Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[C:12]([Cl:16])[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[C:18]=[O:19]>C(Cl)Cl.C1COCC1>[Cl:16][C:12]1[C:13]([C:14]#[N:15])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:18]([NH:17][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:7][CH:6]=2)[CH:9]=[CH:10][N:11]=1
Reactant: N#Cc1c(-c2ccc(N)cc2)ccnc1Cl
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc(Cl)c3C#N)cc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.1 %

Procedure:
A mixture of Example 35C (0.1 g, 0.43 mmol), 1-isocyanato-3-methylbenzene (0.06 mL, 0.43 mmol) in CH2Cl2 (3 mL) and THF (3 mL) was stirred at room temperature overnight, then treated with an additional 0.02 mL of 1-isocyanato-3-methylbenzene, stirred for 5 more hours at room temperature then for 2.5 h at 50° C. The resulting precipitate was collected via filtration to give 0.1 g of the title compound. MS (ESI(+)) m/e 363 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[F:33])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:7])=[O:6].[CH2:34]([N:41]=[C:42]=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([NH:41][C:42]([NH:1][CH2:2][CH2:3][N:4]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[F:33])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:6])=[O:7])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)N(CCN)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCNC(=O)NCc2ccccc2)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Yield: 53.4 %

Procedure:
To 1 g of N-(2-aminoethyl)-N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxybenzenesulfonamide (compound 215) dissolved in 20 ml of THF is added 0.266 g of benzyl isocyanate, and, after refluxing for 3 hours, the medium is evaporated to dryness. The residue is chromatographed on a column of silica gel, eluting with an 8/2 (v/v) toluene/ethyl acetate mixture to give 0.65 g of the expected product.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[CH3:28])C.[OH-].[Na+]>C(O)C.O>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[C:6]([CH3:28])[CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In a solution of 10.79 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoic acid ethyl ester in 50 ml of ethanol and 10 ml of water, a solution of 2.0 g of sodium hydroxide in 10 ml of water was slowly added with stirring at room temperature. Then, the reaction mixture was stirred at 80° C. for 2 hours, after the completion of the reaction, ethanol was distilled off under reduced pressure. The residue was adjusted to pH 1-2 with concentrated hydrochloric acid with stirring at 50° C., then continued to stir at the same temperature for 1 hour and then at 5° C. for 1 hour. Precipitated crystal was filtered off, washed with water and dried to obtain 9.36 g of the aimed product as white crystal.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH:13]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47]([CH3:57])([S:53]([CH3:56])(=[O:55])=[O:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:41][CH:40]=1>C1COCC1>[CH:13]1([O:18][C:39]2[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][C:47]([CH3:57])([S:53]([CH3:56])(=[O:55])=[O:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:43][CH:44]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OC1CCCC1
Reactant: CCOC(=O)C(C)(CCc1ccc(O)cc1)S(C)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCc1ccc(OC2CCCC2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Diethyl azodicarboxylate (40%, 220 uL, 0.48 mmol) was added to a solution of cyclopentanol (30.2 uL, 0.333 mmol), triphenylphosphine (120 mg. 0.456 mmol), and (+/−)-ethyl 4-(4-hydroxyphenyl)-2-methyl-2-(methylsulfonyl)butanoate (120 mg, 0.40 mmol) in THF (3 mL) at 0° C. under nitrogen. The reaction was allowed to warm to rt and was stirred overnight. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified via column chromatography using an Analogiz SF10-8 g using EtOAc in Heptane (10-50%) to afford the title compound as a clear oil (100 mg, 67.8%). LC-MS m/z 369.4 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:4].Cl.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:19]([CH2:18][CH2:17][CH2:16][C:15]#[C:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([NH:5][CH:3]([CH3:4])[CH2:2][OH:1])=[O:7])=[O:21]
Reactant: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)O)c1
Reactant: CN
Agent: Cl
Product: CNC(=O)CCCC#Cc1cccc(C(=O)NC(C)CO)c1
Yield: 52.8 %

