Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:17]2[O:35][C@H:18]2C2C=CC(OC)=C(OCC3C=CC=CC=3)C=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[CH3:39][O:40][CH:41]([O:45][CH3:46])[CH2:42][NH:43][CH3:44]>CC(O)CC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@H:17]([OH:35])[C@@H:18]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[N:43]([CH2:42][CH:41]([O:45][CH3:46])[O:40][CH3:39])[CH3:44])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCC(OC)OC
Reactant: COc1ccc([C@@H]2O[C@H]2c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Solvent: CCC(C)O
Solvent: ClCCl
Product: COc1ccc([C@H]([C@@H](O)c2ccc(OC)c(OCc3ccccc3)c2)N(C)CC(OC)OC)cc1OCc1ccccc1

Procedure:
Mixture: 51.7 g (0.11 mol) of rel-(S,S)-3,3'-dibenzyloxy-4,4'-dimethoxystilbene oxide, 1800 ml of dichloromethane, 100 ml of 2-butanol, 25 ml (0.19 mol) of methylaminoacetaldehyde dimethyl acetal, 5 g of silica gel
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:27]([CH3:26])[C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=3)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:9])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: CNc1ccc(OC(F)(F)F)cc1
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccc(OC(F)(F)F)cc1
Yield: 72 %

Procedure:
Following the general methods as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and N-methyl-4-(trifluoromethoxy)aniline, the title compound was isolated as a yellow solid in 72% yield (99% purity by HPLC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH3:16].N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH3:16])[CH:4]=1
Reactant: Br
Reactant: CSc1ccccc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccccc1-c1cc(Br)ccc1F
Temperature: 4 °C
Reaction time: 0.67 h
Yield: 57 %

Procedure:
To a solution of 2-fluoro-2′-(methylthio)biphenyl-5-ylamine (397 mg, 1.70 mmol) in 1,4-dioxane (2.1 ml) was added 48% aqueous hydrobromic acid (8 ml) and the mixture was cooled to 3° C. before the dropwise addition of sodium nitrite (137 mg, 1.98 mmol) in water (0.5 ml) over 5 min, while the temperature was kept below 5° C. The resulting mixture was stirred at 4±1° C. for 2 h 40 min then more sodium nitrite (26 mg, 0.37 mmol) in water (0.1 ml) was added dropwise and the mixture was stirred at 3° C. for 50 min. A cooled (3° C.) solution of copper(I) bromide (744 mg, 5.19 mmol) in 48% hydrobromic acid (2.4 ml) was added and the mixture was stirred at 3° C. for 15 min then heated to 50° C. for 1 h. The mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with ethyl acetate (4×35 ml). The combined organics were washed with 1M aqueous sodium sulphite solution (30 ml), then saturated aqueous ammonium chloride solution (30 ml), dried over anhydrous magnesium sulphate and evaporated to give a brown oil. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (0-2%) gave 5-bromo-2-fluoro-2′-(methylthio)biphenyl as a white solid (287 mg, 57%): δH (360 MHz, CDCl3) 2.40 (3H, s), 7.04 (1H, t, J 9), 7.16-7.24 (2H, m), 7.32 (1H, d, J 8), 7.36-7.51 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28]([C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]>O1CCCC1.C(OCC)(=O)C>[C:28]([C:30]1[CH:31]=[C:32]([S:37]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 70.8 %

