Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([OH:34])[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(OC(C)C)(C)C.CO>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([O:34][CH2:2][C:3]5[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=5)[C:28]=4[C:35]=3[CH3:36])[CH2:22][CH2:23]2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Solvent: CO
Solvent: CC(C)OC(C)C
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Yield: 68 %

Procedure:
Using α-bromo-p-xylene and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 74. Yield 68%. mp. 84–85° C. (diisopropyl ether-methanol). 1H-NMR (CDCl3) δ: 1.36 (3H, s), 1.59 (3H, s), 2.07 (3H, s), 2.24 (3H, s), 2.25 (3H, s), 2.33 (3H, s), 3.05–3.35 (8H, m), 3.78 (3H, s), 4.49 (2H, s), 4.66 (1H, s), 6.86 (2H, d, J=9.2 Hz), 6.97 (2H, d, J=9.2 Hz), 7.13 (2H, d, J=8.2 Hz), 7.23 (2H, d, J=8.2 Hz).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.O.[BH4-].[Na+].C[NH2:16]>CO>[NH2:16][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: CN
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of aldehyde product from Step B (2.0 g, 14 mmol) in methanol (100 mL), 40% methylamine in water (2.27 mL, 27.6 mmol) was added at room temperature over a period of 10 min. The mixture was stirred at room temperature under nitrogen overnight and then was cooled down to 0° C. Sodium borohydride (1.05 g, 27.6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 h. Most of methanol was removed in vacuo, and the residue was diluted with water and extracted (3×) with ether. The combined organic layers were extracted with 2 N HCl (100 mL). The HCl layer was made basic (pH ˜11) with 2 N NaOH and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude 4-(aminomethyl)-indole as a white powder (1.95 g, 88%): 1H NMR (300 MHz, CDCl3) δ8.29 (s, br, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (t, J=2.7 Hz, 1H), 7.16 (t, J=8.0, 7.3 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.64 (t, J=2.0 Hz, 1H), 4.06 (s, 2H), 2.51 (s, 3H); CI MS m/z=160 [C10H12N2+H]+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11]1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20].[NH2:30]/[C:31](/[CH3:37])=[CH:32]\[C:33]([O:35][CH3:36])=[O:34]>CC(O)C>[CH3:5][C:3]1[NH:30][C:31]([CH3:37])=[C:32]([C:33]([O:35][CH3:36])=[O:34])[CH:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:2]=1[C:1]([O:7][CH2:8][CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11]1)=[O:6]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCC1NCc2ccccc21
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC2NCc3ccccc32)C1c1cccc([N+](=O)[O-])c1
Yield: 46.4 %

Procedure:
A solution of 1.54 g (6.2 m mol) of 2-isoindolinylethyl acetoacetate, 0.942 g (6.2 m mol) of 3-nitrobenzaldehyde and 0.717 g (6.2 m mol) of methyl 3-aminocrotonate in 37 ml of 2-propanol was heated at 80° C. under nitrogen for 48 hours. The crude mixture was concentrated in vacuo and subjected to flash chromatography (silica gel, 1:1 petroleum ether/ethyl acetate) to give 1.38 g (46%) of a brown solid, m.p. 63°-69° C. NMR: (CDCl3) δ 2.29 (6H, s), 2.8 (2H, t), 3.5 (2H, s), 3.8 (4H, s), 4.12 (2H, t), 5.0 (1H, s), 6.2 (1H, bs), 7.33 (8H, m).
Reaction SMILES: [C:1]([O:4][CH2:5]C=C)(=[O:3])[CH3:2].C1[CH:12]2[CH:13]3[CH:17]=[CH:16][CH:15]([CH:11]2C=C1)[CH2:14]3>>[CH3:5][O:4][C:1](=[O:3])[CH3:2].[CH:13]12[CH2:14][CH:15]([CH2:16][CH2:17]1)[CH:11]=[CH:12]2
Reactant: C=CCOC(C)=O
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: C1=CC2CCC1C2
Product: COC(C)=O
Temperature: 220 °C

