Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OCC(C)(C)CO2)=[CH:20][CH:19]=1.CCO>COCCOC.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>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)COB(c2ccc(F)cc2)OC1
Reactant: O=C(O)c1cccc(Br)n1
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: CCO
Solvent: COCCOC
Product: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 46 %

Procedure:
A solution of 6-bromopicolinic acid (Aldrich) (2.02 g, 10 mmol) in DME containing 4 mL of 10% aq Na2CO3 was purged with Ar gas. To this mixture was added Pd(PPh3)4 followed by 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2.40 g, 11.5 mmol, Wako Pure Chemical Industries, Ltd) and EtOH (20 mL), and the mixture was purged with Ar gas. The reaction mixture was heated at 100° C. for 2.5 h in a sealed tube. Additional 2-bromopicolinic acid (900 mg) and Pd (OAc)2 was added, and after purging with Ar gas it was heated at 100° C. for 4.5 h. Trifluoroacteic acid (20 mL) was added to the reaction mixture, concentrated and MeOH (150 mL) was added to the residue. The insoluble material was filtered, and the filtrate solution was concentrated. Purification by flash column on silica gel eluting with EtOAc/MeOH//900:100 followed by EtOAc/MeOH/HOAc//700:1500:50 provided the desired product (1.0 g, 40% based on borinane starting material) as a white solid. 1H NMR (CD3OD) δ 8.01 (d, 1H, J=7.7 Hz), 7.94-7.87 (m, 3H), 7.73 (d, 1H, J=7.7 Hz), 7.13 (t, 2H, 8.8 Hz); MS(ESI+) m/z 234 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:39])[N:29]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([NH:41][CH:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[N:9]2)=CC=1.FC(F)(F)C(O)=O>>[F:40][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:39])[N:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([NH:41][CH:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccccn6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccccn6)c5=O)cc4F)c23)CC1
Temperature: 60 °C
Yield: 86.9 %

Procedure:
A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-3-oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxamide (0.014 g, 0.02072 mmol) and 2,2,2-trifluoroacetic acid (TFA) (0.1596 ml, 2.072 mmol) was heated to 60° C. for 18 hours under N2. The mixture was concentrated in vacuo using toluene (3×5 mL) to azeotrope residual TFA. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The phases were separated, and the organic phase washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was triturated with ether and decanted to obtain the product as a brown powder (10 mg, 86%). LRMS (apci pos): >99% purity, 220 nm, m/z 556 (M+H); 1H NMR (400 MHz, CDCl3) δ 11.77 (s, 1H), 8.74 (m, 1H), 7.44 (d, 1H), 8.28 (d, 1H), 8.02 (m, 2H), 7.66 (d, 1H), 7.53 (t, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 6.10 (br s, 1H), 4.55 (bd, 1H), 3.80 (br s, 1H), 3.16 (br s, 2H), 2.44 (m, 10H); 19F NMR (376 MHz, CDCl3) δ −125.2 (m).
Reaction SMILES: [C:1]([C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]#[N:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:19].CCOC(C)=O>[Pt]=O.CCO>[ClH:19].[CH3:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:18][CH2:17][CH2:16]2
Reactant: Cc1cccc(CC#N)c1C(=O)c1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc2c1C(c1ccccc1)=NCC2
Reaction time: 5 h

