Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:17]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC(CCl)OCc1ccccc1
Reactant: CC(C)N
Solvent: O
Product: CC(C)N1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 85 %

Procedure:
21.9 parts of 2-benzyloxy-1,3-dichloro-propane, 59.1 parts of iso-propylamine and 59.1 parts of water were added to an autoclave, and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result 17.4 parts of 3-benzyloxy-1-(iso-propyl)azetidine boiling at 105° - 107° C. under 2 mm Hg were obtained. The yield was 85%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]([CH3:36])[CH3:35]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1
Reactant: O=C(Nc1ccn(Cc2c(O)cccc2Cl)n1)c1c(F)cccc1F
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)COc1cccc(Cl)c1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a solution of N-{1-[(2-chloro-6-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for as preparation see Intermediate 11)(37 mg, 0.102 mmol) in DMF (1 ml) was added potassium carbonate (18 mg, 0.13 mmol) and then 1-bromo-2-methylpropane (0.014 ml, 0.132 mmol, Aldrich). The suspension was stirred at ambient temperature overnight. A further amount of potassium carbonate (7 mg, 0.05 mmol) and then 1-bromo-2-methylpropane (0.014 ml, 0.132 mmol, Aldrich) was added to the suspension. The suspension was stirred at ambient temperature for a further 4 h. The suspension was diluted with methanol (0.5 ml) and then filtered through a cotton wool plug. The filtrate was purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid) (Method A). The solvent was evaporated in vacuo to give the title compound as a colourless gum (4 mg); LCMS: (System 1) MH+=420, tRET=3.63 min.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([O-:21])=[O:20]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (355 mg) in DMF (5 mL) was added sodium hydride (110 mg of 60% in oil) and 4-nitrobenzyl bromide (596 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a light orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([N:13]=[C:14]=[S:15])[CH2:6][CH2:5]2.CO[CH:18](OC)[CH2:19][NH2:20]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([N:13]1[CH:18]=[CH:19][NH:20][C:14]1=[S:15])[CH2:6][CH2:5]2
Reactant: COC(CN)OC
Reactant: Fc1cc2c(cc1F)CC(N=C=S)CC2
Solvent: CN(C)C=O
Product: Fc1cc2c(cc1F)CC(n1cc[nH]c1=S)CC2
Temperature: 85 °C
Yield: 38.2 %

Procedure:
A mixture of (-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.49 g, 2.2 mmol), prepared as in Example 10, and 2,2-dimethoxyethylamine (0.23 g, 2.2 mmol) in DMF was heated at 85° C. under argon for 2.5 hours. The solvent was removed under reduced pressure and the residue was dissolved in 2 to 3 mL of ethanol and 20 mL of 4N hydrochloric acid. The solution was heated at 85° C. for approximately 48 hours and cooled giving a crystalline material. The material was isolated by filtration and dried. Purification by column chromatography on silica gel (elution: 3% methanol/methylene chloride) gave (-)-6,7-difluoro-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.225 g, 0.84 mmol), m.p. 200°-205° C. [α]D25 -77.9°, (c=0.6, 2:1 CHCl3 /CH3 OH).
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:2]([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: CN1CCC(C(Cl)c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CCC(C(c2ccc(Cl)cc2)N2CCNCC2)CC1
Yield: 62 %

Procedure:
A mixture of 4-(chloro(4-chlorophenyl)methyl)-1-methylpiperidine (1.2 g, 4.66 mmol) in butanone (10 ml), anhydrous piperazine (1.58 g, 18.45 mmol), anhydrous K2CO3 (0.63 g, 4.61 mmol) and KI (0.76 g, 4.61 mmol) was refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (30 ml). Drying and removal of the solvent followed by chromatography (CH2Cl2:CH3OH:NH4OH 90:10:0.5) afforded desired product in 62% yield.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1>>[CH3:10][C:5]1[CH:4]=[CH:3][C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: Cc1ccc(I)cc1C=O
Reactant: c1c[nH]nn1
Product: Cc1ccc(-n2nccn2)cc1C=O