Procedure:
Into a suitable high pressure tube reactor were placed allyl acetate and dicyclopentadiene (DCPD) at 4:1 molar ratio based on cyclopentadiene monomer, and heated in a hot oil bath maintained at 220° C., and maintained at that temperature for four hours. At the end of the reaction, the high pressure tube was removed from the bath and quenched in a wet ice bath. The tube was washed then with methanol and dichloromethane and weighed to verify that no leakage had occurred. The resultant crude monomer sample was analyzed by GC-MS, which showed about 7.5% unreacted allyl acetate, 10% exo-/endo-norbornene methanol, 82% exo-/endo-norbornene methyl acetate and 0.6% (1,2,3,4,4a,5,8,8a-octahydro-1,4:5,8-dimethanonaphthalen-2-yl)methanol. Fractional distillation of the crude mixture resulted in the isolation of norbornene methyl acetate of greater than >99.6% purity.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH:12]([C:14]2[S:18][C:17]3=[CH:19][N:20]=[C:21]([Cl:22])[N:16]3[CH:15]=2)[OH:13])[CH2:10][C@@H:9]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[H-].[Na+].[CH3:38]I.[C:40](=[S:42])=[S:41]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH:12]([C:14]2[S:18][C:17]3=[CH:19][N:20]=[C:21]([Cl:22])[N:16]3[CH:15]=2)[O:13][C:40]([S:42][CH3:38])=[S:41])[CH2:10][C@@H:9]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1cn2c(Cl)ncc2s1
Reactant: S=C=S
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(OC(=S)SC)c1cn2c(Cl)ncc2s1
Reaction time: 0.33 h

Procedure:
(3R,5S)-1-Allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-(5-chloroimidazo[5,1-b]thiazol-2-yl)-1-hydroxymethyl]pyrrolidine (a diastereomer mixture) (2.300 g) and 3.3 mg of imidazole are dissolved in 24.5 ml of anhydrous THF. Carbon disulfide (0.44 ml) and 292 mg of 60% sodium hydride are successively added to the solution in an argon atmosphere on ice bath, and the mixture is stirred in this state for 20 min. Methyl iodide (0.32 ml) is added dropwise thereto, and the mixture is stirred in this state for one hr. The reaction solution is diluted with 250 ml of ethyl acetate, washed with semi-saturated saline, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure to give a crude product which is then purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 2.607 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-(5-chloroimidazo[5,1-b]thiazol-2-yl)-1-(methylthiothiocarbonyloxy)methyl]pyrrolidine (a diastereomer mixture) as a yellow viscous material.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.[H-].[Na+]>[CH2:16]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])=[CH:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCc1c[nH]c2ccc(I)cc12
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCc1cn(Cc2ccccc2)c2ccc(I)cc12
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a solution of [2-(5-iodo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Reference Example 5) (35.0 g, 111.4 mmol) in DMF (250 mL), sodium hydride is added (2.81 g, 117 mmol) at RT in portions during 15 minutes. The mixture is then stirred for another 15 minutes, and then cooled to 4° C. A solution of benzyl chloride (14.1 g, 111.4 mmol) in DMF (50 mL) is added during 20 minutes, and the temperature is maintained during 4 to 8° C. The mixture is left stirring over night, and then most of the solvent is removed on the rotavapor. To the residue is added water (500 mL), and the product is extracted with TBME (2×250 mL). The organic layer is washed with brine (2×250 mL), and after removal of the solvent, 28.5 g of a brown oil is obtained. This is dissolved in ethyl acetate (500 mL) and the product is extracted with 4 N Hcl (550 mL). The product is liberated by adding 30% NaOH to the aqueous layer (300 mL), and re-extracted into ethyl acetate (500 mL). The organic layer is washed with brine (2×250 mL), and the solvent removed to leave 20.2 g of brown oil, which is crystallized from di-isopropyl ether and pentane to give the title product (17.3 g, 38%). Concentrating the aqueous layer of the first gives a precipitate (18.8 g), which is recrystallized from ethyl acetate (250 mL) to give 12.3 g of the N-benzyl ammonium chloride of the target.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:10]=1[CH:17]([O:19][C:20]1[C:45]([F:46])=[CH:44][C:23]2[N:24]=[C:25]([NH:27][C:28](=[O:43])[CH2:29][N:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[S:26][C:22]=2[CH:21]=1)[CH3:18].C(=O)([O-])O.[Na+]>ClCCl.C(#N)C>[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:10]=1[CH:17]([O:19][C:20]1[C:45]([F:46])=[CH:44][C:23]2[N:24]=[C:25]([NH:27][C:28](=[O:43])[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:26][C:22]=2[CH:21]=1)[CH3:18]
Reactant: CC(Oc1cc2sc(NC(=O)CN3CCN(C(=O)OC(C)(C)C)CC3)nc2cc1F)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1cc2sc(NC(=O)CN3CCNCC3)nc2cc1F)c1c(Cl)ccc(F)c1Cl
Reaction time: 16 h
Yield: 55.5 %

