Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]1([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1.CO>[C:8]1([CH:14]([CH3:18])[C:15]([O:17][CH3:1])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C(=O)O)c1ccccc1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyl diazomethane (2.0M in hexanes, 40 mL, 80 mmol) was added dropwise to a solution of racemic 2-phenylpropionic acid (10.0 g, 66.6 mmol) in benzene (100 mL) and methanol (20 mL) cooled in an ice bath. After the addition was complete the reaction solution was stirred at room temperature for 2 hours. The solution was then concentrated to give the indicated product. m/z=165.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].[CH:14](OC)=[O:15]>>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][CH:14]=[O:15])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: COC=O
Product: N#CCc1c[nH]c2ccc(NC=O)cc12

Procedure:
A solution of 5-amino-1H-indole-3-acetonitrile (0.5 g) in methyl formate (20 ml) was stirred at room temperature for 24 h. The resulting solid precipitate was filtered off, washed with ether (2×20 ml) and dried in vacuo to give the title compound (0.41 g) as a white microcrystalline solid m.p. 196°-200° (softens 194°).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:35][CH2:36][C:37]1C=CC=[CH:39][C:38]=1OC.Cl>>[ClH:35].[CH3:28][O:27][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:24]=1[CH2:23][S:22][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=1
Reactant: COc1ccccc1CCl
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: COc1ccccc1CSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Yield: 76.6 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-(chloromethyl)-2-methoxybenzene (0.023 mL, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(2-methoxybenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (63.3 mg, 77.3% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 7.79 (d, 1H), 7.57 (m, 2H), 7.49 (d, 1H), 7.45-7.33 (m, 3H), 7.23 (m, 1H), 6.98 (m, 2H), 6.79 (m, 2H), 5.28 (s, 2H), 4.09 (s, 2H), 3.74 (s, 3H), 2.29 (s, 3H); Mass spectrum (apci) m/z=450.0 (100), 359.0 (45), 238.0 (40).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([CH:36]([CH3:38])[CH3:37])=[CH:24][C:10]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1.O.NN>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([CH:36]([CH3:38])[CH3:37])=[CH:24][C:10]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[CH:18]=[CH:17]2)=[S:48])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)c1cc(C(=O)Nc2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: NN
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C(=S)Nc2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Yield: 83 %

Procedure:
Benzamide (A) was treated with Lawesson's reagent (3.46 g, 8.58 mmol, 0.6 equiv.) in 80 mL toluene at 110° C. for three hours. The reaction mixture was cooled to 0° C., and treated with hydrazine hydrate (1.50 g, 30 mmol) at 0° C. for 10 minutes to decompose by-product and excess reagent. Normal EtOAc/water workup, followed by recrystallization in EtOAc/hexane yielded 2,4-dibenzyloxy-5-isopropyl-N-(1-methyl-1H-indol-5-yl)-thiobenzamide (B) as yellow solid (6.20 g, 12 mmol, 83%).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]([O:10][CH2:11][CH2:12][OH:13])(=[O:9])[CH:7]=[CH2:8]>C1COCC1>[CH:2]12[CH2:1][CH:5]([CH:7]([C:6]([O:10][CH2:11][CH2:12][OH:13])=[O:9])[CH2:8]1)[CH:4]=[CH:3]2
Reactant: C=CC(=O)OCCO
Reactant: C1=CCC=C1
Solvent: C1CCOC1
Product: O=C(OCCO)C1CC2C=CC1C2
Yield: 81.3 %

Procedure:
Cyclopentadiene (66 g) and 140 g of 2-hydroxyethyl acrylate were dissolved in 500 g of THF solvent. After the reaction at 30° C. for 24 hours, the solvent was removed by rotary evaporator. The residue was distilled under reduced pressure to obtain 148 g of 2-hydroxyethyl 5-norbornene-carboxylate as a mixture of endo and exo (yield: 72%). NMR spectral data of the resulting compound (21) is shown in FIG. 4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=1)([O-:3])=[O:2].[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:16][N:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(NCC(F)(F)F)nc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CC(F)(F)F)c1ccc([N+](=O)[O-])cn1
Temperature: 50 °C
Yield: 110.4 %

