Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:6][O:7][C:8](=[O:19])[C:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>CN(CCN(C)C)C.C1COCC1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:6][O:7][C:8](=[O:19])[C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: c1ccoc1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
To a cooled (0° C.) solution of furan (5.7 mL, 78 mmol) in TMEDA/THF (81.4 mL, 14/86) is added n-buLi (15 mL, 2.5 M in hexanes). The cold bath is removed and the resulting solution stirred for 45 minutes, then a solution of ZnCl2 in THF added (40 mL, 0.5M). To this solution is added (Ph3P)4Pd (1.0 g, 0.86 mmol) and 2-(4-Bromo-phenyl)-2-methyl-propionic acid methyl ester (4.5 g, 17.5 mmol) (reference example 31 a). The resulting solution is warmed to 60° C. and stirred for 3 hours. The reaction mixture is then cooled, diluted with ether, washed with hydrochloric acid (2M), then brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 5% ether in hexanes) to give 3.84 g of the title compound as a solid. 1H NMR (CDCl3) d 1.60 (s, 6H), 3.67 (s, 3H), 6.45 (m, 1H), 6.63 (d, J=3 Hz, 1H), 7.35 (m, 2H), 7.46 (m, 1H), 7.65 (m, 2H). MS (EI) m/z 245 (M+H)+.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[F:23][C:24]([F:29])([F:28])[CH2:25][CH2:26]O.Cl[CH2:31]Cl>O>[CH:10]([N:8]1[CH2:9][CH:6]([O:5][CH2:31][CH2:26][CH2:25][C:24]([F:29])([F:28])[F:23])[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCC(F)(F)F
Reactant: ClCCl
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: O
Product: FC(F)(F)CCCOC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C

Procedure:
A suspension of 1-benzhydrylazetidin-3-yl methanesulfonate (247 mg, 0.78 mmol) in trifluoropropanol (1 g, 7.8 mmol) was placed under micro-wave irradiations (100 W) and heated at 100° C. during 30 minutes. The reaction mixture was diluted by addition of dichloromethane (50 mL) and water (30 mL). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×20 mL). The combined organic phases were dried over sodium sulphate and concentrated to dryness. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (8:2) as eluent. The title product was isolated as a yellow oil (191 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([NH2:20])=[O:19].N1C=CC=CC=1.[CH2:27]([O:31][CH2:32][C:33](Cl)=O)[CH:28]([CH3:30])[CH3:29].[OH-].[Na+]>C1COCC1>[CH2:27]([O:31][CH2:32][C:33]1[NH:20][C:18](=[O:19])[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=3)=[N:7][C:2]=2[N:1]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)COCC(=O)Cl
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid amide (0.5 g, 1.75 mmol) in anhydrous THF (25 mL) under N2 atmosphere. Add dropwise pyridine (0.325 mL, 4.0 mmol) and isobutoxyacetyl chloride (0.2 mL, 4.04 mmol) to the reaction mixture and stir at room temperature overnight. Add 10% aq. NaOH (10 mL) and stir at 50° C. for 4 hours. Concentrate in vacuum, adjust the pH to 6.0 using AcOH, collect the solid by filtration and purify by column chromatography to give 2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])[N:13]=[C:12]([NH:22][CH3:23])[N:11]=2)[CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[Na].[CH3:26][SH:27]>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])[N:13]=[C:12]([NH:22][CH3:23])[N:11]=2)[CH:7]=[C:6]([S:27][CH3:26])[C:3]=1[C:4]#[N:5]
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCC[C@H]2C)n1
Reactant: CS
Agent: [Na]
Solvent: CN(C)C=O
Product: CNc1nc(-c2cc(F)c(C#N)c(SC)c2)cc(N2CCC[C@H]2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution of 2,6-difluoro-4-{2-(methylamino)-6-[(2R)-2-methyl-1-pyrrolidinyl]-4-pyrimidinyl}benzonitrile (162 mg, 0.492 mmol) in DMF (4 mL), was added methyl mercaptan sodium salt (ca. 15% in water, 319 mg, 0.683 mmol). The solution was stirred at room temperature overnight in a capped 10 mL vial. The mixture was poured onto water (15 mL). The formed solid was filtered, washed by water and dried to afford the title compound (86 mg) as a light yellow solid. LC-MS (ES) m/z=358 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Si:12]([O:19][C@@H:20]([C@H:22]1[C:30](=[O:31])[N:29]2[C@@H:23]1[CH2:24][C:25](=[O:45])[CH2:26][CH:27]=[C:28]2[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>ClCCl>[C:8]([O:45][C:25]1[CH2:24][C@H:23]2[N:29]([C:30](=[O:31])[C@@H:22]2[C@H:20]([O:19][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13])[CH3:21])[C:28]([C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])=[CH:27][CH:26]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCC(=O)C[C@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1=CC=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
Triethylamine (1.1 ml, 7.5 mmol) followed by acetyl chloride (0.295 ml, 4.1 mmol) were added to a solution of 4-nitrobenzyl (7R,8S)-8-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-5,9-dioxo-1-azabicyclo[5.2.0]non-2-ene-2-carboxylate (1.67 g, 3.4 mmol) in anhydrous dichloromethane (220 ml) cooled with an ice bath. After 5 minutes, the reaction mixture was washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue purified by flash chromatography, eluting with dichloromethane/ethyl acetate (95:5) to give 4-nitrobenzyl (7R,8S)-5-acetoxy-8-[(1R)-1-(tertbutyldimethyl-silyloxy)ethyl]-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate (1.4 g, 77%).
Reaction SMILES: [OH:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]1=[O:13].COCCOC.[F:20][C:21]([F:27])([F:26])[S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:21]([F:27])([F:26])[S:22]([O:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]1=[O:13])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=c1oc2ccccc2c(=O)n1O
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: ClCCl
Product: O=c1oc2ccccc2c(=O)n1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
3-Trifluoromethanesulfonyloxy-1,3-benzoxazine-2,4-dione was prepared by the following procedure. To a dried flask with a stirrer, under nitrogen, were added 3-hydroxy-1,3-benzoxazine-2,4-dione (3.35 g, 18.7 mmol) (U.S. Pat. 2,714,105) and 100 mL of dried DME. The mixture was held at -15°, and trifluoromethanesulfonyl chloride (2.00 mL, 18.7 mmol) followed by triethylamine (3.00 mL, 22 mmol) were added dropwise by syringe. After warming to room temperature, the reaction mixture was diluted with 200 mL of methylene chloride and washed successively with water, 2 percent aqueous sodium bicarbonate, and water, and then dried. Evaporation of the solvent gave 5.13 g of white solid: mp 73°-76°. Recrystallization from methylene chloride-hexane gave 3.60 g (62%) of 3-trifluoromethanesulfonyloxy-1,3-benzoxazine-2,4-dione: mp 74°-76°; uv (CH3CN) 237 (11,100), and 289 nm (2180); ir (KBr) 1800 (s), 1742 (vs), 1612 (m), 1465 (s), 1448 (s), 1342 (m), 1228 (vs), 1126 (m), 1090 (m); mass spectrum 310.9686 (calcd for C9H4NO6F3S: 310.9701); 217,0098 (calcd for C9H4O3F3 : 217.0112); 120.0200 (calcd for C7H4O2 : 120.0211). A second crop of product, 0.70 g, raised the overall yield to 73.9%.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:19]([CH:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1)#N.[ClH:29].[O:30]1CCCC1>CCCCCC>[ClH:29].[C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:19]([CH:21]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22]3)=[O:30])=[CH:8][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: N#CC1CN2CCC1CC2
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCCCCC
Product: O=C(c1ccc(-c2ccccc2)cc1)C1CN2CCC1CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of sec-butyl lithium in hexane (1.1M, 67.38 ml) was added to a solution of 4-bromobiphenyl (14.38 g) in dry tetrahydrofuran (128 ml) over a period of 1.5 hours under an atmosphere of argon at -78° C. The reaction mixture was stirred for 30 minutes at -78° C. A solution of 3-cyanoquinuclidine (5.6 g) in dry tetrahydrofuran was added to the reaction mixture whilst maintaining the temperature at -78° C. The reaction mixture was stirred for a further period of 16 hours during which period the reaction mixture was allowed to warm to ambient temperature. 2M aqueous hydrogen chloride solution (50 ml) was added to the reaction mixture and the mixture was stirred for 1 hour. The aqueous phase was separated, washed with diethyl ether, basified with dilute aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extract was dried (MgSO4) and evaporated to give a residue which was purified by flash column chromatography on silica gel using a 95:5 (v/v) mixture of methanol/ammonia (density 0.88 g/cm3) as eluant. The residue was dissolved in ethanol and acidified with a saturated solution of ethanolic hydrogen chloride. The mixture was evaporated to dryness and hexane was added to give 3-(4-phenylbenzoyl)quinuclidine hydrogen chloride as a solid (970 mg), m.p. 255.6° C.; microanalysis, found: C, 71.4; H, 6.7; N, 4.4; Cl, 9.8%; C20H21NO. HCl 1/2 H2O. requires: C, 71.34; H, 6.8; N, 4.2; Cl, 10.5%; NMR (CDCl3): 1.7-1.85 (2H, m), 2.0-2.2 (2H, m), 2.2-2.45 (1H, m), 2.45-2.6 (1H, m), 3.2-3.5 (3H, m), 3.5-3.7 (2H, m), 3.9-4.2 (2H, m), 7.35-7.55 (3H, m), 7.55-7.65 (2H, m), 7.65-7.75 (2H, d), 8.0-8.1 (2H, d) and 12.26 (1H, s).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[H][H].[C:23]1([CH:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][C:30](=[O:31])[CH:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:33][CH3:34])=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: CCC(C(=O)Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C(=O)Oc1cc(=O)n(-c2ccccc2)c2ncccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (1.19 g, 5.0 mmol) in DMF (40 mL) was added sodium hydride (purity of about 60%, 200 mg, 5.0 mmol, 1.0 eq.). The mixture was stirred until no more hydrogen was generated, to obtain a solution. Then, 2-phenylbutyryl chloride (0.92 mL, 5.5 mmol, 1.1 eq.) was added thereto, and the mixture was stirred at a room temperature for 1 hour. To the mixture was added a saturated sodium hydrogencarbonate aqueous solution, and the resulting precipitate was separated by filtration, washed with water, and dried to give 1-phenyl-4-(2-phenylbutyryloxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (1.63 g, yield 85%).
Reaction SMILES: C(N(C)C[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16][CH2:15]2)C=C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH2:17]([N:18]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:30]([C:27]1[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=1)(=[O:32])=[O:31])[CH2:17][CH2:16][CH2:15]2)[CH3:19])[CH:16]=[CH2:15]
Reactant: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: C=CCN(C)CCCCCOc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
In analogy to example 3.6, Allyl-methyl-[6-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-hexyl]-amine and 4-chlorobenzene sulfonylchloride were converted to yield Allyl-{5-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-pentyl}-methyl-amine (70%) as light yellow oil, MS: 462 (M, 1Cl).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C(OC(C)(C)C)(C)(C)C.[K].O.[C:22]([O:26][C:27](=[O:30])[CH:28]=[CH2:29])([CH3:25])([CH3:24])[CH3:23]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)c1ccccc1O
Agent: CC(C)(C)OC(C)(C)C
Agent: [K]
Solvent: O
Product: CC(C)c1ccccc1OCCC(=O)OC(C)(C)C
Temperature: 130 °C
Reaction time: 6 h
Yield: 36.9 %

Procedure:
2-Isopropylphenol (6 g) was dissolved in acrylic acid tert-butyl ester (6.2 g), and to the mixture was added potassium tert-butyloxide (0.3 g). The reaction mixture was stirred at 130° C. for 6 h. To the reaction mixture was added water, the reaction mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=9:1) to obtain the compound (10) 4.3 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:33])[NH:25][O:26]C3C=CC=CC=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:33])[NH:25][OH:26])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CN(C)C(=O)C(Cc1ccc(-c2ccc(CCC(=O)NOc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C(Cc1ccc(-c2ccc(CCC(=O)NO)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 97.3 %

Procedure:
Palladium on BaSO4 (5%, 1.0 g) was added to a degassed solution of the benzyl hydroxamate 47 (1.2 g) in MeOH (60 mL) and the suspension was treated with hydrogen at atmospheric pressure for 4 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 48 (1.0 g, 97%). 1H NMR (DMSO-d6): 10.42 (br, 1H), 7.55 (d, J=7.6 Hz, 4H), 7.32 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 4.57 (m, 1H), 2.94 (s, 3H), 2.73-2.91 (m, 7H), 2.29 (t, J=8.0 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:18]/[C:19](O)=[O:20]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH:11][C:19](=[O:20])/[CH:18]=[CH:17]/[C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)[CH2:4]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccco1
Agent: Cl
Product: O=C(/C=C/c1ccco1)N[C@@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (S)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-furyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent, followed by recrystallization from ethyl acetate/hexane; MS (ES+) 247 (MH+).
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].Cl[CH2:11][C:12]#[C:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1COCC1>CO.O>[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][S:6][CH2:11][C:12]#[C:13][CH2:14][S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCSCC#CCCl
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCSCC#CCSCC(=O)OC
Reaction time: 0.5 h

Procedure:
2.03 ml of a 30% solution of sodium methoxide in methanol were added dropwise (such that the temperature did not exceed 15° C.) to a solution of 980 μl of methyl thioglycolate in 10 ml of methanol at 10° C., under an inert atmosphere. The mixture was maintained under stirring for 30 min and then added to a solution of 2.5 g of 1-chloro-5-thia-2-tridecyne in a mixture of 7 ml of methanol with 3 ml of THF under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oily residue obtained was chromatographed on a silica gel column (CH2Cl2) providing 2.3 grams of methyl 3,8-dithia-5-hexadecynoate in the form of a pale orange-colored oil (yield 71%).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH3:21])[C:11](=[O:22])[C:10]2[C:5](=[CH:6][C:7]([Cl:23])=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].BrN1C(=O)CCC1=O.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[Cl:38][C:39]1[CH:49]=[CH:48][C:42]([O:43][CH2:44][C:45](Cl)=[O:46])=[CH:41][CH:40]=1>C(Cl)(Cl)(Cl)Cl.O1CCCC1.C(N(CC)CC)C>[Cl:38][C:39]1[CH:49]=[CH:48][C:42]([O:43][CH2:44][C:45]([N:32]2[CH2:37][CH2:36][N:35]([CH:1]([C:3]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[O:19][CH2:20][CH3:21])[C:11](=[O:22])[C:10]4[C:5](=[CH:6][C:7]([Cl:23])=[CH:8][CH:9]=4)[N:4]=3)[CH3:2])[CH2:34][CH2:33]2)=[O:46])=[CH:41][CH:40]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: C1CNCCN1
Reactant: CCOc1ccccc1-n1c(CC)nc2cc(Cl)ccc2c1=O
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1-n1c(C(C)N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)nc2cc(Cl)ccc2c1=O

Procedure:
Briefly, 2-amino-4-chlorobenzoic acid was acylated with propionyl chloride in triethylamine (TEA) and tetrahydrofuran (THF). The acylated compound was refluxed with 2-ethoxyaniline in phosphorus trichloride and toluene to produce 2-ethyl-7-chloro-3-(2-ethoxyphenyl)quinazolin-4(3H)-one. The 2-ethyl-7-chloro-3-(2-ethoxyphenyl)quinazolin-4(3H)-one was brominated with N-bromosuccinimide (NBS) in carbon tetrachloride, the product of which was subsequently reacted with piperazine in THF. The piperazinyl moiety was acylated with 4-chlorophenoxyacetyl chloride in THF and TEA to yield the final product.
Reaction SMILES: C1(O)C=CC=CC=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=1)=[O:14].[OH-].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([C:13](=[O:14])[C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:16][C:17]=1[CH3:23])[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(=O)c2cccs2)cc(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C)cc(C(=O)c2cccs2)cc1C
Reaction time: 3 h

Procedure:
There was kept for 3 hours at 60° C. a solution in 150 ml of dimethylformamide of 10 g of the phenol obtained according to (B), 3 g of potassium hydroxide and 9 g of ethyl bromoacetate. The mixture was filtered, the solvent evaporated, the residue dissolved in ethyl ether, and the impurities extracted in a basic aqueous solution. After concentration of the solvent, 11.2 g of the ester were obtained which melted at 89° C.
Reaction SMILES: N1CCCCC1.C1C2C(COC([N:24]3[CH:29]4[CH2:30][N:31]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:40]([N:42]5[CH2:56][C:45]6=[C:46]7[N:51]([N:52]=[C:44]6[CH2:43]5)[C:50]([CH3:53])=[C:49]([Cl:54])[C:48]([CH3:55])=[N:47]7)=[O:41])[CH2:32][CH:25]3[CH2:26][O:27][CH2:28]4)=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C.O>[ClH:54].[ClH:54].[Cl:54][C:49]1[C:48]([CH3:55])=[N:47][C:46]2[N:51]([N:52]=[C:44]3[CH2:43][N:42]([C:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[CH2:33][N:31]4[CH2:32][CH:25]5[NH:24][CH:29]([CH2:28][O:27][CH2:26]5)[CH2:30]4)=[O:41])[CH2:56][C:45]3=2)[C:50]=1[CH3:53]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CN1CC2COCC(C1)N2C(=O)OCC1c2ccccc2-c2ccccc21)C3
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CN1CC2COCC(C1)N2)C3
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 214.7 %

Procedure:
Piperidine (0.4 mL) was added to a solution of 7-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid 9H-fluoren-9-ylmethyl ester (354 mg, 0.44 mmol) in DMF (4 mL). The resulting mixture was stirred at RT for 30 min, then diluted with water (20 mL). The precipitate was filtered off and washed with water (2×). After purification by flash chromatography (silica, DCM/EtOH/28% aqueous ammonia), the parent compound was dissolved in water (8 ml) and the solution was lyophilized to give the title compound as a yellow solid (170 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ 10.92 (br s, 2H), 10.01 (br s, 1H), 7.95-7.78 (m, 2H), 7.72-7.60 (m, 2H), 5.01 (s, 1H), 4.99 (s, 1H), 4.85 (s, 1H), 4.80 (s, 1H), 4.46 (s, 2H), 4.19-4.04 (m, 4H), 3.97-3.70 (m, 6H), 2.86 (s, 1.5H), 2.82 (s, 1.5H), 2.63 (s, 1.5H), 2.57 (s, 1.5H). HPLC (max plot) 100%, Rt 2.26 min. UPLC/MS: (MS+) 467.3 ([M+H]+), (MS−) 465.4 ([M−H]−).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH:8]1([Mg]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH4+].[Cl-]>C1COCC1.CCOCC.C(OCC)(=O)C>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Br[Mg]C1CCCCC1
Reactant: BrCCCCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: BrCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 1,5-dibromopentane (16 gm, 69.97 mmol) in THF (20 ml) and a solution of (Li2CuCl4 in ether, 14 ml) under nitrogen at 5-10° C. was stirred for 25 minutes and then cyclohexyl magnesium bromide (10 gm, 69.97 mmol) was added dropwise over 30 minutes. The reaction was stirred at 0° C. for another 1 h, then at room temperature for 12 hr. The reaction mixture was cooled to 0° C., saturated with NH4Cl solution (20 ml), diluted with ethyl acetate (100 ml) and the combined organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography using hexane as an eluent. The pure product was an oily liquid (12.84 gm). 1H NMR (CDCl3): 0.8 (t, 2H, J=10.2 Hz), 1.00-1.38 (m, 9H), 1.52-168 (m, 6H), 1.70-1.80 (m, 2H), 3.38 (t, 2H, J=7.2 Hz).