Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[CH:28]([C:31](Cl)=O)([CH3:30])[CH3:29]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH:28]([C:31]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:19][C@H:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[C:13]4[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=4[C:11]3=[O:26])[CH:7]=[CH:8][CH:9]=2)[N:27]=1)([CH3:30])[CH3:29]
Reactant: CC(C)C(=O)Cl
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(C)C)n3)c1)C2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 110.1 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (120 mg, 0.31 mmol) obtained in Step 1 was dissolved in pyridine (1.5 mL), and the mixture was stirred overnight at 90° C. after adding isopropylcarbonyl chloride (0.039 mL, 0.38 mmol) under ice-cooled conditions. The mixture was diluted with chloroform, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-5-[3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (149 mg, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.C(NC1C=CC([O:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([O:42][Si](C(C)(C)C)(C)C)[CH2:38][CH2:37]2)=O)=NC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.CCCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:34]([N:36]3[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]3)=[O:33])=[N:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(=O)N2CCC(O)CC2)nc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A solution of 4-chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide (0.50 g, 2.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (0.90 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in dimethylformamide (10 mL) was stirred overnight at room temperature. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane, filtered over a short pad of silicagel and washed with ethyl acetate:heptane 50:50. The solvent was evaporated in vacuo and the residue was redissolved in acetonitrile and hydrofluoric acid (min. 40% in water, 0.50 mL) was added. After stirring overnight at room temperature the solvent was evaporated in vacuo. Dichloromethane and triethylamine (1 mL) were added and the solution was extracted twice with water, dried over sodium sulphate, filtered and evaporated in vacuo. Crystallisation from ethyl acetate:heptane yielded the title compound (321 mg, 43% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=O)[CH:18]=[CH:19]N(C)C)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]([NH2:28])=[NH2+:27].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([C:17]3[CH:18]=[CH:19][N:25]=[C:26]([NH2:28])[N:27]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Reactant: NC(N)=[NH2+]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)nn3ccccc23)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)pyrazolo[1,5-a]pyridine (60 mg, 0.19 mmol), guanidinium hydrochloride (36 mg, 0.38 mmol), and K2CO3 (105 mg, 0.76 mmol) in N,N-dimethylformamide (3 mL) was stirred in a 110° C. oil bath for 8 h. Additional guanidinium hydrochloride (36 mg, 0.38 mmol) was added, and the mixture stirred in a 110° C. oil bath for 16 h. The mixture was cooled to room temperature, and water (20 mL) added. The resulting tan precipitate was collected by filtration, washed with water, air-dried, the dried under high-vacuum to afford the title compound, 0.033 g (57%). 1H NMR (CDCl3) δ 8.57 (d, 1H, J=6.0 Hz), 8.51 (d, 1H, J=8.9 Hz), 7.98 (d, 2H, J=5.7 Hz), 7.64 (m, 2H), 7.46 (m, 1H), 7.22 (m, 2H), 7.04 (m, 1H), 6.47 (d, 1H, J=5.8 Hz), 5.76 (s. 2H). MS (+ve ion electrospray) 306 (100), (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C@@:13]3([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[C:9]([CH3:27])([CH3:26])[O:8][C:5]2=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[C:4]3[C@@:13]4([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[N:14]4)[C:10]4([CH2:11][CH2:12]4)[C:9]([CH3:27])([CH3:26])[O:8][C:5]3=[CH:6][CH:7]=2)=[O:37])=[N:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21CC1
Reactant: COc1cnc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(COC(NC(=O)OC(C)(C)C)=N2)C2(CC2)C(C)(C)O3)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a mixture of tert-butyl [(4′R)-6′-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (100 mg, 0.268 mmol), 5-methoxypyrazine-2-carboxylic acid (45 mg, 0.30 mmol) and 1H-benzotriazol-1-ol (40 mg, 0.29 mmol) in dichloromethane (2 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol). The mixture was stirred at room temperature for 3 hours and directly purified by silica gel column chromatography (precolumn: NH-silica gel, main column: neutral silica gel, hexane/ethyl acetate=2:1-1:1-0:1) to afford tert-butyl [(4′R)-6′-{[(5-methoxypyrazin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (108 mg).
