Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Cl.[F:4][C:5]1[C:10]([C:11]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1>C1COCC1>[F:4][C:5]1[C:10]([C:11]2[CH2:16][CH2:15][CH2:14][C:13]([CH3:1])([OH:17])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C1C=C(c2cccnc2F)CCC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)C=C(c2cccnc2F)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 3.0 M solution of methylmagnesium chloride in tetrahydrofuran (4.88 mL, 14.64 mmol) was added slowly to a solution of 3-(2-fluoropyridin-3-yl)cyclohex-2-enone (2.00 g, 10.46 mmol) in THF (20 ml) at −78° C. After completion of the addition the reaction mixture was stirred overnight while it gradually warmed up to RT. It was cooled in an ice water bath and distilled water (5 ml) was added slowly. The mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate (200 ml) was added, and it was extracted EtOAc (3×100 ml). The combined organic layers were washed by brine and dried over sodium sulfate. Filtration and concentration under reduced pressure gave (rac)-3-(2-fluoropyridin-3-yl)-1-methylcyclohex-2-enol as a light yellow liquid. MS (ESI, pos. ion) m/z: 208.0 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:17]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:18](O)=[O:19])[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:17]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:18]([N:4]([O:3][CH3:2])[CH3:5])=[O:19])[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of N-methoxymethanamine hydrochloride (2.75 g) in acetonitrile (120 mL) was neutralized with triethylamine (9.83 mL), 2-[3-chloro-4-(methylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (8.16 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (6.77 g) and 1-hydroxybenzotriazole (541 mg) were added under ice-cooling. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate, and washed with water and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (8.64 g, yield 94%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][N:6]([CH3:8])[CH3:7].[CH:10]([NH2:13])([CH3:12])[CH3:11].C[O-].[Na+]>>[CH3:7][N:6]([CH3:8])[CH2:5][CH2:4][C:3]([NH:13][CH:10]([CH3:12])[CH3:11])=[O:2]
Reactant: COC(=O)CCN(C)C
Reactant: CC(C)N
Agent: C[O-]
Agent: [Na+]
Product: CC(C)NC(=O)CCN(C)C
Reaction time: 72 h
Yield: 98.1 %

Procedure:
Methyl-3-dimethylaminopropionate (131 g) is stirred as isopropylamine (71 g) as added followed by 30% methanolic sodium methoxide solution (18 g). After 3 days at ambient temperature, GC analysis indicated 98% conversion. Excess isopropylamine is evaporated off under reduced pressure leaving 3-dimethylamino-N-isopropylpropanamide (155 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][C@H:2]([C@@H:5]([CH3:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][NH2:4].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(=O)([O-])O.[K+]>O1CCOCC1.O>[CH3:1][C@H:2]([C@@H:5]([CH3:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11])[CH2:3][NH:4][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)=CCC[C@H](C)[C@@H](C)CN
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)=CCC[C@H](C)[C@@H](C)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Separate solutions of 2(R),3(S),7-trimethyl-1-amino-6-octene (0.87 g, 5.2 mmol) in 8 mL of dioxane, and benzyl chloroformate (0.86 mL, ~6 mmol) in 8 mL of dioxane were added dropwise simultaneously to a stirred solution of 1.05 g (10.5 mmol) of potassium hydrogen carbonate in 20 mL of water at 0° C. After the additions, the mixture was stirred 8 hrs at room temperature. Most of the volatile solvents were removed in vacuo. The remaining reaction mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate. Solvent removal gave the crude product which was purified on silica gel using 10% ethyl acetate in hexane as solvent to give 1.4 g of the desired carbamate as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].ClCCC(OCC)=O>CN(C=O)C>[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:2]=[CH:3]2)#[N:11]
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)CCBr
Agent: CCOC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 1H-indazole-5-carbonitrile (D1) (3.88 g, 27.3 mmol) in DMF (85 ml) was added Cs2CO3 (17.8 g, 54.6 mmol) and then ethyl 3-bromopropanoate (3.5 ml), 27 mmol) and ethyl 3-chloropropanoate (3.3 g, 24.2 mmol) were added. The reaction mixture was stirred at 80° C. for 4 hours and then allowed to cool. The solvent was removed in vacuo and the crude material was partitioned between EtOAc and water, the organics were separated, washed with brine, dried and evaporated. The crude was azeotroped with toluene and then purified by flash chromatography (EtOAc/hexane 1:9 to 1:1) to give 3.84 g of a yellow gum. MS data as for previous example.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: Fc1ccccc1NCc1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 6 g. portion of 3-(2-fluorophenylaminomethyl)pyridine was dissolved in 50 ml. of acetone, and 5 g. of potassium carbonate and 5 g. of methanesulfonyl chloride were added. The mixture was stirred at ambient temperature overnight, and then under reflux for 6 hours. The mixture was cooled and filtered, and the filtrate was concentrated under vacuum to obtain 7.4 g. of an oil, which was chromatographed on silica gel, eluting with 1:4 acetone:toluene. Combination of the product-containing fractions and evaporation gave 9.7 g. of the desired product, m.p. 120°.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@H:10]1[CH3:21])=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].ClCCl.O1CCCC1>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:8][C@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][C@H:10]1[CH3:21]
Reactant: C[C@@H]1Oc2ccccc2NC(=O)[C@@H]1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1Oc2ccccc2NC(=O)[C@@H]1N

