Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[F:12][C:10]1[CH:11]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[C:7]([OH:13])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)cc(F)c2c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 6-bromo-8-fluoro-2-naphthol (0.39 g, 1.62 mmol) with 4-methoxyphenyl boronic acid (0.34 g, 2.27 mmol) according to method A to yield 0.35 g (81%) of a white solid: mp 150-151° C.; 1H NMR (DMSO-d6): δ 3.81 (3H, s), 7.05 (2H, d, J=8.75 Hz), 7.16-7.20,(2H, m), 7.57 (1H, dd, J=1.21 Hz, J=12.76 Hz), 7.74 (2H, d, J=8.74 Hz), 7.89-7.92 (2H, m), 10.10 (1H, s); MS (ESI) m/z269 (M−H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:46])[CH:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]([C:30]([C:32]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][C:33]=3[CH2:41][CH2:42][CH2:43][CH3:44])=[O:31])[CH3:29])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[Br:45])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CO>[Br:45][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]([C:30]([C:32]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][C:33]=3[CH2:41][CH2:42][CH2:43][CH3:44])=[O:31])[CH3:29])=[CH:23][CH:22]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:46])=[O:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)OC)c(Br)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)O)c(Br)c2)cc1
Yield: 92.4 %

Procedure:
1 N NaOH (2.28 mL, 2.28 mmol) was added under nitrogen to a solution of methyl2-[(3-bromo-4′-{[[(2-butyl-1-benzofuran-3-yl)carbonyl](methyl)amino]methyl}-1,1′-biphenyl-4-yl)oxy]-3-phenylpropanoate (995 mg, 1.52 mmol), prepared in the previous step, in 100 mL of methanol plus 10 mL of water. After the addition the reaction was refluxed for 5 h. The reaction was filtered, acidified with 2.5 mL of 1 N HCl and concentrated under reduced pressure to remove the methanol. The solid that was present was collected by filtration and dried under reduced pressure to give the title compound (900 mg, 92%) as a white solid, mp 79-86° C. Elemental Analysis for C36H34BrNO5Calc'd: C, 67.50; H, 5.35; N, 2.19. Found: C, 6 7.16; H, 5.42; N, 2.09
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:32]#[N:33].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[CH2:10][CH2:11][C:32]#[N:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCC#N)c1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1.88 g (4.16 mmol) Toluene-4-sulfonic acid 3-tert-butoxycarbonylamino-3-(3-nitro-phenyl)-propyl ester were dissolved in 5 ml DMF and 306 mg (6.24 mmol) sodium cyanide were added. The mixture was stirred for 5 h at 60° C. The reaction mixture was poured into 50 ml water, the precipitate was filtered, washed with water and dried in vacuo. The crude product was used without further purification.
Reaction SMILES: [CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][C:8](=[O:9])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:10][C:11]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:15]=1
Reactant: O=C=NCCCCCCN=C=O
Reactant: Nc1cccnc1
Solvent: Cc1ccccc1
Product: O=C(NCCCCCCNC(=O)Nc1cccnc1)Nc1cccnc1

Procedure:
A solution of hexamethylene di-isocyanate (1.68g.) in toluene (10ml.) was added to a solution of 3-aminopyridine (1.88g.) in toluene (18ml.) and the mixture was heated on a steam-bath for 10 minutes. The mixture was cooled, and the product was filtered off, washed with toluene and dried, to give 1,6-bis[3-(pyrid-3-yl)ureido]hexane, m.p. 197°-199°C., the starting material for compound 67.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[C:37]([C:41]1[CH:74]=[CH:73][C:44]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[C:50]([CH3:72])[CH:49]=2)=[O:46])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([C:41]1[CH:74]=[CH:73][C:44]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:70])[CH3:71])[C:65]([OH:67])=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[C:50]([CH3:72])[CH:49]=2)=[O:46])=[CH:43][CH:42]=1)([CH3:38])([CH3:40])[CH3:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3C)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: Cc1cc(NC(=O)c2ccc(C(C)(C)C)cc2)ccc1-c1ccc2c(c1)C(=O)N([C@H](C(=O)O)C(C)C)C2
Yield: 82 %

Procedure:
The compound of example 468 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 467.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:15]=[CH:16][C:17]=1[NH2:18]
Reactant: [H][H]
Reactant: COc1cc(OCCN2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCOCC2)ccc1N
Yield: 87.6 %

