Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C@@H:6]1[O:20][C@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@H:7]1[O:8][C:9](=[O:12])[CH2:10][CH3:11])(=O)CC.[CH3:33][S:34][Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCCl.C(Cl)(Cl)Cl>[C:9]([O:8][C@@H:7]1[C@@H:13]([O:14][C:15](=[O:18])[CH2:16][CH3:17])[C@@H:19]([C@@H:21]([CH2:27][O:28][C:29](=[O:32])[CH2:30][CH3:31])[O:22][C:23](=[O:26])[CH2:24][CH3:25])[O:20][C@H:6]1[S:34][CH3:33])(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](OC(=O)CC)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Reactant: CS[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CCC(=O)OC[C@@H](OC(=O)CC)[C@H]1O[C@@H](SC)[C@H](OC(=O)CC)[C@H]1OC(=O)CC
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
1,2,3,5,6-Penta-O-propanoyl-β-D-glucofuranose (614 mg, 1.3 mmol) was dissolved in 1,2-dichloroethane (5 mL) and cooled to 0° C. (Methylthio)trimethylsilane (567 μL, 4.0 mmol) was added dropwise followed by trimethylsilyl trifluoromethanesulfonate (72 μL, 0.4 mmol). After 20 min at room temperature, the mixture was heated at 50° C. for 3 h, cooled, diluted with CHCl3, washed with 50% aqueous NaHCO3 (30 mL), brine, dried (MgSO4) and concentrated in vacuo. Flash silica chromatography of the residue, eluting with 10% ethyl acetate in petroleum ether, gave methyl 2,3,5,6-tetra-O-propanoyl-1-thio-β-D-glucofuranoside as a colourless solid (470 mg, 81%). A sample was recrystallised from ethanol to give colourless needles, mp 62-63° C. (from EtOH), [α]D22=−50.5 (c 1.0 in CHCl3), (Found: C, 52.7; H, 7.2; S, 7.4. C19H30O9S requires C, 52.5; H, 7.0; S 7.4%); δH (CDCl3) 5.37 (1H, d, J 4.2, 3-H), 5.33 (1H, ddd, J 9.3, 5.1 and 2.5, 5-H), 5.07 (1H, d, J 2.2, 2-H), 5.00 (1H, d, J 2.2, 1-H), 4.62 (1H, dd, J 12.3 and 5.1, 2.5, 6a-H), 4.36 (1H, dd, J 9.3 and 4.2, 4-H), 4.17 (1H, dd, J 12.3 and 5.1, 6b-H), 2.39 (2H, q, J 7.6, CH2), 2.37 (2H, q, J 7.6, CH2), 2.35 (2H, q, J 7.6, CH2), 2.26 (2H, q, J 7.6, CH2), 2.23 (3H, s, SCH3) 1.16 (3H, t, J 7.6, CH3), 1.14 (3H, t, J 7.6, CH3), 1.13 (3H, t, J 7.6, CH3), 1.09 (3H, t, J 7.6, CH3); δC (CDCl3) 174.4, 173.3, 173.1, 173.1 (4×C═O), 89.6 (1-C), 81.6 (2-C), 79.1 (4-C), 74.7 (3-C), 68.4 (5-C), 63.4 (6-C), 27.7 (4×CH2), 9.4, 9.2, 9.2, 9.1 (4×CH3); m/z (FAB) 435.169691 (MH+, C19H31O9S requires 435.168880).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C@H:9]([C@H:11]([CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:12]([OH:15])[CH:13]=[CH2:14])[CH3:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:15][C@H:12]([C@@H:11]([CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[C@@H:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=1)[CH3:10])[CH:13]=[CH2:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=C[C@H](O)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[C@H](OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
To a solution of (3S,4R)-4-((S)-1-((4-methoxybenzyl)oxy)ethyl)-7-methyloct-1-en-3-ol (2.34 g, 7.64 mmol) in DMF (15.3 mL) was added NaH (0.611 g, 15.3 mmol, 60% dispersion in mineral oil) at 0° C. After 20 min, benzyl bromide (2.27 mL, 19.1 mmol) was added and the reaction was stirred at 0° C. for 20 min, warmed to 45° C., and stirred at this temperature for 16 h. The reaction was cooled to room temperature and quenched with sat. aq. NH4Cl (40 mL). The mixture was extracted with Et2O (3×50 mL), and the combined organics were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified using flash column chromatography (120 g SiO2, 0→20% EtOAc/hexanes) to afford the title compound (2.75 g, 6.93 mmol, 91%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.38-7.34 (m, 2H), 7.32-7.25 (m, 3H), 7.22-7.17 (m, 2H), 6.87-6.78 (m, 2H), 5.78 (ddd, J=17.4, 9.9, 7.3 Hz, 1H), 5.27-5.18 (m, 2H), 4.58 (d, J=12.4 Hz, 1H), 4.42 (d, J=11.2 Hz, 1H), 4.29 (d, J=11.2 Hz, 1H), 4.26 (d, J=11.9 Hz, 1H), 4.04-3.96 (m, 1H), 3.77 (s, 3H), 3.64 (p, J=6.3 Hz, 1H), 1.73-1.63 (m, 1H), 1.55-1.42 (m, 2H), 1.43-1.21 (m, 3H), 1.15 (d, J=6.3 Hz, 3H), 0.86 (d, J=6.