Procedure:
A mixture of (5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (230 mg, 1.04 mmol), cesium carbonate (730 mg, 2.07 mmol) and iodomethane (0.59 mL, 4.18 mmol) in DMF (4 mL) was heated in a sealed tube at 50° C. for 3 hr. The reaction mixture was evaporated to dryness and the crude was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to give methyl-(5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (270 mg, crude) as a brown solid, which was directly used in the next step reaction without further purification. LCMS calcd for C8H8F3N3O2 (m/e) 235, obsd 236 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:4]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C=O)ccn1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C=O)cc(Br)n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (2.00 g) in N,N-dimethylformamide (20 mL) was added N-bromosuccinimide (1.56 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:1) to give the title compound as a white solid (yield 2.28 g, 86%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH:12]([N:15](CC)C(C)C)(C)C.CN>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:12][NH2:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Agent: CN
Solvent: C1CCOC1
Product: NCc1c(Br)cccc1[N+](=O)[O-]

Procedure:
A solution of 3-bromo-2-fluoronitrobenzene (1 g) in THF (8.3 ml) is heated in the presence of N,N-diisopropylethylamine (690 μA) and of methylamine (2.54 ml) in a microwave reactor (105° C., 30 min). The reaction medium is concentrated and then taken up in ethyl acetate, and then washed with water and then with brine. The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. (2-Bromo-6-nitrophenyl)methylamine (1 g) is isolated in the form of an orange solid, and is used as it is in the next stage.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:16]([NH:18][C:19](=[O:20])[C:14]=12)=[O:17]>C1(C)C(C)=CC=CC=1>[N:2]1([O:1][CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][CH:21]=[C:15]3[C:16]([NH:18][C:19](=[O:20])[C:14]=23)=[O:17])[CH:6]=[CH:5][CH:4]=[N:3]1
Reactant: On1cccn1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1NC(=O)c2c(CCCOn3cccn3)cccc21
Reaction time: 1 h
Yield: 101.3 %

Procedure:
26 g of 1-hydroxypyrazole are added to a suspension of 10 g of sodium hydride (80 percent strength in oil) in 500 ml of xylene. The mixture is stirred for 1 hour, after which 84 g of 3-bromopropylphthalimide are added and the mixture is refluxed for 2 hours. After cooling, the mixture is filtered, the filtrate is evaporated down, the crystalline residue is suspended in diethyl ether and the product is filtered off under suction. 85 g of the title compound of melting point 116°-118° C. are obtained.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(337 mg, 1.0 mmol) and 4-bromobenzenesulfonamide [CAS 701-34-8] (307 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (150 mg, 30%). MS (ISP) 493.2 [(M+H)+]; mp 254° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:31].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[C:15]([NH2:31])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Reaction time: 3 h

Procedure:
A solution of N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (6.63 g, 17.0 mmol) in 90 mL of CHCl3 was treated with MPCBA (6.29 g, 25.5 mmol, 70%). After 3 h, HPLC and LC/MS indicated complete conversion to the intermediate 5-N-oxide. The reaction mixture was then treated with concentrated ammonium hydroxide solution (30 mL, 30%). The biphasic reaction mixture was stirred vigorously while p-toluenesulfonyl chloride (3.40 g, 17.9 mmol) was added. After 45 min, LC/MS indicated complete conversion to the 4-amine. The reaction mixture was diluted with 30 mL of water and 45 mL of CHCl3 and separated. The organic portion was washed with 10% Na2CO3 solution (50 mL) and water (50 mL). The combined aqueous portions were then back-extracted with CHCl3 (25 mL). The combined organic portions were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield a tan solid. The solid was purified by chromatography (SiO2, 96:4 CHCl3:MeOH) to give 5.90 g of 7-benzyloxy-2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as a light tan solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][C:18]([CH3:22])([CH3:23])[C:19]([O:1][CH2:2][C:3]2[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=2)=[O:20])=[CH:15][CH:14]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: COC(=O)c1cnc(CO)s1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(COC(=O)C(C)(C)Oc2ccc(Cl)cc2)s1

