Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[NH:13][C:14](=[O:18])[C:15]=1[N:16]=O>O>[NH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[NH:13][C:14](=[O:18])[C:15]=1[NH2:16]
Reactant: COc1ccccc1-c1nc(N)c(N=O)c(=O)[nH]1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reaction time: 0.83 h
Yield: 43.8 %

Procedure:
Sodium dithionite (8.7 g.) was added slowly to a stirred mixture of 4-amino-2-(2-methoxyphenyl)-5-nitrosopyrimid-6-one (6.15 g.) and water (90 ml.) at 70°-80° C., and stirring at that temperature was continued for a further 50 minutes. The mixture was then cooled, the yellow solid was filtered off, washed with water and dried to give 4,5-diamino-2-(2-methoxyphenyl)pyrimid-6-one (2.54 g.), m.p. 222°-223° C. (with decomposition), pure enough for use as a starting material in the next stage of the synthesis. Recrystallisation of a sample from ethanol gave analytically pure 4,5-diamino-2-(2-methoxyphenyl)pyrimid-6-one, m.p. 223°-224° C. (with decomposition).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=3)[N:14]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Product: Cc1ccc(S(=O)(=O)Nc2cccc(COc3ccc(C(F)(F)F)cc3)n2)cc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-chloro-4-methyl-benzenesulfonyl chloride (0.074 g) as an off-white solid (0.105 g). MS (ESI−): 455.2 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])C)=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[C:27](C1C=CC(O)=CC=1)(=[O:29])[CH3:28]>>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:29][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: CC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
4-Acetylphenyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoate-Using 4-acetylphenol, the title compound was synthesized as a white solid. PMR (CDCl3): δ 1.36 (6H, s), 1.38 (6H, s), 1.76 (4H, s), 2.64 (3H, s), 7.34 (2H, d, J~8.4 Hz), 7.48 (1H, d, J~8.4 Hz), 7.98 (1H, dd, J~8.4 Hz, 2.4 Hz), 8.07 (2H, d, J~8.4 Hz), 8.19 (1H, d, J~2.4 Hz).
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[CH2:12][NH:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Br:28][CH2:29][C:30](Cl)=[O:31].C1(SC2CN[C@H](C(O)=O)C2)C=CC=CC=1>C(Cl)Cl>[Br:28][CH2:29][C:30]([N:11]1[CH2:12][C@@H:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C@H:10]1[C:13]([OH:15])=[O:14])=[O:31]
Reactant: O=C(O)[C@@H]1C[C@H](Sc2ccccc2)CN1
Reactant: O=C(Cl)CBr
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C(O)[C@@H]1CC(Sc2ccccc2)CN1
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H](Sc2ccccc2)CN1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (4S)-4-(phenylthio)-L-proline (2.2 g., 10 mmole) in methylene chloride (50 ml., freshly distilled) is added bis(trimethylsilyl)acetamide (7.35 ml., 30 mmole). The reaction mixture is stirred at room temperature for 2 hours until it becomes almost clear. The reaction mixture is then cooled to -5° and bromoacetyl chloride (1.9 g., 1.0 ml., 12 mmole) is added dropwise keeping the temperature at -5°. After stirring overnight (-5° to room temperature), the reaction mixture is concentrated to about 50% of its volume, partitioned between saturated sodium bicarbonate/ethyl acetate and the layers are separated. The organic layer is extracted once more with saturated sodium bicarbonate. The combined aqueous layers are acidified to pH 2.0 with 10% potassium bisulfate and extracted with ethyl acetate (3×). The ethyl acetate fractions are combined, dried (Na2SO4) and concentrated to give 3.5 g. of (4S)-1-bromoacetyl)-4-(phenylthio)-L-proline as a viscous oil.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].N([O-])=[O:27].[Na+].C(O)(=O)C>O.C(#N)C>[C:20]1([C:18]([NH:17][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:27])[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCCCC(NC(=O)c1ccccc1)C(=O)NCc1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: O=C(NC(CCCCO)C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
2-(N-Benzenecarbonyl)amino-6-amino-N-benzylhexanamide (105) (48 mg) obtained in Step 1-4 was dissolved in water (1.6 ml) and acetonitrile (1.1 ml). To the solution were added sodium nitrite (156 mg) and acetic acid (40.6 mg) under cooling with ice, and the mixture was stirred for 1 hour under cooling with ice. After 1 hour, the reaction liquid was warmed to room temperature and stirred for 1.5 hours. Subsequently, the reaction liquid was heated to 70° C. and stirred for an additional 20 minutes. The reaction liquid was concentrated and extracted with ethyl acetate (60 ml). The organic layer was washed with brine (100 ml), dried over anhydrous sodium sulfate, and filtered. After that, the filtrate was concentrated and the residue was purified by silica gel flash column chromatography (developing solvent: n-hexane:ethyl acetate=2:1 to n-hexane:ethyl acetate=1:6) to give a compound (106) (19.5 mg, yield: 41%) as a pale yellow solid. 1H NMR data on the compound (106) is shown below.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([O:9][C:10]1[C:11](Br)=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:7]=[CH2:8].[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH2:6]([O:9][C:10]1[C:11]([CH:20]([C:19]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:18]=2[F:17])[OH:21])=[N:12][CH:13]=[CH:14][CH:15]=1)[CH:7]=[CH2:8]
Reactant: O=Cc1cc(F)ccc1F
Reactant: C=CCOc1cccnc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCOc1cccnc1C(O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, a tetrahydrofuran solution (1.5 ml, 3 mmol) of isopropylmagnesium chloride was added dropwise to a tetrahydrofuran (2 ml) solution of 3-allyloxy-2-bromopyridine (642 mg, 3 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 60 minutes. Under ice cooling, 2,5-difluorobenzaldehyde (328 μl, 3 mmol) was added dropwise to the resulting brown solution. The temperature of the reaction mixture was raised gradually to room temperature. A saturated aqueous solution of ammonium chloride was added and then, the mixture was extracted with ethyl acetate. The solvent was dried, followed by concentration under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1), whereby the title compound (375 mg, 45%) was obtained as an oil.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7](B(O)O)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[C:22]1[CH:33]=[CH:32][C:25]([CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)=[CH:24][CH:23]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:27]1([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:7]3[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:9][C:8]=3[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:33][CH:32]=2)[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: Brc1ccc(Cn2cncn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)Cc1cc(-c2ccc(Cn3cncn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Yield: 66.6 %

