Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][C:5]([C:10](Cl)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[NH3:13]>C(#N)C>[C:10]([C:5]12[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]1)[CH2:3][CH2:4]2)#[N:13]
Reactant: N
Reactant: O=C(Cl)C12CCN(CC1)CC2
Agent: Cl
Solvent: CC#N
Product: N#CC12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Quinuclidin-4-ylcarbonylchloride hydrochloride (Example 8, Step 4) (3.4 g 0.0016 moles) was dissolved in acetonitrile (150 ml) and treated with 35% ammonia solution (50 ml). The mixture was stirred for 18 hours at ambient temperature then concentrated to dryness in vacuo. 1 g of the residue was then treated with phosphoms oxychloride (8 ml) at reflux for 5 hours. The mixture was then concentrated in vacuo and the residue partitioned between saturated potassium carbonate and diethylether (4×50 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Column chromatography on silica gel elutin with 0-5% methanol/chloroform gave the title compound 0.34 g (75%); 1H NMR (CDCl3) 1.85 (6H t, J 10 Hz), 2.91 (6H, t, J 10 Hz).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[CH:11]=[N:15]/[OH:16])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1
Reactant: NO
Reactant: CC1(C)OB(O)c2cc(C=O)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2cc(/C=N/O)ccc21
Reaction time: 2 h

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (9.0 g, 47.4 mmol) and NH2OH.HCl (3.92 g, 56.9 mmol) in THF (100 mL) and H2O (25 mL) at rt was added NaOAc (5.83 g, 71.1 mmol). The reaction mixture was stirred for 2 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude compound (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH:7]12[CH2:15][CH:11]([CH2:12][NH:13][CH2:14]1)[CH2:10][N:9]([CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH2:8]2.[OH-].[Na+]>C(Cl)Cl>[C:24]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH:17]([OH:28])[CH2:16][N:9]2[CH2:8][CH:7]3[CH2:15][CH:11]([CH2:12][N:13]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:14]3)[CH2:10]2)=[CH:27][CH:26]=1)#[N:25]
Reactant: N#Cc1ccc(OCC(O)CN2CC3CNCC(C3)C2)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
Ethylchloroformate (930 mg; 8.4 mmol) was added to a stirred solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (2.3 g; 7.6 mmol; see Example G above) and NaOH (1.5 mL; 10 M) in DCM (60 mL). The solution was stirred at rt. for 1 h, washed with water and the organic layer was separated, dried (Na2SO4) and concentrated. Purification using column chromatography (DCM:MeOH; 19:1) gave the title compound (1.4 g).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][C@H:6]1[CH2:21][OH:22])=[O:4].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[O:4]=[C:3]1[CH2:2][O:22][CH2:21][C@@H:6]2[CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:9][CH2:10][N:5]12
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)CBr)[C@H](CO)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCN2C(=O)COC[C@@H]2C1
Temperature: 25 °C
Yield: 23 %

Procedure:
Benzyl (3S)-4-(bromoacetyl)-3-(hydroxymethyl)piperazine-1-carboxylate (1.1 g, 2.9 mmol was dissolved in toluene (25 mL) and to the resultant solution was added potassium carbonate (4.0 g, 28.8 mmol). The mixture was heated to reflux overnight, cooled to RT and then the solids were filtered off. The solvent was removed by evaporation and the product was purified by chromatography on silica gel (methanol-methylene chloride 1% to 10%). There was obtained 0.19 g (23%) of benzyl (9aS)-4-oxohexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3): 2.6-3.0 (m, 3H), 3.4-3.6 (m, 2H), 4.0 (d, 1H), 4.1-4.3 (m, 4H), 4.5 (d, 1H), 5.1 (s, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 150 mg (0.37 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 3 mL THF and 0.82 mL 1M 4-chlorophenylmagnesium bromide. Yield: 73 mg of a white solid. LC-MSD, m/z for C22H14BrClN2O2 [M+H]+=453.0, 455.0; HPLC retention time: 2.6 min.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=3)[N:10]([C:23](=[O:31])[NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]1>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][C:20]([N:33]4[CH2:36][CH2:35][CH2:34]4)=[O:22])[CH:15]=3)[N:10]([C:23]([NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)=[O:31])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCCC(=O)O)cc12
Reactant: C1CNC1
Agent: Cl
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCCC(=O)N3CCC3)cc12

Procedure:
4-(1′-Acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)butanoic acid and azetidine hydrochloride
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:23][CH2:24][CH2:25]Br>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH2:24][Br:23])=[CH:11][C:10]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)c(F)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(OCCBr)ccc1OCc1ccccc1

