Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([Li])C=CC=CC=1.[N:8]([CH:11]([CH3:32])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=[CH:23][C:22](C(OS(C)(=O)=O)=O)=[CH:21][CH:20]=3)=[N+:9]=[N-:10].C([O:35]CC)C.[Cl-].[NH4+]>O.O1CCCC1>[N:8]([CH:11]([CH3:32])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=[CH:23][C:22]([OH:35])=[CH:21][CH:20]=3)=[N+:9]=[N-:10]
Reactant: CC(Cn1ccc2c1-c1cc(C(=O)OS(C)(=O)=O)ccc1C2)N=[N+]=[N-]
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]c1ccccc1
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cn1ccc2c1-c1cc(O)ccc1C2)N=[N+]=[N-]
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A 2M phenyllithium solution was added dropwise over 5 minutes to a solution, cooled to 0°, of 3.55 g of (RS)-1-(2-azido-propyl)-7-mesyloxycarbonyl-1,4-dihydro-indeno[1,2-b]pyrrole, 90 ml of anhydrous diethyl ether and 90 ml of anhydrous tetrahydrofuran. After 15 minutes at this temperature, an additional 5.87 ml of the phenyllithium solution were added dropwise and the mixture was stirred for an additional 5 minutes. Subsequently, the reaction mixture was treated with 50 ml of a saturated ammonium chloride solution and 25 ml of water. The mixture was extracted once with 50 ml of ethyl acetate and the aqueous phase was made slightly acidic with 1N hydrochloric acid and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a vacuum. 2.7 g (99%) of (RS)-1-(2-azido-propyl)-7-hydroxy-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a brown oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=[O:6])[OH:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:24]([N:26]([CH:29](O)[CH3:30])[CH2:27][CH3:28])[CH3:25].C(N(CC)CC)C>C(Cl)Cl.O.CN(C=O)C>[F:16][C:14]([F:15])([F:17])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:25][CH2:24][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]
Reactant: CCOP(=O)(O)Cc1cccc(C(F)(F)F)c1
Reactant: CCN(CC)C(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCCN(CC)CC
Temperature: 0 °C
Reaction time: 4 h
Yield: 10.7 %

Procedure:
Ethyl 3-trifluoromethylbenzylphosphonic acid, (7.55 g, 28 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. under nitrogen. After the oxalyl chloride (28 mmol) had been added, 0.5 mL of DMF was slowly added in 3 portions, and the resultant mixture was stirred at room temperature for 3 hours. Evaporation in vacuo gave the crude acid chloride which was dissolved in 90 mL of CH2Cl2 and added dropwise to a mixture of N,N-diethylaminoethanol (3.29 g, 28 mmol) and triethylamine (3.42 g, 34 mmol) in 60 mL of CH2Cl2 cooled at 0° C. The resultant mixture was allowed to warm to room temperature and stirred for 4 hours. Water was added (100 mL) and the aqueous phase was extracted 3 times with CH2Cl2. The combined organic extracts were dried with anhydrous Na2SO4, and evaporated to give the crude product as an oil. Purification was accomplished through column chromatography on silica gel using CH2Cl2 containing 2% MeOH and 0.1% NH3 and gave 1.1 g of the analytical product as an orange oil. D.C.I.M.S.[MH+, 368].
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>O>[CH2:7]([NH:11][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: C=CC(=O)OC
Solvent: O
Product: CCCCNCCC(=O)OC
Reaction time: 2 h

Procedure:
Methyl acrylate (344 g; 4 moles) was placed in a flask and 642.4 g (8.8 moles) of n-butylamine were added thereto while stirring by cooling with water to keep it at not higher than 50° C. After two hours, the addition reaction was complete but an impurity, namely butoxyamine-N,N-bis-3-propionic acid methyl ester, was produced in an amount of about 12% in terms of the ratio of the area of its peak that of to methyl beta-butylaminopropionate on a gas chromatogram.
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)(=O)C.[ClH:31].C(#N)C>C(O)C>[ClH:31].[CH:14]1([C:12](=[O:13])[CH:11]([N:8]2[CH2:9][CH2:10][CH:5]([SH:4])/[C:6](=[CH:24]/[C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)/[CH2:7]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:16][CH2:15]1
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cnccn1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)/C(=C/c2cnccn2)C1
Yield: 60 %

