Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[O:13]1[CH:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14]1>C(N(CC)CC)C>[ClH:1].[OH:13][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Oc1ccc(OCCNCC(O)COc2ccccc2)cc1
Yield: 15.6 %

Procedure:
A mixture of p-(2-aminoethoxy)phenol hydrochloride, (1.89 g) triethylamine (1.01 g) and 1,2-epoxy-3-phenoxy-propane (1.5 g) was heated under reflux for 24 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between dichloromethane (100 ml) and 10% w/v potassium carbonate solution. The organic layer was separated, dried (MgSO4), and the solvent was evaporated. The residual oil was dissolved in ethyl acetate and dry hydrogen chloride was passed through the solution until no further solid precipitated. The precipitate was collected and recrystallised from methanol and ethyl acetate to give p-(2-[2-hydroxy-3-phenoxypropylamino]ethoxy)phenol hydrochloride (0.53 g) mp, 171° C.; microanalysis: found C, 60.3; H, 6.7; N, 4.0; Cl, 10.6%; required for C17H22NClO4 : C, 60.1; H, 6.5; N, 4.1; Cl, 10.5% NMR: 3.09 (dd, 1H, CHOH.CH2NH), 3.28 (dd, 1H, CHOH.CH2NH), 3.47 (t, 2H, NHCH2CH2), 4.15 (m, 2H, NHCH2CH2), 4.25 (m, 1H, CHOH), 5.01 (br s, 1H, CHOH), 6.67+6.79 (2d, 4 aromatic H), 6.92 (m, 3 aromatic H), 7.26 (t, 2 aromatic H), 9.1 (br s, NH2+ +phenolic OH). [Note: p-(2-[(2-hydroxy-3-phenoxypropylamino]ethoxy)phenol in addition to being a valuable intermediate also shows significant thermogenic properties in its own right (sub-cut.ED50 in test (b): 0.51 mg/kg; SI in test (c) >100) and is provided together with its pharmaceutically acceptable salts, and compositions, as a further feature of the invention.]
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([N:13]1[C@H:17]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:16][S:15][CH2:14]1)=[O:12].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([N:13]1[C@H:17]([C:18]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:19])[CH2:16][S:15](=[O:33])[CH2:14]1)=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C([C@@H]1CSCN1C(=O)CC1Cc2ccccc2C1)N1CCCC1
Solvent: ClC(Cl)Cl
Product: O=C([C@@H]1CS(=O)CN1C(=O)CC1Cc2ccccc2C1)N1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
Dissolved in 100 ml of chloroform were 5 g of 3-(2-indanacetyl)-4(R)-(1-pyrrolidinecarbonyl)thiazolidine (a compound according to Preparation Example 2 set forth in Japanese Patent Application Laid-Open No. 262557/1990). While chilling with ice water, 3.3 g of meta-chloro-perbenzoic acid were gradually added to the solution. After stirring the mixture for 3 hours, the resultant liquid reaction mixture was washed successively with a 5% solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:chloroform=5:95), thereby obtaining 3.8 g of the title compound as a diastereomeric mixture. Yield: 73%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:7]([OH:8])[CH2:6][C@H:5]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[C:17]([I:18])[C:12]3=[C:11](C)[N:10]=2)[O:4]1.[OH-].[NH4+:21]>>[NH2:21][C:11]1[N:10]=[C:9]([C@@H:5]2[O:4][C@H:3]([CH2:2][OH:1])[CH:7]([OH:8])[CH2:6]2)[N:14]=[C:13]2[NH:15][N:16]=[C:17]([I:18])[C:12]=12
Reactant: [NH4+]
Reactant: Cc1nc([C@H]2CC(O)[C@@H](CO)O2)nc2[nH]nc(I)c12
Agent: [OH-]
Product: Nc1nc([C@H]2CC(O)[C@@H](CO)O2)nc2[nH]nc(I)c12

