Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[CH:14][NH:15]4)=[CH:11][CH:10]=3)[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Clc1cncc(Nc2ccc3cc[nH]c3c2)n1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1cc(-c2cncc(Nc3ccc4cc[nH]c4c3)n2)ccn1
Yield: 36.4 %

Procedure:
A mixture of (6-chloro-pyrazin-2-yl)-(1H-indol-6-yl)-amine (0.070 g, 0.2868 mmol), pyridine-4-boronic acid (0.042 g, 0.344 mmol), sodium carbonate (0.150 g, 1.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0165 g, 0.0143 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield N-(6-pyridin-4-ylpyrazin-2-yl)-1H-indol-6-amine (0.030 g, 36.5%) as a yellow solid. 1H NMR (CD3OD) δ 8.73-8.72 (d, J=5.68 Hz, 2H), 8.51 (s, 1H), 8.23-8.20 (m, 4H), 7.56-7.54 (d, J=8.46 Hz, 1H), 7.22 (d, J=2.99 Hz, 1H), 7.14 (dd, J=10.18, 1.74 Hz, 1H), 6.45 (d, J=2.75 Hz, 1H); MS (API-ES/Positive); m/z: 288 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH2:6][CH:7]([OH:27])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])=[O:17])[CH2:11][CH2:10]1.[C:32](OC(=O)C)(=[O:34])[CH3:33].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][CH2:6][CH:7]([O:27][C:32](=[O:34])[CH3:33])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][C:19]2[C:20]([CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=2[CH3:25])=[O:17])[CH2:11][CH2:10]1
Reactant: COc1ccccc1OCC(O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccccc1OCC(CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1)OC(C)=O
Reaction time: 2 h

Procedure:
One g of 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine is dissolved in 25 ml of pyridine and cooled in an ice bath to 0°-5° C. Acetic anhydride (0.6 g) is slowly added and the reaction is stirred for 2 hours. After the addition of 100 ml of water, the reaction mixture is extracted twice with 100 ml portions of diethylether. After combining, the ether extract is washed twice with 100 ml of water and evaporated to dryness to produce 1-[3-(2-methoxyphenoxy)-2-acetoxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine as an oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.OP([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C.O>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[S:6][C:5]([NH2:7])=[N:4][N:3]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: Nc1nnc(Br)s1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nnc(N2CCOCC2)s1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-ylamine, K2HPO4 (5.7 g), and 5.3 ml of morpholine in 20 ml of DMF is heated at 80° C. under nitrogen for 18 hours, then diluted with 50 ml of water. The clear solution is placed in a continuous extractor and extracted with a brisk flow of dichloromethane for 18 hours. The solution is dried over MgSO4 and concentrated under reduced pressure, with toluene azeotropes to remove DMF. Recrystallization of the residual solid from 50 ml of acetonitrile and 100 ml of toluene affords 3.92 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(OCC)(=O)C.CCCCCC>CO>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:24])([CH3:23])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:31])=[CH:28][CH:27]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 91 %

Procedure:
By using (+)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 91%. Melting point: 251-253° C. (Ethyl acetate-hexane) [α]D=+74.4° (c=0.501, methanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[C:5]2=[CH:4][CH:3]=1.[Li][CH3:32]>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])([CH3:32])[CH3:15])[C:5]2=[CH:4][CH:3]=1
Reactant: [Li]C
Reactant: CC(=O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ketone 75-1 (210 mg, 0.497 mmole) in THF was added MeLi (0.466 mL, 1.5 eq, 1.6 M in THF) dropwise, at 0° C. The resulting mixture was stirred at RT overnight, then was heated at 50° C. for 2 hours. After cooling to RT, the reaction mixture was poured in water, extracted with dichloromethane, dried over MgSO4 and concentrated. The residue was purified by column chromatography using dichloromethane and methanol, followed by a purification by prep HPLC on RP SunFire Prep C18 OBD-10 μm,30×150 mm, and mobile phase (0.25% NH4HCO3 solution in water, CH3CN) to give 11 mg of the desired compound 75. LCMS m/z=441 (M+H)+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.05 (m, 2 H), 1.11-1.22 (m, 2 H), 1.17 (s, 6 H), 1.43-1.53 (m, 2 H), 1.74 (br. s., 1 H), 1.79-1.91 (m, 2 H), 2.82-3.05 (m, 1 H), 4.40 (t, J=7.5 Hz, 2 H), 5.39 (s, 2 H), 7.11 (d, J=5.0 Hz, 1 H), 7.20 (d, J=8.3 Hz, 1 H), 7.64 (d, J=8.3 Hz, 1 H), 8.31 (d, J=5.0 Hz, 1 H), 8.70 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+]>CN(C)C=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:9]2[C:10](=[O:23])[C:11]3[CH:16]=[N:15][N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]=3[N:13]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([S:32][CH3:31])=[CH:7][CH:6]=2)=[CH:25][CH:26]=1
Reactant: C[S-]
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(Br)cc2)n1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (2.50 g, 5.23 mmol) in dry N,N-dimethyl-formamide (20 mL), sodium thiomethoxide (0.55 g, 7.84 mmol) is added and the resulting mixture is stirred at 80° C. After 1.5 h, the reaction mixture is concentrated and the crude product obtained is purified by column chromatography (silica gel, 60-120 mesh) to afford 5-(4-chloro-phenyl)-6-(4-methylsulfanyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=[C:4]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:3]=1>N[C@@H](CO)C>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][S:14][C:4]1[N:3]=[C:2]([NH:10][C@H:9]([CH3:12])[CH2:8][OH:13])[C:11]2[N:10]=[C:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=1
Reactant: Cc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]c1=O
Agent: C[C@@H](N)CO
Product: Cc1nc2c(N[C@H](C)CO)nc(SCc3cccc(F)c3F)nc2[nH]c1=O

