Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:11])[CH2:9][O:10][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(F)c1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(3-bromophenyl)-2-fluoroethanol (example 39, step b) (1.38 g) and imidazole (1.29 g) in DMF (14 mL) was cooled in ice-water, treated with tert-butyldimethylchlorosilane (1.049 g), then removed from the cooling bath and stirred at room temperature overnight. The solution was poured into water and extracted twice with diethyl ether. The combined organic extracts were washed twice with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 10% dichloromethane in isohexane to afford the subtitled compound as a colourless oil. Yield 1.94 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[OH2:15]>CN(C)C=O.[Cu]>[F:12][C:11]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:9])=[O:15])=[CH:4][C:3]=1[C:11]([F:12])([F:14])[F:13]
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Reactant: O
Agent: [Cu]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C(F)(F)F)c1
Yield: 71 %

Procedure:
Activated copper (45 g) was added to a solution of 2-bromo-5-nitro-benzotrifluoride (50 g) in 100 ml of dimethylformamide and the mixture refluxed for 5 hours. The cooled mixture was poured into excess water and the resulting brown precipitate collected by filtration, washed with water and dried. Chromatography over silica gel gave 25 g (71% yield) of ##STR6## 2,2'-bis(trifluoromethyl)-4,4'-dinitro-1,1'-biphenyl, recrystallized as shiny yellow prisms from ether, m.p. 138°-140° C.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]([CH2:24][C:25](O)=[O:26])=[O:23])=[CH:18][CH:19]=2)[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:28])[CH2:13][C:12]1([CH3:36])[CH3:35])(=[O:10])[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]([CH2:24][C:25]([O:7][CH2:1][C:2]3[O:6][CH:5]=[CH:4][CH:3]=3)=[O:26])=[O:23])=[CH:18][CH:19]=2)[C:14]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:28])[CH2:13][C:12]1([CH3:36])[CH3:35])(=[O:10])[CH3:9]
Reactant: CC(=O)N1c2ccc(NC(=O)CC(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: OCc1ccco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)CC(=O)OCc3ccco3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of furfuryl alcohol (17 μl) and 1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) under the agency of HATU (29 mg) and N,N-diisopropylethylamine (33 μl) in tetrahydrofuran (2 ml) was performed according to the method described in example 11.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:50][CH:51]1[CH2:54][NH:53][CH2:52]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:53]3[CH2:54][CH:51]([OH:50])[CH2:52]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(Br)c1
Product: Cc1cc(-c2nc(-c3ccc(C4(C(F)(F)F)CC4)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1

Procedure:
Analogously to the process described in Example 1, 500 mg (0.993 mmol) of the compound from Example 2A and 464 mg (1.49 mmol) of the compound from Example 8A were used to obtain 289 mg (58% of theory) of the title compound. It was possible here to dispense with the second component step of the process (silyl ether cleavage with TBAF), since the protecting group had already been detached in the course of the first component step. The crude product was purified by means of MPLC (silica gel, eluent: 1:1 cyclohexane/ethyl acetate) and subsequent extractive stirring in a mixture of 25 ml of pentane, 1 ml of diisopropyl ether and 125 μl of dichloromethane.
Reaction SMILES: C(O)(C)C.O.[C:6]([C@@:14]([C:29]([OH:31])=[O:30])([OH:28])[C@@:15]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:19])[C:16]([OH:18])=[O:17])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][CH:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]>CO>[C:20]([C@@:15]([C:16]([OH:18])=[O:17])([OH:19])[C@@:14]([C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:28])[C:29]([OH:31])=[O:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][C@H:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 0.38 h

