Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.CCCCCC.[CH2:20]([C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][CH:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH2:23][CH3:24].Cl>CN(P(N(C)C)(N(C)C)=O)C>[OH:32][CH:31]([CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:25]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:35][CH:34]=1)[CH2:33][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCCCCc1ccc(OCC2CO2)cc1
Reactant: C#CCCCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a dry flask under N2 was placed 150 ml of HMPA (distilled over NaH) and 15.61 g (0.14 mole) of 5-hexynoic acid, the product of Example 1b, and the mixture cooled in an ice-water bath. A solution of 190 ml of n-BuLi in hexane (0.295 mole) was added dropwise into the flask with stirring. Stirring was continued for an additional 2 hr and 37 g of 2-(4-pentylphenoxymethyl)oxirane, the product of Example 7a, was added. After 2 days stirring, the resulting reaction mixture was poured into an ice water mixture and acidified with 3N HCl. The aqueous solution was extracted with Et2O three times. The organic layers were combined and then washed with aqueous 3N NH4OH. The NH4OH solution was acidified with 3N HCl and was extracted with Et2O. The ether solution was dried over MgSO4 and solvent removed to give an oil. The oil was purified by silical gel column chromatography (CHCl3 -MeOH) and then recrystallized in petroleum ether-EtOAc to give the title compound, mp 54°-57° C.
Reaction SMILES: [OH-].[Li+].[N:3]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[C:19]([F:22])([F:21])[F:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1.O>[N:3]1([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:19]([F:20])([F:21])[F:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.6 %

Procedure:
Lithium hydroxide (2.83 g, 67.5 mmol, 2 eq.) was added to a solution of methyl 4-piperidin-1-yl-3-(trifluoromethyl)benzoate (9.7 g, 33.7 mmol, 1 eq.) in THF (50 mL) and water (5 mL) and the reaction mixture was stirred at room temperature for 12 hours. The solvent was removed in vacuo and the residue taken up in water. The aqueous layer was washed with DCM, acidified to pH 2 with conc. HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound (3.0 g, 95%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][OH:27])C(=O)OC(C)(C)C)[C:12]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:11][S:10]2)=[C:4]([O:35][CH3:36])[CH:3]=1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:14][CH2:15][CH2:16][NH:17][CH2:25][CH2:26][OH:27])[C:12]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[CH:11][S:10]2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CCO)C(=O)OC(C)(C)C
Agent: Cl
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCNCCO

Procedure:
The compound (850 mg) obtained in the above (2) was treated in a similar manner to in Example 9 (2) to give the title compound (758 mg) as hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[CH:34]=[N:33]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:38]3[CH:39]=[C:40]4[C:35]([CH:34]=[N:33][NH:32]4)=[CH:36][CH:37]=3)[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc3cn[nH]c3c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
To a solution of Example 57c (0.500 g, 0.758 mmoles) in DMF (4.5 ml), ethanol (2.3 ml) and water (2.3 ml), Indazole-6-boronic acid pinacol ester (0.462 g, 1.89 mmoles) and sodium carbonate (0.502 g, 4.74 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.215 g, 0.186 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.080 g, 16% yield). MP: 206-208° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.19(s,1H), 8.14(s,1H), 8.08(s,1H),8.05(dd, J=7.9,1.5Hz, 1H), 7.90(d, J=8.3Hz, 1H), 7.86(m,1H), 7.71(s,1H), 7.69(d, J=8.4Hz, 1H), 7.53(t, J=7.1Hz, 1H), 7.39(dd, J=8.2,1.1Hz, 1H), 7.30(m,2H), 7.07(dt, J=8.7,2.6Hz, 1H), 6.92(br m, 2H), 6.06(q, J=7.1Hz, 1H), 1.91(d, J=7.0Hz, 3H). Mass: 517.96(M+).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C=O)C>[CH3:13][S:14]([O:5][CH2:4][C@@H:2]1[O:3][CH2:1]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (S)-(−)-glycidol (8.6 mL, 130 mmol) and triethylamine (36.2 mL, 260 mmol, 2.0 equiv.) in DMF (250 mL) was cooled over an ice bath and methanesulfonyl chloride (10.1 mL, 130 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred for 1.5 hr at room temperature affording a 0.47 M solution of (R)-glycidyl methanesulfonate in DMF, which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)=[CH2:2]>CO.[Pd]>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A mixture of 5-vinylbenzo[d][1,3]dioxole (6.0 g, 40.5 mmol) and 10% Pd/C (840 mg) in MeOH (50 mL) was hydrogenated for 8 h at 10 atm. Then Pd/C was filtered and the MeOH was removed to give compound 5-ethylbenzo[d][1,3]dioxole (3.0 g, 50%) as colorless liquid. 1H-NMR (DMSO-d6): δ 1.11 (t, 3H, J=7.2 Hz), 2.50 (q, 2H, J1=7.2 Hz, J2=16 Hz), 5.93 (s, 2H), 6.64 (d, 1H, J=8 Hz), 6.77 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH3:21])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15](OCC)=[O:16])[O:14][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH3:22]>>[OH:1][CH:2]([CH3:21])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15]([NH2:22])=[O:16])[O:14][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(C)O)cccc2o1
Product: CC(O)COc1cccc2oc(C(N)=O)cc(=O)c12