Reaction SMILES: S([Cl:11])(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:26]=[C:25]([CH2:27]O)[C:24]([C:29]([F:32])([F:31])[F:30])=[CH:23][C:22]=1CO.Cl[CH2:38][Cl:39]>CN(C)C1C=CN=CC=1>[F:19][C:20]([F:36])([F:35])[C:21]1[CH:26]=[C:25]([CH2:27][Cl:11])[C:24]([C:29]([F:32])([F:31])[F:30])=[CH:23][C:22]=1[CH2:38][Cl:39]
Reactant: ClCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cc(C(F)(F)F)c(CO)cc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc(CCl)c(C(F)(F)F)cc1CCl
Reaction time: 4 h
Yield: 62 %

Procedure:
Tosyl chloride (3.9 g, 20.4 mmol), 4-dimethylaminopyridine (936.3 mg, 7.7 mmol), and distilled triethylamine (1.73 mL, 12.4 mmol) were added sequentially to a solution of compound 23 in dichloromethane (30 mL) under Ar at room temperature. The reaction mixture was stirred at this temperature for 4 h. The resulting solution was evaporated and the residue was diluted with hexane (100 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous MgSO4, evaporated, and purified by column chromatography (hexane as eluent) to give product 25 as a white solid (700 mg, 62%); 1H NMR (300 MHz, CDCl3): 7.98 (2H, s), 4.78 (4H, s); 19F NMR (282 MHz, CDCl3): −60.6; HR-MS (EI) calcd. for C10H6F6Cl2 (M+): 309.9745, found: 309.9738.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=1)=[O:3].Cl.CCOCC>C(Cl)Cl>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:9]1[C:8]2[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=[CH:6][CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNc2ncnc3c(C(N)=O)cccc23)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Yield: 97 %

Procedure:
The title compound was prepared as light yellow solid in 97% yield by treating tert-butyl [3-({[8-(aminocarbonyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate with 2N HCl/ether in DCM overnight. The precipitate was filtered, washed with ether and dried. Mass: M+H+: 294.
Reaction SMILES: [NH2:1][C@H:2]([CH:21]([CH3:23])[CH3:22])[C:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([CH3:20])([CH3:19])[CH2:6]1)=[O:4].[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40](O)=[O:41])[CH:35]=1)=[O:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C@@:8]2([OH:11])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:40]([C:36]3[CH:35]=[C:34]([C:29]4[C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:39]=[CH:38][CH:37]=3)=[O:41])[CH:21]([CH3:23])[CH3:22])[CH2:6][C:7]2([CH3:19])[CH3:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccccc1-c1cccc(C(=O)O)c1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccccc1-c1cccc(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)c1
Yield: 64.5 %

Procedure:
(R)-2-Amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one (40 mg, 0.107 mmol), 2′-(methoxycarbonyl)biphenyl-3-carboxylic acid (33 mg, 0.128 mmol), HOBT (20 mg, 0.128 mmol), EDC (25 mg, 0.128 mmol) and triethylamine (0.030 mL, 0.213 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then worked up by adding methylene chloride and washing with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (3:1 to 1:1 Hexanes/EtOAc) to obtain methyl 3′-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)biphenyl-2-carboxylate (40 mg, 0.069 mmol, 65.0% yield) as a white glass. MS found: (M+H)+=577.31.
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=1)([OH:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[CH:11][CH:10]=[C:9]([CH3:26])[N+:8]=1[O-:35])([OH:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CCCCOc2ccc(C)nc2/C=C/CC(=O)O)cc1
Solvent: ClCCl
Product: COc1ccc(CCCCOc2ccc(C)[n+]([O-])c2/C=C/CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2-(E-2-Carboxymethylethenyl)-3-[4-(4-methoxyphenyl)butyloxy]-6-methylpyridine (13.6 g, 38.2 mmol) was dissolved in dry CH2Cl2 (100 mL,) and cooled to 0° C. To this was added 50% mCPBA (13.2 g, 38.3 mmol) in three portions over 10 minutes. The cooling bath was removed and the reaction was stirred for 15 h at room temperature. The reaction was poured into aqueous NaHCO3 and the product extracted into CH2Cl2. The organic extract was washed with H2O and brine and dried (MgSO4). The crude product was obtained as a yellow solid and was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8](=[O:21])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][C:3]=1[C:23]([O:25][CH3:26])=[O:24].O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:7]1[C:8](=[O:21])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]2[C:5]([N:6]=1)=[CH:4][C:3]([C:23]([O:25][CH3:26])=[O:24])=[C:2]([F:1])[CH:11]=2
Reactant: COC(=O)c1cc2[nH]c(=O)c(=O)n(Cc3ccc(OC)cc3)c2cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2nc(Cl)c(=O)n(Cc3ccc(OC)cc3)c2cc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Methyl 7-fluoro-1-(4-methoxybenzyl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (35.0 g, 98 mmol) was added to POCl3 with stirring overnight at 130° C. and concentrated in vacuo. The product was precipitated via the addition of methanol (150 ml) and collected by filtration to afford methyl 3-chloro-7-fluoro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (25.0 g, 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[N:3]=1.C(OC1C=CC(CO)=CC=1)C1C=CC=CC=1.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+]>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:3]=2)=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCc2ccc(OCc3ccccc3)cc2)n1
