Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(C2=CCN(Cc3ccccc3)CC2)ccc1Cl

Procedure:
1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidine-4-ol (1.5 g) was dissolved trifluoroacetic acid (35 ml) and refluxed for 24 hours and then CH2Cl2 (200 ml) was added. The phases were separated and then the organic phase was washed with two portions of 10%-Na2CO3, dried (MgSO4), filtered and evaporated to dryness. Yield 1.5 g. MS m/z (relative intensity, 70 eV) 351 (M+, 27), 172 (9), 92 (11), 91 (bp), 65 (21).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:15]([C:14]2[CH:18]=[CH:19][C:11]([F:10])=[CH:12][CH:13]=2)=[O:16])=[C:5]([OH:9])[CH:4]=1)[CH3:2]
Reactant: CCc1cccc(O)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCc1ccc(C(=O)c2ccc(F)cc2)c(O)c1
Yield: 5.3 %

Procedure:
3-Ethylphenol (24.4 g) and 4-fluorobenzoyl chloride (34.9 g) were reacted together as in Example 2 giving three main fractions: B (11.4 g) 126°-129° C. at 0.07 mmHg; C (7.9 g), 129°-132° C. at 0.06 mmHg; D (5.9 g), 132°-150° C. at 0.06 mmHg, all containing ~ 80% of the required isomer. B (4.0 g) was separated by preparative thin layer chromatography to give the title compound (2.6 g), m.p. 44°-48° C. The same compound was obtained using the method of Example 4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH:45][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)=[CH:42][CH:41]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 4-chlorobenzylamine and potassium carbonate essentially as described above in example 4. Purity by LC/MS (APCI)=100%, [M+H]+=399 m/e.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7](O)([CH3:11])[CH2:8][CH2:9][OH:10].[C:13](#[N:15])[CH3:14]>>[CH3:14][C:13]1[O:10][CH2:9][CH2:8][C:7]([CH3:11])([CH3:6])[N:15]=1
Reactant: CC(C)(O)CCO
Reactant: CC#N
Agent: O=S(=O)(O)O
Product: CC1=NC(C)(C)CCO1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
Acetonitrile (22.6 g, 0.25 mol) was dripped into concentrated H2SO4 (150 mL) at 0° C. Upon complete addition of acetonitrile, 3-methyl-butane-1,3-diol (Fluka, 22.6 g, 0.55 mol) was added over 0.5 h maintaining the reaction temperature at or below 5° C. The resulting mixture was stirred for 1.5 h at 5° C. then poured onto crushed ice. When the ice had melted, the aqueous was extracted with ether (2×250 mL). The organic was discarded and the aqueous was treated with 40% NaOH to pH 12. The basic aqueous was extracted with ether. The organic was washed with brine and dried (MgSO4). The ether was removed under vacuum at 25° C. affording the desired product as a colorless oil (25.4 g, 50%): 1H NMR (DMSO-d6) δ 4.04 (t, 2H, J=6 Hz), 1.72 (s, 3H), 1.61 (t, 2H, J=6 Hz), 1.07 (s, 6H).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[C:25](Cl)(=[O:36])[O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1>O1CCCC1>[N+:33]([C:30]1[CH:31]=[CH:32][C:27]([O:26][C:25]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[O:36])=[CH:28][CH:29]=1)([O-:35])=[O:34]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: O=C(CCNC(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1

