Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[F:8][C:9]1[CH:10]=[C:11]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH:12]=[CH:13][CH:14]=1.C(N(CCCC)CCCC)CCC>[OH-].[Na+].O>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[C:21]([OH:22])=[N:1][C:2]3[N:3]([N:4]=[C:5]([CH3:7])[N:6]=3)[C:16]=2[OH:17])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nc(N)n[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Cc1nc2nc(O)c(-c3cccc(F)c3)c(O)n2n1
Yield: 88.7 %

Procedure:
5 g (51.87 mmol) 3-Amino-5-methyl-1,2,4-triazole, 16.2 g (67.4 mmol) diethyl (3-fluorophenyl)malonate and 20.4 mL tributylamine are stirred at 180° C. over night. The mixture is diluted with 2N NaOH solution and water and extracted three times with methyl-tert. butylether. These organic extracts are discarded. The aqueous phase is acidified at 0° C. with concentrated HCl until pH 3. The white precipitate is collected by filtration, washed with water (4 L) and dried in vacuo at 50° C. 11.97 g (88.7%) of the product are obtained and are used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)=[CH:13][N:12]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1ccc(Nc2cc3ccccc3o2)nc1
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: [K+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(Nc3cc4ccccc4o3)nc2)cn1
Temperature: 100 °C

Procedure:
A suspension of 3-benzofuran-2-yl-5-bromopyridin-2-ylamine (65.2 mg, 0.226 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56.7 mg, 0.272 mmol, 1.2 eq), Pd(PPh3)4 (18.6 mg, 0.0161 mmol, 7 mol %), and potassium carbonate (101.1 mg, 0.732 mmol, 3.2 eq) in a 4:1 mixture of DME:H2O (2.5 mL) was evacuated and charged with nitrogen several times, after which the sample was heated in the microwave reactor to 100° C. for 45 min. EtOAc was added to dilute the reaction, which was then washed with water (2×) and brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to dryness. The crude material was purified by column chromatography on silica gel [0.5″×10″ glass column, eluting with CH2Cl2:EtOAc 1:0→4:1→1:1→2:3→3:7→1:9→0:1]. Fractions containing product were combined and concentrated in vacuo. DCM and heptane were added to the residue and the solvent was concentrated in vacuo until all CH2Cl2 had been removed; a solid precipitated at this point. The solid was triturated in hot heptane and filtered off, giving the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=3.86 (s, 3H), 6.28 (br s, 2H), 7.24-7.37 (m, 2H), 7.39 (d, J=0.8 Hz, 1H), 7.64-7.70 (m, 2H), 7.86 (d, J=0.8 Hz, 1H), 8.11 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 8.31 (d, J=2.3 Hz, 1H). MS (ES+): m/z=291.09 (100) [MH+]. HPLC: tR=2.65 min (ZQ3, polar—5 min).
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]([C:17]#[N:18])[CH:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OCc1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(CO)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, grey solid (68 mg, 82%), MS (ISP) m/z=332.5 [(M+H)+], mp 265° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[N:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([F:31])=[CH:4][N:3]=1.CO.[ClH:34]>O1CCOCC1>[ClH:1].[ClH:34].[NH2:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([F:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:22]=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Into a reaction flask were added tert-butyl [5-(2-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (48 mg, 0.11 mmol), methanol (0.50 mL) and 4.0 M of hydrogen chloride in 1,4-dioxane (0.50 mL). The reaction mixture was stirred at rt for 2 h and then concentrated under vacuum to give the desired product as an off-white powder (35 mg, 97%). LCMS for C17H16ClFN5 (M+H)+: m/z=344.0.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>CN(C=O)C>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: Nc1ccccc1F
Reactant: O=C(CBr)Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1F)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 63.8 %

