Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]#N)[CH:10]=[N:11][CH:12]=1.C(=O)(O)[O-:17].[Na+].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:14](=[O:17])[CH2:13][C:9]1[CH:10]=[N:11][CH:12]=[C:7]([Br:6])[CH:8]=1)[CH3:22]
Reactant: N#CCc1cncc(Br)c1
Reactant: O=C([O-])O
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cncc(Br)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a mixture of ethanol (10 mL) and conc. H2SO4 (4 mL) was added the title compound from Example 53 Step B (0.50 g, 2.5 mmol) in 3 mL of ethanol at room temperature. The mixture was stirred at 90° C. overnight. The reaction was poured into ice and made basic with saturated aqueous sodium bicarbonate solution. It was then extracted with ethyl acetate (2×30 mL), the organic layer was dried, concentrated and purified by flash chromatography on silica gel (petroleum ether:ethyl acetate=10:1) to give the title compound: LCMS m/z 244 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.44 (s, 1H), 7.82 (s, 1H), 4.17-4.20 (m, 2H), 3.61 (s, 2H), 1.27-1.30 (m, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:13]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCc1ccccc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(CCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of N2, a mixture of imidazole (788 mg, 11.57 mmol, 2.1 equiv) and potassium carbonate (370 mg, 2.68 mmol, 1 equiv) in dry THF (18 mL) was stirred at rt for 10 min. To this was added a solution of (2-bromoethyl)benzene (1.00 g, 5.40 mmol, 1 equiv) in THF (1 mL) and the mixture was heated at reflux temperature for 14 h. The mixture was filtered and the filtrate was concentrated to a clear oil. The oil was dissolved in CH2Cl2 and the organic phase was washed with water (2×). The CH2Cl2 layer was then extracted with dilute aqueous HCl (3×). The aqueous extract was then neutralized with solid NaHCO3, and the free base extracted using CH2Cl2 (3×). The combined organic extracts were dried (Na2SO4) and concentrated. High-vacuum drying gave QC-207 (420 mg, 2.44 mmol, 45%) as a clear oil: 1H NMR (400 MHz, CDCl3): δ 3.05 (t, J=7.0 Hz, 2H), 4.17 (t, J=7.0 Hz, 2H), 6.83 (s, 1H), 7.01-7.09 (m, 3H), 7.22-7.34 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 38.0, 48.6, 118.9, 127.1, 128.7, 128.9, 129.6, 137.2, 137.6.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1.CCOCC>[CH2:17]([O:16][C:14](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH3:12])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(F)ccc1Br
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(F)cc1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Magnesium (0.644 g, 26.5 mmol) was added wit THF (4 mL) and a small amount of iodine. After the mixture was stirred, the mixture was added dropwise with a solution of 1-bromo-4-fluoro-2-methylbenzene (5.00 g, 26.5 mmol) in THF (50 mL). The mixture was stirred at room temperature for 30 minutes, and then cooled at −78° C. and added dropwise with a solution of ethyl chloroformate (3.80 mL, 39.8mmol) in THF (40 mL). The mixture was warmed slowly up to room temperature and stirring was continued at room temperature for 2 hours. The reaction mixture was diluted with ether and washed with water, saturated aqueous sodium bicarbonate solution, and then with saturated brine, and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated, and the resulting oily substance was purified by silica gel column chromatography (hexane/ether) to obtain the title compound (3.65 g, yield: 76%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Br)(=[O:7])[CH3:6].[CH:9]([NH:11][C:12]([CH3:21])([CH3:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10]>ClCCCl>[CH:9]([NH:11][C:12]([CH3:21])([CH3:20])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:5](=[O:7])[CH3:6])=[CH:16][CH:15]=1)=[O:10]
