Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:25](=[C:26]([C:37]3[CH:45]=[CH:44][C:40]4[O:41][CH2:42][O:43][C:39]=4[CH:38]=3)[C:27]=1[CH2:28]OCC1C=CC=CC=1)[C:21]1[O:22][CH2:23][O:24][C:20]=1[CH:19]=[CH:18]2)=[O:14])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:25](=[C:26]([C:37]3[CH:45]=[CH:44][C:40]4[O:41][CH2:42][O:43][C:39]=4[CH:38]=3)[C:27]=1[CH3:28])[C:21]1[O:22][CH2:23][O:24][C:20]=1[CH:19]=[CH:18]2)=[O:14]
Reactant: [H][H]
Reactant: O=C(OCCCOCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(C(=O)OCCCO)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Yield: 93 %

Procedure:
A mixture of 6 (48 mg, 0.079 mmol) and 10% Pd/C (12 mg) in dry THF (5 mL) was stirred for 14 h at room temperature under 1 atm of hydrogen. The mixture was filtered, and the filtrate evaporated at reduced pressure. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (40:1, v/v) to yield 7 (30 mg, 93%) as a yellow oil. 1H NMR (CDCl3) δ 8.32 (s, 1H, H4), 7.50 (d, 1H, H5, J=8.7 Hz), 7.18 (d, 1H, H6, J=8.7 Hz), 6.87 (d, 1H, H5′, J=7.8 Hz), 6.72 (d, 1H, H2′, J=1.5 Hz), 6.68 (dd, 1H, H6′, J=1.5, 7.8 Hz), 6.05 (AB, 2H, 3′,4′-OCH2O—, Δδ=9.6 Hz, J=1.5 Hz), 5.83 (AB, 2H, 7,8-OCH2O—, Δδ=1.5 Hz, J=1.5 Hz), 4.54 (t, 2H, 3-COOCH2(CH2)2OH, J=6.3 Hz), 3.83 (t, 2H, 3-COO(CH2)2CH2OH, J=6.3 Hz), 2.34 (s, 3H, 2-CH3), 2.06 (quintet, 2H, 3-COOCH2CH2CH2OH, J=6.3 Hz); MS (EI) m/z 408 [M]+.
Reaction SMILES: [CH2:1]([N:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]1=S)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N([O-])=[O:23].[Na+].[OH-].[Na+]>Cl>[CH2:1]([N:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11]1=[O:23])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: S=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 3.02 g of (E)-1-cinnamyl-3-(3-pyridyl)imidazolidine-2-thione dissolved in 40 ml of 4N hydrochloric acid, 10 ml of an aqueous solution of 1.03 g of NaNO2 was added dropwise. After stirring at room temperature for 1 hour, the mixture was made alkaline by addition of a sodium hydroxide solution, and the precipitated crystals were collected by filtration. The crystals obtained were washed with water, dried and then purified by silica gel column chromatorgraphy (solvent: chloroform-methanol=30:1), followed by recrystallization from ethanol, to give 1.74 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCOCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
42 g of sodium hydride (60%) is introduced at room temperature in portions into 900 ml of absolute DMF. 88.6 ml of 1,4-butanediol in 450 ml of absolute DMF is added in drops to the suspension that is cooled to −20° C. in such a way that the internal temperature does not exceed −15° C. After the addition has been completed, a solution of 121 ml of benzyl bromide in 870 ml of absolute DMF is quickly added in drops, and then the reaction mixture is stirred for 30 minutes at room temperature. The reaction is completed by careful addition of 315 ml of water. For working-up, the reaction mixture is stirred into 1.5 l of water and extracted 3 times with 1 l of ether in each case. The ethereal phases are combined, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography on silica gel with a hexane-ethyl acetate gradient yields 105 g of 4-benzyloxy-butan-1-ol as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:18]1([NH2:22])[CH2:21][CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: NC1CCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1nc(NC2CCC2)c2c(n1)C(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (160 mg, 0.60 mmol) in NMP (2 mL) was added cyclobutanamine (129 mg, 1.81 mmol) dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (177 mg, 0.57 mmol, 94% yield), which was used for the next step without any purification. LC-MS (M+H)+=300.1
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[C:6]2[C:7]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2].[H-].[Na+].Cl.Cl[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[CH2:1]([C:3]1[CH:20]=[C:6]2[C:7]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[N:16]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[N:17]=3)=[CH:8][C:9]([F:11])=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CCc1cc2c(C3=NNC(=O)CC3C)cc(F)cn2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(C3=NN(Cc4cccnc4)C(=O)CC3C)cc(F)cn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
The compound of Example 199 (100 mg) was dissolved in DMF (3.6 mL) and 60% sodium hydride (32 mg) was added at 0° C. The mixture was stirred at room temperature for 30 min. Subsequently, 3-(chloromethyl)pyridine-hydrochloride (65.8 mg) was added and the mixture was stirred at 60° C. for 6 hours. The reaction was terminated by adding a saturated aqueous ammonium chloride solution and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=1:4) afforded the title compound as a yellow powder (98.5 mg).