Procedure:
A mixture of 4-[2-(3-methoxy-4-nitrophenoxy)ethyl]morpholine (1.2 g, 4.3 mmol) and 5% Pd—C (0.2 g) in ethyl acetate (75 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 0.95 g of the product as a light grey oil, in 87% yield: 1H NMR (CDCl3) δ 2.57 (t, J=4.6 Hz, 4H), 2.77 (t, J=5.7 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 3.82 (s, 3H), 4.05 (t, J=5.7 Hz, 2H), 6.34 (dd, J=8.4 Hz, J=2.5 Hz, 1H), 6.47 (d, J=2.5 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[Br:21]Br.O>O>[Br:21][C:17]1[C:18]([Cl:20])=[CH:19][C:4]2[N:3]=[C:2]([Cl:1])[N:6]([C@@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:5]=2[CH:16]=1
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](O)[C@@H]1O
Reactant: BrBr
Solvent: O
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Br)cc32)[C@H](O)[C@@H]1O
Reaction time: 6 h

Procedure:
To a suspension of 0.110 g (0.313 mmol, as C12H12Cl2 N2O4MeOH) of 2,5-dichloro-1-β-D-ribofuranosylbenzimidazole (73) in 3 mL of H2O was added dropwise 10 mL of a sat. solution of Br2 /H2O at room temperature. After the addition had been completed, stirring was continued for 6 hr. The reaction mixture was filtered and the solid was washed with portions of H2O, and then recrystallized from MeOH to give 0.091 g (73%, 2 crops) of 99 as white crystalline needles. MP 158°-159° C. MS (El) m/e 395.9274 (5% M+ =395.9279). 1H NMR (DMSO-d6): δ 8.69 (s, 1, 7-H), 7.96 (s, 1,4-H), 5.88 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.41 (t, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.42 (m, 1, 2'-H, J2'-3' =5.5 Hz), 5.30 (d, 1, 3'-OH, J3'4' =1.5 Hz), 4.01 (m, 1, 4'-H, J4'-5' =J4'-5'=2.5 Hz), 371 (m, 2, 5'-H and 5"-H, J5'-5" =1.20 Hz). Anal. Calcd. for C12H11BrCl2N2O4 : C, 36.21; H, 2.79; N, 7.04. Found: C, 36.14; H, 2.90; N, 6.90.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([F:32])([F:30])[F:31])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1cccc2[nH]c3ccccc3c12
Yield: 18.2 %

Procedure:
Prepared from 260 mg (1.09 mmol) of 4-[(2S)-oxiranylmethoxy]-9H-carbazole and 229 mg (1.09 mmol) of 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine according to the procedure used for Example 2 to give 0.089 g of the title compound as a white solid (Et2O, EtOAc/hexane).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH2:24]=[O:25]>C1(C)C(C)=CC=CC=1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH2:24][OH:25])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-n1ccnc1
Reactant: C=O
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 5-(trifluoromethyl)-2-(imidazol-1-yl)benzophenone is heated in a bomb with paraformaldehyde in xylene to 140° C. to give 5-(trifluoromethyl)-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=1
Reactant: COC(=O)CCCCCCCNc1ccc(OC)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(F)cc1)c1ccc(OC)cc1

Procedure:
As described in example 3(b), the reaction is carried out with 5.6 g (20 mmol) of 8-(4-methoxyphenylamino)-caprylic acid methyl ester, 5 g (50 mmol) of triethylamine, 150 cc. of toluene and 4 g (25 mmol) of 4-fluorobenzoic acid chloride. Reaction time: 5 hours, reaction temperature: 25° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:14][CH2:15]O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CCO
Reactant: O=C(O)c1cc(Br)cc2c1OCC2
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)cc2c1OCC2
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-2,3-dihydro-1-benzofuran-7-carboxylic acid (1.0 g) in EtOH (15 mL), sulfuric acid (0.5 mL) was added, and the solution was heated at reflux for 30 hours. The reaction mixture was cooled to room temperature, and EtOH was removed. To the residue was added water, and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the titled compound (1.07 g) as pale yellow powder.
Reaction SMILES: II.O[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1/[N:11]=[N:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>O1CCCC1>[N:11]1[N:12]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=2[CH3:21])[CH:4]=[C:5]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2
Reactant: Cc1cc(O)cc(C)c1/N=N/c1ccccc1CO
Agent: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1-n1cc2ccccc2n1
Reaction time: 0.67 h

