Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:33][O:32][C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])=[O:24])(=[O:21])=[O:20]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(C(=O)OCOC(=O)C(C)(C)C)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 50 °C
Yield: 41.5 %

Procedure:
Bumetanide (1.2 g, 3.29 mmol) was dissolved in dimethylformamide (DMF, 10 mL) and chloromethyl pivalate (575 uL, 3.9 mmol) was added followed by triethylamine (0.70 mL) and sodium iodide (545 mg, 3.6 mmol). The reaction was heated to 50° C. for 10 hours, at which time TLC and LC/MS indicated the reaction was complete. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, water and brine, and dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure and the product was purified via flash chromatography to yield 653 mg (60%) of pure t-butylcarbonyloxymethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Yield: 78 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyrimidine (10.0 g, 51.7 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (10.6 g, 51.7 mmol, 1.0 equiv) in acetonitrile (250 mL) was added at rt drop by drop N-ethyl diisopropylamine (45.2 mL 34.4 g, 266 mmol, 5.1 equiv). Then, the reaction mixture was heated to reflux for 16 h, poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 14.4 g (78%) of the title compound as a colorless solid. MS (ISP): 357.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:27])CC)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([F:27])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Benzyl-4-phenyl-piperidin-4-ol (0.45 g, 1.69 mmol) in DCM (20 mL) was cooled to −78° C. Diethylaminosulphur trifluoride (2 mmol) was added and the mixture stirred for 0.5 hour and allowed to warm to room temperature. The mixture was diluted with DCM and washed with water, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The oil was used without further purification. LCMS m/z 270.3 [M+H]+. R.T.=2.87 min (Analytical Method 4).
Reaction SMILES: [Br:1]Br.[C:3]1(=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:8]1[CH2:7][CH2:6][CH2:5][C:4](=[O:9])[C:3]1=[O:10]
Reactant: BrBr
Reactant: O=C1CCCCC1=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCCC(Br)C1=O
Temperature: 25 °C

Procedure:
Step AAE (1): Followed the method of B. Miller and H.-S. Wong Tetrahedron 1972, 28, 2369. Bromine (0.651 mL, 12.6 mmol) in was added dropwise to a solution of cyclohexane-1,2-dione (1.35 g, 12.0 mmol) in CCl4 (30 mL) at 0° C. The reaction mixture was allowed to warm to rt. The resulting solution was concentrated in vacuo to afford 3-bromocyclohexane-1,2-dione. The crude product, which is prone to decomposition, was used for subsequent chemistry without purification or characterization.
Reaction SMILES: [CH:1]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][NH2:12].Cl>>[CH3:11][NH:12][S:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: CN
Agent: Cl
Product: CNS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexanesulfonyl chloride (500 mg) was added to methylamine (12.3 mL, 2M solution in tetrahydrofuran) and the reaction mixture was stirred at room temperature for one hour. The solution was added to 1M aqueous HCl and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=3)[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].C([O-])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C(#N)C.CCOC(C)=O>[CH:20]([N:19]([CH2:18][C:17]1[CH:23]=[CH:24][CH:25]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:16]=1)[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COCc1cc(-c2nc(-c3cccc(CNC(C)C)c3)no2)ccc1-c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCc1cc(-c2nc(-c3cccc(CN(CC(=O)OC(C)(C)C)C(C)C)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
N-(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)propan-2-amine (64 mg, 0.15 mmol) was dissolved in ACN (2 mL). K2CO3 (83 mg, 0.60 mmol) and tert-butyl bromoacetate (48 μl, 0.32 mmol) were added and the mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, and then dried over MgSO4. After concentration under vacuum, the crude product was purified by flash chromatography (silica, cHex/EtOAc) to give the title compound as a colorless oil (58 mg, 72%). HPLC (Method A) Rt 5.54 min (Purity: 97.7%).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][S:7][C:8]1[S:9][C:10]([CH:16]=O)=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[NH2:18]O.Cl.C(O)=O>O>[CH3:6][S:7][C:8]1[S:9][C:10]([C:16]#[N:18])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: NO
Reactant: CSc1sc(C=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CSc1sc(C#N)cc1[N+](=O)[O-]

