Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:27][CH2:28][CH2:29][CH3:30].C(OCC)(=O)C>CN(C)C=O>[CH2:27]([N:14]([CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)[C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH2:28][CH2:29][CH3:30]
Reactant: COc1ccc(-c2csc(NCc3ccc(C#N)cc3)n2)cc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(Cc1ccc(C#N)cc1)c1nc(-c2ccc(OC)cc2)cs1
Temperature: 25 °C

Procedure:
1.0 g 4-{[4-(4-Methoxy-phenyl)-thiazol-2-ylamino]-methyl}-benzonitrile was dissolved in 150 ml dimethylformamide. 150 mg sodium hydride (24% in mineral oil) were added and the reaction mixture stirred at room temperature for thirty minutes. Then 0.43 ml 1-Iodobutane were added and the reaction mixture stirred at room temperature for two hours. Then 100 ml ethyl acetate were added and the mixture was washed three times with portions of 50 ml water and then dried over MgSO4. The solvents were removed in vacuo to obtain 1.2 g 4-({Butyl-[4-(4-methoxy-phenyl)-thiazol-2-yl]-amino}-methyl)-benzonitrile.
Reaction SMILES: O[C:2]1([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH2:6][C:5](=[O:16])[CH:4]=[CH:3]1.[CH3:25][CH2:26][O:27]CC.C(=O)(O)[O-].[Na+].C(=O)=O>C(OC(=O)C)(=O)C>[C:26]([O:16][C:5]1[CH:4]=[CH:3][C:2]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:7]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH:6]=1)(=[O:27])[CH3:25]
Reactant: CC1(CCC2CC(=O)C=CC2(O)C#Cc2ccccc2)OCCO1
Reactant: CCOCC
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C#Cc2ccccc2)c(CCC2(C)OCCO2)c1
Temperature: 25 °C

Procedure:
4-Hydroxy-5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-4-(phenylethynyl)-2-cyclohexen-1-one (3.0 g, 9.2 mmole, prepared in a manner similar to that in Example 7b) was dissolved in acetic anhydride (25 mL) and stirred at RT under argon. After stirring 5 hr at RT, the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to RT, poured into about 100 mL of ether, about 200 mL of saturated sodium bicarbonate added and the solution stirred. After evolution of CO2 was complete, solid sodium bicarbonate was added cautiously until foaming ceased. The layers were separated, the aqueous layer extracted twice with 100 mL portions of ether, the ether layers combined, washed with two 100 mL portions of sodium bicarbonate solution, two 100 mL portions of ether, the ether layers combined, washed with two 100 mL portions of saturated sodium bicarbonate solution, two 100 mL portions of water and 75 mL of saturated brine. After drying over anhydrous sodium sulfate, the organic layer was filtered and concentrated in vacuo to give 3.2 g of the title compound, a dark orange oil.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[N:3]1[C:7]2([CH2:12][CH2:11][N:10]([N:13]([CH3:15])[CH3:14])[CH2:9][CH2:8]2)[C:6](=[O:16])[CH:5]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[C:4]1=[O:26].C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O1CCCC1>[CH2:39]([O:38][C:36](=[O:37])[O:16][C:6]1[C:7]2([CH2:12][CH2:11][N:10]([N:13]([CH3:14])[CH3:15])[CH2:9][CH2:8]2)[N:3]([N:2]([CH3:1])[CH3:27])[C:4](=[O:26])[C:5]=1[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH3:40]
Reactant: Cc1cc(C)c(C2C(=O)N(N(C)C)C3(CCN(N(C)C)CC3)C2=O)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(N(C)C)C12CCN(N(C)C)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
150 mg 1,8-Bis-dimethylamino-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione (PREPARATION EXAMPLE 1) is dissolved in 3 ml tetrahydrofuran, 75 mg triethylamine is added, and the mixture is cooled to 0° C. 44 mg ethyl chloroformate is added and the resulting suspension stirred for 3 hours, thereby warming to room temperature. Then the mixture is partitioned between water and ethyl acetate, the organic layer separated and washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue is purified by chromatography on silica gel with ethyl acetate/heptane (1:1) as a solvent. Thus, 145 mg Carbonic acid 1,8-bis-dimethylamino-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester is obtained as a solid, mp 105° C. 1H-NMR (CDCl3): 6.83 ppm (s, 2H), 4.02 ppm (q, 2H), 3.05 ppm (m, 2H), 2.94 ppm (s, 6H), 2.80 ppm (m, 2H), 2.43 ppm (s, 6H), 2.40 ppm (m, 2H), 2.23 ppm (s, 3H), 2.17 ppm (s, 6H), 1.86 ppm (m, 2H), 1.08 ppm (t, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([Cl:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([O:21]C)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C([O-])(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([Cl:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cn(C2CC2)c2c(OC)c(Cl)c(F)cc2c1=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 92 %