Procedure:
The title compound was synthesized in analogy to the procedure described for building block K49 from 5-iodo-2-methylbenzaldehyde [65874-26-2] and 1H-1,2,3-triazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]=[CH:6]2.[Li:14]CCCC>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]([Li:14])[CH:7]=[CH:8]2
Reactant: [Li]CCCC
Reactant: COc1cc2c(cc1OC)CC=C2
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: [Li]C1C=Cc2cc(OC)c(OC)cc21
Reaction time: 4 h
Yield: 98 %

Procedure:
5,6-Dimethoxy-indene (4.82 g, 27.35 mmol) was dissolved in a mixture of 20 mL of toluene and 180 mL of hexane and 16.25 mL of 1.6 M n-BuLi were added dropwise via a syringe over a 5 min period forming a white precipitate. The reaction mixture was stirred for 4 h then filtered. The solids were washed with 60 mL of hexane and allowed to dry under reduced pressure to afford the desired anion as a light pink solid (4.62 g, 98 percent yield).
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][N:16]1[CH2:32][CH2:31][C:19]3([N:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:22][NH:21][C:20]3=[O:30])[CH2:18][CH2:17]1)[CH2:8][CH2:7]2.[BH4-].[Na+]>CO.O>[F:33][C:3]([F:2])([F:34])[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([OH:14])[CH:9]([CH2:15][N:16]1[CH2:32][CH2:31][C:19]3([N:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][NH:21][C:20]3=[O:30])[CH2:18][CH2:17]1)[CH2:8][CH2:7]2
Reactant: O=C1c2ccc(C(F)(F)F)cc2CCC1CN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1CCc3cc(C(F)(F)F)ccc3C1O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
8-[(6-(Trifluoromethyl)-1,2,3,4-tetrahydro-1-oxo-2-naphthal-enyl)methyl]-1-phenyl-1,3,8,-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (0.65 g, see example 184) is slurried in methanol (10 ml) and, with cooling, treated with a solution of sodium borohydride (0.27 g) in water (2 ml). The resulting mixture is stirred at room temperature under nitrogen for 16 hours, diluted with water (10 ml), and extracted with methylene chloride. Concentration of the dried organic solution followed by trituration with absolute ethanol yields the free base of the title alcohol as a tan powder (0.5 g), melting point 238°-240° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.ClC[C:35]1[C:36](C)=[N:37][O:38][C:39]=1[CH3:40]>ClCCl>[CH3:35][C:36]1[C:2]([CH2:1][O:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=4[C:11]([NH2:15])=[N:12][C:13]=3[CH:14]=2)=[C:39]([CH3:40])[O:38][N:37]=1
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(OCc4c(C)noc4C)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 4-(Chloromethyl)-3,5-dimethylisoxazole (160 mg, 1.1 mmol) was added dropwise over a period of 10 minutes. After 3 hours an additional equivalent of cesium carbonate was added in a single portion followed by the dropwise addition of an equivalent of 4-(chloromethyl)-3,5-dimethylisoxazole. After 1 additional hour the heat source was removed; the reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-5% methanol in dichloromethane for over 1000 mL and then with 5% methanol in dichloromethane over 400 mL. The resulting solid was recrystallized from acetonitrile to provide 156 mg of 7-[(3,5-dimethylisoxazol-4-yl)methoxy]-2-propylthiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 178.0-180.0° C. MS (ESI) m/z 369 (M+H)+; Anal. calcd for C19H20N4O2S: C, 61.94; H, 5.47; N, 15.21. Found C, 61.98; H, 5.25; N, 15.26.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][N:17]1[Si:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][Si:18]1([CH3:25])[CH3:24]>CN(C)C=O>[CH3:22][Si:21]1([CH3:23])[CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[N:17]1[CH2:16][CH2:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: C[Si]1(C)CC[Si](C)(C)N1CCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C[Si]1(C)CC[Si](C)(C)N1CCCN1C(=O)c2ccccc2C1=O
Temperature: 75 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
About 3.36 g of potassium phthalimide, 4.89 g of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane, and 12 mL of N,N-dimethylformamide were mixed in a flask. The mixture was stirred for 5 hour while the flask was kept in an oil bath maintained at 75° C. The N,N-dimethylformamide was removed under vacuum. The residue was extracted with 90 mL of toluene and filtered. The filtrate was evaporated under vacuum. The residue was triturated with 80 mL of hexane, cooled with dry ice, and then filtered to give N-[3-(2,2,5,5-tetramethyl-1-aza-2,5-disila-1-cyclopentyl)-1-propyl]phthalimide (TMADSCPPI) as a white solid (4.3 g, 68% yield). 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product: δ 7.41 (multiplet, 2H, aromatic protons), 6.81 (multiplet, 2H, aromatic protons), 3.55 (multiplet, 2H, CH2 protons), 2.79 (multiplet, 2H, CH2 protons), 1.77 (multiplet, 2 H, CH2 protons), 0.70 (singlet, 4H, CH2—Si protons), 0.06 (singlet, 12H, Si—CH3 protons).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][C:11]([SH:15])([CH2:13][CH3:14])[CH3:12].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:15][C:11]([CH3:12])([CH3:10])[CH2:13][CH3:14])([CH3:9])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCC(C)(C)S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC(C)(C)CC