Procedure:
5-iso-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (0.479 g, 1.5 mmol, see Example 1(c) above), 1-(4-bromobenzyl)-1H-[1,2,4]triazole (0.238 g, 1 mmol, see step (a) above), Pd(OAc)2 (15.7 mg, 0.03 mmol), triphenyl phosphine (15.7 mg, 0.06 mmol) and NaOH (0.16 g, 4 mmol) were dissolved in 4 mL of toluene/ethanol (4:1) in a thick walled glass tube, and were then heated to 80° C. for 1 h. The reaction mixture was cooled to rt, extracted with ethyl acetate and water and subsequently dried over K2CO3. The solvent was evaporated and the reaction mixture was separated on a silica column (dichloromethane+1% methanol to dichloromethane+4% methanol) to yield 0.288 g of the sub-title compound (65% yield).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)=O.[F:20][C:21]([F:26])([F:25])[CH2:22][NH:23][NH2:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][C:9]1[CH:8]=[C:7]([C:5]2[N:23]([CH2:22][C:21]([F:26])([F:25])[F:20])[N:24]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: NNCC(F)(F)F
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(C(F)(F)F)nn2CC(F)(F)F)ccc1[N+](=O)[O-]
Yield: 21.6 %

Procedure:
A toluene solution of 4,4,4-trifluoro-1-(3-methyl-4-nitro-phenyl)-butane-1,3-dione (1.8 g), 2,2,2-trifluoroethylhydrazine (1.2 g) and a catalytic amount of p-toluenesulfonic acid were refluxed for 6 hours. After cooling, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 3-(3-methyl-4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-5-trifluoro-methyl-1H-pyrazole (IX-5) (1.1 g) and 5-(3-methyl-4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-3-trifluoromethyl-1H-pyrazole (1-6) (0.5 g), respectively.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([CH3:32])[C:25]=1[N:33]=[C:34]=[S:35]>>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([CH3:32])[C:25]=1[N:33]=[C:34]1[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:35]1
Reactant: Cc1cc(C#N)cc(Cl)c1N=C=S
Reactant: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(C#N)cc(Cl)c1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S) -1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Chloro-4-cyano-6-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1c to give (4S)-2-(2-chloro4-cyano-6-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2f to afford (4S)-2-(2-chloro-4-cyano-6-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine trifluoroacetate salt.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[Br:13][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH3:12])[C:2]([OH:1])=[CH:11][CH:10]=1
Reactant: COC(=O)c1cccc(O)c1C
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(Br)ccc(O)c1C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of methyl 3-hydroxy-2-methylbenzoate (114a, 3.557 g, 21.40 mmol) in dichloromethane (100 mL) in a dry ice/acetonitrile bath (˜−45° C.) was added bromine (1.15 mL, 22.5 mmol) dropwise. The reaction was stirred at −45° C. for 2 hours before Na2S2O3 (sat. aq., 2 mL) was added. The reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The dichloromethane layer was concentrated under vacuum, and the resulting crude product was purified by column chromatography (0-40% ethyl acetate/heptane) to give methyl 6-bromo-3-hydroxy-2-methylbenzoate (114b, 4.8 g, 92% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[N:3]=1.[CH3:17][N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25](=[O:42])[NH:26][C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH:20]=[N:19]1>>[OH:9][CH2:8][C:6]1[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[N:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:25]([NH:24][CH2:23][C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)=[O:42])=[CH:28][CH:29]=2)[N:7]=1
