Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3](C(O)=O)=[N:2]1.C(=O)(O)[O-].[Na+].[I-:17].[Na+].II>ClC(Cl)C.O.ClCCl>[I:17][C:3]1[C:4]2[CH2:8][CH2:7][CH2:6][C:5]=2[NH:1][N:2]=1
Reactant: O=C(O)c1n[nH]c2c1CCC2
Reactant: [I-]
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Ic1n[nH]c2c1CCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 75.4 %

Procedure:
To a mixture of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid (0.5 g, 3.29 mmol), and sodium bicarbonate (911 mg, 422 μL, 10.8 mmol) in dichloroethane (5 mL) and water (5 mL) were added in one portion sodium iodide (1.28 g, 8.54 mmol) and iodine (1.08 g, 4.27 mmol) and the mixture heated at to 100° C. (oil bath temperature) with vigorous stirring for 24 h. After cooling to 25° C. the mixture was diluted with dichloromethane then washed with 10% Na2S2O3 and saturated NaHCO3. The organic phases were combined, dried (MgSO4) and concentrated to a yellow solid which was dissolved in dichloromethane, cyclohexane added to promote solid formation and allowed to stand. The solid was separated by filtration and dried to give 3-iodo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (580 mg, 2.48 mmol, 75%) as needles. MS (M+H)+=234.9; 1H NMR (CDCl3) δ: 2.71-2.99 (m, 31H), 2.39-2.66 (m, 4H).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH3:20])=[CH:7][C:6]=1[C:21](=[O:23])[CH3:22].[CH:24](OCC)=O.Cl>O>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]2[C:6]([C:21](=[O:23])[CH:22]=[CH:24][NH:4]2)=[CH:7][C:8]=1[O:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC=O
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of sodium methylate (270 mmol, 14.75 g, favorable prepared from sodium metal and methanol before use), 1,2-dimeythoxyethane (122 ml) and 1-(2-amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (6.68 g 24 mmol) was stirred at 0° C. for 1 hour. Ethyl formate (10.7 ml, 9.81 g, 132 mmol) was added to the reaction mixture, that was allowed to come to room temperature and stirred for further 4 hours. The mixture was diluted with water (50 ml) and acidified to pH 1 by adding hydrochloric acid (1N, 185 ml). The precipitate was filtered, washed with water and dried to give 6.51 g of product [D]. Yield: 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[Li][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:6]=[CH:5]2
Reactant: [Li]c1ccccc1
Reactant: Cc1cc2ncccc2cc1Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccccc3)ccc2cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into a solution of 6-chloro-7-methylquinoline (1000 mg, 5.644 mmol) in THF (5 mL), which was cooled in ice/water bath under N2, was added PhLi (1.9 M in THF, 2.971 mL) dropwise over 5 min. After stirring at 0° C. for 15 min, the ice/water bath was removed and the reaction mixture was stirred at rt. After 4 h, MeOH (5 mL) was added to quench the reaction and the reaction mixture was stirred at rt overnight. After that time, the mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in acetonitrile (30 mL) and DDQ (1282 mg) was added and the solution was stirred under N2 at rt for 24 h. After that time, the reaction mixture was poured into aqueous NaOH (3 N, 50 mL) and extracted with EtOAc (2×75 mL). The extracts were washed with aqueous NaOH (3N, 2×50 mL), water (2×50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compounds; 1H NMR (CDCl3, 400 MHz) δ 2.60 (s, 3H), 7.47-7.55 (m, 3H), 7.83-7.86 (m, 2H), 8.04 (s, 1H), 8.10-8.16 (m, 3H); MS (ES): 254.1/256.1 (M/M+2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: OB(O)c1ccccc1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3ccccc3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and phenyl boronic acid were reacted to give 135. MS: (ESI+) 446.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]2[N:9]=[C:10]([CH3:18])[S:11][C:12]=2[C:13]([O:15]CC)=[O:14])[CH:7]=1.[OH-].[K+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]2[N:9]=[C:10]([CH3:18])[S:11][C:12]=2[C:13]([OH:15])=[O:14])[CH:7]=1
