Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21]=1[C:30]([OH:32])=[O:31])(=[O:18])=[O:17].C(O)(=O)C.[C:37]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38]1.C([BH3-])#N>CN(C=O)C>[CH:37]1([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]=2[C:30]([OH:32])=[O:31])(=[O:18])=[O:17])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C1CCCC1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCC[C@@H]2CCCCN2)ccc2c1CCCC2
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCCC2CCCCN2C2CCCC2)ccc2c1CCCC2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 401A (0.022 g, 0.044 mmol) in DMF (1.0 mL) was treated with acetic acid (0.05 mL) and cyclopentanone (0.005 mL, 0.06 mmol). The mixture was shaken at 50° C. for 20 minutes, treated with macroporous polystyrene bound cyanoborohydride resin (47 mg, 0.13 mmol), shaken at 70° C. for 15 hours, concentrated, and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 526 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 13.21 (br s, 1H), 7.54 (d, 1H), 7.40 (t, 1H), 6.93 (br s, 1H), 6.84 (d, 1H), 6.65 (t, 2H), 6.03 (br s, 1H), 4.02 (br s, 1H), 3.63 (br s, 1H), 3.35 (br s, 3H), 2.99 (br s, 1H), 2.70 (br s, 2H), 2.63 (br s, 2H), 2.00 (br s, 4H), 1.83 (br s, 3H), 1.65-1.54 (m, 13H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5](I)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:13][N:14](C)C=O>C(OCC)(=O)C>[NH2:9][C:6]1[C:5]([C:13]#[N:14])=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: Nc1ncc(C(F)(F)F)cc1I
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (3-a with R4=CF3, 1.6 g, 9.87 mmol) (Maybridge Chemical company, Cornwall, England) in N,N-dimethylformamide (30 mL) was treated at room temperature with silver sulfate (3.1 g, 9.87 mmol) and iodine (2.5 g, 9.87 mol). The reaction mixture was stirred for 14 h and filtered. The filtrated solution was concentrated in vacuo. The residue was chromatographed (SiO2, 25% ethyl acetate in hexanes) to give 5-(trifluoromethyl)-3-iodopyridin-2-amine (3-b, with R4=CF3). The iodide (3-b, with R4=CF3, 1.0 g, 3.47 mmol) and cuprous cyanide (CuCN, 78 g, 8.68 mmol) was dissolved in N,N-dimethylformamide (6 mL) and heated under the microwave at 100 C for 30 min, cooled to ambient temperature, and diluted with ethyl acetate. The precipitates were removed by filtration. The filtrated solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with hexanes afforded the desired product, 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3). 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3, 545 mg, 29.2 mmol) was stirred in methanol (10 mL, saturated with ammonia) under hydrogen atmosphere in the presence of Pd/C (200 mg) overnight. The reaction mixture was filtered and the filtrate solution was concentrated in vacuo to afford the crude amine (3-d, with R4=CF3). A solution of (S)-2-phenylbutanoic acid (300 mg, 18.3 mmol) and diisopropylethylamine (888 uL, 52.4 mmol) in N,N-dimethylformamide (5 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 953 mg, 18.3 mmol). After 15 min, 3-(aminomethyl)-5-(trifluoromethyl)pyridin-2-amine (500 mg, 26.2 mmol) was added. The reaction mixture was stirred for 2 h, partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give the desired product (3-g); HRMS (M+1)=338.1405.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[Li]CCCC.[C@@H:21]12[C:30](=[O:31])[O:29][C:27](=[O:28])[C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.[Cl-].[NH4+]>C1COCC1.O>[CH:11]1([O:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[C:30]([C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[C:27]([OH:29])=[O:28])=[O:31])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)[C@H]2CCCC[C@H]2C(=O)O)cc1OC1CCCC1
Temperature: -90 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
4-Bromo-2-cyclopentyloxy-1-methoxybenzene (16.3 g, 60 mmol) was dissolved in THF (200 ml) and cooled with an ethanol/N2 bath to -90° C. BuLi (41 ml, 66 mmol) was added dropwise while keeping the temperature below -80° C. and stirred for another 15 min after the last addition. This mixture was then quickly added under a nitrogen atmosphere to a cooled solution (-90° C.) of cis-1,2-cyclohexanedicarboxylic anhydride (11.1 g, 72 mmol) in THF (200 ml). After stirring for 2 h at -80° C. solid ammoniumchloride was added and the reaction mixture was allowed to warm slowly to room temperature. Water (300 ml) was added and the anorganic layer was washed with ethyl acetate (200 ml). The combined organic extracts were washed with water (300 ml) and brine (2×300 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane and purified by chromatography (petroleum ether (60°-95° C.)/ethyl acetate: 7/13) and crystallized from petroleum ether (60°-95° C.)/ethyl acetate to give the title compound (10.1 g) as a white solid. M.p. 120°-121° C.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([NH:7][C:8]([C:10]1[S:14][C:13]2[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:12]=2[C:11]=1[CH:20]=O)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([NH:7][C:8]([C:10]1[S:14][C:13]2[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:12]=2[C:11]=1[CH:20]=[N:1][NH2:2])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC1(C)Cc2sc(C(=O)NC(C)(C)C)c(C=O)c2C1
Reactant: NN
Solvent: C1CCOC1
Product: CC1(C)Cc2sc(C(=O)NC(C)(C)C)c(C=NN)c2C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 85% aqueous hydrazine (10 mL) in THF (180 mL) was added 282f (5.6 g, 20.0 mmol) in anhydrous THF (20 mL) over a period of 5 minutes. It was stirred at 20° C. for 3 h. The reaction mixture was concentrated under reduced pressure to afford 282g as black solid (6.0 g, yield: 95%, purity: 95%). MS-ESI: [M+H]+ 294.0
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:24])([F:23])[CH2:20][CH2:21][OH:22]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH2:21][CH2:20][C:19]([F:24])([F:23])[F:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(OCCC(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3,3,3-trifluoropropanol. Off-white solid. MS (m/e): 276.3 ([M+H-Me2C═CH2]+, 100%)
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][N:16]=[CH:17][N:8]2[C:7]1=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>C1COCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9]3=[N:15][N:16]=[CH:17][N:8]3[C:7](=[O:18])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c(=O)n2cnnc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2cnnc2c2[nH]c(Br)nc21
Temperature: 70 °C
Yield: 6.9 %

