Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:21])=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(SCCN2CCOCC2)ccnc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c(SCCN2CCOCC2)ccnc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Hydroxymethyl-3-methyl-4-(2-morpholinoethylthio)pyridine (6.2 g) was dissolved in chloroform and thereto was dropwise added thionyl chloride (2 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into ice-water and made alkaline with potassium carbonate, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 6.0 g of 2-chloromethyl-3-methyl-4-(2-morpholinoethylthio)pyridine as an oily substance. The substance was added to ethanol (60 ml) containing a solution of 5-methoxycarbonyl-2-mercaptobenzimidazole (5.1 g) and sodium hydroxide (1.6 g) in water (10 ml) and the mixture was refluxed under heating for 3.5 hours. After the completion of the reaction, the ethanol was distilled away and the residue was dissolved in water. The aqueous layer was washed with chloroform and dilute hydrochloric acid was dropwise added until crystals precipitated in the aqueous layer. The resultant crystals were collected by filtration to give 2-((3-methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole-5-carboxylic acid 7/2 hydrate, melting point 120°-124° C.
Reaction SMILES: [CH2:1]=[O:2].Cl.CON=C[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])[C:11]([F:27])=[CH:10][C:9]=1[Cl:28].O>C(O)(=O)C>[Cl:28][C:9]1[CH:10]=[C:11]([F:27])[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:13][C:8]=1[CH:1]=[O:2]
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: C=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C=O)c(Cl)cc2F)c1=O

Procedure:
150 ml of a 30% by weight aqueous formaldehyde solution and 150 35 ml of concentrated hydrochloric acid were added dropwise to a solution of 189.9 g (0.50 mol) of 2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)benzaldehyde (O-methyl)oxime in 0.75 l of glacial acetic acid. The mixture was subsequently refluxed for two hours. After cooling, 0.75 l of water were added, whereupon the solid product of value formed was separated off and washed first with water until the reaction was neutral and then with petroleum ether. Yield: 140 g;
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[C:16]([NH:15][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])[CH:17]=[CH:18][C:19]=1[F:24])#[N:22]
Reactant: N#Cc1cc(N)ccc1F
Reactant: COCCNc1nonc1C(Cl)=NO
Product: COCCNc1nonc1C(=NO)Nc1ccc(F)c(C#N)c1
Yield: 100 %

Procedure:
The desired compound was prepared according to the procedure of Example 13, step A, using N-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride [made according to Example 1, steps A through E] and 5-amino-2-fluorobenzonitrile [Aldrich, product #639877] as the starting materials in 100% yield. LCMS for C13H14FN6O3 (M+H)+: m/z=321.0.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12](Cl)=[O:13])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[BH4-].[Na+].Cl.O>O1CCCC1.C(OCC)C>[OH:13][CH2:12][C:11]1[N:2]([CH3:1])[C:3](=[O:21])[C:4]2[C:9]([C:10]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cn1c(C(=O)Cl)c(-c2ccccc2)c2ccccc2c1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(CO)c(-c2ccccc2)c2ccccc2c1=O
Reaction time: 0.5 h

