Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:25][C:26]1[N:31]=[C:30]([NH:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[C:29]([Cl:33])=[CH:28][N:27]=1
Reactant: C#CCNC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reaction time: 48 h
Yield: 3.9 %

Procedure:
2-Amino-N-prop-2-ynyl-benzamide (4.20 g, 24.1 mmol) was dissolved in N,N-dimethylformamide (100 mL, 1.290 mol) and potassium carbonate (5.00 g, 36.2 mmol) was added. 2,4,5-Trichloro-pyrimidine (3.32 mL, 28.9 mmol) was added and the reaction was stirred for 48 hours. The reaction was concentrated under reduced pressure and the residue was taken up in DCM (300 mL) and washed with water (300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-prop-2-ynyl-benzamide as a pale yellow solid (298 mg, 4%). m.p.=188-191° C.; LCMS (m/e) 321 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.53 (s, 1H), 8.76 (d, 1H, J=8.5 Hz), 8.25 (s, 1H), 7.66-7.53 (m, 2H), 7.23-7.14 (m, 1H), 6.39 (bs, 1H), 4.34-4.25 (m, 2H), 2.34 (t, 1H, J=2.5 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH:26]([NH:29][CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([N:29]([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])=[O:9])[CH3:2]
Reactant: CCOc1cc(C(=O)O)ccn1
Reactant: CC(C)NC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(=O)N(C(C)C)C(C)C)ccn1
Reaction time: 2 h

Procedure:
To a solution of 2-ethoxyisonicotinic acid (20 g, 120 mmol) in CH2Cl2 (500 mL) was added oxalyl chloride (10.4 mL) followed by one drop of DMF. The solution was stirred for 2 hr then triethylamine (33.4 mL, 239 mmol) and diisopropyl amine (25 mL, 179 mmol) were added dropwise. The solution was allowed to stir for 12 hr then worked up with CH2Cl2 and sat. NaHCO3. The crude mixture was purified by silica gel chromatography (100% hexanes to 100% EtOAc) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:33](=[O:41])[C:32]=1[C:42]#[N:43]>O1CCOCC1.CCOC(C)=O.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>[CH:38]1([CH2:37][N:34]2[CH:35]=[CH:36][C:31]([C:6]3[CH:5]=[CH:4][C:3]([NH:17][CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[C:2]([Cl:1])[CH:7]=3)=[C:32]([C:42]#[N:43])[C:33]2=[O:41])[CH2:39][CH2:40]1
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)c(Cl)c2)OC1(C)C
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(NC3CCOCC3)c(Cl)c2)ccn(CC2CC2)c1=O
Yield: 15.8 %

Procedure:
To a solution of intermediate 16 (0.57 g, 1.7 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was added intermediate 8 (0.43 g, 1.7 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.19 mg, 0.17 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 2 (0.103 g, 16%).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH2:22][C:23](Cl)=[O:24].[BrH:26]>O.C(#N)C.C1COCC1>[Br:26][CH2:8][C:23](=[O:24])[CH2:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14]
Reactant: O=C(Cl)Cc1c(F)cccc1Cl
Reactant: CCCCCC
Reactant: Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: O=C(CBr)Cc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To a 2 M solution of trimethylsilyl-diazomethane in hexane (6.54 ml, 13.07 mmol) cooled to 0° C. under argon was added dropwise a solution of 2-chloro-6-fluoro-phenylacetyl chloride (1.23 g, 5.94 mmol) in 24 ml of a mixture of THF and ACN (1:1). The mixture was stirred at 0° C. for 5 h. Then 48% aqueous hydrobromic acid (5.91 ml, 52.28 mmol) was added dropwise and the solution was stirred at room temperature overnight. Then 40 ml of water were added. The aqueous phase was extracted twice with EA, and the combined organic phases were washed with water, a saturated solution of sodium hydrogencarbonate and brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 95:5) to give 1.20 g of the title compound as a white powder having a melting point of 47° C.
Reaction SMILES: Cl[C:2]([O-:4])=[O:3].ClC(Cl)(Cl)C(OCC(CO)OC(=O)C(Cl)(Cl)Cl)=O.CC([CH2:26][CH:27]1[C:32](=[O:33])[O:31]C(=O)C1)=C.[NH2:34]CCNCCNCCNCCN.[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC>[C:2](=[O:3])([O:4][CH2:26][CH2:27][CH:32]([OH:33])[OH:31])[NH2:34]
Reactant: NCCNCCNCCNCCN
Reactant: C=C(C)CC1CC(=O)OC1=O
Reactant: O=C([O-])Cl
Agent: O=C(OCC(CO)OC(=O)C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: NC(=O)OCCC(O)O
Temperature: -2 °C
Reaction time: 0.67 h

