Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][NH:3]1.[H-].[Na+].[CH2:14](I)[CH3:15].O>CN(C=O)C>[CH2:14]([N:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:7][C:2]1=[O:1])[CH3:15]
Reactant: COC(=O)c1ccc(=O)[nH]c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)OC)ccc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
Methyl 2-oxo-1,2-dihydropyridine-5-carboxylate (400 mg, 2.61 mmol) obtained in Step 3 was dissolved in DMF (3 mL), and 55% sodium hydride (125 mg, 2.87 mmol) and ethyl iodide (0.230 mL, 2.87 mmol) were added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford methyl 1-ethyl-2-oxo-1,2-dihydropyridine-5-carboxylate (375 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Reaction time: 4 h
Yield: 65 %

Procedure:
A solution of 2-amino-3-chlorobenzoic acid (7.0 g, 0.041 mol) in anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) was cooled to 0° C. in a 250 mL 3-necked flask which was fitted with a magnetic stirring bar and a constant additional funnel. Bromoacetyl bromide was added dropwise over a 27 min period while keeping the internal temperature between 0° C. and 2° C. After the addition was complete, the ice-bath was removed and stirring was continued for 4 h. The reaction mixture was cooled using an ice-bath, water (100 mL) was added, and then the yellow precipitate which formed was filtered. The filtered solid was washed with water and then dried in a vacuum oven for 2 days, yielding 7.7 g (65%) of the title compound as a light yellow crystals: mp 173°-175° C.; 1H NMR (CD3OD) δ7.88 (dd, 1H, J=1.6, J=6), 7.68 (dd, 1H, J=1.2, J=6.8), 7.39 (t, 1H, J=8), 6.6 (bs, 1H, NH), 4.06 (s, 2H); 13C NMR (CD3OD) δ176.57, 168.38, 134.84, 134.40, 131.95, 130.53, 129.15, 129.05, 28.66; MS (EI, m/z) 293 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:10][CH2:9]2)=[C:4]([Cl:25])[CH:3]=1.[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30].C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:25][C:4]1[CH:3]=[C:2]([NH:1][C:29]([C@@H:28]2[CH2:32][CH2:33][CH2:34][N:27]2[CH3:26])=[O:30])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1C(=O)Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from example 120 step (ii) (0.1 g), N-methyl-L-proline (0.044 g), N,N-diisopropylethylamine (0.17 ml), 1-hydroxybenzotriazole (0.043 g), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.103 g) in N,N-dimethylformamide (3 ml) were stirred at room temperature overnight then partitioned between ethyl acetate and water. The organic layer was washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 4% methanol/dichloromethane. Yield 0.038 g.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[OH-].[K+].[CH3:25]I>CC(C)=O>[CH3:25][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3ccccc3[nH]2)CC1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The tert-butyl 4-(1H-benzimidazol-2-yl)piperidine-1-carboxylate (50.0 mg, 0.166 mmol) was dissolved in 2 mL of acetone with freshly ground potassium hydroxide (46.4 mg, 0.830 mmol). The mixture was stirred for 10 minutes at ambient temperature, and then methyl iodide (11.4 μL, 0.183 mmol) was added. After 10 minutes, the reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL). The sample was diluted with EtOAc (3×30 mL), washed with water (2×20 mL), and washed with brine (2×20 mL). The organic layer was dried over sodium sulfate, filtered, concentrated to give tert-butyl 4-(1-methyl-1H-benzimidazol-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Br:15]Br>ClCCl>[Br:15][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH:7]=1
Reactant: BrBr
Reactant: Cc1ccc(C)c(SCCC(=O)O)c1
Solvent: ClCCl
Product: Cc1cc(SCCC(=O)O)c(C)cc1Br
Temperature: 5 °C
Yield: 99 %

Procedure:
25.23 g (0.12 mol) of the title compound of Example 1, Step A was dissolved in 250 mL of dichloromethane and cooled to 5° C. A solution of 19.12 g (0.12 mol) of bromine in 25 mL of dichloromethane was added dropwise over 45 minutes, keeping the reaction temperature at 5° C. The reaction was then allowed to warm to room temperature, diluted with 200 mL of dichloromethane and washed twice with 400 mL of water. The organice layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 34.35 g of the title compound of step A as a white solid melting at 105-107° C. 1H NMR (CDCl3): δ2.33 (s,3H), 2.34 (s, 3H), 2.67 (t, 2H), 3.10 (t, 2H), 7.18 (s, 1H), 7.36 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15](=O)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][Br:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO.[H][H]>C1COCC1>[Br:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][CH2:15][N:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)[CH:24]([CH3:26])[CH3:25]