Procedure:
(2S,3R)-3-amino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetate salt was prepared from (2S,3R)-3-t-butyloxycarbonylamino-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (Robl, et al., Bioorg. & Med. Chem. Lett. 1994, 4, 1789–1794) by treatment with a solution of trifluoroacetic acid—dichloromethane—tetrahydrofuran (1:10:10) at room temperature, followed by solvent evaporation and coevaporation with tetrahydrofuran under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](C2CCNCC2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:15]2[C:16]([CH2:23][CH2:24][CH2:25][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[C:17]3[C:22]([CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14]2)=[CH:31][CH:30]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Clc1ccc(C2CCNCC2)cc1
Product: Fc1ccc(N2CCN(CCCc3c4c(nn3-c3ccc(Cl)cc3)CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2-(4-chlorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 12 and 1-(4-fluorophenyl)piperazine are used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 2-(4-chlorophenyl)-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole is obtained.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[NH:29]C=O)=[O:21])[CH2:16][CH2:15]2)[C:10](=[O:32])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)C>[NH2:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:20]([CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:11]2[C:10](=[O:32])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[CH2:15][CH2:16]1)=[O:21]
Reactant: O=CNc1cc(F)ccc1C(=O)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(F)ccc1C(=O)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1

Procedure:
A mixture of 2.3 parts of N-[2-[1-[2-(1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl)ethyl]-4-piperidinylcarbonyl]-5-fluorophenyl]-formamide, 33 parts of concentrated sulfuric acid and 144 parts of ethanol is stirred and refluxed for 1 hour. The reaction mixture is poured onto crushed ice and alkalized with a dilute sodium hydroxide solution. The precipitated produce is filtered off and crystallized from 4-methyl-2-pentanone, yielding 0.4 parts of 3-[2-[4-(2-amino-4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione; mp. 269.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:7][CH:6]=1)=[O:4].[C:27](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:27])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(CNCC2CCCCN2C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(CN(C)CC2CCCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 72 h
Yield: 50.5 %