Reactant: CCOC(=O)c1sc(C)nc1-c1cc(Cl)ccc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1-c1nc(C)sc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylate (520 mg, 1.67 mmol) and potassium hydroxide (125 mg) in THF (18 mL) and water (4.5 mL) was stirred for 20 hours at room temperature and then at 75° C. for a further 8 hours. The solution was treated with 1M HCl aq. (pH 2) and extracted with DCM. The organics were evaporated to dryness to give 450 mg (95%) of 4-(5-chloro-2-methoxyphenyl)-2-methylthiazole-5-carboxylic acid as a white solid. LCMS (ESI) m+H=284.3; 1H NMR (400 MHz, DMSO-d6): δ 7.43 (dd, 1H); 7.31 (d, 1H); 7.10 (d, 1H); 3.71 (s, 3H); 2.69 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[S:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].CS(O[CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[Br:40])(=O)=O>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[S:17][C:16](=[O:18])[N:15]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[CH:32][C:31]=3[Br:40])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CS(=O)(=O)OCc1cc(C(F)(F)F)ccc1Br
Reactant: C[C@@H]1NC(=O)S[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)SC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one (50 mg, 0.152 mmol) in THF (1 ml) was added NaH (7.59 mg, 0.190 mmol) at −20° C. 30 Minutes later, a solution of 2-bromo-5-(trifluoromethyl)benzyl methanesulfonate (50.6 mg, 0.152 mmol) in THF (0.5 ml) was added. Stirring of the reaction continued for 1 hour. A crude NMR spectrum showed only 25% product formation. The reaction temperature was increased to −10° C., and stirring was continued for another 1 h. The reaction mixture was left in the freezer under N2 atmosphere overnight. NMR and LCMS indicated around a 65% conversion to the desired isomer, with no undesired epimerized product. The reaction was cooled to −10° C., and additional NaH (2.429 mg, 0.061 mmol) was added. Stirring of the reaction mixture was continued for 20 minutes. 2-Bromo-5-(trifluoromethyl)benzyl methanesulfonate (20.2 mg, 0.061 mmol) was added, and the reaction was continued for another 2 hours at −10° C. The reaction mixture was quenched with ice water, and the mixture was diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by PTLC by using 35% EtOAc in hexane. 1H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H); 7.85 (s, 2H); 7.76 (d, J=8.3 Hz, 1H); 7.59 (s, 1H); 7.48 (d, J=8.5 Hz, 1H); 5.15 (d, J=7.0 Hz, 1H); 5.02 (d, J=16.0 Hz, 1H); 4.45 (d, J=16.0 Hz, 1H); 4.10-4.11 (m, 1H); 0.97 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Br-:1].[Br-:2].[Br-].[Al+3].BrBr.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1>O>[Br:1][C:9]1[C:10]([Br:2])=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[F:7]
Reactant: Cc1ccc(F)cc1
Reactant: [Br-]
Agent: BrBr
Agent: [Al+3]
Solvent: O
Product: Cc1ccc(F)c(Br)c1Br
Temperature: -15 °C
Yield: 4 %

Procedure:
2.67 g of aluminum tribromide and 16.0 g of bromine were added to 110 g of 4-fluorotoluene, which had been cooled to -15° C. After increasing the temperature to +10° C., hydrolysis was carried out with water, the mixture was extracted by shaking with methylene chloride and the methylene chloride phase was washed and dried. After distilling off the solvent and the excess 4-fluorotoluene, 5.5 g of a mixture consisting of 88% of 2-bromo-4-fluorotoluene, 8% of 3-bromo-4-fluorotoluene and 4% of dibromo-4-fluorotoluene were obtained at a boiling point of 172° to 184° C. (normal pressure). Relative to the 4-fluorotoluene reacted, the yield of 3-bromo-4-fluorotoluene was 2.3%.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:8]1[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[OH:7])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:14][C:9]1[C:8]([CH:6]([OH:7])[CH2:5][CH2:4][OH:3])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)CC(O)c1cccnc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-chloropyridin-3-yl)-3-hydroxypropanoic acid ethyl ester (66.7 mmol) in 47 mL THF was added a suspension of LiAlH4 (100 mmol) in 219 mL THF at 0° C. The mixture was stirred at 0° C. for 1 h and was then quenched by adding consecutively 3.8 mL water, 3.8 mL 15% aq. NaOH solution and 11.4 mL water. The mixture was filtrated and the residue was washed with MTBE and EtOAc. The filtrate was dried over MgSO4 and concentrated in vacuo to obtain the desired product as yellow solid.