Procedure:
In a 25 mL round bottom flask Isopropanol (1.25 mL) and Dibenzoyl-L-tartaric acid monohydrate (0.462 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (0.5 g) dissolved in methanol (1.0 mL) was added into reaction mixture at 60-65° C. over a period of 15 min. It was stirred for 15-30 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature and stirred for 30-60 min. The salt was filtered and washed with a mixture of IPA: MeOH (2:1, 3 mL). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt off (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-0.358 g, % Y-37.8%, Purity by HPLC-97.5%, % Chiral purity by HPLC of R-isomer 99.6%). % of weight loss by TGA-4.7%. m.p.-156-160° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]1[CH:19]=[N:20][NH:21][CH:22]=1)=[CH:13][CH:12]=2.[CH:23]12[O:28][CH:27]1[CH2:26][O:25][CH2:24]2>CN(C=O)C>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]1[CH:22]=[N:21][N:20]([CH:27]3[CH2:26][O:25][CH2:24][CH:23]3[OH:28])[CH:19]=1)=[CH:13][CH:12]=2
Reactant: Clc1cc2cc(-c3cn[nH]c3)ccc2cn1
Reactant: C1OCC2OC12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC1COCC1n1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A mixture of Cs2CO3 (34 mg, 0.105 mmol), 3-chloro-6-(1H-pyrazol-4-yl)isoquinoline (16 mg, 0.070 mmol) and 3,6-dioxabicyclo[3.1.0]hexane (Preparation 37, 24 mg, 0.279 mmol) in DMF (3 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction was cooled, concentrated in vacuo and purified using Biotage silica gel column chromatography eluting with 50-75% EtOAc/cyclohexane to give the title compound as white solid (10 mg, 46%).
Reaction SMILES: C(O[C:4]([NH:6]/[C:7](/[C:14]([F:17])([F:16])[F:15])=[CH:8]\[C:9]([O:11]CC)=O)=[O:5])C.[CH:18]([NH2:21])([CH3:20])[CH3:19].O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH:18]([N:21]1[C:9](=[O:11])[CH:8]=[C:7]([C:14]([F:15])([F:16])[F:17])[NH:6][C:4]1=[O:5])([CH3:20])[CH3:19]
Reactant: CCOC(=O)/C=C(\NC(=O)OCC)C(F)(F)F
Reactant: CC(C)N
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1c(=O)cc(C(F)(F)F)[nH]c1=O
Yield: 61 %

Procedure:
A stirred mixture of ethyl 3-[(ethoxycarbonyl)amino]-4,4,4-trifluorocrotonate, (Z)-(2.04 g, 8 mmol), isopropylamine (0.567 g, 9.6 mmol), and 1,8-diazabi-cyclo[5,4,0]undec-7-ene (DBU, 1.46 g, 9.6 mmol) in xylene (15 mL) is heated at 100° C. for 3 hours, cooled, and diluted with ethyl acetate. Water is added, and the resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and aqueous 2 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a solid. The solid is crystallized from methanol/water to give the title product as a solid (1.08 g, 61% yield) which is identified by 1H and 19F NMR spectral analyses.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.O.[OH-].[Na+]>C1COCC1.O>[NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(CO)cc1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
A! 4-(Aminomethyl)benzoic acid (20 g, 0.132 mole) was added to a suspension of lithium aluminium hydride (5.5 g, 0,145 moles) in 300 ml of THF, at room temperature. The suspension was refluxed for 4 hours, the cooled to room temperature and added with, successively, a mixture THF/water 7:1 (32 ml), 32% sodium hydroxide (10 ml) and water (40 ml). The formed solid was filtered off and the solvent evaporated under vacuum to provide 7 g of 4-(aminomethyl)benzyl alcohol che was directly used in the next step.
Reaction SMILES: BrC1C=CC(OC)=C(OC)C=1.Br[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].[CH2:26]([O:33][C:34]1[CH:43]=[C:42]2[C:37]([CH:38]=[C:39](Br)[CH2:40][CH2:41]2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[CH:43]=[C:42]2[C:37]([CH:38]=[C:39]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=3[N+:23]([O-:25])=[O:24])[CH2:40][CH2:41]2)=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1OC
Reactant: BrC1=Cc2ccc(OCc3ccccc3)cc2CC1
Agent: COc1ccc(Br)cc1OC
Product: COc1cc(C2=Cc3ccc(OCc4ccccc4)cc3CC2)c([N+](=O)[O-])cc1OC
Yield: 21.8 %

