Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]#[N:5].[N:21]([Sn](CCCC)(CCCC)CCCC)=[N+:22]=[N-:23].[ClH:37]>C(OCC)C>[ClH:37].[CH3:1][N:2]([CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4]1[NH:23][N:22]=[N:21][N:5]=1
Reactant: CN(CC#N)CCC(c1ccccc1)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Product: CN(CCC(c1ccccc1)c1ccccc1)Cc1nnn[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A mixture of 0.132 g (0.5 mmol) N-methyl-N-cyanomethyl-3,3-diphenylpropylamine (from step 2) and 0.183 g (0.55 mmol) azidotributyltin (Aldrich) was stirred at 80° C. under argon for 16 hours. The reaction mixture was suspended with 1 M solution of hydrogen chloride in diethyl ether (Aldrich) and the precipitated yellow wax was purified by preparative TLC with 10% methanol in ethyl acetate to give 0.06 g (yield 35%) N-methyl-N-[(1H-tetrazol-5-yl)methyl]-3,3-diphenylpropylamine hydrochloride (Compound A146)as a white powder. 1H NMR (DMSO-d6, 300 MHz) 7.30-7.16(m, 10H),4.11 (s, 2H), 3.97 (t, I H), 2.60 (br. s, 2 H), 2.45 (s, 3H), 2.36 (br. s, 2H).
Reaction SMILES: [Cl:1][C:2]1([Cl:21])[CH2:4][C:3]1([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][CH:6]=1.C(Cl)(Cl)Cl.N1C=CC=CC=1.I[Si](C)(C)C>CCOCC.C(Cl)Cl.CC(C)=O>[Cl:1][C:2]1([Cl:21])[CH2:4][C:3]1([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: COc1ccc(C2(c3ccc(OC)cc3)CC2(Cl)Cl)cc1
Agent: C[Si](C)(C)I
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: Oc1ccc(C2(c3ccc(O)cc3)CC2(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Placed in an oven-dried, three-necked flask was 1.615 g (5 mMol) of 1,1-dichloro-2,2-Bis-(p-methoxyphenyl) cyclopropane which was flushed with argon and sealed with a rubber septum. Using oven-dried syringes, 10 ml of chloroform, 0.32 g (4 mMol) of pyridine and 2.9 ml (20 mMol) of iodotrimethylsilane were injected into the flask in the order specified above (the chloroform and pyridine had been dried previously over anhydrous magnesium sulfate). The mixture turned yellow and a white precipitate was noted with the addition of iodotrimethylsilane. The mixture was heated to reflux without stirring for 72 hours. Thin layer chromatography was performed with methylene chloride and a small amount of starting material still was present. Anhydrous methanol, dried with magnesium sulfate, in the amount of 2.5 ml was added and the mixture turned golden brown. It was cooled to room temperature and transferred to a round bottom flask with 10 ml of chloroform. The volatile components were removed on a rotary evaporator to yield a yellow solid which was dissolved in 50 ml of ether. The insoluble pyridium hydrochloride was filtered. The ether was evaporated to afford a yellow solid whose NMR and thin layer chromatography (with methylene chloride-acetone (95:5)) showed starting material along with some polar components. These components were separated by column chromatography on silica gel (125 g) with methylene chloride-acetone (95:5) as eluent. Unreacted starting material was eluted first and 0.4 g was recovered. Compound 1,1-dichloro-2-(p-methoxyphenyl)-2-(p-hydroxyphenyl) cyclopropane was eluted next and recrystallized in hexane with trace of ethanol to give colorless fine needles. The column was then washed with acetone, and compound 1,1-dichloro-2,2-Bis-(p-hydroxyphenyl) cyclopropane as a red brown solid was obtained upon evaporation of the solvent. This solid was recrystallized in chloroform to give a light pink solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:20]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cccc(I)c1
Solvent: Cc1ccccc1
Product: NC(=S)c1cccc(I)c1
Yield: 98.8 %

Procedure:
A mixture of 3-iodobenzamide (500 mg, 2.0 mmol) in toluene (5 mL) was treated with Lawesson's reagent (404 mg, 1 mmol) and the mixture heated at reflux for 1.6 hours. After cooling, silica gel chromatography afforded 260 mg (99% yield) of 3-iodothiobenzamide, as a yellow solid.
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[NH2-].[Na+].C1(C)C=CC=CC=1.Cl[CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1>O>[CH:16]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1)[C:8]#[N:9])([CH3:18])[CH3:17]
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)(CCN1CC2CCC(CC2)C1)c1ccccc1)C(C)C

