Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C([Cl:5])=O.C(Cl)(Cl)=O.[CH:11]1([NH:17][S:18](=[O:21])(=O)[OH:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>ClCCCl>[CH:11]1([NH:17][S:18]([Cl:5])(=[O:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=S(=O)(O)NC1CCCCC1
Reactant: CN(C)C(=O)Cl
Agent: O=C(Cl)Cl
Solvent: ClCCCl
Product: O=S(=O)(Cl)NC1CCCCC1
Temperature: 83 °C
Yield: 58 %

Procedure:
A solution of 15 parts of dimethylcarbamic acid chloride in 310 parts of 1,2-dichloroethane is saturated with 30 parts of phosgene at 25° C and 89.5 parts of cyclohexylsulfamic acid are then added. The reaction mixture is heated to 83° C whilst continuing to introduce phosgene. In total, 330 parts of phosgene are introduced in the course of 13 hours. After removing the solvent and the dimethylcarbamic acid chloride under reduced pressure, the residue is distilled, and 57 parts (58% of theory) of cyclohexylsulfamic acid chloride of boiling point 208°-127° C/0.1 mm Hg and melting point 42°-44° C are obtained.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][CH2:35][C:34](=O)[C:33]=2[C:38]=1[NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42]>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][CH2:35][C:34](=[CH2:1])[C:33]=2[C:38]=1[NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42]
Reactant: CC(C)(C)[O-]
Reactant: O=C1COc2ccc(Cl)c(NC(=O)C(F)(F)F)c21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C1COc2ccc(Cl)c(NC(=O)C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of potassium tert-butoxide (2.0) and methyltriphenylphosphonium iodide (7.1 g) was added dry toluene (70 ml) and the mixture stirred at room temperature for 30 min, then heated under reflux for 30 min. The mixture was cooled to room temperature, a solution of Intermediate 22 (1.0 g) in toluene (30 ml) added dropwise and the mixture heated under reflux for 30 min. The mixture was cooled and quenched by the dropwise addition of saturated ammonium chloride solution. The mixture was partitioned between ethyl acetate and water and the organic phase washed with water. The combined aqueous layers were re-extracted with ethyl acetate and the combined organic layers dried over sodium sulphate and concentrated in vacuo to give a dark brown oil. Purification by column chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane, gave the title compound as a rose coloured solid (0.5 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:36][O:37][C:38]1[CH:48]=[CH:47][C:46](/[CH:49]=[CH:50]\[C:51]2[CH:56]=[C:55]([O:57][CH3:58])[C:54]([O:59][CH3:60])=[C:53]([O:61][CH3:62])[CH:52]=2)=[CH:45][C:39]=1[O:40][CH2:41][C:42](O)=[O:43]>ClCCl.O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:42](=[O:43])[CH2:41][O:40][C:39]3[CH:45]=[C:46](/[CH:49]=[CH:50]\[C:51]4[CH:56]=[C:55]([O:57][CH3:58])[C:54]([O:59][CH3:60])=[C:53]([O:61][CH3:62])[CH:52]=4)[CH:47]=[CH:48][C:38]=3[O:37][CH3:36])[S:9][C:5]=2[CH:4]=1
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(C(F)(F)F)cc2s1
Yield: 783.2 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic ac id (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8i) (450 mg, 80% yield)
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([C:22]([NH:24][NH2:25])=O)[CH2:21][CH2:20][CH2:19]1>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([C:22]2[N:10]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[N:25][N:24]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: NNC(=O)C1(c2ccccc2F)CCC1
Reactant: COC1=NCCCCCC1
Product: Fc1ccccc1C1(c2nnc3n2CCCCCC3)CCC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
8-Methoxy-2,3,4,5,6,7-hexahydroazocine (47 μl, 0.412 mmol) was added to the solution of 1-(2-fluorophenyl)cyclobutanecarbohydrazide, and the reaction was stirred at 120° C. overnight. After cooling, the solution was concentrated, and the product was purified by preparative HPLC as the trifluoroacetate salt. The salt was added to a saturated sodium bicarbonate solution and extracted with ethyl acetate to give the freebase. The extract was dried over magnesium sulfate, filtered and evaporated to give the purified triazole (2-34) as a solid (12.5 mg).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][C:4](=[O:6])[NH2:5].