Procedure:
To (2-benzoyl-3-methylphenyl)acetonitrile (3.3 g) were added EtOH (40 mL), 4 M HCl/EtOAc (5 mL), and platinum oxide (IV) (0.53 g), followed by stirring under a hydrogen atmosphere for 5 hours. The reaction liquid was filtered through celite and then concentrated. Toluene was added to the concentrate, followed by extraction with an aqueous 1 M HCl solution. A 28% aqueous ammonia solution was added to the aqueous layer, which was then extracted with toluene and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in toluene to which 4 M HCl/EtOAc (5 mL) was then added, followed by concentration. iPrOH and diisopropyl ether were added to the resulting residue, and the precipitated solid was collected to obtain 8-methyl-1-phenyl-3,4-dihydroisoquinoline hydrochloride (1.5 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]CCC(OCC)=O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1COCC1.CC([O-])(C)C.[K+].Cl>O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[C:16]([SH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CCSc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(-c2ccc(-c3ccccc3S)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution consisting of ethyl 3-(4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-ylthio)propanoate (7.7 g, 19.4 mmol) and THF (60 mL) was added t-BuOK (4.3 g, 38.8 mmol) and the mixture stirred for 1 hour at rt. The reaction mixture was poured into water (100 mL) and the system brought to a pH=5-6 with 1 M HCl. The mixture was, extracted with EtOAc (80 mL×3) and the combined extracts dried over Na2SO4, filtered and concentrated to dryness to give 4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-thiol (4.6 g, 80%). MS (ESI): mass calcd. for C16H12FN3S, 297.07; m/z found, 298.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH2:27][OH:28])[C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](Cl)=[O:35]>>[CH3:1][N:2]([CH2:26][CH2:27][O:28][C:34]([C:30]1[O:29][CH:33]=[CH:32][CH:31]=1)=[O:35])[C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N(C)CCO
Reactant: O=C(Cl)c1ccco1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccco1

Procedure:
N-methyl-N-(2-furoyloxyethyl)erucamide was prepared by the procedure of example 1 from 39.5 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)erucamide and 13 gms. (0.1 mole) of furoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C@H:5]2[C:6](=[O:37])[CH2:7][C@H:8]3[C@:29]([CH3:30])([C@@H:4]12)[C@@H:28]1[C@H:11]([C@H:12]2[C@:25]([CH3:31])([CH2:26][CH2:27]1)[C@@H:15]([C@H:16]([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[CH2:10][C@H:9]3[O:32][S:33]([CH3:36])(=[O:35])=[O:34].O>O1CCCC1>[O:3]1[C@H:5]2[CH:6]([OH:37])[CH2:7][C@H:8]3[C@:29]([CH3:30])([C@@H:4]12)[C@@H:28]1[C@H:11]([C@H:12]2[C@:25]([CH3:31])([CH2:26][CH2:27]1)[C@@H:15]([C@H:16]([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[CH2:10][C@H:9]3[O:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](OS(C)(=O)=O)[C@H]4CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](OS(C)(=O)=O)[C@H]4CC(O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.42 h

Procedure:
To 1-molar diborane-tetrahydrofuran complex (not stabilized with sodium borohydride, 157 ml) cooled in an ice bath, was added dropwise over about 25 minutes a solution of 1α,2α-epoxy-6β-methylsulfonyloxy-5α-cholestan-25-ol-3-one (20.0 g, 0.392 mole), in tetrahydrofuran (100 ml), with stirring under an atmosphere of nitrogen. After the addition was complete, the solution was stirred for about 25 minutes. Water was cautiously added to the reaction mixture cooled in an ice bath. The mixture was stirred for about 10 minutes and then evaporated at a bath temperature of 35° C in vacuo. The residue was partitioned between methylene chloride and water (ca. 1:1) and the organic layer was separated. The organic phase was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate gave 1α,2α-epoxy-25-hydroxy-6β-methylsulfonyloxy-5α-cholestan-3-ol, as a white foam.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@H:5]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+]=[N-].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[C:19]([O:18][C:16]([NH:15][C@@H:5]1[CH2:6][C@@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9][C@@H:4]1[NH2:1])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](N)[C@H](NC(=O)OC(C)(C)C)C1
Yield: 114.5 %

Procedure:
Ethyl (1S,3R,4S)-4-azido-3-(tert-butoxycarbonylamino)cyclohexane-1-carboxylate (4.0 g) was dissolved in a mixed solvent of ethanol (150 ml) and ethyl acetate (150 ml), and 5% palladium on carbon (0.5 g) was added to stir the mixture at room temperature for 17 hours in a hydrogen atmosphere. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.2 g) as a pale yellow oil.
Reaction SMILES: CCCCCC.[H-].[Na+].[C:9]([C:13]1[NH:17][N:16]=[CH:15][N:14]=1)([O:11][CH3:12])=[O:10].[CH3:18][N:19]1[N:23]=[N:22][C:21]([C:24]2[CH:34]=[C:33]([CH3:35])[C:27]([O:28][CH2:29][CH2:30][CH2:31]Br)=[C:26]([CH3:36])[CH:25]=2)=[N:20]1>CN(C=O)C>[C:9]([C:13]1[N:14]=[CH:15][N:16]([CH2:31][CH2:30][CH2:29][O:28][C:27]2[C:26]([CH3:36])=[CH:25][C:24]([C:21]3[N:22]=[N:23][N:19]([CH3:18])[N:20]=3)=[CH:34][C:33]=2[CH3:35])[N:17]=1)([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ncn[nH]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ncn(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)n1
Reaction time: 1 h
Yield: 39.8 %