Procedure:
Using the procedure of Example 3, methyl 2-hydroxymethyl-thiazole-5-carboxylate and p-chlorophenoxy-isobutyric acid chloride were reacted in toluene and triethylamine to obtain methyl 2-[α-(p-chlorophenoxy)-α,α-dimethylacetoxymethyl]-thiazole-5-carboxylate melting at 80° C.
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:64][O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:21][O:22][C:23](=[O:63])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]1[CH2:36][CH:35]([OH:37])[CH2:34][CH:33]1[CH:38]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[O:39][CH:40]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:84]1(=[O:90])[O:89][C:87](=[O:88])[CH2:86][CH2:85]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH:40]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)[O:39][CH:38]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:33]2[N:32]([C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]([O:22][CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:64][O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[O:63])[CH2:36][CH:35]([O:37][C:84](=[O:90])[CH2:85][CH2:86][C:87]([OH:89])=[O:88])[CH2:34]2)=[CH:46][CH:45]=1
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1)OCCCCCCCCCCCCCCCCCC
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCC(COC(=O)NCCCCCC(=O)N1CC(OC(=O)CCC(=O)O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1)OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
Referring to scheme 5, Compound 12 (5.6 g, 4.8 mmol) was mixed with succinic anhydride (0.727 g, 7.26 mmol) and DMAP (0.062 g, 0.5 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (20 mL), triethylamine (1.52 g, 2 mL, 15 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (50 mL) and washed with ice cold aqueous citric acid (5% wt., 50 mL) and water (2×50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 14 as white solid (2.85 g, 47% yield; Rf=0.65 in 10% MeOH/CHCl3).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[O:18]1[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22].[Si:25]([O:32][CH2:33][C@H:34]([OH:36])[CH3:35])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][CH2:33][C@H:34]([O:36][CH2:20][C@H:19]([OH:18])[C:21]([O:23][CH3:24])=[O:22])[CH3:35])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@@H]1CO1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Product: COC(=O)[C@@H](O)CO[C@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
Magnesium trifluoromethanesulfonate (1.165 g, 3.61 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (1.475 g, 14.45 mmol) and (R)-1-(tert-butyldimethylsilyloxy)propan-2-ol (CAS no. 136918-07-5) (2.75 g, 14.45 mmol) cooled to 10° C. The resulting suspension was stirred at 10° C. for 10 minutes and then warmed to 45° C. and stirred for 2 days. The crude product was purified by flash silica chromatography, eluting with 0 to 30% EtOAc in isohexane to afford the product (1.680 g, 39.8%). 1H NMR (400 MHz, DMSO) δ0.00 (s, 6H), 0.83 (s, 9H), 0.98 (d, 3H), 3.35-3.45 (m, 2H), 3.47-3.65 (m, 3H), 3.66 (s, 3H), 4.09-4.15 (m, 1H), 5.37 (d, 1H).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].CO[C:11]([C:13]1[N:14]=[N:15][N:16]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O>C1(C)C=CC=CC=1>[F:36][C:35]([F:37])([F:38])[C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=1)[CH2:24][N:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:13]([C:11]2[NH:7][CH2:6][CH2:5][N:8]=2)[N:14]=[N:15]1
Reactant: COC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Cn2nnc(C3=NCCN3)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 19 %

Procedure:
To a solution of Me3Al (1.36 mL, 2M soln in toluene) at 0° C. under N2, add ethylenediamine (185 μL, 0.36 mmol) and stir for several minutes warming to RT. Add 1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (750 mg, 1.69 mmol) dissolved in toluene to this solution. Reflux reaction for 3.5 hours at 110° C. Cool to RT and stir for 12 hours. Quench reaction with MeOH (2 mL), add H2O (2 mL) and extract with CH2Cl2 (4 mL×2). Dry over Na2SO4 and concentrate to afford title compound (30 mg, 4%). MS (IS) 440.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:44]=[N+:45]=[N-:46])(C)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)([C:22]2[CH:23]=[CH:24][C:25]([C:26]3[NH:46][N:45]=[N:44][N:27]=3)=[CH:28][CH:29]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C2(c3ccc(C#N)cc3)CCN(Cc3ccccc3)CC2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1cccc(C2(c3ccc(-c4nnn[nH]4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzonitrile (0.24 g, 0.63 mmol) in toluene (5 mL) were added dibutyltin oxide (0.025 g, 0.1 mmol) and trimethylsilyl azide (0.15 g, 1.26 mmol). The reaction mixture was heated for 60 hours. The mixture was then cooled to room temperature and concentrated under vacuum. The residue was dissolved in methanol (5 mL) and then concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (5 mL) and ethyl acetate. The aqueous layer was washed with ethyl acetate (3×10 mL). The combined extracts were dried (MgSO4) and concentrated. Purification by flash chromatography with CH2Cl2/MeOH (9:1) afforded 0.19 g (71% yield) of 1-Benzyl-4-(3-methoxy-phenyl)4-[4-(1H-tetrazol-5-yl)-phenyl]-piperidine. 1HNMR (400 MHz, CD3OD) δ 7.95 (d, 2H), 7.44-7.41 (comp, 7H), 7.23-7.18 (m, 1H), 6.90-6.77 (comp, 2H), 6.76 (d, 1H), 6.70 (d, 1H), 4.21 (s, 2H), 3.64 (s, 3H), 3.30-2.41 (comp, 8H); MS (M+1) 426.2.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1([CH2:17][NH2:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1([CH2:17][NH:18][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:23]3[N:22]=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=3)[CH:27]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: NCC1(N2CCc3ccccc3C2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(N2CCc3ccccc3C2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 30 %