Procedure:
Compound 8 (6.8 g, 17.35 mmol) was stirred in 200 mL of concentrated ammonium hydroxide (sealed container) at room temperature for 36 h. The mixture was evaporated and the residue was precipitated from acetonitrile-ether. The solid was filtered and dried: 5.36 g (82%) yield. NMR and spectral data on this compound is identical to
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C2C=C3[C:33]4([C:41]5[C:36](=[CH:37]C=C[CH:40]=5)N[C:34]4=[O:42])COC3=CC=2ON=1.BrCC1CCOCC1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:40][CH:41]1[CH2:36][CH2:37][O:42][CH2:34][CH2:33]1)[C:10]3=[O:18]
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: BrCC1CCOCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc2c(c1)OCC21C(=O)N(CC2CCOCC2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 4-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (84%) as a colorless foam; 1H NMR (300 MHz, CDCl3) δ 7.31 (dd, J=7.5, 1.2 Hz, 1H), 7.15 (dd, J=7.5, 1.2 Hz, 1H), 7.04 (dd, J=7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.36 (dd, J=8.4, 2.4 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.03-3.94 (m, 2H), 3.77 (s, 3H), 3.80-3.30 (m, 4H), 2.21-2.05 (m, 1H), 1.74-1.38 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.8, 162.1, 161.5, 142.7, 132.6, 128.7, 123.9, 123.3, 123.2, 120.8, 108.5, 107.5, 96.6, 80.6, 67.4, 67.3, 57.5, 55.5, 46.0, 33.9, 30.8, 30.7; MS (ES+) m/z 366.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])=[C:4]([F:22])[CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])=[C:4]([F:22])[CH:3]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1F
Reactant: CN(C)CC[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cn1
Yield: 64 %

Procedure:
To 250 mg of 4-(4-chloro-2-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 204 mg (64%) of 4-(4-chloro-2-fluoro-phenylamino)-6-(2-dimethylamino-ethoxy)-[1,7]naphthyridine-3-carbonitrile as a yellow solid: melting point 150-152° C.; mass spectrum (m/e): M+H 385.9.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:2].[Br:12]N1C(=O)CCC1=O>FC(C1C=CC=CC=1)(F)F.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH:1]([C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cc(F)ccc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: CC(Br)c1cc(F)ccc1C#N
Temperature: 100 °C
Yield: 93.5 %

Procedure:
To a solution of 2-ethyl-4-fluoro-benzonitrile (prepared according to WO 07039178, page 116) (1.14 g, 7.6 mmol) in trifluoromethyl-benzene (30 mL) was added N-bromosuccinimide (1.63 g, 9.1 mmol, 1.2 eq.) followed by azobisisobutyronitrile (0.025 g, 0.15 mmol, 0.02 eq.). The mixture was heated to 100° C. for 18 hr under an atmosphere of nitrogen and then cooled to room temperature. The mixture was filtered and filtrate partitioned with aqueous sodium sulphite solution (1M, 20 mL). The organic phase was washed with water (20 mL) and then evaporated under reduced pressure to give the title compound as a beige solid (1.62 g, 93%).
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O.[F:16][C:17]([F:22])([F:21])[CH2:18][NH:19][NH2:20].O.N1C=CC(=O)N=1>C(O)(=O)C>[F:16][C:17]([F:22])([F:21])[CH2:18][N:19]1[C:4](=[O:14])[CH2:5][C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:20]1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NNCC(F)(F)F
Agent: O=C1C=CN=N1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(c2ccccc2)=NN1CC(F)(F)F

Procedure:
0.75 Mole (144 g) of benzoylacetic acid ethyl ester and 0.75 mole (126 g) of 2,2,2-trifluoroethylhydrazine hydrate were stirred for 3 hours in 900 ml of boiling acetic acid. The reaction mixture was poured out on 9 l of water. After 1 hour of stirring at room temperature the pyrazolone derivative was filtered and recrystallized from methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[C:13]1[NH:17][C:16](=[S:18])[NH:15][C:14]1=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][C:3]2[CH:12]=[C:13]3[NH:17][C:16](=[S:18])[NH:15][C:14]3=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C=C1NC(=S)NC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc2cc3[nH]c(=S)[nH]c3nc2c1
Temperature: 180 °C
Reaction time: 0.3 h
Yield: 55.4 %

