Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([O:56]C)=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[OH-].[K+].Cl>CO>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([OH:56])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(=O)O)C3
Reaction time: 2.5 h

Procedure:
To a solution of 1.1 g of methyl Boc-L-tyrosylmethionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate in 10 ml of methanol is added 10 ml of water. The pH is adjusted to 13.0 with a 4 M solution of potassium hydroxide and held at pH 13-13.5 for 2.5 hours. The pH is adjusted to 11.0 with 12 N hydrochloric acid, and the methanol is removed under vacuum. The residual aqueous solution is adjusted to pH 2.0 by the slow addition of hydrochloric acid causing the product to crystallize. The product is collected by filtration and washed with water then dried for two hours at 50° C. and 0.1 mm of pressure. The residue is dissolved in a 6 N solution of ammonia. The excess ammonia is removed under vacuum and the remaining aqueous solution is adjusted to pH 4.0 with 1 N acetic acid. The product crystallizes and is collected by filtration, washed with water and dried for 16 hours at 50° C. and 0.1 mm pressure to give Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylic acid which is represented by the following formula ##STR26##
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:45])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40][N:39]=2)[CH:33]=1)=O)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:45])[CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40][N:39]=4)[CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (139 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([C:20]4[CH:32]=[CH:31][O:30][C:21]=4[CH2:22][O:23]3)=[CH:18][CH:17]=2)C(OC)=O)(=[O:10])=[O:9])=[C:4](/[CH:33]=[CH:34]\[CH2:35]O)[CH:3]=1.C([N:40]([CH:43]([CH3:45])C)[CH2:41]C)(C)C.CS(Cl)(=O)=O.N1CCC1>C(Cl)Cl.C1(C)C=CC=CC=1>[N:40]1([CH2:35]/[CH:34]=[CH:33]\[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH:11][C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([C:20]4[CH:32]=[CH:31][O:30][C:21]=4[CH2:22][O:23]3)=[CH:18][CH:17]=2)(=[O:9])=[O:10])[CH2:41][CH2:45][CH2:43]1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCc1occc1-2
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCC2)ccc2c1OCc1occc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a suspension of methyl 7-{N-[4-fluoro-2-((Z)-3-hydroxy-prop-1-enyl)-benzenesulfonyl]-N-(methoxycarbonyl)amino}-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 92, 0.150 g) in DCM (10 mL) was added N,N-di-isopropyl-N-ethylamine (0.112 g) and methanesulfonyl chloride (0.040 g). The mixture was stirred at room temperature for 15 minutes. A solution of azetidine (0.083 g) in toluene (2 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM, washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%. The resultant product was triturated with diethyl ether to give methyl 7-{2-[(Z)-3-azetidin-1-yl-prop-1-enyl]-4-fluorobenzene-sulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylate (0.030 g) as a white powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Li+].CC([N-]C(C)C)C.[F:27][C:28]1[N:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1.[B:41](OC(C)C)([O:46]C(C)C)[O:42]C(C)C>O1CCCC1>[F:27][C:28]1[C:29]([B:41]([OH:46])[OH:42])=[CH:30][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:32][N:33]=1
Reactant: Fc1ccc(CN2CCOCC2)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: OB(O)c1cc(CN2CCOCC2)cnc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of diisopropylamine (13.51 mL, 96 mmol) in tetrahydrofuran (66 mL) was treated with 2.0 M n-butyl lithium in hexane (48.2 mL, 96 mmol) at −40° C. and stirred for 1 h. The resulting LDA solution was cooled to −78° C. and a solution of 4-((6-fluoropyridin-3-yl)methyl)morpholine (15.767 g, 80 mmol) in THF (50 mL) was added via cannula over 20 min. The deep-red mixture was stirred at −78° C. for 1.5 h. A solution of triisopropyl borate (27.7 mL, 121 mmol) in THF (22 mL) was added slowly. The resulting mixture was stirred at −78° C. for 30 min and then the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The mixture was quenched with 1 N NaOH(aq) (50 mL) and stirred. The aqueous layer was separated and the organic layer was extracted with 1 N NaOH (2×20 mL). The combined aqueous layers were carefully acidified with 5 N HCl until acidic (pH 5 to about 6) and the resulting cloudy mixture was extracted with EtOAc (3×100 mL). The aqueous layer was lyophilized. The resulting residue was diluted with 1:1 MeOH/DCM and placed into a sonicator for 5 min. The mixture was filtered through a fine-fritted funnel The filtrate was concentrated to give 2-fluoro-5-(morpholinomethyl)pyridin-3-ylboronic acid (19.000 g, 79 mmol, 99% yield) as a tan oil. 1H NMR (400 MHz, d4-MeOH) δ 8.46 (s, 1H); 8.32 (d, J=6.06 Hz, 1H); 4.42 (s, 2H); 3.82-4.00 (m, 4H); 3.23-3.36 (m, 4H); 2.01 (s, 1H). m/z (ESI, +ve ion) 241.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1>C(NCCCC)CCC>[CH2:12]([N:13]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)=[CH:8][CH:7]=1)[CH2:14][CH2:19][CH2:18][CH3:17])[CH2:9][CH2:8][CH3:7]
Reactant: ClCCCOc1ccc(-c2cn3ccccc3n2)cc1
Solvent: CCCCNCCCC
Product: CCCCN(CCCC)CCCOc1ccc(-c2cn3ccccc3n2)cc1
Yield: 192 %