Reactant: C[C@H]1COCCN1c1cc(CO)nc(Cl)n1
Reactant: Cn1cc(CNC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cn1
Product: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)NCc3cnn(C)c3)cc2)n1

Procedure:
The preparations of [2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (1.00 g, 4.10 mmol) and 3-[(1-methylpyrazol-4-yl)methyl]-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea were described earlier.
Reaction SMILES: [C:1]12([O:14]CCO1)[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=1[CH2:3][CH2:2]2.[C:15](Cl)(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[O:14]=[C:1]1[C:9]2[C:4](=[C:5]([NH:10][C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2c1CCC21OCCO1
Reactant: CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a vigorously stirred solution of Example 25 (3.9 g, 20.6 mmol) in pyridine (40 mL) was slowly added acetyl chloride (1.6 mL, 22.6 mmol). The reaction was stirred at room temperature for about 15 minutes and then the solvent was removed under vacuum. The residue was dissolved in acetone (38 mL) and water (12 mL) and p-toluenesulfonic acid (3.9 g, 20.6 mmol) was added. The mixture was heated to reflux for about 1 hour, cooled, and concentrated under vacuum. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (1:1) as the mobile phase to provide the desired product. MS (ESI): m/z 188 (M−H)−.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[O:11].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:30][C:31]([Si](C)(C)C)([F:33])[F:32]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:11])[C:31]([F:33])([F:32])[F:30]
Reactant: O=Cc1cc2ccccc2o1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cc2ccccc2o1)C(F)(F)F
Yield: 43.8 %

Procedure:
According to Reference Example 8-12, by use of benzofuran-2-carbaldehyde (300 mg, 2.05 mmol) dissolved in tetrahydrofuran (6 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (1.03 mL, 1.03 mmol) and (trifluoromethyl)trimethylsilane (0.516 mL, 3.49 mmol), the mixture was stirred and reacted at room temperature for 5 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=100/1) was performed to give 1-(benzofuran-2-yl)-2,2,2-trifluoroethanol (Compound DR) (194 mg, yield: 44%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([C:16]([OH:18])=O)=[CH:3]1.[NH2:19][N:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.CN(C1C=CC=CN=1)C.ON1C2C=CC=CC=2N=N1>[O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][NH:5][C:4]([C:16]([NH:19][N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])=[O:18])=[CH:3]1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: NN1CCNC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NN1CCNC1=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid (12.26 g, 0.05 mol) and 1-amino-2-imidazolidinone (5.56 g, 0.055 mol) were suspended in 120 ml of dimethylformamide. To the suspension was added 0.3 g of dimethylaminopyridine and 0.4 g of N-hydroxybenzotriazole. After stirring for 30 minutes at room temperature, a solution of 11.35 g of dicyclohexylcarbodiimide (0.055 mol) in 50 ml of dimethylformamide was added dropwise and the mixture was stirred overnight at room temperature. The precipitate (dicyclohexylurea) was filtered off and the filtrate evaporated in vacuo. The remaining syrup crystallized on treatment with aqueous sodium bicarbonate, yielding 11.7 g of the title compound, melting point 158°-160° C. An additional crop of 0.8 g of product, melting point 162°-164° C., crystallized from the aqueous filtrate.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Brc1ccc2sc3ccccc3c2c1

