Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]#[C:59][C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:67][CH3:68])[CH2:65][CH3:66])[CH2:61][CH3:62]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:57][C:58]#[C:59][C:60]([CH2:71][CH3:72])([O:63][Si:64]([CH2:69][CH3:70])([CH2:65][CH3:66])[CH2:67][CH3:68])[CH2:61][CH3:62])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C#CCBr)(CC)O[Si](CC)(CC)CC
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#CCO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 71.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (58.9 mg, 0.105 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol), 15-crown-5 (10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=19:1, developed once) to give the title compound as a colorless oil (60.2 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cnc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
To a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.83 mmol) in acetic acid (10 mL) was added iron (2.465 g, 44.1 mmol) in one portion. The mixture was stirred at 80° C. for 15 min. The mixture was filtered and concentrated and then washed with aqueous NaOH and extracted with EA. The crude material was purified by silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=8:1, Rf=0.6) were combined and concentrated to yield a yellow solid of 6-chloro-5-(trifluoromethyl)pyridin-3-amine (1 g, 4.58 mmol, 51.9% yield): 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.86 (d, J=8.60 Hz, 1H), 7.53 (d, J=8.60 Hz, 1H), 7.46-7.26 (m, 5H), 4.16-4.11 (m, 2H), 3.81 (s, 2H), 1.47 (t, J=6.62 Hz, 3H); ES-LCMS m/z 197.0 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13]1>ClCCl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCCC(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
25 gms of Aluminium chloride was added to 50 ml of dichloromethane and 4.5 ml of fluorobenzene. To this a solution of 50 ml of dichloromethane containing 10 gms of glutaric anhydride and 4.5 ml of fluorobenzene was added. Reaction mass was stirred at room temperature. After completion of reaction, reaction mass was quenched with ice & HCl solution at 0-10° C. Filtered the reaction mass. The obtained wet solid was dissolved in aq NaHCO3 solution at 60-70° C. and insoluable material was filtered. Cooled the filtrate and adjust pH to 2.0 by adding hydrochloric acid. Obtained solid was filtered and dried at 60-70° C. under vacuum to get 10 gm of 5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(Cl)cc(C=O)cc1OC
Yield: 44.8 %

Procedure:
The compound was prepared according to general procedure E with 5-chlorovanillin (2.7 mmol) in dry acetone (25 ml), anhydrous K2CO3 (3.5 mmol), and ethylbromoacetate (4.05 mmol) at reflux for 1 h30. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 957 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 330 mg of purified compound were obtained (45% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.27 (t, J=7.2 Hz, 3H), 3.98 (s, 3H), 4.22 (q, J=7.2 Hz, 2H), 4.87 (s, 2H), 7.50 (s, 1H), 7.58 (s, 1H), 9.90 (s, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.1, 57.5, 62.1, 70.5, 112.3, 125.8, 128.9, 134.0, 149.7, 154.5, 169.5, 191.2. MS (ESI): m/z 272.9 and 274.9 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][CH3:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Yield: 96.4 %

Procedure:
Potassium carbonate (1.65 gm; 12 mmol) was added to a solution of 2-methoxy-5-nitro phenol (1.69 g; 10 mmol) and benzyl bromide (1.71 gm; 10 mmol) in acetone (60 ml). The reaction mixture was refluxed for 12 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was separated, washed with water (2×50 ml), dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 2.5 g of 1-Benzyloxy-2-methoxy-5-nitrobenzene (Yield=96.5%)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11]1[S:10][CH2:16][C:14](=[O:15])[N:13]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2ccccc2Cl)=N1

Procedure:
Similar procedure as described in example 10c was used, starting with 2-chloro-benzylamine, rhodanine, mercuric chloride and DIEA to give 2-(2-chloro-benzylamino)-thiazol-4-one. LC-MS m/e 241 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:18])C=1.[OH-].[Na+]>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:18])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1ccc(C=O)nc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
In dichloromethane (25.0 ml), 5-ethyl-2-methyl-pyridine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (2.31 g) was dissolved. After having been cooled to 0° C., the reaction solution was added with m-chloroperbenzoic acid (4.43 g) and the whole was stirred at room temperature for 2.5 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off. The resultant was dissolved in dichloromethane (40.0 ml). The reaction solution was added with trifluoroacetic anhydride (5.6 ml) and the whole was refluxed under heating for 3.5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off. The resultant was dissolved in methanol (80.0 ml). After having been cooled to 0° C., the reaction solution was added with a 12.5% sodium methoxide/methanol solution to adjust the reaction solution to pH 10, followed by stirring at room temperature for 16.5 hours. After the solvent was distilled off, the residue was added with distilled water and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off. The resultant was dissolved in chloroform (50.0 ml). The reaction solution was added with manganese dioxide (chemically processed product) (7.44 g) and then stirred at room temperature for 18 hours. The reaction solution was filtrated through Celite. The solvent in the filtrate was distilled off and the resultant residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (515.6 mg) as a yellow oily substance.
Reaction SMILES: [H-].[CH3:2][O:3][C:4](=[O:7])[CH2:5][OH:6].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1>CN(C)C=O>[CH3:2][O:3][C:4](=[O:7])[CH2:5][O:6][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[N:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: COC(=O)CO
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(Br)n1
Yield: 80.2 %

