Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C([O:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][N:27]=1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([CH2:28][C:23]2[C:22](=[O:21])[NH:27][CH:26]=[CH:25][N:24]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)Oc1nccnc1C=O
Reactant: Fc1ccccc1C(F)CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]ccnc1CN1CCC(CC(F)c2ccccc2F)CC1
Reaction time: 8 h
Yield: 5.3 %

Procedure:
After dissolving 64 mg of 4-[2-fluoro-2-(2-fluorophenyl)ethyl]piperidine in 3 ml of tetrahydrofuran, 61 mg of 3-tert-butoxy-2-pyrazinecarboxaldehyde and 90 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate). Two milliters of a 4N hydrogen chloride/ethyl acetate solution was added to the obtained product while stirring, and the stirring was continued for 2.5 hours at room temperature. A 1N sodium hydroxide solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether/n-hexane was added to the residue and the insoluble portion was filtered out to obtain the title compound (5 mg, 5% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8](=[O:12])[NH:9][C:10](=[O:11])[N:5]2[CH:4]=[CH:3]1.[H-].[Na+].O.C(OCC)(=O)C.[Br:22][CH2:23][CH2:24][CH2:25]Br>CN(C)C=O>[Br:22][CH2:23][CH2:24][CH2:25][N:9]1[C:10](=[O:11])[N:5]2[CH:4]=[CH:3][N:2]([CH3:1])[C:6]2=[N:7][C:8]1=[O:12]
Reactant: BrCCCBr
Reactant: Cn1ccn2c(=O)[nH]c(=O)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccn2c(=O)n(CCCBr)c(=O)nc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
After suspending 8-methyl-8H-imidazo[1,2-a][1,3,5]triazine-2,4-dione (CAS 67464-13-5) (100 mg) in N,N-dimethylformamide (2 ml), 1,3-dibromopropane (0.18 ml) and sodium hydride (60% in oil) (27 mg) were added and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The obtained solid was washed with diethyl ether to obtain the title compound (68 mg).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(=O)C)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[CH:31]([OH:33])[CH3:32])[CH2:4][CH3:5])[CH3:2].Cl.[CH3:35]O>O1CCOCC1>[CH2:4]([CH:3]([N:6]1[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:20][CH:21]=3)[N:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[CH:31]([O:33][CH3:35])[CH3:32])[CH2:1][CH3:2])[CH3:5]
Reactant: CO
Reactant: CCC(CC)n1c(C(C)O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CC)n1c(C(C)OC)cc2cnc(Nc3ccc(N4CCNCC4)cc3)nc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-{4-[7-(1-ethyl-propyl)-6-(1-hydroxy-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone (19 mg, 0.042 mmol) in MeOH (1 mL) is added 4N HCl in dioxane (1 mL). The reaction mixture is stirred at 60° C. for 2 h. The mixture is loaded on Solid Phase Extraction column (Sorbent: benzenesulfonic acid), washed with MeOH, eluted with EtOAc:MeOH:Et3N (1:1:0.05), concentrated in vacuo. The residue is purified by preparative HPLC to give 10 mg of [7-(1-ethyl-propyl)-6-(1-methoxy-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(4-piperazin-1-yl-phenyl)-amine.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.[C-:17]#[N:18].[Na+]>CN(C=O)C.[OH-].[Na+]>[C:17]([CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1)#[N:18]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cnc(CC#N)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 65.7 %

Procedure:
A mixture of tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (0.75 g, 2.60 mmol) and NaCN (0.255 g, 5.21 mmol) in DMF (5 mL) was stirred at room temperature for 50 min. The reaction mixture was cooled down to room temperature, diluted with 0.5 N NaOH (10 mL) and extracted with EtOAc (2×20 mL), and EtOAc layers were combined, washed with 0.5 N NaOH (10 mL), dried (Na2SO4), concentrated and the crude residue was purified by flash chromatography on silica gel eluted with gradient EtOAc/CH2Cl2 (0-20%) to afford tert-butyl 5-(cyanomethyl)pyrazin-2-ylcarbamate (0.40 g, 65.6% yield). LCMS (MH+-tBu): 179.0 (MH+), 0.68 min; 1H NMR (400 MHz, CDCl3) δ ppm 9.28 (s, 1H), 8.32 (s, 1H), 7.59 (br. s., 1H), 3.91 (s, 2H), 1.57 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([Cl:26])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3ccncc3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[O:8])=[CH:9][CH:10]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)N(C(=O)c1ccc(Br)cc1)C(C)C
Reaction time: 8 h