Procedure:
A sodium methyl mercaptide solution was prepared by adding 5 ml of methylmercaptan to 1.75 g of Na in 60 ml of absolute ethanol. While stirring and cooling this solution to below 10° C. it was added to a solution of 17.6 g of 2-bromo-3-nitro-5-formylthiophene in 200 ml of ethanol. After stirring at room temperature for another 2 hours, 200 ml of water were added, after which the formed precipitate was sucked off, washed with water-ethanol mixture (1:1 v/v), and recrystallized from isopropanol. 6.5 g of 2-methylthio-3-nitro-5-formylthiophene of melting point 129°-131° C. were obtained. Then 2.35 g of NaHCO3, 3.1 g of 2-methylthio-3-nitro-5-formylthiophene, and 1.2 g of NH2OH.HCl were added successively to 50 ml of formic acid. The reaction mixture was refluxed for 1 hour, after which, water was added and the formed precipitate was sucked off. After recrystallization from isopropanol the desired 2-methylthio-3-nitro-5-cyanthiophene was obtained in a yield of 2.3 g; melting point 150° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:16]1([NH:19][C:20]([C:22]2[S:35][C:25]3=[N:26][C:27](S(C)=O)=[C:28]([Cl:31])[C:29]([CH3:30])=[C:24]3[C:23]=2[NH2:36])=[O:21])[CH2:18][CH2:17]1>C1COCC1>[CH:16]1([NH:19][C:20]([C:22]2[S:35][C:25]3=[N:26][C:27]([O:4][CH2:3][CH2:2][CH2:1][OH:5])=[C:28]([Cl:31])[C:29]([CH3:30])=[C:24]3[C:23]=2[NH2:36])=[O:21])[CH2:18][CH2:17]1
Reactant: OCCCO
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a solution of 1,3-propanediol (1.053 g, 13.84 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. for 1 hour, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.240 g, 67%). Mass (m/z): 356.2 (M++1), 354.1 (M+−1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH:16]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)=[O:21])[CH2:17][CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:27]1[C:28]2[C:24](=[CH:23][C:22]([C:20]([NH:19][CH:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:17][CH3:18])=[O:21])=[CH:30][CH:29]=2)[CH:25]=[CH:26]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)c1ccc2c(ccn2C(=O)c2ccccc2)c1)c1ccccc1

Procedure:
Benzoyl chloride (1.1 equiv) was added to a solution of N-(1-phenylpropyl)-1H-indole-5-carboxamide in CH2Cl2, Et3N (1.3 equiv) at room temperature. After the reaction was completed, the solvent was evaporated and the residual was purified by silica gel column chromatography to get the product. LC-MS 383 (M+H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1.[CH3:28][S:29]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2)(=[O:31])=[O:30].[Cl-].[NH4+]>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:38]2[C:37]3[C:41](=[C:33]([CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH:34]=[CH:35][CH:36]=3)[NH:40][CH:39]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: COc1cc(Cl)ccc1C(O)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1cc(Cl)ccc1C(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1C#N

Procedure:
104 mg (0.47 mmol) of indium(III) chloride and 0.05 ml (0.70 mmol) of trifluoroacetic acid were added to 93.0 mg (0.39 mmol) of the compound from Example 163A and 112 mg (0.47 mmol) of the compound from Example 86A with a purity of 88% under argon in 5 ml of 1,2-dichloroethane, and the mixture was heated under reflux for 2 h. Addition of the reaction mixture to saturated aqueous ammonium chloride solution was followed by extraction with dichloromethane, drying over magnesium sulfate, filtration and concentration. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 30.5 mg (18% of theory) of diastereomer 1 and 28.0 mg (17% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Br[CH2:10][CH2:11][CH2:12][OH:13]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: OCCCBr
Solvent: Cc1ccccc1C
Product: C[C@@H]1CCC[C@H](C)N1CCCO