Procedure:
A suspension of 178 mg of sodiura hydride (80% dispersion in mineral oil) in 4 ml of dimethylformamide is mixed under argon atmosphere, stirring and ice cooling with a solution of 361 mg of glycolic acid methyl ester in 2 ml of dimethylformaraide and stirred for 3 hours at room temperature. Then, a solution of 948 mg of 2,6-dibromopyridine in 2 ml of dimethylformamide is added under ice cooling and the mixture is stirred for 48 hours at room temperature. The reaction mixture is poured on ice and extracted with ethyl acetate. The organic phase is washed 4 times with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 790 mg of 2-(6-bromo-2-pyridyloxy)acetic acid methyl ester is obtained as oily crude product.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)=[O:17]>CC(C)=O.C(OCC)(=O)C>[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 19 °C

Procedure:
14.5 cm3 of benzyl bromide and 16.75 g of potassium carbonate were added, at a temperature in the region of 19° C., to 15 g of 4-hydroxyacetophenone dissolved in 180 cm3 of acetone. The reaction medium was heated and maintained at the reflux temperature of the acetone for 4 hours. After cooling to a temperature in the region of 19° C., the reaction medium was suction-filtered through a sinter funnel and the insoluble material was rinsed again with 10 cm3 of acetone. The organic phase was evaporated under reduced pressure (2 kPa; 45° C.) and the solid obtained was dissolved in 300 cm3 of ethyl acetate. The organic solution was washed with twice 100 cm3 of water and then with 100 cm3 of saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 45° C.). The solid residue was triturated in 20 cm3 of pentane, suction-filtered through a sinter funnel and oven-dried under reduced pressure (10 kPa; 20° C.). 23.1 g of 4-benzyloxyacetophenone were obtained in the form of a white solid melting at 99° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH2:19]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:19][CH3:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (6 g, 27.27 mmol) in dichloromethane (100 ml) was added potassium carbonate (7.5 g, 54.27 mmol). This was followed by the addition of CH3NH2 (20 ml, 33% aqueous), which was added dropwise with stirring at room temperature. The resulting solution was stirred for 2 h at room temperature, extracted with dichloromethane (2×200 ml), and the organic layers combined and concentrated under vacuum to afford 4-bromo-N-methyl-2-nitroaniline as a red solid (6.1 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Cl)c(Cl)c1
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-chlorophenyl isocyanate (0.60 ml, 5.01 mmol) in THF (20 ml) was added Et3 N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-chlorophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-[N′-(2-chlorophenyl) ureido]phenylacetate (1.35 g, 76%) as a colorless powder. 1H-NMR (CDCl3) δ 3.58 (s, 3H), 3.71 (s, 2H), 7.04 (m, 3M), 7.18 (dd, J=8.5, 2.0 Hz, 1H), 7.27–7.39 (m, 3H), 8.07 (m, 2M); MS (ESI) m/z 353 (M++1), 355 (M++3), 357 (M++5).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:6]1)=[O:4].[OH-].[Na+].O>CO>[C:33]([O:32][C:30]([N:7]1[CH2:8][CH2:9][C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Cl)c(OCCOc2ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)cc2)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a sol. of compound (rac.)-(3R*,4S*)-4-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.15 g, 0.27 mmol) in MeOH (1 mL) was added aq. 1M NaOH (1 mL). The mixture was stirred at 70° C. for 2 h. Water was added, and the mixture was extracted with EtOAc. The org. phase was washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude residue was purified on a pad of silica gel to yield the title compound (93 mg, 65%). LC-MS: tR=1.12 min, ES+=524.24.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:11]1([S:17]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1F
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
To a solution of 2-fluoro benzaldehyde (5.00 ml, 47.6 mmol) in dimethyl sulfoxide (45 ml) was added benzene sulfinic acid sodium salt (8.60 g, 52.4 mmol) and the resulting mixture heated to 100° C. Upon heating the sulfinic acid salt dissolved. The solution was heated at 100° C. for 3 days. The reaction was cooled to room temperature and water (50 ml) added. This mixture was extracted with ethyl acetate, the combined organic extracts were washed with saturated brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica eluting with 25% ethyl acetate: petroleum ether (40-60° C.) to 33% ethyl acetate: petroleum ether (40-60° C.) to give (4.12 g, 16.7 mmol, 35%). δH (300 MHz, d6-DMSO) 10.68 (1H, s, CHO), 8.26-8.17 (1H, m, Ar), 8.08-7.99 (2H, m, Ar), 7.99-7.89 (3H, m, Ar) and 7.80-7.62 (3H, m, Ar).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3C[O:11]3)[CH:7]=[CH:6][C:5]=12>C(O)C>[N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=12
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: OCc1ccc2nnnn2c1

