Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36](O)=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1([N:45]=[C:46]=[N:47]C2CCCCC2)CCCCC1.ON1C(=O)CCC1=O.N#CN.[Na]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([NH:47][C:46]#[N:45])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CN
Agent: O=C1CCC(=O)N1O
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)NC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A mixture of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (0.030 g, 0.052 mmol; Example 141), N,N′-dicyclohexylcarbodiimide (10.64 mg, 0.052 mmol) and N-hydroxysuccinimide (5.94 mg, 0.052 mmol) in 3 mL of THF was stirred while cooling with an ice bath for 3 h. The reaction mixture was filtered and the filtrate was added dropwise to a solution of monosodium cyanamide (10.90 mg, 0.170 mmol) in 2 mL of water at an ice bath temperature. The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was purified by reverse phase HPLC (40 to 90% water/acetonitrile gradient with 0.1% TFA). Desired fractions were then collected and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.CON(C)[C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[CH3:36].O1CCOCC1>O.CCOC(C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:29]([C:30]3[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=3)=[O:37])=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:10])=[O:11])=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CON(C)C(=O)c1cccnc1C
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (1 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (0.33 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 90 minutes, followed by the slow addition of N-methoxy-2,N-dimethyl-nicotinamide (135 mg, 750 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 MHCl in dioxane (1 mL, 4.0 mmol) and H2O (0.33 mL), and then stirred at 80° C. for two hours. The resultant solution was diluted with EtOAc, washed with water, saturated sodium bicarbonate, and brine; dried with MgSO4, and evaporated employing reduced pressure. The crude residue was subsequently purified via automated flash chromatography to afford the desired sulfonamide: 1H NMR (400 MHz, CDCl3) δ 10.9 (s, 1H), 8.58 (d, 1H), 8.22 (d, 2H), 7.81 (d, 2H), 7.53-7.46 (m, 3H), 7.20-7.14 (m, 1H), 2.30 (s, 3H), 1.31 (s, 9H); MS (ES) M+H expect 444.1. found 444.5.
Reaction SMILES: II.Cl[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1>O1CCCC1>[C:8]1([CH3:11])[CH:9]=[CH:10][C:5]([CH2:4][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCl)cc1
Agent: II
Solvent: C1CCOC1
Product: Cc1ccc(CCc2ccc(C)cc2)cc1
Reaction time: 3 h
Yield: 92.4 %

Procedure:
200 ml of anhydrous tetrahydrofuran (THF), 3.35 g (0.138 mol) of Mg turnings and a crystal of I2 were placed in a 500-ml three-necked round-bottomed flask equipped with a 100-ml dropping funnel, thermometer and reflux condenser. Then a solution of 35.15 g (0.25 mol) of α-chloro-p-xylene in 50 ml of anhydrous THF was added drop by drop. Heating was required to start the reaction, then self-heating was observed. After 3 hours, all of the Mg had dissolved. The reaction mixture was kept under reflux for 3 hours, then left to rest for one night. All the THF was evaporated at reduced pressure and the residue was treated with a mixture of 150 ml of hexane and 150 ml of 10% HCl. The organic phase was separated, washed with aqueous NaCl (3 times) and dried over Na2SO4. After evaporating the solvent, white crystals were isolated, and these were dried under vacuum at 70° C. 24.3 g of 1,2-di-p-tolylethane was obtained (yield: 92.4%).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7](C(Cl)=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si](C=[N+]=[N-])(C)C.[BrH:21].[C:22]([OH:25])(=O)[CH3:23]>C(#N)C>[C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([C:22](=[O:25])[CH2:23][Br:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Br
Reactant: Cc1oc(C(C)(C)C)cc1C(=O)Cl
Reactant: CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Product: Cc1oc(C(C)(C)C)cc1C(=O)CBr
Reaction time: 0.33 h
Yield: 77 %

Procedure:
A solution of 1 g (5 mmol) of 5-(tert-butyl)-2-methylfuran-3-carbonyl chloride (Maybridge, Cornwall, UK) dissolved in dry acetonitrile (4 mL) and 6.25 mL (12.5 mmol) of 2 M trimethylsilyldiazomethane in hexanes (Aldrich, Milwaukee, Wis.) was stirred 1.75 h at room temperature and the mixture was cooled on an ice bath for 5 min. To this, 30% hydrogen bromide in acetic acid (2 mL, 10 mmol) was added dropwise over 10 min. This was stirred an additional 20 minutes on an ice bath. Evaporation of the solvents gave 1-[5-(tert-butyl)-2-methyl(3-furyl)]-2-bromoethan-1-one (1 g, 77%) as a brown oil. 1H-NMR (DMSO-d6; 300 MHz) δ6.50 (s, 1H), 4.57(s, 2H), 2.52 (s, 1H), 1.24 (s, 9H). Mass spectrum (LCA, m/z): Calcd. for C11H15O2Br, 259.1 and 261.1 (M+H), found 259.1 and 261.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-])=O)=[N:6][CH:7]=1>C(O)C.[Pd]>[NH2:8][C:5]1[C:4]([OH:11])=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ncc(F)cc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1ncc(F)cc1O

Procedure:
5.6 g of 5-fluoro-2-nitropyridin-3-ol (Example 10A; 36 mmol) were dissolved in 2 l of ethanol, a catalytic amount of palladium on activated carbon (10%) was added and the mixture was hydrogenated under hydrogen standard pressure for 16 h. The mixture was filtered off through kieselguhr and the filtrate was concentrated (product batch 1). The residue was rinsed with methanol until the colour of the filtrate was no longer yellowish. The filtrate was concentrated, giving a second product batch. This gave a total of 4.26 g (85% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH2:13](O)[CH3:14]>S(=O)(=O)(O)O.C(OCC)(=O)C>[OH:1][C:2]1[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCO
Reactant: COc1cnc(C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc(OC)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
3-hydroxy-5-methoxypicolinic acid (200 mg, 1.18 mmol) was dissolved in ethanol (10 mL). To the mixture was added one drop of sulfuric acid. The mixture was refluxed with stirring for 3 days. After cooling to room temperature, the mixture was concentrated in vacuo to afford an oil. The residual oil was dissolved in ethyl acetate and washed with aq. sodium bicarbonate and brine. The extract was dried over sodium sulfate and concentrated in vacuo to afford an oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:3 to 1:1) to afford 178 mg (76%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][OH:7].[C:9]1([C:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][O:7][C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CSC(=S)NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CSC(=S)NCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (7.5 g) in pyridine (40 ml) is added triphenylmethyl chloride (15 g), and the mixture is left to stand overnight at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with diluted hydrochloric acid and water, dried and concentrated to remove the solvent. The residue is crystallized from a mixture of dichloromethane and ether to give N-(2-triphenylmethoxyethyl)dithiocarbamic acid methyl ester (14.73 g).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1COC1C=CC([C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:23][CH:22]=2)=O)=CC=1.[C:39]1([Li])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[OH2:46]>C1COCC1>[N:30]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][O:46][C:39]1[CH:44]=[CH:43][C:42]([C:25]2[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:25][CH:26]=3)=[C:23]([CH2:24][OH:27])[CH:22]=[CH:21][CH:26]=2)=[CH:41][CH:40]=1
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-quinolylmethoxy)phenyl ketone (0.520 g, 1.05 mmol) in anhydrous THF (10 mL) at -78° C. phenyl lithium (0.873 mL, 1.57 mmol) was added and the reaction mixture was allowed to warm to room temperature. Water was then added to the reaction mixture and the product was extracted with EtOAc (233 ). The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with Et2O to give 400 mg of (bis(4-(2-quinolylmethoxy)phenyl)-phenyl)methanol as a cream solid.
Reaction SMILES: Cl.[S:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:4]=[N:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26].Cl>CN(C)C=O.O>[CH3:26][O:25][CH:24]([O:27][CH3:28])[CH2:23][CH2:22][N:11]1[CH:12]=[C:7]([C:5]2[CH:4]=[N:3][S:2][CH:6]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cnsc2)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cnsc2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.44 %

Procedure:
5-(4-isothiazolyl)-2,4(1H,3H)-pyrimidinedione hydrochloride (Prep23, 300 mg, 1.036 mmol) was dissolved in N,N-Dimethylformamide (DMF) (4 ml) to give a pale yellow suspension. K2CO3 (215 mg, 1.554 mmol) was added ant the reaction mixture was stirred at room temperature for 1 h. 3-bromo-1,1-bis(methyloxy)propane (0.173 ml, 1.140 mmol) was added. Mixture was stirred at room temperature for 3 days, then diluted with water, acidified with diluted HCl until pH ˜5, and extracted with EtOAc. The organic phase was washed with water (3 times), brine, dried over Na2SO4, filtered and the solvent evaporated. The obtained residue was purified by flash chromatography eluting with cyclohexane/EtOAc 1:1. Obtained 60 mg (13.44% yield) of a 9:1 mixture of the title compound and the corresponding bis alkylated derivative.
Reaction SMILES: [O:1]([CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH3:3].C([Li])CCC.[Cl-].[CH2:16]([N:19]([CH2:33][CH2:34][CH3:35])[C:20]([C:22]1[CH:23]=[C:24]([CH:29]=[C:30](I)[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:21])[CH2:17][CH3:18]>O1CCCC1.C(OCC)C.C(OCC)(=O)C.[Zn]>[CH2:33]([N:19]([CH2:16][CH2:17][CH3:18])[C:20]([C:22]1[CH:23]=[C:24]([CH:29]=[C:30]([C:6]2[N:5]([CH2:4][O:1][CH2:2][CH3:3])[CH:9]=[CH:8][N:7]=2)[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:21])[CH2:34][CH3:35]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: CCOCn1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nccn2COCC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of 1-ethoxylmethylimidazole (J. Am. Chem. Soc. 1978, 100, 3918) (420 mg, 3.3 mmol) in tetrahydrofuran (10 mL) is added n-butyllithium (1.6 M in hexanes, 2.3 mL, 3.6 mmol). After 30 min, zinc. chloride (9.9 mL of a 1 M solution in diethyl ether, 9.9 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is then added methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (1.17 g, 3 mmol) followed by palladium(0)tetrakis(triphenylphosphine) (173 mg, 0.15 mmol). The reaction mixture is heated at reflux for 2 h. The reaction mixture is diluted with ethyl acetate (50 mL)), washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1-5% methanol/methylene chloride) provides the title compound in pure form. 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 8.19 (s, 2H), 5.28 (s, 2H), 3.95 (s, 3H), 3.59 (q, J=7 Hz, 2H), 3.49 (m, 2H), 3.21 (m, 2H), 1.70 (m, 2H), 1.54 (m, 2H), 1.25 (t, J=7 Hz, 3H), 0.99 (m, 3H), 0.75 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH:11]([CH2:18][CH2:19]OS(C)(=O)=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:27]1([CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH2:19][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:35][CH2:36]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccc(Cl)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)CC(CCN1CCN(Cc2ccccc2)CC1)c1ccccc1)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 44.7 %

Procedure:
N-(4-Chlorophenyl)-beta-(2-methanesulfonyloxyethyl)-N-methyl-benzenepropanamide (0.93 g) in DMF (10 mL) was treated with N-phenylmethylpiperazine (1.03 g) and the mixture heated at 80° C. for 2 hours. The cooled reaction mixture was diluted the EtOAc (50 mL) and water (50 mL) and the aqueous phase removed. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts, washed with water (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 10% MeOH:CH2Cl2 gave the title compound (0.5 g). Mass spectrum (FAB): 476.3.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.Cl.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:33]1[CH2:34][CH2:35][CH:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])[CH2:32]1
Reactant: COc1ccccc1C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1C1CCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 120 °C

Procedure:
Toluene-4-sulfonic acid (R)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl ester (0.156 mmol), 3-(2-methoxyphenyl)pyrrolidine.HCl (1.55 mmol, 32 mg), K2CO3 (0.342 mmol, 47 mg) and acetonitrile (1 ml) were mixed and heated in a microwave reactor at 120° C. for 2.5 h. The reaction mixture was filtrated and the solution was absorbed on silica. Flash chromatography, using a gradient of heptane/EtOAc as eluent, gave 20 mg g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1.N1[CH:20]=[CH:19][CH:18]=[CH:17]C=1>C(OCC#[C-])(=O)C.[Cu+].O>[C:2]([O:7][CH2:20][CH2:19][C:18]#[C:17][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)(=[O:1])[CH3:3]
Reactant: c1ccncc1
Reactant: Ic1ccc(OC2CCCCO2)cc1
Agent: [Cu+]
Agent: [C-]#CCOC(C)=O
Solvent: O
Product: CC(=O)OCCC#Cc1ccc(OC2CCCCO2)cc1

Procedure:
20 Grams of p-tetrahydropyranyloxyiodobenzene and 70 ml of anhydrous pyridine containing 11.3 g of copper (I) 3-acetyloxy-1-propyn-1-ide were refluxed for 6 hours under an atmosphere of argon gas. After the reaction was finished the reaction mixture was poured into water and the whole mixture was extracted with chloroform. The chloroform layer was washed with water, dried and the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: chloroform: n-hexane=1:1) to yield 8 g of 4-[4-(2-tetrahydropyranyloxy)phenyl]-3-butynyl acetate in the form of colorless oily substance.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH:8]([C:13](=[O:36])[NH:14][C@H:15]1[CH2:33][C:32]2=[CH:34][N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=32)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:35])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:11][CH:10]([CH3:12])[CH2:9][CH:8]([C:13](=[O:36])[NH:14][C@H:15]1[CH2:33][C:32]2=[CH:34][N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=32)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:35])[CH2:7][C:6]([OH:37])=[O:5]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reaction time: 2.5 h

Procedure:
The less polar stereoisomer of (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-yl-carbamoyl)hexanoic acid t-butyl ester (300 mg) was covered with 5 mL of a 10% trifluoroacetic acid/methylene chloride solution and left to stir. After 2.5 hours, TLC indicated that the reaction was complete. All volatiles were removed under reduced pressure. The residue was taken up in CH2Cl2 (40 mL) and transferred to separatory funnel and washed consecutively with 0.5% HCl (40 mL) and brine (40 mL). The organic phase was dried (MgSO4), filtered and concentrated to provide the less polar stereoisomer of (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BrH:10].[Br:11]Br>O>[BrH:10].[Br:10][CH:2]([Br:11])[C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: BrBr
Agent: Br
Solvent: O
Product: O=C(c1cccnc1)C(Br)Br
Temperature: 57.5 °C
Yield: 99.4 %

Procedure:
3-Acetylpyridine (50 g, 0.41 mol), 47% aqueous HBr solution (106.6 g, 1.5 equivalent amount relative to 3-acetylpyridine) and water (80 ml) were charged in a reaction vessel and the mixture was stirred at 55-60° C. Bromine (135.2 g, 2.05 equivalent amount relative to 3-acetylpyridine) was added dropwise and the mixture was stirred for one more hour. The mixture was cooled to 5° C. under ice-cooling, and filtered to give 146.7 g of the titled compound as crystals (yield 99.0%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15](Cl)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3Cc2ccccc2)CC1

Procedure:
1.65 g (0.005 mol) of 1-benzyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 2.5 cm3 of 1-methylpiperazine and 12 cm3 of pyridine were heated under reflux for 9 hours. The reaction product was isolated as indicated in Example 35 and purified by recrystallisation from methylcellosolve (20 cm3). 1 g of 1-benzyl-6-fluoro-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 266° C., was obtained.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:12])[CH:11]=1)[CH:7]=[O:8].Cl>CO>[Br:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([Br:12])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Sodium borohydride (0.75 g) was added portionwise to a stirred suspension of 3,5-dibromobenzaldehyde (10.46 g) in methanol (50 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes, allowed to warm to room temperature and then its pH was adjusted to 2 using concentrated hydrochloric acid. Evaporation under vacuum provided a residue which was partitioned between ethyl acetate and water. The organic phase was washed with water, dried(MgSO4), then evaporated under vacuum to furnish the title compound as a solid (10.0 g), m.p. 103°-104° C. Found: C, 31.98; H, 2.23. C7H6Br2O requires C, 31.61; H, 2.77%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>OS(O)(=O)=O>[Cl:5][C:6]1[CH:13]=[C:12]([F:14])[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Fuming HNO3 (2.9 mL, 64 mmol) was added dropwise to a solution of 2-chloro-4-fluorobenzonitrile (5.0 g, 32 mmol) in conc. H2SO4 (5 mL) at 0° C. The mixture was stirred at 0° C. for 15 min and at rt for 30 min whereafter it was poured into ice. The precipitate was filtered off, washed with water and dried under vacuum.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].OC[C:23]([CH:26]1[O:31][CH2:30][C:29]2([CH2:36][O:35][CH:34]([C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])[O:33][CH2:32]2)[CH2:28][O:27]1)([CH3:25])[CH3:24].[CH3:42][O-:43].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][C:17]([O:19][CH2:20][C:23]([CH:26]2[O:31][CH2:30][C:29]3([CH2:32][O:33][CH:34]([C:37]([CH3:41])([CH3:40])[CH2:38][O:39][C:17](=[O:18])[CH2:16][CH2:15][C:7]4[CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:42]([OH:43])=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:6]=4)[O:35][CH2:36]3)[CH2:28][O:27]2)([CH3:24])[CH3:25])=[O:18])[CH:8]=[C:9]([CH:12]([CH3:13])[CH3:14])[C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CCc1cc(C(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[O-]
Reactant: CC(C)(CO)C1OCC2(CO1)COC(C(C)(C)CO)OC2
Agent: [Na+]
Product: CC(C)c1cc(CCC(=O)OCC(C)(C)C2OCC3(CO2)COC(C(C)(C)COC(=O)CCc2cc(C(C)C)c(O)c(C(C)(C)C)c2)OC3)cc(C(C)(C)C)c1O

Procedure:
Using a mixture of 33.6 g (0.121 mole) of methyl 3-(3-tertbutyl-4-hydroxy-5-isopropylphenyl)propionate, 15.3 g (0.0503 mole) of 3,9-bis(2-hydroxy-1,1-dimethylethyl)-2,4,8,10-tetraoxaspiro[5.5]-undecane and 0.82 g (0.015 mole) of sodium methoxide, reaction; after-treatment and purification were carried out in the same manner as in Preparation example 1 to obtain 29 g of 98%-purity 3,9-bis[2-[3-(3-tert-butyl-4-hydroxy-5-isopropylphenyl)propionyloxy]-1,1-dimethylethyl]-2,4,8,10-tetraoxaspiro[5.5]undecane as a colorless glassy product (Compound I-2). m.p., 47°-57° C.