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 158.92, 139.07, 137.94, 131.19, 129.17, 128.19, 127.77, 127.47, 116.82, 113.65, 81.13, 75.03, 70.36, 70.07, 55.22, 48.17, 38.66, 28.62, 23.67, 22.61, 16.84; ESIMS m/z 419 ([M+Na]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16].[I-].[CH3:25][N:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:36][N+](C)(C)C)=[CH:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:36][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:26]([CH3:25])[CH:27]=2)[C:6]1=[O:16]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: COC(=O)[C@@H](C1CCCCC1)n1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C1CCCCC1)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a mixture of (R)-cyclohexyl-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (100 mg, 0.32 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (160 mg, 0.47 mmol) in DMF (2.5 mL) is added potassium carbonate (K2CO3) (100 mg, 0.72 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, dilute with EtOAc (50 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated. The resulting residue is triturated with EtOAc and hexanes to afford (R)-cyclohexyl-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid methyl ester (124 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:16][C:17]2[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=2[N+:25]([O-:27])=[O:26])[S:11][C:12]=1[C:13]([NH2:15])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:16][C:17]2[CH:22]=[C:21]([CH2:23][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)[CH:20]=[CH:19][C:18]=2[N+:25]([O-:27])=[O:26])[S:11][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccccc1Cl
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccccc4Cl)c(C(N)=O)s3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.1 %

Procedure:
To a mixture of 0.20 g (0.50 mmole) of 4-(2-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.20b), 0.63 g (3.0 mmole) of sodium triacetoxyborohydride and 15 mL of dichloromethane was added 0.12 mL (1.08 mmole) of 1-methylpiperazine. The mixture was stirred at room temperature for 3 days. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-15:85) to give 0.20 g of 4-(2-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.20c).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:11][CH:10]=2)[C:6]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:5][C:4]=1[Cl:28].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:24]([C:6]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[CH:13][CH:14]=2)[C:3]([CH2:2][NH:1][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:4]([Cl:28])[N:5]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CCOC(=O)Cl
Product: CCCCc1nc(Cl)c(CNC(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-(ethoxycarbonylaminomethyl)imidazole was prepared from 5-aminomethyl-2-n-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloroimidazole using ethyl chloroformate and the Schotten-Baumann procedure described in Example 209, Part B: m.p. 144.0°-147.0°. NMR (200 MHz, DMSO-d6) δ 12.74 (s, 1H); 7.73 (d, 1H, J=7Hz); 7.63-7.27 (m, 5H); 7.03 (d, 2H, J=10Hz); 5.27 (s, 2H); 4.60 (bd, 2H, J=7Hz); 3.90 (q, 2H, J=7Hz); 3.34 (s, 2H); 2.47 (t, 2H J=7Hz); 1.48 (t of t, 2H, J=7,7Hz); 1.24 (t of q, 2H, J=7,7Hz); 1.06 (t, 3H, J=7Hz); 0.78 (t, 3H, J=7 Hz). Anal. Calcd. for C25H28ClN3O4.(H2O)0.33 : C, 63.17; H, 6.06; N, 8.83. Found: C, 63.30; H, 6.35; N, 8.44.