Procedure:
2-(4-Benzyloxy-3-fluorophenoxy)ethyl bromide was prepared from 4-benzyloxy-3-fluorophenol (5.45 g, 0.025 mol), potassium carbonate (8.63 g, 0.625 mol) and 25 mL of 1,2-dibromoethane as a pale yellow solid (6.6 g, 81%): mp 63-65° C. 1H NMR (CDCl3) 3.606 (t, J=6.3 Hz, 2 H), 4.218 (t, J=6.3 Hz, 2 H), 5.082 (s, 2 H), 6.582 (m, 1 H), 6.699 (m, 1 H), 6.914 (m, 1 H), 7.318-7.440 (m, 5 H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][CH2:25][CH:26]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:1]1[C:10]2[CH:9]([NH:11][CH2:26][CH2:25][CH2:24][CH2:23][N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]3=[O:12])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: NC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione was prepared following the general procedure B for reductive amination. To a solution of 5,6,7,8-Tetrahydro-quinolin-8-ylamine (1.0609 g, 7.1 mmol) and 4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (1.4079 g, 6.8 mmol) (prepared according to the procedure for COMPOUND 18) in methylene chloride (64 mL) was added NaBH(OAc)3 (4.07 g, 19.2 mmol) and the reaction stirred at room temperature for two hours. The reaction was quenched with 1N NaOH (45 mL), extracted with methylene chloride (2×55 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—MeOH—NH4OH) provided 1.16 g (52%) of 2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione. 1H NMR (CDCl3) δ 1.57-1.66 (m, 3H), 1.69-1.84 (m, 4H), 1.93-2.03 (m, 1H), 2.07-2.13 (m, 1H), 2.69-2.86 (m, 4H), 3.70-3.77 (m, 3H), 7.03-7.07 (m, 1H), 7.35 (d, 1H, J=7.2 Hz), 7.67-7.73 (m, 2H), 7.80-7.85 (m, 2H), 8.37 (d, 1H, J=3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:6]2[NH:7][C:8](=[O:18])[CH2:9][N:10]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:11][C:5]=2[CH:4]=1.[F-].[Cs+].[C:26](#N)C.CI>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH3:26])[C:8](=[O:18])[CH2:9][N:10]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:11][C:19]=2[C:20]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)C(F)(F)F)C2
Reactant: CC#N
Agent: [Cs+]
Agent: [F-]
Solvent: CI
Product: COc1ccc2c(c1[N+](=O)[O-])CN(C(=O)C(F)(F)F)CC(=O)N2C
Yield: 91.5 %

Procedure:
A mixture of 7-Methoxy-8-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (3.00 g, 0.00900 mol), Cesium fluoride (3.40 g, 0.022 mol), Acetonitrile (100 mL, 2 mol) and Methyl iodide (1.68 mL, 0.026 mol) were reacted in an analogous manner to example 736-C to give 7-Methoxy-1-methyl-6-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (2.86 g, 91%). Mp 71-74° C.; LCMS (m/e) 348 (M+1); 1H-NMR (DMSO, 400 MHz) δ 8.06 (s, 0.5H), 805 (s, 1H), 7.75 (s, 1H), 7.65 (s, 0.5H), 4.77 (s, 1H), 4.73 (s, 2H), 4.09 (s, 1H), 4.03 (s, 2H), 3.96-95 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])[CH2:16][CH2:15]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC(F)F)CC1)C(F)(F)F
Yield: 64.9 %

Procedure:
A solution of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (438 mg, 2.07 mmol), (R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide (438 mg, 2.07 mmol) and DIPEA (1 mL) in EtOH (4 mL) was heated at 155° C. in the microwave for 5 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale orange gum (518 mg). A portion of this gum (39 mg, 0.10 mmol) in dry THF (2 mL) was treated with sodium hydride (60% in mineral oil, 5 mg, 0.12 mmol). After stirring at room temperature for 10 min, iodomethane (0.01 mL, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 2 hr. The reaction was repeated on the remaining (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide. Water (50 mL) was added carefully and the mixture was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure to give (R)—N-(1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (518 mg). This gum (514 mg, 1.29 mmol) was dissolved in MeOH (20 mL) and treated with ammonium formate (325 mg, 6.15 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85° C. for 2 hr. After cooling to room temperature the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (50 mL) and water (30 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford (R)—N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide as a pale yellow gum (348 mg, 46% over three steps). 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 6.19 (tq, J=55.4, 4.4 Hz, 1H), 4.65-4.15 (m, 3H), 3.40-3.10 (m, 4H), 3.10 and 2.97 (2s, 3H), 2.80 (br s, 2H), 2.10-1.70 (m, 6H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[N:7]=[C:8]([C:16]2[CH:17]=[N:18][C:19]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)[S:9][C:10]=1[C:11]([O:13]CC)=[O:12])=[O:5])[CH3:2].[OH-].[Li+]>CO>[CH2:1]([NH:3][C:4]([C:6]1[N:7]=[C:8]([C:16]2[CH:17]=[N:18][C:19]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)[S:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc(C(=O)NCC)c(C(=O)OCC)s2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)Nc1ccc(-c2nc(C(=O)NCC)c(C(=O)O)s2)cn1
Temperature: 50 °C
Yield: 66683.7 %

