Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][C:45]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([N:47]4[CH2:48][CH2:49][CH2:50][CH2:51]4)=[O:46])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2N6O3 [(M+H)+] 719.3238, observed 719.3242.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5])[CH3:2].CC(C[AlH]CC(C)C)C>C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([OH:11])[N:7]1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCC(O)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A solution of 10.0 g of 167 (38.9 mmol) in 100 ml of anhydrous THF was cooled to −78° C. and added very slow with 85.5 ml of DIBAL-H (85.5 mmol, 2.2 eq., 1 M/THF). After one hour, the reaction was terminated by adding 10 ml of isopropanol at low temperature, followed by addition of 240 ml of a K—Na tartrate solution (1.77 M), and the mixture was slowly thawed, initially to 0° C. and subsequently to RT. The resulting phases were separated, the organic phase was extracted with 3×200 ml of MTBE, and the combined organic phases were washed with 100 ml of saturated NaCl solution. After drying over MgSO4, the solvent was removed to obtain 9.69 g of 205 (37.4 mmol, 96%) as a yellowish oily residue which was further reacted without purification. For analytical purposes, a small sample was purified using silica gel column chromatography (EE/CH 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[SH:17]>>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:17][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: Sc1cccs1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: O=[N+]([O-])c1ccc(Sc2cccs2)c(Cl)c1
Yield: 32 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 2-thiophenethiol to give 2-chloro-4-nitrophenyl 2-thienyl sulphide in 32% yield.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1.S(OC)(O[CH3:28])(=O)=O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O.C1(C)C=CC=CC=1>[CH3:28][NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:4]=2[CH3:3])=[CH:8][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(N)c([N+](=O)[O-])c1
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CNc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a solution of sodium hydroxide (10.2 g in 10.5 mL water) was added toluene (15 mL), 4-(2-methyl-4-nitrophenoxy)-2-nitrobenzenamine (2.00 g, 6.92 mmol), dimethyl sulfate (750 μL, 7.88 mmol) and tetrabutylammonium sulfate (0.277 g, 0.816 mmol). After stirring at room temperature, the cooled (0° C.) reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was chromatographed (dichloromethane) to provide the product (1.90 g, 91%).
Reaction SMILES: [Br:1][C:2]1[C:14]([CH:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:16]2)=[CH:13][C:12]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH3:63])=[CH:57][CH:56]=2)=[C:11]([Cl:64])[C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[C:14]([CH:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[O:16]2)=[CH:13][C:12]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH3:63])=[CH:57][CH:56]=2)=[C:11]([Cl:64])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1c(Cl)c(Cc2ccc(OCC)cc2)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1Br
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(OCC(=O)O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of ethyl 2-(2-bromo-6-chloro-5-(4-ethoxybenzyl)-3-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H- pyran-2-yl)phenoxy)acetate (1.09 g, 1.14 mmole) in a mixture of THF/MeOH/H2O (12 mL/4 mL/4 mL) was added LiOH.H2O (144 mg, 3.42 mmole). The resulting solution was stirred at rt overnight. The reaction mixture was concentrated in vacuo and diluted with water. The resulting solution was acidified with 1N—HCl solution followed by extraction with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield the title compound (1.03 g, 98%) as a brown gum.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[S:44]1[C:48]2[CH:49]=[CH:50][C:51]([C:53](O)=[O:54])=[CH:52][C:47]=2[CH:46]=[CH:45]1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:53]([C:51]3[CH:50]=[CH:49][C:48]4[S:44][CH:45]=[CH:46][C:47]=4[CH:52]=3)=[O:54])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1ccc2sccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc5sccc5c4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 1-benzothiophene-5-carboxylic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford benzo[b]thiophene-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.5 g, 53%) as a white solid: mp 261-263° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.22 min. (99%); 1H NMR (DMSO-d6) δ 2.07-2.11 (m, 1H), 2.55-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.99 (d, J=5.6 Hz, 2H), 5.16-5.22 (dd, J=5.0 and 12.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 7.79-7.92 (m, 5H), 8.11 (d, J=8.4 Hz, 1H), 8.48 (s, 1H), 9.24 (t, J=5.5 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.99, 30.93, 38.44, 48.88, 121.85, 122.50, 122.91, 122.95, 124.39, 127.14, 128.84, 130.39, 131.54, 133.07, 134.79, 139.18, 139.38, 141.92, 166.79, 166.97, 167.55, 169.83, 172.74; Anal. Calcd. for C23H17N3O5S+0.2H2O: C, 61.24; H, 3.89; N, 9.32; S, 7.11. Found: C, 61.04; H, 3.57; N, 8.96; S, 7.19.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH3:16].Cl>CCCCCC.C(OCC)(=O)C>[C:1]([O:14][CH2:15][CH3:16])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CCO
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 85.3 %