Procedure:
To a mixture of 6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (0.12 g, 0.487 mmol) in THF (5 mL) in a microwave reaction tube was added N-bromosuccinimide (0.20 g, 1.1 mmol). The mixture was heated at 70° C. in microwave oven for 12 min. After cooling down to room temperature, it was purified using preparative LCMS to provide the product (0.011 g). LCMS calculated for C11H14BrN6O (M+H): 325.0, 327.0. found: 325.0, 327.0.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1.[CH:11]([B-](F)(F)F)=[CH2:12].[K+]>CCO>[CH:11]([C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1)=[CH2:12]
Reactant: Cc1c(Br)cncc1C#N
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Product: C=Cc1cncc(C#N)c1C

Procedure:
A mixture of 5-bromo-4-methylpyridine-3-carbonitrile (4.40 g, 22.3 mmol), potassium vinyltrifluoroborate (3.70 g, 27.9 mmol) and Pd (dppf)2Cl2 (0.4 g) in 30 mL of EtOH and 30 mL of TEA was refluxed under Ar for 4 hours. Concentrated, the residue was purified by column chromatography (petrol ether: EtOAc=50:1) to afford 5-ethenyl-4-methylpyridine-3-carbonitrile.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[N:17]1([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: NCCN1CCCC1
Product: O=c1[nH]c2ncccc2c2cc(NCCN3CCCC3)ccc12
Yield: 18.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (100 mg, 0.43 mmol) and 2-pyrrolidin-1-ylethanamine (0.22 mL, 1.73 mmol) to provide 474 (24 mg, 18% yield) as a white powder. LC-MS (M+H=309, obsd.=309). 1H NMR (400 MHz, DMSO-D6) δ 11.59 (s, 1H), 9.65 (s, 1H), 8.75 (d, J=8.0, 1H), 8.39 (m, 1H), 8.05 (d, J=8.7, 1H), 7.42 (s, 1H), 7.28 (dd, J=4.6, 7.9, 1H), 6.95 (d, J=8.7, 1H), 3.65 (s, 4H), 3.41 (s, 2H), 3.10 (s, 2H), 1.96 (d, J=59.8, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].Cl.Cl.[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH:28]([NH2:34])[CH2:27]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH:28]([NH:34][CH2:22][C:19]1[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]13[CH2:17][CH:12]4[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]4)[CH2:15]1)[CH2:9]3)=[O:5])[CH2:27]2
Reactant: NC1CN2CCC1CC2
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNC2CN3CCC2CC3)ccc1Cl
Yield: 3.3 %