Reaction SMILES: NN.O=C1C2C(=CC=CC=2)C(=O)[N:5]1[O:14][CH2:15][C:16]1[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]3[N:26]=[N:27][N:28]=[C:20]3[C:19]=2[N:29]=1.ClCCl.[CH3:43][C:44]([CH3:46])=O>C(O)C>[CH3:25][C:22]1[N:21]2[N:26]=[N:27][N:28]=[C:20]2[C:19]2[N:29]=[C:16]([CH2:15][O:14][N:5]=[C:44]([CH3:46])[CH3:43])[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[C:18]=2[C:23]=1[CH3:24]
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)C(C)C)c12
Reactant: CC(C)=O
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)C(C)C
Reaction time: 4 h

Procedure:
Anhydrous hydrazine (0.91 mL, 29 mmol) was added to a stirred suspension of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]-2-methylpropanamide (4.90 g, 9.71 mmol) in ethanol (100 mL). Dichloromethane (50 mL) was added. After four hours, acetone (50 mL) was added and the reaction mixture was stirred overnight. A solid was removed by filtration and washed with methanol. The filtrate was concentrated to provide a solid that was triturated with 1:1 saturated aqueous sodium bicarbonate/water. The solid was isolated by filtration, washed with water, and dissolved in chloroform (300 mL). The solution was washed with water (2×50 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to afford N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}-2-methylpropanamide that was used in the next experiment.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>CO>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:23]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: COC(=O)C(Sc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
Methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate (7.11 g) is reacted with 3.61 g of 4-chlorothiophenol in methanol, as in Example 16, to give a yellow oil which is bulb distilled at 0.01 mm to afford colorless oil (188° C) which solidifies to give white crystals, mp 71°-75° C. A portion is recrystallized from hexane to give white nedles, mp 74°-75.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12](Cl)=[CH:13][C:14]=1[Cl:15].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>CN(C)C=O.O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:13][C:14]=1[Cl:15]
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(Cl)nc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Fc1cccc(Cl)c1-c1c(Cl)cc(-c2ccccn2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.8 g (0.26 mol) of 3-(2-chloro-6-fluorophenyl)-2,4,6-trichloropyridine (see Example Ab), 83.6 g (0.29 mol) 2-tri-n-butylstannylpyridine and 4.8 g (5.2 mmol) tetrakistriphenylphosphinepalladium(0), dissolved in 600 ml of dimethylformamide and 400 ml 1,4-dioxane, were boiled under reflux for 8 h and then stirred at room temperature overnight. The volatile components were removed under reduced pressure, and 400 ml of water were then added, the mixture was extracted five times with in each case 150 ml of methyl tert-butyl ether and the combined extracts were washed once with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on silica gel using cyclohexane/ethyl acetate and triturated with n-pentane. Yield 36.0 g of a colorless solid of m.p. 45° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccn2)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccn2)nc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A solution of 5-methyl-[2,2′]bipyridinyl (3.96 g, 23.264 mmol) in CCl4 (80 mL) was bubbled with argon gas. NBS (5.507 g, 30.94 mmol, 1.33 eq) and (PhCOO)2 (0.2922 g, 1.21 mmol, 5 mol %) were added. The mixture was refluxed under argon atmosphere for 2 days. After being cooled to room temperature, the solid was removed by filtration, the filtrate was evaporated, and the residue chromatographed on a silica gel column eluted with a mixed solvent of CH2Cl2 and EtOAc (1:1, v/v). A mixture of three components was obtained (3.88 g). The mixture contained the desired monobromide of 5-(bromomethyl)-[2,2′]bipyridinyl (69.8 wt. %, 10.87 mmol, yield 46.7%), a dibromo by-product (20.2 wt. %, yield 10.3%) and the unreacted starting methylbipyridine (10 wt. %, 9.8% of starting amount). 1H NMR (CDCl3, 300.16 MHz) for the monobromide δ (ppm) 8.71-8.67 (m, 2H), 8.40 (d, J=8.0 Hz, 2H), 7.87-7.80 (m, 2H), 7.35-7.26 (m, 1H) and 4.54 (s, 2H) ppm. MS for the monobromide (ESI) m/z: 249 and 251 (M+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1)=[N+:2]=[N-:3].Cl.[NH2:14][OH:15].C(N(CC)CC)C>CO>[OH:15][NH:14][C:9]([C:8]1[CH:7]=[N:6][C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:12][CH:11]=1)=[NH:10]
Reactant: NO