Reaction SMILES: [Cl:1]Cl.[Cl:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O>C(O)(=O)C>[Cl:1][C:12]1[CH:13]=[C:8]([S:5]([CH2:4][Cl:3])(=[O:6])=[O:7])[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: ClCl
Reactant: O=S(=O)(CCl)c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(CCl)c1ccc(O)c(Cl)c1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
14.2 g (0.2 mole) of chlorine was passed into a solution of 41.5 g (0.2 mole) of 4-chloromethylsulphonylphenol in 200 ml acetic acid at 20° C. The mixture was stirred for a further 10 minutes and the solvent was then stripped off under reduced pressure. 100 ml of water were added to the residue and after crystallization the product was filtered off. 44.8 g (93% of theory) of 2-chloro-4-chloromethylsulfonylphenol were obtained in the form of a beige powder of melting point 108° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](/Cl)\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH3:5].C([Li])(C)(C)C.[CH2:35]1[O:37][CH2:36]1.O>O1CCCC1>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)/[CH2:35][CH2:36][OH:37])=[CH:13][CH:14]=1)[CH2:4][CH3:5]
Reactant: CCN(CC)CCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Reactant: C1CO1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
Clomiphene (6.06 g, 14.9 mmol) was dissolved in tetrahydrofuran (100 ml) and cooled to -40° C. t-Butyl lithium (1M in pentane, 24 mmol) was added slowly. After 5 minutes, ethylene oxide (14.6 ml, 290 mmol) was added, and the reaction mixture was stirred for 6 hours, poured into water and extracted with ether. The ether layer was evaporated and chromatographed on a silica gel column using 1:1:0.1 ether/petroleum ether/triethylamine as eluant to yield trans product (1.96 g, 27.1%, oil): and cis product (1.56 g, 21.5%, oil): Assignment of 1HNMR for aliphatic protons are presented in Table 1.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11](Br)[C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24]>>[CH2:1]([S:8][C:9]1[C:10]([Cl:17])=[C:11]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=[O:24])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1
Reactant: Fc1cc(Br)c(Cl)c(SCc2ccccc2)c1
Product: O=C1CCCCN1c1cc(F)cc(SCc2ccccc2)c1Cl

Procedure:
Intermediate 35 (4 g, 12.06 mmol) was coupled with piperidin-2-one (1.434 g, 14.47 mmol) in close analogy to the procedure described in step 1.6). After workup the crude oil is purified by chromatography on silica gel (n-heptane-ethyl acetate 4:1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17]O)[N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:31]3[C:27](=[O:37])[C:28]4[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30]3=[O:32])[N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:26])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](CO)N(C(=O)OC(C)(C)C)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](CN1C(=O)c3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
To a mixture of the above 2-amino-5-(S)-hydroxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (2.00 g, 5.20 mmol), phthalimide (0.92 g, 6.24 mmol) and triphenylphosphine (1.64 g, 6.24 mmol) in dry tetrahydrofuran (30 ml) cooled to 0° C. under a nitrogen atmosphere was added diethyl azodicarboxylate (DEAD) (0.98 ml, 6.24 mmol). The reaction mixture was allowed to stir overnight, slowly warming to room temperature. Next day the reaction mixture was again cooled to 0° C. and phthalimide (0.46 g, 3.12 mmol), triphenylphosphine (0.82 g, 3.12 mmol) and diethyl azodicarboxylate (DEAD) (0.49 ml, 3.12 mmol) was added in sequence and the reaction mixture was allowed to stir overnight, slowly warming to room temperature. The volatiles were evaporated in vacuo and the resultant solid dissolved in dichloromethane (20 ml). The residue was subjected to flash column chromatography using a mixture of ethyl acetate/hexane (1:2) as eluent. Fractions were collected affording after evaporation in vacuo 1.0 g of the desired compound contaminated with phthalimide. Recrystallization from ethanol gave 0.23 g (9%) of pure 2-amino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[Br:17]Br.O>ClCCl.[Fe]>[Br:17][C:7]1[C:2]([OH:1])=[C:3]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=[C:5]([CH3:8])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)c(O)c(C(=O)c2ccccc2)c1
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