Procedure:
Ethyl 2-bromoisobutyrate (33.9 g, 0.174 mole), 2-methyl-2-butanethiol (20.0 g, 0.192 mole), potassium hydroxide (12.2 g, 0.192 mole), ethyl alcohol (100 g) were combined and the reaction mixture was refluxed for approximately 10 hours prior to quenching. Crude yield: 63.5%; after column chromatography 18.1%.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[F:14][C:15]([F:35])([F:34])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([O:29][Si](C)(C)C)C#CC(OC)=O)=[CH:18][CH:17]=1.CC(O)C>CC(C)=O>[F:14][C:15]([F:34])([F:35])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:29])=[CH:18][CH:17]=1
Reactant: COC(=O)C#CC(O[Si](C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Under cooling in an ice-bath, a 8N Jones' reagent (50 ml) was added dropwise to a solution of the crude product of silyl ether 8a obtained above in 170 ml of acetone over 15 minutes. After completion of the addition, the mixture was stirred for 35 minutes and then 11.4 ml (150 mmoles) of 2-propanol was added. The mixture was allowed to warm to room temperature while being stirring for 1 hour. The reaction mixture was filtered and the residual chromium sulfate was washed with acetone. The washing was combined with the reaction mixture, and the mixture was concentrated in vacuo. The residue was dissolved in 40 ml of ethyl acetate, 150 ml of water and 120 ml of n-hexane were added to the solution, and then the solution was extracted. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. n-Hexane (80 ml) was added to the residue, the insoluble materials were filtered off, the filtrate was concentrated in vacuo and the residue was dried in vacuo at 40° C. for 30 minutes with stirring to give 21.6 g (84.6% from compound 7a) of the crude product of the desired compound III-a as an oil. When this was stored in a refrigerator overnight, it gave crystals with low melting point. However, this was used in the next reaction without further purification. Melting point: 28°-29° C. (methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C@@:9]([OH:19])([C:14]#[C:15][CH:16]2[CH2:18][CH2:17]2)[C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]2[NH:6][C:20](=[O:21])[O:19][C@:9]([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)([C:10]([F:12])([F:13])[F:11])[C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1

Procedure:
A solution of (S)-4-chloro-2-(4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)aniline (4.42 g, 15.3 mmol), 1,1′-carbonyl diimidazole and toluene (50 mL) was stirred at room temperature for 10 minutes. The reaction was quenched with ice-water (10 mL). The two layers were separated, ethyl acetate (10 mL) was added to the toluene layer and the mixture was washed with brine (2×30 mL) and the two layers were separated. The organic layer was evaporated to dryness to give an orange oil and further crystallized with hexanes to give (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-ben zoxazin-2-one as a white or off-white solid. 1H NMR (CDCl3) δ 9.64 (s, 1H), 7.49 (a, s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 1.43-1.36 (m, 1H), 0.97-0.91 (m, 2H), 0.88-0.86 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(COc2ccccc2-c2ccc[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccccc1-c1ccc[nH]1