Reaction SMILES: C([S@@]([NH:7][C@@H:8]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:12][CH:11]=1)[CH3:9])=O)(C)(C)C.[ClH:23]>>[ClH:23].[NH2:7][C@@H:8]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH3:9]
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Product: C[C@@H](N)c1ccc(C(=O)O)cc1
Temperature: 60 °C

Procedure:
To a vial containing tert-butyl 4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate (0.065 g, 0.20 mmol) was added hydrochloric acid (2.0 mL, 8.0 mmol, 4.0 M in 1,4-dioxane). This vial was capped and heated at 60° C. for 2 h, and then completely evaporated to afford (R)-4-(1-aminoethyl)benzoic acid hydrochloride as a white solid. LC-MS: (FA) ES+ 166.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16])(=[O:5])=[O:4].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10](=[O:15])[C:9]2=[O:16])(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of N,N-dimethyl-2,3-dioxoindoline-5-sulfonamide (0.639 g, 2.51 mmol) in dry DMF (10 ml), cooled at 0° C. under nitrogen, NaH (60% dispersion in mineral oil, 0.111 g, 2.76 mmol) was added. The mixture turned dark blue. After stirring at 0° C. for 30 minutes, tert-butyl bromoacetate (0.446 ml, 3.02 mmol) was added, and the mixture was stirred at room temperature for 36 hours. The mixture was partitioned between ethyl acetate and brine and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness affording tert-butyl 2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetate (0.926 g, 2.51 mmol). MS/ESI+ 368.9 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH3:7])[C:4](=[O:6])[CH3:5].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14].[Na].Cl.NC(N)=N>C(O)C>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:5][C:4](=[O:6])[C:3]([O:8][CH3:9])([O:2][CH3:1])[CH3:7]
Reactant: COC(C)(OC)C(C)=O
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: N=C(N)N
Agent: [Na]
Solvent: CCO
Product: COC(C)(OC)C(=O)C=CN(C)C
Temperature: 110 °C
Reaction time: 30 h
Yield: 80.1 %

Procedure:
A mixture of 3,3-dimethoxy-2-butanone (25 g, 189.2 mmol) and N,N-dimethylformamide dimethylacetal (22.5 g, 189.2 mmol) were stirred at 110° C. for 30 hours and then distilled (115° C., 1 mmHg) thus obtaining 1-(dimethylamino)-4,4-dimethoxypent-1-en-3-one, as a yellow solid (27.3 g, 146 mmol, 77%). Onto a solution of sodium (3.48 g, 151.6 mmol) in anhydrous ethanol (400 mL), solid guanidine hydrochloride (14.5 g, 151.6 mmol) was added at r.t., to give a white suspension into which a solution of 1-(dimethylamino)-4,4-dimethoxypent-1-en-3-one (28.4 g, 151.6 mmol) in anhydrous ethanol (50 mL) was added. The mixture was refluxed for 19 hours. After cooling, the precipitate was filtered and washed with ethanol and with plenty of water, thus obtaining a white solid (8.56 g). The ethanolic solutions were concentrated to dryness, taken up with boiling ethyl acetate (1 L), filtered while hot and then cooled to yield a second crop. Total amount of 4-(1,1-dimethoxyethyl)pyrimidin-2-amine: 17.66 g, 63.5%. A solution of the said amine (17.5 g, 95.5 mmol) in formic acid was stirred at r.t. for 6 hours and concentrated to dryness and the residue was stirred in ethanol (50 mL) and then filtered thus obtaining 1-(2-aminopyrimidin-4-yl)ethanone (9.2 g, 70%). To a solution of 1-(2-aminopyrimidin-4-yl)ethanone (412 mg, 3 mmol) in glacial acetic acid (1 mL) and 48% aq. HBr (0.3 mL), bromine (0.153 mL) in acetic acid (0.4 mL) was added and the resulting orange solution was stirred at room temperature for 15 hours. After diluting with ethyl acetate (15 mL), the precipitate was filtered and washed with ethyl acetate thus affording the title compound as a whitish solid (580 mg, 65%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[F:48][C:49]([F:60])([F:59])[C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1.[O:61]1[CH2:66][CH2:65][CH:64]=[CH:63][C:62]1=[O:67]>O1CCOCC1>[F:48][C:49]([F:60])([F:59])[C:50]1[CH:51]=[C:52]([CH:64]2[CH2:65][CH2:66][O:61][C:62](=[O:67])[CH2:63]2)[CH:53]=[CH:54][CH:55]=1