Procedure:
By the Method of Example 1 (c) 32 parts of 5-(2-hydroxy propoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester were treated with ethanolic ammonia to give 23.3 parts of 5-(2-hydroxy propoxy)-4-oxo-4H-1-benzopyran-2-carboxamide, which crystallised from a mixture of ethanol and chloroform as a white solid, melting point 229°-231° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[CH3:11][C@H:12]1[CH2:17][N:16]([CH2:9][C:6]2[CH:7]=[N:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19]
Reactant: CNc1ccc(C=O)cn1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cn1

Procedure:
The title compound was prepared from 6-(methylamino)-3-pyridinecarbaldehyde (D95) and 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate using a method similar to that described for D81 in Description D81A. δH (CDCl3, 400 MHz) 7.97 (1H, d), 7.44 (1H, dd), 6.38 (1H, d), 4.51 (1H, m), 4.17 (1H, br.s), 3.79 (1H, d), 3.38 (1H, d), 3.26 (1H, d), 3.07 (1H, td), 2.92 (3H, d), 2.74 (1H, m), 2.57 (1H, m), 2.09 (1H, dd), 1.96 (1H, m), 1.45 (9H, s), 1.20 (3H, d). MS (ES+): 343.2 (MNa+), 265.2, no molecular ion (MH+) observed.
Reaction SMILES: [Br-].[K+].[OH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].Cl[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Cl-].[Na+].CC1(C)CCCC(C)(C)[NH+]1[O-]>[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1O
Agent: CC1(C)CCCC(C)(C)[NH+]1[O-]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCC1=O
Temperature: 5 °C
Yield: 76.3 %

Procedure:
2,2,6,6-Tetramethylpiperidine-N-oxide (2.2 g, 14.2 mmol) and potassium bromide (8.5 g, 71 mmol) are added to a solution of racemic trans-tert-butyl N-[2-hydroxycyclopentyl]carbamate (75 g, 283 mmol) in dichloromethane (285 mL). The mixture is cooled to 5° C. with stirring. A freshly prepared ice cooled (5° C.) sodium hypochlorite aqueous solution (766 mL, 566 mmol, pH adjusted to 7.5-8 by addition of 10 g of solid potassium carbonate) is added with stirring to the reaction mixture while keeping the temperature below 5° C. The mixture is stirred at 5° C. for an additional 30 min. The reaction mixture is diluted with saturated aqueous sodium chloride solution (150 mL). The organic layer is separated and evaporated. The oily red residue is purified over a silica gel pad, eluting with EtOAc/hexanes (1/3) to obtain the title compound as a cream colored solid (43 g, 76%). 1H-NMR (300 MHz, DMSO-d6) δ 6.99 (d, 1H, NH), 3.76 (q, 1H), 1.63-2.31 (m, 6H), 1.37 (s, 9H).
Reaction SMILES: [OH:1][C@H:2]([C@@H:16]([NH:38]C(=O)OC(C)(C)C)[CH2:17][C@H:18]([CH2:22][NH:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])[CH:19]([CH3:21])[CH3:20])[CH2:3][NH:4][C:5](=[O:15])[C:6]([CH3:14])([CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:7].[ClH:46]>>[ClH:46].[NH2:38][C@H:16]([C@@H:2]([OH:1])[CH2:3][NH:4][C:5](=[O:15])[C:6]([CH3:14])([CH:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[CH3:7])[CH2:17][C@@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:22][NH:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)C(C)(C)C1CCOCC1)C(C)C
Agent: Cl
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](N)[C@@H](O)CNC(=O)C(C)(C)C1CCOCC1)C(C)C