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[NH2:36][C@H:37]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][CH:40]=1.Cl.CN1CCOCC1>ClCCl.CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:36][C@H:37]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[CH:43][CH:44]=1)=[O:9])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Boc-Asn-OH (3.5 g 15 mmol) is dissolved in dichloromethane (100 ml amylene stabilised free of alcohol) and HOBt (2.24 g dry 16.5 mmol) is added. The mixture is cooled in an ice/water bath and DIC (2.45 ml 16 mmol) is added. The mixture will be allowed to react for 20 min. The HOBt on the bottom will react and a precipitate of DIU (on top) will form. H-Tyr(tBu)-OtBu×HCl (5.1 g 15.4 mmol) is dissolved in DMF (30 ml dry). The dichloromethane mixture containing the activated ester is filtered from the DIU directly into the DMF solution. The combined mixture is cooled in ice/water and NMM (1.75 ml 15.8 mmol) is added. The mixture is allowed to react over night. The solvents will be removed in vacuo. Ethyl acetate 200 ml is added and a precipitate is removed and the solution is washed with citric acid (2×50 ml 10%), sodium hydrogen carbonate (2×50 ml saturated) and brine (2×50 ml). The solution is dried with magnesium sulfate and the solvent removed in vacuo ending at 0.2 mBar for 30 min. The raw product will be suspended in pentane (40 ml) and filtered from a precipitate of DIU. The pentane will be removed in vacuo yielding the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH3:14][O:15][CH2:16]Cl.C(N(C(C)C)CC)(C)C.[OH-].[Na+:28]>CN(C)C=O.O>[Na+:28].[Na+:28].[CH3:14][O:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([C:11]([O-:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([O-:8])=[O:7]
Reactant: COCCl
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxyphthalic acid (0.45 g, 2.47 mmol) in anhydrous N,N-dimethylformamide (5 ml) under nitrogen was added chloromethyl methyl ether (1.13 ml, 14.8 mmol) and diisopropylethylamine (2.6 ml, 14.8 mmol). The reaction was stirred at ambient temperature for 18 h. and then concentrated in vacuo. The crude material was partitioned between ethyl acetate (50 ml) and water (15 ml). The layers were separated, the organic layer washed with water (3×10 ml), brine (2×10 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in ethanol (5 ml) and sodium hydroxide (0.12 g, 7.4 mmol) dissolved in water (1 ml) was added to the reaction. The solution was stirred at ambient temperature for 48 h. and then concentrated in vacuo affording 4-methoxymethoxy-phthalic acid di-sodium salt which was used without purification.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.[CH2:19](O)[CH3:20]>>[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][CH:7]=1
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(N)c2c1OCCO2
Temperature: -40 °C
Reaction time: 1 h

Procedure:
23.5 g (0.198 mol) of thionyl chloride are introduced slowly into a 2 1 three-necked round-bottomed flask containing 772 ml of ethanol cooled to −40° C., with stirring, the stirring is continued at this temperature for 1 h, 38.6 g (0.198 mol) of 8-amino-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid dissolved in 100 ml of ethanol are added slowly, over 15 min, and the mixture is allowed to warm to room temperature overnight.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:12]OC(OC)N(C)C.S(O)(O)(=O)=O.[CH3:25][S:26][C:27](=[NH:29])[NH2:28].C([O-])(=O)C.[Na+]>O.CN(C)C=O>[C:2]([C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:12][N:28]=[C:27]([S:26][CH3:25])[N:29]=1)([CH3:11])([CH3:10])[CH3:1]
Reactant: CSC(=N)N
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(SC)nc1C(C)(C)C
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4,4-dimethyl-3-oxopentanoate (10 g) and N,N-dimethyl formamide dimethyl acetal (9.5 mL) was stirred at 75° C. for 2 hours. To the reaction mixture were added N,N-dimethyl formamide (100 mL), S-methylisothiourea sulfate (2:1) (9.7 g), and sodium acetate (11.4 g), followed by stirring at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, and water was added thereto. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain methyl 4-tert-butyl-2-(methylsulfanyl)pyrimidine-5-carboxylate (8.4 g) as a colorless oily substance.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[N:13]([O-])=O.[Na+].O.O.[Cl:19][Sn]Cl>>[ClH:19].[N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][NH2:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2ncccc2c1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of quinolin-6-ylamine (5 g, 35 mmol) in cone. HCl (12 mL) was added dropwise an aqueous solution (4 mL) of NaNO2 (2.42 g, 35 mmol) at 0° C. The resulting mixture was stirred for 1 h and then treated dropwise with a solution of SnCl2.2H2O (15.8 g, 70 mmol) in cone. HCl (15 mL) at 0° C. The reaction mixture was stirred for 2 h at RT. The precipitate was collected and washed with EtOH and Et2O to yield 1-(quinolin-6-yl)hydrazine hydrochloride (4.3 g, 77% yield) as a yellow powder, which was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:15][O:16][C:17](=O)[O:18]C.Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[C:17]([O:16][CH3:15])=[O:18]
Reactant: COC(=O)OC
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1