Procedure:
Synthesized from 1-bromo-3,4-dimethoxybenzene according to an analogous synthetic method to Preparation Example 108, 1-bromo-4,5-dimethoxy-2-nitrobenzene (7.5 g) and 7-benzyloxy-3-bromo-1,2-dihydronaphthalene (4.5 g) were used according to an analogous synthetic method to Preparation Example 107 to provide 7-benzyloxy-3-(4,5-dimethoxy-2-nitrophenyl)-1,2-dihydronaphthalene (1.3 g). The total amount of this compound was used according to an analogous synthetic method to Example 30 to provide the title compound (822 mg).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[N+:30]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)([O-:32])=[O:31].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:2][O:3]/[CH:4]=[CH:36]/[C:35]1[CH:38]=[CH:39][CH:40]=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO/C=C/c1cccc([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of (methoxymethyl)triphenylphosphonium chloride (6.79 g 19.85 mmol) in anhydrous THF (50 mL) was cooled to −20° C. and potassium tert-butoxide (2.67 g. 23.82 mmol) was added in lots to give a red reaction mass. The mixture was cooled to −30° C. and a solution of 3-nitrobenzaldehyde (2.0 g, 12.12 mmol) in toluene (15 mL) was added gradually over 30 minutes. The mixture was stirred for 1 hour then EtOAc (2 mL) followed by saturated ammonium chloride were added at 0° C. The reaction mixture was extracted with EtOAc (2×75 mL). The combined organic extracts were washed with brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude compound was purified by column chromatography on neutral silica gel using DCM to afford the title compound (1.8 g, 76%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:44])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.023 ml benzoylchloride (0.2 mmol). After 4 h of stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 85 mg yellow solid which was purified by column chromatography (10 g silicagel, dichloromethane/methanol 30:1). 71 mg product as a light yellow solid (73%) was obtained. MS (ISP) 605.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:29][CH2:28][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1.O>C(Cl)Cl.CCOC(C)=O>[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][C:46]([N:8]2[CH2:29][CH2:28][C:11]3([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=4)[CH2:12]3)[CH2:10][CH2:9]2)=[O:47])=[CH:43][CH:44]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccc3ccccc3c1)C(=O)O2
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2CCC3(CC2)CN(Cc2ccc4ccccc4c2)C(=O)O3)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound A7 (0.50 g, 1.26 mmol) was dissolved in DCM (3 mL) and combined with trifluoroacetic acid (3 mL). The reaction mixture was stirred for 5 min at RT and the solvent was then removed under a vacuum. The residue was combined repeatedly with toluene and the solvent was then removed again. The residue was then combined with sat. aq. NaHCO3 solution and repeatedly extracted with EtOAc. The combined organic phases were dried over Na2SO4 and the solvent was removed under a vacuum. The residue was redissolved in anhydrous THF (5 mL) and combined with a little triethylamine. The reaction mixture was combined with 4-methoxyphenyl isocyanate (202 mg, 1.35 mmol), stirred for 18 h at RT and combined with water and EtOAc. The organic phase was separated off and the aqueous phase repeatedly extracted with EtOAc. The combined organic phases were dried over Na2SO4 and the solvent was removed under a vacuum. The residue was purified by column chromatography (SiO2, heptane/EtOAc 2:1). After crystallisation from heptane and DCM, 237 mg (42% of theoretical) of the desired product 3-naphthalen-2-ylmethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid (4-methoxyphenyl)amide (52) were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[CH2:9]([N:11]([CH2:19][CH3:20])[C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)[CH3:10].C(O)(C(F)(F)F)=O>C(O)(C)C>[CH2:19]([N:11]([CH2:9][CH3:10])[C:12]1[S:16][C:15]([CH:17]=[N:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]#[N:8])=[CH:14][CH:13]=1)[CH3:20]
Reactant: N#Cc1ccsc1N
Reactant: CCN(CC)c1ccc(C=O)s1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)c1ccc(C=Nc2sccc2C#N)s1

Procedure:
In a round bottom flask (50 mL), 30 mg of 2-amino-thiophene-3-carbonitrile was added to 20 mL isopropanol to which was further added 5-diethylamino-thiophene-2-carbaldehyde (48 mg) and a catalytic amount of TFA. The mixture was refluxed for 3 hours. Complete removal of the solvent leads to an orange oil which was purified by flash chromatography (SiO2). The title compound was isolated as an orange solid (63%). 1H-NMR (300 MHz, [D] acetone): δ=8.44 (s, 1H), 7.54 (d, 1H, 3J=4.5 Hz), 7.09 (s, 2H), 6.13 (d, 1H, 3J=4.5 Hz), 3.54 (q, 4H, 3J=7.1 Hz), 1.27 (t, 6H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=166.1, 153.2, 141.2, 131.9, 127.9, 123.3, 118.8, 116.0, 104.5, 101.5, 48.2, 12.4.
Reaction SMILES: C([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:14])C1C=CC=CC=1.[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>CCO.[OH-].[OH-].[Pd+2]>[OH:21][C:15]([C:17]([F:20])([F:19])[F:18])=[O:16].[NH2:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[OH:8]
Reactant: N[C@@H]1CCC[C@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (1R,2R)-2-(benzyloxy)cyclopentanamine (3.5 g, 18.3 mmol) in EtOH (20 mL) was added TFA (1.6 ml, 21.5 mmol), followed by addition of Pd(OH)2/C (20% wt, 627 mg). The reaction mixture was degassed and stirred at ambient temperature under H2 for 3 days, then the solid was removed by filtration and the residue was rinsed with EtOH. The filtrate was concentrated to yield (1R,2R)-2-aminocyclopentanol TFA salt as a yellow oil. (4.3 g, 100%). NMR: 400 MHz 1H (DMSO-D6) 7.96 ppm, 2H, m; 3.95 ppm, 1H, m; 3.17 ppm, 1H, m; 2.02 ppm, 1H, m; 1.87 ppm, 1H, m; 1.66 ppm, 2H, m; 1.48 ppm, 2H, m; 1.07 ppm, 1H, m.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C1C=CC(C2(C[O:30][S:31]([CH3:34])(=O)=[O:32])CCCC2)=CC=1>>[CH3:34][S:31]([O:15][CH2:14][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:32])=[O:30]
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Reactant: OCC1(c2ccc(Cl)c(Cl)c2)CCCC1
Product: CS(=O)(=O)OCC1(c2ccc(Cl)c(Cl)c2)CCCC1

Procedure:
(1-(3,4-Dichlorophenyl)cyclopentyl)methyl methanesulfonate (484) was synthesized from (1-(3,4-dichlorophenyl)cyclopentyl)methanol (483) following the procedure described for methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([C:6](=[CH:12][CH:13]([CH3:15])[CH3:14])C(OCC)=O)#[N:5]>O.C(O)C>[CH:13]([CH:12]([CH2:6][C:4]#[N:5])[C:1]#[N:2])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C(C#N)=CC(C)C
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)C(C#N)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of potassium cyanide (5.81 g, 89.52 mmol) in water (12 mL) was added to a solution of ethyl 2-cyano-4-methyl-pent-2-enoate (6.5 g, 38.92 mmol) in ethanol (20 mL) at room temperature and the reaction mixture was stirred overnight. The resulting mixture was refluxed for 2 h and then cooled to room temperature. The ethanol was evaporated and the residue dissolved in dichloromethane. The dichloromethane layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-isopropylbutanedinitrile (3.5 g, 74%) as a liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:18]([C:20]1[C:25]([N:26]=[C:27]=[S:28])=[C:24]([CH2:29][CH3:30])[N:23]=[C:22]([CH3:31])[N:21]=1)[CH3:19]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:27](=[S:28])[NH:26][C:25]1[C:24]([CH2:29][CH3:30])=[N:23][C:22]([CH3:31])=[N:21][C:20]=1[CH2:18][CH3:19]
Reactant: CCc1nc(C)nc(CC)c1N=C=S
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: CCc1nc(C)nc(CC)c1NC(=S)Nc1c(Cl)ccc(C(=O)OC)c1NCCCO
Temperature: 65 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (3.30 g, 12.8 mmol) and 4,6-diethyl-5-isothiocyanato-2-methylpyrimidine (5.28 g, 25.5 mmol) in tetrahydrofuran (25 mL) was stirred at 65° C. for 3 days. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-3-{[(4,6-diethyl-2-methylpyrimidin-5-yl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate as a yellow solid (3.22 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.40 mmol 2-chloro-6-nitrobenzothiazole (CA=[2407-11-6]), 4.19 mmol of piperazine and 4.19 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 10 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([CH2:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:18])=O>CN(C)C=O>[C:1]([CH2:11][CH2:12][C:13]([Cl:18])=[O:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A solution of 5 grams of beta-carbobenzyloxypropionic acid (IV) in 50 ml. of thionyl chloride containing 0.5 ml of anhydrous dimethylformamide is allowed to stand, sheltered from moisture, for two days. The excess thionyl chloride is distilled off under a high vacuum, and the residue, which is a yellow oil, is heated in a flask to 110°C under an abs. pressure of 0.4 mmHg in order to strip the head fractions. The undistilled residue is taken up with ethyl ether, decolorized with charcoal, filtered and concentrated again. There are obtained about 3.48 grams (64% of theory) of (V) which is employed as such for the following stage.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[CH2:10][CH:11]2[C:20](=[O:21])[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]2)=[CH:4][CH:3]=1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>>[O:21]=[C:20]1[NH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]1[CH2:10][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:25](=[O:26])[N:24]([CH3:23])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1)=[O:22]
Reactant: O=C(CC1Nc2ccccc2NC1=O)Nc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(NC(=O)CC2Nc3ccccc3NC2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from N-(4-hydroxyphenyl)-2-(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (20%, yellow solid). HPLC-MS: m/z=431.2 (M+1); Rt: 3.55 min.