Procedure:
200 mg (0.57 mmol) of commercially available 4-methylbenzenesulphonic acid-benzyl beta-alaninate and 229 mg (1.14 mmol) of 4-nitrophenyl chlorocarbonate were taken up in 15 ml of tetrahydrofuran and the reaction mixture was then heated to reflux for 30 min. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was purified by means of preparative HPLC. After concentration of the corresponding fractions and drying of the residue under high vacuum, 86 mg (44% of theory) of the title compound were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29]C)=[O:28].[OH-].[Li+]>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
A solution of methyl 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate (5.20 g, 11.73 mmol) in tetrahydrofuran (150 mL) and water (80 mL) was cooled to 0° C. under nitrogen and lithium hydroxide (1.13 g, 47.4 mmol) was slowly added. The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to ambient temperature, stirred for an additional 16 h and concentrated in vacuo. The residue was poured into cold (0° C.) 1 M hydrochloric acid (100 mL), causing a precipitate to be deposited. The mixture was stirred for 2 h at ambient temperature and filtered. The solid was washed with water and hexanes to afford 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (5.08 g, 99%) as a colorless solid: mp 254-258° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 8.03-8.00 (m, 2H), 7.59-7.44 (m, 2H), 7.21-7.16 (m, 2H), 7.04-7.00 (m, 1H), 6.73-6.71 (m, 1H), 6.50 (s, 1H), 6.31 (s, 1H), 5.24-4.60 (m, 5H), 4.15-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.7, 170.7, 155.2, 144.7, 141.7, 138.5, 136.3, 132.56, 132.3, 130.0, 129.7, 129.3, 128.9, 128.6, 124.1, 123.7, 120.9, 111.6, 109.1, 99.5, 80.0, 64.5, 63.9, 58.1, 43.6; MS (ES+) m/z 429.7 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[C:14]2[C:9](=[CH:10][CH:11]=[N:12][C:13]=2[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:8]=1)(=O)=O.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:28]([NH:35][C:7]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:15]=2[C:14]2[C:9](=[CH:10][CH:11]=[N:12][C:13]=2[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:8]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: CCCCOc1nccc2nc(OS(=O)(=O)C(F)(F)F)c3ccncc3c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCOc1nccc2nc(NCc3ccccc3)c3ccncc3c12
Temperature: 80 °C

Procedure:
To a solution of 1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-yl trifluoromethanesulfonate (127 mg, 0.253 mmol) in THF (2531 μl), benzylamine (111 μl, 1.013 mmol) was added. The reaction mixture was heated at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. Aqueous sodium hydrogen carbonate (saturated) was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford N-benzyl-1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-amine as a brown oil. LRMS (APCI) calc'd for (C22H23N4O) [M+H]+, 359.2; found 359.1.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17][C:18](N(C)C)=[N+](C)C)[C:12]2N=CC=CC=2N=N1.CONC.C(N(CC)CC)C.[CH:36]1([CH2:39][C:40]([OH:42])=O)[CH2:38][CH2:37]1>C(Cl)Cl>[CH:36]1([CH2:39][C:40]([N:8]([O:17][CH3:18])[CH3:12])=[O:42])[CH2:38][CH2:37]1
Reactant: O=C(O)CC1CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (19.0 g), N-methoxymethanamine (5.0 g), and triethylamine (15.1 g) were added to a solution of 2-cyclopropylacetic acid (5.0 g) in CH2Cl2 (200 mL) at 0° C. The mixture was stirred at room temperature for 3 h. The reaction mixture was then washed with water and the aqueous washing phase was extracted with ethyl acetate (5×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 20:1→5:1) to give the title compound. Yield: 4.1 g (58% of theory).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH:10]2[N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[Cl:26])[CH2:17]1)=[O:6]>CO.O.CC(C)=O>[Cl:26][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:24](=[O:25])[N:16]([CH:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=3)[CH2:12][CH2:11]1)[CH2:17]2
Reactant: COC(=O)c1ccc2c(c1)C(N1Cc3cccc(Cl)c3C1=O)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(N1Cc3cccc(Cl)c3C1=O)CC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
LiOH (5 equiv.) was added to a suspension of 3-(4-chloro-3-oxo-1,2-dihydro-isoindol-2-yl)-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (D-01) (11.75 mmol) in methanol (90 ml) and water (30 ml) and the reaction mixture was stirred at 25° C. for 72 h. Methanol was distilled off, the aqueous residue was acidified with 1N HCl and the mixture was filtered. The white solid obtained was taken up in a mixture of 350 ml of acetone and 50 ml of methanol and the mixture was stirred for 1 h. After filtration, the white solid was dried in vacuo to obtain 3-(4-chloro-3-oxo-1,2-dihydro-isoindol-2-yl)-2,3-dihydro-1H-indene-5-carboxylic acid (G-01). Yield: 66%
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23](OCC)=[O:24])(=O)[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][NH:34][NH2:35])=[CH:31][CH:30]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:16]([O:15][C:6]1[C:5]2[C:23](=[O:24])[N:34]([CH2:33][C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)[N:35]=[C:1]([CH3:2])[C:4]=2[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Reactant: NNCc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 120 °C

