Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:9]([CH3:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:1]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:9]([CH3:18])[C:10]([C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:28][CH2:27]1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Yield: 43 %

Procedure:
A solution of ethyl(4S)-4-(dibenzylamino)-3-oxopentanoate (500 mg) synthesized according to the method described in Journal of Organic Chemistry, vol. 62, pp. 2292-2297 (1997), 1,2-dibromoethane (0.19 mL) and potassium carbonate (405 mg) in acetone (15 mL), was stirred under reflux overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→2/1) to give the title compound as a colorless oil (yield: 231.4 mg, 43.0%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCc1cccnc1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Solvent: CC(=O)O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (1.00 mmol, 209 mg) and 3-(aminomethyl)-pyridine (1.00 mmol, 26 mg) in glacial acetic acid (4 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The crude product was used without purification.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([N+:23]([O-:25])=[O:24])[C:21]=1F)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([N+:23]([O-:25])=[O:24])[C:21]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
Cyclopropylmethyl alcohol (0.921 ml, 11.4 mmol) was added to a stirring suspension of NaH (455 mg, 11.4 mmol) in DMF (20 ml) under an argon atmosphere. The resulting solution was allowed to stir at RT for 20 min. 6-chloro-7-fluoro-8-nitro-9H-β-carboline (500 mg, 1.9 mmol) was added to the stirring solution and the resulting mixture was allowed to stir at RT. Upon addition of H2O, a brown solid precipitated out which was filtered to give the desired 6-chloro-7-cyclopropylmethyoxy-8-nitro-9H-β-carboline (510 mg, 85%). 1H-NMR (300 MHz, DMSO-d6): δ 0.35 (m, 2H), 0.59 (m, 2H), 1.32 (m, 1H), 4.04 (d, 2H), 8.21 (d, 1H), 8.46 (d, 1H), 8.90 (s, 1H), 9.02 (s, 1H), 12.32 (b, 1H). Retention Time (LC, method: ammonium acetate standard): 2.63 min. MS (M+H+): 318.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=O)C.Cl.[NH2:15][C:16]([NH2:18])=[NH:17].CC(C)([O-])C.[K+]>CO>[NH2:17][C:16]1[NH:18][C:4](=[O:3])[CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)C1CCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Nc1nc(C2CCCC2)cc(=O)[nH]1
Temperature: 60 °C
Yield: 87.6 %

Procedure:
To a solution of 3-cyclopentyl-3-oxo-propionic acid ethyl ester (5.0 g, 27.4 mmol) and guanidine hydrochloride (3.1 g, 33.0 mmol) in MeOH (50 mL) at 23° C. was added potassium tert-butoxide, portionwise (16.7 g. 149 mmol) over 15 min with vigorous stirring and the reaction warmed to 60° C. The reaction was cooled to room temperature (rt) and stirred overnight and the precipitated salt was removed by filtration. The solution was concentrated to approximately 10 mL then diluted with 10 mL of water and adjusted to pH=5 by the addition of 6.0 N HCl (6.1 mL). The resulting precipitate was filtered and dried via suction then vacuum to yield a white solid (4.3 g, 87%) that was used without further purification. 1H NMR (MeOD): 10.71-10.54 (m, 1H), 6.58-6.32 (m, 2H), 5.44-5.37 (m, 1H), 2.66 (p, J=8.1, 1H), 1.91-1.73 (m, 2H), 1.72-1.48 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[O:16][CH:15]=[N:14][C:13]=1[C:17]([O:19]CC)=[O:18].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[O:16][CH:15]=[N:14][C:13]=1[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)c1ncoc1-c1ccc([N+](=O)[O-])cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1-c1ocnc1C(=O)O

