Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Br)c(OCc3ccc(F)cc3)c2s1
Yield: 19 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6, potassium carbonate and p-fluoro-benzyl-bromide in DMF was reacted to give 0.013 g (19%) of the desired compound 13. 1H NMR (DMSO) δ 1.08 (t, 3H, J=8 Hz CH2CH3), 3.18 (m, 2H, CH2), 5.16 (s, 2H, OCH2Ar), 6.73 (br s, 1H, NH), 7.26 (dd, 2H, J=4, 4 Hz, ArH),7.36 (d, 1H, J=8 Hz, ArH), 7.56 (d, 1H, J=4 Hz, ArH), 7.58 (d, 2H, J=4 Hz, ArH), 10.89 (br s, 1H, NH). HPLC retention time 3.61 minutes.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.C(I)C>O1CCCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH2:1][CH3:2]
Reactant: [Li]CCCC
Reactant: Fc1cncc(Br)c1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c(F)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-butyl lithium (92.3 mL, 0.147 mol, 1.6 M) was added to a solution of diisopropyl amine (20.1 mL, 0.147 mol) in tetrahydrofuran (120 mL) at −78° C. and allowed to stir for 30 min at 0° C. The reaction mixture was cooled to −78° C. and a solution of 3-bromo-5-fluoro-pyridine (20.0 g, 0.113 mol) in tetrahydrofuran (20 mL) was added and stirred for 30 min. Ethyl iodide (8.85 mL, 0.124 mol) was added to reaction mixture and allowed to stir at room temperature for 2 h. The reaction mixture was quenched with saturated ammonium chloride (100 mL) solution and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with saturated sodium chloride, dried over sodium sulphate and concentrated to provide 3-bromo-5-fluoro-4-ethyl pyridine. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1 H), 8.31 (s, 1 H), 2.87-2.82 (m, 2 H), 1.22-1.19 (t, J=4.0 Hz, 3 H). MS (M+1): 205.8.
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[K+].[K+].[K+].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Mg+2:30].[K+]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Mg:30]
Reactant: [Mg+2]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [K+]
Product: [Mg]

Procedure:
Each patient underwent five phases of study: placebo, potassium chloride, potassium citrate, magnesium citrate, and potassium-magnesium citrate. The results (mean values for the two patients) are outlined in Table 1. Compared to potassium chloride, potassium magnesium citrate gave a higher urinary pH, magnesium, and citrate. Compared to potassium citrate, potassium magnesium citrate produced a greater citrate excretion as well as enhanced magnesium excretion. Compared to magnesium citrate, potassium magnesium citrate gave higher values for urinary pH and citrate. Finally, compared to the placebo, potassium magnesium citrate produced higher values for urinary pH, magnesium, potassium and citrate, and lower values for urinary calcium and oxalate.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=O.[CH:15]([C:17]([CH2:19][CH3:20])=[O:18])=[CH2:16].Cl>CO>[CH3:16][C:15]1[C:17](=[O:18])[CH2:19][CH2:20][C:4]2([CH3:3])[C:5]=1[CH2:6][CH2:7][C:8]1[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1C(=O)CCc2ccccc21
Reactant: C=CC(=O)CC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1=C2CCc3ccccc3C2(C)CCC1=O
Temperature: -15 °C
Reaction time: 4 h
Yield: 103.6 %

Procedure:
Potassium hydroxide in the amount of 2.24 g (40 mmol) was dissolved in 50 ml of 90 % methanol in 100-ml three-necked flask, and the obtained solution was then cooled with ice under agitation in a stream of nitrogen gas. A methanol solution (8 ml) containing 5.17 g (32 mmol) of 1-methyl-2-tetralone was added dropwisely to the above obtained solution over a period of 10 minutes. The reaction vessel was then cooled to -15° C., and 2.67 g (31 mmol) of ethyl vinyl ketone was added dropwisely to the reaction vessel. The temperature of the resulted mixture was brought to room temperature over a period of 4 hours under agitation in a stream of nitrogen gas. The mixture had been allowed to stand over night, and then the mixture was refluxed under heating for 3 hours in an atmosphere of nitrogen gas. After the temperature of the mixture had been brought to room temperature, the mixture was made acidic with hydrochloric acid and then extracted with ether. The ether layer was removed and washed with water, and then dried with sodium sulfate. The ether was distilled off to obtain 7.27 g of oily yellow residue. This residue was allowed to stand to obtain 5.54 g of crystals. These crystals were recrystallized twice from cyclohexane to obtain 3.95 g of colorless needle-like crystals.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.N1CCCCC1>C1C=CC=CC=1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(Br)cc1)c1ccccc1
Yield: 38.2 %