Procedure:
A solution of 16 parts of α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 5 parts of sodium amide in 200 parts by volume of toluene is heated to about 100° C. over a period of 15 minutes and then 20 parts of 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane in 100 parts by volume of toluene is added slowly over a period of 20 minutes. This mixture is heated at 105°-110° C. for an hour and then cooled to room temperature when 200 parts by volume of water is added. The organic layer is separated, dried over calcium sulfate, concentrated, and then distilled to afford 2-[2-(diisopropylamino)ethyl]-2-phenyl-4-(3-azabicyclo[3.2.2]non-3-yl)butyronitrile, as an oil. This compound is represented by the following structural formula ##STR16##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[C:18](=[O:19])[N:17]4[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:16]4=[N:15][CH:14]=3)=[N:9]2)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Br.[CH:42]([C:45]1[N:46]=[C:47]([NH2:50])[S:48][CH:49]=1)([CH3:44])[CH3:43].Cl>CN(C)C=O>[CH:42]([C:45]1[N:46]=[C:47]([NH:50][C:24]([C:22]2[CH:21]=[CH:20][N:17]3[C:18](=[O:19])[C:13]([C:10]4[N:11]=[N:12][N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=5)[N:9]=4)=[CH:14][N:15]=[C:16]3[CH:23]=2)=[O:25])[S:48][CH:49]=1)([CH3:44])[CH3:43]
Reactant: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)O)ccn4c3=O)n2)cc1
Reactant: CC(C)c1csc(N)n1
Agent: Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnc(-c3cnc4cc(C(=O)Nc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
3-[2-(4-Methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4-oxo-4H-pyrido[1,2-a]-pyrimidine-8-carboxylic acid (250 mg, 0.66 mmol) was dissolved in dimethylformamide (6 ml), added with N,N-carbonylbis-1H-imidazole (abbreviated as “CDI” hereinafter, 160 mg, 0.991 mmol) and heated to 90° C. with stirring. After 1 hour and 30 minutes, the reaction solution was further added with CDI (170 mg), further stirred for 1 hour, and then further added with CDI (170 mg). The reaction solution was stirred further 2 hours, then returned to room temperature, added with 4-isopropyl-1,3-thiazol-2-amine hydrobromide (1.32 mmol) and stirred at room temperature for 2 hours and 30 minutes. The reaction solution was added with 2 N hydrochloric acid (7 ml), and the deposited crystals were collected by filtration and washed with water. The resulting yellow crystals were dissolved in chloroform and washed with saturated brine, and the collected organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound as yellow crystals without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].C(N(CC)C(C)C)(C)C.OC(C(F)(F)F)=O.[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]([CH3:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([C:50](O)=[O:51])=[CH:46][N:45]=2)[CH2:39][C@@H:38]1[CH3:53])=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]([CH3:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([C:50](=[O:51])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][C:10]([F:12])([F:11])[F:13])[CH:4]=3)=[CH:46][N:45]=2)[CH2:39][C@@H:38]1[CH3:53])=[O:36])([CH3:31])([CH3:32])[CH3:33]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Br)c(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(=O)Nc2ccc(Br)c(OC(F)(F)F)c2)cn1
Temperature: 50 °C
Yield: 36.5 %

Procedure:
To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (190 mg, 0.74 mmol) and N,N-diisopropylethylamine (0.65 mL, 3.73 mmol; in N,N-dimethylacetamide (3 mL) was added a solution of (2S,5R)-4-(5-carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester TFA (330 mg, 0.74 mmol; Preparation 26) and HCTU (401 mg, 0.97 mmol) in N,N-dimethylacetamide (3 mL). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated by rotary evaporation, extracted with ethyl acetate/sat. sodium carbonate, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (0-50% ethyl acetate:hexanes) to provide the title compound (155 mg, yield 36%). (m/z): [M+H]+ calcd for C24H28BrF3N4O4 573.12, 575.12 found 575.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][CH:10]=O.C(=O)(O)[O-].[Na+].C(O)C>O>[N:1]1[CH:9]=[CH:10][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: O=CCCl
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccn2ccnc2c1

Procedure:
A mixture of 47 g. of 2-aminopyridine, 120 g. of a 45% chloroacetaldehyde solution in water and 50.4 g. of sodium bicarbonate in 400 ml. of anhydrous ethanol and 100 ml. of water is heated to reflux for 3 hrs. The reaction mixture is cooled, treated with 900 ml. of water and extracted with diethyl ether (3 × 700 ml.). The combined extracts are dried over sodium sulfate and concentrated to a brown oil. Distillation gives 18.8 g. of the desired intermediate as a light yellow oil, b.p. 70° C./0.02 mm.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:27]=[C:26]([N:1]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1)[CH2:28][C:29]#[N:30]
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Reactant: c1nc(N2CCCC3(CCCN3)C2)c2cc[nH]c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 110 °C
Reaction time: 1.25 h
Yield: 84.6 %