Procedure:
The chloroformate of glycerol di(trichloroacetate), 42.3 g, is dissolved in 200 ml toluene. 300 Grams of a monosuccinimide dispersant composition (prepared by reacting 1 mole of polyisobutenyl succinic anhydride, where the polyisobutenyl group has a number average molecular weight of about 950, with 0.87 mole of tetraethylene pentaamine then diluting to about 50% actives in diluent oil) is dissolved in 200 ml toluene. Both solutions are cooled to below 0° C. (approximately -2° C.) using a salt ice-water bath. The solutions are poured together into a 2-liter flask equipped with a mechanical stirrer and a drying tube. The reaction solution is mixed with strong stirring and kept below 0° C. for 40 minutes and then is allowed to warm to room temperature. After stirring at room temperature for several hours, about 65 mls of the reaction mixture is added to 130 mls hexane and 65 mls 1N NaOH in a separatory funnel in order to remove the trichloroacetate group. The mixture is intermittently shaked for 30 minutes. After phase separation, the organic layer is washed several times with brine, is dried over anhydrous magnesium sulfate, is filtered and stripped to yield dihydroxypropyl carbamate derivatives of the monosuccinimide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:9])[CH:4]=1.[H-].[Na+].[CH3:12][O:13][C:14](=[O:23])[CH:15](Br)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCCC1>[CH3:12][O:13][C:14](=[O:23])[CH:15]([N:6]1[C:5](=[O:9])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[N:7]1)[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1cn[nH]c(=O)c1
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(OC)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A solution of 5-methoxy-2H-pyridazin-3-one (500 mg, 3.96 mmol) in tetrahydrofuran (19.8 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (190 mg, 4.75 mmol). The reaction was stirred at 25° C. for 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 1.02 g, 4.36 mmol). The reaction was then warmed to 50° C. where it stirred overnight. After this time, the reaction was cooled to 25° C., was poured into water (100 mL) and was extracted into ethyl acetate (3×75 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO 80 g, 40% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (488 mg, 43%) as a clear oil; ES+-HRMS m/e calcd for C14H20N2O4 [M+H+] 281.1496 found 289.1495. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92-1.16 (m, 2H), 1.33-1.64 (m, 6H), 1.63-1.78 (m, 1H), 1.89-2.03 (m, 1H), 2.16 (ddd, J=13.9, 10.9, 5.4 Hz, 1H), 3.61 (s, 3H), 3.82 (s, 3H), 5.39 (dd, J=10.7, 4.4 Hz, 1H), 6.32 (d, J=2.7 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][CH:7]=1.C([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C.[CH:28](N(C(C)C)CC)(C)[CH3:29]>CN(C=O)C>[CH2:28]([N:10]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]([C:5]1[N:4]=[N:3][CH:2]=[CH:7][CH:6]=1)=[O:9])[CH3:29]
Reactant: CCNCc1ccccc1Oc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(=O)c1ccc(Cl)nn1
Solvent: CN(C)C=O
Product: CCN(NCc1ccccc1Oc1ccccc1)C(=O)c1cccnn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.3 %

