Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Br)[C:9]=1[OH:10])[C:5]#[N:6].C(O)(=O)C.[N:16]([O-:18])=[O:17].[Na+].O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]=1[OH:10])[C:5]#[N:6]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 116.2 %

Procedure:
To a 5-l, 3-neck round-bottom flask fitted with a thermocouple, stirring paddle, and nitrogen line were added 3,5-dibromo-4-hydroxybenzonitrile (95 g) and glacial acetic acid (3.3 l). Sodium nitrite (120 g) was then added in small portions. The mixture was heated to 50° C. and stirred overnight at this temperature. The mixture was then allowed to cool and poured into a large extractor containing water (10 l). ethyl acetate (10 l) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (4 l) and the combined organic layers were washed with water and brine, and then dried over magnesium sulfate and concentrated in vacuo to provide 96.9 g of the desired product. Mass spectrum (ESI) 243.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCOCC1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCOCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[5,6-difluoro-1-(tetrahydro-pyran-4-ylmethyl)-1H-benzoimidazol-2-yl]-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Light brown solid (95%). MS (Turbo Spray): m/z=511.9 (M+H).
Reaction SMILES: [CH3:1][N:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][NH:39][O:40][CH3:41].Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:10]([O:9][C:7](=[O:8])[N:2]([CH2:3][C:4]([N:39]([O:40][CH3:41])[CH3:38])=[O:6])[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNOC
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.7 %

Procedure:
1.01 g of Z-SAR-OH (available from Kokusan Chemical Co., Ltd.), 4.72 mL of diisopropylethylamine, 1.83 g of 1-hydroxybenzotriazole monohydrate, and 1.32 g of N,O-dimethyl hydroxylamine hydrochloride were dissolved in 15 mL of N,N-dimethylformamide, then 2.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added thereto under an ice-cold condition, and the mixture was stirred for 2.5 hours at room temperature. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the solution was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1), to obtain 1.02 g of benzyl{2-[methoxy(methyl)amino]-2-oxoethyl}methylcarbamate [2-1] (hereinafter, referred to as the compound [2-1]) as a pale yellow oily product.
Reaction SMILES: O[C:2]1[C:3]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]2)=[N:4][CH:5]=[CH:6]C=1.Cl.ClCC1N=C(C)[S:24]C=1.[OH-].[Na+]>>[CH3:6][C:5]1[S:24][CH:2]=[C:3]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:10]2)[N:4]=1
Reactant: CC(=O)Nc1ccn(Cc2ncccc2O)n1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccn(Cc2csc(C)n2)n1

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 41, replacing the benzyl halide by 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (MAYBRIDGE). 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (MAYBRIDGE) was also liberated using NaOH (1N, aq) at room temperature. 1H NMR (300 MHz, DMSO-d6) ppm: 10.37 (s, 1H), 7.62-7.63 (m, 1H), 7.25 (s, 1H), 6.43-6.44 (m, 1H), 5.20 (s, 2H), 2.59 (s, 3H), 1.93 (s, 3H). [ES+MS] m/z 237 (MH+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:11][C@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12](CC3C=CC=CC=3)[C@H:6]1[CH2:7][CH2:8][C@@:9]2([N:42]=[N+:43]=[N-:44])[O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)(=[O:3])[CH3:2].C(O)(=O)C.[ClH:49]>C(OCC)(=O)C.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:49].[C:1]([NH:4][C@@H:5]1[CH2:11][C@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:12][C@H:6]1[CH2:7][CH2:8][C@@:9]2([N:42]=[N+:43]=[N-:44])[O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:29]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(N=[N+]=[N-])OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)N[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@@]2(N=[N+]=[N-])OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-6-Acetamidoazido-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 104; 240 mg, 0.40 mmol) was dissolved in ethyl acetate (10 ml) and glacial acetic acid (1 ml) then 10% palladium hydroxide (30 mg) added and the mixture hydrogenated at 45 psi overnight. The reaction mixture was then filtered and the mixture further hydrogenated with fresh catalyst (30 mg) overnight. The reaction mixture was filtered then concentrated in vacuo, basified (saturated sodium hydrogen carbonate solution), extracted with dichloromethane (×3), dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography [10% methanol in dichloromethane] to give an oil which when concentrated with iso-hexane gave a white solid. The hydrochloride salt was made by dissolving in diethyl ether and adding 1 equivalent of hydrogen chloride in diethyl ether. The title compound was filtered off and dried in vacuo at 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)O)c3)c3ccc(Cl)cc32)cn1
Reactant: CS(N)(=O)=O
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)NS(C)(=O)=O)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in the synthesis of Example 117 using the following starting materials: {3-[6-Chloro-1-(1-propyl-1H-pyrazol-4-yl)-2-methyl-1H-indol-3-ylsulfanyl]-phenyl}-acetic acid and methanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13]C)=[C:6]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:7]=1.B(Br)(Br)Br>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1CS(N)(=O)=O
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Product: NS(=O)(=O)Cc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a suspension of (5-chloro-2-methoxy-phenyl)-methanesulfonamide (0.03 g, 0.13 mmol) in dichloroethane (1.5 mL) was added boron tribromide solution (1M in dichloromethane, 0.26 mL, 0.26 mmol). The reaction was stirred for one hour at ambient temperature. The reaction was quenched with water, saturated with sodium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (0.025 g).
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:6]3=[N:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:10]=[C:5]3[O:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc2occ(Br)c2n1
Reactant: CSc1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc2occ(-c3ccc(SC)cc3)c2n1
Yield: 32 %