Reactant: [H][H]
Reactant: CC(C)N(C(=O)CCOCCCBr)C1CCN(Cc2ccccc2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N(CCCOCCCBr)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a stirred solution of N-(1-benzylpiperidin-4-yl)-N-isopropyl 3-(bromopropoxy)propionamide (28.2 g, 66 mmol) in THF (300 mL) was added BH3-THF (100 mL, 2.0 M in THF, 200 mmol) and the reaction mixture was refluxed for 48 h. The reaction mixture was then allowed to cool to room temperature and methanol was added dropwise until evolution of hydrogen gas stopped. The mixture was then concentrated under reduced pressure and dissolved in dichloromethane (500 mL). The reaction mixture was washed with 1 N hydrochloride acid (500 mL) and the organic layer removed. The aqueous layer was then made basic to pH 12 using 1 N sodium hydroxide and extracted with dichloromethane (500 mL). The combined organic layers were washed with water (400 mL), brine (400 mL), dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The resulting crude product was purified by silica gel chromatography (dichloromethane/methanol/aqueous ammonia: 9/0.5/0.05) to afford 20.5 g of the title intermediate (76% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](C=O)=[C:14]([CH:18]([CH3:20])[CH3:19])[N:13]=[C:12]([O:21][CH3:22])[C:11]=2[CH2:23][O:24][CH3:25])=[CH:6][CH:5]=1.O.O.C(O)(=O)C(O)=O.[O:34]1C[CH2:37][CH2:36][CH2:35]1>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](/[CH:37]=[CH:36]/[CH:35]=[O:34])=[C:14]([CH:18]([CH3:20])[CH3:19])[N:13]=[C:12]([O:21][CH3:22])[C:11]=2[CH2:23][O:24][CH3:25])=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: COCc1c(OC)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCc1c(OC)nc(C(C)C)c(/C=C/C=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
804 (3.1 mmol) of diethyl 2-(cyclohexylamino)-vinyl-phosphate dissolved in 6 ml of dry tetrahydrofuran are added dropwise under nitrogen to a suspension of 59 mg (2.5 mmol) of sodium hydride in 6 ml of dry tetrahydrofuran at -5° C. After 30 min, 0.65 g (2.05 mmol) of the compound from Example 9 in 15 ml of dry tetrahydrofuran is added dropwise at the same temperature and the mixture is heated to reflux for 30 min. After cooling to room temperature, the mixture is added to 200 ml of ice-cold water and extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. After concentration in vacuo, the residue is taken up in 5 ml of toluene, treated with a solution of 0.9 g (7 mmol) of oxalic acid dihydrate in 12 ml of water and heated to reflux for 90 min. After cooling to room temperature, the phases are separated, and the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is dissolved in methylene chloride and filtered through silica gel.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH:23]=O)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51](Br)(Br)([Br:53])[Br:52]>O>[Br:52][C:51]([Br:53])=[CH:23][CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:27])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:25][CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCC(CC=C(Br)Br)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (300 mg, 0.0008 mol) in DCM (4 mL, 0.06 mol) cooled at 0° C., triphenylphosphine (800 mg, 0.003 mol) and carbon tetrabromide (500 mg, 0.002 mol) were added. The reaction was stirred at 0° C. for 10 min, water was added and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by prep LC-MS (ACN, water, NH4OH) to give 4-[1-(4,4-dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as an amorphous solid (50 mg, 10%). 1H NMR (400 MHz, CDCl3): δ 8.9 (s, 2H), 8.4 (s, 1H), 8.3 (s, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 6.9 (m, 1H), 6.4 (m, 1H), 5.7 (s, 2H), 4.2 (m, 1H), 3.6 (m, 2H), 2.8 (m, 2H), 2.1 (m, 1H), 2.0 (m, 1H), 1.0 (m, 5H), LC/MS (M+H)+: m/z=556
