Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC([N+]([O-])=O)=CC=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:30]([NH:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[O:31])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)Nc3ccncc3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of (S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 15a, 346 mg, 1.0 mmol) and 4-nitrophenyl pyridin-4-ylcarbamate (Example 28a, 518 mg, 2.0 mmol) in DMF (10 mL) was added potassium carbonate (414 mg, 3.0 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The compound was purified via preparative RP HPLC (10 to 90% acetonitrile in water to provide the desired product (120 mg, 28%). 1H NMR (DMSO-d6, 400 MHz): 1.47 (m, 1H), 1.65 (m, 4H), 1.80 (m, 1H), 3.12 (t, 1H, J=12.0 Hz), 4.03 (m, 1H), 4.17 (m, 1H), 4.61 (t, 1H, J=10.4 Hz), 4.93 (br s, 1H), 6.61 (d, 1H, J=8.4), 6.89 (d, 1H, J=8.4), 7.48 (m, 3H), 7.99 (br s, 1H), 8.30 (d, 2H, J=5.6 Hz), 8.35 (br s, 1H), 8.92 (s, 1H), 10.94 (s, 1H). M+H=431.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].Br[CH2:19][CH2:20][C:21]#[N:22]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:19][CH2:20][C:21]#[N:22])[CH:10]=1)=[O:8]
Reactant: O=C(Nc1nccs1)c1c[nH]c2ccccc12
Reactant: N#CCCBr
Product: N#CCCn1cc(C(=O)Nc2nccs2)c2ccccc21

Procedure:
The title compound was prepared using 1H-indole-3-carboxylic acid thiazol-2-ylamide and 3-bromo propionitrile as R5X.
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([N:17]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH2:4][CH2:3][CH2:2]1.C(N(CC1C=CC=CC=1)[C@@H](CC)C(O)=O)C1C=CC=CC=1>>[CH:1]1([CH2:5][C@H:6]([N:17]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(OCc1ccccc1)[C@H](CC1CCC1)N(Cc1ccccc1)Cc1ccccc1
Agent: CC[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Product: O=C(O)[C@H](CC1CCC1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Similarly, following the procedure of Example 2A, but replacing (S)-benzyl 2-(dibenzylamino)pentanoate with (S)-benzyl 3-cyclobutyl-2-(dibenzylamino)propanoate, (S)-2-(dibenzylamino)butanoic acid is prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].I[CH2:29][CH3:30].Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[N:16]([CH2:29][CH3:30])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCI
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h

Procedure:
Methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (F) (5.30 g) was added to a stirred suspension of oil-free sodium hydride (0.424 g) in dry N,N-dimethylformamide (25 ml), under an atmosphere of nitrogen. The dark-red solution was stirred for 15 minutes, and iodoethane (3.04 g) was added. The mixture was stirred for 30 minutes, and was poured into 1M hydrochloric acid (75 ml). The mixture obtained was extracted wih ethyl acetate (2×50 ml). The combined extracts were washed with brine (25 ml), then dried (MgSO4), and evaporated. The yellow oil obtained was purified by flash chromatography on silica gel (600 ml), eluting with 70:30 v/v hexane:ethyl acetate, to give methyl 3-methoxy-4-(1-ethyl-5-nitroindol-3-ylmethyl)benzoate (G) as a yellow oil, which was crystallized from methylene chloride/hexane to give yellow needles (4.88 g, 82%); mp 129°-30° C.; 1.34(t, 3H, CH2CH3), 3.83(s, 3H, CO.OCH3), 3.92(s, 3H, OCH3), 4.11 (s, 2H, CH2Ar), 4.23(q, 2H, CH2CH3), 7.27(d, 1H), 7.48(m, 2H), 7.64(d, 1H), 7.99(dd, 1H, H6 -indole), 8.49(d, 1H, H4 -indole).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:20])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][CH:9]=2)=[N:6][CH:7]=1.CC1C(C(O)=O)=C(C)N(C2C=CC(C(F)(F)F)=CN=2)[N:23]=1>>[F:20][C:4]1[CH:3]=[C:2]([NH2:23])[CH:7]=[N:6][C:5]=1[C:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH:9]=1
Reactant: Fc1cc(Br)cnc1C1=CCC(N2CCOCC2)CC1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)c(C)c1C(=O)O
Product: Nc1cnc(C2=CCC(N3CCOCC3)CC2)c(F)c1