Procedure:
4-(1,7-Diazaspiro[4.5]dec-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (30 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (38 mg), N,N-diisopropylethylamine (42 μl) and 1,4-dioxane (1 ml), and the mixture was stirred at 110° C. for 75 minutes. The mixture was cooled to room temperature, and then thereto was added saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/2, followed by chloroform/methanol=25/1 to 20/1) to give the titled compound (32 mg).
Reaction SMILES: N.[C:2]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([O:16]C)[CH:12]=[CH:11]2)(=[O:4])[CH3:3].C(O)(C)(C)C.[Na].[Cl-].[Na+]>C(O)(=O)C.C1COCC1>[C:2]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)(=[O:4])[CH3:3]
Reactant: COc1ccc2cccc(NC(C)=O)c2c1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c1CC(=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
Ammonia (300 mL) was condensed in a flask containing 8-Acetamido-2-methoxynaphthalene (24.5 g, 115 mmol), t-butyl alcohol (34 g, 0.46 mol) and THF (300 mL). Sodium (8 g, 0.35 mol) was added in portions and the mixture was stirred for 3 h and allowed to warm to room temperature. The mixture was poured onto ice and saturated sodium chloride, and then extracted with THF (3×). The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give a dark solid. The residue was dissolved in 50% acetic acid and heated at 95° C. for 18 h. After evaporation, the residue was suspended in dimethyl ether and collected by filtration and dried. The filtrate was purified by silica gel chromatography (3:2 EtOAc:hexane) and combined with the other product to give a tan solid (10 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[CH2:16][N:15]([C@H:22]1[C@H:27]([OH:28])[CH2:26][CH2:25][O:24][CH2:23]1)[C:14]2=[O:29])[C:5]#[N:6].C(=O)([O-])[O-:31].[K+].[K+].OO>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[CH2:16][N:15]([C@H:22]1[C@H:27]([OH:28])[CH2:26][CH2:25][O:24][CH2:23]1)[C:14]2=[O:29])[C:5]([NH2:6])=[O:31]
Reactant: Cc1c(Cc2ccc(C#N)cc2F)cc2c(c1C)CN([C@@H]1COCC[C@H]1O)C2=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(Cc2ccc(C(N)=O)cc2F)cc2c(c1C)CN([C@@H]1COCC[C@H]1O)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
To a mixture of rac-3-fluoro-4-((2-(trans-4-hydroxytetrahydro-2H-pyran-3-yl)-6,7-dimethyl-3-oxoisoindolin-5-yl)methyl)benzonitrile (0.08 g) and potassium carbonate (0.08 g) in DMSO (2.00 mL) was added 35% aqueous hydrogen peroxide (0.17 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate-THF. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (0.07 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([N+]([O-])=O)[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[OH2:23]>[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:16][C:17](=[O:23])[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(C=C(C)[N+](=O)[O-])ccc1Oc1ccccc1
Reactant: O
Agent: [Fe]
Agent: Cl
Product: COc1cc(CC(C)=O)ccc1Oc1ccccc1
Yield: 80 %

Procedure:
953 mg of 1-(3-methoxy-4-phenoxyphenyl)-2-nitropropene, 1.31 g of iron, 9.5 mg of ferric chloride and 5 ml of water were mixed, and 1.5 ml of 6N hydrochloric acid was dropwise added over a period of 1.5 hours under reflux and heating. The reaction solution was subjected to celite filtration, and the filtrate was extracted with ethyl acetate. The extract solution was washed with a saturated sodium hydrogen carbonate aqueous solution and then, dried over anhydrous sodium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain 688 mg (yield: 80%) of the above identified compound as a colorless oily substance.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:38][NH:39]2)C1C=CC=CC=1)C>>[NH:17]1[C:18]2[C:14](=[C:13]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([NH:39][CH3:38])=[O:3])[CH:21]=[CH:20][CH:19]=2)[CH:15]=[N:16]1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]ncc12
Product: CNC(=O)C=C(c1ccccc1)c1cccc2[nH]ncc12

Procedure:
3-(1H-Indazol-4-yl)-N-methyl-3-phenyl-acrylamide CXCII was prepared from 3-(1H-indazol-4-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:26])[CH:6]=[CH:5][C:4]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1.[Br:33]N1C(=O)CCC1=O>C(#N)C>[Br:33][C:6]1[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)=[N:13][C:12]=2[CH3:26])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:27]2[NH:31][C:30](=[O:32])[O:29][N:28]=2)[CH:5]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1-c1noc(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c(Br)cc1-c1noc(=O)[nH]1
Temperature: 70 °C
Yield: 29.9 %