Procedure:
6-[3-(2-Hydroxy-1-methyl-ethylcarbamoyl)phenyl]-hex-5-ynoic acid (4)(0.400 g, 1.37 mmol) was reacted using method C with methylamine hydrochloride (0.609 g) to give 3-(5-methylcarbamoyl-pent-1-ynyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (22) (0.221 g, 0.724 mmol; 53% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:5][C@H:4]([C:6]([OH:8])=[O:7])[CH2:3]1.ClCCCl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:5]2[C:2](=[O:1])[CH2:3][C@H:4]2[C:6]([OH:8])=[O:7])=[CH:16][CH:15]=1
Reactant: O=C1C[C@@H](C(=O)O)N1
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: ClCCCl
Product: O=C(O)[C@@H]1CC(=O)N1c1ccc(Cl)cc1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of (S)-4-oxo-azetidine-2-carboxylic acid (1.0 g; 8.689 mmol) in 1,2-dichloroethane (35 mL) 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (3.1 mL; 20.854 mmol) is added at room temperature. After 10 min di-μ-hydroxy-bis[N,N,N′,N′-tetramethylenediamine)-copper (II) chloride (Cu-TMEDA) (1.614 g; 3.476 mmol) is added to the clear solution. The mixture is stirred for 10 min and 4-chlorophenylboronic acid (1.495 g; 9.558 mmol) is added. After 20 hours, solvent is evaporated in vacuo, the concentrate taken up in saturated sodium bicarbonate solution (150 mL) and the aqueous layer is washed with ethyl acetate (3×100 mL). The aqueous layer is treated with 1N hydrochloric acid to pH 2 and extracted with ethyl acetate (3×100 mL). Combined organic extracts washed with brine (2×50 mL), dried over anhydrous sodium sulfate and solvent removed in vacuo to give the title compound as an off-white solid, m/z 226 [M+H+]
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:8])[CH2:6][OH:7].Cl[C:10]1[C:11]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[NH:38][N:39]=[CH:40][CH:41]=3)=[CH:33][CH:32]=2)=[CH:12][C:13]2[N:17]=[C:16](S(C)(=O)=O)[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=2[CH:30]=1>C1COCC1.C(#N)C>[N:39]1[NH:38][C:37]([C:34]2[CH:35]=[CH:36][C:31]([C:11]3[CH:10]=[CH:30][C:14]4[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:16]([O:7][CH2:6][C:5]([OH:4])=[O:8])=[N:17][C:13]=4[CH:12]=3)=[CH:32][CH:33]=2)=[CH:41][CH:40]=1
Reactant: COC(=O)CO
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccn[nH]4)cc3)c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(OCC(=O)O)nc2cc(-c3ccc(-c4ccn[nH]4)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial equipped with a septum cap and a magnetic stirring bar was charged under N2 with NaH (18.0 mg, 60% suspension in mineral oil, 0.45 mmol). A solution of hydroxyacetic acid methyl ester (81.0 mg, 0.90 mmol) in THF (1.5 mL) was added dropwise to the vial. Immediately after the addition was complete, a solution of 6-chloro-2-methanesulfonyl-5-[4-(2H-pyrazol-3-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (compound 45-1, 75.0 mg, 0.150 mmol) in THF (1 mL) was added. The resulting suspension was stirred at rt for 5 min, then diluted with ACN (2 mL) and quenched by slow addition of water (2 mL). The resulting solution was stirred at rt for 5 min, and then additional 15 min at 65° C. The solution was acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and washed with 5% aqueous HCl and water and evaporated to dryness in vacuo to give the title compound as yellowish oil. LR-MS (API-ES): mixture of two N-SEM isomers, calculated for C24H27ClN4O4Si 498.2, observed m/e 499.0 (M+H)+ (Rt 3.01, 3.15 min). The compound was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[O:42]1[C:46]2[CH:47]=[CH:48][C:49](B(O)O)=[CH:50][C:45]=2[CH2:44][CH2:43]1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:25]=[C:24]([C:49]3[CH:48]=[CH:47][C:46]4[O:42][CH2:43][CH2:44][C:45]=4[CH:50]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc2c(c1)CCO2
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)CCO3)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 2,3-dihydrobenzofuran-5-boronic acid. LC/MS indicated a purity of 93% as measured by UV 214 nM.
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[C:1]1([O:11][C:12]2[CH:17]=[CH:16][N+:15]([O-:26])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(Oc3ccncc3)cccc2c1
Solvent: ClCCl
Product: [O-][n+]1ccc(Oc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of Example 136 A (6.62 g 29.9 mmol) in dichloromethane (40 ml) is treated with m-chloroperbenzoic acid, 80% strength (7.10 g; 32.9 mmol), stirred at room temperature for 24 h and then heated to reflux for a further 2 h. The reaction mixture is washed twice with satd aqueous NaHCO3 solution. The combined aqueous phases are extracted with dichloromethane and the combined dichloromethane phases are dried (Na2SO4) and concentrated in vacuo. The residue is crystallized from dichloromethane/petroleum ether.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH2:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:28]>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:30]3[N:29]([CH2:27][CH3:28])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CCn1c(N2CCNCC2)nc2ccccc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 10 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-ethyl-2-(piperazin-1-yl)-1H-benzimidazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([NH:11][C:19](=[O:20])[O:21][CH3:22])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(N)Cc1ccc(Br)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NC(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-bromophenyl)propan-2-amine (0.5 g, 2 mmol) in methylene chloride (5 mL) was added pyridine (380 uL, 4.7 mmol) and methyl chloroformate (270 uL, 3.5 mmol, Aldrich, Cat. No. M35304). The reaction mixture was stirred at r.t. overnight, and concentrated under reduced pressure. The residue was dissolved in EtOAc, and washed with NaHCO3 aqueous solution, 1N HCl aqueous solution and brine. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatograph on a silica gel column using 25% Ethyl acetate in hexane to afford the desired compound. LCMS (M+H)+: m/z=272.2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Br:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH2:15][N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]2)[N:14]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC1CCCNC1
Product: CC1CCCN(Cc2cccc(Br)n2)C1