Procedure:
The titled compound was prepared from the product of example 35, step (b) (2.00 mg) and D-alaninol (120 μl) using the method of Example 2, step (f).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17][C:16]=3[CH:15]=[CH:14][C:13]=2[Br:25])=[CH:8][CH:7]=1.[OH-].[K+]>O1CCCC1.CO>[Br:25][C:13]1[CH:14]=[CH:15][C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[C:20]=2[C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:26])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)COc1ccc(-c2c(Br)ccc3sc4ccccc4c23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(-c2c(Br)ccc3sc4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a solution of [4-(2-bromo-dibenzothiophen-1-yl)-phenoxy]-acetic acid methyl ester (0.449 g, 1.05 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL) was added an aqueous solution of potassium hydroxide (1N, 1.26 mL, 1.2 eq) dropwise at room temperature. After stirring 1 hour at room temperature the solvents were removed and the residue was disolved in water (50 mL) and the reaction mixture was acidified with 10% hydrochloric acid. After stirring 15 minutes the white solid was collected on a sintered glass funnel, washed with water and dried in vacuo at 58° C. overnight to give the title compound as a white solid (0.405 g, 93%); mp 209.5-210.5° C.; NMR (DMSO, d6): δ 13.06 (broad singlet), 8.02 (d, J=8 Hz, 1H), 8.01 (dd, J=8,1 Hz, 1H), 7.82 (d, J=8 Hz, 1H), 7.40 (ddd, J=8,7,1 Hz, 1H), 7.26-7.20 (m, 2H), 7.18=7.07 (m, 3H), 6.54 (d, J=8 Hz, 1H), 4.81 (s, 2H); MS [EI] M*+ m/z=412(98%), 414(100%), 1bromine isotope pattern detected, Anal. Calc. for C20H13BrO3S: C, 58.12, H, 3.17, N, 0.00. Found: C, 57.96, H, 2.95, N, 0.03.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[N:15]=[N:16][NH:17][CH:18]=3)=[C:9]([O:19]C)[C:8]2=[S:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[N:15]=[N:16][NH:17][CH:18]=3)=[C:9]([OH:19])[C:8]2=[S:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(Cc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1c(Cc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 67.3 %

