Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C@H:3]([CH2:19][CH2:20][CH3:21])[CH2:4][C:5]([N:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:9][C:8]1=[O:18])=[O:6].[CH3:22]I>C1COCC1>[CH3:22][C@H:4]([C@H:3]([CH3:2])[CH2:19][CH2:20][CH3:21])[C:5]([N:7]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:9][C:8]1=[O:18])=[O:6]
Reactant: CI
Reactant: CCC[C@@H](C)CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: CCC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a 1M THF solution of Sodium hexamethyldisylamide (16.2 g, 88.3 mmol) at −78° C. was added via canular a 0° C. solution of (R)-3-((R)-3-methyl-hexanoyl)-4-phenyl-oxazolidin-2-one (18.7 g, 67.9 mmol) in 70 mL dry THF. The resulting solution was stirred at −78° C. for 30 minutes. Methyl Iodide (48.2 g, 339.5 mmol) was added and stirring at −78° C. was continued for 4 hours. The reaction was quenched with saturated ammonium chloride solution, extracted into CH2Cl2 and washed with 1M sodium Bisulfite. The solution was dried over MgSO4, concentrated and chromatographed in 10% ethylacetate in hexane to give the titled compound (11.1 g, 56.5% yield) as an oil. MS, m/z (relative intensity): 1H NMR (400 MHz, CDCl3) δ ppm 0.8 (t, J=7.0 Hz, 3H) 0.9 (d, J=6.6 Hz, 3H) 1.0 (d, J=6.8 Hz, 3H) 1.0 (d, J=8.5 Hz, 1H) 1.1 (m, 1H) 1.4 (m, 1H) 1.7 (m, 1H) 3.7 (m, 1H) 4.2 (dd, J=8.8, 3.4 Hz, 1H) 4.6 (t, J=8.7 Hz, 1H) 5.4 (dd, J=8.7, 3.3 Hz, 1H) 7.2 (m, 2H) 7.3 (m, 3H). MS, m/z (relative intensity):290 [M+1H, 100%].
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:19]([OH:20])[C@H:18]([OH:21])[C@H:13]2[NH:14][C:15](=[O:17])[O:16][C@H:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.CCOC(C)=O>[C:22]([O:21][C@@H:18]1[C@H:13]2[NH:14][C:15](=[O:17])[O:16][C@H:12]2[CH2:11][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C@H:19]1[O:20][C:9](=[O:8])[C:10]1[CH:19]=[CH:18][CH:13]=[CH:12][CH:11]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 178.8 %

