Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[CH2:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH:35]=[CH2:36]>>[CH2:34]([N:37]1[CH2:42][CH2:41][N:40]([C:22]2[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([S:11][C:9]4[CH:8]=[CH:7][C:6]5[O:1][CH2:2][CH2:3][O:4][C:5]=5[CH:10]=4)=[C:13]([C:24]([F:25])([F:26])[F:27])[CH:14]=3)[CH:19]=[CH:20][N:21]=2)[CH2:39][CH2:38]1)[CH:35]=[CH2:36]
Reactant: C=CCN1CCNCC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: C=CCN1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-allylpiperazine. A yellow solid 136 was obtained (0.037 g, 73%). 1H-NMR (CDCl3, 400 MHz) δ 2.10-2.55 (br m, 6H), 3.24-3.45 (br m, 2H), 3.7 (d, J=7.0 Hz, 2H), 4.06-4.20 (br, 2H), 4.28-4.34 (m, 4H), 5.54 (d, J=7.2 Hz, 1H), 5.61 (d, J=10.2 Hz, 1H), 6.06 (m, 1H), 6.88 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.02-7.06 (m, 2H), 7.09 (d, J=1.9 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.82 (s, 1H), 8.26 (d, J=5.9 Hz, 1H); MS (APCI) m/z 514 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:19]([O-:21])=[O:20])=[C:9]([C:12]([CH3:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[CH2:10][OH:11])[CH2:4][CH3:5])[CH3:2].[CH3:22][N:23]=[C:24]=[O:25]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:22][NH:23][C:24](=[O:25])[O:11][CH2:10][C:9]1[C:12]([CH3:18])=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:8]=1[N+:19]([O-:21])=[O:20]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(CO)c1[N+](=O)[O-]
Reactant: CN=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(COC(=O)NC)c1[N+](=O)[O-]
Yield: 91.6 %

Procedure:
A mixture of 3-[(1-ethylpropyl)amino]-6-methyl-2,4-dinitrobenzyl alcohol (1.0 g; 0.0033 mol), methyl isocyanate (used in excess over theory), triethylamine (1 drop) and benzene (10 ml) is refluxed for 2 hours. The precipitated solid is collected to afford 1.1 g (91.6%) title product, melting point 117°-120° C.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]2=[O:20])[N:3]=[CH:4][CH:5]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1>C(#N)C>[N:1]1[N:2]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:15][CH2:16][N:17]([C:35]4[CH:44]=[N:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)[CH2:18][CH2:19]3)[C:10]2=[O:20])[N:3]=[CH:4][CH:5]=1
Reactant: O=C1N(Cc2ccccc2-n2nccn2)CCCC12CCNCC2
Reactant: Clc1cnc2ccccc2n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N(Cc2ccccc2-n2nccn2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 120 °C
Yield: 66 %

Procedure:
To a stirred solution of 2-(2-(2H-1,2,3-triazol-2-yl)benzyl)-2,9-diazaspiro[5.5]undecan-1-one (TFA salt) (200 mg, 0.354 mmol, contains 2.0 moleq. TFA) and diisopropylethylamine (0.64 mL, 3.61 mmol) in acetonitrile (1 mL) was added 2-chloroquinoxaline [1448-87-9] (121 mg, 0.72 mmol). The mixture was heated at 120° C. for 40 min under microwave conditions. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude mixture was purified by flash-column chromatography over silicagel (eluent: gradient 10%-100% ethyl acetate/heptane) to yield the title compound (106 mg, 65%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.81 (s, 1H), 8.11 (s, 2H), 7.80 (d, 1H), 7.59-7.63 (m, 1H), 7.56-7.59 (m, 2H), 7.44-7.55 (m, 2H), 7.33-7.40 (m, 1H), 7.24-7.29 (m, 1H), 4.54 (br. s, 2H), 4.19-4.29 (m, 2H), 3.39-3.49 (m, 2H), 3.13 (t, 2H), 1.99-2.10 (m, 2H), 1.84-1.92 (m, 2H), 1.73-1.83 (m, 2H), 1.54-1.65 (m, 2H); LCMS RtA=1.16, [M+H]+=454.4].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:37]=[CH:36][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[N+:38]([C:41]1[CH:53]=[CH:52][C:44]([CH2:45][O:46][C:47]([NH:49][CH:50]=N)=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([CH:50]=[N:49][C:47]([O:46][CH2:45][C:44]4[CH:52]=[CH:53][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=4)=[O:48])[CH2:32][CH2:31]3)=[O:29])[CH2:11]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: N=CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 2 h
Yield: 76 %

