Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([CH2:17][O:18][CH3:19])[CH:8]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH2:17][O:18][CH3:19])[CH:8]=2)=[CH:4][C:3]=1[C:22]([F:23])([F:24])[F:25]
Reactant: COCc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ccc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of methyl 4-[4-chloro-3-(trifluoromethyl)phenoxy]-2-(methoxymethyl)benzoate (Preparation 34, 0.140 g, 0.000374 mol) in tetrahydrofuran (3.00 mL) and water (3.00 mL) was added lithium hydroxide (0.050 g, 0.00209 mol) and the reaction stirred at room temperature under nitrogen for 2 hours. Then more lithium hydroxide (0.500 g, 0.0209 mol) was added and the reaction stirred at room temperature under nitrogen for 16 hours. The reaction was diluted with ethyl acetate (10.0 mL) and washed with water (10.0 mL). The organic layer was separated, dried with sodium sulphate, filtered and concentrated in vacuo to yield title compound as a pale yellow foam (0.134 g, 0.000374 mol, 99% yield).
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[CH2:25]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: c1ccc(OCc2nc3ccccc3[nH]2)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(COc2ccccc2)nc2ccccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A 500 mL flask fitted with a stir-bar, addition funnel, and Ar inlet was charged with 2-(phenoxymethyl)-1H-benzimidazole (61) (10.0 g, 44.6 mmol) and K2CO3 (12.3 g, 89.2 mmol). DMF (120 mL) was added followed by 1-bromo-2-methylpropane (9.17 g, 66.9 mmol). The suspension was heated in a 90° C. bath for 18 hr. Another 900 mg of 1-bromo-2-methylpropane were then added, and the mixture stirred another 3 hr until the starting material was down to 2% as measured by HPLC. The mixture was cooled to rt, and the solids were filtered off and rinsed with EtOAc (250 mL). The filtrate was then washed with saturated NH4Cl (2×200 mL), H2O (2×200 mL), and brine (100 mL), filtered through phase separation paper, and concentrated in vacuo to a yellow oil. Upon standing the oil crystallized, and was subsequently triturated with hexanes:EtOAc 20:1 (30 mL). The crystals were filtered and rinsed with hexanes (2×10 mL). Upon drying, 10.2 g of Compound #10 were obtained as an off-white, crystalline solid (84%). 1H NMR (300 MHz, CDCl3): δ 7.82 (m, 1H), 7.42-7.28 (m, 5H), 7.12 (d, 2H), 7.02 (t, 1H), 5.40 (s, 2H), 4.14 (d, 2H), 2.35 (sept, 1H), 0.98 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.9 min and 2% starting material with a retention time of 3.4 min. Extension of the reaction time should reduce the percentage of starting material.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:2]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:18])[CH3:17]
Reactant: COC(=O)c1cccc(-c2ccsc2)c1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1cccc(-c2ccsc2C(C)=O)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of methyl 3-(thiophen-3-yl)benzoate (2 g) in acetic anhydride (2 g) was heated to 75° C. The oil bath was removed and phosphoric acid (0.063 ml) was added thereto. The reaction mixture was stirred at 140° C. for 2 hours and cooled to room temperature. The mixture was diluted with ethyl acetate and washed successively with water, an aqueous sodium carbonate solution (×2) and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane:ethyl acetate (10:1) to afford methyl 3-(2-acetylthiophen-3-yl)benzoate (1.44 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][Cl:14])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:23]=[O:25])=[CH:7][CH:6]=1)[CH2:12][CH2:13][Cl:14]
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Reaction time: 0.12 h

Procedure:
The known compound phenylisocyanate N-mustard 19 can be prepared by following the literature procedure35,36 with modification (Scheme 3). The commercially available 4-fluoronitrobenzene (15) is reacted with diethanolamine under refluxing to give 4-[N,N-bis(2-hydroxyethyl)amino]nitrobenzene (16), which is then converted to 4-[N,N-bis(2-chloroethyl)amino]nitrobenzene (17) by treating with thionyl chloride. Catalytic hydrogenation (10% Pd/C, H2) of compound 17 in ethyl acetate affords N,N-bis(2-chloroethyl)benzene-1,4-diamine (18), which is immediately treated with HCl in ethyl acetate to yield hydrochloride salt of 18. The hydrochloride salt 18 is suspended in CHCl3 and cooled in an ice-bath. To the suspension is added triethylamine and stirred in Argon atmosphere for 5 to 10 min. and then is added dropwise triphosgene solution in CHCl3 and continuously stirred for 20 min. The reaction mixture is evaporated under reduced pressure and the residue is the triturated with THF, filtered and the filtrate containing phenylisocyanate 19, which is used directly for the next reaction without purification. Compound 18 and 19 can be used for the synthesis of the newly invented compounds.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][C:8]([N+:15]#[C-:16])([CH3:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O>Cl(O)(=O)(=O)=O>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[N:1]=[C:2]2[N:6]=[CH:5][NH:4][N:3]2[C:16]=1[NH:15][C:8]([CH3:14])([CH3:7])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1nc[nH]n1
Reactant: O=Cc1ccccc1Br
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccccc2Br)nc2nc[nH]n12