Procedure:
16] 3-Methylpiperidine (0.33 mL, 2.8 mmol) was added to a solution of 6-bromo-2-pyridine-carboxaldehyde (350 mg, 1.88 mmol) to give 2-bromo-6-[(3-methylpiperidyl)methyl]pyridine as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][N:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18](/[C:21](=[N:24]/[N:25]5[CH2:29][C:28](=[O:30])[NH:27][C:26]5=[O:31])/[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: NN1CC(=O)NC1=O
Product: C/C(=N\N1CC(=O)NC1=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 50 %

Procedure:
The title compound (20 mg, 51%) was synthesized from 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (30 mg, 0.1 mmol) and 1-aminoimidazolidine-2,4-dione (22.77 mg, 0.198 mmol) using the same procedure as described in the synthesis of example 37. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 9.05 (d, 1H), 8.70 (d, 1H), 8.32 (d, 1H), 8.12 (d, 2H), 7.98 (d, 1H), 7.87 (d, 1H), 7.77 (m, 1H), 4.83 (s, 2H), 4.54 (s, 2H), 2.40 (s, 3H). LCMS (method B): [MH]+=401.1, tR=1.64 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:5][N:6]=1.[C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:22])[CH2:18][C:19]([O-])=[O:20]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]3=[N:1][C:17]([OH:22])=[CH:18][C:19](=[O:20])[N:6]3[N:5]=2)=[CH:8][CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(-c2nnc(N)s2)cc1
Reactant: O=C([O-])CC(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)c1ccc(-c2nn3c(=O)cc(O)nc3s2)cc1
Yield: 96.6 %

Procedure:
A mixture of 9.3 g of 2-amino-5-(4-tert-butylphenyl)-1,3,4-thiadiazole, 20 g of 2,4,6-trichlorophenyl malonate and 50 ml of Dowtherm A was heated at a temperature of 120° to 130° C. for 2 hours. After allowing the mixture to cool, the precipitate was separated by filtration, washed successively with isopropanol and diethyl ether to obtain 11.6 g of 2-(4-tert-butylphenyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a colorless, crystalline powder having a melting point of 265° to 268° C. (decomposition).
Reaction SMILES: CCO[C:4]([CH:6]1[CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:13]1[O:10][C:9]2([CH2:8][CH2:7][CH:6]([CH2:4][OH:5])[CH2:12][CH2:11]2)[O:15][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl cyclohexanone-4-carboxylate (335 g.), 550 ml. ethylene glycol and 21 g. of p-toluenesulfonic acid in 5.5 liters of benzene were heated at reflux with stirring for 24 hours while water was separated by means of a water trap. The mixture was cooled and poured into 4 liters of ice water. The benzene layer was separated, washed with 1 liter of 5% sodium bicarbonate, 1 liter of water and 1 liter of saturated sodium chloride solution, dried and evaporated to dryness to give, after distillation, 245.6 g. of ethyl cyclohexanone-4-carboxylate ethylene ketal; b.p. 95-99.5°C. (0.07 mm.); N25D 1.4620. A solution of 35 g. of the ketal-ester in 50 ml. of dry tetrahydrofuran was added dropwise to 5.7 g. of lithium aluminum hydride in 250 ml. of dry tetrahydrofuran, and the mixture was heated at reflux for 5 hours and cooled to room temperature. A saturated sodium chloride solution (11.4 ml.) was added dropwise and heating at reflux was continued for one hour. The mixture was cooled and filtered, and the filtrate was dried and evaporated to dryness to give 26.9 g. of 4-hydroxymethylcyclohexanone ethylene ketal as a clear, colorless oil which was used without further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C1COCC1>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: N#CCCCN1CCC(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a stirred solution of 4-(4-phenylpiperidin-1-yl)butyronitrile (3.81 g, 16.7 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 58.5 mL, 58 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6N, 100 mL) was added and stirring was continued for 2 hours at 55°-60° C. The mixture was basified to pH 9 by addition of 6N aq. NaOH and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2 Cl2 (20 mL) and treated with HCl in ether (1.0M, 35 mL). The solvents were removed, ether (200 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water (50 mL) was added to the resulting white solid, the pH was adjusted to 10-11 with 1N NaOH, and the aqueous phase was extracted with CH2Cl2 (3×100 mL). Drying over MgSO4 followed by removal of solvents gave 3.54 g of 1-(4-aminobutyl)-4-phenylpiperidine (light yellow solid, 91%) which was characterized spectroscopically.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[OH:11][C:12]1[C:13](=[O:28])[O:14][CH:15]([CH2:18][CH2:19][C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]=1[OH:17]>C(O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:11][C:12]1[C:13](=[O:28])[O:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]=1[OH:17]
Reactant: O=C1OC(CCC#Cc2ccccc2)C(O)=C1O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: O=C1OC(CCCCc2ccccc2)C(O)=C1O