Procedure:
add 0.73 cm3 of trifluoroacetic acid to a solution of 0.385 g of 1,1-dimethylethyl 4-[2-({6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}amino)-2-oxoethyl]piperazine-1-carboxylate in 45 cm3 of dichloromethane. Stir for 16 hours at a temperature close to 20° C. The reaction mixture is then evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 15 cm3 of water. The mixture obtained is adjusted to pH 8-9 with an aqueous solution of sodium hydrogen carbonate and then extracted three times with 40 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulphate, then filtered and evaporated to dryness under reduced pressure (2 kPa). The white solid obtained is solidified in 5 cm3 of acetonitrile, filtered and then dried under reduced pressure. We obtain 0.178 g N-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-2-(piperazin-1-yl)acetamide in the form of a cream-coloured powder, which has the following characteristics:
Reaction SMILES: [C:1]([C:9]1[C:10]([F:20])=[C:11]([C@H:16]([NH2:19])[CH2:17][CH3:18])[CH:12]=[CH:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[C:24]([NH2:28])(=[O:27])[CH:25]=[CH2:26]>CO>[C:1]([C:9]1[C:10]([F:20])=[C:11]([C@H:16]([NH:19][CH2:26][CH2:25][C:24]([NH2:28])=[O:27])[CH2:17][CH3:18])[CH:12]=[CH:13][C:14]=1[Cl:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(N)=O
Reactant: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Solvent: CO
Solvent: CCO
Product: CC[C@@H](NCCC(N)=O)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Temperature: 100 °C
Yield: 38.1 %

Procedure:
To (1R)-1-(3-benzoyl-4-chloro-2-fluorophenyl)propan-1-amine (0.1 g, 0.34 mmol) in a microwave tube was added ethanol (0.4 ml) water (0.4 ml), acrylamide (0.025 g, 0.35 mmol) and MnCl2 (0.056 g, 0.28 mmol) heated 100° C., 200 W for a total of 1 hour. The reaction was diluted with MeOH and filtered and filtrate evaporated then purified by Prep HPLC to give 3-{[(1R)-1-(3-benzoyl-4-chloro-2-fluorophenyl)propyl]amino}-propanamide (0.047 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.I[C:11]1[CH:16]=[CH:15][C:14](O)=CC=1.[CH3:18][C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2>>[Cl:9][C:4]1[CH:3]=[C:2]([N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:27]=[C:19]2[CH3:18])[CH:7]=[CH:6][C:5]=1[O:8][CH2:26][CH2:27][CH2:19][N:20]1[CH2:14][CH2:15][CH2:16][CH2:11]1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: Cc1cc2ccccc2[nH]1
Reactant: Oc1ccc(I)cc1
Product: Cc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)c(Cl)c1