Procedure:
A solution of 4-((bromoacetyl)amino)nitrobenzene (12.0 g, 46.3 mmol) and 2-fluoroaniline (11.0 g, 102 mmol) in anhydrous DMF (60 mL) was heated to 90°-100° C. for 2 days with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then extracted with CH2Cl2 (200 mL). The organic layer was dried (MgSO4) and filtered, a small amount of silica gel was added to the CH2 Cl2 solution, and then the mixture was concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (3:1), afforded 8.54 g (63.7%) of the title compound as yellow crystals, mp 150°-153° C.; 1H NMR (DMSO-d6) δ10.65 (s, 1H), 8.22 (d, J=9.2, 2H), 7.86 (d, J=9.2, 2H), 7.04 (ddd, J=9.6, J=8.4, J=1.6, 1H), 6.94 (dt, J=7.2, J=1.2, 1H), 6.65-6.61 (m, 2H), 5.80 (bs, 1H), 4.02 (s, 2H); 13C NMR (DMSO-d6) δ170.06, 150.91 (d, J=236), 144.99, 142.23, 136.31 (d, J=11.3), 124.98, 124.75 (d, J=3.5), 118.90, 116.36 (d, J=6.4), 114.44 (d, J=17.6), 112.17 (d, J=14.0), 46.79; MS (El, m/z) 289 (M+). Anal. Calcd for C14H12N3 O3F: C, 58.12; H, 4.18; N, 14.53. Found: C, 58.04; H, 4.20; N, 14.36.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[N:8].C[O-].[Na+].[NH:12]([C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=O)[NH2:13].C(O)(=O)C>CO>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[NH:13][N:12]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:8]=1
Reactant: N#Cc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnccn3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of pyrazinecarbonitrile (2.0 g, 19 mmol) in methanol (20 mL) was treated with sodium methoxide in methanol (25 wt %, 1.3 mL, 5.7 mmol) at room temperature. After 30 minutes, a solution of tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (4.6 g, 19 mmol) in methanol (20 mL) was added and the reaction was heated to reflux for 19 hours. The reaction mixture was concentrated, dissolved in ethoxyethanol (50 mL) and heated to reflux for 22 hours. The reaction was cooled to room temperature, quenched with acetic acid (0.38 mL, 6.6 mmol) and concentrated. The residue was suspended in ether and filtered to give tert-butyl 4-(5-pyrazin-2-yl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate as a solid. HRMS (M+H+): observed=331.1876, calculated=331.1877; 1H NMR (400 MHz, CD3OD): δ 9.29 (d, J=1.6 Hz, 1H), 8.70 (dd, J=2.4, 1.6 Hz, 1H), 8.64 (d, J=2.4 Hz, 2H), 4.19-4.15 (m, 2H), 3.15-3.09 (m, 1H), 2.97 (m, 2H), 2.07-2.03 (m, 2H), 1.84-1.75 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][N:1]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:9][CH2:8][N:7]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:6][CH2:5][N:4]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:3][CH2:2]1
Reactant: OCC(O)CCl
Reactant: C1CCNCCNCCNCCNC1
Product: OCC(O)CN1CCCCN(CC(O)CO)CCN(CC(O)CO)CCN(CC(O)CO)CC1

Procedure:
From 1,4,7,10-tetraazacyclotetradecane (1.1.4), 1-chloro-2,3-propanediol (commercially available) and base.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CN(C)C=O>[C:16]([O:15][C:14]([NH:13][CH2:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:9])[CH3:10])=[CH:7][C:2]=1[O:1][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:20])([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(O)c1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(C(C)C)ccc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl N-[2-(2-hydroxy-4-isopropylphenyl)ethyl]-carbamate (0.234 g) and 0.116 g of potassium carbonate were suspended in 5 mL of N,N-dimethylformamide. To the stirred suspension was added dropwise 0.126 mL of ethyl 4-bromobutyrate at room temperature, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added 10 mL of 1 mol/L hydrochloric acid and then 20 mL of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.283 g of ethyl 4-[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenoxy]-butyrate.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH2:32](Br)[CH2:33][CH2:34][CH3:35]>C(#N)C>[CH2:32]([NH:15][CH:13]1[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[O:10])[CH2:12]1)[CH2:33][CH2:34][CH3:35]
Reactant: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (0.09 M in acetonitrile, 500 μL, 0.045 mmol), prepared using procedures similar to those described in Example 2, was added triethylamine (20 μL, 0.135 mmol) and n-butylbromide (6.14 μL, 0.054 mmol) followed by additional acetonitrile (1.0 mL). The reaction mixture was stirred at room temperature for 16 h, at which time it was purified directly by reverse phase HPLC to afford the title compound (8.4 mg). 1H NMR (400 MHz, CDCl3): 8.50 (s, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.35 (br s, 2H), 4.00 (br s, 1H), 3.87 (br s, 1H), 3.74-3.68 (m, 1H), 3.20 (br s, 3.5H), 2.56 (t, 2H), 2.03 (s, 2H), 1.50-1.42 (m, 2H), 1.39-1.29 (m, 2H), 0.91 (t, 3H). MS (EI) for C20H21F3IN3O: 504 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>>[CH3:29][N:30]([CH:32]=[C:14]1[CH2:15][CH2:16][N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[C:11]2[CH:21]=[CH:20][CH:19]=[N:18][C:12]=2[C:13]1=[O:17])[CH3:31]
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc2C1=O