Procedure:
(E)-4-(Acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-[(pyrazin-2-yl)methylidene]piperidine (Example 31, free base, 540 mg) was treated with hydrogen chloride in ethanol in a similar manner to that described in Example 133, and the crude product was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v) to afford the title compound (295 mg, yield: 60%) as a colourless amorphous solid.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH2:5]([NH:12][C:13](=[O:35])[N:14]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][C:23]=2[OH:34])[CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:5]([NH:12][C:13](=[O:35])[N:14]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][C:23]=2[O:34][CH2:2][CH2:3][CH3:4])[CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCC)c1
Temperature: 60 °C

Procedure:
100 μL (1.0 mmol, 1.5 eq) of 1-iodopropane are added to a solution of 285 mg (0.67 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 6 ml of methyl ethyl ketone in the presence of 200 mg (1.45 mmol, 2.2 eq) of potassium carbonate. The reaction medium is heated at 60° C. for 16 hours. The solid is filtered off and the solvent is evaporated off. The methyl 3-[3′-(3-heptyl-1-methylureido)-2-propoxybiphenyl-4-yl]propanoate obtained in oil form is used in the following reaction without further purification.
Reaction SMILES: [CH2:1]1[S:6][C:4](=[O:5])[NH:3][C@@H:2]1[C:7]([OH:9])=[O:8].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)[OH:11]>>[C:4]([S:6][CH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[NH2:3])([OH:11])=[O:5]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: O=C1N[C@H](C(=O)O)CS1
Product: N[C@@H](CSC(=O)O)C(=O)O

Procedure:
L-2-oxothiazolidine-4-carboxylate, in vivo, is subjected to the action of 5-oxo-L-prolinase in the presence of adenosine triphosphate to produce S-carboxyl cysteine. S-carboxyl cysteine is then decarboxylated to produce cysteine. Cysteine is then metabolized to provide glutathione. See, U.S. Pat. Nos.: 4,355,210; 4,434,158; 4,438,124; 4,665,082; and 4,647,571 the disclosures of which are incorporated herein by reference.
Reaction SMILES: COP([CH2:7][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)OC.[H-].[Na+].[CH3:23][Si:24]([CH3:33])([CH3:32])[C:25]1[O:29][CH:28]=[C:27]([CH:30]=O)[CH:26]=1>O1CCCC1>[O:20]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])/[CH:7]=[CH:30]/[C:27]1[CH:26]=[C:25]([Si:24]([CH3:33])([CH3:32])[CH3:23])[O:29][CH:28]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCCCCCCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)/C=C/c1coc([Si](C)(C)C)c1
Reaction time: 0.5 h