Procedure:
1-[3-Chloro-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2-methyl-1H-indole was synthesized by a method analogous to that used for Example 4, using 4-bromo-2-chlorophenol in the first step rather than 4-iodophenol and 2-methylindole in the final step. LC-MS (C22H25ClN2O calc'd 368) m/z 369, 371 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.58-7.54 (m, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.20 (dd, J=8.7 Hz, 2.7 Hz, 1H), 7.11-7.02 (m, 4H), 6.38 (s, 1H), 4.19 (t, J=6.3 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H), 2.77 (m, 4H), 2.24-2.15 (m, 2H), 1.91-1.87 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Cl:25][C:26]1[CH:32]=[C:31]([CH3:33])[C:29]([NH2:30])=[C:28]([O:34][CH3:35])[CH:27]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:30][C:29]3[C:31]([CH3:33])=[CH:32][C:26]([Cl:25])=[CH:27][C:28]=3[O:34][CH3:35])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: COc1cc(Cl)cc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCn1c(Nc2c(C)cc(Cl)cc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 22.8 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 470 mg, 1.27 mmol), 4-chloro-2-methoxy-6-methylaniline (650 mg, 3.81 mmol) and p-toluenesulfonic acid (241 mg, 1.27 mmol) and xylene (5.0 mL) was irradiated by microwave at 150° C. for 4 hr. After cooling, the reaction mixture was extracted with ethyl acetate (×3). The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (120 mg, 0.289 mmol, 18.7%) as a brown amorphous
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:24][CH:25]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: FCCOc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OCCF)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 1-(bromomethyl)-4-(2-fluoroethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.80 min.; [M+H]+: 388.23 g/mol.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:7]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][NH2:24])=O)=[CH:16][CH:15]=1>C(O)CCC>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=3)=[N:23][N:24]=2)[N:4]=1
Reactant: Clc1ccc(-c2nccs2)nn1
Reactant: NNC(=O)Cc1ccc(O)cc1
Solvent: CCCCO
Product: Oc1ccc(Cc2nnc3ccc(-c4nccs4)nn23)cc1
Temperature: 120 °C
Yield: 37.2 %

Procedure:
3-Chloro-6-thiazol-2-yl-pyridazine (20 mg, 0.10 mmol) and (4-Hydroxy-phenyl)-acetic acid hydrazide (20 mg, 0.12 mmol) were combined in butanol (5 mL), fitted with water filled condenser and heated to 120° C. overnight. The reaction was concentrated in vacuo followed by purification by HPLC (10-80% CH3CN over 25 min) resulting in the title compound (11.5 mg, 37%) as a white solid. 1H-NMR (CD3OD/CDCl3): δ 8.26-8.24 (1H, d, J=9.6 Hz), 8.17-8.15 (1H, d, J=9.6 Hz), 8.05-8.04 (1H, d, J=3.2 Hz), 7.82-7.81 (1H, d, J=3.0 Hz), 7.32-7.30 (2H, t, J=8.6 Hz), 6.77-6.74 (2H, d, J=8.3 Hz), 4.53 (2H, s). ESI-MS (m/z): Calcd. For C15H11N5OS: 309.07; found: 310.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]2[N:6]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cc1ccc(-n2c(CC)nc3cc(Cl)c(Cl)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(=O)O)cc1
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a stirred solution of ethyl [4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetate (step 3, 1.30 g, 3.4 mmol) in methanol was added 2N aqueous NaOH (3.4 mL) at room temperature. After 1 h, the mixture was concentrated and the residue was diluted in water (200 mL) and the mixture was washed with diethyl ether (100 mL). The aqueous layer was acidified with 2N hydrochloric acid and extracted with ethyl acetate/THF (v/v, 1:1, 300 mL). The organic extract was washed with water (200 mL), brine (200 mL), and dried (MgSO4). Removal of solvent gave 1.02 g (86%) of the title compound as a white powder: 1H-NMR (CDCl3) δ 7.94 (1H, s), 7.56–7.45 (4H, m), 7.26 (1H, s), 3.72 (2H, s), 2.72 (2H, q, J=7.3 Hz), 1.22 (3H, t, J=7.5 Hz).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][CH:9]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][N:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25](Cl)=[O:26])[CH3:23].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:22]([O:24][C:25]([N:19]1[CH2:18][CH2:17][CH:9]2[N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10]2)[CH2:21][CH2:20]1)=[O:26])[CH3:23]
Reactant: c1ccc(C2c3ccccc3CC3CCNCCN32)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC2Cc3ccccc3C(c3ccccc3)N2CC1