Procedure:
3-Chloro-pyridazine-6-carboxamide (1.53, 9.69 mmol), N-ethyl-N-(2-(phenoxy)benzyl)amine (2.2 g, 9.69 mmol) and di-isopropylethylamine (3.87 g, 30 mmol) in DMF (19 ml) was heated to 135° C. for 20 hours. The reaction was cooled to ambient temperature and allowed to stand for 48 hours. It was partitioned between ethyl acetate/H2O, the aqueous layer extracted with ethyl acetate and the organic layers washed with water (4×), dried (MgSO4) and evaporated. The residue was subjected to chromatography (eluant: ethyl acetate/hexane) to give 6-(N-ethyl-N-(2-phenoxybenzylamino)-pyridazine-3-carboxamide as a brown solid (1.53 g, 43%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH:15]=O)([CH3:14])[CH3:13].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:15]([C:5]2([CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH2:4]2)[C:6]([NH2:8])=[O:7])[C:12]([CH3:13])([CH3:14])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)C=O
Reactant: NC(=O)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(n1nnc2ccccc21)C1(C(N)=O)C=CC(I)=CC1

Procedure:
A suspension of 4-iodobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example IC to provide the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:40][CH3:41])=[C:34]([CH2:38][CH3:39])[CH:35]=2)[CH2:30]1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([N+:26]([O-])=O)[CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=C([C@@H](O)CN(CC2C=CC=CC=2)C2CC3C(=CC(CC)=C(CC)C=3)C2)C=CC=1OCC1C=CC=CC=1>>[NH2:26][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:29]2[CH2:30][C:31]3[C:36](=[CH:35][C:34]([CH2:38][CH3:39])=[C:33]([CH2:40][CH3:41])[CH:32]=3)[CH2:37]2)[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCc1cc2c(cc1CC)CC(N(CC(=O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)Cc1ccccc1)C2
Agent: CCc1cc2c(cc1CC)CC(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c(N)c1)C2
Product: CCc1cc2c(cc1CC)CC(N(CC(=O)c1ccc(OCc3ccccc3)c(N)c1)Cc1ccccc1)C2
Reaction time: 48 h

Procedure:
1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanone is prepared from 2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)ethanone (1.50 g) by an analogous procedure to that used to prepare (R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanol in Example 19. The reaction is shown to be complete by TLC after 48 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is purified by flash column chromatography (silica, n-hexane/ethyl acetate 4:1). TLC (silica, n-hexane/ethyl acetate 2:1 Rf=0.70).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=O)=[O:4].O.[NH2:24][NH2:25]>C(O)C>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[N:24][NH2:25])=[O:4]
Reactant: NN
Reactant: CC(C)(C)C(=O)Nc1ccncc1C(=O)c1ccccc1F
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccncc1C(=NN)c1ccccc1F
Temperature: 0 °C
Yield: 68.2 %

Procedure:
A solution of [4-(2,2-dimethylpropionamido)-3-pyridinyl]-2-fluorophenylmethanone (9.8 g) and hydrazine monohydrate (3.3 g) in 100 mL ethanol was stirred at reflux for five hours, cooled, stirred with ice-water and extracted with ethyl acetate-ether. The dried organic layer was filtered and evaporated. The residue was eluted through silica with dichloromethane then 15% ethyl acetate in dichloromethane via flash column chromatography and then was triturated with hexane-ether to yield 7 g of [4-(2,2-dimethylpropionamido)-3-pyridinyl]-2-fluorophenylmethanone-hydrazone, as a solid, m.p. 78°-82° C. Four grams were converted to the maleate salt in methanol-ether and thereafter recrystallized from methanol-ether to yield 2.3 g of crystals, d 161°-162° C.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2].[CH2:9]=O>C(O)(C)C>[CH:1]([N:4]1[CH2:5][CH2:6][CH2:7][NH:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)NCCCN
Reactant: C=O
Solvent: CC(C)O
Product: CC(C)N1CCCNC1
Yield: 78 %

