Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:39]([O-])=O)=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[H][H]>C1COCC1.CCO>[NH2:39][C:32]1[CH:31]=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19](=[O:22])[NH:20][CH3:21])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: [H][H]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 75 %

Procedure:
A stirred suspension of 59.5 g (102 mmol) of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate and 6.0 g of 10% Pd(C) in 1.2 L of 2:1 THF/EtOH was saturated with hydrogen by bubbling hydrogen gas through for 10 minutes and then subjected to balloon hydrogenation at RT. After 6 hours LCMS indicated complete reaction. After 24 hours the mixture was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated to dryness at reduced pressure to give a light yellow solid. This material was recrystallized from hot EtOAc to afford 42.2 g of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a white solid. The filtrate was concentrated to dryness at reduced pressure to give an additional 13.0 g of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a light yellow foam determined to be 95% pure by LCMS. The two batches were combined for a total yield of 55.2 g (98%) of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (q, J=4.42 Hz, 1H) 8.16 (s, 1H) 7.91-8.00 (m, 3H) 7.61 (dd, J=8.98, 2.73 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H) 7.15 (s, 1H) 6.76-6.86 (m, 3H) 3.79 (s, 3H) 3.28 (s, 3H) 2.83 (d, J=4.68 Hz, 3H) 2.25-2.38 (m, 1H) 0.82-1.10 (m, 3H) 0.42 (m, 1H). LCMS(ESI): 552 (M+H+).
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].C(OP(C[C:28]([OH:30])=[O:29])(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.C([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=2[F:47])=[CH:36][CH:35]=1)(=O)C>C1COCC1>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[C:37]1[CH:36]=[CH:35][C:34]([C:5]([CH3:6])=[CH:7][C:28]([OH:30])=[O:29])=[CH:39][CH:38]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)CP(=O)(OCc1ccccc1)OCc1ccccc1
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 12 h

Procedure:
A solution of 21.4 g. of lithium diisopropylamide in 200 ml. of THF is added to a stirred solution of 32 g. of α-dibenzylphosphonoacetic acid (carboxymethylphosphonic acid dibenzyl ester) in 300 ml. of THF at -80°. Then a solution of 23.2 g. of 4-acetyl-2',4'-difluorobiphenyl in 250 ml. of THF is asdded. The mixture is stirred for 12 hours more, during which it is allowed to come to room temperature. The product Z--C(CH3)(OLi)--CH[P=O (OCH2C6H5)2 ]COOLi (Z is 2',4'-difluoro-4-biphenylyl), which is formed, is hydrolyzed with dilute acetic acid/ice. The customary work up gives 3-(2',4'-difluoro-4-biphenylyl)-2-butenoic acid, m.p. 193°-195°.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].O>C1COCC1>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:13]1[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCOC(=O)c1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A 40 ml of 2.5 M solution of n-butyllithium in hexane was transferred under argon dropwise to a solution of 14 ml of diisopropylamine in 200 ml of anhydrous THF at −20° C. over 10 minutes. The solution was stirred at −20° C. for 3 hours and at 0° C. for fifteen minutes to form a lithium diisopropylamide (LDA) solution. The LDA solution was then cooled to −78° C. and a solution of 15.65 g ethyl thiophene-2-carboxylate in 25 ml THF was added dropwise. After the solution thus obtained was stirred for 1 hour at −78° C., 30 ml of tributyltin chloride in 25 ml of THF was added dropwise. The reaction was then stirred at −78° C. for another hour and at room temperature overnight. After 200 ml of water was slowly added, the organic layer was collected, dried with Na2SO4, and concentrated and then vacuum distilled at about 650 mTorr. The fraction between 162-165° C. was collected to give 26.71 g (60.0%) of the desired product as a light yellow liquid, whose chemical structure was confirmed by NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:4]=1[C:5]#[N:6].C1C(=O)N([Br:21])C(=O)C1>>[Br:21][CH2:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(C#N)c(OC)cc1C
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(CBr)c(OC)cc1C#N

