Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]2([CH3:24])[CH3:23].[Br-:25].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Br:25][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]3([CH3:24])[CH3:23])[C:5]=1[O:9][CH3:10]
Reactant: [Br-]
Reactant: COc1cccc(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 6-(2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthalene (340 mg, 1.05 mmol) in dichloromethane (10 mL) was added pyridinium tribromide (335 mg, 1.05 mmol) and the reaction mixture stirred at room temperature overnight. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: ethyl acetate/hexane, 0.5:9.5) to give 0.24 g (57%) of 6-(5-bromo-2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthalene. 1H NMR (500 MHz; CDCl3): δ 1.28 (s, 6 H); 1.31 (s, 6 H); 1.70 (s, 4 H); 3.35 (s, 3 H); 3.73 (s, 3 H); 7.14 (dd, J1=1.5 Hz, J2=8.5 Hz, 1 H); 7.15 (dd, J1=2.0 Hz, J2=8.5 Hz, 1H); 7.30 (d, J=8.0 Hz, 1H); 7.36 (d, J=1.5 Hz, 1H); 7.45 (d, J=8.0 Hz, 1 H), 7.95 (br, 1 H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.Cl.[NH2:32][OH:33].C(N(CC)CC)C>O1CCCC1.CO>[OH:33][NH:32][C:25](=[NH:26])[C:24]1[CH:27]=[CH:28][C:21]([S:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:30])([F:29])[F:1])=[CH:4][CH:5]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: NO
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: N=C(NO)c1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
517 mg 4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile were dissolved in a mixture of 10 ml tetrahydrofuran and 10 ml methanol. 1.68 g hydroxylamine hydrochloride were added followed by the addition of 3.35 ml triethylamine. The reaction mixture was stirred at 65° C. for eight hours. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 550 mg N-hydroxy-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzamidine as an oil. C22H18F3N3O3S (461,47), MS (ESI): 462.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][C:13]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=2[N:15]=1>>[CH3:27][O:26][C:16]1[C:14]2[N:15]=[C:11]([NH:10][C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:8])[S:12][C:13]=2[C:19]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 97 %

Procedure:
Using 5-methyl-thiophene-2-carbonyl chloride and 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol the title compound was obtained as a yellow solid in 97% yield. MS: m/e=390 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][C@H:13]3[CH2:15][C@H:16]([NH2:18])[CH2:17][C@H:12]3[CH2:11][O:10]2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:18][C@H:16]2[CH2:15][C@@H:13]3[O:14][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[O:10][CH2:11][C@@H:12]3[CH2:17]2)[CH:25]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](N)C[C@@H]3O2)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2OC[C@@H]3C[C@@H](Nc4cc(Cl)ncn4)C[C@@H]3O2)cc1
Temperature: 110 °C

Procedure:
A sealed tube containing (4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-amine (120. mg, 0.481 mmol), 4,6-dichloropyrimidine (143 mg, 0.963 mmol), DIPEA (0.0920 mL, 0.528 mmol) and EtOH (30.0 mL) was heated to 110° C. for 20 h. The cooled mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM (120. mg, 69%). LC/MS: Rt=1.74 min, ES+ 362 (AA standard).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C[C:11]([N:13](C)C)=O>[C-]#N.[Zn+2].[C-]#N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:11]#[N:13]
Reactant: Cc1cccc(F)c1I
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc(F)c1C#N
Temperature: 80 °C