Procedure:
A solution of N-isopropyl-1,3-propanediamine (116 g, 1 M) in isopropyl alcohol (1 l ) maintained ca 10° was treated dropwise with 40% aqueous HCHO solution (75 ml, 1 M). After 1 hour the solvents were evaporated under reduced pressure and the residue distilled to give N-isopropylhexahydropyrimidine (100 g, 78%), Bp 65° /20 mbar.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH2:24][CH2:25][CH3:26])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8][CH2:7][C:6]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH2:24][CH2:25][CH3:26])[N:5]1[C:11]2[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8][CH2:7][C:6]1=[S:29]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCC(C(=O)OC)N1C(=O)CN=C(c2ccccn2)c2cc(Br)ccc21
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCC(C(=O)OC)N1C(=S)CN=C(c2ccccn2)c2cc(Br)ccc21

Procedure:
A mixture of 0.01 mole of 7-bromo-2,3-dihydro-α-propyl-5-(2-pyridyl)-2-oxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester, 0.0105 mole of phosphorus pentasulfide and 100 ml. of pyridine is heated under reflux for about 24 hours. The mixture is evaporated and the residue thus obtained is dissolved in methylene chloride-water. The organic layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The residue thus obtained is chromatographed on silica gel and eluted to give 7-bromo-2,3-dihydro-α-propyl-5-(2-pyridyl)-2-thioxo-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([F:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC1N=CC2N=CNC(=O)C=2C=1.C(N(CC)CC)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>[Cl-].[Na+].O.C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:2]2[C:3]3[CH:11]=[C:10]([F:12])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc2c(Cl)ncnc2cn1
Agent: O=c1[nH]cnc2cnc(F)cc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3cnc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
According to the method described in J. Med. Chem., 39:1823-1835 (1996), 4-chloro-6-fluoropyrido[3,4-d]pyrimidine was derived from 6-fluoropyrido[3,4-d]pyrimidine-4(3H)-one (1.48 g, 8.96 mmol). Triethylamine (3.75 mL, 26.9 mmol) and N-tert-butoxycarbonylpiperazine (2.00 g, 10.7 mmol) were added to a methylene chloride solution (25 mL) of this partially purified product, followed by stirring at room temperature overnight. Saturated brine was added to the reaction solution, the mixture ma was extracted with chloroform, the extract was dried over anhydrous sodium sulfate, then the solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give the target compound (1.73 g, 5.20 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:18]([O:17][C:15]([NH:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4])=[O:16])[CH:19]=[CH2:20]
Reactant: N[C@H](CO)COCc1ccccc1
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)N[C@H](CO)COCc1ccccc1
Yield: 94.2 %

Procedure:
A solution of (R)-2-amino-3-benzyloxy-1-propanol (5 g, 27.6 mmol) in CH2Cl2 (250 mL) was treated with allyl chloroformate (3.2 mL, 30 mmol) and saturated aqueous NaHCO3 (250 mL) for 18 h. The organic layer was separated and concentrated in vacuo. Purification by chromatography eluting with 30% EtOAc/hexanes afforded 6.9 g (94%) of (R)-2-(allyloxycarbonylamino)-3-benzyloxy-1-propanol as an amorphous solid: 1H NMR (CDCl3) δ 2.56 (br s, 1H), 3.69 (m, 3H), 388 (m, 2H), 4.54 (s, 2H), 4.58 (d, 2H, J=5.6 Hz), 5.23 (dd, 1H, J=10.4, 1.1 Hz), 5.33 (dd, 1H, J=17.1, 1.1 Hz), 5.42 (m, 1H), 5.93 (m, 1H), 7.35 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[Cl:17][CH:18]([CH3:31])[CH2:19][CH2:20][CH2:21][N:22]1[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[NH:24][C:23]1=[O:30].[Cl-].[NH4+]>CN(C=O)C>[ClH:17].[CH3:28][C:26]1[C:25](=[O:29])[NH:24][C:23](=[O:30])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:31][N:11]2[CH2:12][C@H:13]3[C@:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=4)([CH2:14]3)[CH2:10]2)[CH:27]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1cn(CCCC(C)Cl)c(=O)[nH]c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cn(CCCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Product: Cl
Temperature: 100 °C
Yield: 35.1 %

