Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:3]=1[C:4]([NH:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:33])[CH2:14][C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:9][C@H:8]1[OH:34])=[O:5].[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(O)(=O)C>[C:41]([NH:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:3]=1[C:4]([NH:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:33])[CH2:14][C:15]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH2:9][C@H:8]1[OH:34])=[O:5])(=[O:43])[CH3:42]
Reactant: COc1cccc(N)c1C(=O)N[C@@H]1CCN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cccc(NC(C)=O)c1C(=O)N[C@@H]1CCN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2.72 parts of trans-4-[(2-amino-6-methoxybenzoyl)amino]-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide in 20 parts of acetic acid were added 0.56 parts of acetic acid anhydride. After stirring overnight at room temperature, the reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried at 80° C., yielding 2.45 parts (83.5%) of trans-4-[[2-(acetylamino)-6-methoxybenzoyl]amino]-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 146.5° C. (compound 61).
Reaction SMILES: O1C2CCCC([NH2:10])C=2C=C1.[S:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH2:12]1>>[S:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([NH2:10])[CH2:13][CH2:12]1
Reactant: NC1CCCc2occc21
Reactant: O=C1CCSc2ccccc21
Product: NC1CCSc2ccccc21

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 2,3-dihydro-4H-thiochromen-4-one and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ 7.30, 7.07, 4.07, 3.28, 2.96, 2.16, 1.61; (MS/CI) calcd for C9H11NS+H 166.3, found 166.3.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11](SC)[N:12]=2)=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:17])[C:10]([C:15]#[N:16])=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1nc(Cc2ccc(Cl)cc2)[nH]c(=O)c1C#N
Reactant: C1CCNC1
Product: N#Cc1c(N2CCCC2)nc(Cc2ccc(Cl)cc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(4-chlorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 244 mg (3.43 mmol) of pyrrolidine to give 45 mg (42% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:8]([O:9][CH2:10][CH:11]=[CH2:12])[CH:7]2[CH2:13][N:3]1[N:4]([CH2:18][C:19](O)=[O:20])[C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=12.O.O[N:24]1[C:28]2C=CC=[CH:32][C:27]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N)CC>CN(C=O)C.CCCCCCC.CCOC(C)=O>[O:1]=[C:2]1[N:8]([O:9][CH2:10][CH:11]=[CH2:12])[CH:7]2[CH2:13][N:3]1[N:4]([CH2:18][C:19]([NH:24][CH2:28][CH2:27][CH3:32])=[O:20])[C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=12
Reactant: On1nnc2ccccc21
Reactant: C=CCON1C(=O)N2CC1c1ccccc1N2CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCN
Solvent: CCCCCCC
Product: C=CCON1C(=O)N2CC1c1ccccc1N2CC(=O)NCCC
Reaction time: 0.33 h
Yield: 37.8 %

Procedure:
480 mg of the acid obtained in Example 25 are dissolved in 5 ml of DMF. 336.5 mg of 1-hydroxybenzotriazole hydrate and then 350 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added at 0° C. After 20 min at 0° C., 107.9 g of propylamine are added and then the mixture is left at 0° C. for 20 min. The reaction medium is treated with a heptane/AcOEt (1:2) mixture and NaH2SO4 (1M aqueous solution). After extracting with AcOEt and then washing the organic phase with water, the organic phase is dried over MgSO4 and the solvent is evaporated. The residue is chromatographed on silica (eluent: CH2Cl2; 6% acetone). 207 mg of the expected product (38%) are isolated.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][S:8][CH2:7]1)=O.[CH3:19][C:20]1[N:21]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=2)[CH:22]=[CH:23][N:24]=1>>[CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[C:6]2[CH2:7][S:8][CH2:9][CH2:10][C:11]=2[N:34]=[C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH3:19])=[CH:26][CH:27]=2)[N:33]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: COC(C(=O)C1CSCCC1=O)c1ccccc1
Product: COC(c1ccccc1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CSCC2
Yield: 11 %