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17]([O:20][CH2:21][CH2:22]O)[C:18]#[CH:19].C(N(CC)CC)C>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16][CH2:22][CH2:21][O:20][CH2:17][C:18]#[CH:19])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C#CCOCCO
Reactant: O=C(O)COc1ccc(Cl)c2cccnc12
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: C#CCOCCOC(=O)COc1ccc(Cl)c2cccnc12
Yield: 16.4 %

Procedure:
5.0 g (0.021 mol) of 5-chloroquinolin-8-oxyacetic acid are heated at 70° C. in 70 ml of thionyl chloride for one hour. The excess thionyl chloride is then distilled off in vacuo and the residue is suspended in 150 ml of carbon tetrachloride. 2.10 g (0.021 mol) of 2-propargyloxyethanol are added dropwise to this suspension, 2.30 g (0.023 mol) of triethylamine are then added dropwise and the mixture is heated under reflux for 12 hours. The suspension is then washed with in each case 70 ml of 2N HCl and 5 percent strength sodium hydroxide solution, the organic phase is dried over magnesium sulfate and the solvent is stripped off in vacuo. The residue is recrystallized from n-heptane. 1.1 g (16.3% of theory) of 2-(propargyloxy)ethyl 5-chloroquinolin-8-oxyacetate of melting point 53° C. are thus obtained.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.OO.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:18]>>[N:1]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N+:8]2([O-:18])[CH3:9])[CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCCC1c1cccnc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OO
Product: C[N+]1([O-])CCCC1c1cccnc1
Temperature: 80 °C

Procedure:
500 g of nicotine (3.08 mol) are slowly added dropwise to an equimolar 30% hydrogen peroxide solution containing 5.9 g of citric acid (30.8 mmol), the temperature being maintained below 90° C. After the addition has ended, the mixture is heated at 80° C. for 5 hours.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11].[OH-].[Na+]>CO>[CH3:9][CH2:8][CH2:7][CH2:6][C:3]([CH2:10][OH:11])([CH2:4][OH:5])[CH2:1][CH3:2]
Reactant: C=O
Reactant: CCCCC(C=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(CC)(CO)CO

Procedure:
BEPD was prepared by a semi-batch process out of 2-ethylhexanal (2-EH), having a purity of over 90 weight-%, and formaline. The concentration of the formaline aqueous solution was 37 weight-% HCHO and it contained 10 weight-% CH3OH. First, 1207 g (9.225 moles) of 2-EH and 1911 g (23.546 moles) of HCHO were fed into the reactor to make up the reaction mixture, after which 927 g (11.125 moles) in total of sodium hydroxide was fed into the reaction mixture. The concentration of the sodium hydroxide aqueous solution was 48 weight-%, and it was fed for 6 hours at three input rates, namely 93 g/h (1.1161 moles per hour) during the first hour of the reaction (beginning at time T1), 135 g/h of NaOH (1.6201 moles/h; beginning at time T2) during the following two hours and, finally, 188 g/h (2.2562 moles/h; beginning at time T3) during the third to the 6th hour.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]2[CH:38]3[CH:33]([CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:32][CH2:31]2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([N:30]5[CH:38]6[CH:33]([CH2:34][CH2:35][CH2:36][CH2:37]6)[CH2:32][CH2:31]5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: O=C(c1cc(Cl)ncn1)N1CCC2CCCCC21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCC5CCCCC54)ncn3)CC1)C(=O)N2

Procedure:
705 mg (2.56 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 680 mg (2.56 mmol) (6-chloro-pyrimidin-4-yl)-(octahydro-indol-1-yl)-methanone and 0.871 mL (5 mmol) DIPEA were stirred in 10 mL DMF for 2 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and the ACN was eliminated by rotary evaporation. The aqueous phase was made alkaline with 4M NaOH and extracted with EtOAc. The organic phase was dried, filtered and the filtrate was concentrated to dryness by rotary evaporation. The residue was crystallised from a mixture of MeOH and diethyl ether and the solid was suction filtered and dried.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:4]1)[CH3:2].[H-].[Na+].[CH3:22][O:23][CH2:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]=[C:27]1S(C)(=O)=O.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:27]3[N:26]([CH2:25][CH2:24][O:23][CH3:22])[C:30]4=[N:31][CH:32]=[CH:33][CH:34]=[C:29]4[N:28]=3)=[CH:15][CH:14]=2)=[N:4]1)[CH3:2]