Procedure:
Reaction of 153a (0.28 g, 0.93 mmol) and 1M BBr3 in CH2Cl2 (1.5 equiv) within 48 h as described for the synthesis of 148a gave compound 154a (0.178 g, 67%) as olive green solid. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=16.6 Hz, 1H), 8.39 (s, 1H), 7.79 (dd, J=6.6, 1.3 Hz, 1H), 7.69 (m, 2H), 7.46 (m, 3H), 6.97 (dd, J=7.7, 1.2 Hz, 1H), 6.69 (dd, J=7.6, 6.8 Hz, 1H), 5.94 (s, 2H). 13C NMR (100 MHz, CDC3) δ 168.59, 155.12, 141.60, 136.66, 131.65, 129.69, 128.99, 122.57, 120.60, 114.04, 112.47, 77.30, 76.99, 76.67, 52.08. HRMS (EI) calcd for C14H12N4OS [M]+ 284.0730. found 284.0732.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][C:37]=4[F:40])[CH2:32]3)=[O:30])[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43](O)=[O:44])[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.S([O-])(O)(=O)=O.[K+]>C1(C)C=CC=CC=1.O>[F:40][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:38]=1[CH2:39][N:31]([C:29]([O:28][C@H:26]1[CH2:25][N:22]3[C:23](=[O:24])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH:15]=[CH:16][C@@H:17]4[CH2:42][C@@:18]4([C:43](=[O:44])[NH:64][S:61]([CH:58]4[CH2:60][CH2:59]4)(=[O:63])=[O:62])[NH:19][C:20](=[O:41])[C@@H:21]3[CH2:27]1)=[O:30])[CH2:32]2
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCOCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCOCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCOCC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@H]1CCOCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylic acid (0.072 g, 0.11 mmol) in toluene (3 mL) was added di(1H-imidazol-1-yl)methanone (0.024 g, 0.15 mmol) in rt. The reaction was stirred at 60° C. for 3 hrs. Cyclopropanesulfonamide (0.021 g, 0.17 mmol) was added, followed by addition of DBU (0.043 ml, 0.29 mmol). The reaction was then stirred at rt for 17 hrs. Water (5 mL) was added and acidified with saturated potassium hydrogen sulfate until pH=2˜3. The mixture was extracted with ethyl acetate (20 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Ethyl acetate) to (2R,6S, 13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.057 g, 68%). MS: Calcd.: 733. Found: [M+H]+ 734. 1H NMR (400 MHz, d6-DMSO) δ 1.08 (s, 1H), 9.03 (d, J=10.8 Hz, 1H), 7.34 (m, 1H), 7.11-7.33 (m, 3H), 5.46 (m, 1H), 5.30 (s, 1H), 5.23 (m, 1H), 4.67 (s, 4H), 4.42 (m, 1H), 4.28 (m, 1H), 3.95 (m, 1H), 3.69 (m, 1H), 3.56 (m, 1H), 3.41 (m, 1H), 3.32 (m, 1H), 3.26 (m, 1H), 2.91 (m, 1H), 2.18-2.40 (m, 5H), 1.92 (m, 1H), 1.75 (m, 1H), 1.61 (m, 2H), 1.00-1.28 (m, 13H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[N:12]=[CH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:11]([N:9]2[CH:10]=[C:6]([CH2:4][OH:3])[N:7]=[CH:8]2)[N:12]=1
Reactant: CCOC(=O)c1cn(-c2cc3ccccc3cn2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cn(-c2cc3ccccc3cn2)cn1

Procedure:
Following the general method described in example 298, 1-isoquinolin-3-yl-1H-imidazole-4-carboxylic acid ethyl ester was reacted with lithium aluminum hydride followed by hydrolytic workup and chromatography. The title compound was obtained as an off-white waxy solid. MS: m/e=226 (M+H+).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([O:23][C:24](=[O:35])[CH2:25][CH2:26][C:27]1[O:31][CH:30]=[N:29][C:28]=1[C:32](O)=[O:33])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CC#N>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:32]([C:28]2[N:29]=[CH:30][O:31][C:27]=2[CH2:26][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:35])=[O:33])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)CCc1ocnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCc1ocnc1C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 2.18 g, 7.50 mmol), 5-(3-tert-butoxy-3-oxopropyl)-1,3-oxazole-4-carboxylic acid (Reference Example 22, 1.90 g, 7.88 mmol), triethylamine (1.52 g, 7.88 mmol), EDCI (1.51 g, 7.88 mmol) and HOBt (1.21 g, 7.88 mmol) in MeCN (40 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with 10% NaHCO3, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 9:1-2:3 hexane/ethyl acetate) to give the title compound (2.81 g) as a light yellow oil.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>O1CCCC1.[Ni]>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(N=Cc2ccccc2)c(F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Fc1ccc(NCc2ccccc2)c(F)c1

Procedure:
195.4 g (0.9 mol) of N-benzal-2,4-difluoroaniline are dissolved in 900 ml of tetrahydrofuran in an autoclave. 19 g of Raney nickel and 2 g of acetic acid are added, and the mixture is hydrogenated at 60° to 85° C. and a hydrogen pressure of 100 bar. The end point of the reaction is determined by thin-layer chromatography or gas chromatography. The suspension is filtered and the solution is evaporated on a vacuum rotary evaporator. The residue is distilled in vacuo at 102° C. and 3.6 mbar, to give 125.6 g (64% of theory) of a pale yellow liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:23])=[C:7]([CH:22]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)#[N:2].[Br:24]N1C(=O)CCC1=O.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:23][Br:24])=[C:7]([CH:22]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=1)#[N:2]
Reactant: Cc1ccc(C#N)cc1OCCNC(=O)c1ccc(C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)NCCOc2cc(C#N)ccc2CBr)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
12.0 g (39.3 mmol) of N-[2-(5-cyano-2-methylphenoxy)ethyl]-4-cyanobenzamide was dissolved in 200 ml of carbon tetrachloride. 7.00 g (39.3 mmol) of N-bromosuccinimide and 700 mg (4.26 mmol) of azoisobutyronitrile were added to the solution. After stirring at 100° C. for 3 days, 16.8 g (94.4 mmol) of N-bromosuccinimide and 2.1 g (12.8 mmol) of azoisobutyronitrile were added to the resultant mixture, and they were stirred for additional 2 days. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][C:25](=[O:37])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[CH:28][CH:27]=3)=[N:23][C:18]2=[CH:17][CH:16]=1>>[OH:34][CH2:33][C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:24][C:22]2[S:21][C:19]3[C:18]([N:23]=2)=[CH:17][CH:16]=[C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[NH:2][CH3:1])=[CH:6][CH:7]=2)[N:20]=3)=[O:37])=[CH:27][CH:28]=1)([CH3:36])[CH3:35]
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Product: CNC(=O)c1ccc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)CO)cc4)sc3n2)cc1
Yield: 15 %

