Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([O:21]C(C)C)=[O:20])[N:13]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].C1COCC1.[Li+].[OH-].Cl>O>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20])[N:13]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
A 25-mL, 3-necked, round-bottomed flask was charged with a solution of (Z)-isopropyl 3-(3-(4-chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (1.33 g) in 1:1 THF:water (26 mL). The solution was treated with solid LiOH (0.53 g, 4 eq.) and stirred at room temperature for 4 h before being diluted with 400 ml water, acidified to pH=2-3 with dilute aqueous HCl, and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 0.8 g of crude compound (yield: 66%).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:10]([CH:11]=[O:12])=[C:9]([Cl:13])[N:8]=[CH:7][N:6]=1.O>O1CCCC1>[Cl:4][C:5]1[C:10]([CH:11]([OH:12])[CH3:1])=[C:9]([Cl:13])[N:8]=[CH:7][N:6]=1
Reactant: C[Mg]Br
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1c(Cl)ncnc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
Methylmagnesium bromide solution (1.4 M in toluene/tetrahydrofuran (75:25); 2.4 mL, 3.4 mmol) was added to a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 500 mg, 2.8 mmol) in tetrahydrofuran at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. Water was added and the mixture was extracted with ethyl acetate (3×25 mL). The organic layers were washed with water and brine, dried (sodium sulfate), filtered, and evaporated to give 1-(4,6-dichloro-pyrimidin-5-yl)-ethanol (540 mg, 100%) which was used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.19 (d, 3H, J=6.3 Hz), 2.62 (br s, 1H), 5.48-5.54 (m, 1H), 8.68 (s, 1H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[Br:10][CH:11]([CH3:20])[C:12]([NH:14][C:15]1[CH:19]=[CH:18][O:17][N:16]=1)=[O:13]>C(Cl)(Cl)Cl.C(#N)C>[Br-:10].[OH:9][C@@H:3]1[CH:4]2[CH2:7][CH2:8][N+:1]([CH:11]([C:12](=[O:13])[NH:14][C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[CH3:20])([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(Br)C(=O)Nc1ccon1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C(=O)Nc1ccon1)[N+]12CCC(CC1)[C@@H](O)C2
Product: [Br-]
Temperature: 90 °C

Procedure:
To a stirred solution of (R)-1-aza-bicyclo[2.2.2]octan-3-ol (0.267 g, 2.1 mmol) in chloroform/acetonitrile (1:1) (4 ml) is added 2-bromo-N-isoxazol-3-yl-propionamide [G(i)](0.5 g, 2.28 mmol) and the reaction mixture heated in a microwave at 90° C. for 3 hours. Purification using C-18 reverse phase column chromatography (eluent: water-acetonitrile) yields the titled compound.
Reaction SMILES: ON1C(=O)CCC1=O.[NH:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][C:11]([O:13]N1C(=O)CCC1=O)=O.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].C(N(CC)CC)C>CS(C)=O.O>[NH:9]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:10][C:11]([NH:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30])=[O:13]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h
Yield: 41.5 %

Procedure:
Boc-Gly-Ala-OH was prepared by an N-hydroxysuccinimide coupling procedure. Boc-Gly-OSu (7.67 g, 28.2 mmol) was dissolved in 10 mL of dimethylsulfoxide, and the resulting solution was added to a solution consisting of H-Ala-OH (3.76 g, 42.3 mmol) and triethylamine (5.89 mL, 42.3 mmol) in 20 mL of water. After stirring overnight, a precipitate was removed by filtration. The remaining solution was diluted with water and then acidified with hydrochloric acid. An aqueous phase separated from which product was extracted by addition of ethyl acetate. The ethyl acetate extract was washed with 0.2N hydrochloric acid and then saturated sodium chloride prepared in 0.2N hydrochloric acid. The washed ethyl acetate solution was then dried over sodium sulfate and filtered. Solvent was then evaporated, leaving a foamy product, which was crystallized from ethyl acetate:hexane to yield 2.88 g of Boc-Gly-Ala-OH (m.p. 128°-130°).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3=[N:16][CH:17]=[N:18][C:19]([NH:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:14]3[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].BrC1C=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30]N=1.C(=O)([O-])[O-].[K+].[K+].[CH3:44][N:45]([CH:47]=O)C>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3=[N:16][CH:17]=[N:18][C:19]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:44]5[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:36])[F:35])=[CH:47][N:45]=5)[CH2:23][CH2:22]4)=[C:14]3[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(NC4CCNCC4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1ccc(-n2ncc3c(NC4CCN(c5ccc(C(F)(F)F)cn5)CC4)ncnc32)cc1
Temperature: 165 °C
Yield: 32 %