Procedure:
In 50 ml of methanol were added 15.0 g (0.051 mol) of 5-(2-methoxy-4-nitrophenyl)-4-carboethoxyoxazole obtained in Example 1-(1) and 9.8 g (0.061 mol) of a 25% aqueous solution of sodium hydroxide, and the mixture was allowed to react at 40° C. for 4 hours. The reaction mixture was filtered to collect sodium 5-(2-methoxy-4-nitrophenyl)-4-oxazolecarboxylate as a wet cake, which was dissolved in 1000 ml of water and adjusted to pH 2 with 35% hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 12.2 g (0.046 mol, 90.2% based on the 5-(2-methoxy-4-nitrophenyl)-4-carboethoxyoxazole) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:30])([CH3:29])[CH2:12][C@:13]([CH2:19][S@:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=O)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:30])([CH3:29])[CH2:12][C@:13]([CH2:19][S:20][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)([OH:18])[C:14]([F:17])([F:15])[F:16])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(Br)cc3c2OCC3)C(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(SC[C@](O)(CC(C)(C)c2cc(Br)cc3c2OCC3)C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
To a suspension of (S)-4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (11.5 g, 22.8 mmol) and sodium iodide (10.2 g, 68.1 mmol) in 180 mL of anhydrous acetone at −40° C. was added a solution of trifluoroacetic acid anhydride (16.0 mL, 113 mmol) in 30 mL of anhydrous acetone dropwise by syringe over 20 minutes. A greenish brown mixture was formed instantaneously. After 20 minutes, the reaction mixture was quenched with saturated aqueous sodium sulfite solution and neutralized with saturated aqueous sodium carbonate solution. The brown color disappeared and the crude was concentrated to remove most of the acetone solvent. The resulting material was diluted with 350 mL of water and extracted with three 600 mL portions of ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (S)-4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-p-tolylsulfanylmethyl-pentan-2-ol as a yellow oil (11.1 g, 99%).
Reaction SMILES: [Cl-].C([Al+]CC)C.Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH2:16]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CCCCCC.O1CCCC1.[Zn].[Cu]Br>[OH:31][CH:30]([C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCCCCCCCCc1ccccc1C=O
Agent: [Cu]Br
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCc1ccccc1C(O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
A solution of diethylaluminum chloride (54.7 mmol) in hexane was added to a slurry of zinc dust (74.5 mmol) and a catalytic amount of copper (I) bromide (2.5 mmol) in anhydrous tetrahydrofuran (300 ml) while stirring under argon at 20° C. The resulting mixture was then cooled to 0° C. in an ice-methanol bath. A solution of t-butyl bromoacetate (49.8 mmol) and 2-dodecylbenzaldehyde of Example 1(c) (54.7 mmol); in anhydrous tetrahydrofuran was added slowly over 60 minutes. The reaction was stirred for about 24 hours and was permitted to warm slowly to room temperature. The mixture was filtered to remove zinc, concentrated, acidified with 3N hydrochloric acid and extracted with ether. Organic extracts were dried over magnesium sulfate, filtered, and evaporated to afford crude product. This material was then flash chromatographed on silica using 8% ethyl acetate in hexane to give the desired product in 79% yield.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][C@H:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:10](=[O:26])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1.I[CH2:38][C:39]#[N:40]>O1CCCC1.O>[C:39]([CH2:38][N:13]1[C@H:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:10](=[O:26])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[C:4]1=[O:3])#[N:40]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC#N

Procedure:
Sodium hydride (60% in mineral oil, 11 mg, 0.28 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18A, 50 mg, 0.10 mmol) in tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 20 min 2-Iodoacetonitrile (7 μL, 0.10 mmol) is added, and the mixture is stirred over night. Another portion of 2-iodoaceto-nitrile (7 μL, 0.10 mmol) is added, and the mixture is stirred over night. Another portion of 2-iodoacetonitrile (14 μL, 0.20 mmol) is added, and the mixture is stirred for 2 h, diluted with water and purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 6 mg; ESI mass spectrum [M+H]+=529; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: C1(OC([N:10]2[CH2:15][CH2:14][C:13]([CH3:26])([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C(C)C)[CH:17]=3)[CH2:12][CH2:11]2)=O)C=CC=CC=1.Br.C(O)(=O)C>O>[OH:22][C:18]1[CH:17]=[C:16]([C:13]2([CH3:26])[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)Oc1cccc(C2(C)CCN(C(=O)Oc3ccccc3)CC2)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC1(c2cccc(O)c2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A solution of 4-methyl-4-(3-(1-methylethoxy)phenyl)-1-piperidinecarboxylic acid phenyl ester (Preparation 52, 2.4 g, 6.80 mmol) in 1:1 47% aqueous hydrobromic acid:glacial acetic acid (8 ml) was heated under reflux for 16 h. The solution was allowed to cool to room temperature and water (5 ml) was added. The aqueous layer was extracted with methyl tert-butyl ether (3×10 ml) to remove phenol as by-product. The pH was adjusted to 10.3-10.5 with 15% w:v aqueous sodium hydroxide solution and the mixture was left at room temperature for 2 h to allow the product to precipitate. After cooling to 0° C. the precipitate was filtered and washed with cold water (5 ml) to give 4-(3-hydroxyphenyl)-4-methylpiperidine as a solid (776 mg, 60%).
Reaction SMILES: C([O:8][C:9]([CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)=[O:10])C1C=CC=CC=1>[Pd].CO.O1CCCC1>[C:9]([CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)([OH:10])=[O:8]
Reactant: COC(=O)c1ccc(OCC(=O)OCc2ccccc2)c(-n2cccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC(=O)O)c(-n2cccc2)c1
Yield: 60 %