Procedure:
5.4 g of (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline was dissolved in 75 cc of chloroform and 30 cc of water are added. 4.3 g of chloroformic acid ethyl ester and subsequently a solution of 1.58 g of sodium hydroxide in 30 cc of water were added dropwise at a temperature of 0°-5°. The reaction mixture was stirred for another hour without cooling. The layers were then separated and the organic phase was washed twice with water. After drying with magnesium sulphate and concentration by evaporation of the filtered chloroform solution, the (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline-3-carboxylic acid ethyl ester was obtained in crude form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([C:12]2[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[N:14]([CH2:21][CH3:22])[CH:13]=2)=O)C=[CH:6][C:7]=1[F:8].Cl.[CH3:25][NH:26][C:27]([NH2:29])=[NH:28].[C:30]([O-:33])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCO>[NH2:29][C:27]1[N:26]([CH3:25])[C:30](=[O:33])[C:10]([C:9]2[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([F:8])[CH:6]=2)([C:12]2[CH:16]=[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])[N:14]([CH2:21][CH3:22])[CH:13]=2)[N:28]=1
Reactant: CCn1cc(C(=O)C(=O)c2ccc(F)c(Br)c2)cc1S(C)(=O)=O
Reactant: CNC(=N)N
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCn1cc(C2(c3ccc(Br)c(F)c3)N=C(N)N(C)C2=O)cc1S(C)(=O)=O
Temperature: 105 °C

Procedure:
A solution of 1-(3-bromo-4-fluoro-phenyl)-2-(1-ethyl-5-methanesulfonyl-1H-pyrrol-3-yl)-ethane-1,2-dione (0.32 g, 0.79 mmol) in dioxane and EtOH was treated with N-methylguanidine hydrochloride (0.17 g, 1.6 mmol) and Na2CO3(0.18 g, 1.66 mmol), heated to 105° C. for 18 h and concentrated in vacuo. The residue was dissolved in CHCl3, washed with H2O and brine, dried (Na2SO4) and evaporated to dryness at reduced pressure. Chromatography of this residue (silica gel, EtOAc and 1%-2% MeOH-EtOAc as eluent) yielded a solid; 1H NMR (400 MHz, CDCl3) δ: 1.44 (t, 3H, J=7.3 Hz), 3.08 (s, 3H), 3.10 (s, 3H), 3.97 (brs, 2H), 4.21 (q, 2H, J=7.3 Hz), 6.85 (d, 1H, J=2.1 Hz), 6.90 (d, 1H, J=2.1 Hz), 7.06 (t, 1H, J=8.5 Hz), 7.51 (m, 1H), 7.77 (dd, 1H, J=2.3, 6.6 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>O1CCCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][O:17][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(COCC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 0.76 g, 19 mmol) in anhydrous tetrahydrofuran (38 mL) was stirred at room temperature under a nitrogen atmosphere. A solution of 1-benzyl-4-hydroxymethyl piperidine (3.82 g, 18.6 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred for 2 h. 4-Fluorobenzyl bromide (2.4 mL, 19 mmol) was added dropwise, then the reaction mixture was stirred for 72 h. Water (50 mL) was added and the resulting mixture was extracted three times with ethyl acetate. Drying over magnesium sulfate, filtration and concentration in vacuo gave an oil. Vacuum distillation (170° C. (Kugelrohr oven), 1.0 Torr) gave a colorless oil (3.45 g, 59% yield): 'H-NMR: 7.34-6.98 (m, 9H), 4.46 (s, 2H), 3.50 (s, 2H), 2.93-2.87 (m, 2H), 2.02-1.59 (m, 5H), 1.39-125 HR-MS Calcd.: 313.1478; Found: 313.1479; (m, 2H); Anal. Calcd.: for C20H24FNO: C,76.65, H,7.72, N,4.47; Found: C,77.27, H,7.69, N,4.45.
Reaction SMILES: C([N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])C.[Cl:16][CH2:17][C:18](=O)[CH2:19][C:20](OCC)=[O:21].OS(O)(=O)=O>>[C:4]([NH:3][C:9]1[CH:10]=[C:11]2[C:12]([C:18]([CH2:17][Cl:16])=[CH:19][C:20](=[O:21])[O:15]2)=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CCOC(=O)N(CC)c1cccc(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1ccc2c(CCl)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A suspension of ethyl 3-hydroxyphenylurethane (1.81 g, 0.01 mmole), ethyl 4-chloroacetoacetate (1.81 mL, 0.011 mole) and 70% H2SO4 (50 mL) is stirred for 4 hours at room temperature. The clear solution is poured into 400 mL of ice-water, with constant stirring, to yield a yellowish precipitate. The solid is filtered, washed with water and dried. The product is recrystallized from methanol to give colorless needles (86%).