Agent: O=C([O-])[O-]
Agent: OCc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Product: c1ccc(COc2ccc(COc3cncc(N4CCNCC4)n3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-{[4-(benzyloxy)benzyl]oxy}pyrazine (1.15 g, 3.52 mmol; obtained according to the procedure of example 50, step 1, starting from 4-benzyloxybenzyl alcohol), piperazine (0.894 g, 10.4 mmol) and K2CO3 (0.486 g, 3.52 mmol). The yield of the title compound was 0.57 g (43%) which was obtained as a colorless viscous oil that solidified upon standing. Fragmenting mass analysis supports the stated structure. HRMS m/z calcd for C22H24N4O2 (M)+ 376.1899, found 376.1892.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:15][C:16]#[CH:17])[C:5](=[O:18])[C:4]=1[CH2:19][C:20](OC)=[O:21])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.CCOCC>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]([CH2:15][C:16]#[CH:17])[C:5](=[O:18])[C:4]=1[CH2:19][CH2:20][OH:21])[CH3:2]
Reactant: C#CCn1c(-c2ccccc2)nc(CC)c(CC(=O)OC)c1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C#CCn1c(-c2ccccc2)nc(CC)c(CCO)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 1.35 g (4.4 mmol) of 6-ethyl-5-methoxycarbonylmethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 105) in 30 mL of THF was cooled in an ice bath and a slurry of 0.10 g (2.6 mmol) of lithium aluminum hydride in 10 mL of ether was added. The ice bath was allowed to melt and the reaction mixture was stirred at room temperature for 3 h. An additional 0.05 g (1.3 mmol) of lithium aluminum hydride was added. The mixture was stirred for 1 h at room temperature. The mixture was poured into 100 mL of water and 100 mL of ether and allowed to stand for 1 h. The layers were separated and the aqueous layer was extracted with 100 mL of ethyl acetate. the combined organic extracts were washed with 50 mL of 5% aqueous NaOH and dried over MgSO4. Removal of the solvent left 1.36 g of crude product as an amber syrup. Flash chromatography on 30 g of silica gel, eluting sequentially with 20, 40, 60, 80 and 100% ethyl acetate in hexanes afforded 6-ethyl-5-(2-hydroxyethyl)-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 274) as an oil. 1H-NMR (CDCl3) 1.2(3H,t), 2.35(1H,t), 2.65(2H,q), 2.90(2H,t), 3.85(2H,t), 4.55(2H,d), 7.5(3H,m), 7.7(2H,m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH3:17])=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2C[C@@H]2CN2CCC[C@@H]2C)=[CH:21][CH:20]=1.[NH3:35]>>[CH3:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:35])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: CC1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: N
Product: CC1CCCN1C[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
The title compound was prepared using the procedure described in Example 1E substituting 1-[2-(4-bromo-phenyl)-(1S,2S)-cyclopropylmethyl]-2-methyl-pyrrolidine (the product from Example 5A) for 1-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine (the product from Example 1D). 1H NMR (300 MHz, CD3OD) 0.98 (m, 1H), 1.1 (m, 1H), 1.20 (d, J=6 Hz, 2H), 1.34 (m, 1H), 1.49 (m, 1H), 1.84 (m, 3H), 2.06 (m, 2H), 2.51 (m, 1H), 2.61 (m, 1H), 3.06 (dd, J=12 Hz, J=6 Hz, 0.5H), 3.22 (dd, J=12 Hz, J=6 Hz, 0.5H), 3.34 (m, 1H), 7.22 (dd, J=12 Hz, J=6 Hz, 2H), 7.59 (d, J=9 Hz, 2H), 7.77 (s, 4H)<MS (DCl—NH3) m/z 317 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1/[CH:7]=[C:8]1/[C:9](=[O:21])[C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:11]=2[CH2:19][CH2:20]/1.[ClH:22].C(O)C>[Pd].ClCCl.CO>[ClH:22].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[CH2:20][CH2:19][C:11]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:10]=2[C:9]1=[O:21]
Reactant: Cc1[nH]cnc1/C=C1\CCc2sc3ccccc3c2C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: Cc1[nH]cnc1CC1CCc2sc3ccccc3c2C1=O

Procedure:
A mixture of (E)-3,4-dihydro-2-[(5-methyl-1H-imidazol-4-yl) methylene]-1(2H)-dibenzothiophenone (599 mg), 2N hydrochloric acid (2 ml) and ethanol (50 ml) was hydrogenated at atmospheric pressure and room temperature using a 10% palladium on charcoal catalyst (60 mg) for 20 h. The suspension was warmed on a steam bath for 10 min and then filtered. The filtrate was evaporated to give an oil which was purified by FCC eluting with System A (100:10:1) to give a solid. A solution of this solid in a mixture of dichloromethane (20 ml) and methanol (5 ml) was treated with a slight excess of ethereal hydrogen chloride. The solution was evaporated to give the title compound (449 mg), m.p. 266°-269°, t.l.c. (System A 100:10:1) Rf 0.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(-c3cccc(S(C)(=O)=O)c3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 3-methylsulfonylphenylboronic acid.
