Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[S:10][N:9]=[C:8]2[CH:11]=[C:12]([CH2:15][CH2:16][OH:17])[CH:13]=[CH:14][C:7]=12.C(N(CC)CC)C>ClCCl>[N:6]1[S:10][N:9]=[C:8]2[CH:11]=[C:12]([CH2:15][CH2:16][O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=[CH:14][C:7]=12
Reactant: OCCc1ccc2nsnc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2nsnc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
Methanesulfonyl chloride (0.45 ml, 5.8 mmol) was added dropwise to an ice-cooled solution of 2-benzo[1,2,5]thiadiazol-5-yl-ethanol (c) (1.0 g, 5.5 mmol) and triethylamine (0.85 ml, 6 mmol) in dichloromethane (20 ml) The reaction mixture was allowed to warn to room temperature and stirred for 16 hours. The organic solution was washed with water, dried over magnesium sulfate and evaporated to dryness. The oily residue was triturated with diisopropyl ether. The solid was collected by filtration and dried to give methanesulfonic acid 2-benzo[1,2,5]thiadiazol-5-yl-ethyl ester (1.2 g, 78%) which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[P:11]([Cl:16])(Cl)(Cl)(Cl)[Cl:12].Cl.C(O)=[O:19]>C(Cl)(Cl)(Cl)Cl>[Cl:12][P:11]([Cl:16])([NH:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=CO
Reactant: NC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NP(=O)(Cl)Cl)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A mixture of 19.5 g (0.14 mole) of 4-fluorobenzamide, 29.2 g (0.14 mole) of phosphorus pentachloride and 175 ml of carbon tetrachloride was heated at 60°-70° for 30 min. or until the HCl gas evolution had nearly stopped. The reaction was cooled to 25°-30° and 6.7 g (0.14 mole) of 97% formic acid was added dropwise. Stirring was continued for another 60 min. before the precipitate was collected by filtration, washed with AR carbon tetrachloride and air-dried to give 20.4 g, m.p. softens 109°, melts 110°-112°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:16](=[O:17])[CH2:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8]2=[O:18])[CH2:2]1.[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22]([Cl:34])[N:21]=1>C(O)CC(C)C>[ClH:34].[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([N:7]3[C:8](=[O:18])[CH2:9][C:10]4([CH2:14][CH2:13][CH2:12][CH2:11]4)[CH2:15][C:16]3=[O:17])[CH2:2]2)[N:21]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C1CC2(CCCC2)CC(=O)N1C1CCCNC1
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCCC(N4C(=O)CC5(CCCC5)CC4=O)C3)nc(N)c2cc1OC
Product: Cl

Procedure:
The mixture of 3.75 g of 8-(3-piperidinyl)-8-azaspiro [4,5]decan-7,9 -dione, 3.59 g of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 100 ml of isoamyl alcohol is stirred and refluxed under nitrogen for 24 hours. It is cooled to 20°, the solids filtered off, washed with isoamyl alcohol and diethyl ether and recrystallized from the mixture of 160 ml of methanol and 110 ml of water, to yield the 8-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-3-piperidinyl]-8-azaspiro[4,5]decan-7,9-dione hydrochloride melting at 311°-312° with decomposition.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8](=[O:10])[CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C(O)CC1=CCCCC1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CC1=CCCCC1

Procedure:
Following General Procedure B′ above, and using cyclohex-1-enyl acetic acid (Alfa) and L-alanine isobutyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 49° C.-51° C. The reaction was monitored by tlc on silica gel (Rf=0.40 in 1:3 EtOAc:hexane) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:11][C:10]2[C:5](=[N:6][C:7]([CH2:12][NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[O:11][C:10]2[C:5](=[N:6][C:7]([CH2:12][N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CC1(C)C=Cc2nc(CNc3ccccc3)ccc2O1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N(Cc2ccc3c(n2)C=CC(C)(C)O3)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 25a (60 mg, 0.226 mmol) in DCM (3 mL) was added triethylamine (0.06 mL, 0.452 mmol) and 3,4-dimethoxybenzoyl chloride (54 mg, 0.271 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was washed with dH2O (×2) and sat. NaHCO3 (×2), dried over MgSO4 and concentrated in vacuo. Purification by column: silica gel: 3:1 DCM/EtOAc gave a quantitative yield of a light yellow oil. 1H NMR (CDCl3): δ 7.26-7.17 (m, 3H), 7.17-7.08 (m, 3H), 7.06-6.97 (m, 2H), 6.95 (t, J=5.0 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.53-6.40 (m, 1H), 5.92-5.79 (m, 1H), 5.16 (s, 2H), 3.83 (s, 3H), 3.66 (s, 3H), 1.46 ppm (s, 6H). 13C NMR (CDCl3): δ 169.9, 150.3, 149.0, 148.6, 147.9, 144.7, 140.6, 135.1, 129.0, 127.8, 127.2, 126.3, 124.0, 123.6, 123.0, 122.3, 112.6, 109.9, 77.4, 77.0, 77.0, 76.7, 55.8, 55.7, 55.6, 28.2 ppm. HRMS (ESI) m/z calcd for C26H27N2O4 [(M+H)+] 431.1971. found: 431.1951.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)=[O:19])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([O:29][C:28]([F:27])([F:39])[F:40])=[CH:31][CH:32]=2)[CH2:13][CH2:12]1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H](C1CCC(N)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C1CCC(NC(=O)c2ccc(OC(F)(F)F)cc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material prepared in Step B of Example 24 (0.020 g, 0.054 mmol) in DMF (2 mL) was added 4-(trifluoromethoxy)benzoic acid (0.0090 g, 0.059 mmol), HOAT (0.0080 g, 0.059 mmol), N,N-diisopropylethylamine (0.047 mL, 0.27 mmol) and HATU (0.022 g, 0.059 mmol). After 24 h at ambient temperature the reaction was diluted with 100 mL of ethyl acetate and washed with 100 mL of 0.5 M aqueous sodium bicarbonate. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated in vacuo. Purification by reverse phase HPLC (30%-60% acetonitrile in H20 gradient) afforded the title compound as a white solid. LC/MS 506.3 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[N:16]=[CH:15][N:14]=[C:10]3[N:11]=[CH:12][NH:13][C:9]=23)[O:4][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25]Br>CN(C)C=O>[CH2:6]([NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:10]2[C:9]=1[N:13]=[CH:12][N:11]2[CH2:25][CH2:24][Br:23])[C:3]1[O:4][CH:5]=[CH:1][CH:2]=1
Reactant: BrCCBr
Reactant: c1coc(CNc2ncnc3nc[nH]c23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrCCn1cnc2c(NCc3ccco3)ncnc21
Yield: 60 %

Procedure:
Kinetin (2 g, 9.3 mmol) and K2CO3 (2.4 g, 23 mmol) were mixed in 100 ml dimethylformamide (DMF). 1,2-Dibromoethane (5.2 g, 27.6 mmol) was added to the reaction mixture and then it was mixed at room temperature for 12 h, humidity was regulated by CaCl2 tube. Solvent was evaporated to dryness in vacuo to yellow solid and then 100 g ice was added. The mixture was shaken at least 1 h to until a white precipitate was formed. The solid was filtered off, washed with water and dried at 50° C. The product was recrystallised from methanol. Yield: 60%. 1H NMR (DMSO-d6): 3.95 (2H, t, J=5.91), 4.58 (2H, t, J=5.91), 4.69 (2H, s (br)), 6.23 (1H, d, J=2.94), 6.36 (1H, t, J=2.94), 7.54 (1H, d, J=2.94), 8.15 (2H, m), 8.24 (1H, s)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:8]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#CCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-propionic acid (380 mg, 1.4 mmol), in methylene chloride (4 mL) and N,N-dimethylformamide (1 drop) at 0° C. was treated with oxalyl chloride (1.22 mL, 14.0 mmol). The reaction was warmed to 25° C. and stirred at 25° C. for 18 h. At this time, the reaction mixture was concentrated in vacuo. The resulting residue was dissolved in methylene chloride (4 mL) and added to a solution of 2-aminothiazole (280 mg, 2.79 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol) in methylene chloride (8 mL) at 25° C. The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was poured into a 0.5N aqueous hydrochloric acid solution (50 mL) and extracted into ethyl acetate (1×100 mL). The organic extract was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a half-saturated aqueous sodium chloride solution (1×50 mL). The aqueous layer was back extracted with ethyl acetate (1×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded the 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (159 mg, 72%) as an off-white solid: mp 220-222° C.; EI-HRMS m/e calcd for C20H22N2O2S (M+) 354.1402, found 354.1388.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:15]COCC>>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCC(=O)O
Reactant: CCOCC
Product: COC(=O)CCCO[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95 %

Procedure:
CH2N2 (1.04 g, 248.1 mmol) in ether (10 mL) was added to 4-[tert-butyl(dimethyl)silyl]oxybutanoic acid (5.41 g, 24.81 mmol) in a flask. The mixture was stirred overnight, concentrated to give the title compound (5.44 g, 95%). 1H NMR (400 MHz, CDCl3): δ 0.03 (6H, s), 0.88 (9H, s), 1.81-184 (2H, m), 2.39 (2H, t, J=7.2 Hz), 3.63 (2H, d, J=6.4 Hz), 3.66 (3H, s). [M+H] Calc'd for C11H24O3Si, 233. Found, 233.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:42][CH2:43][Cl:44])(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>C(OC(C)C)(C)C>[Cl-:44].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:21][CH:22]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CC(C)OC(C)C
Product: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)C(C)(C)C)C=N1)c1ccc(F)cc1F
Product: [Cl-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone(0.5 g) and chloromethyl pivalate (3.1 g) was stirred for 2 hours at 100° C. After having been cooled, the mixture was diluted with diisopropyl ether (10 ml), and the resulting powder was collected by filtration. The powder was subjected to silica gel flush chromatography (eluent: ethyl acetate→acetone→acetone/ethanol=10/1→acetone/ethanol=5/1) to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(2,2-dimethylpropanoyloxy)methyl]-1H-1,2,4-triazolium chloride (Compound 1, 0.34 g) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:24]([C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C2NCCc3ccsc32)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCc3ccsc3C2c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
was prepared from 7-(4-methoxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin (80 mg) in toluene (10 ml), 4-methoxybenzoyl chloride (66.5 mg) and triethylamine (90 uL) as described in example 2. Yield 80% of the title compound, MS: M+=379.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][N:16](CC3C=CC=CC=3)[CH2:17][CH2:18][CH:19]=2)=[CH:10][C:9]=1[C:27]([F:30])([F:29])[F:28]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][N:16]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:17][CH2:18][CH:19]=2)=[CH:10][C:9]=1[C:27]([F:30])([F:28])[F:29]
Reactant: FC(F)(F)c1cc(C2=CCCN(Cc3ccccc3)C2)ccc1Cl
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC=C(c2ccc(Cl)c(C(F)(F)F)c2)C1
Reaction time: 5 h

Procedure:
2.5 ml of distilled ethyl chloroformate were added to a mixture of 5 g of 3-(4-chloro-3-trifluoromethylphenyl)-1-benzyl-1,2,5,6-tetrahydropyridine and 55 ml of anhydrous, distilled benzene and the mixture was refluxed with stirring under an inert atmosphere for 5 hours. The mixture was evaporated to dryness to obtain 5 g of ethyl 3-(4-chloro-3-trifluoromethyl-phenyl)-1,2,5,6-tetrahydropyridine-1-carboxylate.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][C@@H:28]([CH2:34][CH3:35])[CH2:29][C:30](OC)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C@@H:28]([OH:27])[CH2:34][CH3:35])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC[C@H](O)CC(=O)OC
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC[C@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (99 mg, 93%), MS (ISP) m/z=427.3 [(M+H)+], mp 140° C., was prepared in accordance with the general method of example 46 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (S)-methyl 3-hydroxypentanoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.Cl[C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].CCN(C(C)C)C(C)C.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:10]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)Nc1cncc(Br)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
A solution of 5-bromo-pyridin-3-ylamine (1.73 g, 10 mmol) and 4-nitrophenyl chloroformate (2.2 g, 11 mmol) in dry THF (40 ml) was stirred and heated at 60° C. under N2 for 3 hours. After cooling to RT, DIPEA (5.2 ml, 30 mmol) and 2,2,2-trifluoroethylamine (1.6 ml, 20 mmol) were added and the solution was stirred at RT for 16 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and 1N NaOH. The organic layer was washed with H2O (×1) and brine (×1), then dried (MgSO4), filtered and evaporated. The residue was triturated with CH2Cl2. The solid was collected by filtration, washed with Et2O and dried under vacuum to give the title compound (1.7 g) as a colourless solid. 1H NMR (400 MHz, DMSO-d6): 9.18 (1H, s), 8.49 (1H, d), 8.28 (1H, d), 8.25 (1H, t), 7.06 (1H, t), 3.99-3.88 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[C:6]2[C:14]=1[CH2:13][C@H:12]1[C@@H:7]2[CH2:8][NH:9][CH2:10][CH2:11]1.CCN(CC)CC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl>[CH2:32]([O:31][C:29]([N:9]1[CH2:8][C@H:7]2[C@H:12]([CH2:13][C:14]3[C:6]2=[CH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:2]=3[CH3:1])[CH2:11][CH2:10]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(-c2ccccc2)cc2c1C[C@@H]1CCNC[C@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(-c4ccccc4)cc3[C@H]2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of cis-8-methyl-6-phenyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (22 mg, 0.084) in CH2Cl2 was added Et3N (43 mg, 0.42 mmol) followed by ethyl chloroformate (18 mg, 0.17 mmol). The reaction mixture was stirred at 20° C. for 2 h and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give cis-8-methyl-6-phenyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (20 mg, 0.060 mmol).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:28][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([OH:29])[CH2:6]1)=[N+]=[N-].[H][H]>[Pd].O1CCCC1>[NH2:1][CH2:4][C@H:5]1[O:28][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:7]([OH:29])[CH2:6]1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1O)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CN)C[C@@H]1O)(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
A slurry of 3.78 g of product from Example 276, 0.562 g of 10% palladium on carbon and 50 ml of tetrahydrofuran is hydrogenated under a balloon of hydrogen for 1 hour. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give 3.4 g of the desired product.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:19]>[OH-].[Na+].O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:19])[S:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: [NH4+]
Reactant: COc1ccc(-c2nsc(S)n2)cc1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2nsc(SN)n2)cc1
Reaction time: 0.25 h

Procedure:
A solution of 25 g of 5-mercapto-3-(4-methoxyphenyl)-1,2,4-thiadiazole in 350 ml of 5% sodium hydroxide and a solution prepared by diluting 220 ml of 5.25% NaOCl to 350 ml with water were added simultaneously to 950 ml of ammonium hydroxide solution while maintaining the mixture at 0°. The resulting mixture was stirred for 15 minutes and the precipitated solid was collected, washed with water and dried (P2O5 /high vacuum) to give 15.6 g of solid, m.p. 136°-139°.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[OH2:23].[CH2:24]([O:26][C:27]([C:29]1[O:30][C:31]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[C:32]2[C:37]=1[CH:36]=[CH:35][CH:34]=[CH:33]2)=[O:28])[CH3:25]>C(O)(=O)C>[CH2:24]([O:26][C:27](=[O:28])[C:29]([C:37]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:31](=[O:30])[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)=[O:23])[CH3:25]
Reactant: CCOC(=O)c1oc(-c2ccc(Cl)cc2)c2ccccc12
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
11.5 G. of cerium (IV) ammonium nitrate are dissolved in 20 ml. of water and 20 ml. of glacial acetic acid. Thereafter, there are added 3.0 g. of 3-(p-chlorophenyl)-isobenzofuran-1-carboxylic acid ethyl ester and the mixture is boiled for 2-3 minutes until the color of the solution obtained changes from orange to light-yellow. After cooling, there are added 150 ml. of ice-water and the mixture is stirred for 1 hour in an ice-bath. The product which first separates as an oil solidifies. The solid is separated by decantation of the aqueous solution and is dissolved in ether. The ethereal solution is washed with 2-N sodium carbonate and water, dried over sodium sulfate and evaporated. After crystallization of the residue from ethanol, there is obtained [o-(p-chlorobenzoyl)-phenyl]glyoxylic acid ethyl ester in the form of colorless crystals having a melting point of 79°-81° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:35]1[CH:40]=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=C[CH:36]=1.C(C1C=CC(C(Cl)=O)=CC=1)CC>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([CH2:36][CH2:35][CH3:40])=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: CCCc1ccc(C(=O)Cl)cc1
Product: CCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)cc1
Yield: 91 %

Procedure:
The compound of example 169 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-(n-propyl)benzoyl chloride.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:11]=1>>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Product: COc1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Product: Cl
Reaction time: 0.5 h

Procedure:
400 mg of trans-1,4-diaminocyclohexane is taken to approximately 150° C. then 172 mg of the product obtained in Stage 1 above is added, the reaction medium is left under agitation for 2 hours and 30 minutes then left to return to ambient temperature. After evaporating the solvents, the residue is chromatographed on silica (eluent: MeOH/NH4OH 98/2). The residue is taken up in an ethanolic solution of hydrochloric acid, followed by evaporating the solvents, impasting in ether, separating, drying under reduced pressure at ambient temperature and 188 mg of expected product is recovered.