Procedure:
To a solution of (3aR,4R,5R,6R,7aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroxyhexahydrobenzo[d]oxazol-2(3H)-one (2.21 g, 7.00 mmol) and 4-dimethylaminopyridine (30 mg, 0.24 mmol) in pyridine (20 mL) at 0° C. was added benzoyl chloride (3.92 g, 27.9 mmol) dropwise. The mixture was stirred at room temperature for 20 h. The reaction was diluted with EtOAc (300 mL), washed with saturated aqueous NaHCO3 water (2×150 mL), 0.5 N HCl (2×100 mL) and brine and dried over MgSO4. The solvent was evaporated to give the crude product. This was purified by basic alumina column, eluted with 10-30% EtOAc in hexanes to provide (3aS,4R,5R,6R,7aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (3.29 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.92-7.97 (m, 4H), 7.49-7.53 (m, 2H), 7.35-7.39 (m, 4H), 6.07 (s, 1H), 5.53 (t, J=10.1 Hz, 1H), 5.13 (dd, J=9.6 Hz, 6.6 Hz, 1H), 4.91-4.94 (m, 1H), 3.89 (t, J=7.0 Hz, 1H), 3.79 (dd, J=10.0 Hz, 4.0 Hz, 1H), 3.61 (dd, J=10.0 Hz, 2.6 Hz, 1H), 2.40 (dt, J=15.5 Hz, 3.0 Hz, 1H), 2.27-2.36 (m, 1H), 2.03-2.11 (m, 1H), 0.87 (s, 9H), −0.03 (s, 3H), −0.07 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Br:18])[C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[CH:16][C:17]=1[Br:18])[C:22]([CH:19]1[CH2:21][CH2:20]1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: N#Cc1ccc(Br)c(CNCc2ccccc2)c1
Product: N#Cc1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
3-(Benzylamino-methyl)-4-bromo-benzonitrile and cyclopropanecarbonyl chloride were reacted as described in Example 2, Step 3 to provide cyclopropanecarboxylic acid benzyl-(2-bromo-5-cyano-benzyl)-amide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([CH2:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:17]([N+:30]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn].Cl.C([O-])(O)=O.[Na+]>CO>[NH2:30][C:17]1[C:18]([CH2:20][S:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[N:19][C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)nc1CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)nc1CS(=O)(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
A stirred mixture of 6-(4-benzylpiperazin-1-yl)-3-nitro-2-[(phenylsulfonyl)-methyl]pyridine (1.81 g, 4.00 mmol) and granular tin (2.09 g, 17.6 mmol) in methanol is treated with conc. HCl, heated under nitrogen at 50° C. for 7 h, stirred at ambient temperatures for 16 h, poured into aqueous NaHCO3 and extracted with EtOAc. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, EtOAc as eluent) to afford the title compound as a yellow solid, 1.47 g (87% yield), mp 175-176° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([CH2:57][C:58]1[O:59][CH:60]=[CH:61][CH:62]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][CH2:57][C:58]2[O:59][CH:60]=[CH:61][CH:62]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C=NCc1ccco1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccco1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2-(isocyanatomethyl)furan as the starting materials in 40% yield. LCMS for C30H33ClN7O3 (M+H)+: m/z=574.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([O:33][C:34]1[CH:35]=[C:36]([CH:40]([NH:55][CH3:56])[CH2:41][N:42]2[CH2:46][CH2:45][CH:44]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:43]2)[CH:37]=[CH:38][CH:39]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH:5]1[O:1][C:2]([CH2:10][C:11]([N:55]([CH:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:35]=2)[CH2:41][N:42]2[CH2:46][CH2:45][CH:44]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:49])[CH3:50])[CH2:43]2)[CH3:56])=[O:13])=[C:3]2[CH:4]=[CH:9][CH:8]=[CH:7][C:6]=12
Reactant: O=C(O)Cc1cc2ccccc2o1
Reactant: CNC(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCc2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1occ2ccccc12)C(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of 3-benzofuran acetic acid (1.446 g, 8.01 mmol) in THF (5 mL) at room temperature was added carbonyldiimidazole (1.31 g, 8.09 mmol). After stirring for 2 hours, a solution of Example 5 (2.68 g, 6.09 mmol) in THF (10 mL) was added. After stirring for 16 hours, all volatiles were removed in vacuo and the residue dissolved in ethyl acetate (300 mL). This solution was washed with saturated sodium hydrogencarbonate solution, then water, then saturated NaCl solution (50 mL of each). After drying (MgSO4) and concentration in vacuo, column chromatography (60:40 ethyl acetate:heptane) gave the desired product, 3.04 g, 83%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:15][C:16]([OH:18])=[O:17].O>CS(C)=O>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][O:9][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: O=C(O)CCl
Reactant: CSc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(CCOCC(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
6.27 g of 4-methylthiophenethyl alcohol in 100 ml of dimethyl sulfoxide were treated with 3.58 g of a 50% sodium hydride dispersion in mineral oil and the mixture was stirred at 60° C. for 10 minutes. 3.53 g of chloroacetic acid were added and the heating was continued at 80° C. for 3 hours while stirring. The mixture was cooled, poured into water and washed with ethyl acetate. The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was separated, washed well with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was recrystallized from toluene/hexane to give 3.89 g (46%) of 2-(4-methylthiophenyl)ethoxyacetic acid of melting 58°-60° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][N:4]1[C:10](=[O:11])[CH2:9][C:8]2[CH:12]=[CH:13][CH2:14][CH2:15][C:7]=2[CH2:6][CH2:5]1.[OH:17][N:18]=C1C2C=CCCC=2CCN(C)C1=O>>[OH:17][N:18]=[C:9]1[C:8]2[CH:12]=[CH:13][CH2:14][CH2:15][C:7]=2[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([CH3:16])[CH3:1])[C:10]1=[O:11]
Reactant: CC(C)CN1CCC2=C(C=CCC2)CC1=O
Reactant: CN1CCC2=C(C=CCC2)C(=NO)C1=O
Product: CC(C)CN1CCC2=C(C=CCC2)C(=NO)C1=O

Procedure:
Following the procedure described for Example 7-A (Step B) and using 3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one, 1-hydroxyimino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one was prepared.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=O)=[CH:5][CH:4]=1)[CH3:2].CN(C)C=O.[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCc1ccc(Cc2ccccc2C(=O)O)cc1
Reaction time: 6 h

