Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8](Br)(C)[C:9](OCC=C)=O.C(OCC)(=O)C>[Cu]Br.C(#N)C>[CH3:7][CH2:8][CH2:9][CH2:6][O:5][C:1]([CH:2]=[CH2:3])=[O:4]
Reactant: C=CC(=O)OC
Reactant: C=CCOC(=O)C(C)(C)Br
Agent: [Cu]Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CC(=O)OCCCC
Temperature: 80 °C

Procedure:
To a 30 mL pyrex tube were added methyl acrylate (5 mL, 4.78 g, 55.5 mmole), allyl 2-methyl-2-bromopropionate(0.354 mL, 460 mg, 2.2 mmole), copper (I) bromide (318 mg, 2.22 mmole), 2,21-bipyridyl (1.04 g, 6.66 mmole), ethyl acetate (4 mL) and acetonitrile (1 mL). The mixture was degassed by three freeze-pump-thaw cycles and then sealed. The mixture was heated to 80° C. for 3 hours and then after cooling to ambient temperature, the mixture was diluted with ethyl acetate (20 mL). An insoluble precipitate was filtered off and the filtrate was washed twice with dil. HCl and once with NaCl solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield a poly(butyl acrylate) having an alkenyl group at one end and a bromine atom at the other end (3.93 g, 75%). The molecular weight and the molecular weight distribution of the polymer were found to be 2700 and 1.48, respectively, by GPC analysis (based on polystyrene standard). The number of alkenyl groups introduced into the polymer was 0.81 based on 1H NMR analysis.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:11]=[N:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][CH:15]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:24][NH2:25]>C(O)(=O)C>[O:16]([C:13]1[N:12]=[CH:11][C:10]([C:9]2[NH:25][N:24]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=2)=[CH:15][N:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cnc(Oc2ccccc2)nc1
Reactant: NN
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cnc(Oc3ccccc3)nc2)[nH]n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a mixture consisting of the solid comprising ethyl 2,4-dioxo-4-(2-phenoxypyrimidin-5-yl)butanoate (Step A, 1.00 mmol theory) in acetic acid (10 mL) was added hydrazine (0.40 mL, 410 mg, 13 mmol). The stirring mixture was heated to 60° C. for one hour and was subsequently cooled to room temperature and stirred overnight. The off-white solid which had precipitated was collected by filtration and washed with hexane. The solid was purified by silica gel flash chromatography using a 9:1 to 1:1 v/v hexane-ethyl acetate gradient through a 40-g Silicycle® flash silica cartridge to afford the title compound as a white solid (100 mg, 32% yield); Rf 0.50 with 1:1 v/v hexane-ethyl acetate; 1H-NMR (300 MHz; DMSO-d6) δ 9.12 (s, 2H), 7.50 (s, 1H), 7.43 (dd, 2H), 7.20-7.28 (m, 3H), 4.26 (q, 2H), 1.25 (t, 3H); MS (ESI−) m/z 309 (M−1); H-PGDS FPBA IC50: 1.3 μM; H-PGDS inhibitor EIA IC50: 0.13 μM.
Reaction SMILES: [CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][P:11]=[O:12]>CO>[OH:9][C:2]([P:11]([OH:12])[OH:10])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)=O
Reactant: O=PO
Solvent: CO
Product: CCCCCCC(C)(O)P(O)O
Temperature: 25 °C