Procedure:
This compound was synthesized from (4-(3,4-dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-yl)methan amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mg, yield 30%). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.91-7.89 (d, J=7.5 Hz, 1H), 7.59-7.55 (t, J=7.8 Hz, 1H), 7.17-7.15 (m, 3H), 7.12-7.07 (m, 2H), 3.96-3.93 (m, 4H), 3.86-3.85 (d, J=4.8 Hz, 2H), 3.74-3.68 (m, 2H), 2.95 (m, 4H), 2.15-2.07 (m, 2H), 1.58-1.55 (m, 2H). MS (ESI) m/z: Calculated for C25H25F3N4O3: 486.19. found: 487.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1([CH:15]=O)[CH2:14][CH2:13]1.C(OC(=O)C)(=O)C.Cl[C:25](Cl)([F:30])[C:26]([O:28][CH3:29])=[O:27]>[Zn].[Cu]Cl.O1CCCC1>[F:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:15][C:12]1([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Yield: 44 %

Procedure:
The method of Example 1 was repeated using zinc powder (1.3 g), copper (I) chloride (0.22 g), molecular sieve 4A (1.6 g), tetrahydrofuran (20 ml), 1-(2-fluoro-4-tri-fluoromethylphenyl)-1-formylcyclopropane (1.39 g), acetic anhydride (0.58 ml) and methyl dichlorofluoroacetate to yield the title compound (0.81 g, 44%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH:17]([C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:38])[CH2:18][NH:19][C:20](=[O:36])[CH2:21][NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24]>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH2:21][C:20]([NH:19][CH2:18][CH:17]([C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:38])[NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:36])(=[O:25])=[O:24]
Reactant: NC(CNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NCC(NC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with N-[2-amino-2-(piperidinocarbonyl)ethyl]-2-(2-naphthalenesulphonamido)-acetamide to give 2-(2-naphthalenesulphonamido)-N-{2-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide in 41% yield, m.p. 200-202° C.;
Reaction SMILES: [CH3:1][NH2:2].[CH:3]([N:6]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[CH2:8][S:7]1(=[O:15])=[O:14])([CH3:5])[CH3:4]>CO>[CH:3]([NH:6][S:7]([CH2:8][C:9](=[O:13])[CH:10]=[C:11]([NH:2][CH3:1])[CH3:12])(=[O:15])=[O:14])([CH3:5])[CH3:4]
Reactant: CN
Reactant: CC1=CC(=O)CS(=O)(=O)N1C(C)C
Solvent: CO
Product: CNC(C)=CC(=O)CS(=O)(=O)NC(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A slow stream of dry methylamine was introduced at 20°-25° during 1 hour into a suspension of 4 g of 2-isopropyl-3-methyl-1,2-thiazin-5(6H)-one 1,1-dioxide in 40 ml of methanol, whereby a clear yellow solution resulted after about 30 minutes. Thereupon, the mixture was stirred further at room temperature for 5 hours, concentrated to dryness under reduced pressure and the crystalline residue was recrystallized from isopropyl. There were obtained 3.8 g of N-isopropyl-4-methylamino-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 83°-85°.