Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2([CH2:14][CH3:15])OCC[O:10]2)=[CH:4][C:3]=1[F:16]>Cl.O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9](=[O:10])[CH2:14][CH3:15])=[CH:4][C:3]=1[F:16]
Reactant: CCC1(c2cc(F)c(Br)c(F)c2)OCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(=O)c1cc(F)c(Br)c(F)c1
Reaction time: 8 h
Yield: 79 %

Procedure:
2-(4-Bromo-3,5-difluorophenyl)-2-ethyl-1,3-dioxolane (1.20 g) was dissolved in 1 N hydrochloric acid/tetrahydrofuran/acetic acid (1/1/1, 30 ml). The reaction liquid was stirred overnight with heating under reflux, then diluted with ethyl acetate, and washed with aqueous saturated sodium hydrogencarbonate solution. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated off, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain the entitled compound (806 mg) as a pale yellow oil.
Reaction SMILES: [N:1]([C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])/[C:7](=[O:16])[NH:8]2)=[N+]=[N-].O.O.[Sn](Cl)Cl>CCO>[NH2:1][C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])/[C:7](=[O:16])[NH:8]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N=[N+]=[N-])c21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N)c21
Temperature: 25 °C

Procedure:
To a suspension of (Z)-4-azido-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (160 mg, 0.51 mmol) (from Example 43 above) in EtOH (10 mL), was added, at r.t., tin dichloride dihydrate. The heterogeneous mixture was heated at reflux for 6 h then cooled to r.t. The orange solid was collected by suction filtration, washed with ether and dried in a vacuum oven overnight to yield (Z)-4-amino-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 45 mg, 31%).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([OH:9])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[C:14]([CH3:21])[C:13]=1[S:22][CH2:23][CH:24]1[CH2:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC.Cl.C(N(CC)CC)C.[C-]#N.[K+]>CC(C)(O)C#N.C(#N)C.C(Cl)Cl>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([C:8]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:5][N:6]([CH3:10])[C:7]=2[OH:9])=[O:17])=[C:14]([CH3:21])[C:13]=1[S:22][CH2:23][CH:24]1[CH2:26][CH2:25]1
Reactant: Cc1c(C(=O)O)ccc(Cl)c1SCC1CC1
Reactant: Cn1nc(C2CC2)cc1O
Agent: CC(C)(O)C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(C(=O)c2c(C3CC3)nn(C)c2O)ccc(Cl)c1SCC1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
161 mg (1.17 mmol) of 3-cyclopropyl-5-hydroxy-1-methylpyrazole and a few drops of N,N-dimethylaminopyridine were added to 272 mg (1.06 mmol) of 4-chloro-3-cyclopropylmethylthio-2-methylbenzoic acid. 244 mg (1.27 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the mixture was stirred at RT for 16 h. For work-up, 3 ml of 1M HCl were added, and the organic phase was freed from the solvent. 214 mg (2.12 mmol) of triethylamine, 10 drops of acetone cyanohydrin and a spatula tip of KCN were added to the residue in 15 ml of acetonitrile. This reaction mixture was stirred at RT for 16 h and then freed from the solvent. 2 ml of 1M HCl were added to the residue in 15 ml of CH2Cl2. The organic phase was freed from the solvent, and the residue was then purified chromatographically. This gave 154 mg of pure product.
Reaction SMILES: Cl[C:2]1[CH2:19][C:18]2[C:17]([OH:20])=[C:16]3[C:7]([C:8](=[O:22])[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]3=[O:21])=[C:6]([OH:23])[C:5]=2[CH2:4][CH:3]=1.C(O)(=[O:26])C>>[OH:23][C:6]1[C:5]2[CH2:4][CH2:3][C:2](=[O:26])[CH2:19][C:18]=2[C:17]([OH:20])=[C:16]2[C:7]=1[C:8](=[O:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]2=[O:21]
Reactant: O=C1c2ccccc2C(=O)c2c(O)c3c(c(O)c21)CC=C(Cl)C3
Reactant: CC(=O)O
Product: O=C1CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Temperature: 25 °C
Yield: 76 %

