Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>C1CCCCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:25](=[O:26])[CH2:24][CH2:23][CH3:27])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C1CCOC1
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Product: CCCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of 50 mL (65 mmol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (7.7 g, 32.5 mmol) in 100 mL of THF keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to −10° C. and then the bath replaced. After the temperature had cooled to −60° C., 4.3 g (32.5 mnmol) of N-methoxy-N-methylbutanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 22 hours. It was then poured into a mixture of 200 mL of ether and 200 mL of 0.5N HCl. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated at reduced pressure to give 9.9 g of crude 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-pentanone. This material was dissolved in 100 mL of methylene chloride and 20 ML of trifluoroacetic acid and stirred for a total of 23 hours. The mixture was washed with water, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 2.19 g of 4-methoxy-2-propyl-1H-indole as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>O1CCCC1.C(N(CC)CC)C>[CH3:8][S:9]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (20 g) in tetrahydrofuran (150 mL) and triethylamine (28.5 mL) is slowly added methanesulfonyl chloride (15.5 mL), while keeping the temperature below 30° C. The mixture is stirred for 12 hours at room temperature. The precipitate is filtered off and washed twice with tetrahydrofuran. The combined organic phases are concentrated and partitioned between ethyl acetate and water. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 29.4 g; TLC: rf=0.36 (silicagel, petrole ether/ethyl acetate 1:1); Mass spectrum (ESI+): m/z=198 [M+NH4]+.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:36]=1>CN(C)C=O.O1CCCC1.O>[Br:1][C:2]1[N:6]([S:41]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)(=[O:43])=[O:42])[CH:5]=[C:4]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:3]=1
Reactant: CN(Cc1c[nH]c(Br)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A solution (3 mL) of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (410 mg) in N,N-dimethylformamide was added to a suspension (10 mL) of sodium hydride (60% in oil, 204 mg) in tetrahydrofuran at 0° C., 15-crown-5 (938 mg) and pyridin-3-ylsulfonyl chloride hydrochloride (456 mg) were added at the same temperature. After stirring at room temperature for 2 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→3:1) to give the title compound as a pale-yellow powder (yield 522 mg, 85%).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C[O-].[Na+].CO.C(OC([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=O)[C:24]([NH:26][CH3:27])=[O:25])C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Cl-].[Na+].O>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[N:4][O:3][CH3:2])[C:24]([NH:26][CH3:27])=[O:25]
Reactant: CCOC(C)OCc1ccccc1C(=O)C(=O)NC
Reactant: CON
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
Methoxyamine hydrochloride (0.22 g, 0.0026 mol) was dissolved in methanol (2 ml), and a 28% sodium methoxide-methanol solution (0.58 g, 0.003 mol) was added to the solution to obtain a suspension. A mixed solution of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl)-N-methyl-2-oxoacetamide (0.53 g, 0.002 mol) and methanol (2 ml) was added to the suspension. The mixture was stirred under ref lux for 3 hours, and then cooled to room temperature. After cooling, p-toluenesulfonic acid monohydrate (0.19 g, 0.001 mol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, half-saturated brine (80 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.37 g, Yield: 83.2%, E/Z=97/3) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:11]([O:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2CC1
Temperature: 25 °C

Procedure:
According to scheme 10, to a stirred solution of 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester (XXX) in dichloromethane was added at −60° C. m-chloroperbenzoic acid (MCPBA). The mixture was allowed to slowly warm to room temperature overnight and 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester (XXXI) was obtained. To a solution of 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in ethanol was added water, ammonium chloride and sodium azide. The mixture was stirred at 75° C. over night, to give 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXII). 4-Azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester in methanol was hydrogenated in the presence of palladium on charcoal (10%) to yield 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXIII). 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 1,1′-carbonyl-diimidazole in dimethylformamide are stirred at room temperature for about 16 hours. 4-Amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester was added and stirring was continued for 16 hours at room temperature. It was obtained 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester (XXXIV). To a solution of 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester in dimethylsulfoxide was added triethylamine, dichloromethane and a solution of sulfur trioxide pyridine complex in dimethylsulfoxide. The mixture was stirred for 18 hours at room temperature. After purification 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester (VIII) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C.CN(CCCN=C=NCC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:12][N:13]([O:14][CH3:15])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a mixture of 4-fluorobenzoic acid (5.0 grams (hereinafter “g”), 36 millimoles (hereinafter “mmol”)) and N,O-dimethylhydroxylamine hydrochloride (3.8 g, 39 mmol) in 200 mL of CH2Cl2 at 0° C. was added triethylamine (5.0 milliliters (hereinafter “mL”), 36 mmol). The solution was warmed to room temperature and 4-dimethylaminopyridine (0.2 g, 1.6 mmol) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide (6.8 g, 36 mmol) were added. The resulting solution was stirred for 16 hours (hereinafter “h”). Next, the solution was diluted with 200 mL of ethyl acetate and washed with 100 mL of saturated NaHCO3, 50 mL of H2O, twice with 50 mL of 1N HCl, and 50 mL of H2O. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a light yellow oil. The oil was purified by chromatography through a plug of silica gel with 50% ethyl acetate/hexane to give title compound as a light yellow oil (5.5 g, 85%). ES(+)MS m/e=184 (MH+)
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[C:9]([CH3:26])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[C:9]([CH3:26])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To tert-butyl 4-(4-(cyclopropylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (1.490 g, 4.15 mmol) was added Hydrochloric acid solution (8.72 mL, 34.9 mmol) in dioxane at 23° C. The reaction was stirred at 23° C. for 30 min. The resulting suspension was diluted with E2O (10 mL), filtered, rinsed with E2O (3×5 mL), and the resulting solid was dried in vacuo to provide N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (1.37 g, 4.15 mmol, 100% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51-0.61 (m, 2H) 0.61-0.70 (m, 2H) 2.28 (s, 3H) 2.82 (tq, J=7.41, 3.99 Hz, 1H) 3.02-3.13 (m, 4H) 3.14-3.29 (m, 4H) 7.05 (d, J=8.34 Hz, 1H) 7.62-7.69 (m, 2H) 8.32 (d, J=4.29 Hz, 1H) 9.38 (br. s., 2H). ESI-MS:m/z 260.2 (M+H)+. mp=171.5-172.8° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:25])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[C:48]1([C:54]2[NH:58][N:57]=[C:56]([SH:59])[N:55]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.N1C=CC(C2NC(S)=NN=2)=CC=1.Cl>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[CH:2]([S:59][C:56]3[NH:55][C:54]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[N:58][N:57]=3)[C:7](=[O:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1n[nH]c(-c2ccccc2)n1
Agent: Cl
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Sc3nnc(-c4ccccc4)[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one Step 1 of example C(40), was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Phenyl-1H-1,2,4-triazole-3-thiol was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 1.53-1.85 (m, 10H), 2.17-2.34 (m, 1H), 2.69-2.75 (m 2H), 2.95 (d, J=17.0, 1H), 3.08 (d, J=17.0 Hz, 1H), 3.90 (s, 3H), 7.08 (d, J=8.4 Hz, 1H) 7.22-7.26 (m, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.40-7.53 (m, 4H), 7.91-7.94 (m, 2H), 12.0 (brs, 1H); Anal. Calcd. For C27H28ClN3O4S.1.0 HCl.1.0H2O: C, 55.86; H, 5.38; N, 7.24; Found: C, 55.75; H, 5.17; N, 7.17. ESIMS (MH+): 527