Procedure:
A solution of dimethyl-2-oxotridecylphosphonate (984 mg. 3.21 mmol) in tetrahydrofuran (25 ml) was added to a suspension of sodium hydride (78 mg, 3.21 mmol) in tetrahydrofuran (5 ml) at 0° C. (u.c.) under argon. After 30 min, a solution of 5-trimethylsilyl-3-furaldehyde (450 mg. 2.68 mmol) in tetrahydrofuran (15 ml) was added. Stirring was contained overnight while the cooling bath attained room temperature. The reaction mixture was quenched with saturated ammonium chloride and the organic layer separated. Evaporation of the dried (magnesium sulfate) organic layer gave a residue, which was purified by flash chromotography on a silica using 5% ethyl acetate/hexane to give the title compound.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][NH2:32])[CH3:22]>C(#N)C>[CH3:22][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][NH:32][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH3:20]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CN(C)CC1CCCCN1CCN
Solvent: CC#N
Product: CN(C)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 53 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(dimethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 53% of theory. Colourless crystals, m.p. 189-190 (acetonitrile).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[S:13][C:6]=12.[H-].[Na+].Br[CH2:29][CH2:30][O:31][CH3:32]>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:29][CH2:30][O:31][CH3:32])[CH:18]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4c[nH]cn4)sc23)c(F)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
To a solution of 93 (300 mg, 0.84 mmol) in dry DMF (3 ml) at 0° C. was added NaH (40 mg, 60% dispersion in oil, 1.0 mmol). The mixture was allowed to warm to room temperature over 0.5 h then re-cooled to 0° C. Bromoethylmethyl ether (123 mg, 0.88 mmol) was added and mixture was allowed to warm to room temperature over 20 hours, concentrated and partitioned between EtOAc and water. The EtOAc phase was dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (eluents hexane and acetone/hexane 75:25) to afford the title compound 94 (126 mg, 36% yield) as a pale yellow solid. MS (m/z) 415.1.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[H-].[Na+].I[CH3:18].O>O1CCCC1>[CH3:18][NH:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: CI
Reactant: Nc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a solution of 8-nitroquinolin-7-amine (1.89 g, 10 mmol) in tetrahydrofuran (THF) (10 mL) was added sodium hydride (60% wt in mineral oil, 800 mg, 20 mmol). The mixture was stirred at room temperature for 30 minutes, then iodomethane (1.42 g, 10 mmol) was added. The mixture was stirred at room temperature for 5 h. Then water (10 mL) was added. The mixture was extracted with EtOAc, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 2:1) to give N-methyl-8-nitroquinolin-7-amine as a yellow solid (1.6 g, yield 79%). ESI MS: m/z 204 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[NH:13][CH:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26](Cl)=[O:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[N:13]([CH:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19])[C:26](=[O:27])[CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20]
Reactant: Cc1cc2ccccc2c(NC2CCOC2=O)c1C
Reactant: COCCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCCOCC(=O)N(c1c(C)c(C)cc2ccccc12)C1CCOC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 15.3 g of N-(2,3-dimethylnaphtyl)-N-(2-oxo-tetrahydrofuran-3-yl)-amine in 120 ml of toluene are added dropwise 12.2 g of 2-methoxyethoxy-acetyl chloride (MAC) in 20 ml of toluene and afterwards 8.1 g of triethylamine in 20 ml of toluene. The temperature of the reaction rises to 35° and is then raised to 40° for 2 hours. There are subsequently added dropwise a further 2 g of MAC and 1.5 g of triethylamine. The temperature is held overnight at 40°, and afterwards a further 2 g of MAC are added dropwise. After 4 hours, the reaction mixture is cooled to room temperature and filtered, and the filtrate is concentrated by evaporation to yield a resinous residue, which is purified through silica gel 60 using ethyl acetate as the eluant. The solid product occurring from the residue is recrystallised from isopropanol with the addition of active charcoal. The resulting product is the colourless diastereoisomeric mixture of the compound No. 32, m.p. 142°-146°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11]([O:13][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@@H]1c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1C[C@@H]1c1ccc(O)cc1
Temperature: 40 °C
Yield: 58.6 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 50 mL of acetone. To the stirred solvent was added (1R,2S)-2-(4-hydroxyphenyl)cyclopropanecarboxylic acid (0.51 g, 2.86 mmol). The reaction mixture was brought to 0° C., potassium bicarbonate (0.28 g, 2.8 mmol), stirred for 10 minutes, benzyl bromide (0.3 mL, 2.8 mmol) was added drop wise. The reaction mixture was heated at 40° C. for 2 h. The reaction mixture was concentrated to distill off the solvent; water (25 mL) was added and extracted with ethyl acetate (25 mL). The organic layer was washed with brine solution (25 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow liquid (0.44 g, yield: 57.2%). 1H NMR (300 MHz, CDCl3): δ 7.30 (s, 4H), 7.19 (s, 1H), 6.89-6.92 (d, 2H), 6.66-6.68 (d, 2H), 5.08 (s, 2H), 4.89 (s, 1H), 2.41-2.48 (m, 1H), 1.78-1.84 (m, 1H), 1.49-1.56 (m, 1H), 1.17-1.24 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:47])[CH:5]=[C:6]([Cl:46])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.Cl.[C:49](Cl)(=[O:59])[O:50][C@@H:51]1[CH:56]2[CH2:57][CH2:58][N:53]([CH2:54][CH2:55]2)[CH2:52]1.N1C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:47])[CH:5]=[C:6]([Cl:46])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:38]([C:49]([O:50][C@@H:51]2[CH:56]3[CH2:57][CH2:58][N:53]([CH2:54][CH2:55]3)[CH2:52]2)=[O:59])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[CH:33][CH:32]=1)(=[O:29])=[O:30])=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(CNc3ccccc3F)cc2)cc1OC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3F)cc2)cc1OC
Temperature: 80 °C
Yield: 16.3 %