Procedure:
4-[4-(5-Bromo-3-fluoropyridin-2-yl)cyclohex-3-en-1-yl]morpholine (2.28 g) was used in place of 1-(5-bromopyridin-2-yl)-c-4-(tert-butyldimethyl silanyloxy)-r-1-cyclohexanecarbonitrile in Reference Example 144 (2) and (3), and reacted and treated in a similar manner to give the titled compound (1.68 g) as a pale yellow solid. MS (ESI) m/z: 278 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][CH2:27][O:28][CH2:29][CH3:30])[CH2:12]1)[C:8](=[O:31])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO>[CH2:29]([O:28][CH2:27][O:26][CH:11]1[CH2:10][CH:9]2[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]3[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]2=[O:31])[CH2:23]3)[CH2:12]1)[CH3:30]
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)OCC)CC3C=CCCCCN(C)C(=O)C2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCOC1CC2C(=O)NC3(C(=O)O)CC3C=CCCCCN(C)C(=O)C2C1

Procedure:
A solution of the ester (115) (1.48 g, 3.39 mmol) in 1:1:1 THF-methanol-aq. 1M LiOH (102 ml) was stirred at 60° C., then at room temperature overnight. The reaction mixture was then concentrated into approximately ⅓ of the volume, diluted with water (30 ml) and acidified to approx. pH 4 using aq. 10% citric acid (60 ml), then washed with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (1×100 ml), then dried (Na2SO4), filtered and concentrated. Column chromatography of the residue using 9:1 ethyl acetate-methanol as eluent gave the title compound as a slight yellow (The coloring from the previous step was removed during work up and chromatography). Yield: 1.35 g, 97%. LR-MS: Calcd for C21H31N2O6: 407. Found: 407 [M−H].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[NH2:15][CH:16]([CH:32]([CH3:34])[CH3:33])[C:17]([N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18]>ClCCl>[CH2:25]([N:19]([CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])[C:17](=[O:18])[C@@H:16]([NH:15][C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)=[O:12])[CH:32]([CH3:33])[CH3:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(N)C(=O)N(CCN(C)C)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)Nc1ccc(OC(F)(F)F)cc1)C(=O)N(CCN(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
4-(Trifluoromethoxy)phenyl isocyanate (0.18 g, 0.86 mmole) was slowly added to a solution of 13 (0.20 g, 0.72 mmole) in dichloromethane (20 mL) at 0° C. The solution was allowed to warm to room temperature and stirred for 18 h. The reaction was then quenched with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The organic residue was purified by flash chromatographey on silica gel, eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4) to give 14a (0.24 g, 69%) as a white solid; MS (EI)=480 (M+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:3]([O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([O:15][C:18]1[C:19]2[C:26]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=3)=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1)[CH3:14])([CH3:4])([CH3:6])[CH3:5]
Reactant: CC(O)CCCCC(=O)OC(C)(C)C
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(OC(C)CCCCC(=O)OC(C)(C)C)c23)cc1

Procedure:
Add 49 mg (1.24 mmol) sodium hydride (60% dispersion in mineral oil) to a solution of 200 mg (0.99 mmol) 6-hydroxyheptanoic acid tert.-butyl ester in 5 ml THF. After stirring for ten minutes, add a solution of 407 mg (90% purity, 1.04 mmol) 4-chloro-5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidine in 5 ml THF and 18 mg (0.05 mmol) tetra-n-butylammonium iodide. Stir the reaction mixture for 40 hours at 75° C. After adding water and ethyl acetate, wash the separated organic phase with 1 N hydrochloric acid and concentrate by vacuum evaporation. Take up the residue in acetonitrile/DMSO and purify by preparative RP-HPLC (gradient: water/acetonitrile). 104 mg (19% of theor.) of the desired product (racemate) is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[OH:5][C:6]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:17])[NH:11]2.C(=O)([O-])[O-].[K+].[K+].C(Br)C#C>O>[CH2:4]([O:16][C:13]1[CH:14]=[CH:15][C:6]([OH:5])=[C:7]2[C:12]=1[NH:11][C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]#[CH:1]
Reactant: CC(C)=O
Reactant: O=C1CCc2c(O)ccc(O)c2N1
Agent: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#CCOc1ccc(O)c2c1NC(=O)CC2