Procedure:
To a stirred solution of ethyl 4-ethylcarbamoyl-2-[6-(3-ethyl-ureido)-pyridin-3-yl]-thiazole-5-carboxylate (Example 59, 0.210 mg, 0.538 mM) in methanol (4 mL) was added 2 N lithium hydroxide (2 mL). The reaction mixture was heated to 50° C. overnight, then cooled to room temperature, and concentrated to dryness. Water was added and the pH was adjusted with 2N hydrochloric acid to pH 2. The precipitated solid was filtered and dried under vacuum to afford 0.13 g (66.6%) of the title compound as a solid. NMR: 1.11 (t, 3H), 1.23 (t, 3H), 3.19 (q, 4H), 7.71 (d, 1H), 7.81 (br s, 1H), 8.41 (d, 1H), 9.01 (s, 1H), 9.66 (s, 1H), 9.83 (br s, 1H).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:11]([CH2:17][N:18]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[C@H:19]([C:24]([NH:26][C@H:27]([C:31]([O:33][CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:8][C@@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:11]([OH:10])[CH2:17][N:18]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[C@H:19]([C:24]([NH:26][C@H:27]([C:31]([O:33][CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(CC1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)C)C(=O)OCc1ccccc1)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(CC(O)[C@@H](N)CC(C)C)C(=O)OCc1ccccc1)C(C)C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
A solution of 177 mg (nom. 0.27 mmol) of N-[N-[[(4S)-3-[(t-butyloxy)carbonyl]-2,2-dimethyl-4-(2-methylpropyl)-5-oxazolidinyl]methyl]-N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valine, methyl ester (Isomer A) in 1.7 ml of dry dichloromethane was cooled in an ice bath under nitrogen, then treated with 0.85 ml of distilled trifluoroacetic acid. After 11/2 hours, the reaction was concentrated in vacuo to an oil, dissolved in 1 ml of distilled tetrahydrofuran, and treated with 0.6 ml (0.6 mmol) of 1N hydrochloric acid. After four hours, the reaction was worked up by treating with 6 ml of saturated sodium bicarbonate (aqueous), then extracting with 2×6 ml of chloroform, washing the organic extracts with brine, drying (magnesium sulfate), and concentrating to afford 127 mg of the title compound as a crude oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:4].C([O-])([O-])=O.[K+].[K+].C[C:26]([N:28](C)[CH3:29])=O>C1COCC1>[C:15]([C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:28]([CH3:29])[CH3:26])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(2-tert-butyl-5-nitro-phenyl)-acetamide (80 g, 253 mmol) and K2CO3 (70 g, 506 mmol) were combined in a 3-L 3-neck round bottom flask fitted with a mechanical stirrer, N2 inlet, and pressure equalizing addition funnel. THF (1.75 L) was added and the mixture was cooled to 0° C. under N2. DMA (400 mL of a 2 M solution in THF, 800 mmol) was added to the mixture through the pressure equalizing addition funnel over 30 min. The mixture was gradually warmed to RT with stirring overnight. The reaction was quenched by filtering it under vacuum and then concentrating the filtrate under reduced pressure. The recovered material was eluted through a 36×7 cm column of silica gel with 50% EtOAc:Hexanes giving N-(2-tert-butyl-5-nitro-phenyl)-2-dimethylamino-acetamide as a brown solid.
Reaction SMILES: C([CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)=O.Cl>CO.O1CCCC1>[CH3:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)sc2-c2ccc(NCC=O)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNc1ccc(-c2sc(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.5 %