Procedure:
To a solution of 100 mg of 3-{2-methoxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one in 1 ml of acetonitrile was added 0.08 g of N-bromosuccinimide. The resulting mixture was heated to 70° C. overnight, concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 94/6) and washed with 94/6 dichloromethane/methanol to give 35 mg of 3-{5-bromo-2-methoxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.B.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2c(F)ccc(Br)c2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(Br)c2c1CN(Cc1ccccc1)CCO2
Temperature: 60 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
To a solution of 4-benzyl-9-bromo-6-fluoro-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (1.40 g, 4.00 mmol) in tetrahydrofuran (30 ml) was added under ice-cooling 1M borane tetrahydrofuran solution (16.0 ml, 16.0 mmol), and the mixture was stirred at 60° C. for 3 hr. Under ice-cooling, methanol (20 ml) and sodium hydroxide (1.60 g, 40.0 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure. The residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (350 mg, 26.1%) as an oily substance.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([CH3:11])[C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].C([Mg]Cl)(C)C.I[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH:35]([CH3:37])[CH3:36])=[N:33][N:34]=2)[N:31]=1>C1COCC1.CN(C=O)C.[Cl-].[Zn+2].[Cl-].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.[O-]S([O-])(=O)=O.[Zn+2]>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[N:9][CH:8]=[CH:7][N:6]2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH:35]([CH3:37])[CH3:36])=[N:33][N:34]=2)[N:31]=1
Reactant: Cc1nccn2c(Br)c(-c3ccc(F)cc3F)nc12
Reactant: CC(C)c1nnc2ccc(I)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nccn2c(-c3ccc4nnc(C(C)C)n4n3)c(-c3ccc(F)cc3F)nc12
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
In a dry three-neck flask, 3-bromo-2-(2,4-difluorophenyl)-8-methylimidazo[1,2-a]pyrazine (1.00 g, 3.09 mmol, prepared using General Procedure C.1 from 2-(2,4-difluorophenyl)-8-methylimidazo[1,2-a]pyrazine (prepared according to WO 2007/028051, Preparation #K.1) with NBS) was dissolved in THF (10 mL) under an atmosphere of nitrogen. The reaction mixture was cooled to about −30° C. and then i-PrMgCl (2.0 M in THF, 1.90 mL, 3.80 mmol) was added drop-wise. The reaction mixture was stirred at about −30° C. for about 15 min. In a separate dry flask, zinc chloride (0.57 g, 4.2 mmol) was dissolved in THF (5 mL) and cooled to about 0° C. The zinc chloride solution was added dropwise to the heteroaryl Grignard mixture. The reaction mixture was stirred at about −15° C. for about 30 min. A flask containing 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.85 g, 2.9 mmol; Preparation #H.1) and Pd(Ph3P)4 (0.14 g, 0.12 mmol, Strem) in DMF (10 mL) was stirred at about 80° C. until all of the solids were in solution. This solution was poured into the zincate suspension and the mixture was immediately heated to about 50° C. in an oil bath. After heating at about 50° C. for about 18 h, the mixture was cooled to ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 mL), washed with water (5×100 mL), washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography using DCM/MeOH (gradient, 100:0 to 95:5) as eluent. The solid was then dissolved with heating in MeOH, sonicated, concentrated under reduced pressure to dryness under reduced pressure, then dried in a heated vacuum oven (about 60° C.) to afford a cream solid as the title compound (0.37 g, 29%): LC/MS (Table 1, Method a) Rt=2.85 min; MS m/z: 406.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[NH:18][N:19]=[C:20]4[CH2:25][CH2:24][NH:23][CH2:22][C:21]=34)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[C:26]([N:23]1[CH2:24][CH2:25][C:20]2=[N:19][NH:18][C:17]([CH2:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)=[C:21]2[CH2:22]1)(=[O:28])[CH3:27]
Reactant: Fc1ccc(N2CCN(CCCc3[nH]nc4c3CNCC4)CC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2n[nH]c(CCCN3CCN(c4ccc(F)cc4)CC3)c2C1

Procedure:
3-(3-(4-(4-Fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (0.3 g) obtained in Example 141 was dissolved in a mixed solution of chloroform (5 ml) and saturated aqueous sodium hydrogencarbonate solution (5 ml), and acetyl chloride (0.3 ml) was added dropwise under ice-cooling. After the dropwise addition, the chloroform layer was partitioned and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give 5-acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.