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Sn](CCCC)(CCCC)(Cl)Cl.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)(=O)C>[CH3:26][CH2:25][O:24][C:22]([C:21]1[N:1]=[C:2]2[N:3]([CH:4]=[CH:5][CH:6]=[CH:7]2)[CH:20]=1)=[O:23]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccccn1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a solution of 2-aminopyridine (292, 1.1022 g; 11.71 mmol) and Bu2SnCl2 (431 mg; 1.3 mmol) in DME (20 mL), ethyl 3-bromopyruvate (1.56 mL; 11.16 mmol) was added to give an instant yellow precipitate. The suspension was stirred at room temperature for 2 h, then solid K2CO3 (2.6 g; 18.8 mmol) was added and the mixture stirred for additional 20 h at the same temperature. The reaction mixture was then diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium chloride. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluent 50% ethyl acetate in dichloromethane), to afford the title compound 293 (1.31 g, 59% yield) as a white crystalline material. 1H NMR (400.2 MHz, DMSO) δ (ppm): 8.54 (m, 1H); 8.53 (d; J=0.9 Hz; 1H); 7.59 (ddd; J=1.3, 2.0, 9.2 Hz; 1H); 7.33 (ddd; J=1.3, 6.7, 9.2 Hz; 1H); 6.98 (dt; J=0.9, 7.8 Hz; 1H); 4.30 (q; J=7.0 Hz; 2H); 1.32 (t; J=7.0 Hz; 3H). MS: calc: 190.0; found: 191.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.CCCCCCC=CCCC>O1CCCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:12]2[CH2:13][CH2:14][CH:10]([OH:9])[CH2:11]2)[N:3]=1
Reactant: OC1CCNC1
Reactant: Brc1cccc(Br)n1
Agent: CCCC=CCCCCCC
Solvent: C1CCOC1
Product: OC1CCN(c2cccc(Br)n2)C1
Reaction time: 11 h
Yield: 100.9 %

Procedure:
A mixture of 5.7 g of 2,6-dibromopyridine, 2.5 g of 3-hydroxypyrrolidine, 3.6 ml of 1,8-diazbicyclo[5.4.0]-7-undecene (DBU) and 20 ml of tetrahydrofuran was heated under stirring for 11 hours in an oil bath kept at 70° C. The mixture was partitioned between ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 10-30% ethyl acetate/hexane, to give 5.9 g of 2-bromo-6-(3-hydroxypyrrolidine-1-yl)pyridine.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]>[Pd].CO>[NH:5]1[CH:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[N:3]=[CH:4]1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1c[nH]cn1
Reaction time: 5 h

Procedure:
Urocanic acid (3-(1H-imidazol-4-yl)-acrylic acid) (138 mg, 1 mmol) was placed in a round-bottom flask and dist MeOH was added thereto until urocanic acid was completely dissolved. To this solution, 10% Pd/C (30 mg) was added, replaced with H2 and stirred. After five hours, the loss of raw materials was confirmed, filtered, and the filtrate was concentrated under a reduced pressure to give the objective product.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>C(O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:9]
Reactant: NCCCn1ccnc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Solvent: CCO
Product: Nc1ccc(Cl)cc1C(=O)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 7.92 g of 5-chloroisatoic anhydride, 5.0 g of 1H-imidazole-1-propanamine and 75 ml of ethanol was stirred at room temperature for 20 hours and concentrated. The residue was washed onto a filter with ethanol, then washed with ether to give the desired product, mp 155°-157° C.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[N:11]=[C:10]([NH:24][CH:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:9]=1>C1C=CC=CC=1>[Cl:23][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[C:10]([NH:24][CH:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:9]=[C:8]([O:4][CH:1]([CH3:3])[CH3:2])[N:13]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CC(C)O
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OC(C)C)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of isopropanol (2 mL) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH—CHCl3) to afford the title compound E21 as an off-white solid (0.30 g, 94%). mp 136-138° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 30.06 min, 98.78% purity; MS (CI): m/z 406 (M+H, 100).