Procedure:
To a stirred, cold solution (0° C.) of 275 g. of dibenzothiophene in 1 liter of chloroform is added over 30 minutes 253 g. of bromine in 500 ml. of chloroform. After sixteen hours of stirring the mixture is heated to its reflux temperature and maintained at reflux for about 30 minutes. The mixture is then evaporated, and 900 ml. of ethanol are added to the residue. The white solid collected by filtration is 2-bromodibenzothiophene, m.p. 112°-116° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH:12]=[C:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.[OH-:17].[Na+].OO>C1COCC1.O>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][C@@H:11]([CH2:14][OH:15])[C@H:12]([OH:17])[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OC[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
A mixture 1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol (0.367 mol) and THF (1000 ml) was stirred at -70° C. and a solution of borane in THF (1 M) was added dropwise thereto. After the addition, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 18 h. The reaction mixture was cooled to -10° C. and water (23 ml) was added dropwise, NaOH (3M in water, 18 ml) was added dropwise and hydrogen peroxide (30% solution in water, 28 ml) was added dropwise at the same time. Then, simultaneously, NaOH (3M in water, 36 ml) and the hydrogen peroxide (30% solution in water, 29 ml) was added dropwise. Again NaOH (50% in water, 80 ml) was added. The reaction mixture was stirred at reflux for 4 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated. The resulting precipitate was dissolved in water (500 ml) and saturated with K2CO3. The product was extracted with CH2Cl2. The resulting solution was dried over MgSO4 and evaporated. The residue was crystallized from DIPE/CH3CN. After several crystallizations a total yield of 40, 8 g of (±)-trans-1-(phenylmethyl)-3-hydroxy-4-piperidinemethanol was obtained (Yield: 50.1%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[O:5])C>Cl>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH:7]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1c1cccs1
Agent: Cl
Product: O=C(O)C1CCN(Cc2ccccc2)CC1c1cccs1
Yield: 98 %

Procedure:
The product from step b) (2.9 g, 8.8 mmol) was treated with 4 M HCl (200 ml) at 100° C. for 16 hours. Next, the reaction was evaporated to dryness, azeotroped with toluene (2×50 ml) and placed on the high vacuum to give the subtitle compound (2.9 g, 98%). MS calculated for C17H19NO2S−H 300, observed 300.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[C:4]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:3]=1.[CH2:17]([O:20][C:21]1([CH3:50])[CH2:26][CH2:25][N:24]([C:27]2[N:32]3[N:33]=[C:34]([CH2:36]I)[CH:35]=[C:31]3[N:30]=[C:29]([CH3:38])[C:28]=2[C@H:39]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][CH2:22]1)[CH:18]=[CH2:19].[H-].[Na+]>CN(C=O)C>[CH2:17]([O:20][C:21]1([CH3:50])[CH2:22][CH2:23][N:24]([C:27]2[N:32]3[N:33]=[C:34]([CH2:36][O:10][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=4[O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH3:9])[CH:35]=[C:31]3[N:30]=[C:29]([CH3:38])[C:28]=2[C@H:39]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:25][CH2:26]1)[CH:18]=[CH2:19]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1C(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COC(C)c4ccc(C)cc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
A mixture of 1-(4-methyl-2-((S)-pent-4-en-2-yloxy)phenyl)ethanol (41.5 mg, 0.188 mmol) and (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 0.171 mmol) in DMF (5 mL) was added sodium hydride (7.53 mg, 0.188 mmol) at 0° C. It was then stirred at 0° C. for 4 h and then quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was then purified by biotage, eluting with 25% EtOAc/hexane to isolate (2S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-((1-(4-methyl-2-((S)-pent-4-en-2-yloxy)phenyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (20 mg, 0.030 mmol, 17.27% yield) as an oil. LCMS (M+1)=677.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10](=[O:12])[CH2:17][C:16]([O:15][CH3:14])=[O:21])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Agent: [K+]
Product: COC(=O)CC(=O)Cc1cc(Cl)cc(Cl)c1
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield from 2-(3,5-dichlorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A.