Procedure:
2,5-Dimethoxy-4-methylbenzonitrile (4.06 g, 21.5 mmol) is brominates with NBS according to Example 1A to give 4-bromomethyl-2,5-dimethoxybenzonitrile. 1H NMR (400 MHz, CDCl3) δ (ppm) 6.95 (s, 1H), 6.91 (s, 1H), 4.43 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:19][CH3:20])(C)[CH2:11][C:12](=[CH:16][CH:17]=1)[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]CN(C(C)C)C(C)C.C1CN([P+](O[N:47]2[N:55]=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.NN>C(Cl)Cl.C1COCC1>[CH2:1]([O:8][C:9]1[C:17]([CH3:21])=[CH:16][C:12]([C:13]([NH:47][NH2:55])=[O:15])=[CH:11][C:10]=1[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(C)CC(C(=O)O)=CC=C1OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-benzyloxy-3-ethyl-3-methyl-benzoic acid (8.3 g, 30.7 mmol) in DCM (300 mL) is added DIPEA (10.7 mL) and the mixture is cooled to 0° C. before PyBOP (14.5 g, 33.8 mmol) is added. After 10 min, a solution of 1M hydrazine in THF (100 mL) is added dropwise and the mixture is slowly warmed to rt during 2 h. The reaction mixture is then washed with sat. aq. NaHCO3 followed by brine. The org. phase is collected, dried over MgSO4, filtered and evaporated to give the title compound as a yellow wax (24 g, 40% purity). LC-MS: tR=0.82 min; [M+H]+=285.10.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].[CH:34]1([NH:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(O)C>[CH:41]1([NH2+:40][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1.[CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:9]1([C:14]([O-:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: CCO
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: CCOC(=O)CCN(C1(C(=O)[O-])CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A solution of 3.10 g (6.5 mmol) of crude 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid in 30 mL of ethanol was treated with 1.28 mL (6.5 mmol, 1 equivalent) of dicyclohexylamine at ambient temperature producing solids within five minutes. This mixture was stirred at ambient temperature overnight and then at 0° C. for five hours. White solids were isolated by filtration, washed with 10 mL of cold ethanol, and air dried giving 2.89 g (67%) of 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzene sulfonyl]amino}cyclopentanecarboxylic acid, dicyclohexylaminium salt.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[N:22]=1)[C:17](Cl)=[O:18].Cl.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Cl:23])[N:22]=1)[C:17]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:18]
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cc(Cl)nc(Cl)c1)n1ccnc1