Temperature: 30 °C
Reaction time: 1.17 h

Procedure:
At 40° C. a solution of 4-bromophenylacetic acid methyl ester (52 g) in THF (100 mL) is carefully added over a period of 40 min to a suspension of NaH (15.6 g) in dry THF (450 mL). Stirring is continued for 70 min without heating and the temperature drops to 27° C. The evolution of gas has stopped before dimethylcarbonate (76.42 mL) is added dropwise while the temperature of the mixture is maintained at 29-31° C. Stirring is continued for 22 h at rt. The mixture is cooled to −10° C. and then carefully neutralized to pH 6-7 with aq. HCl before bulk of the THF is removed in vacuo. The residue is dissolved in EA (700 mL), washed three times with 1 N aq. HCl and once with brine, dried over MgSO4. Most of the EA is evaporated before hexane is added. The product crystallizes over night at 4° C. The crystals are collected, washed with hexane and dried to give 2-(4-bromophenyl)-malonic acid dimethyl ester (45.9 g) as pale yellow crystals. 1H-NMR(D6-DMSO): 3.66 (s, 6H), 5.07 (s, 1H), 7.30-7.34 (m, 2H), 7.55-7.59 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:22]C(=O)OC(C)(C)C)[C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][N:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][N:15]=2)[NH2:22])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nnc(-c2ccccc2)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](Cc1cc(F)cc(F)c1)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
(S)-tert-Butyl 2-(3,5-difluorophenyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethylcarbamate (17A, 110 mg, 0.27 mmol) was dissolved in 2.7 mL of methanol and to it was added 0.7 mL of 4M HCl in 1,4-dioxane. The reaction mixture was allowed to stir at ambient temperature for 1 hour and the solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with methanol/methylene chloride to afford 90 mg of (S)-2-(3,5-difluorophenyl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanamine (0.26 mmol) which was dissolved in 5 mL of DMF and to it were added 2-(5-fluoro-1H-indol-3-yl)acetic acid (61 mg, 0.31 mmol) and N,N-diisopropylethylamine (0.226 mL, 1.3 mmol). The reaction mixture was cooled down to 0° C. and to it was added HATU (119 mg, 0.31 mmol). The reaction mixture was allowed to stir at ambient temperature for overnight and then purified by reverse phase HPLC eluting with acetonitrile/water (0.1% TFA) to afford the desired product. 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.79 (d, J=8.2 Hz, 1H), 7.94-7.73 (m, 2H), 7.56 (m, 3H), 7.27 (dd, J=8.7, 4.5 Hz, 1H), 7.12 (m, 2H), 7.00 (m, 3H), 6.84 (td, J=9.2, 2.5 Hz, 1H), 5.44 (m, 1H),), 3.52-3.12 (m, 4H). MS (m/z): 477.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)=[C:9]([C:19](O)=[O:20])[C:8]=3[CH:22]=2)[CH2:3][CH2:2]1.C[CH2:29][N:30](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.C1COCC1>CN(C=O)C.O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[O:11][C:7]3[CH:6]=[C:5]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:22][C:8]=3[C:9]=2[C:19]([NH:30][CH3:29])=[O:20])=[CH:17][CH:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(Cl)cc3)c(C(=O)O)c2cc1C1CC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a solution of 5-cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (5 g, 11.52 mmol) in dry DMF (30 mL) was added DIPEA (3.3 g, 25.34 mmol) and HATU (5.15 g, 13.5 mmol) at 20° C. After 15 minutes, 2M Methylamine in THF (23.04 mL, 46.08 mmol) was added dropwise and the mixture was stirred for another 2 hours before water (60 mL) was added. The mixture was extracted with EA (3×200 mL), washed with water (2×200 mL), dried and concentrated to afford 2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide as a brown solid (4.7 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (br. s., 1H) 8.45 (q, 1H) 7.90 (d, 2H) 7.53-7.64 (m, 3H) 7.16 (s, 1H) 3.06 (s, 3H) 2.83 (d, 3H) 2.21-2.37 (m, 1H) 0.94-1.05 (m, 2H) 0.64-0.73 (m, 2H). LCMS (m/z, ES+)=419 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][O:14][CH2:15][CH2:16][OH:17])[CH3:12].O[C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1)[CH3:12]
Reactant: CC(=NOCCO)c1ccc2ccccc2c1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc2ccccc2c1
Yield: 82.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 459 mg of 2-[1-(2-naphthyl)-ethylideneaminooxy]ethanol (prepared as described in Preparation 13), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 858 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[N:6]([CH3:23])[C:5]1=[O:24])[C:14](=[O:17])[CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]3.Br[CH2:26][CH2:27][CH2:28][Cl:29]>O>[Cl:29][CH2:28][CH2:27][CH2:26][C:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:7]3[N:6]([CH3:23])[C:5](=[O:24])[N:4]([CH3:3])[C:8]=3[CH:9]=2)[C:14]1=[O:17]