Procedure:
10% Palladium on carbon (0.5 g) was added to a solution of methyl 4-benzyloxycarbonylmethoxy3-(pyrrol-1-yl)benzoate (5.0 g) in methanol (50 ml) and tetrahydrofuran (20 ml) and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed by filtration and filtrate was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 8 with potassium carbonate. The separated aqueous layer was adjusted to pH 2 with 6N-hydrochloric acid and the mixture was extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 4-carboxymethoxy3-(pyrrol-1-yl)benzoate (2.26 g).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C([O-])(O)=O.[Na+]>>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][CH:17]([F:20])[F:16])(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Temperature: 84 °C
Yield: 64.1 %

Procedure:
Triflic anhydride (27.9 g, 99.1 mmol) was placed in a flask and cooled with an ice bath. 2,2-Difluoroethanol (8.1 g, 99.1 mmol) was added and the reaction was heated to 84° C. for 1 hour. The reaction was cooled in an ice bath and poured into 100 ml cold 5% NaHCO3 solution. The mixture was extracted with diethyl ether, dried over MgSO4, and concentrated under reduced pressure to remove the ether. The residue was vaccuum distilled to give 2,2-difluoroethyl trifluoromethanesulfonate as a clear liquid (13.6 g, 64%, bp˜55° C.). 1H NMR (400 MHz, CDCl3) δ ppm 6.17-5.88 (1H), 4.61-4.13 (2H)
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2[CH:22]=[CH:23][C:14]=1[C:12]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:13]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccc2c(n1)CCCC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccc3c(n2)CCCC3)sc2ccccc12
Yield: 29.9 %

Procedure:
A mixture of methyl thiosalicylate (0.43 g, 2.5 mmol), 2-cyano-5,6,7,8-tetrahydroquinoline (0.40 g, 2.5 mmol), triethylamine (0.50 ml, 3.8 mmol) and toluene (2.0 ml) was refluxed for 17 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.22 g, 30%).
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[OH:5][CH2:6][C:7]([CH3:11])([CH2:9][OH:10])[CH3:8]>>[CH3:8][C:7]1([CH3:11])[CH2:9][O:10][P:1]([Cl:4])[O:5][CH2:6]1
Reactant: ClP(Cl)Cl
Reactant: CC(C)(CO)CO
Product: CC1(C)COP(Cl)OC1

Procedure:
For example, Japanese Unexamined Patent Publication No. HEI 2(1990)-273688 (Patent Document 3) discloses that phosphorus trichloride is added to and reacted with neopentyl glycol under ice cooling to obtain 5,5-dimethyl-2-chloro-1,3,2-dioxaphosphorinane.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][NH:7]1)=[O:5].C([O-])(O)=O.[Na+].[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>C1COCC1.O.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:9][CH2:8][N:7]1[C:25](=[O:26])[C:24]([CH3:29])([CH3:28])[CH3:23])=[O:5]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)[C@H]1NCC[C@@H]1c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1[C@@H](c2ccc(O)cc2)CCN1C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 137.9 %