Procedure:
Compound 47 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) 1,1,3,3-tetramethylbutylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-bromobenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([CH2:20][C:21]#[N:22])=[C:15]([Cl:23])[CH:14]=1.CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:12][C:13]1[CH:14]=[C:15]([Cl:23])[C:16]([CH:20]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH:8]([CH3:10])[CH3:9])[CH:6]=2)[C:21]#[N:22])=[C:17]([Cl:19])[CH:18]=1
Reactant: N#CCc1c(Cl)cc(N)cc1Cl
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C#N)c2c(Cl)cc(N)cc2Cl)nnc1Cl
Temperature: 60 °C
Yield: 76.6 %

Procedure:
A solution of 3,6-dichloro-4-isopropyl pyridazine (7) (5.54 g, 29.0 mmol) in tetrahydrofuran (116 mL) in a 500 mL round bottom flask (caution: use an extra large flask) was treated with (4-amino-2,6-dichloro-phenyl)-acetonitrile (44) (5.81 g, 28.9 mmol). The reaction mixture was equipped with a cold water condenser and heated to 60° C. The flask was then raised out of the oil bath and potassium tert-butoxide (6.85 g, 57.99 mmol) was added. The mixture was heated to 60° C. for 45 min. The reaction was cooled to room temperature, transferred to a separatory funnel, diluted with ethyl acetate (500 mL) and was washed with a saturated aqueous sodium chloride solution (2×250 mL). The organic layer was separated, dried with magnesium sulfate, and was filtered. Silica gel 60 (70-230 mesh) was added to the filtrate and the solvent was concentrated under vacuum. The resulting mixture was purified by flash chromatography (Biotage 75L) using silica gel eluted with 15%-30% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford (4-amino-2,6-dichloro-phenyl)-(6-chloro-5-isopropyl-pyridazin-3-yl)-acetonitrile (45) (7.87 g, 77%) as an orange foam; LRMS for C15H13Cl3N4 (M+H) m/z=355. This compound was used without further purification. Molecular Weight=355.6567; Exact Mass=354.0206
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:24]=[CH:23][N:22]=[CH:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2ccnc2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2ccnc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(1H-imidazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 392.38 g/mol.
Reaction SMILES: [CH2:1]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[H-].[Na+].CS(OCC1CCN([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)C(=C=O)C1)(=O)=O.O.[CH3:34][N:35]([CH:37]=[O:38])[CH3:36]>ClC(Cl)(Cl)Cl>[CH2:1]([S:5]([NH:8][CH2:24][CH:25]1[CH2:30][CH2:36][N:35]([C:37]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:38])[CH2:34][CH2:26]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)OCC1CCN(OCc2ccccc2)C(=C=O)C1
Reactant: CN(C)C=O
Reactant: CCCCS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCS(=O)(=O)NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butylsulphonamide (500 mg) in DMF (5 ml) was added dropwise to a suspension of sodium hydride (150 mg, 60% dispersion in mineral oil) in DMF (10 ml) and the mixture was stirred for 10 minutes. 4-Methanesulphonyloxymethyl-N-benzyloxy-carbonylpiperidine (1.09 g) was added and the mixture heated at 80° C. for 16 hours. The mixture was cooled, poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (3×50 ml) and saturated aqueous sodium chloride (50 ml), dried (MgSO4) and concentrated. The residual oil was purified by flash column chromatography, eluting with methanol/dichloromethane (1:99) to give a colourless semi-solid. This mixture was dissolved in warm tetrachloromethane (6 ml) and cooled to give 4-n-butylsulphonylaminomethyl-N-benzyloxycarbonylpiperidine (230 mg) as colourless prisms, mp 83°-85° C. NMR (d6DMSO) δ0.9(3H,t), 0.9-1.1(2H,m); 1.3-1.5(2H,m); 1.5-1.8(5H,m); 2.7-2.9(4H,m); 2.95(2H,m); 4.0(2H,d); 5.1(2H,s); 7.0(1H,t); 7.3(5H,m). m/e 369(M+H)+ ; 391(M+Na)+ ; calculated for C18H28 N2SO4 : C, 58.7; H, 7.7; N, 7.6; found: C, 58.5; H, 7.8; N, 7.6%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCCCCC.CN(C)C=O>[CH2:20]([O:19][C:17]([CH2:16][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)COc1ccc(C(=O)OCC)cc1