Reactant: ClCCCBr
Reactant: CCOC(=O)C1CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1(CCCCl)CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
60% Oily sodium hydride (832 mg) was added to a solution of ethyl (±)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylate (5.0 g) obtained in Reference Example 138 in dimethylformamide,and the mixture was stirred at 60° C. for 1 hour. 1-Bromo-3-chloropropane was added thereto, and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was allowed to cool, and water was added to decompose excessive sodium hydride. Then, the mixture was extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]([C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])([CH3:3])C.C[C:13]([O-:16])(C)C.[K+].[I-].[CH3:19][S+](C)C>C(O)(C)(C)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([OH:5])([CH2:1][CH2:3][CH3:19])[CH2:13][OH:16])[CH:7]=1
Reactant: C[S+](C)C
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C(=O)c1cccnc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCC(O)(CO)c1cccnc1
Temperature: 65 °C

Procedure:
20 g (0.134 mol) of 3-pyridyl isopropyl ketone and 30.2 g (0.268 mol) of potassium tert-butylate were dissolved in 200 ml of tert-butanol. Thereafter, 37.4 g (0.208 mol) of trimethylsulfonium iodide were added and the mixture was heated at 65° C. for 1.5 hours. The inorganic salts were separated off and the reaction solution was evaporated down, after which 75 ml of half-concentrated H2SO4 were added to the crude product and the mixture was heated at 60°-70° C. for 8 hours. The pH was then brought to 9 with 4N NaOH solution and extraction was carried out with methylene chloride. The organic phase was dried and evaporated down and the product was then purified by chromatography.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:4]2[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[C@H:48]1[CH2:52][CH2:51][CH2:50][NH:49]1.C(N(C(C)C)CC)(C)C>O.CN(C=O)C>[F:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=1[C@H:48]1[CH2:52][CH2:51][CH2:50][N:49]1[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:4]2[N:3]=1
Reactant: Fc1ccc(F)c([C@H]2CCCN2)c1
Reactant: N#Cc1cnn2ccc(O)nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A flask was charged with the product from Step A (2.80 g, 17.5 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (9.28 g, 21.0 mmol) and dry DMF (35 mL). The suspension was stirred at ambient temperature for 2 minutes and (R)-2-(2,5-difluorophenyl)pyrrolidine (Preparation A, 3.84 g, 21.0 mmol) and diisopropylethylamine (6.78 g, 62.5 mmol) were sequentially added (mild exotherm). The mixture was stirred at ambient temperature for 3 hours and poured into H2O (175 mL). The mixture was extracted with 50% EtOAc-hexanes and the combined organic fractions were washed sequentially with 1M HCl, H2O, 1M Na2CO3 and saturated NaCl. The solution was dried over MgSO4/activated carbon and filtered through a short SiO2 plug (350 mL course frit funnel, ¼ full of SiO2, capped with a layer of MgSO4) using 50% EtOAc-hexanes for elution. The solution was concentrated to give the title compound as a brittle white foam that was crushed to a flowing white solid and dried in vacuum (5.50 g, 97%). MS (apci) m/z=326.2 (M+H).
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][N:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>C1C=CC=CC=1.[Al].CCOCC.CO>[CH3:13][NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CN=C1CCc2ccccc21
Agent: [Al]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: CCOCC
Solvent: CO
Solvent: c1ccccc1
Product: CNC1CCc2ccccc21
Reaction time: 20 h
Yield: 88 %

Procedure:
(R,R)-Ethylene-1,2-bis(η5 -4,5,6,7-tetrahydroindenyl) titanium (R)-1,1'-binaphth-2,2'-diolate (30 mg, 0.050 mmol) was dissolved in 4 mL of dry benzene in a Schlenk tube under a nitrogen atmosphere. The tube was wrapped in aluminum foil. A solution of n-butyllithium (41 μL, 0.065 mmol, 1.6M in hexane) was added and the mixture was shaken until it turned a dark red brown color. After 5 min. phenylsilane, (93 μL, 0.75 mmol) was added and the reaction mixture turned blue, then brown, in color. After 10 min. indanone N-methyl imine (72.6 mg, 0.50 mmol) was added. The tube was shaken and left for about 20 hours at room temperature. The resulting solution was diluted with 15 mL of ether and 3 mL of methanol and allowed to stir for 2 hours. The reaction mixture was then washed with 20 mL of water and extracted with 1M HCl (2×20 mL). The aqueous layer was separated, basified with 5 M NaOH (until strongly basic to pH paper), and extracted with ether (2×50 mL). The ether solution was dried over anhydrous sodium sulfate and concentrated to yield 65 mg (0.44 mmol, 88% yield) of N-methyl-1-indanamine as a yellow oil.