Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[C:12]([I:15])=[C:11]([CH3:16])[NH:10][C:9]=1[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[H][H].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([O:14][C:13]1[C:12]([I:15])=[C:11]([CH3:16])[N:10]=[C:9]([CH3:17])[C:8]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: CCCCCCCc1c(C)[nH]c(C)c(I)c1=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCc1c(C)nc(C)c(I)c1OCc1ccccc1
Temperature: 50 °C

Procedure:
Compound 5 (38 mg, 0.11 mmol) was added to a stirred suspension of oil-free NaH (5 mg, 0.11 mmol) in DMF (5 mL). When evolution of hydrogen ceased, benzyl chloride (14 mg, 0.11 mmol) was added and the mixture was heated at 50° C. for 4 h. The reaction mixture was added to water (5 mL), extracted with portions of ethyl ether. The combined organic phase was dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. Elution with 1:1 hexane/ethyl acetate gave 4-(benzyloxy)-3-heptyl-5-iodo-2,6-dimethylpyridine (19) as a light yellow oil: yield 38 mg (80%); silica gel TLC Rf 0.7 (1:1 hexane/ethyl acetate); 1H NMR (CDCl3) δ 0.61-0.89 (m, 3H), 1.26-1.31 (m, 10H), 2.504 (s, 3H), 2.62-2.65 (m, 2H) 2.75 (s, 3H), 4.95 (s, 2H), 7.38-7.43 (m, 4H) and 7.55-7.57 (m, 1H).
Reaction SMILES: [Br:1][CH:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C1COCC1>[Br-:1].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N+:20]=1[CH:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)C(Br)CCc1ccccc1
Reactant: Nc1ccccn1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(CCc1ccccc1)[n+]1ccccc1N
Product: [Br-]
Yield: 54.4 %

Procedure:
To a solution of ethyl 3-bromo-2-oxo-5-phenylpentanoate (1.9 g) in THF (10 ml) was added 2-aminopyridine (600 mg) at room temperature, and the reaction mixture was heated under reflux for 15 hr. The precipitated crystals were collected by filtration, washed with THF to give 2-amino-1-[3-ethoxy-2,3-dioxo-1-(2-phenylethyl)propyl]pyridinium bromide (1.36 g). 2-Amino-1-[3-ethoxy-2,3-dioxo-1-(2-phenylethyl)propyl]pyridinium bromide (1.36 g) was dissolved in ethanol (10 ml), and the mixture was refluxed under heating for 3 hr. The reaction mixture was concentrated, and dissolved in dichloromethane. The solution was washed successively with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-diethyl ether to give the object product (950 mg).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Cl[CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[F:11][C:5]1[CH:6]=[C:7]([O:10][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[CH2:26][N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[CH3:20])=[O:12]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: ClCc1cccs1
Reactant: COC(=O)c1ccc(O)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2cccs2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures D and E using 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5], 2-chloromethyl-thiophene [CAS 2746-23-8], and 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 403.3
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:21]1>>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([C:3]2[C:4](=[O:10])[NH:5][CH:6]([CH:7]([CH3:9])[CH3:8])[C:2]=2[OH:1])[C:21]2[NH:20][C:28]3[C:23]([C:22]=2[CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)C1NC(=O)C=C1O
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(C(C)C)NC2=O)c2ccc(F)cc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with 4-fluoro-benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a yellow solid. MS: 450.3 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]4)=[O:16])=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:38](O)=[O:39].C([O-])(O)=O.[Na+]>O>[OH:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]4)=[O:16])=[CH:11][CH:10]=3)[S:8][C:4]=2[C:3]=1[CH:38]=[O:39]
