Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.C(O)(=O)C.[F:10][C:11]([F:39])([F:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:27](=[O:33])[CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1.C(=O)(O)[O-].[Na+]>CCOCC>[F:39][C:11]([F:38])([F:10])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:27](=[O:33])[C:26]([Cl:4])=[C:25]([C:34]([F:35])([F:36])[F:37])[N:24]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Sulfuryl chloride (0.011 ml) was added to acetic acid (1.3 ml) solution of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-butyl-6-trifluoromethyl-4(3H)-pyrimidinone (60 mg, 0.13 mmol) which had been synthesized in accordance with the method of Example 24, followed by stirring at room temperature for 1 hour. After completion of the reaction, ether (20 ml) was saturated sodium bicarbonate aqueous solution (20 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (10 ml×2). The thus obtained ether layers were combined, washed with sodium bicarbonate aqueous solution (20 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (dichloromethane:hexane=10:3), white solid of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-butyl-5-chloro-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 55] was obtained.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:25])[CH2:13][CH2:14][CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:12]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:17]1[CH3:25])[CH2:13][CH2:14][CH3:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21

Procedure:
To a stirred mixture containing 7.4 g. of phthalic anhydride and 16.0 g. of 1-butyl-2-methylindole at 0°-5° C. was added portionwise 13.3 g. of aluminum chloride. The mixture was diluted with 50 ml. of benzene and stirred overnight at room temperture. The reaction mixture was poured into 200 ml. of 5% hydrochloric acid and the product extracted with benzene. The benzene extracts were shaken with dilute aqueous potassium hydroxide. The aqueous alkaline layer was separated, cooled with ice and brought to pH 4 with acetic acid. The precipitated product was collected and dried to give 2-(1-butyl-2-methyl-3-indolylcarbonyl)benzoic acid, m.p. 88°-92° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27](=[O:35])[C:28]([NH:31]C(=O)O)([CH3:30])[CH3:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][C:28]([CH3:30])([CH3:29])[C:27]([N:25]1[CH2:24][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:26]1)=[O:35]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)NC(=O)O)C3)ccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C(C)(C)N)C3)ccc1-2
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of (2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-1,1-dimethyl-2-oxo-ethyl)-carbamic acid tent-butyl ester (203 mg, 0.36 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred for 1 hour then concentrated in vacuo. The residual solid was triturated with ether, filtered off and air-dried before being dissolved in DCM. The organic solution was washed (aqueous saturated sodium bicarbonate solution, followed by water and then brine), dried (MgSO4) and concentrated in vacuo. The residue was freeze-dried from MeOH/H2O to give 469 as a white solid (116 mg, 71%). LCMS: RT=8.13 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 8.30 (1 H, d, J=8.19 Hz), 8.06 (1 H, s), 7.18 (1 H, dd, J=8.24, 1.86 Hz), 7.00 (1 H, d, J=1.82 Hz), 5.82-5.74 (1 H, m), 4.79 (1 H, s), 4.42 (1 H, s), 4.33 (2 H, t, J=5.13 Hz), 4.19 (1 H, s), 3.77-3.70 (2 H, m), 3.39 (2 H, t, J=5.02 Hz), 1.74 (2H, s), 1.50 (6 H, d, J=6.59 Hz), 1.17 (6 H, s)
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:7]=1[C:8]([O:10]CC=C)=[O:9])[CH3:2].N1CCCC1>C(#N)C>[CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:7]=1[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: C=CCOC(=O)c1cc(C(F)(F)F)ccc1NC(=O)NCC
Solvent: C1CCNC1
Solvent: CC#N
Product: CCNC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
Preparation B1, Step 3: The allyl 2-(3-ethylureido)-5-(trifluoromethyl)benzoate (1.8 g, ca. 5.7 mmol) was dissolved in acetonitrile (50 mL) The solution was charged with pyrrolidine (1.0 mL, 12 mmol) and Ph(PPh3)4 (140 mg, 0.17 mmol) and then stirred for 2 h at RT before being concentrated in vacuo. The residue was diluted with EtOAc and this was washed successively with 1N HCl (2×) and brine (1×) before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was triturated with methylene chloride to afford pure 2-(3-ethylureido)-5-(trifluoromethyl)benzoic acid (0.89 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([NH:18]C(=O)OCC3C=CC=CC=3)=[CH:8][C:9]=1[NH:10]2.Br>CCOCC>[BrH:1].[NH2:18][C:7]1[CH:8]=[C:9]2[C:4]([C:3]3[C:2]([Br:1])=[CH:14][CH:13]=[C:12]([C:15]([NH2:16])=[O:17])[C:11]=3[NH:10]2)=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(NC(=O)OCc3ccccc3)ccc12
Agent: Br
Solvent: CCOCC
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of benzyl 5-bromo-8-carbamoyl-9H-carbazol-2-ylcarbamate (Example 50-3, 2.18 g, 4.97 mmol) in hydrogen bromide (30-35% in acetic acid, 11.9 mL, 59.7 mmol) was stirred at rt for 30 min. The mixture was diluted with ether (100 mL) and the precipitate was collected by filtration, washed with ether and dried to provide 7-amino-4-bromo-9H-carbazole-1-carboxamide, hydrobromide salt, as a light yellow solid (2.20 g). 1H NMR (400 MHz, DMSO-d6) δ 12.02 (1H, s), 8.69 (1H, d, J=8.5 Hz), 8.28 (1H, br. s.), 7.91 (1H, d, J=8.0 Hz), 7.84 (1H, d, J=1.8 Hz), 7.65 (1 H, br. s.), 7.51 (1H, d, J=8.3 Hz), 7.25 (1H, dd, J=8.4, 1.9 Hz). Mass spectrum m/z 304, 306 (M+H)+. The salt was partitioned between EtOAc and NaHCO3 (aq). Residual solid was collected by filtration, washed with EtOAc and water and dried. The organic phase of the filtrate was separated, washed with brine, and dried and concentrated. The solid residue was combined with the filtered solid, dissolved in acetone, filtered to remove undissolved solid, and the filtrate was concentrated to provide 7-amino-4-bromo-9H-carbazole-1-carboxamide, hydrobromide salt, as a light yellow solid (1.62 g, 96%).
Reaction SMILES: [NH2:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:23]([NH:31][C:32]([NH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccccc2F)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)C1
Temperature: 22 °C