Procedure:
Iodine (3980 mg, 15.7 mmol) was added to the orange solution of (E)-4-((2-(hydroxymethyl)phenyl)diazenyl)-3,5-dimethylphenol (2680 mg, 10.46 mmol), triphenylphosphine (4110 mg, 15.7 mmol) and imidazole (2140 mg, 31.4 mmol) in tetrahydrofuran (30 mL) at room temperature. The mixture was stirred for 40 minutes. The solvent was evaporated. The crude was dissolved in EtOAc/MeOH and loaded to the column and purified by ISCO (40 g silica gel, EtOAc/heptane: 0->50%), leading to the desired product as a white/pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.85 (s, 6H) 6.49 (s, 2H) 7.07-7.21 (m, 1H) 7.32-7.42 (m, 1H) 7.75 (d, J=8.58 Hz, 1H) 7.80 (dd, J=8.78, 0.98 Hz, 1H) 7.96 (d, J=0.78 Hz, 1H) 7.99 (s, 1H). LCMS: m/z=239.2 [M+H].
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH3:12])[CH2:9][CH2:8][N:7]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5])C.[OH-].[Na+].Cl>CO.C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:7]2[CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][CH:6]2[C:4]([OH:5])=[O:3])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1CN(C)CCN1S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(S(=O)(=O)c2ccc(F)cc2)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
To a solution of 0.390 (1.182 mmol) of the product of Example 53 dissolved in 12 mL of methanol/THF (1:1) was added 5.9 mmol of 1.0N sodium hydroxide solution and the resulting mixture was stirred for 15 h at room temperature. The reaction was then brought to pH 6 with 5% HCl and extracted with dichloromethane. The organics were dried over Na2SO4, filtered and concentrated in vacuo to provide 0.265 g (74%) of the carboxylic acid as a pale yellow solid. Electrospray Mass Spec: 302.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[O:15]=O.[K+].O1CCOCCOCCOCCOCCOCC1.C(OCC)C.[CH3:41][S:42](C)=O>>[OH:15][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[S:42][CH3:41]
Reactant: O=O
Reactant: Brc1cncc(Oc2ccccc2)c1
Reactant: CS(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOCC
Product: CSc1c(O)cncc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Bromo-5-phenoxypyridine (0.50 g) and potassium superoxide (1.42 g) in dry dimethyl sulphoxide (100 ml) containing 1,4,7,10,13,16-hexaoxacyclooctadecane (3.20 g) were stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The solvent was evaporated under reduced pressure to a small volume and the mixture diluted with water, washed with ethyl acetate (twice) and the basic aqueous phase was acidified to pH 4 with dilute aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (three times), the extracts were combined and washed with water (four times), dried over magnesium sulphate and evaporated under reduced pressure to give an oil. The oil was fractionated by chromatography (silica; diethyl ether) to give the required product, 0.19 g, as a colourless solid, m.p. 131–133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH:12]([NH:11][CH3:10])[CH3:13])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(C)Cc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 87.8 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (1.0 g, 6.17 mmole) in 11 mL of dry acetonitrile is added 1.06 mL (12.3 mmol) of methylethylamine followed by 850 mg (6.17 mmol) of potassium carbonate. The reaction is heated at 80° C. for 5 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 1.0 g (87% yield) of 1-(6-Chloro-pyridin-3-ylmethyl)-methylethylamine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.06 (t, 3H, J=7.1 Hz), 2.14 (s, 3H), 2.40 (q, 2H, J=7.1 Hz), 3.43 (s, 2H), 7.25 (d, 1H, J=8.2 Hz), 7.62 (dd, 1H, J=8.2 and 5.8 Hz); MS (187.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:13][C:4]1[C:5]([Cl:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Br)cc(N)c1Cl
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To stirred solution of methyl 5-bromo-2-chloro-3-nitrobenzoate (3.4 g, 11.6 mmol) in ethanol (19 mL) was added ammonium chloride (3.4 g, 57.8 mmol) dissolved in water (30 mL) and iron powder (5.16 g, 92.5 mmol). The reaction mixture was heated at 80° C. for 1 h. On completion, the reaction mixture was filtered through celite washing with ethanol and ethylacetate. The filtrate was extracted with ethyl acetate and the combined organic layers were washed with water, dried and concentrated under reduced pressure to give methyl 3-amino-5-bromo-2-chlorobenzoate (2.8 g, 92.1%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH2:10].[N+](N[C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)=[CH:17][N:16]=1)([O-])=O>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)=[CH:17][N:16]=1
Reactant: COc1cccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)c1
Reactant: NCCSCc1nccs1
Product: COc1cccc(Cc2cnc(NCCSCc3nccs3)[nH]c2=O)c1
Yield: 41.9 %