Procedure:
Sodium hydride (min. 604 paraffinic dispersion, 2.95 g, about 74 mmol) was washed with anhydrous hexane in a nitrogen stream and suspended in anhydrous dimethylformamide. The obtained suspension was stirred under cooling with ice, followed by the dropwise addition of a solution of ethyl 4-hydroxybenzoate (11.2 g, 67 mmol) in dimethylformamide. The obtained mixture was stirred at room temperature for 30 minutes and cooled with ice again, followed by the dropwise addition of a solution of ethyl bromoacetate (12.9 g, 77 mmol) in anhydrous dimethylformamide. The obtained mixture was stirred at room temperature to complete a reaction. The reaction mixture was filtered to remove insolubles and the filtrate was concentrated under a reduced pressure. The residue was dissolved in diethyl ether and the obtained solution was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of common salt, dried and distilled to remove the solvent. The residue was purified by silica gel column chromatography. Yield: 16.8 g.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOCC.CCCCCC.C(Cl)Cl>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OC(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: C#Cc1ccc(OC(F)F)cc1
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A solution of {[4-(difluoromethoxy)phenyl]ethynyl}(trimethyl)silane (10.0 g, 41.7 mmol) in MeOH/CH2Cl2 (1/1) was treated with cesium carbonate (16.3 g, 50 mmol) at room temperature, stirred for 1.5 h, diluted with CH2Cl2 and filtered through a pad of silica gel. The filtrate was concentrated to dryness to give the title compound (6.8 g, 97%) as an oil, identified by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.[AlH3].N(CC)(C)C>C1COCC1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH2:1])=[CH:8][C:9]=1[O:16][CH3:17])[CH3:15]
Reactant: CCOc1ccc(CC(=O)NCCN)cc1OC
Agent: CCN(C)C
Agent: [AlH3]
Solvent: C1CCOC1
Product: CCOc1ccc(CCNCCN)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Treat a solution of N-(2-amino-ethyl)-2-(4-ethoxy-3-methoxy-phenyl)acetamide (0.7 g, 2.77 mmol) in THF (10 mL) with AlH3.NMe2Et (55 mL, 27.74 mmol) and heat to reflux for 14 h. Cool the resulting mixture to ambient temperature, quench with Na2CO3.10H2O (0.5 g) and stir at ambient temperature for 15 min. Filter the solution through Celite and wash with several portions of CH2Cl2. Concentrate the filtrate in vacuo and purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound as a white oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[N:33]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:41]4[CH2:42][CH2:43][CH:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:39][CH2:40]4)=[C:6]([O:31][CH3:32])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[C:17]([C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:18]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (96 mg), 4-(1-pyrrolidinyl)piperidine (97 mg), and potassium carbonate (145 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (43 mg, yield 41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)C(O)=O.BrC1C=NC=[C:16](C=1)[C:17]([NH2:19])=[O:18].NC1C=NC=C(Br)C=1.C(OC(=O)C)(=O)C>>[C:17]([NH:19][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:10]=1)(=[O:18])[CH3:16]
Reactant: NC(=O)c1cncc(Br)c1
Reactant: O=C(O)c1cncc(Br)c1
Agent: Nc1cncc(Br)c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cncc(Br)c1