Procedure:
A mixture of [1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-4-yl-amine (100 mg, 0.24 mmol), 2-bromo-4-trifluoromethylpyridine (166 mg, 0.73 mmol), and potassium carbonate (102 mg, 0.73 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 20 minutes at 165° C. The crude mixture was purified by HPLC to provide compound A128 as a white solid (41 mg, 32%). Exact mass calculated for C23H22F3N7O2S 517.15, found 518.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([CH2:14][C:15](OC)=[O:16])(=O)[CH2:10][CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCO>[CH3:8][C:7]1[C:2]2=[N:1][C:9]([CH2:10][CH2:11][CH3:12])=[CH:14][C:15](=[O:16])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(=O)CC(=O)OC
Reactant: Cc1cccnc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1cc(=O)n2cccc(C)c2n1
Temperature: -30 °C

Procedure:
A solution of 54.0g of 2-amino-3-methylpyridine, 144.0g of methyl butyrylacetate, 5.0g of p-toluenesulfonic acid, and 750ml of ethylene glycol monomethyl ether is heated in a nitrogen atmosphere, under reflux, for 60 hours. The solution is concentrated to dryness in vacuo, and the residual oil extracted with two 250ml portions of pentane. The pentane solution is concentrated to a volume of 250ml and cooled at -30°C to yield the title compound, melting point 59°-60°C.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[H-].[Na+].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14]>COCCOC.O>[Si:17]([O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][OH:10])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: OCc1ccccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1CO
Reaction time: 1 h

Procedure:
To a solution of 14.074 g (101.86 mM) of 1,2-benzenedimethanol in 100 ml of 1,2-dimethoxyethane was added 4.07 g (102 mM) of a liquid paraffin suspension of 60% sodium hydride at room temperature and the mixture was stirred at the prevailing temperature for one hour. To this reaction mixture was added a solution of 15.4 g (102 mM) of tert-butylchlorodimethylsilane in 50 ml of 1,2-dimethoxyethane dropwise, and the mixture was stirred at room temperature overnight. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 3/1) to provide the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][CH2:17][CH3:18])[C:7](=[CH:14][NH2:15])[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:19]N1C(=O)CCC1=O>N1C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:16][CH2:17][CH3:18])[C:7](=[CH:14][NH2:15])[C:8]2[CH:13]=[C:12]([Cl:19])[S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=Nc2sccc2C(=CN)N1CCC
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCCCC1=Nc2sc(Cl)cc2C(=CN)N1CCC
Temperature: 70 °C

Procedure:
In a sulfonation flask, 0.92 g (3.5 mmol) (2-butyl-3-propyl-3H-thieno [2,3-d] pyrimidine-4-ylidene)methylamine are dissolved in 10 ml of absolute pyridine and heated up to 70° C. Then 0.71 g (5.3 mmol) N-chlorosuccinimide are added and the resulting mixture is heated for 1 h at 70° C. After completion of the reaction, pyridine is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed several times with water and after drying of the organic phase with Na2SO4, the solvent is removed in vacuum. The raw material is purified by column chromatography over silica gel (eluant: hexane/THF 2:1). Yield: 0.95 g of (2-butyl-6-chloro-3-propyl-3H-thieno [2,3-d]pyrimidin-4-ylidene) methylamine in the form of a brown oil (1H-NMR-data see table 5).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=O)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].COC(NS([NH3+])(=O)=O)=O.O>O1CCCC1>[N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]#[N:10])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: NC(=O)c1ccccc1-n1cnnn1
Agent: COC(=O)NS([NH3+])(=O)=O
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1-n1cnnn1

