (d, J=0.8 Hz, 1H), 7.82-7.71 (m, 3H), 7.51 (s, 1H), 4.11 (dt, J=11.9, 5.6 Hz, 1H), 3.82-3.76 (m, 2H), 3.76-3.67 (m, 1H), 3.18 (s, 3H), 3.05 (d, J=4.8 Hz, 3H), 2.47 (s, 3H), 2.30 (tt, J=8.3, 5.6 Hz, 1H), 1.06-0.96 (m, 2H), 0.96-0.87 (m, 1H), 0.54-0.41 (m, 1H).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[O:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]>O1CCCC1>[OH:5][C:6]([CH:1]=[CH2:2])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]
Reactant: CCCCC(=O)C/C=C/I
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC(O)(C/C=C/I)CCCC
Reaction time: 0.5 h

Procedure:
To a stirred solution of 7.8 ml of vinyl magnesium chloride (2.3 M in tetrahydrofuran), at -25° C. is added a solution of 3.55 g of 4-oxo-1-iodo-trans-1-octene in 20 ml of tetrahydrofuran during 15 minutes. After the addition, the solution is stirred at -20° C. to -15° C. for 30 minutes. The reaction is quenched with a mixture of hexane and ice. The aqueous phase is separated and extracted with additional hexane. The combined hexane extracts are washed successively with water and brine. The solution is dried over magnesium sulfate and concentrated. The residue is subjected to dry column chromatography on silica gel with benzene as developing solvent to give a liquid, pmr spectrum (CDCl3): 5.2 (m, terminal CH2), 5.83 (q, CH=CH2), 6.13 (d, ICH=), and 6.52 (m, ICM=CH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2([C:30]#N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1)C1C=CC=CC=1>O1CCCC1.BrCCBr>[CH2:11]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2([C:30]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:22][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: N#CC1(N2CCN(Cc3ccccc3)CC2)CCCCC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: c1ccc(CN2CCN(C3(c4ccccc4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To bromobenzene (0.6 g) and magnesium turnings (0.2 g) in 30 ml dry tetrahydrofuran under nitrogen was added a small crystal of iodine and 10 drops of 1,2-dibromoethane. After small bubbles began to form, the reaction was stirred and heated to reflux for 4 hours. After cooling to room temperature, 1-benzyl-4-(1-cyanocyclohexyl)piperazine (1 g) was added. After 23 hours, the reaction was filtered, 20 ml saturated aqueous ammonium chloride was added and the mixture was extracted with diethyl ether. The ether was dried and removed in vacuo. The residue was chromatographed on silica gel eluted with chloroform to yield pure 1-benzyl-4-(1-phenylcyclohexyl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([O:14]CC)=O)=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.Cl.[CH:18](N)=[NH:19]>C(N)=O>[N:1]1[C:2]2[C:3](=[CH:4][C:5]3[O:10][CH2:9][CH2:8][O:7][C:6]=3[CH:11]=2)[C:12](=[O:14])[NH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2c(cc1N)OCCO2
Reactant: N=CN
Agent: Cl
Solvent: NC=O
Product: O=c1[nH]cnc2cc3c(cc12)OCCO3
Temperature: 130 °C
Yield: 83.9 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of ethyl 7-amino-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.45 g, 6.5 mmol) and formamidine hydrochloride (1.208 g, 15 mmol) in formamide (20 mL) was heated at 130° C. for 8 hours, to afford 7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4(3H)-one as a solid (1.114 g, 84%). 1H NMR (300 MHz, CDCl3 and drops DMSO-d6) δ 11.80 (br, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.13 (s, 1H), 4.36 (m, 4H); LC-MS (ESI) m/z 205 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]([Cl:18])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.COC(C1C(Cl)=CC(C2C=CC=C(C(F)(F)F)C=2)=C(Cl)N=1)=O.CC1C(C(O)=O)=NC=C(C2C=CC=C(C(F)(F)F)C=2)C=1.[N:64]1([CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH2:68][CH2:67][CH2:66][CH2:65]1>>[Cl:1][C:2]1[C:3]([C:19]([N:72]2[CH2:73][CH2:74][CH:69]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)[CH2:70][CH2:71]2)=[O:21])=[N:4][C:5]([Cl:18])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[CH:7]=1
Reactant: O=C(O)c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1Cl
Reactant: C1CCN(C2CCNCC2)C1
Agent: COC(=O)c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1Cl
Agent: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Product: O=C(c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1Cl)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 3,6-dichloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [prepared from 3,6-dichloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 11) by saponification in analogy to the procedure described for intermediate 1B] was reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light yellow amorphous solid. MS: 472.1 (MH+, 2Cl).
Reaction SMILES: [F:1][CH:2]([F:30])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:6]([C:22](=[O:29])[NH:23][CH2:24][CH:25]([OH:28])CO)[CH2:5]1.O>C1COCC1>[F:30][CH:2]([F:1])[CH2:3][N:4]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:6]([C:22](=[O:29])[NH:23][CH2:24][CH:25]=[O:28])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)NCC(O)CO)O2
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)NCC=O)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To tert-butyl 4-(2,2-difluoroethyl)-2-((2,3-dihydroxypropyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (422 mg, 0.96 mmol) in THF (10 mL) was added NaIO4 (522 mg, 2.44 mmol) followed by H2O (4 mL) the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and partitioned between sat. aq. sodium bicarbonate/ethyl acetate. The aqueous layer was extracted further with ethyl acetate (3×50 mL). The organics were combined, washed with sat. aq. sodium bicarbonate (50 mL), dried over MgSO4, and concentrated in vacuo to yield tert-butyl 4-(2,2-difluoroethyl)-2-((2-oxoethyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (377 mg, 96%) as a white solid, which was taken onto the next step without purification. ESI-MS m/z calc. 405.2. Found 406.5 (M+1)+; Retention time: 1.32 minutes (3 min run)
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([Br:15])=[CH:11][CH:12]=2)[C:7]1=[O:16])C.C(NB)(C)(C)C.[OH-].[Na+]>C1COCC1>[Br:15][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH:6]([CH2:5][C:4]([OH:17])=[O:3])[CH:7]2[OH:16])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC1Cc2ccc(Br)cc2C1=O
Agent: BNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC1Cc2ccc(Br)cc2C1O
Temperature: 42.5 °C
Reaction time: 0.5 h