Procedure:
To three separate reaction vessels, each containing racemic tert-butyl 3-amino-3-(2-fluorophenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (0.142 g, 4.58 mmol) and tetrahydrofuran (18 mL), is added benzoyl isothiocyanate (0.784 g, 4.80 mmol). The solutions are stirred at 22° C., and stirred for 15 hours. The solvent is removed under a stream of nitrogen, the residues combined, and concentrated to provide the crude title compound, which is used without further purification. ES/MS (m/e): 474 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:18]([NH2:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOCC.[Cu](I)I>[CH:18]([NH:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8])([CH3:20])[CH3:19]
Reactant: CC(C)N
Reactant: O=Cc1cncc(Br)c1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Nc1cncc(C=O)c1
Temperature: 90 °C

Procedure:
To 5-bromonicotinaldehyde (1.5 gm, 8.06 mmol) in DMF (5 ml), N,N-diethylsalicylidiamide (311 mg, 1.61 mmol), copper iodide (77 mg, 0.403 mmol), potassium phosphate (3.42 gm, 16.12 mmol) and isopropylamine (715 mg, 1.21 mmol) were added and the reaction mixture was heated overnight at 90° C. Then reaction mixture was diluted with ether and filtered. Ether layer was washed with water, brine and dried. Crude residue was column chromatographed (40% ethylacetate/60% Hexanes) to yield 5-(isopropylamino)nicotinaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21](O)=[O:22])[N:11]=[N:12][C:13]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([O:26][CH3:25])[CH:31]=3)=[O:22])[N:11]=[N:12][C:13]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:19])[F:18])=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1nnc(C(=O)O)cc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: COc1cc(CN)on1
Agent: Cl
Product: COc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(O[C@@H](C)C(F)(F)F)nn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridazine-3-carboxylic acid (example AG) and 3-methoxy-5-isoxazole-methanamine hydrochloride as starting materials, 457.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][C:9](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 60.0 g of 2-phenylcyclohexanone in 400 ml of ethanol is stirred and treated with 160 ml of 15% aqueous sodium hydroxide and 53.0 g of benzaldehyde. The resulting solution is stirred at room temperature and the product begins to separate from solution as an oil after 30 minutes. The mixture is seeded with crystalline material and allowed to stand overnight at room temperature. The resulting slurry is poured onto 1.5 liters of ice-water, allowed to stand at room temperature for 2 hours, filtered and washed with cold water. This material weights 81.2 g, melting point 75°-78° C. After crystallization from 200 ml of isopropanol, the product weighs 62.1 g; melting point 85°-87° C. A small sample, recrystallized from ethanol, melts at 86°-88° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=O)[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:39]([F:42])([F:41])[F:40])([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:52])=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[S:52])[CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:39]([F:42])([F:41])[F:40])([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CCN1CCC(OCc2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Product: O=[N+]([O-])c1ccc(NC2CCN(C(=S)CCN3CCC(OCc4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F