Procedure:
150 mg of 10% strength palladium-on-charcoal catalyst are added to 1.5 g (6 millimoles) of 2-(o-benzyloxyphenyl) -pyrrole in 30 ml of methanol and hydrogenation is carried out under slightly superatmospheric pressure. The residue which remains after separating off the catalyst and evaporating the filtrate is recrystallized from toluene/petroleum ether (40°/60° C.). the yield is 0.8 g, ie. 84% of theory; melting point 100-101° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (86 mg, 71%), MS (ISP) m/z=403.4 [(M+H)+], mp 169.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and methoxyacetic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]([CH3:40])([CH3:39])[CH2:35][C:36](O)=[O:37].O.ON1C2C=CC=CC=2N=N1.N=C=N>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][C:34]([CH3:40])([CH3:39])[CH3:33])[CH2:31][CH2:32]3)=[CH:23][CH:22]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)cc2)cc1
Reactant: CC(C)(C)CC(=O)O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)CC(C)(C)C)CC3)cc2)cc1

Procedure:
The title compound is prepared by reaction of 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-yl-phenyl)-urea (0.20 g, 0.46 mmol) with 0.51 mmol of 3,3-Dimethyl-butyric acid, (0.06 g, 0.46 mmol) of 1-Hydroxybenzotriazole hydrate and (0.8 g, 0.46 mmol) of polymer supported carbodiimide, dissolved in 16 mL of CH2Cl2. Mixture is stirred at r.t.o.n. It is filtered and the resin is washed with CH2Cl2 Solvent is evaporated and the residue is purified with an SCX cartridge eluting with NH4OH/CH3OH 2 N. ES+(m/z) 531 [M+H].
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>>[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(OCC=CCO)c1ccccc1
Product: CC(C)(C)C(=O)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl trimethylacetate was prepared by the procedure of Example 1 from 19 gms (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 12 gms (0.1 mole) of trimethylacetyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@@H:35]([CH3:42])[CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@@H:35]([CH3:42])[CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: CC(C)NCC[C@H](C)N
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 56.3 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (27 mg, 0.060 mmol) and free based [(3S)-3-aminobutyl](1-methylethyl)amine (67 mg, 0.51 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (18 mg, 56%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (15 mg, >1.00%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.02 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.54-1.58 (m, 1H), 1.94-2.03 (m, 1H), 2.71-2.76 (m, 1H), 2.82-2.88 (m, 1H), 3.13-3.16 (m, 1H), 4.16-4.19 (m, 1H), 4.30-4.33 (m, 1H), 4.48 (m, 1H), 4.55-4.65 (m, 2H), 4.97-5.00 (m, 1H), 6.97-7.01 (m, 2H), 7.30-7.34 (m, 2H), 8.28 (s, 1H), 10.51 (m, 1H), 12.55 (s, 1H); ES+ MS: 443 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:33])([F:32])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.C(=O)(O)[O-].[Na+]>ClCCl>[N:19]1([C:16]2[CH:17]=[CH:18][C:13]3[N:14]([C:10]([C:9]([F:8])([F:32])[F:33])=[N:11][N:12]=3)[N:15]=2)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Trifluoroacetic acid (25 mL, 324.49 mmol) was added to a mixture of tert-butyl 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazine-1-carboxylate (6.7 g, 17.99 mmol) and dichloromethane (100 mL) at ambient temperature and the resulting solution was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated to give an involatile residue that was treated with saturated aqueous sodium bicarbonate solution (100 mL) and then extracted with dichloromethane (4×200 mL). The organic phases were combined and dried over Na2SO4, filtered, and evaporated to give 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.78 g, 98%) as a white solid that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].C(N(CC)[P:13](Cl)([O-:15])=[O:14])C.Cl>>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([P:13]([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)(=[O:14])[OH:15])[CH:3]=1
Reactant: CCN(CC)P(=O)([O-])Cl
Reactant: Cc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Product: Cc1cccc(P(=O)(O)c2cccc(C)c2)c1

Procedure:
That is, m-bromotoluene (II) is reacted with metallic magnesium to prepare a Grignard reagent (III) which is then condensed with N,N-diethylamidochlorophosphate (IV) obtained by the process described in G. M. Kosolapoff et al., J. Am. Chem. Soc., Vol. 71, pp. 369-370 (1949), followed by hydrolysis with hydrochloric acid to obtain di-(m-tolyl)phosphinic acid (V). The compound (V) is reacted with thionyl chloride. After removing excess thionyl chloride, the reaction mixture is recrystallized from a mixed solution of benzene and hexane to obtain di-(m-tolyl)phosphonyl chloride (VI).