Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH:7]1[CH:9]([C:10]([OH:12])=[O:11])[C:8]1([CH3:14])[CH3:13])[C:3]([Br:6])([Cl:5])[Cl:4].[F:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26]O)[CH:22]=2)=[CH:18][CH:17]=1>>[Br:1][CH:2]([CH:7]1[CH:9]([C:10]([O:12][CH2:26][N:23]2[CH:24]=[CH:25][C:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:29][CH:28]=3)=[CH:22]2)=[O:11])[C:8]1([CH3:14])[CH3:13])[C:3]([Br:6])([Cl:4])[Cl:5]
Reactant: CC1(C)C(C(=O)O)C1C(Br)C(Cl)(Cl)Br
Reactant: OCn1ccc(Cc2ccc(F)cc2)c1
Product: CC1(C)C(C(=O)OCn2ccc(Cc3ccc(F)cc3)c2)C1C(Br)C(Cl)(Cl)Br

Procedure:
Following the procedure of Example 1, 3-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropanecarboxylic acid is reacted with [3-(4-fluorobenzyl)-1-pyrrolyl]methanol to give the final product [3-(4-fluorobenzyl)-1-pyrrolyl]methyl 3-(1,2-dibromo-2,2-dichloroethyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[C:29]1([CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27][NH:28][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.562 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 178 mg (0.843 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of DMF. 162 mg (0.843 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter referred to as WSC hydrochloride) was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[N:9]3[C:12]([CH:15]([OH:17])[CH3:16])=[N:13][N:14]=[C:8]3[CH2:7][N:6]=[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:4]=2[CH:3]=1>C1(C)C=CC=CC=1>[C:15]([C:12]1[N:9]2[C:10]3[S:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:6][CH2:7][C:8]2=[N:14][N:13]=1)(=[O:17])[CH3:16]
Reactant: CC(O)c1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: Cc1ccccc1
Product: CC(=O)c1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
0.4 g of 2-chloro-4-(o-chlorophenyl)-9-(α-hydroxyethyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine are boiled under reflux for 48 hours in 80 ml of dry toluene with 0.6 g of chromtrioxide embedded in graphite. The solid material is filtered off and the solution evaporated. The residue is recrystallized from ethanol, there being obtained 9-acetyl-2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine of melting point 89°-91° C.
Reaction SMILES: [CH2:1]([CH:8]([C:19](=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9](=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>[Pd].C(OCC)(=O)C>[CH2:1]([CH:8]([C:9](=[O:18])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccccc1)C(Cc1ccccc1)C(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)C(Cc1ccccc1)C(=O)CCc1ccccc1
Yield: 69.4 %

Procedure:
4-Benzyl-1,7-diphenyl-1,6-heptadiene-3,5-dione (9b, 0.26 g, 0.7 mmol) and palladium on activated carbon (0.25 g, 10%) were combined in ethyl acetate (50 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 2 hr at room temperature. The resulting mixture was filtered through celite and the filtrate was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford an oil. Hexane was added to the crude oil and the resulting precipitate was filtered. The crude solid was recrystallized twice from hexane to give 0.18 g (69%) of white needles: mp 74-75° C.; 1H NMR: δ enol form: 2.61 (m, 10H), 7.14 (m, 15H); keto form: 2.61 (m, 8H), 3.07 (d, 2H, J=7.2 Hz), 3.90 (t, 1H, J=7.6 Hz), 7.14 (m, 15H); 13C NMR: δ 29.3, 34.3, 44.3, 69.2, 126.1, 126.7, 128.3, 128.4, 128.6, 128.7, 137.9, 140.4, 204.3; Exact mass calcd for C26H26O2: 370.1933, observed (M+H) 371.2014.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:31][CH3:32])=[C:7]([CH:11]([O:27][C:28](=[O:30])[CH3:29])[CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH:8]=[CH:9][CH:10]=1)(=O)C.C([O-])(O)=O.[Na+].CO>O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([CH:11]([O:27][C:28](=[O:30])[CH3:29])[C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[C:6]=3[O:31][CH3:32])[CH2:17][CH2:16]2)=[CH:21][CH:22]=1
Reactant: COc1c(OC(C)=O)cccc1C(OC(C)=O)C1CCN(CCc2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(O)cccc1C(OC(C)=O)C1CCN(CCc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
Stir overnight a mixture of the acetic acid -(3-acetoxy-2-methoxy-phenyl)-{1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl}-methyl ester, Example 1F (5.2 g, 1.1 mmol), NaHCO3 (11 g, 130 mmol), methanol (100 mL) and water (50 mL). Add water (100 mL) and dichloromethane (100 mL), and separate the layers. Extract the aqueous layer with dichloromethane (100 mL), and combine the organic layers. Dry over Na2SO4 and filter. Remove the solvent under vacuum and obtain 5.1 g of product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2].[CH3:19]N(N=O)C(N)=O.[OH-].[K+].CC(O)=O>CCOCC>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2cc(C(=O)O)ccc2c1
Reactant: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc2cc(COC(C)=O)ccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 139.8 %