Procedure:
A mixture of 4-bromobenzoic acid (200 g, 1 mol) and thionyl chloride (300 mL) was refluxed for 3 hours. The mixture was concentrated in vacuo to remove excessive thionyl chloride, and then azeotroped with toluene (3×). The crude residue was dissolved in CH2Cl2 (2 L) and cooled in ice-water bath. To the resulting solution was added dropwise a mixture of triethylamine (330 mL, 2.38 mol) and diisopropylamine (168 mL, 1.19 mol) over 1 hour. The solution was allowed to stir overnight, and then washed with 1N HCl, followed by brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 4-bromo-N,N-diisopropylbenzamide. LRMS calc'd for (C13H18BrNO) [M+H]+, 284; found 284.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=1.C([Li])(C)(C)C.CN([CH:38]=[O:39])C.Cl>C(OCC)C.C1COCC1.C(OCC)(=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([N:5]2[CH:6]=[C:2]([CH:38]=[O:39])[CH:3]=[C:4]2[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(Br)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 73.3 %

Procedure:
To a stirred solution of 4bromo-1-p-methoxyphenylsulfonyl-2-(3,4,5-trimethoxyphenyl)-pyrrole (0.30 g, 0.62 mmol, Example 94b) in ethyl ether/THF (5 ml, 1:1 v/v) tert-butyl-lithium (1.5 equiv., 1.7 M in pentane) is added at −78° C. The reaction mixture is stirred for 20 min at −78° C., and DMF (255 mg, 5 equiv.) is added drop wise. The reaction mixture is kept for 1 h at −78° C., allowed to come to 4° C., and poured onto ice, 1 M aqueous HCl and ethyl acetate. The organic layer is dried (MgSO4), the solvents are evaporated, and the residue chromatographed on SiO2 with ethyl acetate/hexane to yield the title compound (0.196 g, 73%) as a light yellow solid. 1H-NMR (300 MHz, DMSO-d6): 9.86 (s, CHO); 8.44 (d, J=1.9, 1H); 7.38 (d, J=9.0, 2H); 7.01 (d, J=9.0, 2H); 6.56 (d, J=1.9, 1H); 6.36 (s, 2H); 3.82 (s, MeO); 3.72 (s, MeO); 3.67 (s, 2MeO).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([NH:11][C:12](OC(C)(C)C)=O)([CH3:10])[CH2:8][F:9])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[OH2:24]>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[C:7]([NH:11][CH2:12][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])([CH3:10])[CH2:8][F:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(CF)C(=O)OC(C)(C)C
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)CNC(C)(CF)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 3 (200 mg, 0.72 mmol) in dry DMF under an argon atmosphere was added 8 eq of CH3I (0.36 mL) followed by 2 eq of 95% NaH (37 mg). The reaction mixture was stirred overnight at room temperature. The reaction mix was added to 15 mL of H2O and extracted with 3×15 mL of Et2O. The combined organic layers were washed with 3×20 mL H2O followed by the usual work up. Purification of the crude product via silica gel column chromatography (7.5% EtOAc in hexane) afforded the methylated species 4 (181 mg, 86%) as a colorless oil: 1H NMR (CDCl3) δ 1.44 (9H, s), 1.46 (9H, s), 1.51 (3H, s), 2.94 (3H, s), 4.51-5.04 (2H, m). Anal. (C14H26FNO4) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:5]2[OH:26]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:5]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 1,1-dimethylethyl N-((6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (145 mg, 342 μmol) in TFA (2 mL) was stirred at 23° C. After 30 minutes, the reaction was concentrated in vacuo, and diluted with water (25 mL). A white solid precipitated which was collected by filtration, washed with diethyl ether (5 mL), and dried under vacuum, affording 63 mg of N-((6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycine. MS m/e=366.0 (M−H)−. Calculated for C15H14BrNO5 367.01.
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]2[C:23]=1[CH:24]=[C:25]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[NH:26]2
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: COc1ccc(OC)c2[nH]ccc12
Product: COc1ccc(OC)c2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 4,7-dimethoxy-1H-indole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Br)ccc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-2-chloropyridine (1.0 eq.) in chloroform (0.38 M) was added 77% meta-chloroperbenzoic acid (mCPBA) (4.0 eq.) and heated at 60° C. for 20 hours. After cooling to room temperature, Ca(OH)2 (5.3 eq.) was added, and the resulting precipitate was stirred for 30 minutes. The precipitate was filtered and washed with 3:1 CHCl3/methanol. The filtrate was concentrated en vacuo to give a solid, which was stirred in 30% ethyl acetate in hexane and filtered to give the desired N-oxide. The filtrate was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-100% ethyl acetate in hexane to give more of the desired N-oxide. The two batches were combined and carried onto the next step.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1([CH:16]=O)[CH2:15][CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7]1.FC(F)(F)C([O-])=O.C([NH2+]CC1C=CC=CC=1)C1C=CC=CC=1>>[O:9]1[C:8]2([CH2:13][CH2:14][CH2:15][C:6]3([CH2:5][CH2:4][C:3]([CH:2]=[O:1])=[CH:16]3)[CH2:7]2)[O:12][CH2:11][CH2:10]1
Reactant: O=CCCCC1(C=O)CCCC2(C1)OCCO2
Agent: O=C([O-])C(F)(F)F
Agent: c1ccc(C[NH2+]Cc2ccccc2)cc1
Product: O=CC1=CC2(CCCC3(C2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To the 7-(4-oxo-butyl)-1,4-dioxaspiro[4.5]decane-7-carbaldehyde, 12, obtained in the previous step, was added dibenzylammonium trifluoroacetate (0.4 M solution in THF; 12 mL, 4.8 mmol). The resulting mixture was stirred at room temperature for 3 hours after which the solvent was removed in vacuo. The resulting residue was purified over silica (cyclohexane/EtOAc, 8:2 mixture) to provide 2.3 g (72% yield) of the desired product as a colorless oil which was characterized as follows:
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C(C)C)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[CH:29]([C:32]1[C:40]2[O:39][CH:38]([CH2:41][N:42]=[N+]=[N-])[CH2:37][C:36]=2[CH:35]=[CH:34][CH:33]=1)([CH3:31])[CH3:30].[N-]=[N+]=[N-]>[Pd]>[CH:29]([C:32]1[C:40]2[O:39][CH:38]([CH2:41][NH2:42])[CH2:37][C:36]=2[CH:35]=[CH:34][CH:33]=1)([CH3:31])[CH3:30]
Reactant: CC(C)c1cccc2c1OC(CN=[N+]=[N-])C2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(C(C)C)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: CC(C)c1cccc2c1OC(CN)C2
Yield: 69 %