Reactant: O=C1C=CCCO1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC(c2cccc(C(F)(F)F)c2)CCO1
Reaction time: 0.5 h

Procedure:
(Acetylacetonato)bis(ethylene)rhodium (I) (180 mg) was dissolved in 1,4-dioxane (144 mL). Racemic BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthalene) (867 mg) was added at room temperature, followed by stirring for 30 minutes. Subsequently, water (14.4 mL) and 3-(trifluoromethyl)phenylboronic acid (5.29 g) were added, followed by stirring for 10 minutes. Then, 5,6-dihydro-2H-pyran-2-one (2 mL) was added and the mixture was reacted at 100° C. for 12 hours. The reaction solution was partitioned with ethyl acetate and water. Then, the organic layer was washed with a saturated sodium bicarbonate solution and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 60%) to obtain the title compound (2.5 g).
Reaction SMILES: [CH2:1]([N:8]1[C:15]2[CH:14]3[CH2:16][CH:13]3[CH2:12][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.[Zn+2].[Br-].[Br-]>[CH2:1]([N:8]1[C:15]2[CH:14]3[CH2:16][CH:13]3[CH2:12][C:11]=2[C:10]([C:17]2[N:19]=[N:20][NH:21][N:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1nn(Cc2ccccc2)c2c1CC1CC21
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: c1ccc(Cn2nc(-c3nn[nH]n3)c3c2C2CC2C3)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of 2-benzyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonitrile (11.1 g, 47.2 mmol) in DMF (125 mL) was added ZnBr2 (18.4 g, 70.6 mmol) followed by NaN3 (12.2 g, 188 mmol). The mixture was heated to 120° C. and stirred for 18 h under N2 atmosphere. The reaction was cooled to rt and the DMF was removed in vacuo. The crude residue was diluted with EtOAc (200 mL) and HCl (3N aq., ˜100 mL) and stirred for 10 min. The layers were separated and the aqueous phase was back-extracted with EtOAc (150 mL). The combined organics were washed with NaOH (1M aq., 2×250 mL) and the organic layers were discarded. The basic aqueous phase was acidified with 6 N HCl to pH ˜2 and was extracted with EtOAc (2×250 mL). The extracts were washed with brine (150 mL), dried over MgSO4, filtered, and concentrated to give 2-benzyl4-(2H-tetrazol-5-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene as a light brown solid. 1H NMR (400 MHz, MeOD): δ 7.33 (5H, m), 5.42 (1H, d, J=14.8 Hz), 5.35 (1H, d, J=15.2 Hz), 3.01 (1H, dd, J=16.4, 6.4 Hz), 2.88 (1H, d, J=17.6 Hz), 2.28 (1H, m), 2.11 (1H, M), 1.14 (1H, m), 0.33 (1H, m). HPLC/MS: Alltech® Prevail C18 column (5μ, 50×4.6 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 3.5 ml/min, tr=2.14 min, ESI+=279.3 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:18][C:19](=O)[CH3:20]>C(O)C>[CH3:20][C:19]1[C:12]2[C:13](=[O:15])[CH2:14][CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][C:11]=2[O:16][CH:18]=1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1coc2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15 %

Procedure:
To 60% sodium hydride (0.22 g, washed with hexane thrice) was added ethanol (30 ml). To the mixture was added 5-phenylcyclohexane-1,3-dione (1.0 g) and then was added chloroacetone (0.49 g) at 0° C., and the mixture was stirred at room temperature for 20 minutes and refluxed for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:7]=1[C:8]([NH2:10])=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>CCCCC>[F:5][C:6]1[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:7]=1[C:8]#[N:10]
Reactant: NC(=O)c1cc(C(F)(F)F)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1cc(C(F)(F)F)cc(F)c1F
Reaction time: 1 h
Yield: 56 %

Procedure:
Thionyl chloride, 6.0 g (50 mmol) was added to a slurry of 4.0 g (18 mmol) 2,3-difluoro-5-(trifluoromethyl)benzamide and 15 mL dimethylformamide at 0° C. After stirring for 1 hour, the reaction mixture was diluted with 25 mL pentane and neutralized by dropwise addition of a saturated potassium carbonate solution and filtered. The pentane solution was dried and distilled to yield 2,3-difluoro-5-(trifluoromethyl) benzonitrile in 56% yield, bp 65°-70° C./20 mm Hg.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:22][C:21]([CH3:24])([CH3:23])[N:20]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:18]=2[CH:31]=1)#[N:13]>ClCCl>[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:22][C:21]([CH3:24])([CH3:23])[N:20]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N+:26]=3[O-:9])[C:18]=2[CH:31]=1)#[N:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)N=C(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 30 h
Yield: 21.2 %

Procedure:
m-Chloroperbenzoic acid (70% purity, 0.75 g) was added at -20° C. to a solution of 6-cyano-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.40 g) in dichloromethane (10 ml) and the mixture was stirred for 30 hours. The reaction mixture was extracted by addition of an aqueous sodium sulfite solution and ethyl acetate. The organic layer was successively washed with aqueous sodium carbonate and saturated saline solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel, and it was crystallized from isopropyl ether to obtain 2-(6-cyano-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)pyridine N-oxide (0.09 g) (Compound 20). Likewise, Compounds 21 to 29, 32, 36, 38, 43, 45, 47, 49, 51, 56, 58, 60, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 106, 107, 108, 109, 110, 117, 118, 119 and 144 were prepared.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][OH:10])[CH2:8][O:7][CH2:6][O:5][CH2:4]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[C:21]([CH2:23]I)[N:22]=2)=[CH:14][CH:13]=1.[H-].[Na+].FC1C=CC(C2OC=C(CO[C@@H]3CCC[C@H](OCC4C=CC=C(C)C=4C(OC)=O)C3)N=2)=CC=1>CN(C=O)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]=[C:21]([CH2:23][O:1][CH2:2][C:3]3([CH2:9][OH:10])[CH2:8][O:7][CH2:6][O:5][CH2:4]3)[N:22]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2nc(CI)co2)cc1
Reactant: OCC1(CO)COCOC1
Agent: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](OCc2coc(-c3ccc(F)cc3)n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC1(COCc2coc(-c3ccc(F)cc3)n2)COCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g (6.7 mmol) of 5-hydroxymethyl-1,3-dioxan-5-ylmethanol and 0.5 g (16.5 mmol) of 2 were dissolved in 20 ml of dry DMF. 300 mg of 55% NaH in paraffin oil were added, and the mixture was then stirred at room temperature for 1 hour. Work-up was carried out analogously to the synthesis of compound 5b. This gave 28 as a white amorphous solid. TLC (n-heptane/ethyl acetate 1:2). Rf=0.4. C16H18FNO5 (323.33) MS(ESI) 324.2 (M+H+). Methyl 2-{5-[2-(4-fluorophenyl)oxazol-4-ylmethoxymethyl]-1,3-dioxan-5-ylmethoxymethyl}-6-methylbenzoate 29
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)Cl>[Br:31][CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:10]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1c(Cl)cncc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cncc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
(3,5-dichloro-pyridin-4-yl)-methanol (918 mg, 5.15 mmol) was dissolved in dry DCM (25 mL). Triphenylphosphine (2.70 g, 10.3 mmoles) was added, and the mixture was stirred at room temperature for 10 minutes. The solution was then cooled to 0° C., and CBr4 (5.12 g, 15.4 mmoles) was added. The mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated, and the crude was purified by flash chromatography (SiO2, petroleum ether/AcOEt 95/5) to yield 850 mg of the title compound.