Procedure:
28.6 g of methyl 1-cyclopropyl-7-chloro-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.088 mol), 160 ml of acetate acid, 100 ml of water and 18 ml of concentrated sulfuric acid were stirred for 40 minutes at 100-110° C. The resulting mixture was cooled and filtered. The precipitate was re-crystallized from choroform-ethanol to afford 25.2 g of 1-cyclopropyl-7-chloro-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Gaticarboxylic acid, 0.081 mol) in 91.8% yield, mp 195-199° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[O:8])[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>C1(C)C(C)=CC=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][C:7]1([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[O:32][CH2:31][CH2:30][O:8]1
Reactant: OCCO
Reactant: O=C(Cc1ccc(Cl)cc1Cl)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Clc1ccc(CC2(c3cccnc3)OCCO2)c(Cl)c1

Procedure:
2.25 g of 2,4-dichlorobenzyl 3-pyridyl ketone, 2.2 g of p-toluenesulfonic acid monohydrate and 1.0 g of ethylene glycol are heated at reflux for 24 hours in 20 ml of xylene, the resulting water being separated in a water separator. The mixture is then cooled, poured into 2N sodium hydroxide and extracted with diethyl ether, the organic phase is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel with n-hexane/ethyl acetate (1:1) to yield 3-[2-(2,4-dichlorobenzyl)-1,3-dioxolan-2-yl]pyridine, which melts at 76°-78°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[CH3:10][N:11]1[C:15]([CH2:16]O)=[N:14][CH:13]=[N:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:16][C:15]1[N:11]([CH3:10])[N:12]=[CH:13][N:14]=1
Reactant: Cn1ncnc1CO
Reactant: Oc1cc(Br)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cn1ncnc1COc1cc(Br)ccc1F
Reaction time: 8 h
Yield: 37 %

Procedure:
A cooled (0° C.) solution of 5-bromo-2-fluorophenol, (2-methyl-2H-[1,2,4]triazol-3-yl)methanol and triphenylphosphine in tetrahydrofuran was treated dropwise with diisopropyl azodicarboxylate over 10 min. The resulting mixture was stirred overnight and then acetic acid was added. The reaction mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and 0.01N sodium hydroxide solution. The organic phase was washed with water and brine, dried over anhydrous magnesium sulphate and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (10-50%), led to product-containing fractions that were combined. The material was further purified by flash column chromatography on silica gel, eluting with dichloromethane containing 1% ammonia on a gradient of methanol (0.5-3%), to give 5-(5-bromo-2-fluoro-phenoxymethyl)-1-methyl-1H-[1,2,4]triazole as an off-white solid (2.1 g, 37%): δH (360 MHz, CDCl3) 4.01 (3H, s), 5.29 (2H, s), 6.96-6.99 (1H, m), 7.09-7.13 (1H, m), 7.29 (1H, dd, J 5 and 2), 7.88 (1H, s); m/z (ES+) 288 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](Cl)=[O:26])(=[O:21])[CH3:20]>O1CCCC1>[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6])=[O:26])(=[O:21])[CH3:20]
Reactant: Cc1cc(N)cc(C(=O)O)c1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C)cc(C(=O)O)c1
Yield: 51.8 %

Procedure:
3-Amino-5-methylbenzoic acid (1.9 g) is dissolved in a 60% aqueous solution of tetrahydrofuran (30 ml) containing triethylamine (2.3 g), and to the mixture is added dropwise a solution of 2-acetylthiomethyl-3-phenyl-propionyl chloride (3.2 g) in tetrahydrofuran (20 ml) with stirring under ice cooling, and the mixture is stirred at room temperature for 2 hours. Tetrahydrofuran is distilled off under reduced pressure, and the residue is extracted with ethyl acetate (100 ml). The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then ethyl acetate is distilled off under reduced pressure. The residue is dissolved in acetonitrile and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated into dryness under reduced pressure to give the title compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[C:32]1([C:38]2[S:39][CH:40]=[C:41]([CH2:43][NH2:44])[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:44][CH2:43][C:41]3[N:42]=[C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[S:39][CH:40]=3)=[O:23])=[CH:17][C:9]1=2
Reactant: NCc1csc(-c2ccccc2)n1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCc1csc(-c2ccccc2)n1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-phenyl-4-(aminomethyl)thiazole as in General Procedure 10 to give the title compound. LCMS: m/z=619.9 (M+H+); retention time=0.99 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10].[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(N(CC)CC)C.[Pd].[Cu]I>[C:16]1([C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=2)[O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCN(CC)CCOc1cccc(Br)c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1cccc(C#Cc2ccccc2)c1
Yield: 74.4 %