Procedure:
2 liters of acetone and 500 ml of water were added to 150 g of 5,8-dihydroxy-3,4-dihydrocarbostyril, and 138 g of potassium carbonate and 150 g of 2-propynyl bromide were further added thereto. The resulting mixture was heated while refluxing for 3 hours on a water bath. After completion of the reaction, the acetone and the 2-propynyl bromide were evaporated under reduced pressure, and the residue was made acidic with concentrated hydrochloric acid. The mixture was extracted with chloroform, and the chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residual crystals were recrystallized from isopropanol-diethyl ether to obtain 110 g of 8-(2-propynyloxy)-5-hydroxy-3,4-dihydrocarbostyril having a melting point of 141°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(C)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:21])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: OCc1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: O=C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)methanol (0.45 g, 1.9 mmol) in acetone (10 mL) was added Jones's reagent (3 mL) dropwise at 0° C. The reaction mixture was stirred at rt for 1 hr and concentrated under reduced pressure. Water was added to the residue and the solid that separates out was filtered, washed with water and dried to give 1-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.43 g, 1.7 mmol, 89% yield) as a yellow solid.
Reaction SMILES: [F-].[Cs+].CC(C)([O-])C.[K+].[CH3:9][O:10][C:11](=[O:26])[CH2:12][C:13]1[C:14]([CH3:25])=[N:15][NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.[Cl-].[NH4+]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:9][O:10][C:11](=[O:26])[CH2:12][C:13]1[C:14]([CH3:25])=[N:15][N:16]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1
Reactant: OB(O)c1cncnc1
Reactant: COC(=O)Cc1c(C)n[nH]c1-c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Product: COC(=O)Cc1c(C)nn(-c2cncnc2)c1-c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 45 h