Reactant: N#Cc1ccc(CN=[N+]=[N-])nc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCc1ccc(C(=N)NO)cn1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a solution of the azide of Example 51 (11-3) (6.46 g, 40.6 mmol) in methanol (100 ml) was added hydroxylamine hydrochloride (3.95 g, 56.84 mmol), followed by triethylamine (9.6 ml). The solution was heated to 65° C. for four hours. The solvent was removed under reduced pressure and the remaining residue was extracted with ethylacetate (300 ml) and water (100 ml). The water layer was re-extracted with ethylacetate (2×200 ml). The combined organic extracts were washed with brine (2×100 ml), dried over MgSO4 and evaporated to yield the title product (11-4) (7.8 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (1.0 g, 3.44 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (1.38 g, 3.44 mmol) according to the general procedure M. Obtained as an off-white foam (910 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:42][Si:43]([CH3:50])([CH3:49])[CH2:44][CH2:45][O:46][CH2:47]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[N:37]([CH2:47][O:46][CH2:45][CH2:44][Si:43]([CH3:50])([CH3:49])[CH3:42])[C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Reactant: C[Si](C)(C)CCOCCl
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (268 mg, 0.4 mmol) was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (142 μL, 0.8 mmol) to give 5-{-4-[2-(4′-bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-2-(2-trimethylsilanyl-ethoxymethyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[C:27]([I:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([I:29])[CH:26]=1)[CH2:22][N:12]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Clc1cc(I)cc(CBr)c1
Reactant: Fc1ccc(OCc2ncc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(OCc2nccn2Cc2cc(Cl)cc(I)c2)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 2-(4-fluoro-phenoxymethyl)-1H-imidazole in DMF was added freshly ground K2CO3 followed by bromomethyl-3-chloro-5-iodo-benzene. The reaction mixture was stirred at room temperature until most of starting material was consumed. The reaction mixture was then diluted with ethyl acetate and washed with water. The organic phase was dried over MgSO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 95:5 as an eluent to afford the title compound (275 mg, 60%); MS m/z 442 [C17H13ClFIN2O+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[CH3:30][C:31]1[C:35]([NH:36][C:37](=O)[OH:38])=[C:34]([CH3:40])[O:33][N:32]=1>>[CH3:30][C:31]1[C:35]([NH:36][C:37](=[O:38])[NH:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[C:34]([CH3:40])[O:33][N:32]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1noc(C)c1NC(=O)O
Agent: Cl
Product: Cc1noc(C)c1NC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Proceeding as in Example 1, but substituting (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide and 3,5-dimethylisoxazol-4-ylcarbamic acid hydrochloride, gave Compound 172, (S)-2-(3-(3,5-dimethylisoxazol-4-yl)ureido)-3-benzyloxy-N-(4-(4-fluorophenoxy)phenyl)propanamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 11.99 (br s, 1H), 9.62 (br s, 1H), 8.40-8.38 (d, 1H), 7.55 (s, 1H), 7.36-7.19 (m, 8H), 7.07-7.02 (m, 2H), 6.94-6.76 (m, 3H), 4.74-4.69 (m, 1H), 4.53 (s, 2H), 3.77-3.64 (m, 2H), 3.53-3.42 (m, 2H), 2.06 (s, 3H). MS (EI) for C28H27FN4O4. found 503.0 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:16](I)=[C:17]([CH3:19])[N:18]=2)[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH2:21]([CH:23]([C:26]1[C:27]2[N:28]([CH:33]=[C:34]([CH3:36])[N:35]=2)[N:29]=[C:30]([CH3:32])[CH:31]=1)[CH2:24][CH3:25])[CH3:22]>>[CH2:21]([CH:23]([C:26]1[C:27]2[N:28]([C:33]([C:16]3[N:8]4[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]4=[N:18][C:17]=3[CH3:19])=[C:34]([CH3:36])[N:35]=2)[N:29]=[C:30]([CH3:32])[CH:31]=1)[CH2:24][CH3:25])[CH3:22]
Reactant: CCC(CC)c1cc(C(F)(F)F)nn2c(I)c(C)nc12
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(CC)CC)cc(C(F)(F)F)nn34)c(C)nc12
Yield: 51.4 %

Procedure:
Using a procedure analogous to Example 16B, 8-(1-ethyl-propyl)-3-iodo-2-methyl-6-trifluoromethyl-imidazo[1,2-b]pyridazine (0.15 g, 0.37 mmol) and 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.082 g, 0.37 mmol) give the title compound (0.096 g, 0.19 mmol, 53%). 1H NMR (CDCl3): δ 0.89-0.97 (m, 12H), 1.80-1.97 (m, 8H), 2.47 (bs, 6H), 2.54 (s, 3H), 3.35-3.45 (m, 1H), 3.47-3.55 (m, 1H), 6.73 (s, 1H), 7.10 (s, 1H). ES-MS (m/z): calcd for C26H33F3N6 (M+H)+: 487.6. found: 487.3.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH3:17])[CH2:9]2.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:15][CH2:16][CH3:17])[CH2:9]2)(=[O:37])[CH3:36]
Reactant: CCCN(CCCCc1ccccc1)C1CCc2c(N)cccc2C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCCCc1ccccc1)C1CCc2c(cccc2NC(C)=O)C1
Reaction time: 3 h

Procedure:
0.90 g (0.0022 mol) of 5-amino-2-[N-(4-phenylbutyl)-N-n-propyl-amino]-tetraline-dihydrochloride (Example 4.5.4) and 1.00 g (0.0099 mol) of triethylamine are mixed with 15 ml of absolute methylene chloride with stirring and cooling with ice and 0.20 g (2.55 mmol) of acetylchloride in 5 ml of absolute methylene chloride are added. After 3 hours at ambient temperature or 30 minutes refluxing, the mixture is extracted three times with 5 ml of water, dried with sodium sulphate and concentrated by rotary evaporation, finally at 80° C. under a complete water-jet vacuum. The residue is crystallised from diethylether/petroleum ether.