Procedure:
Treatment of (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.15 g, 14.9 mmol) with sodium azide (3.87 g, 59.5 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.30 g, 10 wt. %) generally according to the procedure described for Example 1 gave 2.35 g (69%) of (±)-(7-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 160-164° C. (dec); Anal. calcd. for C12H17NOHCl: C, 63.29; H, 7.97; N, 6.15. Found: C, 63.33; H, 7.98; N, 6.15.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.459 g of 6-(3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 6 ml of N,N-dimethylformamide; 0.048 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 1 hour. Under ice cooling, 0.133 ml of ethyl bromoacetate was added, followed by stirring at room temperature for 4 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (185:15:2). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.235 g of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:13]=1>C1COCC1>[CH3:7][NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=2)[N:13]=1
Reactant: CNc1nc(-c2ccc(C#N)cc2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1nc(-c2ccc(CN)cc2)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
Add 1M lithium aluminum hydride in THF (5.6 mL, 5.6 mmol) under nitrogen to a solution of 4-(2-methylamino-thiazol-4-yl)-benzonitrile (0.4 g, 1.86 mmol) in anhydrous THF (5 mL). After gas evolution stops, heat the reaction mixture to reflux for 30 min. Cool to room temperature, quench by slow addition of water (0.5 mL), 5N aqueous NaOH (5 mL) and additional water (1.5 mL). Add EtOAc (50 mL), stir vigorously for 20 min and filter through Celite®. Separate and dry the organic phase over Na2SO4. Concentrate in vacuo to obtain the title compound (0.4 g, 98%) as a white solid suitable for use without additional purification. MS (ES+) m/z: 220 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23].[CH2:24]([N:26]([CH2:37][CH3:38])[CH2:27][CH2:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:25]>ClCCl.CO.C(O)(=O)C.O>[CH2:37]([N:26]([CH2:24][CH3:25])[CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:13]2[N:12]=[C:11]3[N:10]([CH3:22])[C:9](=[O:23])[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:17][C:16]3=[CH:15][N:14]=2)=[CH:35][CH:36]=1)[CH3:38]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: Cc1ccccc1N1Cc2cnc(S(C)(=O)=O)nc2N(C)C1=O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2ccccc2C)C3)cc1
Temperature: 180 °C
Yield: 10.9 %