Procedure:
To a suspension of 1.08 g (4.43 mmol) of 6-acetoxymethyl-2-naphthoic acid in 150 mL of Et2O at 0° C. was added a cold solution of CH2N2 in Et2O which was prepared from 2.0 g (19 mmol) of N-methyl-N-nitrosourea and 30 mL of 40% aqueous KOH. The mixture was stirred at 0° C. for 10 min when all the solid went into solution. Excess CH2N2 was decomposed with HOAc. The reaction mixture was dried over Na2SO4 and concentrated to give 1.6 g of a white solid, which was purified on 100 g of silica gel (50% EtOAc/hexane) to give 1.04 g (91% yield) of the pure methyl ester. A portion was recrystallized from EtOAc/hexane to give white plates: mp 115°-116° C.; IR (mull) 1720, 1300, 1260, 1200, 1140, 1100, 1040, 980, 940, 900, 840, 820, 760 cm-1 ; 1 H NMR (CDCl3) δ2.15 (s, 3, CH3CO2), 3.98 (s, 3, CO2CH3), 5.28 (s, 2, CH2O), 7.3-8.7 (m, 6, ArH); MS calcd for C15H14O4 258.0892, found 258.0872.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@H:5]([OH:33])[CH2:6][C@H:7]([NH:22][C:23]([C:25]1[CH:29]=[C:28]([C:30](=[O:32])[CH3:31])[NH:27][N:26]=1)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)C.[Li+].[OH-].O.CCO>>[C:30]([C:28]1[NH:27][N:26]=[C:25]([C:23]([NH:22][C@H:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)=[CH:13][CH:14]=2)[CH2:6][C@@H:5]([OH:33])[C:4]([OH:34])=[O:3])=[O:24])[CH:29]=1)(=[O:32])[CH3:31]
Reactant: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(C(C)=O)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(C(=O)N[C@H](Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)O)n[nH]1
Yield: 16.8 %

Procedure:
(2R,4R)-4-[(5-Acetyl-1H-pyrazole-3-carbonyl)amino]-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-pentanoic acid ethyl ester (72 mg, 150 μmol) was stirred at room temperature with LiOH (10.8 mg, 450 μmol) in water (450 μL, 25 mmol) and EtOH (450 μL, 7.7 mmol), overnight. The solvent was removed and the remaining material was purified by preparative HPLC to yield the title compound (11.5 mg) as a TFA salt.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[ClH:24]>O>[ClH:24].[NH:11]1[CH2:10][CH2:9][CH:8]([N:7]2[CH:3]=[CH:4][NH:5][C:6]2=[O:21])[CH2:13][CH2:12]1
Reactant: COC(CNC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: Cl
Solvent: O
Product: O=c1[nH]ccn1C1CCNCC1
Reaction time: 0.33 h
Yield: 99 %

Procedure:
tert-Butyl 4-(3-(2,2-dimethoxyethyl)ureido)piperidine-1-carboxylate (1.62 g, 4.89 mmol) was suspended in water (15 ml). Concentrated hydrochloric acid (15 ml, 183 mmol) was added to the mixture. Reaction was held at room temperature for 20 minutes. Mixture was concentrated by roto-vap. Residue was treated with ethanol and the mixture was then concentrated by roto-vap. Residue was treated with ethyl acetate and then concentrated to dryness. Resulting yellow oil was triturated in 80% acetone-diethyl ether. After 10 minutes a consistent solid was formed. Solids were filtered off and washed with acetone. Solids were dried in vacuo. Title compound was obtained as off-white solid in 99% yield. MS (M+H)+=168.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2c(c1)C(=O)CC2(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)CCC2(C)C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A solution of 3,3,6-trimethylindan-1-one (2.62 g, 15 mmol) in trifluoroacetic acid (12 mL, 150 mmol) was stirred at room temperature under nitrogen as triethylsilane (5.3 mL, 33 mmol) was added dropwise. The solution was stirred overnight. The reaction mixture was treated with saturated sodium bicarbonate, followed by extraction with ether. The combined ether layers were dried over anhydrous sodium sulfate and concentrated. MS analysis of the crude material showed the presence of triethylsilanol and hexaethyldisiloxane as the major by-products. The crude material was subjected to fractional distillation to afford 1,1,5-trimethylindane (307) (2.19 g, 92%) as a colorless liquid. Boiling pt 86-88° C. at 0.8 mmHg; 1H NMR (CDCl3) δ 1.24 (s, 6H), 1.90 (t, 2H), 2.31 (s, 3H), 2.85 (t, 2H), 7.02 (m, 3H).
Reaction SMILES: C(O[C@H:5]1[C@H:10]2[C@H:8]([C:9]2([CH3:12])[CH3:11])[C:7](=[O:13])[O:6]1)(=O)C.Cl.[CH3:15][O:16][NH2:17].[OH-].[Na+].Cl>C(O)C>[CH3:12][C:9]1([CH3:11])[C@@H:10]([CH:5]=[N:17][O:16][CH3:15])[C@H:8]1[C:7]([OH:6])=[O:13]
Reactant: CC(=O)O[C@@H]1OC(=O)[C@@H]2[C@H]1C2(C)C
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C[C@H]1[C@@H](C(=O)O)C1(C)C
Reaction time: 4 h