Procedure:
A suspension of 2-(4-chloropropoxyphenyl)imidazo[1,2-a]pyridine (5.2 g, 14 mmol) in dibutylamine (30 ml) was stirred at reflux for 5 hours. The excess dibutylamine was removed by distillation and the resulting oil was flash chromatographed (silica gel, 9:1 CH2Cl2 :acetone) to give the free base of the title compound (5.1 g, 93% yield) as an oil. The HCl salt was prepared by dropwise addition of concentrated hydrochloric acid to a solution of the free base in methanol, concentrated and recrystalized from methanol acetone to yield 2-(4-dibutylaminopropoxyphenyl)imidazo[1,2-a]pyridine as a white crystalline solid, mp 179° C. to 183° C. IR(KBr): 3400, 2620, 1650, 1620 cm-1. MS: 380 (MH+). 1H NMR (CD3OD): δ 8.80 (d, J=8 Hz, 1H), 8.52 (s, 1H), 7.92-7.49 (m, 5H), 7.18 (d, J=8 Hz, 2H), 4.23 (t, J=4.6 Hz, 2H), 3.50-3.13 (m, 6H), 2.25 (m, 2H), 1.82-1.34 (m, 8H), 1.01 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[C:7]([OH:13])(=O)[CH2:8][C:9]([OH:11])=O.C(OC(=O)C)(=O)C.C(O)C>C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:13])[CH2:8][C:9](=[O:11])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CNC(=O)NC
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CN1C(=O)CC(=O)N(C)C1=O
Reaction time: 6 h
Yield: 73.4 %