Procedure:
Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g, Example 31a), 1-azabicyclo[2.2.2]octan-3-amine dihydrochloride salt (0.18 g), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml). The residue was purified by chromatography over silica gel eluting with ethyl acetate: iso-hexane (1:1) followed by ethyl acetate: ethanol (95:5). Repurification by chromatography over silica gel eluting with dichloromethane: methanol (95:5) then (9:1) gave the title compound as a white gum (0.013 g).
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:10]3[CH:32]=[C:33]([CH3:37])[C:34]([CH3:36])=[CH:35][C:9]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[C:10]3[CH:32]=[C:33]([CH3:37])[C:34]([CH3:36])=[CH:35][C:9]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc2nc(C3CCCCC3)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2nc(C3CCCCC3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1C

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclohexyl-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [I-].[CH2:2]([N+:9]1[CH:10]([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:12][C:13]=1SC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:2]([N:9]1[C:13](=[CH:23][N+:20]([O-:22])=[O:21])[CH2:12][CH2:11][CH:10]1[C:16]([O:18][CH3:19])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCC(SC)=[N+]1Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCC(=C[N+](=O)[O-])N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Benzyl-2-(methoxycarbonyl)-5-(methylthio)-3,4-dihydro-2H-pyrrolium iodide (25.68 g, 65.6 mmol) in dry N,N-dimethylformamide (80 mL) was treated with nitromethane (17.8 mL, 328 mmol) and diisopropylethyl amine (12.6 mL, 72.2 mmol) and stirred overnight at room temperature. The mixture was heated at 60° C. for 5 hours, allowed to cool to room temperature, and concentrated under reduce pressure. The residue was purified by chromatography on silica gel (3:2 hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 277 (M+H)+; 1H NMR (CDCl3) δ 2.22 (m, 1H), 2.34 (m, 1H), 3.39 (5, 1H), 3.69 & 3.75 (dd & dd, 1H), 3.72 (s, 3H), 4.24 (dd, 1H), 4.30 (d, 1H), 4.51 (d, 1H), 6.87 (s, 1H), 7.16 (dd, 2H), 7.35 (m, 3H).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:3]=1.[NH2:29][C:30]1[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=1>>[CH3:12][O:11][CH2:10][CH2:9][CH2:8][C:6]1[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:3]=[C:2]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[CH:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COCCCc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Product: COCCCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-(3-methoxypropyl)-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 33) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:32]=[O:33].O>C1(C)C=CC=CC=1>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:32]=[O:33])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1C(Sc1ccccc1)c1cc(F)ccc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)ncc1C(Sc1ccccc1)c1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-bromo-5-[(2,5-difluorophenyl)(phenylthio)methyl]-4-methyl pyridine (1.2 g, 3.0 mmol) in toluene (30 ml) was cooled to −78° C., and n-butyllithium (1.54 M hexane solution, 2.5 ml, 3.9 mmol) was added in an argon atmosphere. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C., stirred for 30 minutes, and cooled again to −78° C., and N,N-dimethylformamide (302 μl, 3.9 mmol) was added thereto. After stirring for 30 minutes at the same temperature, water was added to the mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=93:7 was concentrated under reduced pressure to obtain the title compound mg, 0.70 mmol, 25%) as a colorless oily substance.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH+:7]=1.[C:16](=[C:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O)([CH3:18])[CH3:17]>CN(C)C=O.C(O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][C:16]1[C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[N+:7]2[CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[CH:17]=1
Reactant: C1=[NH+]CCc2ccccc21
Reactant: CC(C)=C1CCCCC1=O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cc2[n+](c3c1CCCC3)CCc1ccccc1-2

Procedure:
3,4-Dihydroisoquinolinium perchlorate (4.6 g) and 2-isopropylidenecyclohexanone (3 g) were dissolved in dimethylforamide (12 ml) and refluxed for 12 hours. The reaction mixture was cooled, diluted with ethanol, and filtered. The product was purified by recrystallization from methanol. Yield 3 g; m.p. 205°.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6]CC)=O.[CH2:13]([NH:16][C:17]([NH2:19])=[O:18])[CH:14]=[CH2:15]>C(O)C>[CH2:13]([N:16]1[C:2](=[O:10])[CH2:3][C:4](=[O:6])[NH:19][C:17]1=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCNC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: C=CCN1C(=O)CC(=O)NC1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
9.2 g sodium thread (0.4 mol) was added to 300 mL anhydrous ethyl alcohol with stirring at room temperature. After the Na was dissolved completely, 30 mL diethyl malonate (0.2 mol) and 20 g allyl urea (0.2 mol) were added and refluxed for 5 hours. After the completion of reaction, sucking filtration was performed when the reaction solution was still hot. The filter cake was dissolved in 150 mL anhydrous ethyl alcohol and HCl was used to adjust the pH to 2˜3. After sucking filtration, the filtrate was left to stand for crystallization. After sucking filtration again, washing with anhydrous ethyl alcohol and drying, a white solid (19.5 g) was obtained. Yield: 58%, MS: 169 (M+1).
Reaction SMILES: [CH3:1][C:2]1(SC)[CH:8]2[CH:6]([CH2:7]2)[C:5](=[O:9])[CH2:4][C:3]1=[O:10]>CO.[Ni]>[CH3:1][C:2]1[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH2:6][CH2:7][CH:8]=1
Reactant: CSC1(C)C(=O)CC(=O)C2CC21
Agent: [Ni]
Solvent: CO
Product: CC1=CCCC(=O)CC1=O