Reactant: CC(=O)Br
Reactant: CC(C)(Cc1ccccc1)NC=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(CC(C)(C)NC=O)cc1

Procedure:
This was prepared in an identical manner to the compound described in Description 10 using aluminum chloride (26 g), acetyl bromide (115 ml) and N-formyl-2-phenyl-1, 1-dimethylethanamine (101.5 g) in 1,2-dichloroethane, (850 ml). τ(CDCl3). 8.62 (6H, s), 7.45 (3H, s), 7.1+6.85 (2H, s+s), 3.85 (1H, broad) 2.7 (2H, d, J=8 Hz) 2.1 (2H, d, J=8 Hz), 1.9 (1H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[F:14].S(Cl)([Cl:17])=O>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:17])=[O:10])=[CH:7][C:6]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCBr)c(F)c1
Product: O=C(Cl)c1ccc(OCCBr)c(F)c1
Yield: 93 %

Procedure:
4-(2-Bromoethoxy)-3-fluorobenzoic acid (1.08 g, 4.1 mmol) and thionyl chloride (10 mL) were refluxed for 7 h. The excess thionyl chloride was removed by repeated evaporation with dry toluene in vacuo, giving 1.07 g (93%) the subtitle compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.8 Hz, 1H), 7.86 (d, J=11.2 Hz, 1H), 7.04 (dd, J=8.4 Hz, 8.4 Hz, 1H), 4.46 (t, J=6.4 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H).
Reaction SMILES: C([O:8][CH2:9][CH:10]=[CH:11][C@H:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH3:13])C1C=CC=CC=1.[H][H].ClCCl>C(OCC)(=O)C.[C].[Pd]>[F:17][C:16]([F:18])([F:19])[C:15]([NH:14][C@H:12]([CH3:13])[CH2:11][CH2:10][CH2:9][OH:8])=[O:20]
Reactant: C[C@H](C=CCOCc1ccccc1)NC(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](CCCO)NC(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
The product (1.0 g) obtained in Step 1 was dissolved in ethyl acetate (10 mL). To the solution, 10% palladium-carbon (300 mg) was added, and the mixture was stirred at 70° C. for 3 hours in a hydrogen atmosphere. After the completion of reaction, the mixture was returned to room temperature, and dichloromethane (5 mL) was added, followed by filtration through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in methanol. 10% palladium-carbon (200 mg) was added again thereto, and the mixture was stirred at 70° C. for 16 hours in a hydrogen atmosphere. The mixture was returned to room temperature, and dichloromethane (5 mL) was added, followed by filtration through celite. The filtrate was concentrated under reduced pressure to obtain the compound of interest as a colorless oil (676 mg, 98.3%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:6]1[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:8][C:9]2[C:4]([C:5]=1[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)=[CH:3][C:2]([O:1][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:11][CH:10]=2)=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.2 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (1.5 g, 3.5 mmol), methyl bromoacetate (0.92 g, 6.0 mmol), potassium carbonate (0.55 g, 4.0 mmol) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography to give methyl {[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}acetate (1.9 g, yield 94%) as pale-yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH3:18].S(=O)(=O)(O)O.[CH3:24][C:25](=[CH2:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([C:7]1[CH:6]=[C:5]([C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:4]=[C:3]([CH3:18])[C:2]=1[OH:1])([CH3:26])([CH3:24])[CH3:27]
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)c(C)c1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCC(C)(C)c1cc(C)c(O)c(C(C)(C)C)c1

Procedure:
Into 35.0 parts of methyl 5-(4-hydroxy-3-methylphenyl)-5-methyl-hexanoate from Example 9, 2.0 parts of 98% sulphuric acid, and 200 parts of toluene, was passed isobutylene for 2 hours at 75° C. After washing the toluene solution with 10% sodium hydroxide solution and then water, the toluene was stripped off and the residue distilled to give methyl 5-(3-t-butyl-4-hydroxy-5-methylphenyl)-5-methyl-hexanoate b0.3 168°-72° C. with the following percentage composition by weight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[C@H:4]([CH2:56][CH:57]([CH3:59])[CH3:58])[NH:5][C:6](=[O:55])[C@@H:7]([CH2:51][C:52](=[O:54])[NH2:53])[NH:8][C:9](=[O:50])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:39][OH:40])[NH:14][C:15](=[O:38])[C@H:16]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH:17]C(OCC1C=CC=CC=1)=O.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:60])[C@H:4]([CH2:56][CH:57]([CH3:58])[CH3:59])[NH:5][C:6](=[O:55])[C@@H:7]([CH2:51][C:52](=[O:54])[NH2:53])[NH:8][C:9](=[O:50])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:39][OH:40])[NH:14][C:15](=[O:38])[C@H:16]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH2:17]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
Nα -Benzyloxycarbonyl-L-tryptophyl-L-seryl-L-tyrosyl-D-asparaginyl-L-leucine methyl ester, 3.75 g. is dissolved in 200 ml. of absolute methanol, 375 mg. of 20% palladium-on-carbon added and the material reduced with hydrogen during 50 minutes. The catalyst is removed by filtration and the filtrate evaporated under reduced pressure; 1.83 g. The catalyst is extracted with 400 ml. of boiling methanol, separated by filtration and the filtrate evaporated to yield 1.22 g. of additional product.
Reaction SMILES: Cl[C:2]1C=C(C=CC=1)C(OO)=O.[CH3:12][O:13][C:14]1[N:19]=[C:18](SC)[N:17]=[C:16]([O:22][CH:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24])[CH:15]=1.[S:29]([O-:33])([O-])(=[O:31])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[N:19]=[C:18]([S:29]([CH3:2])(=[O:33])=[O:31])[N:17]=[C:16]([O:22][CH:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24])[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(C)Oc1cc(OC)nc(SC)n1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)Oc1cc(OC)nc(S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.81 g of 3-chloroperoxybenzoic acid was added to a solution of 1.40 g of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylthiopyrimidine in 13 ml of chloroform at 0° C. The mixture was stirred at room temperature for 3 hours, then 30 ml of saturated aqueous sodium thiosulfate solution was added to the mixture. The mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with chloroform, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue was subjected to silica gel chromatography to obtain 1.62 g of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylsulfonylpyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cncnc2)cc(C)c1Br
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In a microwave vial 2-bromo-5-iodo-1,3-dimethylbenzene (1 g) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (665 mg) are suspended in N,N-dimethylformamide (15 mL) and Na2CO3 (4 mL of a 2 M aqueous solution). The mixture is purged for 5 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium dichloromethane complex (85 mg) is added, the vial is sealed and the mixture is stirred at 60° C. for 3 hours. After cooling to room temperature the mixture is Partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with brine. Then the organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→50:50) to give the title compound. Yield: 446 mg; LC (method 9): tR=1.05 min; Mass spectrum (ESI+): m/z=263 [M+H]+.