Procedure:
The product from Example 52A in THF was treated with tert-butylaminoborane (1.18 g, 13.5 mmol) and heated at 40-45° C. for 2.5 hours. The mixture was treated with sodium hydroxide solution (1.8 g in water, 40 mL) and heating was continued for 30 minutes. The mixture was allowed to cool to room temperature and the aqueous layer was separated. The organic layer was diluted with isopropyl acetate (40 mL) and water (40 mL) and combined with the aqueous layer. The solution was cooled to 0° C. and the pH was adjusted to 2 by addition of concentrated hydrochloric acid. The mixture was filtered and the fitler cake dried at room temperature. The solid was slurried in dichloromethane (6 mL), refiltered, and redried to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[C:26]1([NH:36][C:37](=[O:38])[NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:11][C:10]4[CH:22]=[CH:23][CH:24]=[N:25][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (150 mg) and 1-naphthyl isocyanate (94 mg) in dry dioxane (3 ml) was stirred at room temperature for 3 hours. The precipitates were collected and washed with isopropyl ether to give 4-[3-[3-(1-naphthyl)ureido]phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.CCCCCC.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[N:28]=[C:29]([NH:38][C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[O:40])[S:30][C:31]=1[C:32](=[O:37])N(OC)C.[N:47]1[CH:52]=[CH:51][CH:50]=[N:49][CH:48]=1.[Cl-].[NH4+]>C1COCC1>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[N:28]=[C:29]([NH:38][C:39]([C:41]2[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=2)=[O:40])[S:30][C:31]=1[C:32]([C:52]1[CH:51]=[CH:50][N:49]=[CH:48][N:47]=1)=[O:37]
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: c1cncnc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccncn2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
2,2,6,6-Tetramethylpiperidine (0.233 mL, 1.38 mmol) was dissolved in THF (6 mL), and a 1.58 mol/L solution of n-butyllithium in n-hexane (0.880 mL, 1.38 mmol) was added thereto in a stream of argon at −78° C., followed by stirring at room temperature for 30 minutes. At −78° C., a solution of Compound 98 (150 mg, 0.419 mmol) and pyrimidine (0.0990 mL, 1.26 mmol) in THF (2 mL) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 375 (11.0 mg, 7%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.C1(CC([NH:22][C@@H:23]2[C:49](=[O:50])[N:25]3[C:26]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)=[O:38])=[C:27]([CH:30]=[CH:31][C:32]4[CH:36]=[CH:35][S:34][N:33]=4)[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.CO>C(Cl)Cl>[NH2:22][C@@H:23]1[C:49](=[O:50])[N:25]2[C:26]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)=[O:38])=[C:27]([CH:30]=[CH:31][C:32]3[CH:36]=[CH:35][S:34][N:33]=3)[CH2:28][S:29][C@H:24]12
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3ccsn3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(COC(=O)C2=C(C=Cc3ccsn3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reaction time: 3 h
Yield: 95.7 %