Procedure:
A suspension of 5.51 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in Preparation 1(ii)] and 2.45 g of N-(4-nitrobenzyloxycarbonyl)formamidine in 10 ml of dry acetonitrile was stirred for 2 hours on a water-bath kept at 50° C. At the end of this time, the reaction mixture was freed from impurities by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 6:4 by volume mixture of ethyl acetate and acetonitrile as the eluent, to give 5.48 g of the title compound, as a powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[N:38][CH:39]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]2[C:8](=[O:11])[N:9]([CH2:33][C:34]3[CH:39]=[N:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=3)[N:10]=[C:6]2[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 50 °C
Reaction time: 1.33 h
Yield: 67.2 %

Procedure:
To a mixture of crude 5-amino-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (26 mg, 0.07 mmol), DMF (0.5 mL), and potassium carbonate (45 mg, 0.32 mmol) was added 5-chloromethyl-2-(trifluoromethyl)pyridine (21.2 mg, 0.11 mmol). The resulting reaction mixture was stirred at 50° C. for 80 min. The reaction mixture was purified by preparative reverse phase HPLC without prior workup to obtain 25 mg of the title compound as a light yellow solid. HPLC/MS: retention time=4.14 min, [M+H]30 =531.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)C.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=1)[C:34]([NH:36][CH2:37][C:38](O)=[O:39])=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:38](=[O:39])[CH2:37][NH:36][C:34](=[O:35])[C:33]2[CH:41]=[CH:42][CH:43]=[C:31]([C:30]([F:29])([F:45])[F:44])[CH:32]=2)[C@H:10]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
A sample of [(1R,3R,4S)-4-amino-3-(3-methyl-butyl)-cyclohexyl]-carbamic acid tert-butyl ester (50 mg, 0.18 mmol) was dissolved in 1:1 CH2Cl2/DMF (2 mL). The resultant solution was charged successively with N,N-diethylisopropylamine (0.16 mL, 0.9 mmol), (3-trifluoromethyl-benzoylamino)-acetic acid (47 mg, 0.19 mmol, prepared as described in WO PCT 0250019), and BOP (116 mg, 0.26 mmol). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography afforded {(1R, 3R,4S)-3-(3-methyl-butyl)-4-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-cyclohexyl}-carbamic acid tert-butyl ester (33 mg). MS found: (M+H)+=514.3.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13](/[C:12](=[CH:7]/[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)/[C:11]([O:17][CH2:18][CH3:19])=[O:16])(=[O:14])[CH3:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C\c1ccc(C#N)cc1)C(C)=O

Procedure:
A solution of 4-cyanobenzaldehyde (2 g, 15.3 mmol), ethyl acetoacetate (1.98 g, 15.3 mmol), piperidine (65 mg, 0.76 mmol), and p-toluenesulfonic acid (131 mg, 0.76 mmol) in toluene (100 ml) is stirred under an argon atmosphere at reflux for 72 hours in a flask equipped with a Dean-Stark trap. The crude reaction mixture is concentrated in vacuo to afford an oil which is chromatographed over silica gel with cyclohexane/ethyl acetate 20:1 as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[OH:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C.ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([F:9])=[C:4]([Cl:10])[C:3]=1[OH:11]
Reactant: O=[N+]([O-])O
Reactant: Oc1c(Cl)c(F)cc(F)c1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(F)c(Cl)c(O)c(Cl)c1F
Reaction time: 2 h