Procedure:
A mixture of 200 mg (0.6 mmol) of 3-(2-methylphenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 300 mg (1.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution combined and evaporated and the residue was evaporated with toluene. The residue was dissolved in 30 ml of dichloromethane, washed twice with 20 ml of saturated aqueous sodium bicarbonate solution each time, dried over magnesium sulfate, filtered and evaporated to give 30 mg (11%) of 7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methyl-3-(2-methylphenyl)pyrimido[4,5-d]pyrimidin-2(1H)-one as a pink solid of melting point 132° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:38]1[CH:39]=[CH:40][C:35]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:36][CH:37]=1
Reactant: Oc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccncc2)CC1
Temperature: 55 °C
Reaction time: 15 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (6.348 g, 31.546 mmol) and triphenylphosphine (10.256 g, 39.432 mmol) were added to a solution of 4-hydroxypyridine (3 g, 31.456 mmol) in tetrahydrofuran (50 ml) at room temperature. Diisopropyl azodicarboxylate (7.66 ml, 39.432 mmol) was subsequently added dropwise and the mixture was then stirred at 55° C. for 15 h. Saturated sodium bicarbonate solution (50 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (4×80 ml). The combined organic phases were washed with sat. sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was subsequently purified by column chromatography (silica gel) with ethyl acetate/hexane (4:1). Yield: 4.11 g (46%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C>CO>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
To a suspension of 3-bromo-4-chloro-benzoic acid (10 g, 42.6 mmol) in MeOH (100 mL) cooled with ice bath, was added acetyl chloride (30.4 mL, 0.43 mol) dropwise. The mixture was then stirred at room temperature for 12 hrs and concentrated to yield 3-bromo-4-chloro-benzoic acid methyl ester as a yellow solid (10.6 g). NMR (CDCl3), δ, 8.28 (1H, s), 7.91 (1H, brs), 7.52 (1H, brs), 3.92 (3H, s).
Reaction SMILES: [K].[F:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH2:10](I)[CH2:11][CH3:12]>>[CH2:10]([N:5]1[CH:4]=[C:3]([F:2])[CH:8]=[N:7][C:6]1=[O:9])[CH2:11][CH3:12]
Reactant: CCCI
Reactant: O=c1ncc(F)c[nH]1
Agent: [K]
Product: CCCn1cc(F)cnc1=O
Yield: 20 %

Procedure:
1-Propyl-5-fluoropyrimid-2-one was prepared as above from the potassium salt of 5-fluoropyrimid-2-one and n-propyl iodide in 20% yield after 48 hours; m.p. =93° C. (ligroin). (Found: C, 54.04; H, 5.82; Calc for C7H9FN2O: C, 53.86; H, 5.81).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9]C)=O)=[CH:3][N:2]=1.O.[NH2:12][NH2:13]>CO>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:12][NH2:13])=[O:9])=[CH:3][N:2]=1
Reactant: NN
Reactant: COC(=O)c1ccnnc1
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccnnc1
Yield: 98.6 %

Procedure:
To a solution of methyl 4-pyridazinecarboxylate (400 mg, 2.9 mmol) in MeOH (5 ml) was added hydrazine monohydrate (23 mmol). The solution was heated to reflux for 12 h. Volatiles were evaporated in vacuo to give 395 mg of the title compound as a yellow pale foam, which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[N:18]=2)[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:35]>C(#N)C>[CH2:1]([C:5]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([O-:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:27])(=[O:28])[N:18]=2)[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[Na+:35]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 104.4 %

Procedure:
A solution of compound of Example 18H (33 mg, 0.07 mmol) in acetonitrile (3 mL) and treated with sodium hydroxide solution (1.0 N, 10 μL, 0.07 mmol) followed by stirring at ambient temperature for 20 min. The solution was frozen and lyophilized to afford the title compound (36 mg, 70% overall yield) as a fluffy white solid. 1H NMR (300 MHz, DMSO-d6): δ 0.52 (d, J=6.25 Hz, 2 H) 0.66 (t, J=7.35 Hz, 6 H) 0.85 (m, 2 H) 1.04 (m, 4 H) 1.68 (m, 2 H) 2.11 (m, 2 H) 7.30 (m, 3 H) 7.53 (m, 2 H) 7.69 (m, 2 H) 15.31 (s, 1 H).