Procedure:
Quinoline (70 μL, 0.6 mmol), 15 mg of 5% Pd/BaSO4 and 61 mg (0.25 mmol) of 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-furanone were combined in 20 mL of ethanol and hydrogenated at atmospheric pressure until 12 mL (0.5 mmol) of H2 was consumed as measured by a H2O filled burette. The catalyst was removed by filtration through two #1 fluted filter papers and the solution was concentrated to a volume of about 5 mL, taken up in SOmL of ether and washed with 3×15 mL of 5% aqueous HCl, 20 mL of H2O and 20 mL of brine, dried (MgSO4) and concentrated to provide 3,4-dihydroxy-5-(4-phenylbutanyl)-2(5H)-furanone as a brown wax: 1H NMR (acetone-d6) δ 7.28-7.13 (m, 5H), 4.66 (dd, J=3.4, 7.2 Hz, 1H), 2.62 (t, J=7.7, 2H), 2.00-1.93 (m, 1H), 1.69-1.42 (m, 5H); 13C NMR (acetone-d6) δ 170.7, 154.9, 143.3, 129.2, 129.1, 126.5, 118.6, 76.2, 36.3, 32.7, 32.1, 24.6. Anal Calcd for C14H16O4 +0.25 H2O: C, 66.52; H, 6.58. Found: C, 66.71; H, 6.75.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1)[CH:22]=[CH2:21]
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2oc(C(=O)OC)cc2c1
Reaction time: 16 h

Procedure:
A mixture of methyl 5-hydroxybenzofuran-2-carboxylate (4.14 g), potassium carbonate (5.95 g) and allyl bromide (3.73 ml) in dry acetone (100 ml) was refluxed and stirred for 16 hours. The solvent was evaporated and the residue was partitioned between water and ether. The ether was washed with water, dried and evaporated to give methyl 5-(prop-2-enyloxy)benzofuran-2-carboxylate (4.7 g) as a solid, characterised by NMR and mass spectral data. This ester (3.74 g) in N-methylpyrrolidinone (30 ml) was refluxed under nitrogen for 2 hr, cooled, and partitioned between water and ethyl acetate. The organic phase was washed with water, dried and evaporated to give the title ester (3.5 g), mp 114°-119°.
Reaction SMILES: O[C@H](C(C)C)[C@@H](N([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)C(OC)=O)C(O)=O.O[C@@H:28]([CH:50]([CH3:52])[CH3:51])[C@@H:29]([N:33]([C:38]1C=CC(C2C=CC=CC=2)=CC=1)[C:34]([O:36]C)=[O:35])[C:30]([OH:32])=[O:31].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:36][C:34](=[O:35])[N:33]([CH3:38])[C@H:29]3[C:30](=[O:32])[O:31][C@@H:28]3[CH:50]([CH3:52])[CH3:51])=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@@H](O)C(C)C
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@H](O)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H]1OC(=O)[C@@H]1N(C)C(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 17 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-4-methyl-2-[(4-phenylphenyl)-methoxy-carbonylamino]-pentanoic acid and (2R*,3S*)-3-hydroxy-4-methyl-2-[(4-phenylphenyl)-methoxy-carbonylamino]-pentanoic acid (0.059 g, 0.17 mmol) in dry CH2Cl2 (7.0 mL), at 0° C., Et3N (0.07 mL, 0.5 mmol) and subsequently TBTU (0.065 g, 0.2 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 80:20) to afford the pure title compound (0.01 g, 17%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 357 [M−NH4]+; (ESI) m/z: 338 [M−H]−. 1H NMR (DMSO-d6) δ 0.89 (d, J=6.79 Hz, 3H), 0.97 (d, J=6.57 Hz, 3H), 1.81-2.12 (m, 1H), 4.26 (dd, J=4.38, 9.11 Hz, 1H), 4.80 (dd, J=4.39, 8.16 Hz, 1H), 5.12 (s, 2H), 7.29-7.54 (m, 5H), 7.63-7.77 (m, 4H), 8.26 (d, J=8.21 Hz, 1H).