Procedure:
A mixture of phenylacetone (4.92 g, 36.7 mmol) and 4-bromobenzaldehyde (6.78 g, 36.7 mmol) in benzene (40 ml) in the presence of piperidine (0.11 ml, 1.47 mmol) was refluxed for 48 hours. After evaporation, the obtained residue was chromatographed on a column of silica gel (300 g) as eluting with ethyl acetate/hexane (1:20 to 1:2) to afford a yellow solid, which was washed with ethyl acetate/hexane to give 4.22 g (38%) of the title compound as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([S:8][C:9]([Cl:12])([Cl:11])[F:10])[CH:5]=[N:4]1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:11][C:9]([Cl:12])([F:10])[S:8][C:6]1[CH:5]=[N:4][N:3]([CH2:2][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(Cl)(Cl)Sc1cnn(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(SC(F)(Cl)Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
0.21 g of 1-(chloromethyl)-4-[(dichlorofluoromethyl)thio]-1H-pyrazole and 0.14 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 2 ml of N,N-dimethylformamide. 0.12 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure to obtain 0.06 g of [(4-{(dichlorofluoromethyl)thio}-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (43), hereinafter) shown by below formula.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1.[Na+]>CN(C)C=O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:3])(=[O:15])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
Thionyl chloride (44.3 mL, 604 mmol, and 6.91 Eq) and N,N-dimethylformamide (DMF)(1 mL) were added to sodium 4-hydroxybenzenesulfonate (20.3 g, 87.2 mmol, and 1.00 Eq) under an argon atmosphere, and the mixture was stirred under reflux at 60° C. for 4 hours. The resultant mixture was cooled to room temperature and ice (160 g) was added thereto. The mixture was stirred and the water layer was extracted with dichloromethane (1×60 mL, 2×40 mL). The obtained organic layer was washed with ice water (40 mL) and dried with sodium sulfate. The solvent was removed by an evaporator and 4-hydroxybenzene sulfonyl chloride (10.4 g, 53.8 mmol, 62%) was obtained as oil.
Reaction SMILES: C1C=C(SSC2N=CC=CC=2)N=CC=1.C(N(CC)CC)C.[SH:22][CH2:23][C:24]([OH:26])=[O:25].[CH:27]([SH:30])([CH3:29])[CH3:28]>O1CCCC1.CCOCC>[CH:27]([S:30][S:22][CH2:23][C:24]([OH:26])=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)S
Reactant: O=C(O)CS
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)SSCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 11 g (50 mmol) of 2-,2′-dipyridyl disulfide and 8.4 mL (60 mmol) of triethyl amine in 100 mL of tetrahydrofuran at 0° C. as added 2.8 mL (40 mmol) of mercaptoacetic acid in 5 mL of tetrahydrofuran. The ice bath was removed and after one hour 6.0 mL (65 mmol) isopropyl thiol was added. The reaction was allowed to stir overnight at ambient temperature before diluting with ether and washing three times with 1N aqueous HCl. The product was then extracted into 10% aqueous NaOH. The aqueous phase was washed twice with ether and then acidified with HCl to pH ˜3.5. The product was extracted with ether, dried with Na2SO4, filtered and evaporated under reduced pressure to give a crude product. This material was distilled by Kugelrohr distillation to give 3.5 g (21 mmol, 42%) of partially purified product. This material was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]4[O:26][N:25]=[C:24]([NH:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]=4[CH:33]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:9]1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH:8]1([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]4[O:26][N:25]=[C:24]([NH:27][CH2:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:23]=4[CH:33]=3)[CH:14]=2)[C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:10][CH2:9]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)CNc1noc2ccc(-c3cccc(CNC4CC4)c3)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1noc2ccc(-c3cccc(CN(C(=O)c4ccccc4)C4CC4)c3)cc12
Temperature: -70 °C
Reaction time: 15 h
Yield: 76.9 %