Procedure:
There was prepared a mixture of glacial acetic acid (0.3 ml and concentrated sulfuric acid) 1.5 ml (which was cooled to 0° C. in an ice water bath). To this acid mixture was added 9-chloro-7,10-dihydro-6,11-dihydroxy-5,12-naphthacenedione (III) in a single batch and the mixture stirred. The mixture was permitted to warm slowly to ambient temperature over 3 hours at which temperature it was stirred for a further 24 hours. At the conclusion of this time the mixture was poured onto ice (ca. 25 g) and the organic layer extracted with chloroform (25 ml,×4) the chloroform extracts were combined, washed with saturated aqueous sodium bicarbonate, and with water, dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure. The residue was washed with ether and further dried in vacuo to yield the "red ketone" 7,10-dihydro-6,11dihydroxy-5,9,12(8H)naphthacenetrione (IV) (18 mg, 76%). This product was shown to be homogeneous by thin layer chromatographic analysis and had the same Rf as an authentic sample (silica gel, 0.7% methanolic chloroform, Rf =0.59.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6]([C:7]2[CH:12]=[C:11]([C:13](OC)=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[F:27])=[CH:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:28])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=2[F:27])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(C(F)(F)F)ccc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.9 %

Procedure:
To a cooled solution of 66.53A (0.4142 g, 1.056 mmol) in dry THF (7.8 mL) at 0° C. was added LAH (1.0 M in THF) (2.2 mL, 2.200 mmol) dropwise. Upon complete addition, the reaction was maintained at 0° C. and was monitored by TLC and LCMS. After 45 minutes, 1N NaOH was added to quench the reaction (gas evolution occurred). The resulting solution was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified by flash chromatography (SiO2 gel 60, eluted with 0%-100% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to afford 66.53B as a colorless oil (257.4 mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (2H, m), 7.40 (2H, m), 7.17 (1H, t, J=8.8 Hz), 5.52 (1H, m), 4.77 (2H, s), 2.24 (2H, td, J=7.0, 2.3 Hz), 1.71 (3H, m), 0.84 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:34])[CH3:33].N1CCCCC1>C1COCC1.C(Cl)Cl>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:34])[CH3:33]
Reactant: Cc1ccc(NC(=O)c2c[nH]c3ccccc3c2=O)cc1N
Reactant: CC(=O)Cl
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(3-amino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (167) (33 mg, 0.11 mmol) and DIEA (49 μL, 0.28 mmol) in THF (1 mL) was added acetyl chloride (16 μL, 0.22 mmol). The reaction was stirred at room temperature for 30 min. LCMS analysis indicated that diacylation had occurred. A solution of piperidine (81 μL, 0.82 mmol) in CH2Cl2 (2 mL) was added and the reaction stirred for a further 30 min at which time only the desired product was detected by LCMS. The reaction solution was concentrated and the residue was dissolved in DMSO and purified by HPLC (10-99% CH3CN/H2O) to yield the product, N-(3-acetylamino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (248) (4 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ 12.95 (d, J=6.6 Hz, 1H), 12.42 (s, 1H), 9.30 (s, 1H), 8.86 (d, J=6.8 Hz, 1H), 8.33 (dd, J=8.1, 1.3 Hz, 1H), 7.85-7.81 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.55 (t, J=8.1 Hz, 1H), 7.49 (dd, J=8.2, 2.2 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 2.18 (s, 3H), 2.08 (s, 3H); HPLC ret. time 2.46 min, 10-99% CH3CN, 5 min run; ESI-MS 336.3 m/z (MH+).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C@:15]12[CH2:32][CH2:31][C@H:30]3[C@@H:20]([CH2:21][CH:22]=[C:23]4[C@:28]3([CH3:29])[CH2:27][CH2:26][C@H:25]([OH:33])[CH2:24]4)[C@@H:19]1[CH2:18][CH2:17][O:16]2.CC(C)=O>O>[CH3:14][C@:15]12[CH2:32][CH2:31][C@H:30]3[C@@H:20]([CH2:21][CH2:22][C:23]4[C@:28]3([CH3:29])[CH2:27][CH2:26][C:25](=[O:33])[CH:24]=4)[C@@H:19]1[CH2:18][CH2:17][O:16]2
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)OCC[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)OCC[C@@H]12
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
0.2 ml of Jones reagent was added dropwise at 0° C. to a mixture of 203 mg of 17-oxaandrost-5-en-3β-ol and 20 ml of acetone, and the mixture was stirred for 20 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with 5% aqueous sodium bicarbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled out, and the resultant 17-oxaandrost-5-en-3-one was dissolved in 10 ml of acetone. After addition of 0.01 ml of concentrated sulfuric acid, the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with 5% aqueous sodium bicarbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled out, and the resultant product was purified by TLC [developing solvent; chloroform: acetone (9:1)] to obtain 102 mg of 17-oxaandrost-4-en-3-one.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]#[N:25]>ClCCCl>[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([CH2:12][C:22]2[N:18]([CH3:17])[C:19]([CH2:23][C:24]#[N:25])=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6]
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: Cn1cccc1CC#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)c1ccc(Cc2ccc(CC#N)n2C)cc1
Temperature: 25 °C