Procedure:
A stirred suspension of 2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride (5.96 g; prepared according to the method of F. Duro et al., Il. Farmaco Ed. Sci., 36,400) in dry tetrahydrofuran (120 ml) was treated, portionwise, with sodium borohydride (1.68 g) and the mixture was stirred at room temperature for 4 hours. A further portion of sodium borohydride (0.4 g) was then added and the mixture was stirred for a further period of 30 minutes. The reaction mixture was then treated, dropwise, with dilute hydrochloric acid (60 ml; 2N) and then with water (80 ml). The mixture was diluted with diethyl ether (200 ml) and the organic phase was separated, washed with water (2×80 ml), dried over magnesium sulphate and evaporated. The resulting residue was crystallised from ethyl acetate, to give 3-hydroxymethyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline (3.5 g) in the form of white crystals, m.p.159°-161° C. [Elemental analysis: C,77.2; H,5.76; N,5.37%; calculated: C,77.0; H,5.70; N,5.28%].
Reaction SMILES: [H-].[Li+].[F:3][C:4]([F:17])([F:16])[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[C:9]([Cl:15])[CH:8]=1)=[O:6].[CH3:18][O:19][C:20]([C:22]1[O:23][C:24]([C:28](=[O:30])[CH3:29])=[CH:25][C:26]=1[CH3:27])=[O:21].C(OC)(C)(C)C>C1COCC1.O>[CH3:18][O:19][C:20]([C:22]1[O:23][C:24]([C:28](=[O:30])[CH2:29][C:5]([OH:6])([C:7]2[CH:8]=[C:9]([Cl:15])[C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[C:4]([F:3])([F:16])[F:17])=[CH:25][C:26]=1[CH3:27])=[O:21]
Reactant: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1oc(C(C)=O)cc1C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)c1oc(C(=O)CC(O)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C
Yield: 106.3 %

Procedure:
LiH (0.41 g) is added to a solution of 2,2,2-trifluoro-1-(3,4,5-trichloro-phenyl)-ethanone (6.76 g) and 5-acetyl-3-methyl-furan-2-carboxylic acid methyl ester (4.46 g) in THF (50 ml). After 3 hours at 60° C. methyl tert-butyl ether (MTBE, 20 ml) is added and the reaction mixture is poured into water (20 ml) at 0° C. The organic phase is extracted once with water and a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo to yield 11.9 g of 3-methyl-5-[4,4,4-trifluoro-3-hydroxy-3-(3,4,5-trichloro-phenyl)-butyryl]-furan-2-carboxylic acid methyl ester. The crude product is used without further purification. MS (HPLC/MS): 459 (MH+). Retention time: 2.01 min.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5]C.[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:14]([OH:15])=[C:11]([O:12][CH3:13])[CH:10]=1.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:15][C:14]1[CH:16]=[CH:17][C:9]([CH:8]=[O:7])=[CH:10][C:11]=1[O:12][CH2:13][C:2]#[C:3][CH2:4][CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CCC#CCBr
Reactant: COc1cc(C=O)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Product: CCC#CCOc1cc(C=O)ccc1OC
Yield: 95.8 %

Procedure:
1-Bromopent-2-yne (0.67 mL, 6.6 mmol) was added to a suspension of vanillin (0.50 g, 3.3 mmol) and potassium carbonate (1.37 g, 9.85 mmol) in acetone (5.0 mL) and treated according to Procedure 3. 4-Methoxy-3-(pent-2-ynyloxy)benzaldehyde (0.69 g, 96%) was obtained as a yellow crystalline solid; mp 38-39° C.; δH (400 MHz, CDCl3) 1.10 (t, J=7.6 Hz, 2H, CH2CH3), 2.20 (tq, J=7.6, 2.0 Hz, 3H, CH2CH3), 3.95 (s, 3H, OCH3), 4.79 (t, J=2.0 Hz, 2H, OCH2), 6.99 (d, J5,6=8.0 Hz, 1H, H5), 7.49 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.54 (d, J2,6=2.0 Hz, 1H, H2), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 12.5, 13.5, 56.1, 57.3, 73.4, 90.5, 110.7, 111.8, 126.9, 129.9, 147.6, 154.8, 190.8; vmax 1007, 1130, 1261, 1508, 1583, 1683, 2230, 2290, 2841, 2976 cm−1.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:5][CH:6]=[N:7][C:8]=2[N:9]([CH2:13][CH2:14][CH3:15])[C:10](=[O:12])[N:11]=1.[H-].[Na+].Cl[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([O:20][CH2:19][N:5]1[C:4]2[C:3]([S:2][CH3:1])=[N:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH3:15])[C:8]=2[N:7]=[CH:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCn1c(=O)nc(SC)c2[nH]cnc21
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)nc(SC)c2c1ncn2COCc1ccccc1