Procedure:
As described for Reference Example 221, 5,6,7,8-tetrahydro-5-(4-nitrobenzoyl)-9H-pyrido[3,2-b]azepin -9-one is reacted with tert-butoxybis(dimethylamino)methane to give the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]([CH3:9])[CH3:8])[N:3]=1.C(O)(=O)C.O=[C:15]1[CH2:20][CH2:19][CH2:18][S:17][CH:16]1[C:21](OCC)=[O:22]>CN(C)C=O>[CH3:8][N:7]([CH3:9])[C:4]1[N:3]=[C:2]2[NH:1][C:15]3[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[C:21](=[O:22])[N:6]2[N:5]=1
Reactant: CCOC(=O)C1SCCCC1=O
Reactant: CN(C)c1n[nH]c(N)n1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C)c1nc2[nH]c3c(c(=O)n2n1)SCCC3
Reaction time: 0.67 h
Yield: 65.3 %

Procedure:
To the solution of 6.35 g (0.05 mole) of 5-amino-3-dimethylamino-1H-1,2,4-triazole, 2.5 ml of acetic acid and 12.5 ml of dimethylformamide, 9.4 g (0.05 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-2-carboxylate are added and the reaction mixture is boiled for 40 minutes. The precipitated product is filtered off from the hot solution, then washed with acetic acid and i-propanol and recrystallized from dimethylformamide. Thus 8.2 g (65.2%) of 2-dimethylamino-5,7,8,9-tetrahydrothiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained. M.p.: higher than 350° C.
Reaction SMILES: O1CCCC1.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C([Li])CCC.[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]=[O:21]>CCCCCC>[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]([OH:21])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1
Reactant: Brc1nccs1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1nccs1)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran (10 ml) solution of 2-bromothiazole (180 μg, 2 mmol) was added dropwise a hexane solution of n-butyl lithium (1.57M, 1.40 ml, 2.2 mmol) at −78° C. After stirring for 10 minutes, 2,5-difluorobenzaldehyde (238 μl, 2.2 mmol) was added and while stirring, the temperature of the mixture was gradually raised to 0° C. The reaction was then quenched by the addition of an aqueous solution of ammonium chloride, followed by the addition of ether. The ether layer was washed with water and brine, and then, dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1), whereby the title compound (358 mg, 79%) was obtained as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1.Br[CH2:15][C:16]#[N:17]>>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:15][C:16]#[N:17])[CH2:2][CH2:3]1
Reactant: N#CCBr
Reactant: c1ccc(CC2CCNCC2)nc1
Product: N#CCN1CCC(Cc2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 2-Piperidin-4-ylmethyl-pyridine (commercially available from Array Biopharma) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=216.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[C:10](=[O:15])[CH:11]([CH3:14])[CH2:12][CH3:13])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH:24]=[C:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[N:35][C:30]=2[CH2:29][O:28][C:27]2[CH:36]=[CH:37][C:38]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:39][C:26]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:16]2[CH2:20][CH2:19][N:18]([CH2:22][CH2:23][CH:24]=[C:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[N:35][C:30]=4[CH2:29][O:28][C:27]4[CH:36]=[CH:37][C:38]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:39][C:26]3=4)[CH2:17]2)[C:10](=[O:15])[CH:11]([CH3:14])[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCC(C)C(=O)C(Cc1ccc(Cl)cc1)N1CCNC1
Solvent: CC(C)O
Product: CCC(C)C(=O)C(Cc1ccc(Cl)cc1)N1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 77 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a heated (77° C.) stirring solution of 1-(4-chloro-phenyl)-2-imidazolidin-1-yl-4-methyl-hexan-3-one (110 mg, 0.374 mmol), 2,6-lutidiene (130 μL, 11.229 mmol) and 5 mL isopropanol was added 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (70 mg, 0.187 mmol) portion-wise over a 30 minute period. The resulting solution was monitored using thin layer chromatography and allowed to stir at 77° C. for 16 hours. The solution was concentrated in vacuo at 35° C. The residue was dissolved in ethyl acetate and subjected to column chromatography (SiO2, Biotage 12M column, gradient elution 100% ethyl acetate→92% ethyl acetate/8% methanol with 1% triethyl amine) to afford 54 mg of 1-(4-chloro-phenyl)-2-(3-{3-[7-(1-hydroxy-1-methyl-ethyl)-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene]-propyl}-imidazolidin-1-yl)-4-methyl-hexan-3-one as a tan foam. LC/MS: tUV=1.68 min, M/Z=588 amu.
Reaction SMILES: [CH3:1]O.[C:3]1([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>OS(O)(=O)=O>[CH3:1][N:10]1[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11]1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 95.7 %