Procedure:
To a solution of 15 g (0.06 mole) of 1-(3-bromophenoxy)-2-diethylaminoethane and 6.12 g (0.06 mole) of phenylacetylene in 150 ml of triethylamine are added, under nitrogen, 420 mg of the palladium complex PdCl2 [P(C6H5)3 ]2 and 228 mg of copper (I) iodide. This reaction mixture is refluxed for 24 hours, then concentrated, and the residue is taken up in water. After extraction with 200 ml of ether, the combined ethereal phases are washed 4 times with water, dried, and evaporated to dryness. The crude product is chromatographed on silica gel and then distilled, affording 13.1 g (75%) of 1-(3-phenylethynylphenoxy)-2-diethylaminoethane with a boiling point of 150°-160° C./0.02 mb and a refractive index of nD25 :1.5858.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](F)=[CH:6][C:5]=1[F:14]>C1COCC1>[F:3][C:4]1[C:5]([F:14])=[CH:6][C:7]([NH:2][CH3:1])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Solvent: C1CCOC1
Product: CNc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of MeNH2 in THF (5.7 mL, 2 M, 11 mmol) was added dropwise to a solution of 1,2,4-trifluoro-5-nitrobenzene (1.0 g, 5.7 mmol) in THF (10 mL) at −20° C. The mixture was stirred at −20° C. for 1 h, concentrated, washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from EtOAc/PE gave the sub-title compound. Yield: 1.0 g (81%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:19]=1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.Cl>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:19]=1[S:26]([NH:14][CH:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[C:2]([F:1])([F:15])[F:16])(=[O:28])=[O:27]
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: O=S(=O)(Cl)c1c(F)cc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 101 mg (0.44 mmol) of 2,4,6-trifluorobenzenesulfonyl chloride in 8 mL of pyridine was stirred at room temperature for 2 hours, and warmed at 70° C. for 18 hours. The mixture was then cooled to room temperature and diluted with 1 N aqueous HCl until acidic and extracted with ethyl acetate. The combined organic layers was washed with 1 N aqueous HCl, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was crystallized from ether-hexanes to afford 40 mg (21%) of the title compound as a colorless powder. MS: m/z 423 (M+1).
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:15]1[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[C:13]([F:12])[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=1
Reactant: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1O
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Reaction time: 3 h
Yield: 121.3 %

Procedure:
Dibromoisocyanuric acid (2.25 g) was added at room temperature to a DMF (90 mL) solution of 2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (3.29 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, then washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and silica gel column chromatography (diol, hexane/ethyl acetate) to obtain the title compound (3.15 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[N:15]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]1[CH2:11][NH:12][CH2:13][CH2:14][N:15]1[CH:16]1[CH2:19][O:18][CH2:17]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO[Si](C)(C)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CNCCN1C1COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
Tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (714 mg, 1.847 mmol) was taken up in DCM (8 mL) and TFA (2.85 mL, 36.9 mmol) was added. The reaction was stirred at rt for 30 min. The solvent was removed in vacuo and the material was dissolved in MeOH. The solution was loaded onto an SCX column (3×5 g, benzenesulfonic acid sorbent) and the columns were flushed with MeOH, then 7N NH3/MeOH to release the product. (+/−) 2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(oxetan-3-yl)piperazine (517 mg) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.CO.C[N+]1([O-])CCOCC1>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C=CC(=O)c2ccccc2)cc1
Agent: [Pd]
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The aromatic enone 46 (321 mg, 1.20 mmol) was dissolved in anhydrous THF (6 mL) and anhydrous MeOH (6 ml). Added 2 small scoops of Pd 10% on activated C, placed under an atmosphere of hydrogen and allowed to stir for 2 hours at room temperature. Purged with nitrogen, filtered through Celite and removed solvent by evaporation under vacuum. The benzylic alcohol is reoxidized to the ketone by the following procedure. The crude was taken back in anhydrous CH2Cl2 (10 mL), with 3 Å molecular sieves, TPAP (1 scoop) was added followed by NMO (212 mg, 1.8 mmol). Stirred at room temperature for 30 minutes and filtered through a plug of silica gel. Solvent was evaporated under vacuum and purified by column chromatography using 10% EtOAc/Hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:13][CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cnc[nH]2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(-c2cncn2COCC[Si](C)(C)C)c1
Yield: 57.8 %