Procedure:
To a stirred solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[4-[(2-fluoroanilino)methyl]phenyl]sulfonylpyrrolidine-2-carboxylate (105 mg, 0.15 mmol) in acetonitrile (3.2 mL) was added (R)-quinuclidin-3-yl carbonochloridate hydrochloride (131 mg, 0.6 mmol) and pyridine (0.12 mL), and the mixture was heated to 80° C. in a microwave for 6 minutes. Further (R)-quinuclidin-3-yl carbonochloridate hydrochloride (34 mg, 0.15 mmol) was added, and the mixture was heated to 80° C. in a microwave for 6 minutes. The solvent was removed in vacuo and the mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The layers were separated and the water was removed in vacuo. Purification of the residue from the aqueous layer was achieved by preparative HPLC to afford the title compound as a white solid (21 mg, 16%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc(Br)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of the product of step (i) (32.25 g, 0.15 mol) in anhydrous dichloromethane (400 mL) was added triethylamine (45 g, 0.45 mol), DMAP (915 mg, 7.5 mmol) and TBSCl (33 g, 0.215 mol) sequentially. The resulting solution was stirred overnight. The reaction mixture was extracted with dichloromethane and washed with water (×3). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with PE to afford the subtitle compound (ii) as a pale brown oil (40 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=3[N:19]=2)=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>[Fe].CCO.C1COCC1.O>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=3[N:19]=2)=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Sc1nc2cc(C)ccc2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(N)cc(Cl)c1Sc1nc2cc(C)ccc2s1
Yield: 68 %

Procedure:
To a solution of 1-[3-chloro-5-nitro-2-(5-methyl-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone (264) (3.87 g, 10.2 mmol) in 2:2:1 of EtOH/THF/H2O, was added ammonium chloride (Aldrich 2.74 g, 51.2 mmol) and iron powder (Aldrich, 2.87 g, 51.2 mmol). The mixture was refluxed for 3 hours. The mixture was filtered through Celite pad while it was hot, washed the Celite pad with EtOAc. The filtrate was diluted with saturated aqueous NaHCO3 solution and was extracted 3× with EtOAc (150 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (0–15% EtOAc in CH2Cl2) to yield 2.42 g (68%) of compound 276 as a pale yellow solid.
Reaction SMILES: CO.Cl.[CH3:4][O:5][NH2:6].[CH3:7][CH:8]1[O:12][CH:11](O)[CH:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1>C(N(CC)CC)C>[CH3:4][O:5][N:6]=[CH:11][CH:10]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH:8]([OH:12])[CH3:7]
Reactant: CON
Reactant: CC1CC(Oc2ccccc2)C(O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=CC(CC(C)O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 88.2 %