Procedure:
6.8 g (0.10 mole) of imidazole and 15.3 ml (0.11 mole) of triethylamine are stirred in 100 ml of tetrahydrofuran. While cooling at 25°-30° C., a solution of 23.1 g (0.11 mole) of 2,6-dichloroisonicotinic acid chloride in 20 ml of tetrahydrofuran is then added dropwise, triethylamine hydrochloride separating. This is filtered off with suction and the filtrate is concentrated to 26.4 g of crude product. Recrystallisation from ethyl acetate yields 20.1 g (83% of the theoretical amount) of pure substance; m.p. 148°-151° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cc(Br)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)nn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
To a solution of 3-bromo-5-methyl-1H-pyrazole (from Ark Pharm, 6.4 g, 40 mmol) in tetrahydrofuran (263 mL) at 0° C. was added sodium hydride (3.2 g, 80 mmol). After stirring for 30 min, [β-(trimethylsilyl)ethoxy]methyl chloride (8.4 mL, 48 mmol) was added and the reaction mixture was allowed to warm to room temperature over 2 h. The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified with flash chromatography (eluting with a gradient of 0-15% ethyl acetate in hexanes) to give the desired product as colorless oil (12 g, 100%). LCMS calculated for C10H20BrN2OSi (M+H)+: m/z=291.1. Found: 291.0.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:16][CH2:17][C:18]1[C:26]2[S:25](=[O:28])(=[O:27])[N:24]=[C:23]([C:29]3[C:30](=[O:49])[N:31]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=4)[C@@H:32]4[C@H:37]([C:38]=3[OH:39])[C@@H:36]3[CH2:40][C@H:33]4[CH2:34][CH2:35]3)[NH:22][C:21]=2[S:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][N:31]2[C:30](=[O:49])[C:29]([C:23]3[NH:22][C:21]4[S:20][CH:19]=[C:18]([CH2:17][NH:16][S:2]([NH:5][C:6](=[O:7])[O:15][CH2:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)(=[O:4])=[O:3])[C:26]=4[S:25](=[O:27])(=[O:28])[N:24]=3)=[C:38]([OH:39])[C@H:37]3[C@@H:32]2[C@H:33]2[CH2:40][C@@H:36]3[CH2:35][CH2:34]2)=[CH:43][CH:44]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Reactant: OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of chlorosulfonylisocyanate (28 μl, 0.32 mmol) in dichloromethane (3 mL) was added benzyl alcohol (28 μl, 0.27 mmol). The reaction was stirred at 25° C. for 30 min. A solution of (1R,2S,7R,8S)-5-(7-aminomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 33f; 0.10 g, 0.21 mmol) and triethylamine (125 μl, 0.90 mmol) in dichloromethane (3 mL) was then added to the above solution via cannula. The reaction was stirred at 25° C. for 1.5 h. The mixture was diluted with dichloromethane (10 mL) and washed with 1.0 M aqueous hydrochloric acid solution (10 mL). The organic was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-3% methanol in dichloromethane) to afford the desired product, benzyl (N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}amino)sulfonylcarbamate (0.13 g, 0.18 mmol, 86%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.19-1.77 (6H, m), 2.57-2.58 (1H, m), 2.83-2.88 (2H, m), 3.46 (1H, m), 4.22 (1H, d, J=15.6 Hz), 4.50 (2H, bs), 5.12-5.18 (3H, m), 6.06 (1H, bs), 7.02-7.07 (3H, m), 7.19-7.23 (2H, m), 7.33-7.39 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(OC([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=O)(C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([NH:21][CH2:22][C:23](=[O:24])[N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:20])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Product: Cl
Product: O=C(NCC(=O)N1CCNCC1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from {4-[2-(2,4-dichloro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid (Example 1.1/e) and piperazine-1-carboxylic acid tert-butyl ester (Aldrich) according to the method described in Example 11.1. MS (EI) 564.2 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[C:16](I)[C:15]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:14](I)[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>CO.[Pd](Cl)Cl>[CH2:1]([C:5]1[O:6][C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]=1[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:14][CH:13]=1)[OH:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(OCCN(CC)CC)c(I)c1
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1oc2ccccc2c1C(O)c1ccc(OCCN(CC)CC)cc1
Yield: 50 %