Procedure:
Hexane washed 60% NaH (22 mg, 0.55 mmol) in 0.5 ml of DMF was added at 20° C. to a solution of 5-carbomethoxy-1,2,4-triazole (63.5 mg, 0.5 mmol) in 0.5 ml of DMF and the mixture was stirred for 1 h. To the above mixture was added at 20° C. 3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propylbromide (163 mg, 0.5 mmol) in 0.5 ml of DMF and the mixture was stirred at 20° C. for 18 h. The mixture was partitioned between ice/water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×), and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/5-1/0; methylene chloride/acetone) to afford 74 mg (40%) of 5-carbomethoxy-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40])=[O:33])([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][C:39]([CH:35]4[CH2:36][CH2:37][CH2:38][N:34]4[C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])=[O:40])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
700 mg (1.91 mmol) of the compound of Example 2, 493 mg (2.29 mmol) of (R)-1-(t-butoxycarbonyl)-2-pyrrolidinecarboxylic acid and 512 mg (2.67 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 20 ml of dichloromethane. 0.77 ml (5.59 mmol) of triethylamine and 24 mg (0.2 mmol) of dimethylaminopyridine were added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. The solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and they were washed with water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane:ethyl acetate=9:1 to 1:4) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[H][H]>CCO.[Pd]>[C:11]1([C:8]2[N:4]3[CH2:5][CH2:6][NH:7][CH2:2][C:3]3=[N:10][N:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1nccn2c(-c3ccccc3)nnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1ccc(-c2nnc3n2CCNC3)cc1
Yield: 100.3 %

Procedure:
Title compound 472 (310 mg, 1.34 mmol) was dissolved in EtOH (25 mL) and 10% Pd/C (75 mg, 25% w/w) was added. The reaction mixture was stirred under 1 atmosphere of hydrogen over night. The catalyst was filtered and the filtrate was evaporated to afford title compound 473 (269 mg, 100%). MS (m/z): 201.1 (M+H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(O)(=O)C.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[CH:15][CH:14]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (8.4, 94 mmol) in 1,2-dichloroethane (150 mL) and acetic acid (4.3 mL, 77 mmol) was added 4-methoxy benzaldehyde (11.5 mL, 94 mmol). After stirring for 10 min, sodium triacetoxyborohydride (49.9 g, 235.5 mmol) was added portion-wise over 20 min. The resulting mixture was stirred at 60° C. for 2 h then cooled to room temperature and quenched with saturated NaHCO3. The aqueous layer was washed with dichloromethane and made basic by the addition of 10N NaOH. The product was extracted with ethyl acetate, concentrated and crystallized from Et2O/hexane to give the title compound as a white solid (11.95 g, 61% yield). 1H NMR (300 MHz, CDCl3) δ: 7.32-7.20 (2H, m), 6.86-6.80 (2H, m), 3.76 (3H, s), 3.58 (2H, s), 3.30 (2H, s), 1.11 (6H, s). LCMS (M+H) calcd for C12H20NO2: 210.14; found: 210.20.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1c2n(c3c(-c4ccc(F)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (59 mg, 75%), MS (ISP) m/z=314.5 [(M+H)+], mp 247° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[S:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([CH:21]([OH:22])[C:20]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[S:18][C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[F:10])[CH2:3][CH2:4]1
Reactant: O=Cc1cc(Cl)ccc1Sc1cc(F)ccc1F
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C(O)c2cc(Cl)ccc2Sc2cc(F)ccc2F)CC1
Yield: 100 %