Procedure:
That is, 276 g (3.14 moles) of 1,3-dimethylurea and 376 g (3.62 moles) of malonic acid were dissolved in 600 ml of glacial acetic acid at 60° to 70° C., and then, after adding thereto 1250 ml of acetic anhydride, the temperature of the mixture was gradually increased to 90° C. Then, after stirring the mixture for 6 hours at the same temperature, the reaction mixture was allowed to stand overnight at room temperature and glacial acetic acid and acetic anhydride were distilled off under reduced pressure. The residue thus formed was added to 500 ml of ethanol while still hot and the crystals thus precipitated were collected by filtration, heat-refluxed for 2 hours with 380 ml of concentrated hydrochloric acid and 400 ml of water, and then allowed to stand for 6 hours under ice-cooling. The crystals thus precipitated were collected by filtration and washed with a small amount of ethanol to provide 360 g of 1,3-dimethylbarbituric acid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[C:6](F)=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>O.C(#N)CC.CN(C)C1C=CN=CC=1>[Cl:4][C:5]1[C:6]([C:1]#[N:2])=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: [C-]#N
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CCC#N
Solvent: O
Product: N#Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
A reactor was charged with a solution of sodium cyanide (73.5 g) in water (150 ml), propionitrile (500 ml), 4-dimethylaminopyridine (16 g), and 3-chloro-2-fluoro-5-trifluoromethylpyridine (149.3 g) added over 30 minutes. After stirring for 5 hours at 20° C., the upper organic phase was separated off and washed with water. The lower aqueous layer was extracted with propionitrile, the two organic layers combined and solvent distilled off under vacuum at 45° C. to give an 83% yield of 3-chloro-2-cyano-5-trifluoromethylpyridine.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH:24][C:25](=[O:28])[CH2:26][Cl:27])[CH:21]([CH3:23])[CH3:22]>C1C=CC=CC=1>[Cl-:27].[CH2:20]([N:24]([P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:25](=[O:28])[CH3:26])[CH:21]([CH3:23])[CH3:22]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)CNC(=O)CCl
Solvent: c1ccccc1
Product: CC(=O)N(CC(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 85.9 %

Procedure:
To a solution of triphenylphosphine (229.8 g, 876 mmol) in dry benzene (800 ml) was added N-isobutyl-2-chloroacetamide (131 g, 876 mmol) (prepared by standard methods from 2-chloroacetyl chloride and isobutylamine) in dry benzene (100 ml). The solution was heated under reflux, with vigorous stirring, for 8 hours. Upon cooling, colourless needles formed. These were collected by filtration and the filtrate heated under reflux for a further 8 hours. A second batch of the produce was collected. The combined batches were washed with dry ether and dried in vacuo to give 310 g (86% of theory) of N-isobutyl-acetamidotriphenyl-phosphonium chloride as colourless needles.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]([CH:15]([CH2:20][CH2:21]O[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:16]([O:18][CH3:19])=[O:17])[C:6]1=[O:40])(=[O:3])[CH3:2].N1C=CC=CC=1.C1C[O:50]CC1>>[C:1]([O:4][C@@H:5]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]([CH:15]([CH:20]([OH:50])[CH3:21])[C:16]([O:18][CH3:19])=[O:17])[C:6]1=[O:40])(=[O:3])[CH3:2]
Reactant: COC(=O)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(OC(C)=O)C1c1ccccc1
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C(C(C)O)N1C(=O)[C@H](OC(C)=O)[C@@H]1c1ccccc1