Procedure:
To a solution of 2-Tetrazol-1-yl-benzamide (1.5 g, 7.9 mmol) in tetrahydrofuran (50 ml) was added (methoxycarbonylsulfamoyl)ammonium hydroxide, inner salt (2.8 g, 11.8 mmol) in three portions over 1.5 h. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine. Drying and solvent evaporation gave 2-Tetrazol-1-yl-benzonitrile; 1H NMR (CDCl3, 400 MHz) δ 9.27 (s, 1H), 7.90 (m, 3H), 7.72 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]([C:8]2[NH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]([C:8]2[N:12]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:11]=[C:10]([C:13]([F:14])([F:15])[F:16])[N:9]=2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cnc(-c2ncc(Br)cc2Cl)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In N,N-dimethylformamide (13 mL) was dissolved 5-bromo-3-chloro-2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (1.27 g), 60% sodium hydride (187 mg) was added to the solution under ice-cooling, and after raising the mixture to room temperature, the mixture was stirred for 1 hour. The reaction mixture was ice-cooled, 2-(trimethylsilyl)ethoxymethyl chloride (1.03 mL) was added to the mixture, and after raising the mixture to room temperature, the mixture was stirred for 1 hour. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 95:5) to obtain 5-bromo-3-chloro-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.56 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][C:5]1=[O:14])[C:2]#[CH:3].I[C:16]1[CH:28]=[CH:27][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[N:21]1([CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:3]#[C:2][CH2:1][N:4]3[CH2:8][C:7]4([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]4)[O:6][C:5]3=[O:14])=[CH:28][CH:27]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: Ic1ccc(CN2CCOCC2)cc1
Reactant: C#CCN1CC2(CCCCC2)OC1=O
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1OC2(CCCCC2)CN1CC#Cc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
3-Prop-2-ynyl-1-oxa-3-aza-spiro[4.5]decan-2-one(55 mg, 0.284 mmol), 4-(4-iodo-benzyl)-morpholine(95 mg, 0.313 mmol), tetrakis(triphenylphosphine)palladium (17 mg, 0.0142 mmol), copper iodide (6 mg, 0.0284 mmol) and triethylamine (0.12 mL, 0.853 mmol) were mixed in acetonitrile (1 mL) under argon. The reaction mixture was stirred at room temperature for 1 hour and then diluted with dichloromethane (6 mL). The mixture was washed with water (4 mL), washed with brine (4 mL), dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 25% ethyl acetate in hexanes. The isolated product was treated with 2M hydrochloric acid in diethyl ether to make the hydrochloric acid salt. The salt was then dissolved in water, washed with hexanes and the aqueous phase then made alkaline using aqueous saturated sodium bicarbonate. The aqueous mixture was then extracted with dichloromethane and the organic phase dried over sodium sulfate and concentrated to give the product as an off-white solid (43 mg, 41%). 1H NMR (300 MHz, CDCl3): δ 7.38 (d, 2H), 7.29 (d, 2H), 4.31 (s, 2H), 3.71 (t, 4H), 3.49 (s, 2H), 3.4 (s, 2H), 2.43 (t, 4H), 1.83 (m, 4H), 1.54 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][C:21]#[C:22][CH3:23])[CH:18]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClC(Cl)C>[C:9]([O:13][C:14]([NH:16][CH:17]([CH2:20][C:21]#[C:22][CH3:23])[CH2:18][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1cccc(Cl)c1
Reactant: CC#CCC(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC#CCC(CNc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 3-chloroaniline (4.33 mL, 40.9 mmol), the product from Step K (ca. 41 mmol), and crushed 4 Å molecular sieves (10 g) in dichloroethane (100 mL) under nitrogen was added sodium triacetoxyborohydride (12.9 g, 61.5 mmol). The reaction was stirred for one hour, then warmed to room temperature. After 3 hours, the solution was poured into EtOAc and washed with water, sat. NaHCO3 soln. and brine. The solution was dried over sodium sulfate and concentrated in vacuo to provide the crude product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH2:30])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)(=[O:3])[CH3:2].Br[CH2:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].CN(C)[C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][C:53]=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:30]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=1)[CH2:32][C:33](=[O:34])[O:35][CH2:45][C:54]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(NC(C)=O)c1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCOc1cc(NC(C)=O)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Yield: 16 %

Procedure:
A mixture of 1.1 g (2.63 mmol) of 3-(acetylamino)-5-(octadecyloxy)benzenamine, 4.2 ml (26 mmol) of benzyl bromoacetate, 1.4 g (6.6 mmol) of 1,8-bis-(dimethylamino)naphthalene and 0.4 g (2.63 mmol) of sodium iodide in 40 ml of acetonitrile and 5 ml of DMF was stirred at reflux for 48 hours. The solvents were removed at reduced pressure and the residue was purified by HPLC using 35% ethyl acetate-hexane to give 0.3 g (16% yield, mp 89°-90°) of N-[3-(acetylamino)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine benzyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([Zn]CC)[CH3:26]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:11][CH3:12])[C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([CH2:25][CH3:26])=[CH:3][C:4]=1[C:15]([F:18])([F:17])[F:16])[CH3:10]
Reactant: CC[Zn]CC
Reactant: CCN(CC)C(=O)c1ccc(Cl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1ccc(C(=O)N(CC)CC)c(C(F)(F)F)c1
Temperature: 120 °C
Yield: 75 %