Procedure:
N-(2,4-Dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 42.8 g, 170 mmol) was dissolved in anhydrous tetrahydrofuran (600 mL) and stirred under a nitrogen atmosphere at −78° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (238 mL, 238 mmol) was added drop wise over 30 minutes maintaining the temperature between −65° C. and −70° C. The reaction mixture was left at −78° C. for 5 minutes, then allowed to warm to −10° C. over 1.5 hours. Upon reaching −10° C., the brown reaction mixture was cooled to −78° C. again, and a solution of 3-cyano-4-fluorobenzene sulfonyl chloride (48.6 g, 221 mmol) in tetrahydrofuran (200 mL) was added drop wise over 30 minutes maintaining the temperature between −65° C. and −70° C. The brown solution was allowed to warm gradually to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, and extracted with further ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown residue. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (52.3 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].ClS([N:14]=[C:15]=O)(=O)=O.CN(C)C=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:15]#[N:14])[CH:9]=1)=[O:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)c1ccc[nH]1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1cc(C#N)c[nH]1
Temperature: -20 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
4-Cyano-1H-pyrrole-2-carboxylic acid methyl ester was prepared as described in Can. J. Chem., 59, 2673-76 (1981). 1H-Pyrrole-2-carboxylic acid methyl ester (2.00 g, 16.00 mmol) was dissolved in acetonitrile (5 mL) and the solution was cooled to −20° C. Chlorosulfonylisocyanate (3.40 g, 24.00 mmol) was dissolved in acetonitrile (5 mL) and added dropwise via syringe over a period of 5 min to the above solution. The solution was allowed to warm to 25° C. and was stirred for 20 h. The solution was cooled back to 0° C., N,N-dimethylformamide (2 mL) was added and the solution was heated to 50° C. for 15 min. The reaction mixture was poured into ice and was extracted with chloroform, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 40% ethyl acetate in hexanes) afforded the desired product, 4-cyano-1H-pyrrole-2-carboxylic acid methyl ester (1.09 g, 7.265 mmol, 45.4% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 3.91 (3H, s), 7.12 (1H, t, J=2.0 Hz), 7.40-7.41 (1H, m), 9.60 (1H, bs). FT-IR (ATR) νmax (neat): 2228, 1691 cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:21](OCC)(OCC)OCC>C(O)=O>[C:15]1([CH2:14][CH2:13][N:12]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=[CH:21]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cnc2ccccc2c1NCCc1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: c1ccc(CCn2cnc3cnc4ccccc4c32)cc1

Procedure:
Using the method of Example 49, 3-amino-4-[2(phenyl)ethylamino]quinoline was reacted with triethyl orthoformate and formic acid to provide 1-[2-(phenyl)ethyl]-1H-imidazo[4,5-c]quinoline, m.p. 105°-108° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[CH3:16][NH2:17].[BH4-].[Na+].O>CCO>[CH3:16][NH:17][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(Oc2cncnc2)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNCc1ccc(Oc2cncnc2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(Pyrimidin-5-yloxy)benzaldehyde (0.344 g, 1.7 mmol) was stirred with 33% methylamine in EtOH (30 mL) at reflux for 3 hours and then concentrated. The residue was dissolved in MeOH and treated with sodium borohydride (0.195 g, 5.2 mmol) over 1 hour and stirred for a further 1 hour. Water was added and the product was extracted three times with EtOAc. The organic phases were combined, washed with brine, dried and concentrated to give 0.267 g (100%) of product that was used without further purification.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[CH3:12]I>CC(C)=O>[CH3:12][S:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1c[nH]c(S)n1
Reactant: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1c[nH]c(SC)n1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a suspension of ethyl 2-mercapto-1H-imidazole-4-carboxylate (4.00 g, 23.3 mmol) in acetone (30 mL) at room temperature, MeI (6 mL, 96.3 mmol) was added. During first 10 min of stirring, the suspension became clear, then it turned cloudy as product began to precipitate out. After being stirred at room temperature overnight, the precipitate was collected, dried on vacuum to give ethyl 2-(methylthio)-1H-imidazole-4-carboxylate (3.47 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16]O>C[Re](=O)(=O)=O>[CH2:9]([N:8]([OH:16])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OO
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: C[Re](=O)(=O)=O
Product: ON(Cc1ccccc1)Cc1ccccc1
Yield: 50 %