Procedure:
1.0 g (5.4 mmol) of the 5-methyl-5-methylsulfanylbicyclo[4.1.0]heptane-2,4-dione isomers II is hydrogenated for 90 minutes under atmospheric pressure in 15 ml of methanol in the presence of 5 g Raney nickel. The mixture is concentrated and purified over silica gel (mobile phase ethyl acetate/hexane 1:1), and 4-methylcyclohept-4-ene-1,3-dione, 1H-NMR (CDCl3): 6.84, m, CH, 3.94, s, CH2, 2.77, m, CH2, 2,59, m, CH2, 1.88 ppm, s, CH3, is obtained as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:24]([NH:28][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccccn1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a cooled solution of picolinic acid (3.6 g, 29.2 mmole, Aldrich) and triethylamine (8 mL, 57.4 mmole) in 80 mL of methylene chloride at 0° C. was added pivaloyl chloride (3.8 mL, 30.8 mmole). The mixture was stirred for 1 hour at 0° C., t-butylamine (4.0 mL, 38.1 mmole) was added, and stirring was continued for 1 hour at 0° C. and 1 hour at room temperature. Saturated NaHCO3 (30 mL) was added, the layers were separated, and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined organic solutions were dried and concentrated, and the residue was chromatographed in silica gel, eluting with 30 to 60% ethyl acetate in hexane, to provide 5.2 g of the title compound as an oil. MS: 179 (M+H)+ ; 1H NMR (CDCl3) δ: 8.52 (m, (1H), 8.18 (dm, J=7.5 Hz, 1H), 8.0 (s, br, 1H), 7.84 (dt, J=7.5, 1.5 Hz, 1H), 7.40 (ddd, J=7.5, 5.0, 1.5 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([NH:12][CH:13]=[O:14])[C:7]([Cl:11])([Cl:10])[CH2:8][Cl:9]>>[Cl:3][CH:6]([NH:12][CH:13]=[O:14])[C:7]([Cl:11])([Cl:10])[CH2:8][Cl:9]
Reactant: O=S(Cl)Cl
Reactant: O=CNC(O)C(Cl)(Cl)CCl
Product: O=CNC(Cl)C(Cl)(Cl)CCl

Procedure:
Thionyl chloride was poured over 20.6 gm of N-(1-hydroxy-2,2,3-trichloro-n-propyl)-formamide, and the mixture was refluxed for 15 minutes. Subsequently, the excess thionyl chloride was distilled off, and the residue was recrystallized from benzene/petroleum ether, m.p. 55°-57° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:7][C:6]=1[CH3:29])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]1[C:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=2)=[N:7][C:6]([CH3:29])=[C:5]([CH:10]=1)[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2Cl)c(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2Cl)cc1C(=O)O
Reaction time: 16 h

Procedure:
A solution of 2.9 g of 5-(2,4-Dichloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid ethyl ester and 230 mg of LiOH in 10 ml of THF and 10 ml of water was stirred at room temperature for 16 h. After 16 h, the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was codistilled twice with dichloromethane and twice with toluene The isolated crude product was used in the next reaction step. Yield: 3 g.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4,6-Trichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,4,6-trichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([CH2:18][CH3:19])=[CH:16][CH3:17])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:20]1([CH3:27])[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][CH:21]=1>B(F)(F)F.CCOCC>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([CH2:16][CH3:17])([C:22]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([CH3:27])[CH:21]=3)[CH2:18][CH3:19])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CC=C(CC)c1ccc2sc(C(=O)OCC)cc2c1
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(O)c(C)c3)ccc2s1
Yield: 78 %

Procedure:
5-(1-Ethyl-propenyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester (5.50 g, 20.0 mmol), o-cresol (4.33 g, 40.0 mmol), and BF3-Et2O (10 mL) are reacted analogous to Example 1C to afford the title compound (5.97 g, 78%).