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.Cl.Cl.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([N:32]2[CH2:37]CNC[CH2:33]2)[N:23]=1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([N:32]2[CH2:37][CH2:18][N:16]([CH2:15][C:4]3[C:5]4[CH2:6][CH2:7][C:8]5[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=5[C:10]=4[NH:2][N:3]=3)[CH2:19][CH2:33]2)[N:23]=1
Reactant: c1ccc2cc(N3CCNCC3)ncc2c1
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CCc1c(CN3CCN(c4cc5ccccc5cn4)CC3)n[nH]c1-2
Yield: 8.9 %

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.40 g), 4-isoquinolin-3-yl-piperazine dihydrochloride (0.31 g) and diisopropylethylamine (1.0 cm3) in DMF (5 cm3) was heated under argon at 80° C. for 48 hours. The mixture was cooled, then poured into water (50 cm3) and extracted with 50% diethyl ether-ethyl acetate (2×50 cm3). The organic extracts were dried (MgSO4), filtered and concentrated to give a brown oil that crystallised on standing. The material was recystallised twice from ethyl acetate-hexane to give the title compound (0.038 g; 9%) as grey granules, m.p. 228°-230° C. (from EtOAc-hexane); Found: C, 75.0; H, 6.3; N, 17.3. C25H25N5.0.25(H2O) requires C, 75.0; H, 6.4; N, 17.5%. δH (360 MHz; d6 -DMSO) 2.54-2.57 [4H, m, N(CH2)2 ], 2.71 (2H, t, J 7.0, --CH2 --), 2.88 (2H, t, J 7.0, --CH2 --), 3.50-3.57 [4H, m, N(CH2)2 ], 3.59 (2H, broad s, --CH2N), 6.94 (1H, s, 1 of ArH), 7.15-7.28 (4H, m, 4 of ArH), 7.53 (1H, t, J 7.8, 1 of ArH), 7.65 (2H, d, J 8.2, 2 of ArH), 7.85 (1H, d, J 8.1, 1 of ArH), 8.96 (1H, s, 1 of ArH), 12.56 and 12.96 (1H, 2 x broad s, NH); m/z (CI+ ; NH3) 396 (MH+ ; 8%), 214 (68), 185 (50), 132 (50), 130 (80), 87 (70) and 61 (100).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)=[N:14][N:15]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].Br.O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)=[N:14][N:15]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2nnc(-c3ccc(OC)cc3)s2)nc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1ccc(-c2nnc(-c3ccc(O)cc3)s2)nc1
Yield: 32.5 %

Procedure:
To 9.0 g of 2-(5-butyl-2-pyridyl)-5-(4-methoxyphenyl)-1,3,4-thiadiazole, 90 g of a solution of hydrogen bromide in acetic acid was added, followed by heating to 100° C. for 95 hours of reaction while gaseous hydrogen bromide was bubbled. After the reaction, the reaction mixture was poured into 1 liter of water to precipitate a crystal. The crystal was washed with water and recrystallized from a mixture solvent of ethanol/water=9/1 to obtain 2.8 g of an objective product.
Reaction SMILES: N[C@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9].[CH2:29]=O.[C:31]([BH3-])#[N:32].[Na+]>CO>[CH3:29][N:32]([CH3:31])[C@H:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:12][C:11]=2[N:10]([CH3:27])[C:8]1=[O:9]
Reactant: C[C@@H](N)CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O
Reactant: [BH3-]C#N
Reactant: C=O
Agent: [Na+]
Solvent: CO
Product: C[C@H](CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of (R)-1-(5-aminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.4 g, 1.0 mmol) in methanol (10 ml) was added formaldehyde (37% in water) (0.4 ml) followed by sodium cyanoborohydride (0.1 g, 1.5 mmol). After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ammonium hydroxide (37% in water)-methanol-ethyl acetate mixture (1:5:10) to give (R)-1-(5-dimethylaminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.20 g, 47% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 88 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 88%). 1H NMR (300 MHz, CDCl3): δ 3.19-3.22 (m, 4H), 3.75-3.78 (m, 4H), 4.16 (s, 3H), 6.89-6.93 (m, 4H), 7.29-7.46 (m, 2H), 7.74-7.76 (m, 1H).