To a solution of 116 g (0.55 mol) of 32 in 200 mL of dry dichloromethane 1.5 g of iron turnings was added, and then a solution of 41.4 mL (136 g, 0.83 mol) of bromine in 500 mL of dichloromethane was added dropwise with vigorous stirring for 20 min. This mixture was refluxed for 30 min, and then 1200 mL of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×300 mL of dichloromethane. The combined organic extract was washed by saturated aqueous Na2SO3, dried over K2CO3, and then evaporated to dryness. Drying the residue in vacuum gave 138 g (86%) of 33 (bp 165-172° C./1 mm).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH2:14][O:13][N:12]=2)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[OH:27][C:28]1[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=1>O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]2[CH2:15][CH2:14][O:13][N:12]=2)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([C:29]1[CH:30]=[N:31][N:32]([CH3:33])[C:28]=1[OH:27])=[O:5]
Reactant: Cn1nccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1C1=NOCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2Cl)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43.60 g (0.13 mol) of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl chloride in 375 ml of anhydrous dioxane and 13.56 g (0.134 mol) of triethylamine in 375 ml of anhydrous dioxane are simultaneously added dropwise at room temperature under a protective gas atmosphere to a solution 12.74 g (0.13 mol) of 5-hydroxy-1-methylpyrazole and 300 ml of anhydrous dioxane. After the reaction mixture had been stirred for 2 hours at room temperature, it was filtered through silica gel and the residue was washed with dioxane. The eluate was concentrated in vacuo to approximately 500 ml, and 17.94 g (0.13 mol) of dried, finely powdered potassium carbonate were added. After the mixture had been refluxed for 6 hours, the solvent was distilled off in vacuo and the residue was taken up in approximately 700 ml of water. Insoluble constituents were filtered off, and the pH of the filtrate was brought to 2-3 by slow addition of 10% strength hydrochloric acid. The precipitate which formed was filtered off with suction. This gave 46.16 g (92% of theory) of 4-[2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-methyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[I:13]Cl.Cl>CO>[NH2:1][C:2]1[C:7]([I:13])=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10]
Reactant: Nc1ccc(Br)cc1S(=O)(=O)O
Reactant: ClI
Agent: Cl
Solvent: CO
Product: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Temperature: 90 °C

Procedure:
To 45 g (176 mmol) of 2-amino-5-bromobenzenesulphonic acid are added 46 g (282 mmol) of iodine chloride, 400 ml of aqueous 1N hydrochloric acid solution and 400 ml of methanol. The mixture is heated at 90° C. for 18 hours and concentrated under reduced pressure, and the residue is crystallized from ethanol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.O=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C:14]2=1
Reactant: COc1ccc(NN)cc1
Reactant: COC(=O)C1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1CCc2[nH]c3ccc(OC)cc3c2C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
(4-Methoxyphenyl)hydrazine hydrochloride (80.0 mg, 0.46 mmol) and methyl 4-oxocyclohexanecarboxylate (85.9 mg, 0.55 mmol) were dissolved in acetic acid (0.5 mL). The mixture was heated at 80° C. with stirring under nitrogen for 3 h, cooled, diluted with water (2 mL) and the resulting precipitate was collected by filtration, gently washed with water and dried in vacuo to yield the title compound (107 mg, 90%) as an off-white solid. C15H17NO3, Mr=259.30; 1H NMR (400 MHz, DMSO-d6) d: 1.81-1.91 (m, 1H), 2.15-2.19 (m, 1H), 2.66-2.84 (m, 4H), 2.90 (dd, J=4.6/14.2 Hz, 1H), 3.65 (s, 3H), 3.72 (s, 3H), 6.61 (dd, J=2.4/8.8 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 10.51 (s, 1H); LCMS (ESI) tR: 2.27 min (>99%, ELSD), m/z: 260.2 [M+1]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([N:15]([CH3:28])[C:16]3[N:20]([CH3:21])[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:18][N:17]=3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:28][N:15]([C:16]1[N:20]([CH3:21])[C:19]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[N:18][N:17]=1)[CH:13]([C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:29]#[N:30])[N:9]=1)[CH3:14]
Reactant: CC(c1nnn(-c2cccc(I)c2)n1)N(C)c1nnc(-c2ccncc2)n1C
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(c1nnn(-c2cccc(C#N)c2)n1)N(C)c1nnc(-c2ccncc2)n1C

Procedure:
The title compound is prepared from {1-[2-(3-Iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH:36]=[C:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:33][CH:34]=[C:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1=CCNCC1
Product: O=C(O)C1=CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,2,3,6-Tetrahydro-pyridine-4-carboxylic acid following general procedure C.