Procedure:
20 mL of methanol and 1.8 g of O-methylhydroxylamine hydrochloride were added to 3.6 g of 5-methyl-3-phenoxyoxolan-2-ol that was a colorless oily product, and thereafter, 2.79 mL of triethylamine was added dropwise to the mixture. The thus obtained mixture was stirred at room temperature for 5.5 hours. Thereafter, methanol was distilled away under reduced pressure, 100 mL of ethyl acetate and 100 mL of water were then added to the residue, and the water layer was then removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure, so as to obtain 3.65 g of 5-(methoxyimino)-4-phenoxypentan-2-ol in the form of a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1.[F-].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C([Sn](CCCC)(CCCC)[CH2:39][CH2:40][CH2:41][OH:42])CCC>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:39]=[CH:40]/[CH2:41][OH:42])[CH:8]=1
Reactant: CCOC(=O)c1noc(-c2cccc(Br)c2)c1N
Reactant: CCCC[Sn](CCCC)(CCCC)CCCO
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCOC(=O)c1noc(-c2cccc(/C=C/CO)c2)c1N
Temperature: 100 °C
Yield: 22.6 %

Procedure:
To a dioxane (4 mL) solution of compound from Example 21C (710 mg, 2.3 mmol) was added Pd3(dba)2-CHCl3 (71 mg, 0.07 mmol, 3% equiv.) and CsF (760 mg, 5.1 mmol, 2.2 equiv.) under N2. P(tBu)3 (10% in hexanes, 0.42 mL, 0.14 mmol, 12% equiv) and 3-tributylstannyl-1-propanol (1.1 g, 3.2 mmol, 1.1 equiv.) were added sequentially. The mixture was flushed with N2 for 2 min and then heated to 100° C. in a sealed culture tube. The mixture was purified by flash column chromatography (50% ethyl acetate in hexanes) to provide the titled compound (150 mg, 22%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH2:6][S:7][CH3:8])[NH2:5].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH2:6][S:7][CH3:8])[NH:5][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COC(=O)[C@@H](N)CSC
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CSC)Nc1ncccc1[N+](=O)[O-]
Yield: 54.1 %

Procedure:
In analogy to Example 2, but using only one mole equivalent of triethylamine, 5 g (27 mmol) of (-)-S-methyl-L-cysteine methyl ester were reacted with 3.51 g (22.5 mmol) of 2-chloro-3-nitropyridine (reaction conditions: 5 hours at 80° C.). Working up was followed by chromatography on silica gel (n-heptane/acetone/methyl t-butyl ether=5:1:1). 3.3 g (45%) of N-(3-nitro-2-pyridyl)-(-)-S-methyl-L-cysteine methyl ester, of melting point 95°-97° C., were obtained.
Reaction SMILES: COP([CH2:7][C:8](=O)[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])(OC)=O.C(=O)CCCCCCCCCCC=O.COP(CC(=O)CP(OC)(OC)=O)(OC)=O>C(O)(C)(C)C>[C:21]1(=[O:22])[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: COP(=O)(CC(=O)C=CCCCCCCCCCCC=O)OC
Agent: COP(=O)(CC(=O)CP(=O)(OC)OC)OC
Agent: O=CCCCCCCCCCCC=O
Solvent: CC(C)(C)O
Product: O=C1C=CCCCCCCCCCCC=C1
Yield: 26 %

Procedure:
The above reaction was repeated, but 15-(dimethylphosphono)-pentadec-12-en-14-on-1-al was replaced by a mixture of 0.79 g (4 mMole) of dodecan-1,12-dial and 1.10 g (4 mMole) of 1,3-bis(dimethylphosphono)-propan-2-one in 10 ml of 90% t-butanol. Identical introduction time and work up gave 229 mg (26%) of cyclopentadeca-2,14-dien-1-one in a similar ratio of isomers.