Procedure:
After 224 mg (1.0 mmol) of Compound b obtained in Reference Example 2 was dissolved in 2 ml of N,N'-dimethylformamide, 48.0 mg (1.2 mmol) of 60% sodium hydride was added to the mixture under ice cooling. 15 minutes after, 209 μl (1.5 mmol) of benzyl chloromethyl ether was added to the mixture. The mixture was stirred for an hour, poured onto 10 ml of water, and extracted 3 times with 5 ml of chloroform. After washing with a saturated aqueous sodium chloride solution, the extracts were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated with ether to give 223 mg (yield, 65%) of Compound f as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:31])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:45](OC(=O)C)([F:47])[F:46]>O>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:45]([F:47])[F:46])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(-n2cccn2)cc1
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of [2-ethyl-8-fluoro-4-oxo-3-(4-pyrazol-1-ylbenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.37 g), N,N-dimethylformamide (10 mL), potassium carbonate (0.18 g) and acetic acid chlorodifluoromethyl ester (0.27 mL) was stirred at 80° C. for 6 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate gave title compound (0.19 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:17]([O:19][CH3:20])[CH3:18])[C:13](OC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>CO>[OH:14][CH2:13][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:17]([O:19][CH3:20])[CH3:18]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@@H](C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (2S,3S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-methoxybutanoate (prepared according to the literature procedure: Bioorg. Med. Chem. Lett. 15 (2005) 1447-1449, 1.60 g, 5.68 mmol) in a 3:1 mixture of tetrahydrofuran and methanol (12 mL), sodium borohydride (0.43 g, 11.38 mmol) was added and the mixture was stirred at room temperature for 2 hours. The volatiles were removed and the residue was dissolved in ethyl acetate (25 mL) and washed with brine (10 mL). Removal of the solvent afforded crude product which was purified by silica gel column chromatography using a gradient of ethyl acetate in pet. ether. Yield: 1.32 g (92%). 1H NMR (400 MHz, DMSO-d6) δ: 1.01 (d, 3H), 3.22 (s, 3H), 3.36-3.42 (m, 3H), 3.57-3.60 (m, 1H), 4.57 (t, 1H), 5.02 (s, 2H), 6.98-7.01 (m, 1H), 7.31-7.37 (m, 5H). MS (ES) MH+: 254.4 for C13H19F3NO4.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:24][C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2c(c1)OCCc1ccsc1-2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)OCCc1cc(Br)sc1-2
Yield: 62.2 %

Procedure:
A solution of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile (240 mg, 1.05 mmol) in 3 ml of DMF was treated with NBS (206 mg, 1.16 mmol) at room temperature for 15 hours. The reaction mixture was diluted with a large volume of EtOAc and the organic was washed with water and saline and concentrated in vacuo to a solid. This residue was filtered onto celite and purified by MPLC on a 14 gram silica column, eluting with 20-80% EtOAc/heptanes to give 200 mg (62%) of 2-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile as a white powder in high purity as determined by LC/MS.
Reaction SMILES: Cl[C:2]1[C:7]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[C:7]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:6][CH:5]=[C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:3]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 78.7 %