Reaction SMILES: [CH3:1][C@@H:2](CCCC1C=CC=CC=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:6][CH3:7])[O:8][CH3:9]
Reactant: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Reactant: BrCCCCCc1ccccc1
Product: COP(=O)(CC(=O)[C@@H](C)CCCCCc1ccccc1)OC

Procedure:
(S)-Dimethyl (3-methyl-2-oxo-8-phenyloctyl)phosphonate was prepared in the same manner as the second alternative preparation of (S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) using the same sequence of reactions except that (5-bromopentyl)benzene was used instead of (3-bromopropyl)benzene. The crude product was purified by silica gel chromatography. Elution with ethyl acetate-heptane (50:50 v/v) afforded the title compound (1.06 g) as a colorless oil; TLC Rf 0.22 (solvent system: 50:50 v/v ethyl acetate:heptanes); MS (ESI+) m/z 327.1 (M+H)+; 1H-NMR (CDCl3) δ 7.27-7.24 (m, 2H), 7.19-7.14 (m, 3H), 3.79-3.76 (m, 6H), 3.13 (s, 1H), 3.08 (s, 1H), 2.76-2.68 (m, 1H), 2.61-2.56 (m, 2H), 1.68-1.56 (m, 4H), 1.35-1.28 (m, 4H), 1.09 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=0.074/(0.01534 g/1.5 mL)(0.5)=+14.10° (c=1.02, CHCl3).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19]O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)[C:51]#[N:52].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CCOCC>[F:27][C:24]([F:26])([F:25])[C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([C:2]([F:28])([F:29])[F:1])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][C:51]#[N:52])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1
Reactant: CC(C)(O)C#N
Reactant: OCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-1,3-dihydroisobenzofuran-1-yl)ethanol (250 mg, 0.60 mmol) and triphenylphosphine (390 mg, 1.5 mmol) in tetrahydrofuran (2.5 mL) at 0° C. was added acetone cyanohydrin (0.163 mL, 1.8 mmol), followed immediately by the addition of diethyl azodicarboxylate (0.234 mL, 1.5 mmol). The reaction was allowed to gradually warm to room temperature in the dewar overnight. The reaction was diluted with ether, washed with water, then saturated sodium bicarbonate, then water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%-->19% EtOAc/Hex) gave 214 mg (84%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.77 (s, 1H), 7.66 (s, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.18 (d, J=6.7 Hz, 1H), 5.14 (s, 2H), 4.64 (s, 2H), 3.65 (s, 2H), 2.38 (m, 2H), 2.22 (m, 1H), 2.07 (m, 1H); 13C-NMR (CDCl3, 126 MHz) δ 140.9, 140.0, 139.4, 131.8 (q, J=33.6 Hz), 128.9, 128.0, 127.2, 123.4 (q, J=273 Hz), 121.7, 121.6, 121.5, 119.7, 88.9, 76.2, 73.1, 72.1, 32.4, 11.8. Mass spec.: 430.09 (MH)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([OH:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.[I-].[Na+]>CN(C=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([OH:43])[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][CH2:4][CH:5]3[C:19](=[O:20])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:41][CH2:42]2)=[CH:33][CH:32]=1
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (5.02 g) and DMF (170 ml) was added diisopropylethyl amine (7.50 ml), 4-(4-chlorophenyl)-4-hydroxypiperidine (4.03 g) and sodium iodide (2.59 g) at room temperature with stirring. The reaction was flushed with nitrogen and warmed to 78°-80° C. for 11 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layers extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude amine product. Purification via flash chromatography (silica gel, 2% Et3N/ether) afforded 2.60 g of the desired product as an oil. Addition of ether, heat, and slow evaporation gave a powder. The ether was then decanted and the powder was washed with pentane to yield 5-[3-(4-(4-chlorophenyl)-4-hydroxy-piperidinyl)-propyl]-6,7-dihydro-3-phenyl-1,2-benzisoxazol- 4(5H)-one, m.p. 147°-148° C.