Procedure:
Ferulic acid (4.85 g) and then ethyl alcohol (50 ml) containing hydrogen chloride (4%) were placed in an egg-plant type flask (200 ml), and heated under reflux for 2.5 hours. The disappearance of the starting material was confirmed by TLC (n-hexane/ethyl acetate=2/1), then the solvent was evaporated under reduced pressure by a rotary evaporator. Benzene was added to the residue, and then, the solvent was again evaporated by a rotary evaporator to obtain the wine-colored crude product (5.79 g). The resulting crude product was separated and purified by silica gel column chromatography (diameter=5.5×7.0 cm; 60 g; n-hexane/ethyl acetate=3/1) to obtain the above-identified compound (5.06 g; 91.2%). The product was crystallized from n-hexane to obtain a white crystal (4.743 g, 85.3%). Melting point: 41°-43° C.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][CH:29]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:3]=12.[CH3:38][Zn]C>C1COCC1>[CH:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]3[N:4]4[CH2:27][CH2:28][CH:29]([CH2:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C:3]4=[C:2]([CH3:38])[C:10]=3[CH:9]=2)=[CH:14][C:15]=1[C:23]([F:26])([F:24])[F:25])([CH3:21])[CH3:22]
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(I)c2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: C[Zn]C
Solvent: C1CCOC1
Product: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C(F)(F)F)c4)cc13)CCC2CC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of tert-butyl 2-(9-iodo-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.778 g, 1.236 mmol) in THF (12.3 mL) under nitrogen was added 2 M solution of dimethylzinc (1.854 mL, 3.71 mmol), followed by bis(tri-t-butylphosphine)Pd(0) (0.057 g, 0.111 mmol). The reaction was stirred overnight, slowly quenched with saturated NaHCO3, diluted with EtOAc, and filtered through Celite®. The organics were washed with water (twice), brine, dried over MgSO4, and filtered. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give the title compound as a solid (0.366 g). LCMS m/z=518.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.94 Hz, 6H), 1.38 (s, 9H), 2.15 (s, 3H), 2.19-2.30 (m, 1H), 2.43-2.48 (m, 1H), 2.69-2.81 (m, 2H), 3.54-3.64 (m, 1H), 3.86-3.96 (m, 1H), 3.98-4.07 (m, 1H), 4.73-4.84 (m, 1H), 5.07 (s, 2H), 6.74 (dd, J=8.65, 2.34 Hz, 1H), 7.00 (d, J=2.27 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.29 (d, J=9.35 Hz, 1H), 7.64-7.71 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=[O:22])=[CH:17][CH:16]=2)=[N:13][NH:12][C:11]=1[NH2:24]>CN(C=O)C.C(O)C.[Cl-].[NH4+].[Zn]>[NH2:24][C:11]1[NH:12][N:13]=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][OH:22])=[CH:17][CH:16]=2)[C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: Nc1[nH]nc(-c2ccc([N+](=O)[O-])cc2)c1-c1nc2ccccc2s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1[nH]nc(-c2ccc(NO)cc2)c1-c1nc2ccccc2s1
Yield: 3.3 %