Procedure:
A 184 mg sample of (1R,4R,5S)-4-acetoxy-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2-one in 2.5 ml of 60% aqueous ethanol was treated with 835 mg of methoxyamine hydrochloride and 40 mg of sodium hydroxide at room temperature. After 4 hours, the resulting mixture was acidified to pH 2 with dilute hydrochloric acid, and extracted with methylene chloride. The organic phase was dried (MgSO4) and stripped to yield 148 mg of the desired (1R,cis)-2,2-dimethyl-3-((methoxyimino)methyl)cyclopropanecarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]#[CH:17]>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:17][C:16]#[CH:15])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: C#CCBr
Product: C#CCN1CC[C@H](NC(=O)OC(C)(C)C)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using propargyl bromide in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is triturated from Et2O/hexanes to give the title compound as a white solid.
Reaction SMILES: C(O[O:4][P:5]([CH:11]([CH2:17][CH:18]([P:29]([O:35]OCC)([O:31]OCC)=[O:30])[P:19]([O:25]OCC)([O:21]OCC)=[O:20])[C:12]([O:14]CC)=[O:13])([O:7]OCC)=[O:6])C>Cl>[P:5]([CH:11]([CH2:17][CH:18]([P:19]([OH:21])([OH:25])=[O:20])[P:29]([OH:31])([OH:35])=[O:30])[C:12]([OH:14])=[O:13])([OH:6])([OH:7])=[O:4]
Reactant: CCOOP(=O)(OOCC)C(CC(P(=O)(OOCC)OOCC)P(=O)(OOCC)OOCC)C(=O)OCC
Agent: Cl
Product: O=C(O)C(CC(P(=O)(O)O)P(=O)(O)O)P(=O)(O)O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
190 g of ethyl 2,4,4-tris(diethoxyphosphono)butyrate are dissolved in 600 ml of concentrated hydrochloric acid and stirred at 100° C. for 16 hours, hydrogen chloride being passed in at the same time. The reaction mixture is then evaporated to dryness, and the residue is dissolved in water and converted into the dipotassium salt using the appropriate amount of KOH. The dipotassium salt was recrystallized from aqueous methanol. 88.5 g (60% of theory) of the product are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCC1CCOCC1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: C(Cl)Cl.[C:4](OC(=O)C)(=[O:6])[CH3:5].[OH:11][C:12]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[C:4]([O:11][C:12]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:6])[CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(N2CCCCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methylene chloride (9.0 mL), pyridine (0.82 mL), and acetic anhydride (0.46 mL) were sequentially added to the obtained 2-hydroxy-5-(piperidin-1-yl)benzoic acid (0.90 g), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resulting mixture was washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.55 g of 2-acetoxy-5-(piperidin-1-yl)benzoic acid as a light yellow solid.
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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:45][C:46]1([CH3:61])[CH2:48][CH:47]1[CH:49](O)[C@@H:50]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH3:51]>C1COCC1>[CH3:61][C:46]1([CH3:45])[CH2:48][CH:47]1[CH:49]([N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[C@@H:50]([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH3:51]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(O)C1CC1(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(C1CC1(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7.3 %