Procedure:
The titled compound (yield=15%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 4-(methylcarbamoyl)phenylboronic acid and 2F (Example 2) were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.82 (d, J=4.55 Hz, 3H) 3.49 (d, J=5.31 Hz, 2H) 4.75-4.81 (m, 1H) 7.58 (d, J=8.84 Hz, 2H) 7.98 (d, J=8.59 Hz, 2H) 8.11 (d, J=8.84 Hz, 2H) 8.17-8.22 (m, 1H) 8.22-8.28 (m, 3H) 8.56 (q, J=4.63 Hz, 1H) 13.02 (s, 1H); ESI-MS: m/z 461.0 (M+H)+.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.NCCCCCC(O)=O.C(O)(=O)C.[CH:26]1[CH:30]=[C:29]([CH:31]=[O:32])[N:28]([CH2:33][CH2:34][CH2:35][CH2:36][C@H:37](N)[C:38]([OH:40])=[O:39])[C:27]=1[CH2:42][OH:43]>O>[CH:42]([C:27]1[N:28]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:29]([CH2:31][OH:32])=[CH:30][CH:26]=1)=[O:43]
Reactant: N[C@@H](CCCCn1c(C=O)ccc1CO)C(=O)O
Agent: NCCCCCC(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc(CO)n1CCCCCC(=O)O
Temperature: 100 °C

Procedure:
Structure 8b was prepared according to the method described by F. Hayase et al., J. Biol. Chem 263: 3758-64 (1989). The procedure was approximately as follows: ε-(2-Formyl-5-hydroxymethyl-pyrrol-1-yl)-caproic Acid (Caproyl Pyrraline or structure 8b) was synthesized for use as a hapten. D-Glucose (18 g) and ε-amino caproic acid (13.1 g) were dissolved in distilled water (20 mL), and the pH was adjusted to 4.0 with acetic acid. The solution was refluxed at 100° C. for 3 h. The resulting brown solution was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated. The concentrate was charged onto a silica gel column for flash chromatography in 3:1 hexane/ethyl acetate. 2,4-Dinitrophenylhydrazine-positive fractions containing caproyl pyrraline were collected and recrystallized from ether/hexane. The yield was 1 g. Proton NMR: (CDCl3) δ 1.33-1.92 (m, 6H, 3×CH2), 2.39 (t 2H, CH2), 4.33 (t, 2H, CH2), 4.72 (s, 2H, CH2OH), 6.23 (d, 1H, pyrrole-4H), 6.99 (d, 1H, pyrrole-3H), 9.46 (s, 1H, CHO). IR 3500, 2950-2860 (br), 1725, 1645, and 1400 cm-1. UVmax 297 nm (H2O) (ε=1.61×104 mol-1 liter cm-2). Chemical ionization mass spectrometry-millimass: C12H17O4N as theoretical ion distribution, M1 =239 1158. Mass spectrometry analysis was performed with a HP 5985A mass spectrometer Crlewlett-Packard). Chemical ionization mass spectrometry was analyzed with methane as the reaction gas. NMR, IR, and UV properties were identical with those of synthetic neopentyl and L-lysyl pyrraline.
Reaction SMILES: C([NH:4][C:5]1[C:10]([S:11]([NH:14][C:15](=[O:17])[CH3:16])(=[O:13])=[O:12])=[CH:9][N:8]=[C:7]([Cl:18])[CH:6]=1)(=O)C.[OH-].[Na+]>O>[NH2:4][C:5]1[C:10]([S:11]([NH:14][C:15](=[O:17])[CH3:16])(=[O:13])=[O:12])=[CH:9][N:8]=[C:7]([Cl:18])[CH:6]=1
Reactant: CC(=O)Nc1cc(Cl)ncc1S(=O)(=O)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NS(=O)(=O)c1cnc(Cl)cc1N

Procedure:
A solution of 0.5 g of 4-acetylamino-5-acetylaminosulfonyl-2-chloropyridine (preceding stage) in 10 cm3 of water containing 0.137 g of NaOH (2 equivalents) is brought to reflux for 15 minutes. After cooling, the solution is adjusted to a pH of 6 and the precipitate obtained is collected on a filter, washed with water and dried.