Procedure:
To a solution of 4-benzothiazol-2-yl-5-(4-nitrophenyl)-2H-pyrazol-3-ylamine (218 mg, 0.65 mmol) in DMF (4 mL) and 95% ethanol (4 mL) at room temperature was added under rapid stirring a suspension of zinc powder (200 mg) in aqueous ammonium chloride (0.15 g in 2 mL of water). The resulting mixture was then stirred for 2 hrs. The residual zinc was removed by filtration and the mother liquor was poured into water (100 mL). A yellow solid was removed by filtration. The aqueous phase was extract with ethyl acetate (2×75 mL). The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting crude material was purified by preparative TLC eluting with 10:1 CH2Cl2:MeOH=10:1 to yield 7 mg (4%) of the title compound as cream coloured solid. MS (m/z, ES+): 324.1 (M+1, 100%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][C:20]=2[CH:21]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].Cl>CO.O>[C:26]1([C:23]2[CH:24]=[CH:25][C:19]3[O:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:3]([OH:32])=[O:2])=[O:14])=[CH:21][C:20]=3[CH:22]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 50 °C
Yield: 84 %

Procedure:
A solution of (R)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 18 (1.39 g, 3.24 mmole) in methanol (30 ml) was treated with a solution of lithium hydroxide monohydrate (149 mg, 3.56 mmole) in water (2 ml) and heated to 50° C. for 3 hrs. It was then cooled to room temperature, acidified with 1M HCl, extracted with ethyl acetate, separated, washed, dried, and evaporated. The residue was crystallized to give about 1.13 g of (R)-2-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid 19, mp. 154-156° C.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[C:33](=[O:34])[NH:32][N:31]=[CH:30]2)[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:17]1([CH2:16][N:32]2[C:33](=[O:34])[N:29]([C:21]3[S:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:19]([CH3:18])[N:20]=3)[CH:30]=[N:31]2)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(CC3CC3)c2=O)nc1C
Yield: 83 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with (bromomethyl)cyclopropane to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 83% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.63 (d, J=7.1 Hz, 2H), 2.64 (s, 3H), 1.35 (t, J=7.1 Hz, 3H), 1.19-1.04 (m, 1H), 0.53-0.42 (m, 2H), 0.36-0.27 (m, 2H); MS (ES+) m/z 309.2 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.Cl.[CH3:13][N:14](CC1NC2C(N=1)=NC=CC=2)[CH3:15]>>[CH3:13][N:14]([CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2)[CH3:15]
Reactant: CN(C)Cc1nc2ncccc2[nH]1
Reactant: OCc1cc2ncccc2[nH]1
Agent: Cl
Product: CN(C)Cc1cc2ncccc2[nH]1

Procedure:
2-Dimethylaminomethyl-4-azaindole is synthesized from 2-hydroxymethyl-4-azaindole by a procedure analogous to that described for the synthesis of 2-dimethylaminomethyl-1H-imidazo[4,5-b]pyridine monohydrochloride in the J. Het. Chem., 6, 759-760 (1969).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B#B.ClC1C(C)=CC=CC=1CO.[O-][O-].[Mg+2]>O1CCCC1.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[O:5]
Reactant: Cc1cccc(C(=O)O)c1Cl
Agent: B#B
Agent: Cc1cccc(CO)c1Cl
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(C=O)c1Cl

Procedure:
2-Chloro-3-methylbenzoic acid was reduced by treating with diborane in tetrahydrofuran and the resulting 2-chloro-3-methylbenzyl alcohol was oxidized with activated magnesium dioxide in methylene chloride to give 2-chloro-3-methylbenzaldehyde.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH2:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:24](=[O:25])[CH2:23][Br:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)CBr
Reactant: CCCCCCNCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCN(Cc1ccccc1)C(=O)CBr
Yield: 58.4 %