Procedure:
U.S. Pat. No. 3,491,151 discloses a method for preparing N,N-dialkylhydroxylamine compounds by allowing hydroxylamines react with alkyl halides, alkyl tosylates or the like. However, this method is also undesirable, because it requires a prolonged reaction time and achieves a yield of no more than about 50%. Tetrahedron Letters, Vol. 37, No. 33 pp. 6025-6028, 1996 discloses a method for synthesizing nitrone compounds by oxidizing dibenzylamine by means of a combination of aqueous hydrogen peroxide and methyltrioxorhenium. According to this synthetic method, an N,N-dibenzylhydroxyl-amine compound is produced in addition to a nitrone compound as a major product. However, its yield is low. Furthermore, the method requires a large amount of methyltrioxorhenium. For these reasons, the method is only disadvantageously applied to practical preparations of N,N-dibenzylhydroxylamine compounds.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][CH:12]=[N:11]1>C(#N)C>[I:1][C:13]1[CH:12]=[N:11][N:10]([CH3:9])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(-c2ccnn2C)cc1
Solvent: CC#N
Product: Cc1ccc(-c2c(I)cnn2C)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
N-Iodosuccinimide (95%, 756 mg, 3.19 mmol) was added to a solution of 1-methyl-5-(4-methylphenyl)-1H-pyrazole (500 mg, 2.90 mmol) in acetonitrile (15 mL), and the reaction was allowed to stir for 1 hour at 85° C. Removal of solvent in vacuo provided a residue, which was chromatographed on silica gel (Gradient: 20% to 50% ethyl acetate in heptane) to provide the product as a brown oil. Yield: 630 mg, 2.11 mmol, 73%. LCMS m/z 299.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.44 (br s, 3H), 3.83 (s, 3H), 7.26-7.33 (m, 4H), 7.57 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=1)[CH3:2].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(=O)C(=CNc1cccc(CO)c1)C(=O)OCC
Solvent: c1ccncc1
Product: CCCC(=O)C(=CNc1cccc(COC(=O)c2ccccc2)c1)C(=O)OCC
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a stirred and cooled (ice-bath) solution of ethyl-2-butyryl-3-(3-hydroxymethylphenylamino)acrylate (29.13 g, 0.1 mol) in pyridine was added dropwise benzoyl chloride (21.09 g, 0.15 mol). The ice bath was removed and the mixture stood for 16 hours, then evaporated, treated with chloroform (200 ml) and washed with saturated aqueous sodium bicarbonate (200 ml), water (200 ml), and 2N hydrochloric acid (2×150 ml). After drying (Na2SO4) and stirring with charcoal, the solution was filtered and evaporated to an oil, which crystallised slowly under petroleum ether (b.p. 40-60) to give the title compound (34.5 g) m.p. 59°-63°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]([CH3:60])[C:57](Cl)=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:57]([N:56]([CH3:60])[CH3:55])=[O:58])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CN(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 84 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and N,N-dimethylcarbamoyl chloride as starting materials in 84% yield. LCMS for C27H32ClN8O2 (M+H)+: m/z=535.2.
Reaction SMILES: [N+:1]([CH2:3][C:4](OC)=[O:5])#[C-:2].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[N+:1]([CH2:3][C:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:5])#[C-:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: C1COCCN1
Product: [C-]#[N+]CC(=O)N1CCOCC1

Procedure:
To stirred and cooled (0° C.) methyl 2-isocyanoacetate (96% technical grade, 1.0 g, 10.09 mmol) was slowly added morpholine (1.05 g, 12.11 mmol). The mixture was stirred for 1 h with continuous stirring at room temperature and then concentrated. The resulting oil was co-evaporated twice from a mixture CH2Cl2:hexane to obtain crude 2-isocyano-1-morpholinoethanone, SLA 19178, as a yellow oil (1.65 g, 99% yield) and used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=1[C:9](O)=O.[BH4-].[Na+].[B].C([O:19]C(C)C)(C)C>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH3:9])[CH2:12][OH:19]
Reactant: COc1cc(C)ccc1C(=O)O
Reactant: CC(C)OC(C)C
Agent: [BH4-]
Agent: [B]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1C
Reaction time: 0.17 h

Procedure:
A solution of 3-methoxy-p-toluic acid (45.32 g) in tetrahydrofuran (280 ml) was added to a suspension of sodium borohydride (9.29 g) in tetrahydrofuran (45 ml) with ice bath cooling under nitrogen atmosphere. After 10 minutes stirring, boron trifuluoride diethyl etherate (41.5 ml) was added to the mixture at 3 to 15° C. and the whole was stirred at room temperature overnight. Water (210 ml) and diisopropyl ether (60 ml) were added to the mixture. The organic layer was separated and the aqueous layer was extracted with diisopropyl ether (100 ml). The combined organic layer was washed successively with 1N sodium hydroxide solution and brine, dried over sodium sulfate, and evaporated in vacuo to give 3-methoxy-4-methylbenzylalcohol (41.63 g) as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:19]1([C:24]2[N:29]=[C:28]([C:30](=O)[CH3:31])[CH:27]=[C:26]([CH3:33])[N:25]=2)[CH:23]=[CH:22][N:21]=[CH:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH:30]([C:28]3[CH:27]=[C:26]([CH3:33])[N:25]=[C:24]([N:19]4[CH:23]=[CH:22][N:21]=[CH:20]4)[N:29]=3)[CH3:31])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)c1cc(C)nc(-n2ccnc2)n1
Reactant: O=C(NCc1ccc2c(c1)OCO2)C1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C(C)N2CCCC2C(=O)NCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.1 %