Procedure:
One mmole (645 mg) of the ketone, (2-n-butyl-3-benzofuranyl) [4-[2-(diethylamino)ethoxyl]-3,5-diiodophenyl] methanone is dissolved in 10 ml of methanol. Palladium dichloride (2 mmole, 354 mg) is added and the mixture is agitated to suspend the palladium dichloride. The temperature of the mixture is adjusted to 20° C. Sodium borohydride (10 mmole, 379 mg) is added and stirring is continued until reaction is complete (~1 hour). The palladium dichloride is removed by filtration and water is added to the filtrate. An ether extraction is performed and the product is removed from the ether phase by evaporation under reduced pressure. The produce is purified by chromatography (silica gel using methylene chloride) and results in >50% yield of the product, m.p. 203° C. (decomposes).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:17]>O.O1CCOCC1.C1(C)C=CC=CC=1>[C:16]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:18][CH2:19][CH:20]1[C:21]2[C:28](=[CH:29][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:25][CH:26]=2)=[O:17]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
trans-4-Hydroxy-L-proline (5.00 g, 38.2 mmol) and NaHCO3 (8.00 g, 95.2 mmol) were suspended in 150 ml H2O/Dioxane (1:1). Fluorenylmethyl chloroformate (11.4 g, 44.0 mmol) in 25 ml toluene was added dropwise. The temperature of the reaction was not allowed to rise above 25° C. during the addition. The mixture was stirred vigorously overnight, and then quenched with 50 ml saturated NaHCO3 solution and 50 ml water. The solution was then extracted with 100 ml diethyl ether. The aqueous layer was acidified to pH 1 with concentrated HCl, and extracted twice with ethyl acetate, and the organic extracts washed with brine. The solution was dried with MgSO4, filtered and the solvent removed in vacuo. The pure product crystallized from the concentrated solution. Yield: 13.4 g (100%). 1H NMR: (CDCl3, 200 MHz) δ 7.75-7.15 (8H, m, ArH), 4.55-4.05 (5H, m, ArCHCH2, H2, H4), 3.65-3.45 (2H, m, 2 H5), 2.35-2.10 (2H, m, 2 H3).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3[CH3:17])(=O)=O)=CC=1.[BrH:19]>C(O)(=O)C>[BrH:19].[BrH:19].[CH3:17][N:13]1[CH2:12][C@@H:11]2[CH2:16][C@H:14]1[CH2:15][NH:10]2
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H]3C[C@H]2CN3C)cc1
Agent: Br
Solvent: CC(=O)O
Product: CN1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Yield: 81 %

Procedure:
60 g (225 mmol) of (1S, 4S)-2-(4-Toluenesul- fonyl)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane was suspended in 900 ml of 30% hydrogen bromide in acetic acid and the mixture was allowed to stir at room temperature. After 6 hours the acetic acid was removed under aspirator pressure to 1/4 of the original volume and 1800 ml of ethylacetate was then added. A solid precipitated and was filtered under an inert atmosphere. The product was recrystallized by dissolving in a minimum amount of methanol at reflux. Cooling followed by the addition of 400 ml of isopropyl alcohol provided a white solid which was filtered and dried under reduced pressure. The product weighed 48 g which represents an 81% yield. M.P.=258°-259° C. (coloration occurs at 234° C.) [α]D =+13.21° (c=0.946, CH3OH)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[CH:16][C:15]([C:19]#[N:20])=[N:14]1.N1C=CC=CC=1.Cl[C:28]([F:32])([F:31])[S:29]Cl.[Cl:33]CCl>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([Cl:33])[CH:15]([C:19]#[N:20])[N:14]1[S:29][CH:28]([F:32])[F:31]
Reactant: ClCCl
Reactant: FC(F)(Cl)SCl
Reactant: N#Cc1cc(O)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: c1ccncc1
Product: N#CC1C(Cl)=C(O)N(c2c(Cl)cc(C(F)(F)F)cc2Cl)N1SC(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 71 %

Procedure:
To the solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-hydroxypyrazole (12.0 g, 37.3 mmol.) and pyridine (3.25 g, 41.0 mmol) in dichloromethane at −50-−60 C. was added chlorodifluoromethanesulfenyl chloride (8.1 g, 46.6 mmol). The resulting solution was gradually warmed up to room temperature. After 20 hr, the organic layer was washed five times with water. It was then washed with brine and dried (Na2SO4) to provide an oil. Upon chromatographic purification of the oil , a total of 11.6 g (26.4 mmol., 71% yield) of the desired product with 97% HPLC puriety was isolated. F-NMR: −30.05 ppm (CCIF2), −63.80 ppm (ArCF3).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][NH2:35])[CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][NH:35][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CC[C@H](CCN)C1
Product: CCN1CC[C@H](CCNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1