Procedure:
20 g of 2,6-dichloro-3,5-difluorophenol are initially introduced in 70 ml of acetic acid, and 8 g of 98% strength nitric acid are added dropwise. Stirring is subsequently continued at room temperature for 2 hours, and the mixture is taken up in 150 ml of dichloromethane and washed twice with water. After the dichloromethane has been distilled off, 18 g of product remain. Purity 94% according to GC analysis.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:13]1(=[O:20])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1CCCCC1.N1C=CC=CC=1>[C:1]([N:19]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:20])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:19]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:20])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: O=C1CCCCCN1C(=O)c1ccc(C(=O)N2CCCCCC2=O)cc1

Procedure:
Terephthaloyl chloride (51 g, 0.25 mol) is added in the course of 30 minutes to a solution of ε-caprolactam (56.6 g, 0.5 mol) in 400 ml of cyclohexane and 117 ml of pyridine at room temperature. The mixture is then refluxed for 4 h. After cooling, the resulting light yellow precipitate is filtered off by suction, washed with water and dried. Yield 81 g (91%).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:19][Si:20]([C:23]#[C:24][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1)([CH3:22])[CH3:21]
Reactant: CCOC(=O)Cc1nccnc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nccnc1C#C[Si](C)(C)C
Temperature: 90 °C
Yield: 72 %

Procedure:
A mixture of the ethyl 2-(3-chloropyrazin-2-yl)acetate (I99) (0.410 g, 2.04 mmol), DMF (6 mL), triethylamine (2 mL), bis(triphenylphosphine)palladium(II) chloride (72 mg, 5 mol %) and copper(I) iodide (19 mg, 5 mol %) in a Schlenk tube was degassed with three vacuum/nitrogen cycles, then trimethylsilylacetylene (0.866 mL, 6.13 mmol) was added under nitrogen. The tube was flushed with nitrogen, sealed and heated to 90° C. After 18 hours the mixture was cooled and poured into water (50 mL). Saturated ammonium chloride (50 mL) was added, and the mixture was extracted with diethyl ether (3×100 mL). The combined ether phases were washed with brine, dried (sodium sulphate) and evaporated. The residue was chromatographed (40 g silica cartridge, 0-30% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I100) (0.386 g, 72% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.47-8.41 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=7.1 Hz), 0.28 (s, 9H). LCMS Method C: rt 6.20 min; m/z 263.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CCO)cc1F
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-fluoro-4-(2-hydroxyethyl)benzonitrile (22.5 g, 136 mmol) and MsCl (23.3 g, 205 mmol) in 200 mL of dry DCM was added dropwise TEA (27.5 g, 273 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight before concentrating to dryness. The residue was dissolved in 300 mL of EtOAc and washed with 1 N HCl and brine, dried over anhydrous Na2SO4 and concentrated to afford crude title compound: LC-MS m/z 244 (M+1)+;
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[C:1]1([CH2:11][C:12]2[NH:18][N:17]=[N:16][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1cccc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(Cc3nnn[nH]3)cccc2c1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A mixture of the above acetonitrile (5.40 g, 32 mmol), ammonium chloride (2.59 g, 48 mmol) and sodium azide (3.15 g, 48 mmol) in N,N'-dimethylformamide (100 ml) was stirred at 125° C. for 16 hours. After cooling the mixture was poured into water (300 ml) and extracted with ethyl acetate (2×150 ml) The combined organic phases were washed with water (100 ml) and evaporated in vacua. The residue was crystallised from diethyl ether (20 ml), filtered off and washed with diethyl ether affording 1.86 g (27%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Reactant: C1CCNCC1
Solvent: CCO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 86.9 %

Procedure:
In a 5 mL volume glass vessel equipped with a stirrer and a thermometer were placed 1.0 g (3.7 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 1.62 g (19 mmol) of piperidine, and 10 mL of ethanol. The resulting mixture was stirred at 80° C. for 5 hours. After the reaction was complete, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 1.02 g (reaction yield: 87%) of 6-methoxy-7-(3-piperidinopropoxy)quinazolin-4-one.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: NC1CCc2ccc(C(F)(F)F)cc2CC1
Reactant: CCOC(=O)CBr
Solvent: c1ccccc1
Product: CCOC(=O)CNC1CCc2ccc(C(F)(F)F)cc2CC1
Yield: 85.9 %