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1B(O)O.Br[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[S:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][CH3:7]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Brc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1cccs1
Temperature: 85 °C
Yield: 243.3 %

Procedure:
To dioxane (113 ml) is added 2-methoxy-5-fluorophenylboronic acid (4.25 g, 24.9 mmol), 2-bromothiophene (3.65 g, 22.7 mmol, 0.9 eq.) and potassium carbonate (2M, 37 ml). Palladium (0) tetrakistriphenylphoshine (0.03 eq.) is then added and the resulting mixture is heated to 85° C. for 3 hours. The reaction is cooled to room temperature and poured into ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate. The organic layers are combined, and dried over sodium sulfate, concentrated to a brown oil and the resulting residue is flash chromatographed in 20% toluene/hexanes to afford 11.5 g of 2-(thien-2-yl)-4-fluoroanisole (90%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[NH2:5].[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[Cl:2][CH2:3][CH:4]([NH:5][C:25](=[O:26])[C:24]1[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=1[F:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a slurry of 1.1 g of (+/-)-α-(chloromethyl)-4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-methanamine hydrochloride in 13 mL of ethyl acetate was added 0.60 g of 2.6-difluorobenzoyl chloride. 0.60 g of sodium bicarbonate, and 3 mL of water. After 15 min, ethyl acetate was added and the organic phase was washed with aqueous NaCl, dried (MgSO4), filtered, and concentrated to dryness. The residue was triturated with toluene/hexanes, filtered, washed with hexanes, and suction-dried to afford 1.22 g of product, m.p. 148-150° C. 1H-NMR (CDCl3): δ4.0 (dq, 2H), 5.6 (m, 1H), 6.75 (br d, 1H), 6.85 (t, 1H, J=60 Hz), 7.0 (t, 2H), 7.4 (m, 1H), 7.5 (d, 2H), 7.6 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[CH2:8]([Br:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16][N:17]([CH3:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.N1CCCCC1>C(O)(C)C.CO>[Br-:15].[CH2:8]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:22][C:21]1[CH:24]=[CH:25][C:18]([N:17]([CH3:26])[CH3:16])=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccn1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: BrCc1ccccc1
Solvent: CO
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CN(C)c1ccc(C=Cc2cccc[n+]2Cc2ccccc2)cc1
Product: [Br-]
Temperature: 100 °C
Yield: 57.3 %

Procedure:
2-Picoline (9.3 g, 0.1 mole) and benzyl bromide (17.1 g, 0.1 mole) were refluxed in isopropanol (50 ml) overnight. The solvent was evaporated giving an oil which was heated at 100° C. for six hours. The resulting crude oil (8.0 g, 0.03 mole) and 4-dimethylaminobenzaldehyde (4.6 g, 0.03 mole) were refluxed in methanol (50 ml) in the presence of piperidine (0.2 ml) under nitrogen for three hours. On cooling dark-coloured crystals were obtained which were collected to give 1-benzyl-2-[4-(dimethylamino)styryl]pyridinium bromide (6.8 g), melting point 250°-251° C.
Reaction SMILES: [C:1]([C-:3]([C:6]#[N:7])[C:4]#[N:5])#[N:2].[K+].[CH2:9]([NH:11][CH3:12])[CH3:10].CS(O)(=O)=O>C(COC)OC>[NH2:2][C:1]([N:11]([CH2:9][CH3:10])[CH3:12])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: N#C[C-](C#N)C#N
Reactant: CCNC
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: COCCOC
Product: CCN(C)C(N)=C(C#N)C#N
Reaction time: 48 h
Yield: 57.4 %

Procedure:
An attempted preparation by the method of Example VI, part C, was unsuccessful. Thus, a mixture of 129 g of potassium tricyanomethanide, 59 g of ethylmethylamine, and 2000 ml of dimethoxyethane was treated with 65 ml (96 g) of methanesulfonic acid added dropwise during 30 min. The reaction was mildly exothermic and solid formation was noted during addition of the methanesulfonic acid. The reaction mixture was heated under reflux for one hour and was allowed to stand two days at ambient temperature. The solids were removed by filtration and the filter cake was washed with toluene. The combined filtrate and washings were evaporated under reduced pressure. The residue was heated to 200° in an oven. The residue was removed from the oven and water was added immediately. The near boiling aqueous suspension was treated with charcoal and filtered through a mat of Filter-Aid® diatomaceous earth in a large, steam heated, Buchner funnel. The aqueous filtrate was allowed to cool, producing crystals. The crystals were collected by filtration, dried, and recrystallized from acetonitrile to yield 86 g of 3-amino-2-cyano-3-(ethylmethylamino)propenenitrile, mp 140°-141°. The ir spectrum was consistent with the assigned structure.