Procedure:
A mixture of 5-[[2-amino-4-(trifluoromethyl)phenyl]methylene]-2-thioxo-4-imidazolidinone (3.63 g, 12 mmol), pyridinium tosylate (1.8 g), and diphenyl ether (5.4 g) was heated at 180° C. under an atmosphere of argon. After 18 minutes, the mixture was cooled, chloroform (60 mL) added and the mixture refluxed. After 30 minutes the solid was filtered off and dissolved in a mixture of water (80 mL) and 10% sodium hydroxide solution (5 mL) with warming. Addition of acetic acid afforded a heavy precipitate which was filtered off, washed with water and dried in vacuo to give 1,3-dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-thione (1.79 g, 52%), m.p. >320° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=O)=[C:24]([F:33])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:47]1([CH2:53][S:54]([NH2:57])(=[O:56])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:53]([S:54]([NH:57][C:30](=[O:32])[CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][CH2:20][C:16]2[CH:15]=[C:14]([C:10]3[C:9]([CH3:34])=[CH:8][C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:12][C:11]=3[CH3:13])[CH:19]=[CH:18][CH:17]=2)=[CH:23][C:24]=1[F:33])(=[O:56])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)NS(=O)(=O)Cc4ccccc4)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
To a solution of 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]propanoic acid (0.186 g, 0.400 mmol) in tetrahydrofuran (5 mL) was added 1,1′-carbonyldiimidazole (97.3 mg, 0.600 mmol), and the mixture was heated under reflux under a nitrogen atmosphere for 1 hr. After cooling the reaction mixture, 1-phenylmethanesulfonamide (91.5 mg, 0.480 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.0897 mL, 0.600 mmol) were added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (0.189 g, yield 76%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[H-].[Na+].CS(O[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)(=O)=O.FC1C=C2C(N=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][CH2:22]2)[CH:2]=[CH:3]1
Reactant: O=c1cc[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1CCN(CCn2ccc(=O)c3ccccc32)CC1
Yield: 76 %

Procedure:
Quinolin-4(1H)-one (250 mg, 1.7 mmol) was deprotonated with sodium hydride (60% in oil, 70 mg, 1.7 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.7 mmol) as described for Intermediate 141. The precipitate formed in the reaction mixture was collected by filtration to give 480 mg (76%) of product as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[C:28]([OH:31])([CH3:30])[CH3:29])[CH2:14][CH2:13]1)[CH2:5]2.C(N(CC)C(C)C)(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>C1COCC1>[CH3:45][O:44][C:42](=[O:43])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[N:20]=[C:19]3[C:28]([OH:31])([CH3:29])[CH3:30])[CH2:16][CH2:17]1)[CH2:5]2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc2c(c1)CC(CN1CCC(n3c(C(C)(C)O)nc4cc(C)ccc43)CC1)C2
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 2-{1-[1-(5-amino-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazol-2-yl}-propan-2-ol (36 mg, 0.096 mmol), N,N-diisopropylethylamine (37 mg, 0.29 mmol) in THF (3 mL) was added methyl chloroformate (9 mg, 0.11 mmol). After stirring overnight, the reaction mixture was quenched with silica-supported diamine-3 (95 mg, Silicycle) to scavenge the excessive amount of methyl chloroformate. The mixture was filtered and concentrated in vacuo, and the residue was purified by flash chromatography eluent to afford (2-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidin-1-ylmethyl}-indan-5-yl)-carbamic acid methyl ester (20 mg, 59%) as white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27]CCCCC.CI>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2csc3ccccc23)C1
Reactant: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cc(C2=CCN(CCc3csc4ccccc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (358 mg, 1 mmol) (obtained from example 29, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Light green semi-solid. Yield: 98 mg (26%); 373 (M+H); 1HNMR (400 MHz, CDCl3): 8.08˜7.82 (m, 3H); 7.40˜6.90 (m, 7H); 6.21˜6.19 (s, 1H); 3.80 (s, 3H); 3.48˜2.60 (m, 10H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[C:6]([C:25](OC)=[O:26])=[C:7]([NH:10][C:11](=[O:24])[CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C:14]2=[O:23])[S:8][CH:9]=1>C(O)C.[Cl-].[Na+].O>[NH:2]([C:25]([C:6]1[C:5]([CH3:4])=[CH:9][S:8][C:7]=1[NH:10][C:11](=[O:24])[CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[O:23])=[O:26])[NH2:3]
Reactant: COC(=O)c1c(C)csc1NC(=O)CN1C(=O)CCc2ccccc21
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1csc(NC(=O)CN2C(=O)CCc3ccccc32)c1C(=O)NN
Temperature: 50 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
Hydrazine monohydrate (0.059 mL, 1.23 mmol) was added to a solution of methyl 4-methyl-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate (221 mg, 0.616 mmol) in ethanol (2 mL) and the resulting solution was stirred at 50° C. for 24 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum to give N-(3-(hydrazinecarbonyl)-4-methylthiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide (174 mg, 0.485 mmol, 79%). Retention time (min)=1.435, method [1], MS (ESI) 359.1 (M+H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:19][O:20][C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:22].O>N1C=CC=CC=1>[CH3:19][O:20][C:21](=[O:22])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:18][C:16]2[S:17][C:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=3)=[N:14][N:15]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CCCCCOc1ccc(-c2nnc(N)s2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCOc1ccc(-c2nnc(NC(=O)c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of 5-(4-pentyloxyphenyl)-1,3,4-thiadiazol-2-yl-amine (20 g) in pyridine (200 ml) was added 4-methoxycarbonylbenzoylchloride (15 g) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried to give N-[5-(4-pentyloxyphenyl)-1,3,4-thiadiazol-2-yl]terephthalamic acid methyl ester (30.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:12][N:11]=1.C=O.[C:37](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=2)=[CH:12][N:11]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(NCc3ccc(C(F)(F)F)cc3)cn2)c(OC)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCc1ccc(Oc2ccc(N(C)Cc3ccc(C(F)(F)F)cc3)cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3-{3-methoxy-4-[5-(4-trifluoromethylbenzylamino]pyridin-2-yloxy}phenyl}-propionate (0.8 g, 1.7 mmol) in methanol (15 mL) were added a 37% aqueous formaldehyde solution (0.38 mL, 5.1 mmol) and acetic acid (0.1 mL, 1,7 mmol). The reaction solution was stirred for 30 minutes at room temperature. After that, sodium cyanoborohydride (0.24 g, 3.4 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred under ice cooling for 40 minutes. To the reaction solution was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 0.62 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.O.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(N)c2)cc1
Yield: 82.2 %

