Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:5])=[O:4].[CH2:12](Br)[C:13]#[CH:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O>[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:14][C:13]#[CH:12])([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=C1NCCN1
Reactant: C#CCBr
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1CCNC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
An ice-cooled mixture of 50 milliliters of dry dimethylformamide and 1.77 grams of a 57% by weight dispersion of sodium hydride in mineral oil, maintained under nitrogen atmosphere, was treated with 5.16 grams of 2-(nitromethylene)imidazolidine. After stirring for 1 hour, 7.97 grams of propargyl bromide was added. The mixture was stirred at 10° for an additional hour, allowed to warm to room temperature, and poured into 400 milliliters of saturated aqueous sodium sulfate. The product was extracted with three 300-milliliter portions of methylene chloride. The combined extract was dried with magnesium sulfate and the solvent was evaporated. Addition of ether to the residual oil gave a solid which was recrystallized from chloroform (charcoal) to give 3.1 grams of 3, as tan crystals, melting point: 146°-147° C.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[O:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:3]3[C:4]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[NH:1][N:2]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:25]1
Reactant: Oc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc2c(c1)Cc1c(-c3ccc(OCCN4CCOCC4)cc3)n[nH]c1-2
Temperature: 25 °C

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol (0.76 g, Example 30) 4-(2-hydroxyethyl)morpholine (0.85 g), triphenylphosphine (1.77 g) and dichloromethane (20 ml) were stirred together with ice/water bath cooling and diethylazodicarboxylate (1.16 g) was added dropwise. The resultant mixture was allowed to warm to room temperature and stirred for about 24 hours. The solvent was evaporated off under reduced pressure and the residue purified by flash column chromatography on silica using ethyl acetate/ethanol (25%) to give a solid. The solid was triturated with diethyl ether (10 ml) and the solid filtered, washed with diether and dried at about 65° C. to give 3-[4-(2-morpholinoethoxy)phenyl]-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 175-6° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:15]2[CH:14]=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=2[F:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
N-Ethylpiperazine (0.96 mL, 7.6 mmol, 1.2 equiv) is added to a mixture of 3,4-difluoronitrobenzene (0.7 mL, 6.32 mmol) and potassium carbonate (1.74 g, 12.6 mmol, 2 equiv) in DMF (10 mL). The reaction mixture is stirred at 90° C. for 17 h, allowed to cool to RT, diluted with H2O and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 97:3) to provide the title compound as a yellow solid: ES-MS: 254.1 [MH]+; tR=2.65 min (system 1); Rf=0.30 (DCM/MeOH+1% NH3aq, 93:7).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Na].[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)#[N:6]>C(O)(=O)C>[CH2:1]([O:3][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[NH:6])[CH3:2]
Reactant: CCO
Reactant: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=N)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C

Procedure:
To a dry flask equipped with stirrer, thermometer and reflux condenser is placed 25 ml. of ethanol and sodium metal, 0.253 g. (0.011 g. atom) is added in portions. When the sodium is completely reacted, 3.14 g. (0.01 mole) of 2-(4-cyanopiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline is added and the resulting mixture is refluxed for 5 hours. After cooling to room temperature, glacial acetic acid is added to neutralize the mixture. After evaporation to dryness, 25 ml. of water and 50 ml. of chloroform are added to the residue. The mixture is transferred to a separatory funnel and the chloroform layer washed again with water, dried over anhydrous sodium sulfate then concentrated to dryness to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>ClCCl>[CH2:9]([O:8][P:4]([CH2:3][CH2:2][NH:1][C:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:27])([O:5][CH2:6][CH3:7])=[O:11])[CH3:10]
Reactant: CCOP(=O)(CCN)OCC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCNC(=O)c1cccnc1)OCC
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
To a mixture of diethyl 2-aminoethylphosphonate (8.1 g), triethylamine (9.1 g) and dichloromethane (100 ml) at 5° C. was added nicotinic acid chloride hydrochloride (10.4 g) in small portions over a period of 15 minutes. After being stirred for additional 1.5 hours, the reaction mixture was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10% methanol in chloroform) to give 11.2 g of N-(2-diethoxyphosphoryl-ethyl)-3-pyridinecarboxamide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.C1C=CC(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([N:35]=[N+:36]=[N-:37])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(/C=C/C(=O)N=[N+]=[N-])c1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a solution of (E)-3-(3-methoxyphenyl)acrylic acid (15 g, 84 mmol) in benzene (100 ml) was added triethylamine (11.73 ml, 84 mmol) followed by DPPA (23.17 g, 84 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as white solid (15 g, 88%). 1H NMR (400 MHz, CDCl3): δ ppm 7.75-7.70 (d, J=20 Hz, 1H), 7.36-6.97 (m, 4H), 6.45-6.40 (d, J=20 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[O:6][CH2:5][C@@H:4]1[NH:20]C(=O)OC(C)(C)C>O1CCOCC1>[ClH:1].[NH2:20][C@@H:4]1[C:3](=[O:2])[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[O:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2c(cccc2-c2ccccc2)NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1COc2c(cccc2-c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.4 mL of a solution of hydrochloric acid in dioxane (4M) are added to a 25 mL round-bottomed flask containing 160 mg of 37 (0.452 mmol). The mixture is stirred for 4 h at RT under argon. The dioxane is concentrated, and taken up in 15 mL of isopropyl ether. The solid formed is disintegrated. 113 mg of amine 38 (cream-coloured solid) are obtained after filtration in hydrochloride form.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:12][C:13]#[N:14].[K+].Cl>O.C(O)(=O)C>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[NH:14][C:13]2=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CN(c2ccccc2)C(=O)N1
Temperature: 90 °C
Yield: 24.5 %