Procedure:
A mixture of octan-2-one (3.76 g, 0.29M) and hypophosphorus acid (91.5%, 2.09 g, 0.029M) is heated at 100° C. for 12 hours in the presence of Dowex 50W×2 ion exchange resin (1 ml, aqueous slurry). The mixture is cooled to room temperature, methanol (50 ml) is added and the Dowex is removed by filtration. The filtrate is evaporated to an oily residue, which is dissolved in ethyl acetate, washed with water, brine, then dried (MgSO4). Removal of the solvent gives 1-hydroxy-1-methylheptylphosphonous acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:12]([O:16][C:17]([NH:19][C@@H:20]1[CH2:25][C@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][NH:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][N:22]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CC(NC(=O)OC(C)(C)C)CN(c2cc(C(=O)O)c(Cl)nn2)C1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of 3,6-Dichloro-pyridazine-4-carboxylic acid (201) (400 mg, 2 mmol) and (3R,5S)-3,5-bis-tert butoxy carbonyl amino piperdine (4) (1.3 g, 4 mmol) in 14 ml DMF containing iPr2NEt (718 ∥l, 4 mmol) was heated at 100° C. for 25.6 h with shaking. The solvent was removed under reduced pressure. After HPLC purification, compound 207 (483 mg, 51.1%) was obtained as a solid. LC-MS (ESI): m/e=472.3 [M+1]+
Reaction SMILES: [C:1]([O:15][C@H:16]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[C:28]([NH:36][C:37](=[O:53])[CH2:38][CH:39]2[C:52]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[O:46][C:45]3[C:40]2=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:27]=1)[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:14])[CH2:2][CH2:3][C:4]([O:6]CC1C=CC=CC=1)=[O:5].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:15][C@H:16]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:33])([CH3:34])[CH3:35])=[C:28]([NH:36][C:37](=[O:53])[CH2:38][CH:39]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=3[O:46][C:47]3[C:52]2=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:27]=1)[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)(=[O:14])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(CC[C@H](CC2CCCCC2)OC(=O)CCC(=O)OCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CC[C@H](CC2CCCCC2)OC(=O)CCC(=O)O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
A solution of 337 mg (0.471 mmol) of (R)-1-(2-{4-t-butyl-3-[2-(9H-xanthen-9-yl)acetamido]phenyl}ethyl)-2-cyclohexylethyl benzyl succinate (prepared as described in Preparation 25) in 10 ml of ethyl acetate was vigorously stirred in a stream of hydrogen in the presence of 173 mg of 10% w/w palladium-on-charcoal. The reaction mixture was then filtered, and the catalyst was washed with ethyl acetate. The filtrate and the washings were combined, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 15 g of silica gel, using a 1:19 by volume mixture of methanol and methylene chloride as the eluent, to give the title compound as a foam-like material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[CH:9]1.[Cl:21]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(=O)c2c(ncn2-c2ccccc2Cl)n(C)c1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2-c2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
7-(2-Chlorophenyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (138 mg) and N-chlorosuccinimide (78 mg) were suspended in N,N-dimethylformamide (1 ml). The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 151 mg of the title compound.
Reaction SMILES: [C:1]1([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:16][C:17]([NH2:19])=[O:18].C(=O)(O)[O-].[Na+]>C(O)C>[C:1]1([CH:7]([NH:14][CH2:16][C:17]([NH2:19])=[O:18])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)CCl
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CNC(c1ccccc1)c1ccccc1

Procedure:
A reaction vessel was charged with 18.3 g (100 mmole) of diphenylmethylamine dissolved in 250 ml of ethanol. Then a mixture of 9.35 g (100 mmole) of chloroacetamide and 8.4 g (100 mmole) of sodium bicarbonate was added and the suspension was brought to reflux and held at reflux for 3 days. Solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried over potassium carbonate and solvent was evaporated. The resulting solid crystallized from a mixture of benzene and cyclohexane.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].CN(C)C=O.Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:1][CH:2]=1
Reactant: CC(C)=CCBr
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccc(C)cc1