Procedure:
(b.1) A solution of 2-(4-ethylbenzoyl)benzoic acid in acetic acid (115 ml) and the dimethylformamide (115 ml) containing 10% palladium on carbon (4.9 g) was shaken in a hydrogen atmosphere at 60 p.s.i. for 6 hours. The solution was then filtered and the filtrate was added to water (2000 ml), producing a precipitate of 2-(4-ethylbenzyl)benzoic acid.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].N([O-])=[O:16].[Na+].NC(N)=O.S(=O)(=O)(O)[O-].C1([N+]#N)C=CC=CC=1>S(=O)(=O)(O)O.O>[OH:16][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: O=N[O-]
Reactant: COc1cc2c(cc1N)C(=O)CCC2
Agent: N#[N+]c1ccccc1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc2c(cc1O)C(=O)CCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
7-Amino-6-methoxy-1-tetralone (0.96 g, 5.0 mmol) was dissolved in a mixture of sulfuric acid (96%, 2.1 mL) and H2O (3.9 mL). The solution was cooled to 0° C., and ice (5.0 g) was added resulting in the crystallization of a solid. A solution of NaNO2 (0.48 g, 7 mmol) in H2O (5 mL) was added dropwise at 0° C. After the solution had been stirred for an additional 10 min, a few crystals of urea were added to decompose any excess sodium nitrite. To the cold solution of benzenediazonium bisulfate was added a solution of cupric nitrate trihydrate (19.0 g, 78.6 mmol) in H2O (150 mL) at 0° C. With vigorous stirring, cuprous oxide (0.72 g, 5.0 mmol) was added to the solution. The solution was stirred for 10 more min, and TLC was employed to monitor the reaction. The mixture was partitioned between ethyl ether and water. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. 7-Hydroxy-6-methoxy-1-tetralone (0.22 g, 1.15 mmol, 23%) was obtained following purification by column chromatography. 1H-NMR (CDCl3, 300 MHz) 2.09 (m, 2H), 2.59 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 5.60 (s, 1H), 6.66 (s, 1H), 7.56 (s, 1H). 13C-NMR (CDCl3, 75 MHz) 23.6, 29.5, 38.6, 56.0, 109.6, 112.2, 126.5, 138.4, 144.4, 151.0, 197.2.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][C:39](O)=[C:40]([O:43][CH3:44])[CH:41]=3)[N:36]=[CH:35][N:34]=2)=[C:30]([F:48])[CH:29]=1.C(P(CCCC)CCCC)CCC.Cl>C(Cl)Cl.CC(C)=O.CO.C(Cl)Cl>[ClH:27].[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][C:39]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:40]([O:43][CH3:44])[CH:41]=3)[N:36]=[CH:35][N:34]=2)=[C:30]([F:48])[CH:29]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CS(=O)(=O)CCCO
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCS(C)(=O)=O
Reaction time: 18 h
Yield: 57.2 %

Procedure:
3-(Methylsulphonyl)propan-1-ol (0.6 g, 4.3 mmol) followed by 1,1′-(azodicarbonyl)dipiperidine (4.2 g, 16 mmol) in portions were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.5 g, 4.7 mmol), (prepared as described for the starting material in Example 2), and tributylphosphine (4.0 ml, 16 mmol) in methylene chloride (50 ml) under nitrogen. The mixture was stirred for 18 hours, the resulting precipitate was collected by filtration and dried to give crude product (1.36g). The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (a gradient from 100/0 to 90/10). The semi-purified product was triturated with acetone and the solid product collected by filtration and dried to give further crude product (0.53 g). The filtrate from the trituration was repurified by column chromatography as before to give freer crude product (0.23 g). The crude products were combined and dissolved in acetone/methanol/methylene chloride and ethereal hydrogen chloride (6 ml of a 1M solution) added. The precipitated product was collected by filtration and recrystalilsed from methanol/methylene chloride/hexane to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3(methylsulphonyl)propoxy)quinazoline hydrochloride (640 mg, 29%).
Reaction SMILES: [CH2:1]([N:5]([C:7]([NH:9][C:10]1[S:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[N:13][N:14]=1)=[O:8])[NH2:6])[CH2:2][CH2:3][CH3:4].[CH2:19]=O.[OH-].[K+]>CO>[CH2:1]([N:5]1[C:7](=[O:8])[N:9]([C:10]2[S:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[N:13][N:14]=2)[CH2:19][NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(N)C(=O)Nc1nnc(S(C)(=O)=O)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1NCN(c2nnc(S(C)(=O)=O)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-n-Butyl-4-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-n-butyl-4-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5]/[C:6](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:7](/[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:27]([O:34][CH2:35][CH2:36]Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:27]([O:34][CH2:35][CH2:36][O:20][C:17]1[CH:16]=[CH:15][C:14](/[C:7](/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH2:5][CH2:4][OH:3])=[CH:19][CH:18]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(O)cc1)c1ccccc1
Reactant: BrCCOCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCC/C(=C(\c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction vessel was charged with toluene (790 ml), 48% aqueous sodium hydroxide (790 ml), tetrabutylammonium bromide (2.12 g, 6.6 mmol) and Z-4-(4-hydroxy-1,2-diphenyl-but-1-enyl)-phenol (50 g, 0.16 mol) prepared by the method described by U.S. Pat. No. 4,996,225. The mixture was refluxed for 30 minutes. Benzyl-(2-bromoethyl)ether (Grobelny D. et al., Tetrahedron Letters 28, 2639-42, 1979) (41.7 g, 0.19 mol) was added to the reaction mixture and the refluxing was continued for 2 hours. Then the mixture was cooled to room temperature, layers were separated and aqueous phase was washed with toluene. Toluene phases were combined, washed with water, dried and evaporated to dryness. The residue was used in the next stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[OH:18].Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45](F)(F)F)=[CH:41][CH:40]=2)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[F:17][C:15]1[CH:14]=[CH:13][C:12]([O:18][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)=[C:11]([CH2:10][CH2:9][N:8]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:30])[CH:16]=1
Reactant: COC(=O)CCCCN(CCc1cc(F)ccc1O)Cc1ccc(C(=O)OC)cc1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: COC(=O)CCCCN(CCc1cc(F)ccc1OCc1ccc(-c2ccc(C)cc2)cc1)Cc1ccc(C(=O)OC)cc1