Procedure:
A solution of tert-butyl (trans)-2-(2-chloro-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (150 mg, 0.364 mmol), 4-chlorophenylboronic acid (67.3 mg, 0.432 mmol) and K2CO3 (149 mg, 1.09 mmol) in acetonitrile:water (4:1) was degassed for 20 min. Tetrakis triphenylphosphine palladium (4.2 mg, 0.00364 mmol) was added and the reaction mixture was heated at reflux for 16 h. After completion, the reaction mixture was poured into ice water (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4 filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using EtOAc:Pet ether (1:9) to afford tert-butyl (trans)-2-(2-(4-chlorophenyl)-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (140 mg, 79%) as white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])[CH2:17][CH2:18]2)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(Nc1ccc(CC2CCNCC2)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CC2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of 2,2,2-trifluoro-N-[4-(piperidin-4-ylmethyl)-phenyl]acetamide (0.5 g, 1.75 mmol) and triethylamine (0.23 g, 2.1 mmol) in dichloromethane (10 mL) was cooled in an ice bath under nitrogen atmosphere. A solution of benzenesulfonyl chloride (0.37 9, 2.1 mmoL) in dichloromethane (1 mL) was added under to the mixture while stirring. After 2 hours, the reaction mixture was quenched with water. The separated organic layer was washed with cold water and brine, dried, and solvents removed in vacuo. The residue was crystallized from ethyl acetate/hexanes to give 2,2,2-trifluoro-N-[4-(1-benzenesulfonyl-piperidin-4-ylmethyl)-phenyl]acetamide (0.43 g, 57%), m.p. 194-195° C.; Analysis for C20H21N2O3SF3: Calc.: C, 56.32; H, 4.96; N, 6.57; Found: C, 56.54; H, 4.99; N, 6.68.
Reaction SMILES: C1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)CC1.BrC1C=CC2[O:17][C:18]([CH3:21])([CH3:20])[O:19]C=2C=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH3:20][C:18]1([CH3:21])[O:19][C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=2[O:17]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: CC1(C)Oc2ccc(Br)cc2O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C=O)cc2O1
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 420 mg of 5-bromo-2,2-dimethyl-benzo[1,3]dioxole [CAS 73790-19-9] (1.83 mmol), 1.38 ml of a 1.6 molar solution of n-BuLi in hexane (2.20 mmol) and 712 μl of DMF (9.17 mmol). The isolated residue was purified by flash column chromatography (1:9 ether/pentane) to give 270 mg of 2,2-dimethyl-benzo[1,3]dioxole-5-carbaldehyde (83%) as a light yellow liquid. 1H NMR (CDCl3, 300 MHz): δ 1.72 (s, 6H), 6.84 (d, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.87 (dd, J=8.0 and 1.7 Hz, 1H), 9.97 (s, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:35]1([CH2:41][C:42]2[CH:43]=[C:44]([CH:58]=[CH:59][CH:60]=2)[O:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49][NH:50][C:51](=[O:57])[CH2:52][S:53][CH2:54][CH2:55][NH2:56])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[N:35]1([CH2:41][C:42]2[CH:43]=[C:44]([CH:58]=[CH:59][CH:60]=2)[O:45][CH2:46]/[CH:47]=[CH:48]\[CH2:49][NH:50][C:51](=[O:57])[CH2:52][S:53][CH2:54][CH2:55][NH:56][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)c1ccccc1
Reactant: NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CSCCNC(=O)c1ccccc1)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
There was dissolved 0.97 g (0.008 mol) of benzoic acid in 60 ml of dichloromethane and added 1.22 g (0.00 mol) of HOBt and 1.65 g (0.0095 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 3.0 g (0.008 mol) of N-[4-[3-(piperidinomethyl) phenoxy]-cis-2-butenyl]-2-(2-aminoethylthio)acetamide and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give 0.9 g of the titled compound as oily matter.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].Br[CH:19](Br)[C:20]([OH:22])=[O:21]>CS(C)=O.O>[CH3:9][C:5]1[C:4]([C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=2)=[CH:3][C:2]2[O:1][CH:19]([C:20]([OH:22])=[O:21])[O:8][C:7]=2[CH:6]=1
Reactant: O=C(O)C(Br)Br
Reactant: Cc1cc(O)c(O)cc1C(=O)c1cccnc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(cc1C(=O)c1cccnc1)OC(C(=O)O)O2