Procedure:
To a suspension of 17.5 g. (0.131 mole) aluminum chloride in 60 ml. 1,2 -dichloroethane is added 24 g (0.131 mole) p-isopropylbenzoyl chloride. The resulting mixture is added slowly and dropwise to a chilled solution (0° C.) of 15.7 g. (0.131 mole) 1 -methylpyrrole-2-acetonitrile in 1 00 ml. of 1,2-dichloroethane. After the addition is complete, the mixture is stirred at room temperature for twenty minutes and heated at reflux for three minutes. The reaction mixture is then cooled and poured into ice-dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3 -propanediamine, dilute hydrochloric acid and a saturated solution of sodium chloride; dried over magnesium sulfate; and the solvent evaporated. The product, 5-(p-isopropylbenzyl)-1 -methylpyrrole-2-acetonitrile, is isolated from the residual oil by column chromatography. The column is packed with acid washed alumina and eluted with benzene, ether and etylacetate. The product is found in the first compound-bearing fraction which absorbs ultraviolet light at approximately 250 μm. It is purified by recrystallization twice in ether: pentane. m.p. 59-64° C. Anal. Calcd. for C17H18N2O: N, 10.53%. Found: N,10.71%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH:35]1([CH2:38][NH2:39])[CH2:37][CH2:36]1>>[CH:35]1([CH2:38][NH:39][C:2]2[N:7]=[C:6]([C:8]3[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]4[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=4[F:33])(=[O:24])=[O:25])[CH:21]=3)[CH:5]=[CH:4][N:3]=2)[CH2:37][CH2:36]1
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: NCC1CC1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCC3CC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (60 mg, 0.11 mmol) and 1-cyclopropylmethanamine (0.1 mL, approx. 1.4 mmol) the title compound was obtained as an off-white solid (25 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (s, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.59-7.79 (m, 1H), 7.33-7.44 (m, 3H), 7.20-7.29 (m, 3H), 6.15 (br. s., 1H), 3.00-3.15 (m, 2H), 2.42-2.45 (m, 1H), 1.34 (d, J=7.0 Hz, 6H), 0.94-1.06 (m, 1H), 0.34-0.42 (m, 2H), 0.16-0.22 (m, 2H). MS (ESI): 560.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH:13]=O.[Br:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][N:21]=[C:22]2[NH:25][NH2:26])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][N:21]3[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[Cl:1])=[N:26][N:25]=[C:22]32)=[CH:18][CH:17]=1
Reactant: O=Cc1c(-c2ccccc2)noc1Cl
Reactant: NNC1=NCc2ccc(Br)cc21
Product: Clc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Yield: 18.9 %

Procedure:
5-Chloro-3-phenylisoxazole 4-carboxaldehyde (1.1 g) and (6-bromo-3H-isoindol-1-yl)hydrazine (1.2 g, 5.3 mmol) were reacted in a similar manner to that described in Example 4 to give the title compound (415 mg, 19%). 1H NMR (400 MHz, d6-DMSO) δ 8.161–8.165 (1H, m), 7.71–7.74 (1H, m), 7.47–7.61 (6H, m), 4.83 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14]C)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc(OC)cc2s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(O)cc2s1
Temperature: 0 °C
Yield: 32.5 %