Procedure:
To the solution of (2S,3R)-3-(4-hydroxyphenyl)pyrolidine-2-carboxylic acid methyl ester hydrochloride (200 mg, 0.76 mmol), prepared in Example 20, in THF/H2O (2 mL/1 mL) was added saturated NaHCO3 (5 mL). To the above mixture was added trimethylacetyl chloride (420 mg, 3.5 mmol) over 20 min. The resulting solution was then stirred at room temperature for 4 hours and was diluted with ethyl acetate to 30 mL. The organic layer was then washed with brine (2×5 mL) and was concentrated to give (2S,3R)-1-(1-oxo-2,2,2-trimethylethyl)-3-(4-hydroxyphenyl)pyrolidine-2-carboxylic acid methyl ester as a white solid (320 mg). This solid was dissolved in 3 mL of EtOH and was stirred with 1N sodium hydroxide (3 mL, 3 mmol) at room temperature for 8 hours. After acidification with 6N HCl, the solvent was removed and the residue was extracted with dichloromethane. After concentration, the residue was washed ether to give (2S,3R)-1-(2,2-dimethyl-1-oxopropyl)-3-(4-hydroxyphenyl)pyrolidine-2-carboxylic acid as a white solid (117 mg). HRMS (M+H): Obs. 292.1556, Cald. 292.1549.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@@H:16]([OH:18])[CH2:15][C@H:14]3[C:19]([NH:21][C:22]3([C:25]#[N:26])[CH2:24][CH2:23]3)=[O:20])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.O>O1CCCC1.CN(C1C=CC=CN=1)C.CO>[C:27]1([S:33]([O:18][C@H:16]2[CH2:15][C@@H:14]([C:19](=[O:20])[NH:21][C:22]3([C:25]#[N:26])[CH2:23][CH2:24]3)[N:13]([C:11]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[O:12])[CH2:17]2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](O)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(c3ccc(Cl)cc3)CC2)CC1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a solution of (2S,4S)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(1-cyanocyclopropyl)-4-hydroxypyrrolidine-2-carboxamide (Example 457b; 5 g) in tetrahydrofuran (22 mL) at 0-5° C., was added benzenesulfonyl chloride (2.89 g, 2.1 ml, 16.2 mmol, Eq: 1.21), dimethylaminopyridine (88.7 mg) and triethylamine (2.41 g) within 5 minutes. The mixture was stirred at 0-5° C. for 15 min, then at 22° C. for 22 hr. Water (6.7 mL) and methanol (15.6 mL) were added at 0-5° C. and the mixture was concentrated in vacuo to afford a gum. This gum was washed with methanol and dried in vacuo to yield 6.82 g (99%) of the title compound as a light brown foam. MS (ESI): m/z=531.15 [M+NH4]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[CH3:13]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:10]([CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)([O:12][CH3:13])=[O:11]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 144 h
Yield: 96.1 %

Procedure:
Dissolve 2-indancarboxylic acid (3.82 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47 mmol) and sulfuric acid (0.8 mL). Stir at room temperature for 6 days. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) and wash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 2-(carbomethoxy)indane as a yellow oil (3.98 g, 96%).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (271 mg, 0.69 mmol) is coupled to 1-bromo-4-(trifluoromethoxy)benzene (200 mg, 0.83 mmol) using Method B to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[C:3]1=[O:18].[CH3:19][Li].O>C(OCC)C>[OH:18][C:3]1([CH3:19])[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:2]1[CH3:1]
Reactant: CC1C(=O)c2ccccc2C=Cc2ccccc21
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC1c2ccccc2C=Cc2ccccc2C1(C)O

Procedure:
To a stirred solution of 5-methyl-6-oxo-dibenzo[a,e]cyclooctene (0.1 g) in anhydrous diethyl ether (10 ml) under nitrogen at 0° C. was added methyl lithium (0.43 ml of a 1.4 M solution in diethyl ether). After stirring for approximately 30 minutes water (10 ml) was added. The phases were separated and the ethereal layer was washed with water (2×10 ml), dried (Na2SO4) and the solvent removed in vacuo to give the title compound as a colourless solid (0.104 g), mP 86°-87° C. δ1.43 (CDCl3 360 MHz,) (3H, s, C--CH3), 1.44 (3H, d, J=7.0 Hz, --CH--CH3), 2.03 (1H, s, --OH), 4.07 (1H, q, J=7.0 Hz, --CH--CH3), 6.75 (1H, d, J=11.8 Hz, CHA =CHB), 6.96-7.21 (8H, m, ArH and CHA =CHB), 7.41 (1H, d J=7.5 Hz, ArH), 7.85 (1H, d J=7.9 Hz, ArH) m/e 250 (M+).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23](Cl)=[N:22][C:21]=12)=[O:16].[NH3:29]>CC(O)C>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([NH2:29])=[N:22][C:21]=12)=[O:16]
Reactant: O=C(Nc1cnoc1-c1ccccc1C(F)(F)F)c1cnn2ccc(Cl)nc12
Reactant: N
Solvent: CC(C)O
Product: Nc1ccn2ncc(C(=O)Nc3cnoc3-c3ccccc3C(F)(F)F)c2n1
Temperature: 120 °C
Yield: 31 %

Procedure:
A mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide (200 mg, 0.49 mmol, 1.0 equiv) and 2M ammonia in propan-2-ol (4 mL) was sealed and heated in a microwave reactor at 120° C. for 40 minutes. The solvent was removed under vacuum and the resultant residue was purified by flash column chromatography on silica gel (gradient: 0 to 5% methanol in dichloromethane) to afford 58.6 mg (31%) of 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide. LCMS (ESI) m+H=389.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.60 (s, 1H), 9.07 (s, 1H), 8.63 (d, 1H), 8.18 (s, 1H), 7.99 (d, 1H), 7.95-7.77 (m, 3H), 7.70-6.60 (br, 2H), 6.39 (d, 1H).