Procedure:
Triethylamine (0.18 mL, 1.29 mmol, 1.5 equiv.) was added to a solution of 5-(3-((cyclopropylamino)methyl)phenyl)-N-neopentylbenzo[d]isoxazol-3-amine (exemplary compound 51) (0.30 g, 0.86 mmol, 1 equiv.) in DCM (10 mL) and the mixture was subsequently cooled to −70° C. Benzoylchloride (0.12 mL, 1.03 mmol, 1.2 equiv.) was added in drops and the mixture was slowly heated to RT and stirred for 15 hours. The reaction mixture was diluted with DCM (80 mL) and extracted with sat. aq. sodium hydrogen carbonate sol. (1×15 mL) and sat. aq. NaCl solution (1×15 mL), dried (MgSO4) and the solvent removed in a vacuum. After column-chromatographic purification (EtOAc/hexane; 10:1), the desired product (0.30 g, 77%) is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([O:15]C)=[O:14])[C:5]=2[O:4][C:3]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.O1CCOCC1.[OH-].[Na+].O>CO>[CH3:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:5]=2[O:4][C:3]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cccc2c(=O)c(C)c(-c3cccnc3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1c(-c2cccnc2)oc2c(C(=O)O)cccc2c1=O
Reaction time: 1 h
Yield: 63 %

Procedure:
A mixture of 6.2 g of methyl 3-propionylsalicylate and 5.8 g of nicotinoyl chloride hydrochloride in 18 ml of anhydrous pyridine was stirred and heated at 100° C. for 2 hours under nitrogen. After that, 16 ml of triethylamine was added and heating was continued for 1 hour at the same temperature. The reaction mixture was cooled to room temperature, poured into 600 ml of water and the precipitate was collected by suction and washed with water, yielding 5.4 g of methyl 2-hydroxy-3-(2-nicotinoyl)propionylbenzoate, which was used without purification in the next step. 3.4 g of this Intermediate was heated at 100° C. for 1.5 hours after dissolution in a mixture containing 15 ml of acetic acid and 1 ml of 37% hydrochloric acid. After cooling to room temperature, the mixture was poured into 150 ml of water and extracted with ethyl acetate. The organic phase was washed with 5% aqueous sodium hydrogen carbonate solution, followed by water, dried on sodium sulfate and evaporated in vacuo, yielding 1.3 g of crude methyl 3-methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran-8-carboxylate. 1 g of the above ester was dissolved in 9 ml of methanol and 15 ml of 1,4-dioxane and slowly added with 1.7 ml of 10N sodium hydroxide, maintaining the temperature between 20° and 25° C. After 1 hour at 50° C., the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate. The aqueous layer was acidified with 1N aqueous hydrochloric acid solution. The precipitate was collected by suction, yielding 0.6 g of 3-methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran-8-carboxylic acid, which was used without purification in the next step. The title compound was prepared according to Example 86, but using the above Intermediate instead of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and carrying out the reaction for 2 hours at room temperature. The base was purified by flash chromatography on silica gel eluting with a mixture of chloroform-methanol (98:2), followed by crystallization from acetone, yielding 0.15 g (m.p. 134.5°-137° C.).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8][C:9]#[N:10].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)=O>C(O)C>[C:15]1(=[C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH3:4])[C:9]#[N:10])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccccc1CC#N
Reactant: O=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Product: COc1ccccc1C(C#N)=C1CCCCC1
Temperature: 85 °C
Yield: 36.4 %