Procedure:
In the same manner as in Reference Example 19 and using ethyl 3-bromofuro[3,2-b]pyridine-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 32%) was obtained as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17](/[C:20](=[CH:6]\[C:5]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])/[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)/C(=C/c1ccc(Cl)cc1[N+](=O)[O-])c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A 2 L flask equipped with a mechanical stirrer was charged with 183 g of 2-nitro-4-chlorobenzaldehyde, 212 g of 4-bromophenylacetic acid and 233 mL of acetic anhydride. To this solution was added 82 g of potassium carbonate and the reaction was stirred overnight at 100° C. The resulting dark mixture was cooled down to room temperature and 1.6 L of water was added followed by 800 mL of 10% HCl. The solution was decanted and taken up in water/ethyl acetate. Layers were separated, organic phase was washed with brine, dried over magnesium sulphate and volatiles were removed under reduced pressure. The residue was triturated in EtOH and the mother liquor was triturated 4 more times with EtOH to afford 219 g of the desired (2E)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.CCOCC.S(=O)(=O)(O)O.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 20 ml of sulfolane were added 1.41 g of 7-ACA, 3.2 ml of boron trifluoride ethyl ether, 0.84 ml of concentrated sulfuric acid and 6.12 ml of trimethyl borate. The mixture was heated at 30° C. for 4 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.86 g. The yield of the desired product was 68%.
Reaction SMILES: CS(C)=O.[NH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>C(N(CC)CC)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:5][CH2:6][CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: NCCCn1ccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 111.4 %

Procedure:
100 ml of DMSO were introduced into a 500 ml three-necked flask and treated with 10.3 g of triethylamine, 12.8 g of 1-(3-aminopropyl)imidazole and 14.4 g of 1-fluoro-4-nitrobenzene. The mixture was stirred at 80° C. for 12 h, cooled to room temperature and subsequently poured onto 1 l of ice. A sample of the resulting oily precipitate was triturated with H2O until crystallization commenced. A sample of the mixture was seeded with the crystals thus obtained and crystallized at room temperature for 1 h. The resulting precipitate was filtered off with suction, triturated with H2O, filtered off with suction again and rewashed with H2O. For the purpose of purification, the 28 g of moist crude product thus obtained were recrystallized from 250 ml of H2O and 114 ml of ethanol. The product was dried in vacuo at 50° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6](S(C)=O)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2].C([N:39]1[CH2:43][CH2:42][C@@H:41]([NH2:44])[CH2:40]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:3]1[C:4]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:23]([NH:25][O:26][CH3:27])=[O:24])=[N:5][C:6]([NH:44][CH:41]2[CH2:42][CH2:43][NH:39][CH2:40]2)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2]
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(S(C)=O)nc(N(C)CC(C)(C)C)c2C#N)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(C)c(Nc2nc(NC3CCNC3)nc(N(C)CC(C)(C)C)c2C#N)c1