Procedure:
Phthalimide (0.147 g), triphenylphosphine (0.34 g), and diisopropyl azodicarboxylate (0.684 ml) were added to a THF (5 ml) solution containing tert-butyl ((2S)-1-(2,2-dimethylcyclopropyl)-1-hydroxypropan-2-yl)carbamate (0.20 g), followed by stirring at room temperature for 1.5 hours. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:0.2). A yellow liquid of tert-butyl ((2S)-1-(2,2-dimethylcyclopropyl)-1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)carbamate (22.4 mg) was thus obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])(O[CH2:11][C:12](C1C=CC=CC=1)([C:16]1C=CC=CC=1)[C:13](C)=[CH2:14])=O>C(=S)=S>[CH3:11][C:12]1([CH3:16])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[O:7][CH2:14][CH2:13]1
Reactant: Oc1ccccc1
Reactant: C=C(C)C(COP(=O)([O-])[O-])(c1ccccc1)c1ccccc1
Solvent: S=C=S
Product: CC1(C)CCOc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dry, ice-cooled flask containing 34.95 g (0.134 mol) of stannic chloride was added quickly under argon 63.0 g (0.669 mol) of phenol. The mixture was stirred at 0° C. for 0.5 hour and then treated with 43.0 g (0.135 mol) of diphenyl-3-methyl-3-buten-1-yl phosphate, followed by a 5 ml carbon disulfide rinse. The mixture was stirred at room temperature for 21 hours and then quenched by pouring onto 700 g ice and 1 liter of 1.5N NaOH. The mixture was extracted with 1×600 ml and 2×300 ml ether. The combined ether fractions were washed with 2N NaOH, saturated NaCl and dried (MgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 2% ether in hexane) to give the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])([O-])=O.[ClH:12]>[C].[Pd]>[ClH:12].[NH2:1][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cc(O)ccc1O
Agent: [Pd]
Agent: Cl
Product: Nc1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 2-nitrobenzene-1,4-diol (1.00 g) and 10% palladium carbon (containing water (50%), 1.00 g) in 1 M hydrochloric acid (13 mL) was stirred at room temperature for 5 hr under a hydrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with ethyl acetate to give the title compound (949 mg).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[C:32]1([C@H:38]([NH2:40])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC#N>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:31])[F:30])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:40][C@@H:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:39])[N:5]=2)[CH:26]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Solvent: CC#N
Product: C[C@@H](NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.20 mmol) and (1R)-1-phenylethan-1-amine (242 mg, 2.00 mmol) in MeCN (3 mL, 57.07 mmol) was stirred at 80° C. for 12 h. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (2#-Analyse HPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBD Column, 19&#65533; 100 mm 5 um 13 nm; mobile phase, Water with 10 mM NH4CO3 and ACN (40% ACN up to 58% in 6 min); Detector, UV 254/220 nm. This resulted in 38 mg of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a off-white solid. LCMS (Method 25) [M+H]+=552.1, RT=1.16 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.72 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.34 (s, 1H), 7.60 (dd, 1H, J=2.7, 9.0 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.31-7.17 (m, 6H), 6.98 (t, 1H, J=73.2 Hz), 4.18 (t, 2H, J=6.0 Hz), 3.70 (q, 1H, J=6.6 Hz), 2.83-2.73 (m, 2H), 1.22 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:11]2[C:12]([CH3:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1c(N2CCC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.1 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-t-butoxycarbonylaminopyrrolidine (200 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (110 mg, DBU) and anhydrous acetonitrile (2 ml) was refluxed for 18 hours. The reacting mixture was concentrated under reduced pressure. The resulting residue was dissolved in chloroform (20 ml), washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the solution of the resulting residue in methanol (2 ml) was added concentrated hydrochloric acid (2 ml) and stirred at room temperature for 15 minutes. After the reacting mixture was neutralized with concentrated aqueous ammonia, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting chloroform-methanol-concentrated aqueous ammonia (10:10:3) and recrystallized from dichloromethane-methanol further to give the title compound (30 mg) as yellow powder, mp 187°-190° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.[OH-:17].[Ba+2:18].[OH-]>C1(C)C=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11]([O-:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11]([O-:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.[Ba+2:18]
Reactant: [OH-]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [Ba+2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccccc1[O-]

Procedure:
The barium nonylphenate is prepared by contacting nonylphenol (0.02 mole) and barium hydroxide (0.01 mole of Ba(OH)2) in the presence of 100 cc. of toluene. The mixture is agitated in the hot (60°-80° C.) until the barium hydroxide has entirely disappeared. About half the solvent is evaporated in vacuum so as to carry over all of the water formed and the concentrated solution is then made up to 100 cc. by means of fresh toluene. In this way there is obtained a solution of anhydrous barium nonylphenate in toluene of a concentration of about 1/10 M.