Procedure:
A mixture of p-cresol and sodium hydroxide was stirred with dimethylformamide and water while 1-bromo-3-methylbut-2-ene (VII; R1 =R2 =CH3, Hal=Br) was added dropwise. The 1-(p-methylphenoxy-3-methylbut-2-ene was isolated as described under Example B(i).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(C)(O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and (6-methylpyridin-3-yl)boronic acid. HPLC (Condition 4) tR=4.22 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=459.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 3H) 2.52 (s, 3H) 3.45-3.61 (m, 4H) 5.41 (s, 1H) 7.34 (dd, J=8.21, 5.47 Hz, 3H) 7.72 (dd, J=8.21, 2.35 Hz, 1H) 7.80-7.88 (m, 2H) 7.97 (d, J=2.35 Hz, 1H) 8.49 (d, J=1.96 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([F:10])([F:9])[F:8].C([N-]C(C)C)(C)C.[Li+].[CH2:19]=[O:20].Cl>C(OCC)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([CH2:19][OH:20])[S:4][C:3]=1[C:7]([F:10])([F:9])[F:8]
Reactant: FC(F)(F)c1sccc1Br
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc(Br)c(C(F)(F)F)s1
Temperature: -10 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a tetrahydrofuran solution (5.0 mL) of 3-bromo-2-(trifluoromethyl)thiophene (500 μL, 2.08 mmol), lithium diisopropylamide (2.06 mL, 2.29 mmol) was added under nitrogen atmosphere at −40° C., and the resultant mixture was stirred for 30 minutes. To the reaction solution, paraformaldehyde (68.8 mg, 2.29 mmol) was added and the resultant mixture was stirred for 30 minutes, followed by raising the temperature of the mixture to −10° C. The mixture was stirred at −10° C. for 4 hours and at 0° C. for 1 hour. After completion of the reaction, a 1 M hydrochloric acid was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (106 mg, yield 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH2:10][S:11][CH3:12].[O-]S(C(F)(F)[F:19])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C.CCCCCC>ClCCCl>[CH3:12][S:11][CH:10]([F:19])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:13]
Reactant: CSCC(=O)c1ccc(F)cc1F
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: ClCCCl
Solvent: CCCCCC
Product: CSC(F)C(=O)c1ccc(F)cc1F
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a 20 ml solution of 0.5 g (2.5 mmol) of 2',4'-difluoro-2-(methylthio)acetophenone [Compound (2a-1)] in 1,2-dichloroethane, 1.1 g (3.8 mmol) of N-fluoro-2,4,6-trimethylpyridinium triflate ("Onoda Florinate FP-T300", trade name; product of Chichibu Onoda Co., Ltd.) were added at room temperature, followed by stirring at the same temperature for 12 hours. The reaction mixture was added to n-hexane. The insoluble matter so precipitated was filtered off. The insoluble matter was then washed with ethyl ether, followed by combination with the hexane layer. The layers so combined were washed successively with water and saturated saline, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby 0.50 g of the title Compound (2b-1) was obtained in the form of a light yellow oil (yield: 91.7%).
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:23]C1C=CC(N)=CC=1>C(O)C>[ClH:1].[Br:23][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:4][CH:5]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(Br)cc2)c2c(ccc3nc[nH]c32)n1

Procedure:
A mixture of 37.9 g. (0.174 m.) of the compound of Example I, C., 30 g. (0.174 ml.) of p-bromoaniline and 500 ml. of ethanol was stirred and refluxed overnight. After concentrating in vacuo the residue was recrystallized from 500 m. of MeOH to give 55 g. m.p. 347°-349° .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[C:9]([O-])([O-])=O.[Cs+].[Cs+].CI>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[N:7]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: Cn1nc(Cl)ccc1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 749.4 %

Procedure:
To a solution of 6-chloropyridazin-3(2H)-one (780 mg, 6 mmol) in CH3CN (40 mL) was added Cs2CO3 (3.9 g, 12 mmol) and CH3I (1 mL, 12 mmol) and the reaction mixture was stirred at 70° C. overnight. Solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/EA=3/1) to afford the title compound as orange oil (6.5 g, 75%). [LCMS: Rt=1.43 min, m/z 145.1 (M+H)+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:25]=[S:22]1[CH2:23][CH2:24][N:19]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:6]=3[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=2)[CH2:20][CH2:21]1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Sc4ccccc4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(Sc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-4-(1-oxido-thiomorpholino)-8-phenylthio-pyrimido-[5,4-d]-pyrimidine (m.p.: 253°-255° C.) and piperazine.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[CH:21]=O)[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:23]=1.[NH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.[BH4-]>C(Cl)Cl>[N:30]1([CH2:29][CH2:28][CH2:27][NH:26][CH2:21][C@@H:19]2[CH2:20][C@H:18]2[CH2:17][N:14]2[CH2:15][CH2:16][N:11]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:25])([F:24])[F:1])=[CH:23][C:7]=4[S:8][CH:9]=3)[CH2:12][CH2:13]2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: O=C[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Reactant: NCCCn1ccnc1
Agent: [BH4-]
Solvent: ClCCl
Product: FC(F)(F)c1ccc2c(N3CCN(C[C@@H]4C[C@H]4CNCCCn4ccnc4)CC3)csc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (1R,2R)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarbaldehyde (36.8 mg, 0.1 mmol) and 1-(3-aminopropyl)imidazole (0.0235 ml, 2.1 mmol) in anhydrous methylene chloride (3 ml) is added to a solution of polymer supported borohydride (0.863 g, 3 mmol) soaked in anhydrous methylene chloride (4 ml). This mixture was shook on an orbital shaker at room temperature overnight. The reaction was then quenched with water (2 ml) and products extracted with ethyl acetate (10 ml), then washed with brine, dried with sodium sulfate, and concentrated in vacuo. Silica gel chromatography eluted with methylene chloride/methanol (95:5) yielded the pure title compound, (3-Imidazol-1-yl-propyl)-{(1R,2R)-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropylmethyl}-amine as verified by NMR and LC/MS, yielding 36.2 mg, 76%.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2CCO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[C@@H:52]([NH:55][C:56](=[O:58])[CH3:57])[CH2:51]1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@@H:52]([NH:55][C:56](=[O:58])[CH3:57])[CH2:51]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(=O)N[C@@H]1CCNC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(=O)N[C@@H]1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-N-(pyrrolidin-3-yl)acetamide. MS(m/e): 428.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[C:13]([OH:14])=[CH:12][C:11]3[O:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[CH:20]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:13]([O:14][CH3:20])=[CH:12][C:11]3[O:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[CH:18][CH:19]=1
Reactant: c1ccccc1
Reactant: COc1ccc(Cc2cc3c(cc2O)OCO3)cc1
Product: COc1ccc(Cc2cc3c(cc2OC)OCO3)cc1