Procedure:
4-(Methoxy(phenyl)methyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (31.5 mg, 11%) was synthesised from 3-(2-methoxy-2-phenylacetyl)dihydro-2H-thiopyran-4(3H)-one and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 444.0 (M+H)+
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([O:38]C)=[O:37]>>[CH3:70][CH:34]([CH3:33])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:61][CH:62]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([OH:38])=[O:37]
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1
Yield: 82 %

Procedure:
The compound of example 124 was prepared analogous to compound of example 98 by hydrolysis of compound of example 123.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[N:13]=[N:12][CH:11]=[N:10]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[N:13]=[N:12][CH:11]=[N:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cn2ncnn2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Cn2ncnn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A mixture of 2-(4-nitrobenzyl)-2H-tetrazole (5 g), 10% palladium carbon (500 mg), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave 2-(4-aminobenzyl)-2H-tetrazole (2.83 g, 66%) as yellow prism crystals. melting point: 86-87° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[OH:29])[C:14]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:32](Br)[CH:33]=[CH2:34].Cl>O.CN(C=O)C.C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH2:34][CH:33]=[CH2:32])[C:14]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C=CCBr
Reactant: O=C(O)c1ccc(OC(=O)c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a solution of 1.17 g (3 mmoles) of 4-[3-(1-adamantyl)-4-hydroxybenzoyloxy]benzoic acid in 100 ml of a 50:50 mixture of THF and DMF, there are added, by small portions, 180 mg (6 mmoles) of sodium hydride (80% in oil). The mixture is stirred at ambient temperature until the cessation of gaseous emission. There are then added 260 μl (3 mmoles) of allyl bromide and the mixture is stirred at ambient temperature for 3 hours. The reaction medium is poured into water, acidified to pH 4 with 1N HCl and extracted with ethyl ether. The organic phase, is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting residue is purified by chromatography on silica eluted with ethyl ether. After evaporation of the solvent, 880 mg (68% yield) of 4-[3-(1-adamantyl)-4-allyloxybenzoyloxy]benzoic acid having a melting point of 260°-261° C. are recovered.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@@H:6]1[N:11]([CH3:12])[CH2:10][CH2:9][N:8]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:7]1)[CH:2]=[CH2:3]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:12][N:11]1[CH2:10][CH2:9][N:8]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:7][C@@H:6]1[CH2:5][O:4][CH2:1][CH2:2][CH3:3]
Reactant: C=CCOC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCOC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1C
Yield: 98.7 %

Procedure:
Stir (R)-10-(3-allyloxymethyl-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (270 mg), 20% palladium hydroxide (Degaussa type, 15 mg) in ethanol (0.014M)) under hydrogen atmosphere (1 atm) for 4 hours at room temperature. Filter and evaporate the solvent to afford the title compound as a yellow solid (268 mg): 1H NMR (CDCl3) δ 0.90 (t, 3H), 1.58 (m, 2H), 2.30 (s, 3H), 2.33 (m, 2H), 2.39 (s, 3H), 2.84 (m, 2H), 3.14 (t, 1H), 3.38 (t, 2H), 3.49 (d, 1H), 3.58 (d, 1H), 3.95 (d, 1H), 4.07 (d, 1H), 4.94 (s, 1H), 6.31 (s, 1H), 6.60 (d, 1H), 6.85 (t, 1H), 6.95 (t, 1H), 7.02 (d, 1H); MS (ESI) m/z (rel intensity) 385 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccccn1
Reactant: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccn2)cc1[N+](=O)[O-]

Procedure:
4-methoxy-3-nitrobenzoyl chloride (1.08 g, 0.005 mol), 2-aminopyridine (0.94 g, 0.01 mol) and DIPEA (1.8 mL, 0.01 mol) were allowed to stir in dichloromethane (10 mL) for 48 hours to form 4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide. Intermediate was purified via silica column chromatography using 0 to 100% ethyl acetate in hexane.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[N:2]1.S([O-])([O-])(=O)=O.[Mg+2].[C:24]1([CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:31][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:2]1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1-c1noc2ccccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C(=NC(c1ccccc1)c1ccccc1)c1ccccc1-c1noc2ccccc12