Procedure:
1-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-3-[4-(4-fluoromethyl-benzyloxy)-piperidin-1-yl]-propan-1-one (26 mg; 0.043 mmol, prepared in accordance with Example 57) is reacted with Lawesson's reagent (9 mg; 0.022 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (7 mg; 0.011 mmol). The structure was confirmed using Protocol I-B. Calculated mass=619; observed mass=619; HPLC retention time=4.79 min.
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:17][OH:18])[CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[ClH:1].[C:2]1([C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([CH2:17][O:18][C:37](=[O:39])[CH3:38])[CH2:13][CH2:12]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 24 h

Procedure:
A mixture of 1.0 part of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-piperidinemethanol hydrochloride, 10 parts by volume of pyridine and 3.0 parts by volume of acetic anhydride is allowed to stand for 24 hours. Volatile material is removed under reduced pressure and the resulting residue is partitioned between dilute sodium hydroxide and ether. The ether layer is separated, washed with water, dried over sodium sulfate and then treated with an excess of a solution of hydrogen chloride in 2-propanol. The solid which forms is separated by filtration and then washed successively with ether, water, and ether, and then air dried to give 1-(3,3,3-triphenylpropyl)-4-phenyl-4-acetoxymethylpiperidine hydrochloride melting at about 211°-213° C and having the following structural formula ##STR19## Replacement of acetic anhydride with 3.0 parts of propionic acid anhydride provides 1-(3,3,3-triphenylpropyl)-4-phenyl-4-propionyloxymethylpiperidine hydrochloride.
Reaction SMILES: CC(C1C=C(C(C)C)C=C(C(C)C)C=1S(O[CH:20]([C:22]1([OH:45])[CH2:25][N:24]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[C:29]=2[NH:36][C:37]2[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=2[F:44])=[O:27])[CH2:23]1)[CH3:21])(=O)=O)C.[H-].[Na+].C(OCC)(=O)C>O1CCCC1>[F:35][C:30]1[C:31]([F:34])=[CH:32][CH:33]=[C:28]([C:26]([N:24]2[CH2:25][C:22]3([O:45][CH:20]3[CH3:21])[CH2:23]2)=[O:27])[C:29]=1[NH:36][C:37]1[CH:42]=[CH:41][C:40]([I:43])=[CH:39][C:38]=1[F:44]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)OC(C)C2(O)CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1OC12CN(C(=O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
1-[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (194 mg, 0.256 mmol) was dissolved in tetrahydrofuran (2 mL) and was cooled to 0° C. Sodium hydride (60 wt % dispersion in oil; 31 mg, 0.775 mmol) was added and the mixture was stirred at 0° C. for 15 minutes. The mixture was quenched with saturated sodium bicarbonate solution and partitioned with ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(2-methyl-1-oxa-5-azaspiro[2.3]hex-5-yl)carbonyl]aniline (120 mg, 0.253 mmol, 99% yield): MS (EI) for C18H14F3IN2O2: 475 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: CC#CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1,3-cyclohexanedione (1.1 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieve 4A (2 g) and tetrahydrofuran (20 ml) was combined with triethylamine (0.48 g), stirred at room temperature for 1 hour, and then heated under reflux for 12 hours. After cooling, insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was stirred at 220° C. for 4 hours. Ethyl acetate and aqueous sodium hydrogen carbonate were added, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was subjected to a column chromatography on a silica gel (EtOAc/hexane) to obtain a crystal which was then recrystallized from ethyl acetate-hexane to obtain 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinoline-5-one (0.20 g) as a colorless crystal.
Reaction SMILES: [CH2:1]([C:11]1[NH:15][N:14]=[N:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C>[CH2:1]([C:11]1[N:12]=[N:13][N:14]([CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=2)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1nnn[nH]1
Reactant: CCOC(=O)Cc1ccccc1Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Yield: 33.9 %