Procedure:
By reaction of 17.3 g (0.075 mol) of (3,4-dihydroxy-6-methylphenyl)-(3-pyridyl)-methanone with 16.5 g (0.075 mol) of dibromoacetic acid, analogously to Example 3, there is obtained 5-methyl-6-nicotinoyl-1,3-benzodioxole-2-carboxylic acid as sand-coloured crystals, m.p. 250°-232° C. (from dimethyl sulfoxide/water).
Reaction SMILES: [CH:1]1([N:5]2[CH:9]=[C:8](C(=O)C)[N:7]=[C:6]2[CH3:13])[CH2:4][CH2:3][CH2:2]1.[CH3:14][C:15]([N:17]([CH3:19])[CH3:18])=O.CN([CH:23]=[O:24])C>>[CH3:18][N:17]([CH3:19])[CH:15]=[CH:14][C:23]([C:9]1[N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:6]([CH3:13])=[N:7][CH:8]=1)=[O:24]
Reactant: CC(=O)c1cn(C2CCC2)c(C)n1
Reactant: CC(=O)N(C)C
Reactant: CN(C)C=O
Product: Cc1ncc(C(=O)C=CN(C)C)n1C1CCC1
Temperature: 25 °C
Yield: 47 %

Procedure:
1-Cyclobutyl-2-methyl-4-acetylimidazole (Method 3; 2.52 g, 14.1 mmol) was dissolved in DMF.DMA (75 mL) and the mixture heated at reflux, under an atmosphere of nitrogen, for 54 hours. The reaction mixture was allowed to cool to ambient temperature the product crystallised. The solid product was collected by filtration, washed with DMF.DMA and then ether and dried under vacuum at 40° C. to give the title compound (1.55 g, 47%) as a pale brown crystalline solid. NMR: 1.72 (m, 2H), 2.28 (m, 2H), 2.39 (s, 3H), 2.64 (m, 2H), 2.95 (m, 6H), 5.22 (m, 1H), 5.50 (d, 1H), 7.39 (s, 1H), 7.51 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15](S(C)(=O)=O)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:29])=[CH:4][CH:3]=1.[C:30]1([CH:36]2[O:41][C@H:40]3[CH2:42][C@@H:43]([OH:46])[CH2:44][O:45][C@@H:39]3[CH2:38][O:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:46][C@H:43]4[CH2:44][O:45][C@H:39]5[C@@H:40]([O:41][CH:36]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[O:37][CH2:38]5)[CH2:42]4)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Reactant: O[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-bromophenyl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (2.6 g, 5.03 mmol), (4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (1.307 g, 5.53 mmol), and cesium carbonate (4.92 g, 15.09 mmol) were dissolved in DMF (25.1 mL). The reaction mixture was stirred overnight at rt, then diluted with EtOAc and saturated NH4C/water (50:50). The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with sat. NaHCO3 and brine, then dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 100 g column by eluting with 10% EtOAc:Hexane to 70% EtOAc:Hexane to yield the desired product. LC-MS: calculated for C31H35BrClN3O5Si 671.12 observed m/e: 671.83 (M+H)+ (Rt 1.37/2 min).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]=[CH:13]1.[Br:19][CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1>C(#N)C>[Br-:19].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N+:12]1[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH:13]=1
Reactant: Clc1ncn(CC2COc3ccccc3O2)c1Cl
Reactant: BrCc1ccc2ccccc2c1
Solvent: CC#N
Product: Clc1c(Cl)[n+](CC2COc3ccccc3O2)cn1Cc1ccc2ccccc2c1
Product: [Br-]
Yield: 57.3 %

Procedure:
1-(Benzo[1,4]dioxan-2-ylmethyl)-4,5-dichloroimidazole (0.28 g, 1 mmol) was combined with acetonitrile (2 mL) and heated until all solid dissolved. 2-(Bromomethyl)naphthalene (0.22 g, 1 mmol) was added and the solution was refluxed for 3 h, during which time a white precipitate formed. The precipitate was collected by filtration and washed with diethyl ether to yield a white solid (0.29 g, 57% yield). 1H NMR (300 MHz, DMSO-d6) 9.65 (1H, s, NCHN), 8.00 (4H, m, Ar), 7.57 (3H, m, Ar), 6.87 (4H, m, Ar), 5.72 (2H, s, CH2), 4.11-4.88 (5H, m, CH2CHCH2O).