Procedure:
A solution of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (0.60 g) and (1,1-dimethyl-2-(5-benzyloxy-1H-indol-3-yl))ethyl amine (1.09 g, 3.55 mmol) in 15 ml of absolute ethanol was heated at reflux for 23 hours under an inert atmosphere. The reaction mixture was concentrated under reduced pressure to give crude product (1.59 g) which was chromatographed on silica gel (95:5:0.5 CH2Cl2 :MeOH:NH4OH) to give 1.27 g of (R)-α-[[(1,1-dimethyl-2-(5-benzyloxy-1H-indol-3-yl))ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][OH:12])([O-:3])=[O:2].CN1CCOCC1.O=C(Cl)[O:23][C:24](Cl)(Cl)[Cl:25]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][O:12][C:24]([Cl:25])=[O:23])([O-:3])=[O:2]
Reactant: CC(CO)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A solution consisting of 7.2 g 2-(2-nitrophenyl)propanol (39.7 mmol) and 4.4 ml N-methylmorpholine (39.7 mmol) in 15 ml absolute THF are slowly added to 5 ml diphosgene (41.4 mmol) in 10 ml absolute THF at 0° C. in a nitrogen atmosphere through a needle. Having stirred for 1 hour at 0° C., some of the precipitate is sucked off and the filtrate is withdrawn at the high vacuum. 6.91 g of (1) is obtained in the form of a brown oil (71%).
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]([CH2:11][OH:12])[CH2:2]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([O:12][CH2:11][CH:3]1[CH2:4][N:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1][CH2:2]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCC2CCCCN2C1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC2CCCCN2C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 90.7 %

Procedure:
Octahydro-2H-quinolizin-3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylanine (1.5 mL, 10.8 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford octahydro-2H-quinolizin-3-ylmethyl methanesulfonate as an orange oil (796 mg, 3.22 mmol, 91% yield). MS (EI) for C11H21NO3S: 248 (MH+).
Reaction SMILES: [Mg].BrCCBr.Br[CH:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:8]([O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]([O:15]C)=O)=[O:9]>C1COCC1>[CH2:28]([C:7]1[C:8](=[O:9])[O:10][C@H:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][C:13]=1[OH:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45 %

Procedure:
To a 1-L, 3-necked, round-bottomed flask fitted with a Claisen adapter with N2 inlet, a West condenser and a thermocouple-J-KEM controller and a rubber septum was added 13.9 g (0.572 g-atom, 3.2 equiv.) of magnesium (from Chromasco) was added. A small flake of 12 (about 45 mg) was added and the mixture was heated to about 80° C. 1,2-Dibromoethane (3.4 g, 18 mmol) and 350 mL of THF were added to the hot Mg/I2 mixture to activate the metal surface. Methyl (3R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoate (82.9 g, 179 mmol) from Example 2,1,2-dibromoethane (33.6 g, 179 mmol) and 400 mL of THF were added to the addition funnel. This mixture was slowly added to the Mg/THF mixture at reflux over about 1 h. The reaction mixture was stirred overnight (14 h) at about 60° C. The resulting yellow solution was decanted away from the metal into a 1-L, round-bottomed flask. The residual Mg metal was rinsed twice with 60 mL of THF. The combined THF solution was concentrated on a rotary evaporator. The syrupy mixture was taken up in 1750 mL of methylene chloride and added to a mixture of 500 mL of water, 200 mL of ice and 98 mL of 10% HCl in a separatory funnel. The aqueous layer was removed, the organic layer washed once with 200 mL of saturated sodium chloride, dried (NaSO4), filtered, and the solvent removed on a rotary evaporator. The crude white solid (66.7 g) was slurried in 100 mL of hexane, cooled to 0° C., filtered, and rinsed twice with 50 mL of cold hexane. The isolated white solid was dried in an oven at 40° C. under reduced pressure (10 mm Hg) overnight resulting in 28.4 g of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one (45-50% yield based on methyl (R)-3-hydroxytetradecanoate).
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]=[C:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.CCOCC>[Cl:1][C:2]1([Cl:7])[C:3](=[O:4])[CH2:8][C:9]21[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]2
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)C2(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
28.42 mL (254.65 mmol) of trichloroacetyl chloride dissolved in 70 mL of dimethoxyethane are added dropwise, at 0° C., to a mixture containing 7.98 g (47.16 mol) of tert-butyl 3-methyleneazetidine-1-carboxylate (WO 2008/124 085) and 36.48 g (282.94 mmol) of zinc-copper amalgam suspended in 200 mL of ether. The reaction medium is stirred at room temperature for 12 hours. The mixture is then poured portionwise into a sodium carbonate solution at 0° C. The solution obtained is filtered through Celite and rinsed thoroughly with water and ether. The aqueous phase is then separated out and extracted several times with ether. The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, the product obtained, in the form of a brown oil, is used without further purification in the following step.