Procedure:
To a stirred suspension of 2.23 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde and 2.6 g of magnesium sulfate in 25 ml of methylene chloride was added 1.7 ml of diphenylmethanamine and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give 3.9 g crude N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine as a gum which slowly solidified. A stirred solution of 0.75 g of N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine in 15 ml tetrahydrofuran was cooled to −65° C. and 2.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 5 min then 4-fluorobenzyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction was diluted with 25 ml of water then extracted with 100 ml then 50 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate then evaporated to give 1.18 g of crude N-(diphenylmethylidene)-2-(1,2-Benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine which was not characterised due to instability. To a solution of 1.1 g of N-(diphenylmethylidene)-2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine in 20 ml of acetone was added 9 ml of 1M hydrochloric acid. The solution was stirred overnight then evaporated and 15 ml of 4M sodium hydroxide solution added. The solution was extracted with 100 ml then 50 ml of methylene chloride. The organic extracts were dried and evaporated to an oil which was purified by flash chromatography eluting with a 19:1 mixture of methylene chloride-methanol to yield the pure amine free base which was dissolved in methanol and acidified with a solution of hydrogen chloride in methanol, evaporated and crystallised from methanol-ether to yield 0.18 g of 2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine hydrochloride, melting at 238-241° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34].[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(Br)cc2)N1c1cc(C(F)(F)F)ccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(-c3ccc(F)cc3)cc2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting from 500 mg (0.91 mmol) of the bromide from Example 11A, reaction in analogy to general method [D] with 152.27 mg (1.09 mmol) of 4-fluorophenylboronic acid, 31.83 mg (0.05 mmol) of bis(triphenylphosphine)palladium(II) chloride and 115.34 mg (1.09 mmol) of sodium carbonate in 10 ml of 1,2-dimethoxyethane and 0.5 ml of water results in 370.7 mg (72% of theory) of the target compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=O>>[CH3:29][N:27]([CH3:28])[C:25](=[O:26])[C:24]1[CH:30]=[CH:31][CH:32]=[C:22]([CH2:20][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CN(C)C(=O)c1cccc(C=O)c1
Product: CN(C)C(=O)c1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-formyl-N,N-dimethylbenzamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzamide.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCOCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCOCc1ccccc1)C(=O)OCC

Procedure:
The compound was prepared by a modification of the method of Ramalingam et al Tetrahedron, 51, 2875-2894 (1995)]. Thus, sodium (1.20 g) was dissolved in absolute ethanol (25 mL) under argon. Diethyl malonate (14.00 g) was added and the mixture was refluxed for 30 min. Benzyl bromoethyl ether (10 g) was added and the mixture was stirred at reflux for 16 hours. The ethanol was removed by rotary evaporation and the residue was partitioned between ether (100 mL) and water (50 mL). The ethereal layer was washed with water (3×50 mL) and dried over sodium sulfate. The ether was removed by rotary evaporation and the residue was distilled in vacuoo. The fraction distilling at 40-55° C. was discarded (unreacted diethyl malonate). The product distilled at 140-150° C. (1 mm), [lit. bp 138-140 C (1 mm)]. The yield was 12.60 g of colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([OH:12])CC=C)=[CH:4][CH:3]=1.C(OC(COC1C=CC(C)=CC=1)CC=C)C1C=CC=CC=1>>[CH3:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]=[O:12])=[CH:4][CH:3]=1
Reactant: C=CCC(O)COc1ccc(C)cc1
Agent: C=CCC(COc1ccc(C)cc1)OCc1ccccc1
Product: Cc1ccc(OCC=O)cc1