Procedure:
Pyrrolidine-2-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide (85 mg, 0.34 mmol) was dissolved in dioxane (2.5 mL). Next, TsOH monohydrate (30 mg) and the 1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethanone (69 mg, 0.34 mmol) were added and the reaction mixture was microwaved for 20 mins at 130° C. Upon completion of heating, the solution was allowed to return to room temperature and the sodium triacetoxyborohydride (145 mg, 0.68 mmol) was added to the reaction vessel and it was allowed to stir at room temperature for an additional 16 hours. After this period, the solution was concentrated under vacuum, diluted in ethyl acetate (50 mL) and transferred to a separatory funnel. The organic layer was washed with 1M NaOH (50 mL), dried over Na2SO4 and concentrated down by vacuum to afford the crude product. This material was purified by Flash Chromatography (0-40% ACN/DCM gradient) to afford 12 mg (8%) of 1-[1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethyl]-pyrrolidine-2-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide. Product isolated as a mixture of diasteromers; [M+H]+ 435.03.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N:8]1[CH2:9][CH2:10][CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:15]=3[S:14][C:13]=12>>[N:8]1[CH2:9][CH2:10][CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([NH:21][C:5](=[O:7])[CH3:6])[CH:19]=[CH:20][C:15]=3[S:14][C:13]=12
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)N1CCCN=C1S2
Product: CC(=O)Nc1ccc2c(c1)N1CCCN=C1S2
Reaction time: 1 h

Procedure:
To 25 parts of acetic acid anhydride are added portionwise 1.3 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine (exothermic reaction: temp. rises to 30° C.). Upon completion, stirring is continued for one hour at room temperature. After cooling to 5°-10° C., the precipitated product is filtered off and dissolved in water. The solution is treated with activated charcoal. The latter is filtered off over hyflo and the filtrate is alkalized with a few drops of ammonium hydroxide. Upon stirring, the product is allowed to crystallize. It is filtered off and dried, yielding 0.8 parts of N-(3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-yl)acetamide; mp. 178° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:31])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCO)c1CCC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Temperature: 7.5 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-hydroxy-hexyl)-phenoxy]-butyric acid ethyl ester (0.85 mmol, 349 mg) and carbon tetrabromide (1.26 mmol, 423 mg) in dichloromethane (10 mL) was added triphenylphosphine (1.07 mmol, 281 mg) at −0° C. The resulting colorless solution was stirred for 3 h at 5-10° C. Then, the solvent was removed under vacuum and the crude was tried to dissolve in a mixture of ethyl acetate and hexanes (1:3, 50 mL). As a result, a cloudy solution containing some precipitate was formed and the cloudy solution was transferred into a separatory funnel and was washed with a mixture of methanol and water (2:1, 150 mL). The aqueous layer was extracted one more time with ethyl acetate and hexanes (1:3, 50 mL). The combined organic extracts were washed with brine solution (100 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a colorless oil which was purified by using a Biotage™ (40M) column chromatography eluting with 10% ethyl acetate in hexanes to obtain the desired 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (350 mg, 87.5%) as a colorless oil: ES(+)-HRMS m/e calculated for C23H35BrO5 (M+Na)+ 493.1560, found 493.1560.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[C:9]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[C:16]([SH:18])=[S:17])([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[C:16]([S:18][CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[S:17])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=Cc1ccncc1
Reactant: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=S)SCCc2ccncc2)cc(C(C)(C)C)c1O

Procedure:
A solution of 6.6 g (0.062 mol) 4-vinylpyridine and 14.1 g (0.05 mol) 3,5-di-t-butyl-4-hydroxydithiobenzoic acid in 50 ml toluene was refluxed for 6 hours. On cooling, the product (via anti-Markovnikov addition) crystallized from the reaction mixture. After recrystallization from chloroform, the product melted at 191°-193° C. Elemental analysis of the product is tabulated in Table I.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C(N(CC)CC)C.Cl>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][N:11]2[C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C)cc(S)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(SN2C(=O)CCC2=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
3,5-Dimethylthiophenol (2.76 g, 0.02 mol) was added by a syringe to an ice cooled mixture of N-chlorosuccinimide (3.34 g, 0.025 mol) and anhydrous dichloromethane (30 mL) under argon atmosphere. After 1 hour, N-chlorosuccinimide (0.4 g, 0.003 mol) was added, then reaction was stirred for 2.5 hours. Triethylamine (3.9 mL, 0.028 mol) was added while stirring for 15 minutes, then dichloromethane and 1N HCl were added. After shaking, organic layer was dried, concentrated to a small volume and passed through a Celite® column. After evaporation of the solvent, the residue was triturated with diethyl ether to give 3.0 g (64%) of title compound, mp 131-134° C. (from diethyl ether).