Reactant: CC1CCN(C(=O)c2ccc(-c3nc4ccc(O)cc4s3)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1CCN(C(=O)c2ccc(-c3nc4ccc(O)c(C=O)c4s3)cc2)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of [4-(6-Hydroxy-benzothiazol-2-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone (120 mg, 0.34 mmol), hexamethylenetetramine (190 mg, 1.36 mmol) and trifluoroacetic acid (2 mL) was stirred in a closed vessel under argon atmosphere at 120° C. for 1 h. The reaction was cooled to room temperature and 10 mL of water was added. The pH of the mixture was adjusted to 8 by dropwise addition of saturated NaHCO3 solution, and extracted with dichloromethane (3×15 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica (Kieselgel 60), eluting with chloroform-methanol 99:1. The title compound (34 mg, 0.089 mmol, 26%) was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:27]C([N-]C(C)C)C.CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][C:9]1([CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To ethyl 1,4-dibenzylpiperazine-2-carboxylate (35.4 g, 0.1 mol) in THF(200 mL) cooled to −78° C. was added dropwise LDA (64 mL, 1.8 M). The reaction was stirred at −78° C. for 1 h then MeI (7.2 mL, 0.11 mol) was added. The reaction was allowed to slowly warm to RT then quenched with sat'd NH4Cl. Water (200 mL) was added and the residue was extracted with EtOAc (200 mL). The EtOAc layer was washed twice with water then the solvent was removed in vacuo. Silica gel chromatography provided ethyl 1,4-dibenzyl-2-methylpiperazine-2-carboxylate (compound 10A) 14.91 g. HPLC RT: 2.42 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm). (M+H)+:353.
Reaction SMILES: [CH3:1][CH:2]1[CH:7](C(OCCCC)=O)[C:6](=O)[CH2:5][C:4](=[O:16])[CH2:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CS(C)=O>[CH3:1][CH:2]1[CH2:3][C:4](=[O:16])[C:5]2[S:24][C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:17][C:6]=2[CH2:7]1
Reactant: CCCCOC(=O)C1C(=O)CC(=O)CC1C
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Product: CC1CC(=O)C2=C(C1)Nc1ccccc1S2

Procedure:
A mixture of ter butyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7c (3.09 g, 13.7 mmole) and 2-aminothiophenol, 6 (X=H, 1.71 g, 13.7 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate was separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4d, (R=H), mp 278° C. occurs as light orange crystals; yield: 0.46 g (15.4%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20])[CH3:17]>O1CCOCC1.C(OCC)(=O)C.CCCCCCC.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:21][C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)C=Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a stirred solution of 23.4 g (0.188 mole) of 3-phenoxybenzaldehyde in 175 mL of 1,4-dioxane was added 45.2 grams (0.130 mole) of ethoxycarbonylmethylenetriphenylphosphorane in one portion. The reaction was allowed to stir at ambient temperature overnight. The solvent was evaporated under reduced pressure, leaving a residue which was dissolved in ethyl acetate. Approximately 30 grams of silica gel was mixed with this solution. This solvent was evaporated under reduced pressure, and the silica gel was placed in a sintered glass filter. The silica gel was eluted with 1000 mL of heptane/ethyl acetate (3:1). The solvent was evaporated under reduced pressure, leaving an oil. This oil was dissolved in 150 mL of heptane/ethyl acetate (9:1), treated with 15 grams of silica gel, and filtered. The filtrate was evaporated under reduced pressure, leaving 26.7 grams of ethyl 3-(3-phenoxyphenyl)acrylate as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:34]3[C:29]([CH:30]=[CH:31][CH:32]=[CH:33]3)=[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=3)[C:27]=2[CH3:45])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C.[CH2:53]([NH2:56])[CH2:54][CH3:55]>O1CCOCC1.O>[CH3:44][O:43][C:41]([C:37]1[CH:36]=[C:35]([C:28]2[C:27]([CH3:45])=[C:26]([C:24]([C:21]3[CH:22]=[CH:23][C:14]([NH:13][C:5](=[O:11])[NH:56][CH2:53][CH2:54][CH3:55])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[O:25])[N:34]3[C:29]=2[CH:30]=[CH:31][CH:32]=[CH:33]3)[CH:40]=[CH:39][CH:38]=1)=[O:42]
Reactant: COC(=O)c1cccc(-c2c(C)c(C(=O)c3ccc(N)c(C(=O)OC)c3)n3ccccc23)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCN
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCNC(=O)Nc1ccc(C(=O)c2c(C)c(-c3cccc(C(=O)OC)c3)c3ccccn23)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.143 mg (0.47 mmol) of triphosgene diluted in 2 ml of dioxane are added, under an inert atmosphere at ambient temperature, to 308 mg (0.68 mmol) of methyl 2-amino-5-({1-[3-(methoxycarbonyl)phenyl]-2-methylindolizin-3-yl}carbonyl)benzoate in 5.6 ml of dioxane. The reaction medium is stirred for 2 hours at ambient temperature and then 0.28 ml (2.03 mmol) of triethylamine, and 0.11 ml (1.35 mmol) of n-propylamine diluted in 4 ml of dioxane are added. After stirring for 2 hours, the reaction medium is hydrolysed with water. The aqueous phase is extracted with dichloromethane. The organic phase obtained is washed with a 1N aqueous solution of hydrochloric acid, and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7](Cl)(Cl)=[S:8].[NH2:11][NH2:12]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]=[C:7]=[S:8].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:8])[NH:11][NH2:12]
Reactant: NN
Reactant: COCCCN
Reactant: S=C(Cl)Cl
Solvent: c1ccncc1
Product: COCCCN=C=S
Product: COCCCNC(=S)NN

Procedure:
The title compound was synthesized in a manner similar to that described in Example 1. 3-Methoxy-n-propyl isothiocyanate was prepared from 3-methoxy-n-propylamine and thiophosgene at high temperature and then reacted with hydrazine in pyridine to give the intermediate 4-(3-methoxy-n-propyl)-3-thiosemicarbazide. 4-(3-Methoxy-n-propyl)-3-thiosemicarbazide (1.64 g) was reacted with 1-ethyl-3-methylpyrazole-5-carboxylic acid chloride (1.73 g, prepared from the acid and oxalyl chloride) to give 2 g of 1-(1 ethyl-3-methylpyrazole-5-carbonyl)-4-(3-methoxy-n-propyl)-3-thiosemicarbazide. Treatment of 1-(1-ethyl-3-methylpyrazole-5-carbonyl)-4-(3-methoxy-n-propyl)-3-thiosemicarbazide with potassium hydroxide in ethanol gave 3-(1-ethyl-3-methylpyrazol-5-yl)-5-mercapto-4-(3-methoxy-n-propyl)-1,2,4-triazole. Reaction of the sodium salt of 3-(1-ethyl-3-methylpyrazol-5-yl)-5-mercapto-4-(3-methoxy-n-propyl)-1,2,4-triazole (0.73 g) with 2-bromo-5-nitrothiazole (0.52 g) yielded crude 3-(1-ethyl-3-methylpyrazol-5-yl)-4-(3-methoxy-n-propyl)-5-[5-(nitrothiazol-2-yl)mercapto]-1,2,4-triazole as in Example 1. Crystallization from ethanol and water gave 0.3 g of 3-(1-ethyl-3-methylpyrazol-5-yl)-4-(3-methoxy-n-propyl)-5-[5-(nitrothiazol-2-yl)mercapto]-1,2,4-triazole, a light brown solid, MP 117°-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH:14]C(OC)=O)=[N:10]2)=[CH:5][CH:4]=1.[OH-].[K+].Cl>O.CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)Nc1ccn(-c2ccc(OC)cc2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2ccc(N)n2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[(methoxycarbonyl)amino]-1H-pyrazole-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide (0.22 g, 0.42 mmol) in 10 mL of 1:1 water/methanol was added potassium hydroxide (2.0 g, 35 mmol). The resulting mixture was stirred at 70° C. for 4 h and then was cooled to ambient temperature and was acidified with aq HCl. The reaction mixture was diluted with ethyl acetate and the organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 75 mg (38%) of the title compound as a white powder. LRMS (ES+): 463.8 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:69]1([CH2:75][C:76](O)=[O:77])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:76](=[O:77])[CH2:75][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2ccccc2)C2CC2)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.56 mmol) in CH2Cl2 (6 mL) are subsequently added Et3N (0.094 mL, 0.67 mmol), 1-hydroxy-benzotriazol hydrate (0.09 g, 0.67 mmol), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (0.129 g, 0.67 mmol) and phenylacetic acid (0.09 g, 0.67 mmol), followed by stirring overnight. The reaction mixture is diluted with CH2Cl2 and then washed with 1N HCl (5 mL), saturated aqueous NaHCO3 and brine, the organic layer is dried over MgSO4 and concentrated. Purification by flash chromatography (eluent: hexane/AcOEt 25:75, then AcOEt 100%) gives the title compound as colorless oil. MS (LC-MS): 652.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/1.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.80 min.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30](O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)(OCC)=O.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: C1COCCN1