Procedure:
To a solution of 4-chloro-N,N-diethyl-2-(trifluoromethyl)benzamide (5.04 g, 18 mmol) in 100 mL of N,N-dimethylformamide was added potassium carbonate (6.2 g, 45 mmol) and diethylzinc (29.5 mL of a 1.1 M solution in toluene, 32.4 mmol). The mixture was degassed and then there was added POPd (Combiphos) (0.27 g, 0.54 mmol). The resulting solution was heated at 120° C. in a sealed tube for 18 h. The mixture was allowed to cool and was diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concnentrated in vacuo. The residue was purified (ISCO, elution with 0-25% EtOAc/hexane) to afford 3.7 g (75%) of the title compound as an oil. LRMS (ESI): 274.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17](C=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH2:28]([NH:30][NH:31][C:32]([NH2:34])=[O:33])C.[CH2:35](O)[CH3:36]>C(O)(=O)C>[CH2:35]([N:31]([C:32]([NH2:34])=[O:33])[N:30]=[CH:28][C:17]1[CH:20]=[CH:21][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:23]([F:25])([F:24])[F:26])[CH2:13][N:12]=2)=[CH:15][C:16]=1[CH3:22])[CH3:36]
Reactant: CCNNC(N)=O
Reactant: CCO
Reactant: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Agent: Cl
Solvent: CC(=O)O
Product: CCN(N=Cc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)C(N)=O
Temperature: 70 °C
Yield: 60 %

Procedure:
A mixture of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzaldehyde (208 mg, 0.520 mmol) and ethyl semicarbazide hydrochloride (109 mg 0.780 mmol) in ethanol (5 mL) and glacial acetic acid (0.1 mL) was heated at 70° C. for 4 h. After cooling, the mixture was concentrated in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (151 mg, 60%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:15][O:14][C:12](=[O:13])[C@@H:11]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Yield: 89.1 %

Procedure:
A solution of 2.48 g (10.00 mmol) of methyl (S)-4-(tert-butyldimethylsilyloxy)-2-hydroxybutanoate (J. Am. Chem. Soc. 2005 127, 1090-1091) in 50 ml of CH2Cl2 was treated with 2.09 ml (15.00 mmol, 1.5 eq) of triethylamine and at 0° C. during 5 min with 0.82 ml (10.50 mmol, 1.051 eq) of methanesulfonyl chloride. After 1 h at 0° C. the reaction was partitioned between 10% aq KH2PO4/Et2O (×3), the organic phases were washed with sat. aq. NaHCO3 solution (freshly prepared) and 10% aq. NaCl solution, dried over Na2SO4 and evaporated to give 2.91 g (89%) of the title compound as yellow oil. MS: 327.1 (MH+).
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:9]2)[CH:4]=1>C(O)C.[Pd]>[ClH:1].[Cl-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:9]2)[CH2:4]1
Reactant: C[n+]1ccn(C2CCN(c3ccc([N+](=O)[O-])cc3)C2)c1
Agent: [Pd]
Agent: [Cl-]
Solvent: CCO
Product: C[NH+]1C=CN(C2CCN(c3ccc(N)cc3)C2)C1
Product: Cl

Procedure:
16 g (0.0518 mol) of the preceding derivative (4) dissolved in 600 ml of ethanol was hydrogenated in the presence of palladium-on-charcoal under a hydrogen pressure of 8 bar. After filtering off the catalyst, the expected derivative (5) was isolated in the form of the hydrochloride.
Reaction SMILES: [CH2:1]([C@@:4]1([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C[NH:39][S:40]([CH:43]1[CH2:45][CH2:44]1)(=[O:42])=[O:41]>>[CH2:1]([C@@:4]1([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:39][S:40]([CH:43]2[CH2:45][CH2:44]2)(=[O:42])=[O:41])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: CNS(=O)(=O)C1CC1
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C2CC2)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one (Example 414, Step B) and N-methylcyclopropanesulfonamide by a procedure similar to the one described in Example 201, Step A. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil. Mass Spectrum (ESI) m/z=665.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=1.Cl>CS(C)=O.C(O)C>[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:1][C:2]2[NH:6][N:5]=[N:4][N:3]=2)=[O:16])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=1
Reactant: COC(=O)c1ccc(OC)cc1OC(C)C
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2nnn[nH]2)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.0 g (35.3 mmol) of anhydrous 5-aminotetrazole in 20 ml of dimethyl sulfoxide is added dropwise to a 15° to 20° C. slurry of 2.8 g (70.0 mmol) of 60% NaH (oil dispersion) in 75 ml of dimethyl sulfoxide under nitrogen atmosphere. The resulting mixture is stirred at 25° C. for 2.5 hours. A solution of 6.50 g (28.98 mmol) of methyl 4-methoxy-2-(1-methylethoxy)benzoate in 25 ml of dimethyl sulfoxide is added dropwise to the reaction and stirred at 25° C. for 18 hours. The reaction is poured onto 600 g of ice-water and the resulting aqueous solution is acidified with aqueous 10% HCl. The product is isolated by vacuum filtration and recrystallization from 95% ethanol gives 1.90 g (8.03 g theoretical, 24%) of the analytically pure 4-methoxy-2-(1-methylethoxy)-N-1H-tetrazol-5-ylbenzamide as fine, white needles having a melting point of 212° -213° C.