Procedure:
A stirred solution of 460 g. of cis-2,6-dimethylpiperidine in 300 ml. of xylene is treated with 278 g. of 3-bromopropanol over a period of 15 minutes. The mixture is stirred and heated at reflux for 2 hours, then allowed to cool while stirring for 16 hours. The mixture is filtered and the filtrate evaporated at reduced pressure. The residue is distilled at reduced pressure to give cis2,6-dimethyl-1-piperidinepropanol; b.p. 147°-149° C./25 mm.
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10](=[O:26])[CH:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>CN(C)C=O.[Pd]>[C:1]([O:7][CH2:8][O:9][C:10](=[O:26])[CH:11]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:12]([OH:14])=[O:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)CC(C(=O)OCOC(=O)C(C)(C)C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)O)C(=O)OCOC(=O)C(C)(C)C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
34.6 grams of isobutylmalonic acid benzyl ester pivaloyloxymethyl ester were dissolved in 150 ml of dimethylformamide and hydrogenated with 3.0 g of 5% palladium/charcoal. After 1 hour, the hydrogen uptake (2160 ml) had finished. The hydrogenation mixture was filtered off from the catalyst and the filtrate evaporated in a high vacuum at room temperature. The oily residue was dissolved in a 10% aqueous sodium bicarbonate solution and extracted twice with diethyl ether. The diethyl ether extracts were rejected. The sodium bicarbonate phase was acidified at 0° with citric acid and extracted twice with diethyl ether. The combined diethyl ether extracts were washed once with water, dried over magnesium sulfate and evaporated under reduced pressure. There was obtained 21.5 g of pure isobutylmalonic acid mono-pivaloyloxymethyl ester in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:26])[CH2:23][C:24]#[CH:25])[CH2:5][CH2:4]1.[O-]S(S([O-])=O)=O.[Na+].[Na+].O.CCO>C([O-])(O)=O.[Na+]>[F:1][C:2]([F:28])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:26])[CH2:23][C:24]#[CH:25])[CH2:5][CH2:4]1
Reactant: C#CCN(C)c1cc(NC)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C#CCN(C)c1cc(NC)c(N)cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-propargylamino]-4-methylamino-5-nitro-benzoic acid amide (60 mg, 0.145 mmol), Na2S2O4 (127 mg and a second 150 mg portion is added after 8 h), 1 mL water and 5 mL EtOH is stirred at 55° C. for 24 h. The mixture is diluted with sat aq NaHCO3 and extracted with EtOAc. The combined organic phases are dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (207 mg, 0.83 mmol) [prepared according to the procedure of Example 164], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (279 mg, 0.83 mmol) [Prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (469 mg, 1.00 mmol) in chloroform (8 mL). DIEA (730 μL, 4.18 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (209 mg, 0.36 mmol, 43%): LC-MS (ES) m/z=517 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[CH2:25][C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]2=[O:28])[CH2:9][CH2:8]1.P(OCC)(OCC)[O:30]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC)(C)(C)C.Cl>C1COCC1>[CH:5]1[CH:6]=[N:1][C:2]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26](=[O:27])[CH:25]([OH:30])[C:20]4([CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:19][C:18]3=[O:28])[CH2:9][CH2:8]2)=[N:3][CH:4]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Buspirone (8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro(4.5)-decane-7,9-dione) (246.5 g, 639.6 mmol) was charged to a 12 L flask equipped with a mechanical stirrer and a React-IR probe under inert gas. Tetrahydrofuran (4.383 kg, 60.8 mol, 4.930 L, 20 mL/g) was charged and the mixture agitated at ambient temperature until homogeneous. Triethyl phosphite (371.9 g, 2.238 mol, 383.8 mL, 3.5 eq) was added and the mixture was cooled to −68 to −75° C. The mixture was agitated at this temperature for at least 10 minutes to allow the React-IR signal to stabilize. 1.0 M Sodium bis(trimethylsilyl)amide in THF (600.4 g, 664.1 mmol, 664.1 mL, 1.00 eq) was charged to the mixture at such a rate so as to maintain the temperature less than −60° C. Small amounts of sodium bis(trimethylsilyl)amide were charged to the mixture until the IR signal for buspirone reached a minimum indicating complete deprotonation of buspirone. Additional buspirone in THF (10-20 mL/g) was then charged to the reaction mixture in small increments until the IR signal indicated a 0.5% to 5% excess of buspirone. Air was sparged into the reaction mixture, controlling the initial rate of sparging so as to maintain the temperature of the reaction mixture less than −60° C. The sparging was continued until the reaction was complete as indicated by HPLC. Methyl tert-butyl ether (384.8 g, 4.365 mol, 520.0 mL) was added followed by 1M hydrochloric acid (1350.8 g, 1.328 mmol, 1328 mL) and the solution was warmed to ambient temperature. The pH was adjusted to between 6.5 and 6.9 using hydrochloric acid and Na3PO4. The phases were separated and the organic phase was washed twice with brine (542.3 g, 493 mL). The solvent of the rich organic layer was then replaced by isopropyl alcohol and the solution was cooled to crystallize the reaction product. There is an option to seed with 0.01 to 5% buspirone at approximately 54 to 56° C. The crystalline slurry was then filtered and the wet cake was washed with isopropyl alcohol and dried to provide 6-hydroxybuspirone (220.0 g, 82%), mp 109.5° C.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8]O)[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1(C)C=CC=CC=1>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: OCC1CCC(F)(F)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(CC1CCC(F)(F)CC1)C(=O)OC(C)(C)C
Temperature: 12.5 °C
Yield: 113.1 %

Procedure:
To 3.9 g of (4,4-difluorocyclohexyl)methanol was added 40 mL of toluene. 10.2 g of triphenylphosphine was added thereto at room temperature, followed by stirring for a while. The mixture was ice-cooled, and 7.2 g of di-tert-butyl azodicarboxylate was portionwise added thereto while maintaining the internal temperature at about 10 to 15° C. The reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 10.7 g of di-tert-butyl 1-[(4,4-difluorocyclohexyl)methyl]hydrazine-1,2-dicarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:26])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C(=O)O)c(F)c2)CC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C(=O)Cl)c(F)c2)CC1

Procedure:
First, 2.1 g (6.4 mmol) of 2-fluoro-4-(2-(trans-4-pentyl-cyclohexyl)ethyl)benzoic acid was mixed with 1.1 g (9.6 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 80° C. for 3 hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude 2-fluoro-4-(2-(trans-4-pentyl-cyclohexyl)ethyl)benzoyl chloride.