Procedure:
A solution of a Grignard reagent is prepared by reaction of 11.35 g of 4-chloro-1-methylpiperidine with 2.3 g of magnesium in 70 ml of tetrahydrofuran and is then treated for 10 minutes with a solution of 16.1 g 2-(2,5-difluorophenylthio)-5-chlorobenzaldehyde in 40 ml of tetrahydrofuran, added dropwise. The mixture is refluxed for 4 hours and, after cooling, decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is washed with water, dried with potassium carbonate and evaporated. There are obtained 21.7 g (100%) crude oily α-(-methyl-4-piperidyl)-2-(2,5-difluorophenylthio)-5-chlorobenzyl alcohol which is used in this state for the final step.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:21]=3[CH:22]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].Br[CH2:25][C:26]1[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:21]=3[CH:22]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:25][C:26]1[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)[C:12]4=[O:20]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.09 g, 0.29 mmol) in 2-butanone (10.0 mL) was added 2-bromomethyl-5-(trifloromethyl)furan (0.08 g, 0.35 mmol) followed by cesium carbonate (0.19 g, 0.58 mmol) at 0° C. The mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (0.06 g, 45%): mp 155-160° C.; 1H NMR (300 MHz, CDCl3,) δ 7.29 (t, 1H), 7.19 (d, 1H), 7.07 (t, 1H), 6.97 (d, 1H), 6.73 (t, 1H), 6.42-6.37 (m, 2H), 6.30 (s, 1H), 5.08 (d, 1H), 4.94-4.84 (m, 2H), 4.65 (d, 1H), 4.18 (s, 2H), 1.19 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.5, 161.2, 161.0, 152.0, 141.4, 132.5, 130.1, 128.8, 124.2, 123.8, 120.1, 116.4, 112.6, 109.3, 108.7, 93.4, 85.5, 80.6, 57.7, 41.4, 36.9, 27.6, 27.5; MS (ES+) m/z 456.5 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([CH:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][O:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:7][CH2:8][CH3:9].[OH-].[Na+].CN([CH:29]=[O:30])C>>[CH:29]([C:14]1[S:15][CH:16]=[CH:17][C:13]=1[O:12][CH2:11][CH:10]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:30]
Reactant: CN(C)C=O
Reactant: CCCCCCC(CCCC)COc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCC(CCCC)COc1ccsc1C=O
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, phosphorous oxychloride (3.5 ml, 40 mmol) was slowly dropped into DMF (70 ml) at 0° C. and stirred for 10 minutes. Then, a DMF (15 ml) solution of 3-(2-butyloctoxy)thiophene (9 g, 30.4 mmol) was slowly dropped into the reaction solution. The reaction solution was then heated for two hours at 70° C. Then, the reaction solution was cooled to room temperature. While cooling the reaction solution in a water bath, a 10% aqueous sodium hydroxide solution was slowly added and stirred for 30 minutes. Then, the reaction solution was extracted with chloroform, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solution was distilled off under reduced pressure. By separating and purifying the obtained reaction mixture by silica gel column chromatography in which a mixed solvent of hexane and ethyl acetate was used as a mobile phase, a target substance was obtained as clear oil (80% yield). 1H-NMR (400 MHZ, CDCl3, TMS) δ 10.00 (s, 1 H), 7.67 (d, J=4.8 Hz, 1 H), 6.84 (d, J=4.8 Hz, 1 H), 4.03 (d, J=4.8 Hz, 2 H), 1.25 (m, 17 H), 0.88 (m, 6 H)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[NH:15][N:14]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][C:9]1[CH:26]=[CH:25][CH:24]=[C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[NH:15][N:14]=2)[CH:10]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CCCCl)Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chlorobutyryl chloride (5.42 g, 38.4 mmol) was added dropwise at ambient temperature to a stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (8 g, 32 mmol; prepared in a manner similar to that described above), triethylamine (5.35 ml, 38.4 mmol) and 1,4-dioxane (40 ml), the mixture was stirred at ambient temperature for 1 hour, then it was poured into ice-water (100 ml). The resulting solid was collected by filtration, washed with water (30 ml) and dried in vacuo to give 4-chloro-N-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]butyramide (12.34 g) as an off-white solid, m.pt. 180–184° C.
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:7]([N:6]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(C(F)(F)F)cc1

Procedure:
Using 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and 4-(trifluoromethyl)phenylboronic acid and by reaction and purification in the same manner as in the method described in Example 30, step 9, the title compound was obtained. MS (API): 507 (M+H)