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4n3CCOC)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a stirred solution of 4-(1-ethyl-6-fluoro-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (57.6 mg) in DMF (4 mL) was added NaH (60% in oil, 5.38 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from EtOH/hexane to give the title compound (38.0 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:27](=[O:28])[CH2:26][N:25]([CH3:29])[C:24]2=[O:30])[CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@:26]32[N:25]([CH3:29])[C:24](=[O:30])[N:23]([C:18]2[CH:17]=[C:16]([Cl:15])[CH:21]=[C:20]([Cl:22])[CH:19]=2)[C:27]3=[O:28])=[CH:4][CH:3]=1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: BrCCCCC(Br)c1ccc(Br)cc1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCCC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(1,5-dibromopentyl)benzene (4.2 g, 10.9 mmol) (Preparation 14) and 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (2.59 g, 10 mmol), the above titled compound was obtained as a white solid (3.1 g, mp=118° C.). 1H NMR (CDCl3): 7.41 (2H, d, J=8.4 Hz), 7.30 (1H, m), 7.00 (2H, d, J=8.4 Hz), 6.90 (2H, m), 3.03 (3H, s), 2.91 (1H, dd, J1=12.9 Hz, J2=3.6 Hz), 2.55 (1H, dq), 2.1–2.3 (1H, m), 1.8–2.05 (5H, m), 1.3–1.6 (1H, m).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([CH3:13])[CH:6]=1.O>C(O)C.O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[C:7]([CH3:13])[CH:6]=1
Reactant: Cc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(Br)ccc1CC#N
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
After carbon tetrabromide (6.7 g, 20 mmol) and triphenylphosphine (5.2 g, 20 mmol) were added to a solution of (4-bromo-2-methylphenyl)methanol (3.7 g, 18.4 mmol) which was synthesized according to the method described in literature (Dawson, M. I., et al., J. Med. Chem., 1984, vol. 27, pp. 1516-1531) under ice-cooling, the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture and the insolubles were removed by filtration. After the obtained filtrate was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/0-10/1) to give a crudely purified 4-bromo-1-(bromomethyl)-2-methylbenzene. Potassium cyanide (1.3 g, 20 mmol) was added to a solution of crude 4-bromo-1-(bromomethyl)-2-methylbenzene obtained in the above in a mixture of ethanol-water (3:1, 40 ml), and the mixture was stirred at 60° C. for 1.5 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=6/1-3/1) to give (4-bromo-2-methylphenyl)acetonitrile as a pale orange solid (2.4 g, two-step total yield: 63%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:21][O:22][C:23]1[N:24]=[CH:25][C:26]([C@H:29]([NH:31][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:30])=[CH:27][N:28]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: COc1ncc([C@@H](C)N)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc([C@@H](C)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (430 mg, 1.51 mmol) and (R)-1-(2-methoxypyrimidin-5-yl)ethanamine (238 mg, 1.56 mmol) (prepared similarly according to the method for Intermediate 16) in acetonitrile (6 mL) and N,N-diisopropylethylamine (2 mL, 9 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=2[O:19][CH2:20][CH:21]2[CH2:23][O:22]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][N:2]([CH2:23][CH:21]([OH:22])[CH2:20][O:19][C:18]1[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: c1ccc(CCCCCCCc2ccccc2OCC2CO2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
1.0 ml of 50% by volume aqueous dimethylamine was added to a solution of 0.41 g of the crude compound containing 2-[2-(7-phenylheptyl)phenoxymethyl]oxirane [prepared as described in step (a) above]in 6 ml of tetrahydrofuran, and the mixture was stirred at room temperature for one day. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 19:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.32 g (yield 69%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 45 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of ethanolamine, to the title compound (110 mg, 45%) which was obtained as a white solid. MS: m/e=402.2 [M+H]+.