Procedure:
The above prepared 6-methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester (0.200 g, 0.900 mmol) was dissolved in 5.5 mL of CH2Cl2, cooled to 0° C., and treated with BBr3 (1.90 mL of 1M solution in CH2Cl2, 2 eq.). After 3 additional h at ambient temperature, the reaction mixture was carefully poured onto crashed ice, twofold extracted with AcOEt, washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) gave 0.061 g of the title compound as light brown solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17]>C(C(C)=O)C(C)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)CNCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of glycine methyl ester hydrochloride (5.00 g, 39.8 mmol) in 80 ml methyl isobutyl ketone is treated with 12.6 g of sodium carbonate and the mixture stirred overnight at RT. Next, a solution of 2-bromo-1-(4-chlorophenyl)ethanone (8.37 g, 35.8 mmol) in 40 ml methyl isobutyl ketone is added dropwise to this suspension. The mixture is stirred for 1 hr more at RT, then the solid is suction-filtered and washed with 55 ml methyl isobutyl ketone. The filtrate is acidified with 12 ml of 6 N hydrochloric acid, then treated with 6.4 ml isopropanol. The precipitated solid is filtered off at the pump, washed with a little methyl isobutyl ketone, then stirred in 240 ml of acetonitrile and again suction-filtered. 3.41 g (34% of theory) of the pure title compound are thus obtained.
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:15][CH2:16][C:17]#[C:18][CH2:19]Cl.[NH4+].[Cl-]>C1COCC1.[Cu]Cl>[Cl:15][CH2:16][C:17]#[C:18][CH2:19][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: ClCC#CCCl
Reactant: C#CCCCCCCCC
Agent: Cl[Cu]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCCCCCC#CCC#CCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
38 ml of a 1M solution of ethyl magnesium bromide in THF were added dropwise, at room temperature, to a solution of 5 grams of 1-decyne in 15 ml of anhydrous THF, under an inert atmosphere. With the addition complete, the mixture was maintained under stirring for 30 min at room temperature and then heated under reflux for 1 h 30 min. The mixture was cooled to room temperature and then 286 mg of copper(I) chloride were added and the mixture was again heated under reflux for 1 hour. It was then cooled to between 40° C. and 50° C. and 12.5 g of 1,4-dichloro-2-butyne dissolved in 25 ml of anhydrous THF were added. The mixture was refluxed for 1 hour and then maintained under stirring for 15 h at room temperature before heating again under reflux for 2 h. The reaction medium was then cooled to 4° C. and hydrolyzed with care with a saturated aqueous solution of NH4Cl. The medium was then extracted 3 times with diethyl ether and the combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried over Na2SO4, filtered and concentrated under vacuum in a rotary evaporator. The oily residue containing 1,4-dichloro-2-butyne in excess was purified by distillation under reduced pressure to give 1-chloro-2,5-tetradecadiyne (b.p.=111-114° C., 0.36 mbar) in the form of an orange-colored oil (yield 52.4%).
Reaction SMILES: CC(C)(C)[C@H](NC1C=CC=C(C(F)(F)F)C=1)C([N:6]1[CH2:11][C@H:10]2[C@H:8]([C:9]2([CH3:13])[CH3:12])[C@H:7]1[C:14]([OH:16])=O)=O.Cl[NH:31]C(CC1CCC1)C(=O)C(N)=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.OS([O-])(=O)=O.[K+]>CC#N>[CH3:13][C:9]1([CH3:12])[CH:8]2[CH:10]1[CH2:11][NH:6][CH:7]2[C:14]([NH2:31])=[O:16]
Reactant: CC(C)(C)[C@H](Nc1cccc(C(F)(F)F)c1)C(=O)N1C[C@H]2[C@@H]([C@H]1C(=O)O)C2(C)C
Reactant: NC(=O)C(=O)C(CC1CCC1)NCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CN1CCOCC1
Solvent: O
Solvent: CC#N
Product: CC1(C)C2CNC(C(N)=O)C21
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.2 %