Procedure:
The diastereomeric mixture of Example 2 (444 mg, 0.793 mmol) in anhydrous THF (4 mL) was treated with HF/pyridine (4.4M, 1.80 mL, 7.93 mmol) at room temperature for 5 days. Quench and work up as in the above Example 5, followed by chromatography (40% ethyl acetate/hexane) gave title compound as a white solid. (139 mg, 54%).
Reaction SMILES: C(OC([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39](O)=[O:40])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si](C(C)(C)C)(C)C)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.CN(C1C=CC=CN=1)C.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].Cl>C(Cl)Cl.O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:40])[CH:32]=2)[O:27]1
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3cccc(C(=O)O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
The product of Example 86 (100 mg, 0.16 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide (36 mg, 0.19 mmol), dimethylaminopyridine (20 mg, 0.16 mmol), and methylsulfonamide (17 mg, 0.18 mmol) were dissolved in 2 mL methylene chloride and stirred overnight at room temperature. The mixture was treated with 0.5 mL 4 M HCl in 1,4-dioxane was added, the solution stirred for 0.5 hours, concentrated to dryness and the residue was purified by preparative HPLC to obtain the title compound (47 mg, 62%). 1H NMR (CD3CN-d3) δ: 8.91 (s, 1 H), 8.76 (d, 1 H), 8.51 (d, 1 H), 8.07 (s, 1 H), 7.97 (t, 1 H), 7.88-7.83 (m, 2 H), 7.62-7.56 (m, 1 H), 7.50-7.47 (m, 2 H), 6.98 (d, 1 H), 5.46 (d, 1 H), 4.54-4.47 (m, 1 H), 3.52 (dd, 2 H), 3.37 (s, 3 H), 3.39-3.25 (m, 2 H), 2.99-2.90 (m, 2 H), 2.14-2.09 (m, 1 H), 1.86-1.79 (m, 1 H). MH+=482.2
Reaction SMILES: CI.[C:3](=O)([O-])O.[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:12][C:11]=1[C:21](=[O:25])[C:22]([OH:24])=[O:23]>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:12][C:11]=1[C:21](=[O:25])[C:22]([O:24][CH3:3])=[O:23]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1cc(-n2cnnn2)ccc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
Methyl iodide (1.87 ml, 4.26 g, 30 mmol) was added to a mixture of sodium hydrogen carbonate (2.52 g, 30 mmol), and 2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoic acid (3.37 g, 13.6 mmol) in dimethylformamide (120 ml) and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) and water (50 ml) were added and mixture was extracted with ethyl acetate (4×100 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×100 ml), dried (MgSO4) and evaporated under reduced pressure to give methyl 2-[2-methoxy-5-(1H-tetrazol-1-yl)phenyl]-2-oxoethanoate as an orange solid (3.36 g, 94%), 1H NMR (CDCl3) δ 9.02 (1H, s), 8.11 (1H, d, J=2.8 Hz), 8.03 (1H, dd, J=9.0, 2.8 Hz), 7.23 (1H, d, J=9.0 Hz), 3.99 (3H, s), and 3.96 (3H, s).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br>C(O)(=O)C.O>[C:4]1([CH:3]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2][C:1]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)C=Cc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CC(Sc1ccccc1)c1ccccc1
Yield: 70.2 %

Procedure:
Cinnamic acid (30.0 g.), benzenethiol (24.0 g.) and 45% w/v hydrogen bromide in acetic acid (21.5 ml) were heated together at 100° for 7 hrs. The reaction mixture was diluted with water and steam distilled to remove unchanged thiol. The hot aqueous layer was decanted from the oily product, which was recrystallised from 60°-80° petrleum ether to give 3-phenyl-3-(phenylthio)propionic acid (36.7 g) m.pt. 85°-90°. A sample recrystallised again from 60°-80° petroleum ether had m.pt. 88°-90°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16].O>C1COCC1.CC(C)([O-])C.[K+]>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:16][CH2:15][CH2:14][CH2:13][NH2:12])=[N:3][CH:4]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: NCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NCCCOc1ccc(C(F)(F)F)cn1
Temperature: 0 °C

Procedure:
2-Fluoro-5-trifluoromethylpyridine (1.831 g, 11 mmol) was dissolved in anhydrous THF (15 mL) with stirring under nitrogen and cooled to 0° C. in an ice bath. To this was added dropwise over 30 minutes a solution of 3-amino-1-propanol (0.76 mL, 10 mmol) in anhydrous THF (15 mL) and 1M potassium tert-butoxide in THF (10 mL, 10 mmol). The yellow solution was allowed to stir and slowly warm to room temperature overnight. The reaction mixture was poured into water (75 mL) and extracted with ether (2×50 mL). The organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and evaporated under vacuum to a yellow liquid, which was nearly pure by NMR and MS, and was used as such without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.C[CH:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:17][CH2:16][N:15](CC(NC(=O)C2C=CC(C)=CC=2)C(C)C)[CH2:14]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][N:18]1[CH2:13][CH2:14][N:15]([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[N+:1]([O-:3])=[O:2])[CH2:16][CH2:17]1
Reactant: O=[N+]([O-])C1=CCCCC1
Reactant: Cc1ccc(C(=O)NC(CN2CCN(Cc3ccc(Cl)c(Cl)c3)C(C)C2)C(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C1CCCCC1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.5 %