Procedure:
The solution of 0.030 g of tert-butyl (1(S)-{1(S)-hydroxy-2-[2-methyl-2-(tetrahydropyran-4-yl)-propionylamino]ethyl}-3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methylpentyl)-carbamate in 1 ml of 4M HCl (in dioxane) is stirred at 0° C. to 20° C. over 2 hours and subsequently concentrated by evaporation to dryness, and the residue is dissolved in 1 ml of tert-butanol, frozen and lyophilized under high vacuum. The title compound is obtained as a white powder. Rf=0.23 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=3.46 (gradient I).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:40])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][NH:24][C:25](=[O:36])OC2C=CC([N+]([O-])=O)=CC=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:41][NH:42][CH3:43]>ClCCl>[Br:1][C:2]1[C:3](=[O:40])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][NH:24][C:25](=[O:36])[N:42]([CH3:43])[CH3:41])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNC
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzylcarbamate (from step 1) (0.350 g, 0.570 mmol) dissolved in dichloromethane (6.0 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of N,N-dimethylamine in tetrahydrorfuran (0.427 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.226 g, 63.3%). 1H NMR (400 MHz, DMF-d6) δ 7.81 (app q, J=7.92 Hz, 1H), 7.40-7.19 (m, 5H), 7.06 (d, J=7.45 Hz, 1H), 6.88 (app t, J=5.84 Hz, 1H), 6.68 (s, 1H), 5.45 (s, 2H), 5.42 (s, 1H), 4.35 (d, J=5.84 Hz, 1H), 2.92 (s, 6H), 2.44 (s, 3H). ES-HRMS m/z 520.1065 (M+H C24H24BrF2N3O3 requires 520.1042).
Reaction SMILES: [OH:1][C@:2]1([C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH:10]=3)[CH2:7][CH2:6]1)[C:3](=[O:5])[CH3:4]>COC1C=CN=CC=1.[Pd]>[OH:1][C@:2]1([C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C@@H:12]([CH2:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH:10]=3)[CH2:7][CH2:6]1)[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)[C@@]1(O)CC[C@H]2C3=CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Pd]
Agent: COc1ccncc1
Product: CC(=O)[C@@]1(O)CC[C@H]2C3=CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a solution of 4 (20 mg) in 4-methoxypyridine (1.5 ml) was added palladium on carbon (20 mg, 10% palladium by weight). The resulting mixture was stirred at room temperature under a hydrogen-filled balloon for 16 h. The catalyst was filtered through a cotton-plugged pipette containing Celite. Removal of solvent by bulb-to-bulb distillation gave crude 5 (20 mg) as a nearly colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:3]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ncccc1-c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.967 g) was added to a suspension of 3-bromopyridin-2-amine (4.82 g), 4-hydroxyphenylboronic acid (5.00 g) and sodium carbonate (5.91 g) in DME (250 mL) and water (50.0 mL) and the mixture was stirred at 80° C. under nitrogen for 4 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and washed with IPE to give the title compound (2.80 g) as a white solid.
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:13]=1)=[O:6].[Li+].[OH-]>C1COCC1.O>[C:24]([Si:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][C:14]1[CH:13]=[C:12]([C:11]2[O:10][CH:9]=[N:8][C:7]=2[C:5]([OH:6])=[O:4])[CH:17]=[CH:16][CH:15]=1)([CH3:26])([CH3:25])[CH3:27]
Reactant: COC(=O)c1ncoc1-c1cccc(CCO[Si](C)(C)C(C)(C)C)c1
Agent: N#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(-c2ocnc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-{3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-phenyl}-oxazole-4-carboxylic acid methyl ester (110 mg, 0.30 mmol) in THF (0.5 mL) and H2O (0.5 mL) was treated with LiOH (18 mg, 0.43 mmol). The reaction mixture was stirred at rt for 2.5 h, extracted with EA (2×5 mL), the organic layer was washed with 1N HCl (2 mL) dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=1.08 min, [M+H]+=348.40.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](/[CH3:20])=[CH:11]/[CH:12]=[CH:13]/[C:14](/[CH3:19])=[CH:15]\[C:16]([OH:18])=[O:17])=[C:6]([CH3:21])[C:5]([CH3:22])=[C:4]([O:23][CH3:24])[CH:3]=1>O1CCCC1>[CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](/[CH3:20])=[CH:11]/[CH:12]=[CH:13]/[C:14](/[CH3:19])=[CH:15]/[C:16]([OH:18])=[O:17])=[C:6]([CH3:21])[C:5]([CH3:22])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)c(C)c1C
Solvent: C1CCOC1
Product: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Crude acetretin (10 g) and butylated hydroxyanisole (0.5 g) were dissolved in tetrahydrofuran (350 ml) at room temperature. The resultant solution was filtered and washed with tetrahydrofuran. The combined filtrate was concentrated under vacuum at 30–35° C. Acetone (100 ml) was added to the residue and stirred for 10 minutes at room temperature. The crystalline product so obtained was filtered, washed with acetone and dried at 25–30° C. under vacuum to obtain pure acitretin (8.2 g, assay 99.4% by HPLC).
Reaction SMILES: O.[OH:2][C@H:3]([CH2:24][NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:32]=1)[C@@H:4]([NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:49][O:50][C:51]([C@H:53]1[CH2:57][CH2:56][CH2:55][NH:54]1)=[O:52].CCN(C(C)C)C(C)C.O1C2C=CC=CC=2C=C1CNC(=O)OC(C)(C)C>C(Cl)Cl.CN(C=O)C>[OH:2][C@H:3]([CH2:24][NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:33]([CH3:34])[CH3:35])[CH:32]=1)[C@@H:4]([NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([N:54]1[CH2:55][CH2:56][CH2:57][C@@H:53]1[C:51]([O:50][CH3:49])=[O:52])=[O:19])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H]1CCCN1
Reactant: CC(C)c1cncc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(C(=O)O)c2)c1
Agent: CC(C)(C)OC(=O)NCc1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CCCN1C(=O)c1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cncc(C(C)C)c2)c1
Reaction time: 1 h
Yield: 30.3 %