Procedure:
The title compound (230 mg, 82%) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (270 mg, 0.803 mmol, prepared in example 1), 3-aminobenzeneboronic acid monohydrate (150 mg, 0.968 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), 2 M sodium carbonate (290 mg in 1.4 mL water) and 1,4-dioxane (5.5 mL) in a manner analogous to the procedure described in Example 2.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.C[O:18][B:19](OC)[O:20]C>C1COCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[B:19]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: Fc1cccc2ccccc12
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccccc2c1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
1-fluoro naphthalene (14.61 g, 100 mmol, Aldrich Chemical) was dissolved in dry THF (50 mL) and cooled to -78° C. Then, a sec-butyl lithium solution (1.3 M in hexane, 100 mL) was added to the mixture over a period of 5 minutes. This mixture was stirred for 20 minutes at -78° C., then trimethylborate (15 mL, 132 mmol, Aldrich Chemical) was added. Stirring was continued at -78° C. for 15 minutes followed by stirring at room temperature for 30 minutes. The reaction was quenched by adding 100 mL of a 3:1 mixture of AcOH: H2O and stirred overnight at room temperature. Next, 500 mL of a 1:1 mixture of ethyl acetate and water was added. The organic layer was washed with 10% HCl (200 mL×1), water (200 mL×2), and brine (100 mL), dried over sodium sulfate, filtered, and solvent was removed to yield 18 grams of a white solid. This material was purified by silica-gel chromatography (350 grams of silica gel, ethyl acetate-hexane 1:1 mobile phase) to yield 16.3 g of the title compound (86%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[C:19](=O)([O-])[O-:20].[Cs+].[Cs+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:19][O:20][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)c(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
A well stirred mixture of 3.00 g (11.2 mmol) N-(4-fluoro-2-nitro-6-trifluoromethyl-phenyl)-acetamide and 6.00 g (18.4 mmol) caesium carbonate in 90 mL methanol was heated for 10 min at 100° C. in the microwave. After cooling the solvent was eliminated i.vac. and the residue remaining was combined with 100 mL water. The aqueous phase was acidified with 10% citric acid and the product was extracted with 100 mL ethyl acetate. The organic phase was dried and evaporated down i.vac. The residue obtained was purified by flash chromatography. The fractions containing product were combined and evaporated down i.vac.