Procedure:
A mixture of 1-nitrocyclohexene (311 mg, 2.45 mmol), dichlorobenzylpiperazine [prepared as described in Example 1](600 mg, 2.45 mmol), and triethylamine (512 μl, 3.68 mmol) in methylene chloride (10 ml) was stirred at room temperature under nitrogen atmosphere for 17 h. The reaction mixture was diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed with hexanes/ethyl acetate (2:1) as the eluant to provide 1-(3,4-dichlorobenzyl)-4-(2-nitrocyclohexyl)piperazine (461 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:31])[CH:9]([NH:11][C:12]([C:14]2[CH:30]=[CH:29][C:17]3[N:18]=[C:19]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:28])[NH:20][C:16]=3[CH:15]=2)=O)[CH3:10])=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:31][C:12]([C:14]3[CH:30]=[CH:29][C:17]4[N:18]=[C:19]([C:21]5[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=5[Cl:27])[NH:20][C:16]=4[CH:15]=3)=[N:11][C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(NC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1)C(=O)c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)oc1-c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
A mixture of 2-(2,6-dichlorophenyl)-3H-benzimidazole-5-carboxylic acid [2-(4-chlorophenyl)-1-methyl-2-oxoethyl]-amide (480 mg, 1.02 mmol) and Burgess Reagent (848 mg, 4.06 mmol) in THF (10 mL) was heated in a microwave apparatus at 150° C. for 30 min. The mixture was poured into ethyl acetate and extracted with water and brine. The organic layer was dried, filtered, and the solvent removed under reduced pressure. The residual oil was triturated with acetonitrile to afford the title compound. H1-NMR (DMSO-d6): δ 8.40 (s, broad, 0.5H), 8.22 (s, broad, 0.5H), 8.0 (m, 1H), 7.72 (m, 8H), 2.47 (s, 3H). MS: m/z 455.9 (M+1); High resolution MS (M+H): theory: 454.0281, measured: 454.0279.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[CH:5]=[CH:6]/[CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH:11]([CH:13]=C)=[O:12].[C:15]1(C=CC(O)=CC=1)O>>[CH3:4][C:3]1[CH:2]([CH3:15])[CH2:1][CH:13]([CH:11]=[O:12])[CH:6]([CH:7]=[C:8]([CH3:10])[CH3:9])[CH:5]=1
Reactant: C/C=C(C)/C=C/C=C(C)C
Reactant: Oc1ccc(O)cc1
Reactant: C=CC=O
Product: CC(C)=CC1C=C(C)C(C)CC1C=O
Yield: 66 %

Procedure:
408 g of allo-ocimene (85% 4E 6Z, 15% 4E 6E) and 202 g of acrolein were placed in a stainless steel vessel which is equipped to withstand a high internal pressure at elevated temperatures. 1 gm of hydroquinone, a polymerisation inhibitor, was added. The air in the vessel was displaced with nitrogen and the vessel closed. The temperature was raised to 145°-150° C. and maintained in the range for 7.5 hours. The maximum pressure recorded was 105 psi. The reaction mixture was then distilled and a mixture of four aldehydes collected which represented a 66% yield of the desired product. The percentages of adducts were A 4%, B 11%, C 74% and D 11% where the letters A, B, C, D represent the isomers denoted as such in Example 1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6]O)[CH2:2]1.C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[S:21]([CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: OCC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (tetrahydrofuran-3-yl)methanol (1.0 g, 9.8 mmol) in CH2Cl2 (5 mL) and triethylamine (1.98 g, 19.6 mmol) was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 12 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×10 mL) The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+.