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8](Cl)[CH:9]=[CH2:10].O.O.[Sn](Cl)Cl>[Cu].O>[OH:7][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:10][CH:9]=[CH2:8]
Reactant: CCCCCC=O
Reactant: C=CCCl
Agent: [Cu]
Agent: Cl[Sn]Cl
Solvent: O
Product: C=CCC(O)CCCCC
Temperature: 30 °C
Reaction time: 8 h

Procedure:
3500 ml water, 200 g hexanal (2 mol) and 305 g allyl chloride (4 mol), 900 g tin(II) chloride dihydrate (2 mol) and 25 g copper powder (0.4 mol) was added into a 61 flask. The reaction mixture was stirred at ca. 30° C. for 8 h. The organic phase was separated by decantation or centrifugation and the crude raw product distilled in vacuo to give 4-hydroxy-1-nonene. MS: m/z 141 (M-1), 101 (M-C3H5), 124 (M-18), 83 (101-18), 55 (83-C2H4).
Reaction SMILES: N[C:2]1C=C(Br)C=CC=1C(OC)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1.N1(C2CCCCCCCCCC2)CCCNCCCCCC1.O>CN(C=O)C>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][CH3:2])=[O:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(Br)cc1N
Agent: C1CCCCCC(N2CCCCCCNCCC2)CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Methyl 2-amino-4-bromobenzoate. To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU; 10.3 mL, 75 mmol) followed by Mel (4.67 mL, 75 mmol). The mixture was stirred for 15 min at 0° C., then was allowed to warm to rt and was stirred overnight. The mixture was poured into water and extracted with EtOAc (2×). The combined organic extracts were washed with water (2×), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90%). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at rt was added SnCl2.2H2O (15.27 g, 67 mmol). After 18 h, the mixture was concentrated, diluted with satd. aq. NaHCO3, and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide the desired aminobenzoate as a white solid (2.89 g, 93%). 1H NMR (400 MHz, CDCl3): 7.70(d, J=8.6, 1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CSCCN1
Product: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Reaction time: 1 h

Procedure:
(ab) 23 ml of thiomorpholine are slowly added dropwise at about 80° to 17.17 g of p-fluoronitrobenzene in such a manner that the internal temperature does not rise above 110°. The mixture is then stirred at 120° for an additional 1 hour, whereupon it is extracted three times with 1 l of dichloromethane each time and the organic phases are washed three times with 500 ml of water each time, dried over sodium sulfate and evaporated. By recrystallization of the crude product from dichloromethane/ether, there is obtained 4-(p-nitrophenyl)-tetrahydro-4H-1,4-thiazine of melting point 142°-144°.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[N:10]=[C:11]([CH2:13][CH3:14])[NH:12][C:7]2=[C:6]([CH3:15])[CH:5]=1.[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:40][C:37]3[CH:36]=[CH:35][C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]4[N:23]([C:22]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[N:24]=[N:25][N:26]=4)=[CH:39][CH:38]=3)[C:11]([CH2:13][CH3:14])=[N:12][C:7]2=[C:6]([CH3:15])[CH:5]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.6 %

Procedure:
To a stirred suspension of NaH (17.2 mmol of an 80% dispersion) in dry dimethylformamide (30 mL) at rt was added 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (1.51 g, 8.62 mmol) in one portion. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (5.29 g, 9.48 mmol) was added in one portion. The resulting mixture was warmed to rt and stirred for 15 hours. The excess NaH was quenched with water and the bulk of the DMF was removed in vacuo at 40°-50° C. The residue was extracted with EtOAc from brine, dried (K2CO3), and concentrated. Purification by flash chromatography (SiO2, solvent gradient: 80% EtOAc/hexanes, 100% EtOAc) gave 4.25 g of 5,7-dimethyl-2-ethyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine: 1H NMR (300 MHz, CDCl3) δ 7.86 (dd, 1H, J=7, 2 Hz), 7.5-7.41 (m, 2H), 7.36-7.21 (m, 10 H), 7.05 (d, 2 H, J=4.5 Hz), 6.95-6.89 (m, 7 H), 6.86 (d, 2 H, J=4.5 Hz), 5.35 (s, 2H), 2.67 (q, 2 H, J=7.5 Hz), 2.65 (s, 3 H), 2.58 (s, 3 H), 1.25 (t, 3 H, J=7.5 Hz).