Procedure:
A mixture of 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonitrile (2.2 g) and concentrated hydrochloric acid (13 ml) in methanol (60 ml) and tetrahydrofuran (40 ml) was stirred at ambient temperature for 2.5 hours. The mixture was concentrated and the residue was triturated in a sodium bicarbonate solution to give a powder. The crude powder was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (4:1) to give a yellow powder of 5-[4-(methylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonitrile (1.4 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].[C:25]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:34][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[O:21])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(OCc2ccc(C(=O)O)cc2)c2ccccc2n1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCc1cc(OCc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
4-[(2-Propylquinolin-4-yloxy)methyl]benzoic acid (240 mg) was added to a mixture of benzene sulphonamide (120 mg), 4-dimethylaminopyridine (90 mg) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (150 mg) in dichloromethane (20 ml) and the mixture stirred overnight. Chloroform (20 ml) was added the mixture was washed successively with 1M citric acid solution (10 ml), water (2×10 ml), saturated sodium chloride solution (5 ml) and then dried (MgSO4). The solvent was removed by evaporation and the residue triturated with methanol to give 4-[(2-propylquinolin-4-yloxy)methyl]-N-phenylsulphonylbenzamide as a white powder (160 mg), m.p. 140° C. (dec.); NMR (d6 -DMSO): 0.95(t,3H), 1.79(m,2H), 2.88(t,2H), 5.5(s,2H), 7.14(s,1H), 7.5-7.7(m,6H), 7.78(dt,1H), 7.87-8.02(m,5H), 8.18(dd,1H); mass spectrum (-ve FAB, DMSO/Gly): 495 (M-H)- ; microanalysis found: C,66.1; H,5.4; N,5.8%; C26H24N2O4S.0.5H 2 O requires: C,66.5; H,5.3; N,6.0%.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[C:6]=1[F:16])=[N+]=[N-].C(OC(=O)C)C.[ClH:23]>[Pd].CO>[ClH:23].[F:16][C:6]1[C:7]([O:11][C:12]([F:14])([F:15])[F:13])=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCc1cccc(OC(F)(F)F)c1F
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NCc1cccc(OC(F)(F)F)c1F
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 1-(azidomethyl)-2-fluoro-3-(trifluoromethoxy)benzene (0.81 g, 3.46 mmol, Step-3), palladium 10% on carbon (0.20 g), 4M hydrochloric acid ethyl acetate solution (4 mL), and methanol (20 mL) is stirred at room temperature under hydrogen atmosphere (1 atm). After filtration through a pad of celite, the filtrate is concentrated under reduced pressure. The residue is crystallized from ether and diisopropyl ether to give 0.85 g (>99% yield) of the title compound as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].COP([CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC)=O.[CH3:24][NH:25][C:26](=[O:46])[C@H:27]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[NH:28][C:29](=[O:36])[C:30](=O)[CH2:31][CH:32]([CH3:34])[CH3:33].O>CN(C)C=O>[CH3:24][NH:25][C:26](=[O:46])[C@H:27]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[NH:28][C:29](=[O:36])[C:30]([CH2:31][CH:32]([CH3:33])[CH3:34])=[CH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=O)CC(C)C
Reactant: COP(=O)(CC(=O)OCc1ccccc1)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=CC(=O)OCc1ccccc1)CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tertiary butoxide (2.1 g., 0.0188 mol.) was suspended in dry dimethylformamide (50 mls.). To the suspension was added benzyl dimethylphosphonoethanoate (4.6 g., 0.0187 mol.) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. N-(4-Methyl-2-oxopentanoyl)-O-methyl-L-tyrosine N-Methylamide (3.0 g., 0.00913 mol) was added portionwise to the reaction mixture over a period of 10 minutes to yield a red solution. The red solution was stirred at room temperature for 4 hours, and then poured into water (500 mls.). The resulting mixture obtained was extracted with ethyl acetate (2×100 mls.) and the ethyl acetate extract was washed with water (2×25 mls.), brine (25 mls.) and dried over anhydrous magnesium sulfate. The ethyl acetate was removed by evaporation in vacuo to yield a crude solid product (4.2 g.). The crude product was purified by recrystallization from a mixture of ethyl acetate and hexane to yield E and Z N-[3-(benzyloxycarbonyl)-2-(2-methylpropyl)propenoyl]-O-methyl-L-tyrosine N-methylamide as a light brown crystalline solid. (m.p. 167°-9° C. Found: C, 68.3; H, 7.1; N, 6.3 %. C25H30N2O5 requires C, 68.5; H, 6.9; N, 6.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.C(O[K])(C)(C)C.[CH:16]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])[CH3:17]>C1COCC1>[CH:16]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])[CH3:17]
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(OC2CCN(C(=O)OC(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
4,6-Dichloro-2-methyl-pyrimidine (163 mg, 1 mmol) was dissolved in 4 mL of THF. A solution of tBuOK (112 mg, 1 mmol) and 2a (187 mg, 1 mmol) in 2 mL of THF was added slowly at room temperature. The mixture was stirred at room temperature for 8 h and quenched with a saturated solution of NH4Cl. The mixture was diluted with water and extracted with DCM. The organic layer was isolated, dried, filtered and evaporated to give 100 mg of 14a.