Procedure:
Prepared by proceeding in a similar manner to Example 58, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67) and 2-((S)-1-ethylpyrrolidin-3-yl)ethylamine (Intermediate 208).
Reaction SMILES: C(O[C:4](=[O:20])[CH:5]([C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=1[F:19])[C:6]([O:8]CC)=O)C.Cl.[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28]([NH2:30])=[NH:29].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOCCOC.C(O)(=O)C.O>[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28]1[N:30]=[C:4]([OH:20])[C:5]([C:11]2[C:12]([F:19])=[CH:13][C:14]([F:18])=[CH:15][C:16]=2[F:17])=[C:6]([OH:8])[N:29]=1
Reactant: N=C(N)c1cnccn1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: COCCOCCOC
Product: Oc1nc(-c2cnccn2)nc(O)c1-c1c(F)cc(F)cc1F
Temperature: 120 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A mixture of 2-(2,4,6-trifluoro-phenyl)-malonic acid diethyl ester (200 g, 0.67 mol), pyrazine-2-carboxamidine hydrochloride (132 g, 0.828 mol) and potassium carbonate (114 g, 0.828 mol) in 2-methyoxyethyl ether (diglyme, 600 mL) is heated to 120° C. and stirred for 4 h, then heated to 140° C. and stirred for an additional 2 h. The mixture is cooled to room temperature (25–30° C.) and water (1200 mL) is added over about 15 min. Acetic acid (50 g) is added over 15 min. and 82 ml of concentrated HCl is added over 15 min and the mixture is stirred for about 15 min. at room temperature at a pH of about 2–3. The solid is filtered and washed with water (2×400 mL) and isopropyl alcohol (IPA) (400 mL) and dried at 60° C./10 mmHg for 24 h to give a white solid 69% yield with 95% HPLC purity. 1H NMR (DMSO-d6): d 12.45 (bs, 2H), 9.41(s,1H), 8.91(s,1H), 8.46(m, 1H), 7.23(m, 2H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[C@H:13]1[CH2:17][C:16](=[O:18])[C:15]([CH2:19][CH:20]=[CH2:21])=[C:14]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[C@@H:13]([O:2][N+:1]([O-:4])=[O:3])[CH2:17][C:16](=[O:18])[C:15]=1[CH2:19][CH:20]=[CH2:21]
Reactant: C=CCC1=C(C)[C@@H](O)CC1=O
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: C=CCC1=C(C)[C@@H](O[N+](=O)[O-])CC1=O
Yield: 97.2 %

Procedure:
Into a mixed solution of 8 g of fuming nitric acid and 24 g of acetic anhydride, kept at a temperature of -5° to 10° C., was added dropwise 6 g of (S)-4-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one ([α]D23 : +10.3° (C=1.17, in chloroform), (R)-isomer/(S)-isomer=15.7/84.3). Thereafter, with the same operations as in Example 1, 7.56 g of crude (S)-3-methyl-4-nitroxy-2-(2-propenyl)-2-cyclopenten-1-one was obtained.
Reaction SMILES: C(O[CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)C.ClCC(Cl)=[O:19].[O:21]1[CH2:26][CH2:25]O[CH2:23][CH2:22]1>>[CH2:22]([O:21][CH2:26][CH2:25][CH2:4][C:5]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:19])[CH3:23]
Reactant: C1COCCO1
Reactant: CCOCCNc1ncccc1[N+](=O)[O-]
Reactant: O=C(Cl)CCl
Product: CCOCCCC(=O)Nc1ncccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To a stirred solution of 42.24 parts of N-(2-ethoxyethyl)-3-nitro-2-pyridinamine in 309 parts of 1,4-dioxane were added 49.7 parts of 2-chloroacetyl chloride. The reaction mixture was stirred for 4 hours at reflux temperature. The whole was evaporated and the residue was taken up in methylbenzene. The organic layer was evaporated again, yielding 57.5 parts (100%) of 2-chloro-N-(2-ethoxyethyl-N-(3-nitro-2-pyridinyl)acetamide as a residue (int. 1).