Procedure:
(1R,2S,5S)-3-((S)-3,3-dimethyl-2-(3-(trifluoromethyl)phenylamino)butanoyl)-6,6-dimethyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (0.043 g, 0.10 mmol), 3-(chloroamino)-4-cyclobutyl-2-oxobutanamide (0.031 g, 0.14 mmol), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDCI, 0.030 g, 0.16 mmol), 1-hydroxybenzotriazole hydrate (HOBt-H2O, 0.005 g, 0.03 mmol) in MeCN (3 mL) was added N-Methylmorpholine (d=0.920) (0.015 ml, 0.14 mmol) in MeCN (1 mL) dropwise over 40 minutes. The mixture was stirred at rt for 2 hrs and saturated KHSO4 (3 mL) was added, extracted with EtOAc (2×10 mL). The combined EtOAc extracts was washed with brine (10 mL), dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:1) to give the (1R,2S,5S)—N-(4-amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(3-trifluoromethyl)phenylamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.017 g, 29%) as white solid. MS: Calcd.: 564; Found: [M+H]+ 565. 1H NMR (400 MHz, d6-DMSO) δ 8.23 (m, 1H), 7.96 & 7.89 (s, 1H), 7.71 & 7.67 (s, 1H), 7.17 (m, 1H), 7.06 (s, 1H), 6.92 (m, 1H), 6.76 (m, 1H), 5.67 (d, J=10.8 Hz, 1H), 4.93 & 4.75 (m, 1H), 4.17 (s, 1H), 3.99 (m, 1H), 3.82 (m, 1H), 3.68 (m, 1H), 2.29 (m, 1H), 1.91 (m, 2H), 1.70 (m, 3H), 1.58 (m, 2H), 1.43 (m, 1H), 1.20 (m, 1H), 0.92-1.00 (m, 14H), 0.61 (s, 1H), 0.57 (s, 1H).
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13](=[O:18])[N:14]([CH2:16][CH3:17])[N:15]=2)[CH:7]=[CH:8][CH:9]=1)C.Br>>[OH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13](=[O:18])[N:14]([CH2:16][CH3:17])[N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOc1cccc(-c2ccc(=O)n(CC)n2)c1
Agent: Br
Product: CCn1nc(-c2cccc(O)c2)ccc1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 81.7 %

Procedure:
To a 2 liter 3-neck round bottom flask, stirring under a nitrogen atomsphere, was charged 64.9 g (1.0 eq., 0.266 moles) of 6-(3-ethoxyphenyl)-2-ethyl-3(2H)-pyridazinone followed by 250 ml of 48% HBr. The reaction was stirred at 90° C.-95° C. with monitoring by glc. After 7 hr. an additional 100 ml of 48%HBr was added and after an additional 10 hr. 100 ml of 48%HBr was added. After 33 hr. of stirring at 90° C.-95° C. the reaction was cooled to room temperature and quenched by pouring into 500 ml of ice water. An oil formed initially which on standing solidified. The solid was broken into small pieces and vacuum filtered, washed with 3×200 ml water and dried in a vacuum oven at ambient temperature and afforded 47.0 g of 6-(3-hydroxyphenyl)-2-ethyl-3(2H)-pyridazinone as a brown red solid. (81.9% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2OCC[O:16]2)=[CH:7][CH:6]=1.Cl>C1COCC1.C(OCC)C>[CH:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1)=[O:16]
Reactant: OCCCc1ccc(C2OCCO2)c2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(CCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.8 %

Procedure:
To a solution of 2-[4-(3-hydroxypropyl)naphthyl]dioxolane (67 mg, 0.26 mmol) in anhydrous THF (5 mL) was added 1 N hydrochloric acid (1 mL). The mixture was stirred at room temperature for 48 hr, diluted with ethyl ether (20 mL), washed with satd. NaHCO3 solution (2×10 mL), dried (MgSO4), concentrated and coevaporated with CHCl3 (3×10 mL) to yield 40 mg (72%) of a colorless oil.
Reaction SMILES: Cl.[CH2:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](O)(=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[N+:14]([O-:18])[CH:13]=1>>[C:11]([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[N+:14]([O-:18])[CH:13]=1
Reactant: CCCCCCCCO
Reactant: O=C(O)c1ccc[n+]([O-])c1
Agent: Cl
Product: CCCCCCCCOC(=O)c1ccc[n+]([O-])c1
Yield: 81.6 %

Procedure:
Hydrogen chloride was bubbled through cold octanol (25 g, 190 mmol) until a weight gain of 4.2 g had registered. Nicotinic acid N-oxide (5.29 g, 38 mmol) was then added and the resulting mixture was stirred and heated at 95°-100° C. for 3 hours and 40 minutes. The excess octanol was then removed by distillation at reduced pressure, and the residue of the distillation was taken up in dichloromethane. The dichloromethane solution was washed with aqueous sodium bicarbonate and then with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized from ligroine to give 7.73 g (31 mmol) of octyl nicotinate N-oxide, mp 69.5°-71° C.