Procedure:
Sodium methylate (5.40 g, 0.10 mol) is dissolved in ethanol (70 ml) and 2-methoxy benzylcyanide (14.70 g, 0.10 mol) is added over 2 min. Cyclohexanone (9.80 g, 0.10 mol) is added to the white suspension. The resulting mixture is heated to 85° C. (bath) for 4.5 h. Under icecooling, formic acid (5.0 ml) is added dropwise, upon which the mixture turns colourless. Standard aqueous workup as described in example 1, followed by a short path distillation at 0.05 mbar/137-146° C. yields 8.28 g of product (37% yield) as a viscous oil, from which a crystalline byproduct is separated via crystallization from hexane. The mother liquor is concentrated and the residue subjected to a fine distillation at 0.05 mbar/136° C. to yield the product as colourless oil (1.81 g, 8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10]C)[CH:5]=[C:6]([O:8]C)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C.O>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(Br)cc(OC)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Oc1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
To a suspension of 5-bromo-1,3-dimethoxy-benzene (15 g, 67.02 mmol) and sodium iodide (100.5 g, 670.2 mmol) in acetonitrile (577 mL) was added trimethylsilyl chloride (42.39 mL, 335.1 mmol) at room temperature. Then, the resulting light yellow suspension was heated to reflux for 48 h. Then, it was cooled to room temperature and diluted with water (150 mL). The organic compound was extracted into ethyl acetate (2×150 mL) and the combined ethyl acetate extracts were washed with saturated sodium thiosulfate solution (300 mL) to remove the iodine color and was also washed with brine solution (300 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by using an ISCO 330 g column, eluting with 5-30% ethyl acetate in hexanes to obtain 5-bromo-benzene-1,3-diol (9.24 g, 73%) as a light brown solid: ES(+)-HRMS m/e calcd for C6H5BrO2 (M+H)+ 189.2341. found 189.2346.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.ClC(OCC)=O>C1COCC1.[Cl-].[Na+].O>[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of BOC-(L)-proline in 60 ml of anhydrous THF, cooled at -10° C. with brine, is added with 6.1 ml of triethylamine and 1 g of 4 A molecular sieves, then, keeping the temperature below -5° C., a solution of 4.16 ml of ethyl chloroformate in 5 ml of anhydrous THF is dropped therein. After 30 minutes under stirring, the reaction mixture is filtered to remove the triethylammonium chloride precipitate and the filtrate is concentrated under reduced pressure to a volume of 30 ml. The resulting solution is dropped into a suspension of 7.5 g of sodium borohydride in 50 ml of anhydrous THF, cooled at -10° C. with brine. After 2 hours the reaction mixture is added with 200 ml of an aqueous saturated solution of sodium dihydrogen phosphate, keeping the temperature at 0° C. with water/ice, then it is extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed repeatedly with an aqueous saturated solution of sodium bicarbonate (3×30 ml), dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue, by crystallization from hexane, yields 6.1 g of BOC-(L)-prolinol, m.p. 59°-60° C., [α]D =-54.9° (c=0.2 in EtOH).
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][C:9]#N)[C:6]#[N:7])[CH:2]([CH3:4])[CH3:3].[OH-:11].[K+:12].[OH2:13]>>[C:6]([C@@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:8][C:9]([O-:13])=[O:11])#[N:7].[K+:12]
Reactant: O
Reactant: CC(C)CC(C#N)CC#N
Reactant: [OH-]
Agent: [K+]
Product: CC(C)C[C@H](C#N)CC(=O)[O-]
Temperature: 30 °C
Reaction time: 24 h
Yield: 31.3 %