Procedure:
The 5-decyl-1H-tetrazole, (4.0 g, 0.019 mol), triethylamine (2.9 mL, 0.021 mol) and ethyl 2-bromophenylacetate (5.09 g, 0.021 mol) were dissolved in 200 mL acetonitrile and heated to reflux for 2 hours. Cooled and concentrated in vacuo to give a yellow oil. Chromatography to separate the regioisomers gave ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate as a clear oil (2.40 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH:10]([CH2:15][CH2:16][CH2:17][Br:18])[C:11](OC)=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[Br:18][CH2:17][CH2:16][CH2:15][CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8]1
Reactant: Nc1ccccc1O
Reactant: COC(=O)C(Br)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C1Nc2ccccc2OC1CCCBr
Yield: 20.3 %

Procedure:
24 g of 2-aminophenol, 55 g of methyl 2,5-dibromovalerate and 30 g of potassium carbonate were heated to reflux for 5 hours in 250 ml of acetone. For work-up, the reaction mixture was diluted with 250 ml of diethyl ether, washed with 200 ml of water and acidified to pH=1 using 12N hydrochloric acid solution. The organic phase was separated, washed twice with 100 ml of water each time, dried and evaporated. The residue was crystallized from methanol. 11 g of 2-(3-bromopropyl)-2H-1,4-benzoxazin-3(4H)one were obtained.
Reaction SMILES: [CH3:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].Cl[CH2:19][CH2:20][O:21]C1CCCCO1>>[OH:21][CH2:20][CH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1=[O:11]
Reactant: CC1(c2ccccc2)C(=O)Nc2ccccc21
Reactant: ClCCOC1CCCCO1
Product: CC1(c2ccccc2)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-methyl-3-phenyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran.
Reaction SMILES: [O:1]([CH:8]=[CH:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[N:15][N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:12]2[CH2:13][CH2:14][N:10]([CH:9]=[CH:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:11]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:22][N:21]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C=COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])N=C1N(C=COc2ccccc2)CCN1Cc1ccc(Cl)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A mixture comprising 2.8 g of 1-(2-phenoxyvinyl)2-nitroiminoimidazolidine, 3.6 g of 2-chloro-5chloromethylpyridine, 3.2 g of potassium carbonate and 15 ml of dimethylsulfoxide was stirred at 70° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluet: ethyl acetate) to give 3.0 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-phenoxyvinyl)-imidazolidine.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8](O)[C:9]([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:6])[CH2:2][C:3]([O:5][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:4]
Reactant: CC(C)(C)CO
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)COC(=O)CC(=O)OCC(C)(C)C
Yield: 94.8 %

Procedure:
Malonic acid (40 g, 0.38 mol) and neopentyl alcohol (77.5 g, 0.88 mol) in 110 ml of toluene in the presence of 0.2 ml of concentrated sulfuric acid are refluxed for 3 hours in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The organic phase is washed 3 times with water and dried over sodium sulfate. After filtration and evaporation of the solvent under vacuum, 88 g (yield: 94%) of dineopentyl malonate are obtained in the form of a colorless oil and used without further purification in the next step.
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:47]=[C:48]([C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62])=[CH:54][CH:53]=2)[CH:49]=[CH:50][CH:51]=1>>[C:33]([C:26]1[CH:27]=[N:28][C:29]2[C:24]([C:25]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[CH:23][C:22]([S:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:11]([NH:45][C:46]1[CH:47]=[C:48]([C:52]3[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62])=[CH:54][CH:53]=3)[CH:49]=[CH:50][CH:51]=1)=[O:12])(=[O:21])=[O:20])=[CH:31][C:30]=2[CH3:32])(=[O:34])[NH2:35]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Reactant: COC(=O)CCCc1ccc(-c2cccc(N)c2)cc1
Product: COC(=O)CCCc1ccc(-c2cccc(NC(=O)c3cccc(S(=O)(=O)c4cc(C)c5ncc(C(N)=O)c(Nc6cccc(OC)c6)c5c4)c3)c2)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 30 in place of 8-aminooctanol. ES/MS calcd. for C42H39N4O7S+ 743.3. Found m/z=743.4 (M+H)+.