Procedure:
A mixture of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (65 mg, 0.18 mmol) and 4-fluorobenzyl hydrazine (0.12 g, 0.88 mmol), and acetic acid (3 drops) in toluene (40 mL) was heated in a sealed tube at 120° C. overnight. The reaction mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluted with 1-5% methanol in ethyl acetate gradient to provide titled product.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30].C1(N2CCC3C=CC(OC4N=CC(N5CCCC5=O)=CC=4)=CC=3CC2)CCC1>>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: O=C1CCCCN1
Agent: O=C1CCCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Product: O=C1CCCCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
Example 218 (E218) was prepared from 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and 2-piperidinone using the method described for Example 217 (E217); MS (ES+) m/e 392 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=3[CH:15]=[C:7]2[C:6]2[N:17]=[C:18]([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)[CH:19]=[CH:20][C:5]=2[O:4]1.CCN(CC)CC.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl.O>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[N:17]=[C:18]([C:21]5[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[CH:23][C:24]6[O:28][C:27]([C:29]7[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=7)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=6[CH:40]=5)[CH:19]=[CH:20][C:5]=4[O:4][CH:3]([CH2:2][NH:1][S:55]([CH3:54])(=[O:57])=[O:56])[N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN)O4)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CNS(C)(=O)=O)O4)cc12
Temperature: 25 °C
Yield: 34.6 %

Procedure:
A mixture of 5-(6-(aminomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.08 mmol), and Et3N (11 mg, 0.12 mmol) in dichloromethane (1 mL) was stirred at room temperature under N2 protection. Then MsCl (11 mg, 0.09 mmol) was added and the solution was stirred at room temperature for overnight. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (dichloromethane:MeOH=15:1) to provide 5-(11-fluoro-6-(methylsulfonamidomethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 35.7%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=4.8 Hz, 1H), 7.83 (s, 1H), 7.96˜8.06 (m, 3H), 7.65˜7.70 (m, 1H), 7.59˜7.63 (m, 1H), 7.57 (t, J=6.4 Hz, 1H), 7.37˜7.44 (m, 3H), 7.24˜7.30 (m, 1H), 7.10 (s, 1H), 6.91˜6.97 (m, 1H), 6.77 (dd, J=6.8 Hz, 4.4 Hz, 1H), 3.37 (dd, J=14.0, 7.2 Hz, 2H), 3.29 (br s, 3H), 2.89 (s, 3H), 2.77˜2.87 (m, 6H). MS (M+H)+: 722.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5](SC)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1(C)C(C)=CC=CC=1.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>C(O)(=O)C.C(O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[CH2:22][CH2:23]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[CH2:22][CH2:23]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: CSC1=Nc2ccccc2N(C)c2cscc21
Reactant: OCCN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CN1c2ccccc2N=C(N2CCN(CCO)CC2)c2cscc21

Procedure:
A mixture comprising 2.6 g. of 4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine (U.S. Pat. No. 3,951,981 -- Ex. 7), 2.6 g. of hydroxyethylpiperazine, 3 drops of acetic acid and 15 ml. of xylene is stirred and refluxed overnight. The mixture is evaporated, washed with water and the residue dissolved in 50 ml. of 2N acetic acid. The solution is filtered. The filtrate is made alkaline with ammonium hydroxide and extracted with chloroform. The extract is dried over magnesium sulfate, filtered and evaporated giving a dark colored oil. This oil is dissolved in 20 ml. of ethanol. A mixture of 1.2 g. of fumaric acid in 25 ml. of ethanol is added and on standing a yellow solid separates. This solid is recrystallized from 75 ml. of ethanol giving the desired product, m.p. 192°-193° C. as the fumarate salt.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[CH2:14](C1C=C(C=C(C)N=1)C(O)=O)C>>[CH2:13]([C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH3:2])[N:12]=1)[C:6]([NH:8][NH2:9])=[O:7])[CH3:14]
Reactant: Cc1cc(C(=O)NN)cc(C)n1
Reactant: CCc1cc(C(=O)O)cc(C)n1
Agent: Cl
Product: CCc1cc(C(=O)NN)cc(C)n1