Procedure:
A 10 L round bottom flask equipped with adapter, thermocouple and stir bar was charged with DMA (6 L) and degassed under vacuum and purged with N2 three times. To the mixture was added Palladium Tetrakis triphenylphosphine (87.5 g, 72.0 mmol) and the mixture was degassed under vacuum and purged with N2 three times. The reaction was heated to 80° C. for 30 min. 3-Fluoro-2-iodotoluene (575 g, 2.4 mol) and Zinc Cyanide (171.7 g, 1.46 mol) were added and the mixture was degassed under vacuum and purged with N2 three times. The reaction mixture was heated to 80° C. for 16 h and then allowed to cool to RT. The solution was added to a 2.0 L aqueous solution of 1N NH4OH and extracted three times with 1.5 L EtOAc. The extracts were washed with 2 L brine, dried over Na2SO4, filtered and concentrated. The crude product was treated with mCPBA in cooled DCM and then purified by chromatography (PE/EA=10:1) to get the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:11](OCC)=[O:12].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.[O-2].[O-2].[Mn+4].C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH:11]=[O:12]
Reactant: CCOC(=O)c1sc2ncccc2c1C
Agent: [Mn+4]
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C=O)sc2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a mixture of ethyl 3-methylthieno[2,3-b]pyridine-2-carboxylate (3.00 g) synthesized above, calcium chloride (3.02 g), ethanol (50 mL) and tetrahydrofuran (50 mL) was added sodium borohydride (2.06 g) at 0° C., and the mixture was stirred at room temperature for 4 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. To a solution (50 mL) of the obtained solid in tetrahydrofuran was added active manganese dioxide (12.5 g), and the mixture was stirred at 50° C. overnight. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (2.07 g, 86%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:20]1[CH:21]=[N:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=1.C([O-])([O-])=[O:29].[K+].[K+].CCOC(C)=O.O>C1COCC1.[Li+].[OH-]>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6](=[O:7])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH2:27])=[O:29])=[N:22][CH:21]=1
Reactant: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2ccc(C#N)nc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2ccc(C(N)=O)nc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-chloro-3-(6-cyano-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide 2-2 (29 mg, 0.077 mmol) in THF (0.5 mL), 1N LiOH (0.5 mL) and K2CO3 (10 mg, 0.073 mmol) were added. After stirring for 48 hrs at room temperature, EtOAc and water were added. The aqueous layer was removed and the organic layer was concentrated, dissolved in MeOH and subjected to preparative LCMS to yield 5-{2-chloro-5-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-pyridine-2-carboxylic acid amide 24-1. MS (M+H)+: 396.0, tR=5.93 min (method 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:14][C@H:10]3[C:11]=2[NH:12][N:13]=1)=[O:5])[CH3:2].I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=1.N1CCCC1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:14][C@H:10]3[C:11]=2[N:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=2)[N:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c2c1C[C@H]1C[C@@H]21
Reactant: COc1ccc(I)nc1
Agent: [Cu]I
Agent: O=C(O)C1CCCN1
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1nn(-c2ccc(OC)cn2)c2c1C[C@H]1C[C@@H]21
Temperature: 75 °C
Reaction time: 15 h
Yield: 36.4 %

Procedure:
A 20 mL scintillation vial was charged with (1aR,5aR)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (492 mg, 2.56 mmol), 2-iodo-5-methoxypyridine (662 mg, 2.82 mmol), DL-proline (58.9 mg, 0.512 mmol), copper(I) iodide (48.7 mg, 0.256 mmol), and potassium carbonate (708 mg, 5.12 mmol). The vial was flushed with nitrogen, and added DMSO (15 mL). The reaction was stirred under nitrogen at 75° C. for 15 h. The reaction was filtered then purified by HPLC to provide the title compound (279 mg) as a white solid. LCMS m/z=300.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.23 (td, J=8.0, 4.8 Hz, 1H), 1.39 (t, J=7.2 Hz, 3H), 2.21-2.27 (m, 1H), 2.77-2.82 (m, 1H), 2.85 (d, J=16.6 Hz, 1H), 2.97 (dd, J=16.6, 6.4 Hz, 1H), 3.90 (s, 3H), 4.38 (q, J=7.2 Hz, 2H), 7.34 (dd, J=8.8, 2.9 Hz, 1H), 7.98 (dd, J=9.0, 0.6 Hz, 1H), 8.13 (dd, J=3.0, 0.5 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22].O1CCOCC1.C(OCC)C>O1CCCC1>[ClH:22].[NH2:14][CH:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12](=[O:13])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)N(Cc2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.6 %

Procedure:
In tetrahydrofuran (6 ml) was dissolved tert-butyl 1-benzyl-5-oxo-3-pyrrolidinylcarbamate (480 mg, 1.65 mmol), followed by adding thereto 4N-hydrogen chloride/dioxane (6.0 ml, 24 mmol), and the resulting mixture was stirred overnight at room temperature. After completion of the reaction, diethyl ether (35 ml) was added to the reaction solution, and the resulting mixture was stirred at room temperature for 30 minutes and the precipitate was collected by filtration. The precipitate was washed with diethyl ether and dried to obtain 4-amino-1-benzyl-2-pyrrolidinone hydrochloride (380 mg, 99%).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=1)[CH2:3][CH3:4].O.NN>>[CH3:1][CH:2]([O:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Product: CCC(C)Oc1ccc(OCCN)cc1