Procedure:
N-hexylbenzylamine (4.2 g, 21.953 mmol) and triethylamine (3.98 ml, 28.539 mmol) were mixed in DCM (20 ml) and cooled in an ice-bath. Bromacetyl chloride (3.455 mg, 21.953 mmol) in DCM (5 ml) was added. The mixture was stirred over weekend and the temperature was allowed going up to room temperature. The mixture was washed with water mixed with 1% hydrochloric acid (water phase pH˜4-5) and brine, dried with magnesium sulphate, and evaporated. Column chromatography of the residue on silica gel using ethyl acetate/heptane (10:90, then 20:80) as eluant gave 4.0 g desired product, yield 58%.
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C1OCCOCCOCCOCCOC1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH2:13][C:14]([N:16]([CH3:17])[CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1
Reactant: COCCCCC1(CC(=O)N(C)C)C=CCCC1
Agent: BrB(Br)Br
Agent: C1COCCOCCOCCOCCO1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Solvent: ClCCl
Product: CN(C)C(=O)CC1(CCCCO)C=CCCC1
Temperature: -30 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of the relevant 2-[1-(4-methoxybutyl)-cyclohex-2-enyl]-N,N-dimethyl-acetamide isomer (5) or (5′) (51.0 g, 201 mmol), Nal (60 g, 400 mmol) and 15-crown-5 (55 g, 250 mmol) in CH2Cl2 (1000 mL) at −30 ° C. was added dropwise BBr3 (1 M solution in CH2Cl2; 241 mL, 241 mmol). The reaction mixture was stirred at −30° C. for 1 hour then a saturated NaHCO3 solution (1000 mL) was added. The organic layer was separated and the aqueous layer extracted with CH2Cl2. The combined organic layers were washed with a saturated Na2SO3 solution and dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue purified over silica (gradient elution: Et2O 100% to Et2O/MeOH, 95:5) to afford 39.9 g (83% yield) of the desired product as a viscous oil which was characterized as follows:
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[S:7])[CH3:6].C(O)C.ICC>ClCCl>[CH2:2]([S:7][C:5](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:3]
Reactant: CC[O-]
Reactant: CC(=S)Nc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCI
Product: CCSC(C)=Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Next, 4.5 g of sodium ethoxide, 9.8 g of thioacetanilide, and 50 mL of ethanol were put in a 100 mL three-neck flask, and stirred at room temperature for 1 hour. Then, 5.3 mL of iodoethane was added to this mixture, and heated and stirred at 60° C. for 5 hours to be reacted. After the reaction, ethanol was distilled off under a reduced pressure to give a brown oily substance. This oily substance was dissolved in dichloromethane, and washed with water and then a saturated aqueous solution of sodium hydrogen carbonate. Anhydrous magnesium sulfate was added to the resulting organic layer for drying. After the drying, the solution was subjected to gravity filtration. The resulting filtrate was concentrated, so that N-[1-(ethylsulfanyl)ethylidene]aniline was prepared (a brown solid, yield: 73%). The synthetic scheme of Step 2 is shown by (b-2).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH3:23])[N:3]=1.[S-2:24].[Na+].[Na+].O.Cl>CN(C=O)C.CO>[OH:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([SH:24])[N:3]=[C:4]([O:22][CH3:23])[C:5]=2[C:20]#[N:21])=[CH:11][CH:12]=1
Reactant: COc1nc(Cl)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.0 g (12.1 mmol) of 2-chloro-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile are dissolved in 16 ml of anhydrous DMF, 1.42 g (18.2 mmol) of anhydrous sodium sulphide are added and the mixture is stirred at room temperature for 2 h. 36 ml of water are added, and with stirring the solution is slowly added dropwise to a mixture, warmed to 50° C., of 61 ml of 1M hydrochloric acid and 20 ml of methanol. The yellow suspension is stirred at RT for 1 h and filtered off with suction, and the precipitate is washed with water and dried at 45° C. under reduced pressure overnight.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].CS(O[CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])(=O)=O>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][CH2:18][CH2:17][N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: COCCCCOS(C)(=O)=O
Reactant: c1nc2c([nH]1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCn1cnc2c1CCCC2
Temperature: 25 °C
Yield: 198.2 %

Procedure:
4,5,6,7-Tetrahydro-1H-benzimidazole (2.45 g) was dissolved in DMF (20 ml), sodium hydride (60% in oil, 880 mg) was added, and the mixture was stirred at room temperature for min. 4-Methoxybutyl methanesulfonate (1.28 g) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (2.90 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[N:3][CH:4]=1)[CH3:17]
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(O)nc1
Yield: 80 %

Procedure:
To a 100 mL three-necked flask, 0.84 g (0.006 mol) of 6-hydroxynicotinic acid, 30 mL of anhydrous ethanol were added, 3 mL of concentrated sulfuric acid was added dropwise slowly, refluxed overnight, evaporated under vacuum to remove excessive ethanol, the residue was poured into water, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate, dried with anhydrous sodium sulfate, and concentrated to obtain 0.8 g of 6-hydroxy-nicotinic acid ethyl ester. Yield: 80%.