Procedure:
0.287 g (2 mmol) of cesium fluoride, 0.103 g (1 mmol) of copper(II) acetate and 0.212 g (2 mmol) of potassium tert-butoxide were added to 0.5 g (2 mmol) of methyl[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]acetate in 10 ml of dichloromethane. 0.234 g (2 mmol) of 5-pyrimidinylboronic acid was then added, and the mixture was stirred at 20° C. for 45 h. The mixture was then added to saturated ammonium chloride solution (10 ml) and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC. This gave 0.040 g of product (5.8% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([O:13][CH2:14][C@@H:15]([OH:25])[CH2:16][N:17]([CH:22]([CH3:24])[CH3:23])S(C)(=O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(C)=C.P(Cl)(Cl)(Cl)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@@H:15]([OH:25])[CH2:16][NH:17][CH:22]([CH3:23])[CH3:24])=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C[C@H](O)COc1ccc(OCc2ccccc2)cc1)S(C)(=O)=O
Agent: C=C(C)OC
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)NC[C@H](O)COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a stirred slurry of (S)-1-(4-benzyloxyphenoxy)-3-[N-mesyl-(1-methylethyl)amino]-2-propanol (78.7 g) in 300 ml toluene was added isopropenyl methyl ether (29 ml) followed by 0.1 ml phosphorus oxychloride. The reaction mixture was stirred for 2 hours at room temperature to ensure formation of the isopropenyl methylether derivative, whereupon 1 ml of triethylamine was added to neutralize the acid catalyst. The solution was then added dropwise over 30 minutes to a stirred solution of sodium bis-(2-methoxyethoxy) aluminum hydride (70% in benzene; 286 ml) and 300 ml toluene which was maintained at 80° throughout the addition. After stirring for an additional 2 hours at 80°, the reaction was cooled and excess reagent was destroyed by the dropwise addition of 30 ml 2N sodium hydroxide and when the reaction had subsided, 300 ml 2N sodium hydroxide were added. The layers were separated and the organic layer was washed in turn with 1N sodium hydroxide (2×) and with brine (2×). The toluene layer was then diluted with ether (300 ml) and extracted using 800 ml 0.5N hydrochloric acid. The acidic extract was washed with ether and the organic layers were backwashed with 0.5N hydrochloric acid (100 ml). The stirred aqueous extracts were basified using 100 ml 10N sodium hydroxide and the resulting solids were removed by filtration and dried. Crystallization of the crude material from ethyl acetate-hexane furnished 54.7 g of (S)-1-(4-benzyloxyphenoxy)-3-(1-methylethyl)amino-2-propanol, mp 94°-96°.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[N:26]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCc1ccccc1CNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccccc1CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.15 g (3.16 mmol) of 2-[2-({[(benzyloxy)carbonyl]amino}methyl)phenyl]ethyl methanesulfonate in 8.0 mL of DMF was added 0.411 g (6.33 mmol) of sodium azide. After stirring at room temperature overnight, an additional 0.205 g (3.15 mmol) of sodium azide was added and the reaction warmed to 40° C. for 4 h. The reaction was cooled to room temperature, treated with saturated sodium carbonate (aq) and extracted with ethyl acetate (3×). The organic extracts were combined, washed with water (1×) and brine (1×), dried over sodium sulfate and concentrated to dryness in vacuo to give 1.2 g of a crude oil. Flash chromatography on silica gel (20% ethyl acetate in hexane) gave benzyl 2-(2-azidoethyl)benzylcarbamate as a colorless oil: 1H NMR (CDCl3, 400 MHz): δ7.39-7.20 (m, 9H), 5.14 (s, 2H), 5.05 (br s, 1H), 4.42 (d, 2H, J=5.6 Hz), 3.56-3.49 (t, 2H, J=7.0 Hz), 2.91 (t, 2H, J=7.0 Hz); MS (Electrospray): M+Na=333.1; TLC Rf=0.32 (20% ethyl acetate in hexane).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[C:8]([O:11]C(=O)C)(=[O:10])[CH3:9]>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[C:8]([OH:11])(=[O:10])[CH3:9].[C:8]([OH:11])(=[O:10])[CH3:9].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: CC(=O)OC(C)=O
Agent: O=Cc1cccs1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)O