Agent: CCOP(=O)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 ml.) under a nitrogen atmosphere at 0°-5° C. was added triethylamine (1.6 ml.) followed by dropwise addition of ethyl dichlorophosphate (1.36 ml.) over 5 minutes. After stirring for 3 hours at 20° C., the reaction mixture was cooled to 0° C. and morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction temperature maintained at 0°-5° C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1ccc(CO)nc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (5-methyl-pyridin-2-yl)methanol and DBU in DME. EI-MS m/e (%): 307 (M+, 76), 290 (28), 278 (16), 122 (100), 106 (78), 79 (30), 77 (38).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[Cl-].Br[CH2:26][O:27][C:28](=[O:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[C:8]2[C:12]([O:14][CH2:26][O:27][C:28](=[O:30])[CH3:29])=[O:13])[CH3:3]
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reactant: CC(=O)OCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2=C(C(=O)OCOC(C)=O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Yield: 48 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.18 g) in dry DMF (3.6 ml) was ice-cooled, and thereto was added triethylbenzylammoniun chloride (0.11 g). To the mixture was gradually dropped bromomethylacetate (0.16 ml) and the mixture was gradually allowed to room temperature and stirred. Forty minutes later, thereto was added ethyl acetate, and the mixture was washed with bicarbonate solution, water and brine, successively. The organic layer was dried over sodium sulfate, concentrated and the residue was purified with silica gel column chromatography (ethyl acetate only) to give (acetyloxy)methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(4-methoxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.15 g, yield 48%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:23]1[N:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[N:27][CH:28]=1>CN(C)C=O>[CH3:32][O:31][C:29]([C:26]1[N:27]=[CH:28][C:23]([O:21][C:18]2[CH:19]=[CH:20][C:13]3[CH2:12][CH2:11][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:16][CH2:15][C:14]=3[CH:17]=2)=[N:24][CH:25]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (6.4 g, 0.16 mol) was added portionwise to a solution of 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (40 g, 0.15 mol) in dry dimethylformamide (200 ml) cooled to 5° C. over 15 minutes. After 15 minutes, the mixture was allowed to warm to room temperature and stirred for 60 minutes. The mixture was cooled in an ice-water bath and methyl 5-chloro-2-pyrazinecarboxylate (31.2 g, 0.18 mol) was added portionwise. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was poured onto water (500 ml) and ice (500 ml) and stirred until the ice had melted. The resulting solid was collected by filtration, washed with water and dissolved in ethyl acetate (1500 ml). The ethyl acetate layer was washed with brine (200 ml), dried under sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:2) to afford the title compound (35.07 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.[CH3:45]OC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.C1(C)C=CC=C(B(O)O)C=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:41]=[CH:42][CH:43]=[C:2]([CH3:45])[CH:3]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: Cc1cccc(B(O)O)c1
Product: COc1ccc(-c2cccc(C)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 27 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with m-tolylboronic acid (36 mg, 0.2625 mmol) to produce the title compound (27 mg, 27% yield).