Procedure:
Reaction of 5-(3-methoxy-phenyl)-1H-imidazole (500 mg, 2.87 mmol), NaH (60%, 112 mg, 2.79 mmol), and SEMCl (598 uL, 3.35 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (505 mg, 60%) as a brown oil. 1H NMR (300 MHz, CDCl3) δ0.00 (s, 9H), 0.93 (t, 2H, J=7.5 Hz), 3.52 (t, 2H, J=9.0 Hz), 3.87 (s, 3H), 5.30 (s, 2H), 6.80-6.83 (m, 1H), 7.26-7.39 (m, 3H), 7.40 (s, 1H), 7.63 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Cl:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1>>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:17]1[C:12]([Cl:11])=[N:13][CH:14]=[CH:15][N:16]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Clc1nccnc1Cl
Product: O=[N+]([O-])c1ccccc1Nc1nccnc1Cl
Yield: 67.6 %

Procedure:
Starting with 41.4 g of 2-nitroaniline and 35.0 g of 2,3-dichloropyrazine, 39.8 g of the title compound was obtained by the same method as the one described in Production Example 120.
Reaction SMILES: N1(O[C:11](=[O:24])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:25][NH:26][C:27]([NH2:29])=[S:28].C(OC(C)C)(C)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:25][NH:26][C:27]([NH2:29])=[S:28])=[O:24])=[CH:17][CH:16]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCOc1ccc(C(=O)On2nnc3ccccc32)cc1
Reactant: NNC(N)=S
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CCCCCOc1ccc(C(=O)NNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 115.6 %

Procedure:
To a solution of 4-n-pentyloxybenzoic acid benzotriazole-1-yl ester (20 g) in N,N-dimethylformamide (100 ml) was added thiosemicarbazide (6.73 g) and stirred for 7 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-n-pentyloxybenzoyl)-3-thiosemicarbazide (20 g).
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26](=[CH:32]N(C)C)[C:27](OCC)=[O:28])[CH:25]=1)#[N:20].Cl.CCN(C(C)C)C(C)C>CC(O)C>[C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26]2[CH:32]=[N:2][N:1]([C:3]3[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:8])=[CH:5][N:4]=3)[C:27]=2[OH:28])[CH:25]=1)#[N:20]
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)cn1
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnn(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c1
Reaction time: 15 h
Yield: 34.2 %

Procedure:
Combined 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (107 mg, 0.427 mmol) and ethyl 2-(4-cyano-1H-pyrazol-1-yl)-3-(dimethylamino)acrylate (100 mg, 0.427 mmol) in 2-propanol (1423 μl) and treated with 1.85N HCl (841 mg, 0.427 mmol). The resulting clear mixture was stirred overnight (15 h) and then Hunig's base (297 μl, 1.708 mmol) was added and the reaction was stirred at ambient temperature for 2.5 h. The reaction mixture was then concentrated in vacuo and purified using HPLC (20-95% ACN in water, TFA-buffered). Product-containing fractions were concentrated in vacuo to give a solid (volume ˜20 mL). The solid was filtered and dried in vacuum to give the title compound (57.4 mg, 34.2% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (qd, J=12.21, 4.29 Hz, 2H) 1.62 (d, J=12.88 Hz, 2H) 1.81 (m, J=10.96, 7.29, 3.76, 3.76 Hz, 1H) 3.20 (t, 2H) 3.27 (t, J=10.86 Hz, 2H) 3.86 (dd, J=11.24, 2.65 Hz, 2H) 8.29 (s, 1H) 8.42 (br. s., 3H) 8.74 (t, J=5.68 Hz, 1H) 8.93 (s, 2H) 13.41 (br. s., 1H). MS m/z [M+H]+394.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([OH:20])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH3:37]I>CS(C)=O.CCOCC>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH:18]([O:20][CH3:37])[CH3:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(C)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 0.026 g (0.057 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidine (diastereomer 2), 0.012 mg (0.23 mmol) of KOH and 0.0042 mL (0.068 mmol) of methyliodide in 1 mL of DMSO was stirred at rt for 30 min. The reaction mixture was diluted with ether and washed with sat'd NaHCO3 and NaCl solutions. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated and purified by chromatography (silica, hexanes:ethylacetate:(2N NH3 in MeOH), 10:10:1) to give the title compound. 1H NMR (CDCl3) δ (key peaks) 7.88-7.91(m, 3H), 7.45-7.55 (m, 4H), 7.20 and 7.10 (d of d, 2H, J=5.5, 8.5 Hz), 7.00 and 6.95 (t, 2H, J=9.0 Hz), 3.40 and 3.24 (s, 3H) 1.25 and 1.02 (d, 3H, J=6.5 Hz), Mass Spectrum (ESI) m/e=475 (M+1).