Procedure:
3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methanesulfinyl-pyrimidin-4-ylamino}-N-methoxy-4-methyl-benzamide (33 mg) and 1-N-Boc-3-(R)-aminopyrrolidine (30 mg), DIEA (0.2 mL) and p-dioxane (2 mL) were heated in a sealed tube at 75° C. for overnight. After the removal of the solvent in vacuo, the product was purified by silica gel column chromatography and treated with TFA/DCM (1:1) in order to remove the Boc-group. The product was then converted to hydrochloride salt by treating it with hydrochloric acid (1 M in ether) (Yield: 20 mg). MS (m/z): 567 (M+H).
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]([O:15][C:16]([C@@H:18]1[CH2:22][C@@H:21]([F:23])[CH2:20][NH:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:24]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([C:36]([NH2:38])=[O:37])[CH:28]=1)=[C:25]=[O:26].C1COCC1.C(N(CC)CC)C>O>[CH2:8]([O:15][C:16]([C@@H:18]1[CH2:22][C@@H:21]([F:23])[CH2:20][N:19]1[C:25](=[O:26])[NH:24][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([C:36](=[O:37])[NH2:38])[CH:28]=1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(=O)n1cc(N=C=O)c2ccccc21
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](F)CN1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-4-fluoro-pyrrolidine-2-carboxylic acid benzyl ester TFA salt (4.45 g, 13.2 mmol), 3-isocyanato-indole-1-carboxylic acid amide (2.65 g, 13.2 mmol) (prepared as described in Scheme A1) and THF (66 mL) was added triethylamine (5.51 mL, 39.6 mmol). The resulting solution was stirred at RT under nitrogen for 1 h until completion of the reaction. The mixture was poured in water and extracted with EtOAc. The organic layer was washed with an aqueous saturated solution of NaHCO3, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1 to pure EtOAc) to give the desired compound. TLC, Rf (CH2Cl2/MeOH 9:1)=0.40; MS: 425.2 [M+H]+; tR (HPLC conditions a): 3.6 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([NH:40]C(OC(C)(C)C)=O)([CH3:39])[CH3:38])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([O:22][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=2)=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(COc1ccc(OCCBr)cc1)NC(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCC(C)(C)N)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
16.6 g (50 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridine-dicarboxylic acid monomethyl ester, 19.4 g (50 mmol) of crude 1-(2-bromoethoxy)-4-[2-(tertiary butoxycarbonylamino)-2-methylpropoxy]-benzene 13.8 g of potassium carbonate and 0.6 g of triethylbenzylammonium chloride are heated at boiling in 500 ml of acetonitrile for 16 hours while stirring and under reflux. The reaction mixture is filtered, concentrated by evaporation and dissolved in 500 ml of ethyl acetate. After washing with 100 ml of water and drying (MgSO4), the solvent is evaporated off and 50 ml of dioxan and 100 ml of formic acid are added to the crude residue without the latter being further purified, and the whole is left to stand in the dark at room temperature for 7-10 hours. After concentration by evaporation in vacuo, the residue is dissolved in 2N hydrochloric acid and the solution is extracted with toluene. The aqueous phase is rendered alkaline with 2N sodium hydroxide solution and extracted with ethyl acetate. After drying the solution (MgSO4) and concentration by evaporation, an oil is obtained from which 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-amino-2-methylpropoxy)-phenoxy]-ethyl}-ester 5-methyl ester, which has a melting point of 141°-142°, is obtained from acetonitrile.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([O:9]N)[CH:6]=[CH:7][CH:8]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.[OH-].[Na+]>OS(O)(=O)=O.C(O)(=O)C.O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[C:12]3[C:13](=[O:17])[CH2:14][CH2:15][CH2:16][C:11]=3[O:9][C:5]=2[CH:4]=1
Reactant: O=C1CCCC(=O)C1
Reactant: NOc1cccc(Br)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2oc3cc(Br)ccc3c21
Temperature: 110 °C
Yield: 64 %