Procedure:
To 4-(1-methylpropoxy)phenol (44.3 mmol) in 25 ml of DMF is added, under N2, potassium carbonate (51.0 mmol) followed by dropwise addition of N-(bromoethyl)phthalimide (51.0 mmol) in 30 ml of DMF. The mixture is stirred at RT overnight. Water is then added and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% sodium hydroxide, with water and with brine, dried and the solent removed to give N-{2-[4-(1-methylpropoxy)phenoxy]ethyl}phthalimide. Following the procedures of Example 7, the above phthalimide (5.7 mmol) is reacted with hydrazine hydrate (5.7 mmol) to give 2-[4-(1-methylpropoxy)phenoxy]ethylamine.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[C:14]([F:16])[C:13]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[C:12]([F:33])[CH:11]=1>>[CH3:31][C:30]1[C:25]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([C:13]3[C:14]([F:16])=[CH:15][C:10]([N:7]4[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:11][C:12]=3[F:33])=[O:18])[CH2:20][CH2:21]2)=[N:26][CH:27]=[C:28]([CH3:32])[CH:29]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CC[C@H](CO)N1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4C(=O)CC[C@@H]4CO)cc3F)CC2)c(C)c1
Yield: 47.3 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (116 mg) and (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 111 and by the reaction and treatment in the same manner as in Example 1, the title compound (210 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]=[O:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[C:19]([CH3:25])[CH:18]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=1[CH3:25])[OH:15]
Reactant: Cn1nc(-c2ccccn2)c(C=O)c1Cl
Reactant: Cc1cc(Cl)ccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(O)c1c(-c2ccccn2)nn(C)c1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazole-4-carbaldehyde (16.38 g, 73.9 mmol) in THF (350 mL) was cooled to about −40 to −50° C. then 0.5 M (4-chloro-2-methylphenyl)magnesium bromide in THF (163 mL, 81 mmol) was added dropwise over about 15 min. The mixture was allowed to warm to rt then cooled in an ice bath. Saturated aqueous NH4Cl (400 mL) was added then the mixture was extracted with EtOAc (2×300 mL). The organic layer was washed by brine (400 mL), dried over Na2SO4, filtered and concentrated in vacuo to give (5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)(4-chloro-2-methylphenyl)methanol (25.7 g, 100%): LC-MS (Table 1, Method g) Rt=2.49 min, m/z 348/350 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.56 (d, J=5.0 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.96-7.90 (m, 1H), 7.40-7.36 (m, 1H), 7.22-7.16 (m, 3H), 7.09-7.05 (m, 1H), 6.23 (d, J=7.8 Hz, 1H), 3.87 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:8]1=[O:22].C([Li])(CC)C.[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br.O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:40][C:39]2[CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=[C:37]([C:36]([F:35])([F:49])[F:50])[CH:38]=2)([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:8]1=[O:22]
Reactant: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)C2=O)cc(OC)c1OC
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine (0.31 g, 0.74 mmol) and tetrahydrofuran (2 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyllithium (0.63 mL, 1.3 M in hexane, 0.81 mmol). After 30 minutes, add a solution of 3,5-di(trifluoromethyl)benzyl bromide (0.25 g, 0.81 mmol) in tetrahydrofuran (1 mL). After 2 hours, warm to ambient temperature. After 12 hours, add water (10 mL). Separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/4 ethyl acetate/hexane to give the title compound: Rf=0.44 (silica gel, 1/4 ethyl acetate/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH2:12][Mg+].[Br-].B(F)(F)F.CCOCC>CCOCC>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]1([NH2:5])[CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CC[Mg+]
Agent: FB(F)F
Agent: [Br-]
Solvent: CCOCC
Product: NC1(c2ccc(F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a stirred solution of 2-bromo-4-fluorobenzonitrile (5 g, 25 mmol) and Ti(Oi-Pr)4 (9.05 mL, 27.5 mmol) in ether (100 mL) at −78° C. was added EtMgBr (18.3 mL, 55 mmol) dropwise. The solution was allowed to warm to room temperature and stirred for 1 hour before BF3-Et2O (6.25 mL) was added and stirring continued at room temperature for another 1 hour. The reaction solution was quenched with 1 N HCl solution, and washed with EtOAc. The aqueous layer was adjusted to pH˜10 with aq. NaOH (2 N) solution and then exacted with EtOAc (3×). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by column chromatography to give title compound (3.0 g, yield 52.2%) as yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:12][CH2:13]OCC2C=CC=CC=2)=[O:10])=[CH:4][CH:3]=1.Br.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)N(CCOCc1ccccc1)Cc1cccnc1
Agent: Br
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1N(Cc2cccnc2)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To 5.81 g (14.7 mmol) of N-(4-chlorophenyl)-N'-(3-pyridylmethyl)-N'-2-(benzyloxy)ethyl urea in a 100 ml round-bottomed flask were added 65 ml of 48% hydrobromic acid at room temperature. The mixture was heated gradually and then heated for 4 hours at 95° to 100° C. The reaction mixture was cooled to room temperature, 20 ml of water were added, and further 50 ml of ethyl acetate were added to extract. The ethyl acetate layer was extracted with 30 ml of 6N hydrochloric acid, which was combined with previous aqueous layer. While cooling this with ice, pH was made to be 12 or higher with potassium hydroxide and extracted thrice with 100 ml of methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and then solvent was distilled off under reduced pressure to obtain 2.28 g (yield 54%) of 1-(4-chlorophenyl)-3-(3-pyridylmethyl)-2-imidazolidinone as brown crystals.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]([N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[N:15]=[C:16]([C:28]#[N:29])[C:17](C#N)=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8]1)([CH3:6])[CH3:5].Cl.O>CO.C(Cl)(Cl)Cl>[CH:4]([N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[N:15]=[C:16]([C:28]#[N:29])[C:17]([O:2][CH3:1])=[N:18][C:19]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:8]1)([CH3:5])[CH3:6]
Reactant: C[O-]
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COc1nc(-c2ccccc2)c(-c2ccc(=O)n(C(C)C)n2)nc1C#N
Temperature: 27.5 °C
Reaction time: 10 h
Yield: 24.6 %