Procedure:
458.5 g (2 mols) of 2-trifluoromethyl-7-amino-6,7,8,9-tetrahydro-[5H]-benzocycloheptene are dissolved in 2000 ml of anhydrous benzene. One mol of ethyl bromoacetate is added thereto and the whole is heated under reflux. A precipitate forms. The refluxing is maintained for 4 hours, then the mixture is allowed to return to room temperature. The hydrobromide precipitate of the starting amine is filtered off and washed in benzene then ether. The solvent is distilled off from the filtrate. The oil obtained is used as such for the subsequent hydrolysis. Ultimately 271 g of 2-trifluoromethyl-7-(N-ethoxycarbonylmethylamino)-6,7,8,9-tetrahydro-[5H]-benzocycloheptene are obtained. (Yield 86%), a sample of which is purified in the form of the hydrochloride, which sublimes towards 270°-280° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]([C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1.C(=O)(O)[O-].[Na+].ClCCl.[C:44](OC(=O)C)(=[O:46])[CH3:45]>O>[C:44]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]([C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:26])[Cl:27])=[O:22])[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1)(=[O:46])[CH3:45]
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Reaction time: 18 h
Yield: 83.7 %

Procedure:
3-(4-(3(S)-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyl-oxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (400 mg, 0.74 mM) was dissolved in water (5 ml) and treated with aqueous sodium bicarbonate solution (5 ml) and dichloromethane (10 ml) in an ice-bath. Acetic anhydride (216 mg, 2 mM) was added, the mixture stirred 18 hours, allowing the temperature to rise to ambient, followed by addition of a further portion of acetic anhydride (216 mg), and a further period of 10 hours stirring. The organic phase was separated, washed with aqueous sodium dihydrogen phosphate (2%, 2×15 ml), brine (10 ml), and dried (magnesium sulfate). Evaporation gave the desired product (338 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2cc3scnc3c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c3ncsc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (70 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added triethylamine (48 mg, 0.49 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (35 mg, 0.25 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>CN(C=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[N:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil, 1.89 g, 47 mmol) in 20 mL of DMF was added tert-butyl ethyl propanedioate (6.5 g, 34.7 mmol) at room temperature. The mixture was stirred for 30 min. A solution of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol) in 10 mL of DMF was added. The mixture was stirred at r.t. overnight. The solvent was removed under reduce pressure. Water was added and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatography with silica gel to give tert-butyl ethyl (5-nitropyridin-2-yl)propanedioate: 1H-NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.51 (d, J=8.8 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 5.00 (s, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.49 (s, 9H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]([O:8]CC)=O.Cl.[CH3:12][NH:13][O:14][CH3:15].C([Mg]Br)(C)C>C1COCC1>[CH3:15][O:14][N:13]([CH3:12])[C:6]([CH:2]1[S:1][CH2:5][CH2:4][S:3]1)=[O:8]
Reactant: CNOC
Reactant: CCOC(=O)C1SCCS1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1SCCS1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A vigorously stirred slurry of ethyl 1,3-dithiolane-2-carboxylate (8, 1.50 mL, 10.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.57 g, 26.2 mmol) in THF (21 mL) was treated dropwise with isopropylmagnesium bromide (52.5 mmol, 26.3 mL, 2 M in THF) over 40 min at −78° C. under argon. The reaction mixture was stirred for 1 h at −78° C. under argon. The reaction mixture was quenched with saturated aqueous NH4Cl/H2O (1:1). The aqueous phase was extracted with ether (3×100 mL). The combined organic extract was washed (water, brine), dried (Na2SO4), concentrated and chromatographed [silica, EtOAc/hexanes (2:1)] to afford a yellow oil that solidified upon storage at 1° C. (985 mg, 49%). The characterization values (1H NMR, 13C NMR, ESI-MS) were consistent with those for the title compound prepared via a different synthetic route.43