Procedure:
Two 125 mL jacketed reaction vessels maintained at 30° C. were each charged with 2-isobutyl-succinonitrile (6.81 g), NIT-102 C2 (1.70 g) and 118.2 mL of reaction buffer. After stirring for 24 h, the product mixtures were decanted, leaving the enzyme catalyst in the reaction vessels. Reaction buffer (20 mL) was added to the each reaction vessel, stirred for approximately 2 min., and then decanted and added to the product mixtures. Reactions were repeated by adding 2-isobutyl-succinonitrile (6.81 g) and reaction buffer (118.2 mL) to each reaction vessel and stirring the reaction mixtures for 24 h. After four reactions were completed in each vessel (total of eight batch reactions), the product mixtures were combined and extracted with MTBE (3×500 mL). The MTBE extracts were removed and the aqueous part adjusted to pH 2.1 with phosphoric acid and extracted with MTBE (2×500 mL). The MTBE extract of the acidified aqueous part was concentrated under vacuum to leave an oil, which was treated with water (100 mL) and KOH (8.5 g). The resulting solution was concentrated under vacuum to give 24.2 g (31.3%) of potassium (S)-3-cyano-5-methylhexanoate. Methyl (S)-3-cyano-5-methylhexanoate was prepared from potassium (S)-3-cyano-5-methylhexanoate and analyzed by chiral GC to reveal an enantiomeric purity of 99.1% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.[Cl-].Cl[C:16](=[N+:18]([CH3:20])[CH3:19])Cl.[OH2:21]>C(#N)C>[CH3:19][N:18]([CH3:20])[C:16]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]#[N:13])[CH:7]=1)=[O:21]
Reactant: C[N+](C)=C(Cl)Cl
Reactant: N#CCn1ccc2ccc(Cl)cc21
Reactant: O
Agent: [Cl-]
Solvent: CC#N
Product: CN(C)C(=O)c1cn(CC#N)c2cc(Cl)ccc12
Yield: 46 %

Procedure:
To a solution of (6-chloro-indol-1-yl)-acetonitrile (0.446 g, 2.34 mmole) in acetonitrile (30 ml) was added dichloromethylene dimethylammonium chloride (phosgene imminium chloride) (0.418 g, 2.57 mmole). The reaction mixture was brought to reflux for 14 h and then poured into water (100 ml). The mixture was extracted into ethyl acetate and purified by column chromatography (silica gel, hexane:ethyl acetate 3:7) to afford the desired 6-chloro-1-cyanomethyl-1H-indole-3-carboxylic acid dimethylamide (0.286 g, 46% yield) in addition to recovered starting material (0.173 g). Step 3
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([OH:12])=O)[CH2:4][F:5].[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH2:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:7]([O:6][CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH:8]=2)=[N:26]1
Reactant: Cc1cc(N)nn1C
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NC(=O)c2cc(OCc3ccccc3)cc(OC(CF)CF)c2)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A solution of 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (2.96 mmol) in DMF (5 mL) was treated with 1,5-dimethyl-1H-pyrazol-3-ylamine (3.11 mmol), DIPEA (5.93 mmol) and HATU (3.85 mmol) and stirred at RT overnight. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3×75 mL). The organics were washed with brine, dried (MgSO4) and evaporated in vacuo before chromatography on solica, eluting with 50-100% ethyl acetate in isohexane, to give the desired compound as a colourless glass (784 mg). 1H NMR δ (d6-DMSO): 2.81 (s, 3H), 3.67 (s, 3H), 4.66 (m, 2H), 4.78 (m, 2H), 5.04 (m, 1H), 5.69 (s, 2H), 6.43 (s, 1H), 6.85 (t, 1H), 7.28 (m, 1H), 7.32 (m, 1H), 7.35 (m, 1H), 7.41 (m, 2H), 7.47 (m, 2H), 10.64 (s, 1H); m/z 416 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][OH:13].CCN(CC)CC>C1COCC1>[OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:3]1
Reactant: OCCCBr
Reactant: OC1CNCC12CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.5 %

Procedure:
To a solution of 7-hydroxy-5-azaspiro[2.4]heptane (1.23 g, 11.0 mmol) in THF (40 mL) was added 3-bromopropanol (2.3 g, 16.65 mmol) and Et3N (2.24 g, 22.2 mmol). The reaction mixture was stirred at rt for 12 hrs and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:50:2(v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as orange oil (1.14 g, 60%).