Procedure:
A solution of 1,1-dimethylethyl 2-((4-(methoxycarbonyl)phenylmethylamino)methyl)-1-piperidinecarboxylate (0.7 g, 2 mmol) in dichloroethane (10 mL) was treated with acetic acid (180 mg, 3 mmol) and formaldehyde (37% solution in water). After the addition of sodium triacetoxyborohydride (487 mg, 2.3 mmol) the reaction was stirred for 3 days. The reaction was poured into water and extracted with methylene chloride (2×). The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification on silica gel using a gradient of ethyl acetate in hexane gave 0.38 g of 1,1-dimethylethyl 2-(((4-(methoxycarbonyl)phenylmethyl)(methyl)amino)methyl)-1-piperidinecarboxylate.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH2:2][OH:3].CCC(C[O:12]C(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:2]([OH:12])(=[O:3])[C:1]([OH:5])=[O:4]
Reactant: O=C([O-])CO
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Reaction time: 4 h

Procedure:
The reaction in Example 16 was repeated using 15.0 g of Hansenula polymorpha transformant GO1 (51 IU glycolate oxidase and 730,000 IU catalase) which had been permeabilized by treatment with 0.1% Triton X-100/1 freeze-thaw. The mixture was stirred at 1250 rpm, which bubbled oxygen through the mixture via the action of the Dispersimax turbine impeller, and at 5° C. under 120 psig of oxygen. After 4.0 h, the yields of glyoxylic acid, oxalic acid, and formic acid were 97.5%, 0%, and 0%, respectively, with 0.6% glycolic acid remaining. The recovered activities of permeabilized-cell glycolate oxidase and catalase were 132% and 129% of their initial values, respectively.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].N1C=CC=CC=1>C(O)C>[C:1](=[N:16][OH:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C(c1ccccc1)c1ccccc1
Yield: 73 %

Procedure:
A solution of benzophenone (10.0 g), hydroxylamine hydrochloride (10.0 g), pyridine (50 ml), and absolute ethanol (50 ml) was pumped through the CMR (15 ml/min; 155°-60° C., 700 kPa). The effluent was cooled and the solvent removed by rotary evaporation, and the residue stirred with cold water (50 ml). The crued oxime was filtered off and recrystallised from ethanol to afford pure product (8.0 g; 73% yield), m.p. 140.5°-141° C., cf lit.5 for a batchwise preparation by microwave heating.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.C(=O)(O)[O-].[Na+].[CH2:20]([C:27]1[NH:28][C:29]2[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:33]=[CH:32][C:30]=2[N:31]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.C(OCC)(=O)C>[CH2:20]([C:27]1[N:31]([CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[Cl:6])[C:30]2[CH:32]=[CH:33][C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:35][C:29]=2[N:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ccc2nc(Cc3ccccc3)[nH]c2c1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)nc(Cc1ccccc1)n2Cc1ccccc1Cl
Temperature: 60 °C
Yield: 18.7 %

Procedure:
N,N-dimethylformamide (15 ml), 2-chlorobenzyl bromide (3.94 g) and sodium bicarbonate (1.23 g) are added to 2-benzyl-5-ethoxycarbonyl-benzimidazole (2.37 g) (example 11) and the solution is heated for one hour at 60° C. After adding ethyl acetate (70 ml) and water (70 ml) and separating the solution, the organic layer is washed with water three times and extraction is performed on the aqueous layer using ethyl acetate three times. By concentrating the obtained organic layer under reduced pressure, a mixture of 2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole (1.06 g) and 2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole (0.640 g) is obtained. Separation and purification is performed using medium pressure silica gel column chromatography (eluate: hexane/ethyl acetate=1/4˜0/100) produces medium pressure silica gel column chromatography (eluate: hexane/ethyl acetate=1/4˜0/100).
Reaction SMILES: [Pb](SC#N)[S:2][C:3]#[N:4].ClCl.[CH2:10]1[O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11]1>C(O)(=O)C>[CH2:10]1[O:18][C:13]2[CH:14]=[CH:15][C:16]([S:2][C:3]#[N:4])=[CH:17][C:12]=2[O:11]1
Reactant: c1ccc2c(c1)OCO2
Reactant: N#CS[Pb]SC#N
Agent: ClCl
Solvent: CC(=O)O
Product: N#CSc1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 161.8 %

Procedure:
Lead thiocyanate (45 g, 139 mmol) was added in portions to a stirred solution of chlorine (20.3 g, 290 mmol) in anhydrous acetic acid (600 ml) under an atmosphere of argon. The mixture was stirred for 15 minutes. 1,2-Methylenedioxybenzene (35 g, 286 mmol) was added in one portion. The mixture was stirred for 1 hour and then filtered. The filtrate was added to ice-water (3.5 liters). The precipitated solid was collected by filtration, dissolved in ethyl acetate and dried (MgSO4). The solvent was removed by evaporation to give 3,4-methylenedioxyphenyl thiocyanate as a pale green oil (40.3 g, 79% yield). The oil solidified and was used without further purification or characterisation.
Reaction SMILES: [Cl:1][C:2]([CH2:4][CH2:5][P:6]([Cl:10])([CH2:8][CH3:9])=[O:7])=[O:3].[CH2:11](P(Cl)Cl)C.C(O)(=O)C=C.C(O)(=O)C(C)=C>C1C=CC=CC=1>[Cl:1][C:2]([CH:4]([CH3:11])[CH2:5][P:6]([Cl:10])([CH2:8][CH3:9])=[O:7])=[O:3]
Reactant: CCP(Cl)Cl
Reactant: CCP(=O)(Cl)CCC(=O)Cl
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)O
Solvent: c1ccccc1
Product: CCP(=O)(Cl)CC(C)C(=O)Cl
Reaction time: 2.5 h
Yield: 37.2 %