Procedure:
H2O (0.0177 g, 0.131 mmol, 1.1 eq) was added to a stirred solution of 3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoic acid (0.055 g, 0.119 mmol, 1 eq) in 2 ml anhydrous CH2Cl2 at 0° C. under Ar. After 30 min EDCI.HCl (0.0197 g, 0.119 mmol, 1.1 eq) was added. After 30 min 1 ml anhydrous DMF was added. In a separate flask (R)-methylpyrrolidine-2-carboxylate hydrochloride (Bachem, 0.0197 g, 0.119 mmol, 1 eq) in 2 ml anhydrous CH2Cl2 under Ar was treated with DIPEA (0.083 ml, 0.062 g, 0.476 mmol, 4 eq). After both solutions had stirred for 1 h, the active ester was treated with the free-base amine. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo. The residue was partitioned between EtOAc/H2O and the layers were separated. The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. Purification via flash chromatography yielded 0.0208 g (0.036 mmol, 31% yield) of (R)-methyl 1-(3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoyl)pyrrolidine-2-carboxylate, which was treated under hydrolysis conditions as described herein to generate (R)-1-(3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2[CH2:14]C2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[C:28](=[O:32])[NH:29][CH2:30][CH2:31][C:26]=3[C:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:24]2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.Cl>CS(C)=O.[Cu]I.CCOC(C)=O>[CH2:36]([O:35][C:33]([C:25]1[C:26]2[CH2:31][CH2:30][N:29]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:9]([OH:11])=[O:10])[CH2:12][CH2:14]4)=[CH:6][CH:7]=3)[C:28](=[O:32])[C:27]=2[N:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[N:24]=1)=[O:34])[CH3:37]
Reactant: O=C(O)C(c1ccc(I)cc1)C1CC1
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(C3(C(=O)O)CC3)cc1)C2=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Part A. 4-Iodophenylcyclopropyl acetic acid (1.93 g, 6.70 mmol) and 1-(4-methoxyphenyl)-3-(ethoxycarbonyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (1.41 g, 4.46 mmol) were stirred in DMSO (4 mL) under N2. K2CO3 (1.84 g, 13.33 mmol, 3.0 eq) was added followed by the addition of 1,10-phenanthroline (0.15 g, 20 mol %) and CuI (0.16 g, 20 mol %). The resulting mixture was stirred at 110° C. overnight. LC-MS showed completion of the reaction. EtOAc was added to the cooled solution. It was acidified with 1N HCl, and the organic layer was washed with H2O, and brine, dried over MgSO4, filtered, and concentrated to afford 1-{4-[3-(ethoxycarbonyl)-1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl]phenyl}cyclopropanecarboxylic acid (1.54 g, yield: 72.6%). LC/MS (ESI+) 476.4 (M+H)+, tR=2.58 min (10–90% CH3CN/H2O in a 4-min run).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:8]2[N:19]=[CH:20][CH:21]=[C:7]2[N:6]=1)[CH2:2][CH:3]=[CH2:4].C1C(=O)N([Br:29])C(=O)C1.O>C(COC)OC.O>[Br:29][C:21]1[CH:20]=[N:19][N:8]2[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][C:5]([CH2:1][CH2:2][CH:3]=[CH2:4])=[N:6][C:7]=12
Reactant: C=CCCc1cc(OCc2ccncc2)n2nccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: COCCOC
Solvent: O
Product: C=CCCc1cc(OCc2ccncc2)n2ncc(Br)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(3-Butenyl)-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine (compound of Example 1), 500 mg, was dissolved in 10 ml of dimethoxyethane-water (3:1). The solution was cooled to 0° C. and 380 mg of NBS was added. The mixture was stirred at 0° C. for 1 hour and further stirred at room temperature for 1 hour. Water was added to the reaction mixture and the crystals precipitated were collected by filtration. The crude crystals were recrystallized from dichloromethane-n-hexane to provide 440 mg of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.