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].C([O:15]O)(C)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)C>C1(C)C=CC=CC=1>[O:15]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH:2]1[CH2:1][OH:10]
Reactant: C=CCCCC/C=C/CO
Reactant: CC(C)(C)OO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CCCCCC1OC1CO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
2.72 g (19.4 mM) (E)-nona-2,8-diene-1-ol (11) is added into the reaction mixture after another 5 minutes. Then, after yet another 5 minutes, 6.9 ml of a 3.39 molar solution in toluene (23.4 mM) of tertiary butyl hydroperoxide is added. The reaction mixture is allowed to react for 3 days at -25° C. Subsequently, the reaction vessel is put into an ice bath and 10 ml (1 ml per mM tetraisopropyl titantate added) saturated aqueous sodium sulfate solution and another 100 ml diethyl ether are added to the reaction mixture. The reaction solution is vigorously agitated for approximately 1 hour until the solution has warmed up to room temperature. The gelatinous orange-colored precipitation is separated out by means of a glass filter, washed twice with 100 ml quantities of ether and dried by suction. The solvent is evaporated from the combined filtrates and the residue is mixed with 100 ml ether and 2 ml dimethyl sulfide in order to destroy excess tertiary butyl hydroperoxide. The solution is agitated for one hour. Then, 50 ml 1 molar sodium hydroxide is added and the mixture is agitated another 3-4 hours. The ether phase is separated out, washed with 2×40 ml water, dried over magnesium sulfate and, after evaporation of the solvent in a vacuum, 2.48 g (15.9 mM) 2S, 3S-2-epoxy-1-hydroxynon-8-ene (III) is obtained by bulb tube distillation at 110° C./0.5 mm pressure. This corresponds to a yield of 82%.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:5](=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:15]
Reactant: O=C(O)c1ccccc1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A mixture of thionyl chloride (6 mL) and the benzoic acid was heated at reflux until the starting benzoic acid dissolved. Excess thionyl chloride was removed under reduced pressure leaving the crude acid chloride as a low melting solid which was used without further purification. The crude acid chloride was dissolved in CH2Cl2 (20 mL) and cooled to −10° C. To this stirred solution was added triethylamine (4 mL), followed by the dropwise addition of diethylamine (1.4 equivalents). The heterogeneous reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The reaction mixture was transferred to a separatory funnel containing H2O (20 mL). The organic layer was separated and washed with 5% HCl (2×25 mL), H2O (25 ml), and dried over Na2SO4. The solvent was removed under reduced pressure to afford the product N,N-diethyl benzamide.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].Cl.[CH3:16][NH:17][CH3:18].C(N(C(C)C)CC)(C)C.Cl>C(#N)C.C(OCC)(=O)C>[CH3:16][N:17]([CH3:18])[C:9]([C@@H:8]1[CH2:13][C@H:11]([SH:10])[CH2:12][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:14]
Reactant: CNC
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2 -thia-5-azabicyclo[2.2.1]heptan-3-one (39.2 mg) in acetonitrile (1 ml) were added dimethylamine hydrochloride (16.5 mg) and diisopropylethylamine (35.7 mg). The mixture was stirred for 3 hours at room temperature. After the reaction was over, 1N-hydrochloric acid (0.092 ml) was added thereto, and the mixture was diluted with ethyl acetate (2 ml) and dried over magnesium sulfate. Distillation of the solent, followed by purifying the residue by silica gel chromatography, gave oily (2S,4S) -N,N-dimethyl-1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarboxamide.