Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([F:18])([F:17])([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:19](=[O:21])=[O:20].Cl>CCCCCC.CCOCC>[F:14][S:13]([F:18])([F:17])([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:19]([OH:21])=[O:20])=[CH:8][CH:9]=1
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of n-butyllithium (9.4 ml of a 1.6 M solution in hexane) was added to a stirred solution of 4-bromophenylsulphur pentafluoride (3.87 g) in ether at -78° C. under an inert atmosphere. After maintaining at -78° C. for 1 hour, solid carbon dioxide (20 g) was added and the mixture allowed to warm to 5° C. during 1.5 hours. Hydrochloric acid (2 M) was added, the mixture stirred for 0.5 hour and the organic phase separated and itself extracted with sodium carbonate solution. The basic extract was washed (ether) and acidified (hydrochloric acid). The precipitated solid was extracted (ether), dried (magnesium sulphate) and evaporated. The residue was triturated (hexane) to give 4-pentafluorosulphanylbenzoic acid as a fawn solid (1.2 g), m.p.188-190° C.
Reaction SMILES: [C:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=O)[O:6]C1=O)(=O)[CH3:2].O.[NH4+:19].[OH-]>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:6])[NH:19][C:1]([CH3:2])=[CH:4]2
Reactant: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(=O)[nH]c(C)cc2c1
Temperature: 100 °C

Procedure:
A suspension of 4-acetyl-6-methoxy-isochroman-1,3-dione (10 g, 43 mmol) in NH4OH (60 ml) in a pressure vessel is heated for 2 h at 100° C. After cooling, the reaction mixture is poured into water. The white solid is filtered, washed with water, and dried to give 6.7 g of 6-methoxy-3-methyl-2H-isoquinolin-1-one. 1H NMR (CDCl3) 11.0 (br s, 1H), 8.28 (d, 1H), 6.98 (d, 1H), 6.81 (s, 1H), 6.23 (s, 1H), 3.89 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]([CH3:22])[C:9](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C(Cc1ccc(Cl)c(Cl)c1)C(=O)O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(=Cc1ccc(Cl)c(Cl)c1)C(=O)O

Procedure:
2-(tert-Butoxycarbonyl-methyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid, conversion 96%, ee 95% (HPLC, Chirobiotic R, 250 mm×4.6 mm, MeOH/0.1% TEA acetate pH 4.75 (40:60), 0.5 ml/min, ambient temperature, detection UV 230 nm, retention times 16.79 minutes and 21.53 minutes).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:21])[NH:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](=O)[CH3:17])([CH3:10])([CH3:9])[CH3:8].[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23].Cl>O1CCCC1>[CH2:26]([O:25][C:22](=[O:24])/[CH:23]=[C:16](\[CH3:17])/[CH2:15][C:14]([NH:13][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:21])([CH3:19])[CH3:20])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CC(=O)CC(C)(C)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Triethyl phosphonoacetate (4.7 g; 20.9 mmol) was dissolved in tetrahydrofuran (36 ml). Potassium tert-butoxide (2.3 g; 20.9 mmol) was added and the reaction mixture was stirred for 40 min at room temperature. (1,1-Dimethyl-3-oxobutyl)carbamic acid tert-butyl ester (2.5 g; 11.6 mmol) was dissolved in tetrahydrofuran (15 ml) and added dropwise to the reaction mixture which was heated to reflux for 12 h. Ethyl acetate (100 ml) and hydrochloric acid (1 N; 100 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with an aqueous solution of sodium hydrogen carbonate (saturated; 100 ml), dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by flash chromatography on silica (120 g) using ethyl acetate/heptane (1:2) as eluent to afford 2.0 g of (2E)-5-tert-butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ethyl ester.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@@H:13]2[CH2:15][C@H:14]2[CH2:16][NH2:17])=[N:5]1.C(N(CC)CC)C.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:17][CH2:16][C@@H:14]2[CH2:15][C@H:13]2[C:10]2[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=2)=[N:5][N:4]([CH3:3])[CH:12]=3)=[O:31])=[CH:28][CH:27]=1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)c3ccc(Br)cc3)cccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of 1-[(1R,2R)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (200 mg, 0.729 mmol) and triethylamine (407 μL, 2.92 mmol) in tetrahydrofuran (7 mL) was added 4-bromobenzoyl chloride (192 mg, 0.875 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give the title compound (247 mg, yield 88%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][O:20][C:21]2=[O:26]>ClCCl>[CH:1](=[N:16]/[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][O:20][C:21]2=[O:26])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 95 %

Procedure:
To a stirred mixture of benzaldehyde (1.91 g, 18 mmol) and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (100 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.24 g, 15 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one (3.38 g, yield 95%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.41 (s, 2H), 7.36-7.37 (d, J=7.6 Hz, 1H), 7.49-7.59 (m, 4H), 7.77-7.78 (d, J=7.6 Hz, 1H), 7.92-7.94 (d, J=8.0 Hz, 2H), 8.55 (s, 1H), LC-MS (ESI) m/z: 238 (M+1)+.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:5]2[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]2=[O:9])=[O:24])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of (4S)-4-isopropyl-1,3-oxazolidin-2-one (2.0 g, 15.5 mmol) in dry THF (20 mL) at −78° C. under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (6.2 mL, 15.5 mmol). After stirring at −78° C. for 15 min, (4-fluorophenyl)acetyl chloride (2.55 mL, 18.6 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 30 min and 0° C. for 15 min, quenched with saturated NH4Cl (5 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%–15% EtOAc/hexane) to give 2.83 g (10.7 mmol, 69%) of (4S)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.30–7.25 (m, 2H), 7.10 (t, 2H, J=8.5 Hz), 4.46–4.41 (m, 1H), 4.36–4.15 (m, 4H), 2.40–2.28 (m, 1H), 0.88 (d, 3H, J=7.6 Hz), 0.79 (d, 3H, J=7.6 Hz); ESMS m/e: 266.2 (M+H)+.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19](O)=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([Cl:26])=[O:20])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 3-(3-p-tolylsulfamoyl-phenyl)-acrylic acid (5d) (0.75 g, 2.36 mmol) in dichloromethane (10.0 ml): oxalyl chloride (0.62 ml, 7.08 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.79 g).
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH2:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH:35]=[CH:34]1>C1(C)C=CC=CC=1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1C=CC(=O)O1
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Solvent: Cc1ccccc1
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)/C=C\C(=O)O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 81.3 %

Procedure:
2.0 g (4.7 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) and 0.61 g (6.2 mmol) of maleic anhydride were dissolved in 50 ml of toluene. Some molecular sieves were added and the reaction mixture was refluxed for 5 hours. After cooling, the reaction mixture was evaporated in vacuo to dryness, dissolved in CH2Cl2 and washed with sat. sol. NaCl, 20% citric acid, sat. sol. NaCl. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of i-Pr2O/EtOAc 70:30 containing 0.5% of 85% formic acid, and then triturated with i-Pr2O to yield 2.0 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:12][NH2:13]>CCO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:12][NH2:13])=[O:5]
Reactant: COC(=O)c1ccccc1Br
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1ccccc1Br

Procedure:
A solution of methyl 2-bromobenzoate (1.0 g, 4.7 mmol) in EtOH (15 mL) was treated with hydrazine (0.18 mL, 5.6 mmol) and heated to reflux for 15 hours. The resulting solution was concentrated to a white powder (998 mg).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][C:23]1[O:27][N:26]=[C:25]([OH:28])[CH:24]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.CC(O)C.Cl>CO>[ClH:21].[NH2:8][CH:9]([CH2:22][C:23]1[O:27][N:26]=[C:25]([OH:28])[CH:24]=1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)Cc1cc(O)no1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: NC(COc1noc2ccc(Cl)cc12)Cc1cc(O)no1

Procedure:
To a solution of 0.38 g of 3-[2-tert-butoxycarbonylamino-3-(3-hydroxy-5-isoxazolyl)propoxy]-5-chloro-1,2-benzoisoxazole in 2 ml of methanol is added 1.2 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for six hours, after which the solvent is removed by distillation under reduced pressure. Ethyl acetate is added to the residue obtained and the crystals precipitated are collected by filtration, to obtain 0.22 g of pale yellow, crystalline 3-[2-amino-3-(3-hydroxy-5-isoxazolyl)propoxy]-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 188.5°-193.5° C. (decomp.).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([CH3:14])[C:7]=1[NH2:8]>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([CH3:14])[C:7]=1[N:8]=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(Cl)cc(Cl)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(Cl)c1N=C=S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.9 %

Procedure:
Thiophosgene (17.0 g, 148 mmol) was added dropwise to a stirred mixture of 2,4-dichloro-6-methylaniline (20.0 g, 114 mmol) in tetrahydrofuran (100 mL) and saturated aqueous sodium hydrogen carbonate (100 mL) at 0° C., and the mixture was stirred at room temperature for 90 minutes. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give the title compound as a colorless powder (14.4 g, 66.0 mmol, 58%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC3CC3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC5CC5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-4-(4-cyclopropylmethyl-piperazin-1-yl)-3-nitro-pyridin-2-ylamine (0.043 g, 0.12 mmol) and EtOH (3 ml) was added 4-methoxybenzaldehyde (0.027 g, 0.18 mmol) with the aid of EtOH (1 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 ml, 0.48 mmol). The reaction mixture was stirred at 70° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 4%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.012 g, 23%). 1H-NMR (500 MHz, DMSO-d6) 0.12 (m, 2H) and 0.50 (m, 2H) (cyclopropyl CH2), 0.90 (m, 1H, cyclopropyl CH), 2.27 (d, J=6.4 Hz, 2H, N—CH2cyclopropyl), 2.67 (br s, 4H, piperazine N(CH2)2), 3.66 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.8 Hz, 2H) and 8.14 (d, J=8.8 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:19]([CH3:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[CH3:21])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:14]([CH3:21])=[CH:15][C:16]([NH:17][C:28](=[O:29])[NH:27][C:25](=[O:26])[C:24]3[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=3[Cl:22])=[CH:18][C:19]=2[CH3:20])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2Cl)cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Temperature: 70 °C
Yield: 74.5 %

Procedure:
To a solution containing 3.0 g of 4-(4-chloro-5,6,7,8-tetrahydro-1-naphthoxy)-3,5-dimethylaniline in 40 mL of toluene under an atmosphere of nitrogen and heated to 70° C. (internal) was slowly added a solution containing 2.7 g of 2-chlorobenzoyl isocyanate in 5 mL of toluene. The resulting mixture was heated at 70° C. for 1/2 hour. The reaction mixture was cooled to 0° C. and filtered. The collected solid was washed with toluene and then hexane. It was dried under vacuum to afford 3.58 g of a white solid, mp. 224°-226° C. NMR (DMSO-d6): 1.7-2.2 (m, 10H, contains singlet at 2.03), 2.7-3.0 (m, 4H), 6.07 (d, J=9 Hz, 1H), 7.07 (d, J=9 Hz, 1H), 7.07 (d, J=9 Hz, 1H), 7.4-7.7 (m, 4H), 10.38 (S, 1H), 11.20 (S, 1H).
Reaction SMILES: [Mg].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH3:8][C:9](=[CH:12][CH2:13][CH3:14])[CH:10]=[O:11].[Cl-].[NH4+]>CCOCC>[CH3:8][C:9]([CH:10]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH2:13][CH3:14]
Reactant: CCC=C(C)C=O
Reactant: CCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC=C(C)C(O)CCCCC
Temperature: 10 °C

Procedure:
2.4 g (0.1 g atom) of magnesium in 50 ml of absolute ether are placed in an apparatus which is customary for Grignard reactions. While stirring and under a protective gas atmosphere (nitrogen) there are subsequently added dropwise 15.0 g (0.1 mol) of n-amyl bromide in 50 ml of absolute ether so that, after initiation of the reaction, the ether constantly boils slightly. After completing the addition, the mixture is held at reflux temperature for a further 30 minutes, then cooled to 10° C. and a solution of 7.85 g (0.08 mol) of 2-methyl-2-pentenal in 20 ml of absolute ether is added dropwise. In order to complete the reaction, the mixture is stirred at room temperature for a further 12 hours. After decomposing the Grignard complex with saturated ammonium chloride solution and ice, the supernatant ethereal solution is washed with saturated sodium chloride solution and subsequently dried. After evaporating the solvent, there remain 13.6 g of crude product which are fractionally distilled. There are thus obtained 8.9 g of pure 4-methyl-3-decen-5-ol of boiling point 103° C./12 mm Hg, nD20 =1.4499.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][CH:16]=[CH:17][CH:18]=3)[C:4]=2[O:3]1>C(O)(=O)C.[Pt]=O>[CH3:1][C:2]1([CH3:25])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH:14]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(CNc3cccnc3-c3ccccc3)c2O1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC1(C)Cc2cccc(CNC3CCCNC3c3ccccc3)c2O1
Reaction time: 8.5 h
Yield: 39.5 %

Procedure:
9.2 g of 3-[(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-phenylpyridine was dissolved in 120 ml of acetic acid, and 1 g of platinum oxide was added. A hydrogenation reaction was carried out at 3 atmospheric pressure for 8.5 hours. After completion of the reaction, the catalyst was filtered off and the solvent was concentrated. After adding ice pieces to the residue and alkalizing it with 50% aqueous sodium hydroxide solution, it was extracted three times with dichloromethane. After drying the extract solution, it was distilled off and purified by a silica gel chromatography (dichloromethane/methanol 30:1-10:1-3:1) to obtain 3.7 g of oily 3-[(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-phenylpiperidine.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.[O:18]=[C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:22][CH2:21][N:20]1[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][N:40]=1)[C:34](OC)=[O:35]>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:34](=[O:35])[C:33]2[CH:38]=[CH:39][N:40]=[C:31]([N:20]3[CH2:21][CH2:22][N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:19]3=[O:18])[CH:32]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccccn3)C2=O)c1
Reactant: NCc1ccc(F)cc1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccccn3)C2=O)c1
Yield: 52 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 4-fluorobenzylamine to react with methyl 2-(2-oxo-3-(pyridin-2-ylmethyl)imidazolidin-1-yl)isonicotinate, the title compound was obtained as a colorless solid in 52% yield: mp 141-142° C.; 1H NMR (300 MHz, CDCl3) δ 8.56-8.53 (m, 2H), 8.35 (d, J=4.8 Hz, 1H), 7.68-6.86 (m, 9H), 4.57-4.54 (m, 4H), 4.06 (t, J=7.9 Hz, 2H), 3.53 (t, J=8.0 Hz, 2H); MS (ES+) m/z 405.7 (M+1).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.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>[CH:4]([C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[N:23][CH:24]=1)=[O:5]
Reactant: Cc1cccc(Cl)c1C=O
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cccc(C)c2C=O)cn1
Temperature: 100 °C

Procedure:
2-chloro-6-methylbenzaldehyde (156 mg, 1.01 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (434 mg, 1.25 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), and 2M K3PO4 (aq) (1.0 mL, 2.00 mmol) were dissolved in 1,4-dioxane (3.0 mL) and heated to 100° C. After 4 h the resulting mixture was cooled to room temperature, diluted with DCM, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C(S([C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:32])=[O:31])=[CH:26][N:25]=1)(=O)=O)CCCCC.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:31])=[O:32])=[CH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCCS(=O)(=O)c1ccc(S(=O)(=O)CCCCCC)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)nc1
Temperature: 25 °C
Yield: 52 %

Procedure:
To 4.33 g of 4-bromophenol dissolved in a 22 ml THF/22 ml DMSO mixture was added 3.1 g of t-BuOK and then 9.39 g of 2,5-bis(n-hexylsulfonyl)pyridine, and the resulting mixture heated at 59° C. for 1 hr. The reaction mixture was cooled to room temperature and then added to approximately 4 to 5 volumes of water. The yellow precipitate which formed was removed by filtration. Recrystallization from CH2Cl2 /ethanol gave the product, 2-(4-bromophenoxy)-5-(n-hexylsulfonyl)pyridine, (52% yield), as white shiny prisms, m.p. 94° C.