Procedure:
The title compound is prepared in analogy to 2,6-dimethyl-isonicotinic acid hydrazide hydrochloride starting from 2-ethyl-6-methyl-isonicotinic acid; 1H NMR S 1.46 (t, J=7.6 Hz, 3H), 2.87 (s, 3H), 3.15 (q, J=7.6 Hz, 3H), 8.14 (s, 1H), 8.16 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][CH:9]=1)=[O:6].B(Br)(Br)Br.CCCCCC.CCOC(C)=O.CCOC(C)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4cccc(N)c4)cc3)sc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Nc1cccc(C(=O)Nc2ccc(-c3nc4ccc(O)cc4s3)cc2)c1
Yield: 61.7 %

Procedure:
Prepared as described in the Demethylation section using 3-amino-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (50 mg, 0.13 mmol) in dry DCM (3 ml) and BBr3 (1.0 M solution in DCM, 0.67 ml, 0.67 mmol) to give the title compound (29 mg, 60%) as a pale brown solid after work-up and flash chromatography (1:1 Hexane/EtOAc followed by EtOAc).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:4]=[C:3]1[SH:13].C(N(CC)CC)C.Cl[CH2:22][C:23](=[O:25])[CH3:24]>CC(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:4]=[C:3]1[S:13][CH2:22][C:23](=[O:25])[CH3:24]
Reactant: Cn1c(-c2ccccc2)cnc1S
Reactant: CC(=O)CCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CSc1ncc(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 4.76 g (0.025 mol) of 1-methyl-5-phenyl-imidazol-2-thiol and 3.15 g (0.031 mol) of triethylamine in 250 mL of acetone was added 2.55 g (0.28 mol) of chloroacetone in 250 mL of acetone. The solution was stirred at room temperature for 16 hours. The acetone was removed by evaporation and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with water, brine, and dried over magnesium sulfate. The solvent was evaporated from the dried solution to obtain as residue 6.16 grams of 1-methyl-5-phenyl-2[(2-oxopropyl)thio]imidazole which was purified by flash chromatography on silica gel using 2 percent methanol in chloroform as eluant.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:14])[C:10]=2[O:9]1
Reactant: CNCC1Cc2cccc(Br)c2O1
Reactant: Cc1ccccc1B(O)O
Product: CNCC1Cc2cccc(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.055 g, 24%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.20 g, 0.826 mmol) and 2-methylphenylboronic acid (0.168 g, 1.24 mmol). mp 166-169° C.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23](=[O:28])N(OC)C)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]([C:2]1[O:1][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)=[O:28])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Reactant: c1cnc2occc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2cccnc2o1
Yield: 32 %

Procedure:
2.5N n-Butylithium in hexanes (2.3 ml, 5.75 mmol) was added dropwise over 10 min to a stirred solution of furo[2,3-b]pyridine (0.57 g, 4.79 mmol) (H. Sliwa, Bull. Soc. Chim. France, 646, 1970) in anhydrous THF (20 ml) at −75° C. under argon. The resultant mixture was stirred for 5 min at −70° C. then a solution of (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (1.41 g, 5.19 mmol) in anhydrous THF (20 ml) was added over 2 min. and the resultant solution stirred at −70° C. for 15 min. The mixture was poured into saturated ammonium chloride (100 ml) and extracted with ethyl acetate (2×50 ml). The combined organics were dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 0-1% ethyl acetate in dichloromethane to give the title compound as a colourless solid (0.51 g, 32%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(Cc3ccccc3)C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(Cc3ccccc3)C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-ethoxycarbonyl-benzylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.