Procedure:
Other representative compounds include (E)-N-methyl-4-[3-(5-acetamidopyridinyl)]-3-buten- 1-amine and (E)-N-methyl-4-[3-(5-carbamoylpyridinyl)]-3-buten-1-amine. These compounds may be produced according to the techniques set forth in C.V. Greco et al., J Heterocyclic Chem. 7(4):761 (1970). More specifically, the commercially available starting material, 5-bromonicotinic acid is converted to both 5-bromonicotinamide and 3-amino-5-bromopyridine. The 3-amino-5-bromopyridine can be acylated with acetic anhydride to give 3-acetamido-5-bromopyridine. 3-Acetamido-5-bromopyridine may then be reacted with N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine (prepared according to the preceeding techniques) using the Heck reaction described hereinabove and set forth in W.C. Frank et al., J. Org. Chem. 43(15):2947 (1978). The reaction gives (E)-N-methyl-N-(tert-butoxycarbonyl)-4-[3-(5-acetamidopyridinyl)]-3-buten-1-amine. The Heck reaction of 5-bromonicotinic acid with N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine gives (E)-N-methyl-N-(tert-butoxycarbonyl)-4-[3-(5-carbamoylpyridinyl)]-3-buten-1-amine. The treatment of either product withaqueous acid effects the removal of the tert-butoxycarbonyl groups from these compounds, giving the 5-acetamido and 5-carbamoyl substituted metanicotinic compounds respectively.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23].CCCCCC>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(CCCCO)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a solution of 4-(4-hydroxy-butyl)-benzoic acid methyl ester (300 mg, 1.44 mmol) in DMF (4 mL) was added imidazole (147 mg, 2.16 mmol) followed by TBDMS-Cl (324 mg, 2.16 mmol). The reaction stirred at room temperature for 2 hours, monitoring by TLC (3:1 Hexane:ethyl acetate). After consumption of the starting material, the reaction was diluted with ethyl acetate and washed with water (3×) and saturated sodium bicarbonate (1×). The organic layer was dried over sodium sulfate, filtered, and concentrated down to obtain a yellow oil (360 mg, 77% yield). This crude oil was taken on to the next step without further purification.
Reaction SMILES: [CH2:1]([C:4]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].S(Cl)([Cl:15])=O.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>CCOCC>[CH2:1]([C:4]1([C:10]([Cl:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH2:17]([NH:21][C:10]([C:4]1([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:11])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: CCCC1(C(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CCCC1(C(=O)Cl)CCCCC1
Product: CCCCNC(=O)C1(CCC)CCCCC1

Procedure:
1-n-propylcyclohexanoyl chloride (bp. 118°-122°/16 mm) was prepared in the usual way from 1-n-propylcyclohexanoic acid and thionyl chloride. A solution of this acid chloride (2.0 g) in ether (20 ml) was added dropwise to a stirred solution of n-butylamine (3.0 g) in ether (100 ml). After 3 hours the ethereal solution was washed with dilute hydrochloric acid and water, dried (MgSO4), and concentrated to give a colourless syrup. Distillation gave N-n-butyl-1-n-propylcyclohexanamide, bp. 116°-8°/1 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][OH:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccccc2)C1

Procedure:
(2S,4R)-1-Benzyloxycarbonyl-2-hydroxymethyl-4-t-butyldimethylsilyloxypyrrolidine (111 g) was dissolved in dry dichloromethane (1100 ml), and triethylamine (36.87 g) was added thereto. After addition of methanesulfonyl chloride (41.81 g) under nitrogen stream while ice-cooling, the resultant mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed with water, aqueous sodium chloride solution, water, aqueous sodium bicarbonate solution and water in order and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-methylsulfonyloxymethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.N1C=CC=CC=1>O1CCOCC1>[Br:12][C:5]1[CH:6]=[C:7]([S:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Nc1ncc(Br)cc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (0.50 g, 1.84 mmol) in anhydrous dioxane (2 mL) cooled to 5° C. was added (0.16 mL, 1.84 mmol) of morpholine followed by (0.174 mL, 2.15 mmol) of pyridine. The reaction mixture was stirred at room temperature for 2 hrs and then heated at 50° C. for 1 hour. After cooling to room temperature, a white precipitate formed which was collected by suction filtration, washing with water and petroleum ether to give the title compound as an off-white solid. (0.539 g, 91% yield). MS(ES)+ m/e 323.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:12]O)[CH:3]=1.O=S(Cl)[Cl:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:12][Cl:16])[CH:3]=1
Reactant: OCc1cccc2cc(Br)ccc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cccc2cc(Br)ccc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A 39.5 g (0.167 mole) portion of 2-bromo-5-(hydroxymethyl)-naphthalene in 300 ml of chloroform was treated at 0°-5° over 0.3 hours with 75 ml (123 g, 1.03 mole) of SOCl2. The reaction mixture was allowed to warm to room temperature over 0.5 hours, heated to reflux over 0.2 hours, and allowed to cool slowly to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was taken up in 150 ml of benzene and again concentrated under reduced pressure to give 43 g (100%) of a light yellow oil which crystallized, m.p. 73°-76°.