Procedure:
Thiophene-2-carboxaldehyde (5.66 g, 0.050 mol) was dissolved in an excess of acetic acid anhydride (10 ml) and 3 drops conc. sulfuric acid added under stirring. The resulting green mixture was allowed to react at room temperature for 2.5 hr. The reaction mixture was then diluted with CHCl3 (25 ml) before washing twice with 10% aqueous NaHCO3 (20 ml). The organic phase was dried (MgSO4) and evaporated. The crude product was dissolved in hexane, and insoluble impurities were removed. The hexane solution was then treated with activated charcoal, to give a colourless liquid. Evaporation of the solvent gave white or weakly pink crystals. The yield was 3.8 g, 35% of the theoretical. 1H- and 13C NMR (CDCl3), d (ppm) rel. to TMS: 7.93 (s, 1H, CH(OAc)2) 7.49, 7.27 and 7.02 (m, 3×1H, Ar-H) and 2.12 (s, 6H, CH3); 168.386, 137.867, 127.179,126.917 and 126.599 (Ar), 86.227 (CH(OAc)2) and 20.663 (CH3).
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[C:11](Cl)(=O)[CH2:12][CH2:13]C>ClCCl.N1C=CC=CC=1.C(O)C>[O:9]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
176 g of 2,2-dimethyl-4,6-dioxo-1,3-dioxane (Meldrum's acid) are dissolved in 550 ml of dichloromethane and 188 ml of pyridine. The mixture is cooled to 0° C. with a water/ice bath and 133 ml of butyryl chloride are added dropwise. When the addition is complete, the mixture is stirred for 3 hours at room temperature. The solution is washed with dilute hydrochloric acid solution, dried over magnesium sulphate and evaporated under vacuum to give an oil. This oil is dissolved in 700 ml of ethanol and the mixture is heated to reflux for 6 hours. The ethanol is evaporated off under vacuum and the residue obtained is distilled to give 145.4 g of ethyl 3-oxohexanoate in the form of a liquid of boiling point b.p.20 98°-100° C.
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1([CH2:36][C:37]([O:39]CC)=[O:38])[CH2:31][C:32]([F:35])([F:34])[F:33]>C(O)C.O>[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=4)=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1([CH2:36][C:37]([OH:39])=[O:38])[CH2:31][C:32]([F:34])([F:35])[F:33]
Reactant: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1(CC(F)(F)F)CCc2cc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)ccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
Lithium hydroxide (0.114 g, 2.72 mmol) was added to a solution of 14B2 (0.3 g, 0.543 mmol) in 6 mL of ethanol-water (3:1) mixture, and the mixture was stirred at room temperature for 5 h. After the solvent was removed in vacuo, the residue was diluted with water. The aqueous layer was acidified with addition of saturated citric acid solution until pH 3 was attained. The resulting solution was cooled to 0° C., and solids obtained were filtered off and dried under vacuum to afford the title compound (0.2 g, 88%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 12.47 (s, 1H), 10.47 (s, 1H), 8.98 (dd, J1=1.9 Hz, J2=7.7 Hz, 2H), 8.53 (dd, J1=2.1 Hz, J2=8.7 Hz, 1H), 8.46 (s, 1H), 8.10-7.93 (m, 3H), 7.88 (d, J=8.7 Hz, 1H), 3.26-2.92 (m, 3H), 2.88-2.64 (m, 2H), 2.58-2.42 (m, 2H), 2.17 (m, 1H). ESI-MS m/z: 525 (M+H)+; HPLC purity: 97%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12]OS(C)(=O)=O)=[CH:5][CH:4]=1.[Na+].[I-:21]>CC(=O)CC>[I:21][CH2:12][CH2:11][C:10]#[C:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCCC#Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: FC(F)(F)c1ccc(C#CCCI)cc1
Temperature: 90 °C
Yield: 98.8 %

Procedure:
To a solution of 3.16 g (10.81 mmol) methanesulfonic acid 4-(4-trifluoromethyl-phenyl)-but-3-ynyl ester in 100 ml 2-butanone was added 3.24 g (21.62 mmol) NaI. The mixture was heated for 2 h at 90° C. The solvent was evaporated and the residue suspended in dichloromethane, ether was added and the suspension was filtrated. Evaporation of the organic phase gave 3.46 g of the title compound as an orange liquid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].[CH2:9](Br)[CH:10]=[CH2:11].[OH-].[K+].ClCCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([C:3]1([CH2:7][O:8][CH2:11][CH:10]=[CH2:9])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CO)COC1
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C=CCOCC1(CC)COC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 91.5 %

Procedure:
To a solution of 23.2 g (0.2 mol) of 3-ethyl-3-hydroxymethyloxetane in 48.4 g (0.4 mol) of allylbromide and 50 g of a 50 wt % aqueous solution of potassium hydroxide in a 300 mL round bottom flask equipped with a magnetic stirrer was added 1.0 g of tetra-n-butylammonium bromide with vigorous stirring at 0° C. After 24 hrs, 100 mL of dichlorometane and 100 mL of water were added to the reaction mixture. The organic phase was washed with water twice, dried over magnesium sulfate, filtered and the solvent removed on a rotary evaporator. The residue was purified by distillation under vacuum, giving 28.6 g of 3-ethyl-3-allyloxymethyloxetane (yield 92%, b.p.:55° C. at 1.5 mm Hg).