Procedure:
5-(4-methylphenoxy)-1-penten-4-ol (Step A-3); 4-benzyloxy-5-(4-methylphenoxy)-1-pentene (Step A-4);
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([N:17]([CH3:19])[CH3:18])([C:15]#N)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:15]([C:12]1([N:17]([CH3:19])[CH3:18])[CH2:13][CH2:14][CH:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C1(C#N)CCC(OCc2ccccc2)CC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.00 g of 4-benzyloxy-1-dimethylaminocyclohexanecarbonitrile were dissolved in 40 ml of tetrahydrofuran, and 10.8 ml of two molar benzylmagnesium chloride solution in tetrahydrofuran were added dropwise under a nitrogen atmosphere, while cooling with an ice bath. After stirring overnight at room temperature, the mixture was again cooled in an ice bath, and 20 ml of cold ammonium chloride solution (20 percent by weight) were added. The phases were separated and extracted twice using 60 ml of diethyl ether each time, the combined organic phases were extracted three times using 50 ml of hydrochloric acid (5 percent by weight) each time, the combined acidic extracts were rendered weakly alkaline (pH 8–9) with aqueous ammonia solution (25 percent by weight) and extracted three times using 60 ml of diethyl ether each time, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. The resulting yellow solid (3.85 g) was separated on silica gel with diethyl ether/hexane (V:V=1:1). 2.45 g of (1-benzyl-4-benzyloxycyclo-hexyl)dimethylamine were obtained in the form of a white solid which, as described for Example 1, was converted into 2.03 g of the corresponding hydrochloride (white solid) using chlorotrimethylsilane and water in 2-butanone.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:26])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc([C@H]2CNC(=O)N2c2ccc(Oc3ccc(Cl)cc3)cc2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C1NC[C@H](c2cccc(O)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 88.2 %

Procedure:
A solution of (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-methoxyphenyl)-imidazolidin-2-one (99 mg, 0.25 mmol) in CH2Cl2 (2 mL) is cooled to −78° C. when BBr3 (1 mmol, 1 mL of 1M solution in CH2Cl2) is added drop wise. After the addition, the mixture is warmed to 0° C. and stirred for 1 h when MeOH (0.5 mL) is added into the mixture to quench the reaction. The reaction mixture is then treated with water (3 mL) and extracted with EtOAc (3×5 mL). The combined organic layers are concentrated and purified by flash column chromatography (silica gel, 0-100% EtOAc/hexane) to provide the titled compound as a white solid (84 mg, 88%). HPLC-MS calculated for C21H17ClN2O3 (M+H+) 381.1, found 381.1.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[CH2:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O>[Cl:1][C:2]1[N:11]=[C:10]([O:20][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCCCCO
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOc1nc(Cl)nc2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
7.3 g of 2,4-dichloroquinazoline (J. Chem. Soc., 1947, 775) was suspended in 40 ml of N,N-dimethylformamide, and with ice cooling, 1.9 g of sodium hydride (oily, 60 %) was added. A solution of 3.7 g of l-pentanol in 5 ml of N,N-dimethylformamide was added dropwise over 5 minutes, and then further stirred at 50° C. for 1 hour. After cooling, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography [eluted with hexane/ethyl acetate (8:1, v/v)] to give 8 g of 2-chloro-4-pentyloxyquinazoline. A portion of this produce was recrystallized from hexane to give a product having the following physical property values.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:15]I>C1COCC1>[CH3:15][O:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: CI
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
(S)-2-Hydroxy-3-phenylpropanoic acid (1.0 g, 6.02 mmol) was dissolved in THF (100 ml), sodium hydride (0.48 g, 12.00 mmol) and methyl iodide (1.71 g, 12.04 mmol) were added, and the mixture was stirred at 65° C. for one hour. After leaving to cool, the reaction solution was concentrated under reduced pressure and adjusted to pH 4 by adding a 6 M aqueous hydrochloric acid solution thereto. The aqueous layer was extracted with ethyl acetate, the organic layer was concentrated, and the resulting residue was purified by column chromatography (dichloromethane:methanol=10:1) to afford the title compound (0.71 g, 59%).