Procedure:
To a solution of sodium methoxide (81.5 mg) in MeOH (3 ml), 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile (172 mg) was added and the mixture was stirred at 25-30° C. for 10 hours. After addition of conc. HCl (1.5 ml), the reaction mixture was stirred at 25-30° C. for 20 hours. Water and CHCl3 were added to the mixture. An organic layer was collected, dried over MgSO4, concentrated under reduced pressure and subjected to column chromatography on silica gel. With elution of a mixture of n-hexane and EtOAc (70:30 v/v) was obtained 6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-methoxy-5-phenyl-2-pyrazinecarbonitrile as a solid (43 mg) and with elution of a mixture of n-hexane and EtOAc (50:50 v/v) was obtained methyl 6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-methoxy-5-phenyl-2-pyrazinecarboxylate as a solid (67 mg).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C@H:8]([CH3:24])[C@@H:9]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C@@H:10]([CH3:13])[CH:11]=O)([CH3:4])[CH3:3].Br[CH:28]([Si](C)(C)C)[CH:29]=[CH2:30].CO.[OH-].[K+]>C1COCC1>[CH3:1][C:2]([Si:5]([O:6][CH2:7][C@H:8]([CH3:24])[C@@H:9]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C@@H:10]([CH3:13])/[CH:11]=[CH:30]\[CH:29]=[CH2:28])([CH3:26])[CH3:25])([CH3:4])[CH3:3]
Reactant: C=CC(Br)[Si](C)(C)C
Reactant: COc1ccc(CO[C@@H]([C@@H](C)C=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A suspension consisting of CrCl2 (12.93 g, 105.38 mmol) and 700 mL anhydrous THF is cooled to 0° C. 2,4-dideoxy-5-O-[(1,1-dimethylethyl)dimethylsilyl]-3-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-lyxose (8.9 g, 23.42 mmol) in 40 mL THF is added dropwise. (1-Bromoallyl) trimethylsilane (22.61, 117.1 mmol) is added neat. After 3 h at room temperature, the reaction mixture is cooled to 10° C. Methanol (270 mL) and 6 N aqueous KOH (550 mL) are added in sequence, keeping the reaction temperature less than 20° C. during the addition. The mixture is stirred overnight at room temperature. The organic layer is separated. The aqueous layer is extracted with ether (3×400 mL). The combined organic phase is washed with brine, dried over NaSO4, and concentrated. Flash chromatography gives the desired compound (6.74 g, 71.2%) as a clear oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][N:11]=[C:10]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O1CCOCC1>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
To the suspension of ethyl 4-(cyclohexylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.77 g, 1.9 mmol) in 1,4-dioxane (12 mL) was added aquoeous NaOH (1 N, 12 mL, 12 mmol). The mixture was stirred at rt for about 48 h. To the mixture was added EtOH (1 mL) and the mixture was heated at about 50° C. for about 24 h. The mixture was concentrated under reduced pressure and aqueous HCl (0.5 M, 10 mL) was added and the mixture extracted with EtOAc (25 mL). The solid in the organic layer was collected by vacuum filtration. The filtrate and aqueous layer were recombined and separated. The solid was dissolved in EtOAc (˜150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo and dried under reduced pressure at about rt to give 4-(cyclohexylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.713 g, 99%): LC/MS (Table 2, Method b) Rt=2.74 min.; MS m/z: 390 (M+H)+.