Procedure:
308.5 g (9.64 mol) of methanol were vaporized dropwise at 155° C. in an electrically heated column with a diameter of 4 cm and equipped with a sintered disk at the lower end and fitted onto a 250 ml two-neck flask over the course of 6 hours and passed through a melt, at 200° C., of 10 g (0.0455 mol) of 3,5-diphenylpyrazole and 0.046 g (0.000455 mol) of concentrated H2SO4. The gaseous discharge from the reaction was condensed and concentrated under reduced pressure. 10.2 g (92.5%) of 1-methyl-3,5-diphenylpyrazole were obtained, boiling point 190° C./3 mbar, with a content of 96.6% (GC).
Reaction SMILES: [CH2:1]=O.[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[C@H:23]2[CH2:28][NH:27][CH2:26][CH2:25][N:24]2[C:29](=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[CH:8][CH:7]=1)[CH3:4]>ClC(Cl)C.ClCCl>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]2[C@H:23]2[CH2:28][N:27]([CH3:1])[CH2:26][CH2:25][N:24]2[C:29](=[O:42])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: C=O
Reactant: CCOc1ccc(-n2c([C@H]3CNCCN3C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ccccc3c2=O)cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOc1ccc(-n2c([C@H]3CN(C)CCN3C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ccccc3c2=O)cc1
Reaction time: 8 h
Yield: 78.2 %

Procedure:
Formaldehyde (37% in water) (0.015 g, 0.18 mmol) was added to a solution of 20 (0.05 g, 0.09 mmol) in dichloroethane (5 mL), followed by Na(OAC)3BH (0.057 g, 0.27 mmol) at room temperature. The mixture was stirred overnight. The solution was diluted with dichloromethane, washed by saturated sodium bicarbonate, water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash column to afford a white solid (40 mg). 1H NMR (CDCl3) 1.42 (t, 3H, J=7.0 Hz), 2.01-2.26 (m, 4H), 2.89 (m, 2H), 3.77 (m, 4H), 4.04 (q, 2H, J=7.0 Hz), 4.46 (m, 1H), 5.41 (m, 1H), 7.01 (m, 3H), 7.06 (m, 1H), 7.41 (m, 5H), 7.71 (m, 1H), 8.21 (d, 1H, J=8.08 Hz). MS (ESI+) 569.2 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:22]([O:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 50 °C

Procedure:
20.0 g (75% pure, 42.5 mmol) of tert-butyl(+/−)-[4-(bromomethyl)phenyl](cyclopentyl)acetate were added to a suspension of 16.3 g (84.9 mmol) of cesium acetate in 80 ml of DMF. The resulting mixture was heated at 50° C. for 1.5 h. After cooling, the mixture was diluted with ethyl acetate, washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1→about 10:1). This gave 11.7 g (76.4% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.Cl.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:15]([C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Br)cc2CN1[C@H]1CC[C@H](O)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.500 g, 1.62 mmol), trans-4-aminocyclohexanol hydrochloride (0.295 g, 1.95 mmol), and potassium carbonate (0.44 g, 3.2 mmol) in ethanol (5.0 mL) was stirred in a sealed vial at 50° C. for 4 h. After cooling, the mixture was diluted with ethyl acetate (10 mL), and was filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with ethyl ether (3 mL). The precipitates were collected by filtration and washed with ethyl ether to afford the desired product. LCMS (M+H)+=309.9/312.0.
Reaction SMILES: IC.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]([OH:21])=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[C:30]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:22][O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:20]([O:21][CH3:30])=[C:14]3[CH2:13]2)=[O:11])=[CH:8][CH:9]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(O)c2C1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(COc2ccccc2)nn2c1CN(C(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.2 %

Procedure:
Iodomethane (0.005 mL, 0.08 mmol) was added to a stirred suspension of (4-fluoro-phenyl)-(3-hydroxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (19 mg, 0.052 mmol) and Cs2CO3 (0.034 g, 0.1 mmol) in DMF (0.5 mL). The mixture was stirred at room temperature for 45 minutes and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield (4-fluoro-phenyl)-(3-methoxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (5 mg, 25% yield) as a colourless oil. C21H20FN3O3 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (br. s., 3H), 4.01 (br. s., 2H), 4.20 (br. s., 2H), 4.80 (br. s., 2H), 5.02 (s, 2H), 6.93-7.00 (m, 1H), 7.03 (d, J=7.9 Hz, 2H), 7.16 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.46-7.53 (m, 2H).