Procedure:
2-(2-Thiazolylmethylthio)ethylamine (2.00 g) and 2-nitroamino-5-(3-methoxybenzyl)-4-pyrimidone (1.58 g) were fused together at 130° for 4 hours. The mixture was triturated with hot water and the residue was recrystallised from 2-propanol to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone (0.93 g), m.p. 122°-4°. A sample was treated with hydrogen chloride in ethanol and after recrystallision from isopropanol/methanol it had m.p. 104°-6° and gave analytical data corresponding to a hemihydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:14]C(=O)C)[CH:13]=1)[NH:10][C:9](=[O:18])[CH2:8][CH2:7]2)([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([OH:14])[CH:13]=1)[NH:10][C:9](=[O:18])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: CC(=O)Oc1cc([N+](=O)[O-])cc2c1NC(=O)CC2
Agent: Cl
Product: O=C1CCc2cc([N+](=O)[O-])cc(O)c2N1
Yield: 82.7 %

Procedure:
Hydrochloric acid (200 ml) was added to 6-nitro-8-acetoxy-3,4-dihydrocarbostyril (20 g) and the mixture was refluxed for 4 hours. After ice cooling, crystals which precipitated were collected by filtration and recrystallized from methanol to give 13.76 g of 6-nitro-8-hydroxy-3,4-dihydrocarbostyril.
Reaction SMILES: [ClH:1].[O:2]1[CH2:6][CH2:5][C:4](=O)[CH2:3]1.[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.C(=O)C1OC=CC=1>>[O:2]1[CH2:6][CH2:5][CH:4]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[C:18]4[C:19]([Cl:1])=[CH:20][N:21]=[CH:22][C:23]=4[CH:24]=[CH:25][CH:26]=3)(=[O:16])=[O:15])[CH2:10]2)[CH2:3]1
Reactant: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: Cl
Reactant: O=C1CCOC1
Solvent: O=Cc1ccco1
Product: O=S(=O)(c1cccc2cncc(Cl)c12)N1CCC(NC2CCOC2)C1

Procedure:
Hydrochloride of the compound obtainable in Example 19 and tetrahydrofuran-3-one can be used in the method of Example 4-1 instead of hydrochloride of (S)-3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine and furfural, respectively, to obtain the title compound.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13]([NH2:17])([CH2:15][CH3:16])[CH3:14].[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:23]
Reactant: CCC(C)N
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: CCC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 66.1 %

Procedure:
3.6 g of D-galactose, 5 g of secondary butylamine and 3.0 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 4.5 g of 1-(2-chloroethyl)-3-sec.butyl-3-D-galactopyranosylurea are thereby obtained as pale brown caramel.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH:7]2[B:14]([OH:16])[OH:15])([O-])=O.C([O-])=O.[NH4+]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH:7]2[B:14]([OH:16])[OH:15]
Reactant: O=C1OC(B(O)O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C(B(O)O)OC2=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
5-Nitroboronophthalide (2.72 g, 15.2 mmol) and 10% palladium on carbon (911 mg) are suspended in 30 mL of anhydrous tetrahydrofuran. Ammonium formate (4.41 g, 70 mmol) is added and the mixture is stirred at 50° C., under nitrogen for 3 hr. After cooling to room temperature, the catalyst is removed by filtration through a pad of Celite, which is then washed with ˜30 mL of methanol. Concentration in vacuo gives a light brown oil that is purified by dissolution in ethyl acetate and filtration through a plug of silica. Recrystallization from ethanol and water gives a light yellow crystalline solid (1.12 g, 7.52 mmol, 49.5%) with a m.p. of 160-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].N[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1>C(O)C>[Br:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Br
Reactant: Nc1cccs1
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccs1)C(=O)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of ethyl 2-(2-bromo-4,5-difluorobenzoyl)-3-ethoxyacrylate (1.1 g) in ethanol (10 ml) is added portionwise 2-aminothiophene (0.3 g). After stirring the mixture at room temperature for 30 minutes, the precipitated crystals are separated by filtration to give ethyl 2-(2-bromo-4,5-difluorobenzoyl)-3-(2-thienyl)acrylate (0.9 g).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2.C(OCC)(OCC)O[CH2:22][CH3:23].S(=O)(=O)(O)O>C(O)C.C(OCC)(=O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2
Reactant: O=C(O)c1ccc2c(c1)CCc1ccccc1C2=O
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CCc1ccccc1C2=O
Yield: 93.9 %

Procedure:
[step 1] 5-Oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid (JP-B-2526005, 19.9 g, 79 mmol) and triethyl orthoformate (17.0 mL, 102 mmol) were dissolved in ethanol (130 mL), followed by adding concentrated sulfuric acid (1.68 mL, 32 mmol) and the mixture was stirred under reflux for 12 hr. The mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10) to give ethyl 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylate (20.8 g, 94%).