Procedure:
A mixture of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (41 mg), 1-(4-chloropentyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (Prep11, 50 mg) and TEA (50 μl) in DMF (0.5 mL) was heated at 100° C. overnight. Ammonium chloride was then added and the solution was extracted with dichloromethane. The organic phase was dried and concentrated in vacuo. The crude product was purified by a SCX cartridge followed by a preparative HPLC [column: ABZ plus 20×100 mm, 5 uM, mobile phase A: H2O+0.1% formic acid, mobile phase B: acetonitrile+0.1% formic acid, gradient: from 1 to 20% (B) in 10 min, flow rate: 20 mL/min, UV wavelength range: 210-350 nm, ionization: ES+, mass range: 100-900 amu (ES+)], to give 29 mg of the title compound which was further purified by flash chromatography eluting with DCM/MeOH/NH4OH from 99/1/0.1, to 98/2/0.1, to 97/3/0.1 to give the free base of the title compound (25 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)(=O)[CH3:15].C(O)C>CN(C)C=O>[N:20]1[CH:21]=[CH:22][C:17]([C:14](=[N:11][NH:10][C:8](=[O:9])[C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH3:15])=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccncc1
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=NNC(=O)c1ccc([N+](=O)[O-])cc1)c1ccncc1
Yield: 78.4 %

Procedure:
A mixture of 3.62 gm (0.02 mole) of p-nitrobenzhydrazide, 2.42 gm (0.02 mole) of 4-acetylpyridine and 100 ml of absolute ethanol is refluxed 3 hours. Sufficient dimethylformamide is added to the mixture at boiling to give a solution. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is chilled in the refrigerator. The product is collected, washed with ether and dried to yield 4.46 gm (79%) of the title compound; mp 251.2°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([Cl:43])=[O:42])=[CH:36][CH:35]=1.[OH-].[Na+]>ClCCl>[ClH:43].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)[C:41](=[O:42])[CH2:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[CH:6][CH:7]=1.[ClH:43]
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: Cc1ccc(CNC2CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-((4-Methylphenyl)methyl)amino-1-phenylmethylpiperidine (800 mg, 2.7 mmol) in dry dichloromethane (30 ml) was added diisopropylethylamine (1.5 ml)followed by 4-methoxyphenylacetyl chloride (997 mg, 5.4 mmol). The reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was concentrated, redissolved in diethyl ether, and extracted with HCl (0.6 N). The aqueous layer was isolated, treated with NaOH (1 N)until basic, and extracted with dichloromethane (20 ml). The organic layer was isolated and dried (Na2SO4), filtered, and concentrated, and redissolved in diethyl ether. The hydrochloride was formed by addition of HCl (4 M in dioxane), and recrystallized from diethyl ether to give the title compound. Yield: 600 mg, 50%; 1H-NMR (CDCl3): δ 1.75 (d, 2 H), 2.32 (s, 3 H), 2.50 (q, 2 H), 2.70 (q, 2 H), 3.38 (d, 2 H), 3.54 (s, 2 H), 3.78 (s, 3 H), 4.06 (d, 2 H), 4.54 (s, 2 H), 4.82 (m, 1 H), 6.78-7.60 (aromatic protons, 13 H); 13C-NMR (CDCl3): δ 21.0, 26.0, 40.3, 46.3, 49.0, 51.8, 55.3, 60.8, 114.2, 125.6, 126.6, 127.9, 129.4, 129.60, 129.62, 130.3, 131.4, 134.8, 137.1, 158.7, 172.9; Mp. 197-200° C.; Elemental analysis: Found C, 71.29; H, 7.25; N, 5.73; calcd for hydrate: C, 71.37; H, 7.43; N, 5.74.