Procedure:
USSR Patent Specification No. 173,763 also describes the preparation of beta-chloroformyl-ethyl ethyl phosphinic acid chloride by reacting ethyldichlorophosphine and acrylic acid in benzene at temperatures of up to 60° C., over a period of 2.5 hours, and distilling the reaction product, which is obtained in a yield of 62.4 % of the theoretical. In the absence of the benzene solvent, the temperature increases spontaneously to 150° C., and the yield falls to 31.6 % of the theoretical. The reaction of ethyldichlorophosphine with methacrylic acid, in the absence of a solvent, produces beta-chloroformyl-beta-methyl-ethyl ethyl phosphinic acid chloride in a yield of 37.2 % of the theoretical.
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:6]=1[O:7][CH2:8][C:9](OC)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:6]=1[O:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)COc1cc(C)ccc1C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C)c(OCCO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
To a solution of (methyl 2-(2-tert-butyl-5-methylphenoxy)acetate (7.16 g, 30.3 mmol) was added a 2.0M solution of LAH in THF (15.2 mL, 30.3 mL) under an ice-water bath. The resulting mixture was allowed to stir at room temperature for 10 minutes before it was quenched with ice chips. The solvent was removed, and 20 mL of 2.0N aqueous HCl solution was added. The resulting mixture was extracted with DCM (30 mL×3). The extract was washed with water, saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by CombiFlash to give 6.22 g of 46.3, which was eluted with 0-40% EtOAc in hexane.). MS ESI (pos.) m/e: 209(+H). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.73 (s, 2H), 4.15 (dd, 2H), 4.04 (dd, 2H), 2.34 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50](=[O:55])[CH2:51][C:52](O)=[O:53].C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.C(Cl)CCl>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:52](=[O:53])[CH2:51][C:50]([NH:49][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[O:42][CH3:41])=[O:55])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: CN(C)CCCOc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cn1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCCN(C)C)nc4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a solution of aniline 380 (0.31 g, 0.71 mmol) and DIPEA (0.7 ml, 0.4 g, 3 mmol) in dry DMF (5 mL) was added acid 27 (0.30 g, 1.4 mmol), HOBt (0.040 g, 0.30 mmol), and EDC×HCl (0.40 g, 2.1 mmol) and the mixture was stirred at r.t. for 18 h. Additional EDC×HCl (0.050 g, 0.26 mmol) was added, and the mixture was stirred for a further 6 h. It was then partitioned between ethyl acetate and water. The organic phase was collected, washed with water, dried (anhydrous MgSO4), filtered, and concentrated. Flash chromatography (chloroform/NH4OH) of the residue followed by re-crystallization (90% ethyl acetate/methanol) provided 378 (0.15 g, 32% yield) as a colorless solid. 1H NMR (400 MHz. DMSO-d6) δ (ppm): 10.58 (br s, 1H); 9.63 (br s, 1H); 8.68 (dd, J=2.7, 0.8, 1H); 8.48 (d, J=5.5, 1H); 8.20 (dd, J=8.6, 2.7, 1H); 8.05 (d, J=7.6, 1H); 8.03 (s, 1H); 7.86 (dd, J=13.1, 2.3, 1H); 7.49 (t, J=8.8, 1H); 7.42 (dd, J=8.8, 1.4, 1H); 7.09-7.03 (m, 2H); 6.94 (dd, J=8.8, 0.7, 1H); 6.92-6.88 (m, 1H); 6.61 (dd, J=5.5, 1.0, 1H); 4.33 (t, J=6.7, 2H); 3.85 (s, 3H); 3.63 (s, 2H); 2.33 (t, J=7.2, 2H); 2.13 (s, 6H); 1.84 (quint, J=7.2, 2H). LRMS (M+H): 630.2.
Reaction SMILES: [C@H]1(NCC2C=C(C(C)(C)C)C=C(C(C)(C)C)C=2O)CCCC[C@@H]1NCC1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1[OH:23].[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1.C(#N)C.CC(C)[O-].[Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:23])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Reactant: CC(C)(C)c1cc(CN[C@H]2CCCC[C@@H]2NCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [Zr+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 55 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A chiral zirconium complex was prepared by stirring zirconium(IV) isopropoxide (0.0345 g, 0.089 mmol) with 2,2′-[(1S,2S)-1,2-cyclohexanediylbis(iminomethylene)]bis[4,6-bis(1,1-dimethylethyl)phenol] (Formula IIIa wherein R6 is C(CH3)3, 0.0613 g, 0.11 mmol) in toluene (2 mL) at ambient temperature. After stirring overnight, the homogeneous solution was evaporated to dryness in vacuo, and the residue redissolved in toluene (1.34 g). Methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.250 g, 1.11 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) was added to the toluene solution, the solution was heated to 55° C., and then an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 2.46 mmol) was added. After 2 hours at 55° C., the solution was diluted with acetonitrile (11.5 mL). Analysis by quantitative and chiral HPLC showed 100% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 84% yield (84% chemoselectivity) and 84% enantiomeric excess of the S-enantiomer.
Reaction SMILES: [CH:1]([C:3]([CH2:5][CH3:6])=[O:4])=[CH2:2].[N+:7]([CH3:10])([O-:9])=[O:8].CN(C)C(N(C)C)=N.O>C(#N)C.C(O)(=O)C>[N+:7]([CH2:10][CH2:2][CH2:1][C:3](=[O:4])[CH2:5][CH3:6])([O-:9])=[O:8]
Reactant: C[N+](=O)[O-]
Reactant: C=CC(=O)CC
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CCC(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.6 %

Procedure:
A! Ethyl vinyl ketone (25 g, 0,297 mole) was slowly added to a solution of nitromethane (80 ml, 1.48 mole) and 1,1,3,3-tetramethylguanidine (3.7 ml, 0.029 mole) in acetonitrile (180 ml) while maintaining the room temperature by cooling with ice. The reaction mixture was stirred for 48 hours at room temperature, then added with water (70 ml), and the pH was corrected to 5 by acetic acid. The solvent was evaporated under vacuum and the aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with chilled water (100 ml) and anhydrified over sodium sulfate, then the solvent was evaporated under vacuum to give 42 g of crude 6-nitrohexan-3-one which was used as such in the next step.