Procedure:
447 mg (0.93 mmol) of methyl 4-({(5-methoxy-5-oxopentyl)[2-(5-fluoro-2-hydroxyphenyl)ethyl]amino}methyl)benzoate from Ex. XII and 277 mg (1.02 mmol) of 4-(chloromethyl)-4′-(trifluoromethyl)-1,1′-biphenyl are dissolved in 10 ml of acetonitrile. 455 mg (1.40 mmol) of caesium carbonate and a spatula tip of potassium iodide are added, and the mixture is heated at reflux for 48 hours. The suspension is filtered and concentrated and the residue is chromatographed over silica gel using cyclohexane:ethyl acetate (5:1).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])C=CC=CC=1.[CH3:29][C:30]1[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]2[C:38]=1[CH:39]=O>>[CH3:29][C:30]1[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]2[C:38]=1[CH:39]=[CH:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: C[Si](C)(C)CCOC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc2ccccn2c1C=O
Agent: [Cl-]
Product: Cc1nc2ccccn2c1C=COCC[Si](C)(C)C
Yield: 96 %

Procedure:
Following procedures analogous to those described in Example 6 and use triphenyl-(2-trimethylsilanyl-ethoxymethyl) phosphonium chloride, 2-methyl-imidazo[1,2-a]pyridine-3-carbaldehyde was converted into 2-methyl-3-[2-(2-trimethylsilanyl-ethoxy)-vinyl]-imidazo[1,2-a]pyridine (96% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29]>>[C:23]([O:22][C:20]([NH:19][C:15]1[CH:14]=[C:13]([N:12]2[C:3]3[CH:4]=[CH:5][C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:2]=3[NH:1][C:28](=[O:29])[C:27]2=[O:31])[CH:18]=[CH:17][CH:16]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc3c(c2N)CCCC3)c1
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1

Procedure:
1-Amino-2-(3-tert-butoxycarbonylaminophenyl)amino-5,6,7,8-tetrahydronaphthalene and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:15]([C:12]1[CH:13]=[N:14][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)=[N:10][CH:11]=1)=[O:17])(=[O:30])=[O:31]
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Reactant: O=C(O)c1cnc(-c2cc(F)cc(F)c2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cc(F)cc(F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A mixture of 2-(3,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid (118 mg, 0.5 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) in dry DMF (5 mL) is treated with diisopropylethylamine (0.09 mL) and stirred at room temperature for 30 min. A solution of 3-methylsulfamoylbenzylamine (150 mg, 0.75 mmol.) in dry DMF (1 mL) is added and the mixture stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and water. The organic phase is separated and washed with saturated NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 30% EtOAc in DCM to afford 2-(3,5-difluorophenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (125 mg, 62%) as a solid. MS: 419 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (d, 3H), 4.64 (d, 2H), 7.43-7.75 (m, 5H), 7.80 (s, 1H), 8.05 (d, 2H), 9.37 (s, 2H), 9.60 (t, 1H); IC50=49 nM.