Procedure:
A mixture of the product of Example 60, step B (9.0 g, 40.1 mmol) and cyclohexane-1,3-dione (6.74 g, 60.1 mmol) in 10% H2SO4/acetic acid (100 mL) was heated at 110° C. for 12 h. After cooling to ambient temperature, the reaction mixture was diluted with water, basified by treating with 10 N NaOH and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material which was purified by flash column chromatography (SiO2, 90:10 hexanes/ethyl acetate) to provide 7-bromo-3,4-dihydrodibenzo[b,d]furan-1(2H)-one (6.8 g, 64%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.91 (d, J=8.1 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.45 (dd, J=8.1, 1.5 Hz, 1H), 3.03 (t, J=6.3 Hz, 2H), 2.61 (t, J=6.3 Hz, 2H), 2.35-2.24 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH:3]=[CH:4][CH2:5][OH:6].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[F:1][C:2]([F:8])([F:7])[CH:3]=[CH:4][CH2:5][O:6][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[Br:9]
Reactant: Oc1ccc(F)cc1Br
Reactant: OCC=CC(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(OCC=CC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
A solution of 2.10 gm (16.7 mMol) 1-trifluoromethylprop-1-en-3-ol, 3.19 gm (16.7 mMol) 2-bromo-4-fluorophenol, and 4.81 gm (18.4 mMol) triphenylphosphine in 25 mL dichloromethane was cooled to 0° C. and then 2.9 mL (18.4 mMol) diethyl azodicarboxylate were added. The reaction mixture was stirred for 1 hour at room temperature and then the reaction mixture was directly subjected to flash silica gel chromatography, eluting with 20:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 6 gm of crude 1-(1-trifluoromethylprop-1-en-3-yloxy)-2-bromo-4-fluorobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Reactant: CCCCCCCCO
Product: CCCCCCCCOc1ccc(Br)cc1C(F)(F)F

Procedure:
Using 4-bromo-1-fluoro-2-(trifluoromethyl)benzene as starting material, standard aromatic fluoro-substitution with n-octanol provided the title compound in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 7.65 (δ, 1H, J=2.4 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 6.85 (d, 1H, J=8.8 Hz), 4.01 (t, 2H, J=6.4 Hz), 1.80 (m, 2H), 1.46 (m, 2H), 1.32 (m, 8H), 0.90 (t, 2H, J=5.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=C)=[O:4].I([O-])(=O)(=O)=[O:32].[Na+].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([CH:5]([CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:19][CH2:20]1)[CH2:6][C:7](=[O:32])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: C=C(CC(C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CC(=O)c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 18 h

Procedure:
Osmium tetroxide (2.5 wt. % in t-BuOH; 0.2 mL, 0.001 mmol) was added to a solution of benzyl 4-[1-(methoxycarbonyl)-3-phenylbut-3-en-1-yl]piperidine-1-carboxylate (2.11 g, 5.19 mmol) in tetrahydrofuran (20 mL). Sodium periodate (3.33 g, 15.6 mmol) in water (17 mL) was added to the reaction mixture. After 18 h, saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate were added and the mixture was extracted with ethyl acetate (4×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 410.1 (M+1).
Reaction SMILES: [SeH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[O:5]=[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])[CH2:3][CH2:2][Se:1][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC[SeH]
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C([Se]CCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reaction time: 3 h

Procedure:
To a chilled solution of 0.5 g. of 1-(3-selenyl-1-oxopropyl)-L-proline dissolved in 5 ml. of pyridine there is added dropwise with stirring 0.3 g. of benzoyl chloride. The mixture is allowed to come to room temperature. After three hours, the solvent is evaporated. The residue is taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and then with water. The solvent is dried, and evaporated to yield 1-[1-oxo-3-[(benzoyl)-selenyl]propyl]-L-proline.