Procedure:
(4-Methoxybenzyl)-3,4-methylenedioxy-6-methoxybenzene was prepared from 6-(4-methoxybenzyl)-3,4-methylenedioxyphenol (L. Jurd, Tetrahedron, Vol. 33, pp. 163-168 (1977)) by methylation as described above in H. Colorless prisms were obtained from benzene-solve F, m.p. 56°-57° (Found: C, 70.5; H, 5.95. Calc. for C16H16O4 : C, 70.6; H, 5.92%); pmr spectrum: δ3.74, 3H, S; δ3.77, 3H, S; δ3.82, 2H, S; δ5.85, 2H, S; δ5.85, 2H, S; δ6.52, 1H, S; δ6.55, 1H, S; δ6.80, 2H, D (J=9 Hz); δ7.11, 2H, D (J=9 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[CH2:17][C:16](=O)[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:16]2[CH2:17][O:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Reaction time: 17 h
Yield: 59.5 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (1.56 g, 8.38 mmol) and oxetan-3-one (500 mg, 6.94 mmol) DCE (60 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (2.34 g, 11.04 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: MeOH; 100:0 to 99:1 to 98:2) to afford 4-Oxetan-3-ylpiperazine-1-carboxylic acid tert-butyl ester as a white solid (1.0 g, 59%). 1H NMR (CDCl3, 400 MHz) δ 4.69-4.58 (m, 4H); 3.51-3.44 (m, 5H); 2.27 (m, 4H) and 1.46 (s, 9H).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[C:10]([O:19][CH3:20])[CH:9]=1)(=O)=O.O[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][S:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][O:5][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=2)=[CH:9][C:10]=1[O:19][CH3:20])(=[O:17])=[O:16]
Reactant: COc1cc(CCOS(C)(=O)=O)ccc1OS(C)(=O)=O
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CCOc2ccc(C=O)cc2)ccc1OS(C)(=O)=O
Yield: 63 %

Procedure:
50 g (0.154 mole) 3-methoxy-4-(methylsulfonyloxy)phenethyl methanesulfonate, 48.8 g 0.4 mole) p-hydroxybenzaldehyde, 65.45 g 0.473 mole) potassium carbonate in 500 ml acetonitrile was refluxed for 4 hours. The precipitate was filtered off and the solvent was evaporated. Dichloromethane was added and the organic phase was washed with water, dried (magnesium sulfate), filtered and the solvent was evaporated to give 34 g (yield 63%) of 4-[2-(4-formylphenoxy)ethyl]-2-methoxyphenyl methanesulfonate.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH2:6])=[O:5])[NH2:3].[C:7](Cl)(=[O:11])[CH:8]([CH3:10])[CH3:9]>C(N(CC)CC)C.ClCCl>[C:7]([NH:3][N:2]([CH3:1])[C:4]([NH2:6])=[O:5])(=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(=O)Cl
Reactant: CN(N)C(N)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NN(C)C(N)=O

Procedure:
1-Methylhydrazinecarboxamide was acylated with isobutyryl chloride in triethylamine and dichloromethane to give 2-isobutyryl-1-methylhydrazinecarboxamide.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.CCN(CC)CC.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][CH2:2][C@@H:3]2[CH2:4][CH2:5][C:6](=[O:8])[O:7]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC[C@@H](CO)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (2.0 g, 17.2 mmol) in DCM (20 mL) was added Et3N (4.8 mL, 34.44 mmol) followed by p-toluenesulfonyl chloride (3.61 g, 18.94 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred at the same temperature for 15 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 50% EtOAc/hexane as eluent) to provide compound A94-1 (4.06 g, 87%) as a white solid.