Procedure:
In 13 ml of methylene chloride were dissolved 913 mg of phosphorus pentachloride and 1.18 ml of pyridine, and 800 mg (1.46 mmol) of p-methoxybenzyl 7β-phenylacetamido-3-[2-(isothiazol-3-yl)vinyl]-3-cephem-4-carboxylate with 3.2 ml of methylene chloride were added therein at -30° C. After stirring for 3 hrs. under ice-cooling, the reaction solution was added to 13 ml of methanol at -30° C. After stirring for 1 hr. at the room temperature, the reaction solution was added to 30 ml of saturated saline solution and 30 ml of methylene chloride under ice-cooling, and stirred for 1 hr. as it was. The reaction solution was separated, and the aqueous layer was further extracted with 20 ml of methylene chloride. The layers of methylene chloride were combined, washed with saturated sodium hydrogen carbonate aqueous solution, and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated off to give 1.15 g of a caramel. The caramel was column chromatographed on silica gel by eluting with chloroform-ethyl acetate to give 600 mg of p-methoxybenzyl 7β-amino-3-[2-(isothiazol-3yl)vinyl]-3-cephem-4-carboxylate.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[CH:7][CH:6]=[N:5]1.[N:10](OCCC(C)C)=[O:11].C(OC(C)C)(C)C.CCCCCC>C(O)C.Cl>[F:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([N:10]=[O:11])[CH:6]=[N:5]1
Reactant: Nc1ccnn1CCF
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: Nc1c(N=O)cnn1CCF
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a solution of 1-(2-fluoroethyl)-1H-pyrazol-5-amine (12 g) in ethanol (30 ml) were added concentrated hydrochloric acid (70 mg) and isoamyl nitrite (10.9 g). The reaction mixture was stirred at 25–38° C. for 2 hours. Diisopropyl ether and hexane were added to the reaction mixture, and the resulting oil was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2→1:1→2:1→1:0) to give-1-(2-fluoroethyl)-4-nitroso-1H-pyrazol-5-amine (4.8 g).
Reaction SMILES: [C:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ccc2c(c1)C(C)(C)CCCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCc1ccc2c(c1)C(C)(C)CCCC2

Procedure:
This alkyne was dissolved in 30 ml of ethy acetate and hydrogenated over 2 g of Pd/C (10%) at room temperature and under 1 atm H2. Filtration over diatomaceous earth and removal of the solvent gave 3.08 g of 2-hexyl-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene as a colorless oil (GC purity: 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH3:14])[C:7]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1)=[C:6]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>ClCCl>[C:36]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:7]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]3[C:5]([C:6]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:16]1)(=[O:38])[CH3:37]
Reactant: COc1ccc2c(=O)n(C)c(C3CCCNC3)c(-c3ccccc3)c2c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(=O)n(C)c(C3CCCN(C(C)=O)C3)c(-c3ccccc3)c2c1

Procedure:
To a dichloromethane (0.100 mL) solution of (±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one (30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol) was added acetyl chloride (0.007 mL, 0.095 mmol). After 24 hours saturated sodium bicarbonate and additional dichloromethane were added. The layers were separated and the organic phase dried with anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by trituration with ether-EtOAc gave a white solid which was isolated by vacuum filtration to give the titled product. ESI+MS: 391.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:35]Br.[OH-].[Na+].O>ClCCl.CCCC[N+](CCCC)(CCCC)CCCC.[Cl-]>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:14]([O:15][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([Cl:40])=[C:32]([Cl:31])[CH:33]=2)[C@H:13]([OH:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reaction time: 7 h
Yield: 92 %

Procedure:
To a solution of di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3,4-dihydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (450 g, 1.05 mol) in dichloromethane (4.50 L) at room temperature is sequentially added 3,4-dichlorobenzyl bromide (144.73 mL, 238.80 g, 995.32 mmol), tetra-N-butylammonium chloride (58.24 g, 209.54 mmol), and a 50% wt/wt aqueous solution of sodium hydroxide (829.80 mL, 15.72 mol). After 7 hours, dilute the reaction with water (1 L) and separate the phases. Extract the organic phase with brine (500 mL), dry over anhydrous MgSO4, filter and concentrate. Purify the residue by chromatography (2.5 kg of SiO2; eluent: hexane/ethyl acetate 12:1 to 0:1) to give the title compound (539 g, 72% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH:24]([NH:38][S:39]([C:42]2[C:43]3[CH:44]=[CH:45][N:46]=[CH:47][C:48]=3[CH:49]=[CH:50][CH:51]=2)(=[O:41])=[O:40])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:54]I.[Cl-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH:24]([N:38]([CH3:54])[S:39]([C:42]2[C:43]3[CH:44]=[CH:45][N:46]=[CH:47][C:48]=3[CH:49]=[CH:50][CH:51]=2)(=[O:41])=[O:40])[CH2:25][N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC(Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)CN1CCN(c2ccccc2)CC1)c1cccc2cnccc12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)CN1CCN(c2ccccc2)CC1)S(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h

Procedure:
470 mg of the amorphous compound obtained in Example 5 was dissolved in 8 ml of dimethylformamide, and to the solution were sequentially added 30 mg of 60% sodium hydride and 0.1 ml of methyl iodide with ice cooling, and after stirring for two hours with ice cooling was added saturated sodium chloride, and the mixture was extracted with 50 ml of ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated under a reduced pressure to obtain a residue, which was then applied to a silica gel column and eluted with hexane/ethyl acetate (1:1) to obtain 413 mg of the title compound in a colorless amorphous form.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:21]=3)=[O:19])[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:21]=3)=[O:19])[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(CS(=O)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(S(=O)Cc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)sulfinyl)methyl)phenyl)propanoate (143 mg) in ethanol (2.6 mL) was added 2N aqueous sodium hydroxide solution (649 μL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was cooled to 0° C., neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (129 mg) as a white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH2:20]([N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1)[CH3:21]>>[CH2:20]([N:22]([CH3:30])[C:23]1[N:24]=[CH:25][C:26]([NH:29][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[O:9][C:10]=2[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:27][CH:28]=1)[CH3:21]
Reactant: O=C(O)c1nc(-c2ccccc2Br)oc1C(F)(F)F
Reactant: CCN(C)c1ccc(N)cn1
Product: CCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3Br)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-ethyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H16BrF3N4O2 (m/e) 469, obsd 470 (M+H).