Procedure:
A solution of N-phenylglycine (Fluka) (30.2 g, 0.2 moles) in 900 ml of water and 1 ml of acetic acid was heated to 60° C. After thirty minutes potassium cyanate (16.2 g, 0.2 moles) in 100 ml of water was added. Heating was continued for 90', then 25 ml of 37% hydrochloric acid were added and the reaction mixture was heated for 15 h at 90° C. After cooling the precipitate was filtered and crystallized from 95% ethanol. 8.65 g of 1-phenylhydantoin were obtained, m.p. 197°-198°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH:23]=[CH:24][CH2:25][CH3:26])([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[C:5]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][CH2:25][CH3:26])([CH3:6])[CH3:7])[CH3:2]
Reactant: [H][H]
Reactant: CCC=Cc1ccc(OCc2ccccc2)cc1OC(C)(C)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCCCc1ccc(O)cc1OC(C)(C)C(=O)OCC
Yield: 90 %

Procedure:
A solution of 2-(5-Benzyloxy-2-but-1-enylphenoxy)-2-methylpropionic acid ethyl ester (0.76 g, 2.06 mmol) in ethanol (50 mL) was treated with 5% Pd/C (0.10 g) and hydrogen (60 psi) at ambient temperature for 6 h. The mixture was filtered and concentrated in vacuo to give a colorless oil (0.52 g, 90%). 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=7.8 Hz, 1H), 6.37 (dd, J=8.3, 2.4 Hz, 1H), 6.20 (s, 1H), 4.66 (br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 1.60 (s, 6H), 1.53 (quintet, J=7.6 Hz, 2H), 1.34 (sextet, J=7.3 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), MS (ES) m/e 281 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[C:10]([OH:11])=[CH:9][C:8]([OH:12])=[N:7][C:6]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[C:10]([OH:11])=[C:9]([N+:18]([O-:20])=[O:19])[C:8]([OH:12])=[N:7][C:6]=1[C:13]([F:14])([F:15])[F:16])[CH3:2]
Reactant: CCOC(=O)c1c(O)cc(O)nc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1c(C(F)(F)F)nc(O)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,6-dihydroxy-2-trifluoromethyl-nicotinic acid ethyl ester (1 g, 3.9 mmol) was dissolved in 10 mL of concentrated sulfuric acid and 2 mL of fuming nitric acid was added dropwise at room temperature. Once the addition was complete, the mixture was stirred at room temperature for 30 minutes. The mixture was then poured into crushed ice and the white precipitate was collected, dissolved in 50 mL of ethyl acetate, washed with 50 mL of water and 50 mL of brine, dried over magnesium sulfate and the solvent was removed in vacuo to give 1.1 g of the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:19][S:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH:2]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(N=Cc1cccnc1)c1ccc(Cl)cc1
Yield: 65 %

Procedure:
In a similar manner to Example 2, 18.5 mmol of 3-pyridinecarboxaldehyde, 18.5 mmol of 4-chlorobenzenesulfonamide and 20 mg of TsOH in 100 mL of toluene reacted under reflux conditions to afford SULF-12 in 65% yield and high purity: 1H NMR (DSMO-d6, TMS ext std) δ9.3 (s,1), 9.2 (d, 1), 8.9 (m, 1), 8.4 (m, 1), 8.0-7.8 (AB. 4).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:27](=[O:33])[C:28]([O:30]CC)=[O:29])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:27](=[O:33])[C:28]([OH:30])=[O:29])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(C(C)(C)C)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccccc2)cc1
Yield: 62.5 %

Procedure:
{1-Benzyl-5-[4-(tert-butyl)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-5-[4-(tert-butyl)phenyl]-1H-indol-3-yl}(oxo)acetate (0.669 g, 1.52 mmol), potassium hydroxide (0.30 g, 5.3 mmol) in THF (15 mL) and water (15 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from acetonitrile and drying at 90° C. furnished the title compound as a light yellow solid (0.391 g, 63%), mp: 210-211° C. (dec.). Mass spectrum (+APCI, [M+H]+) m/z 412; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.7 (s, 1H), 8.4 (d, 1H, J=1.7 Hz), 7.65 (d, 1H, J=8.5 Hz), 7.55-7.6 (m, 3H), 7.5 (dd, 2H, J=6.5 Hz and 1.8 Hz), 7.3-7.35 (m, 5H), 5.6 (s, 2H), and 1.3 ppm (s, 9H). Elemental Analysis for C27H25NO3.0.1 H2O: Calculated: C, 78.46; H, 6.15; N, 3.39. Found: C, 78.34; H, 5.94; N, 3.35.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[N:27]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH2:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:24])=[CH:20][CH:19]=2)[CH:17]=1
Reactant: NCCCN1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NCCCN3CCOCC3)cc2)cn1
Yield: 10 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using 3-morpholin-4-yl-propylamine instead of cyclopropylmethylamine, to the title compound (13 mg, 10%) which was obtained as an off-white solid. MS: m/e=472.0 [M+H]+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[CH:18]([OH:21])([CH3:20])[CH3:19].S(=O)(=O)(O)O>C(OC)(C)(C)C>[C:1]1([S:7]([O:21][CH:18]([CH3:20])[CH3:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)C
Solvent: CN1CCOCC1
Product: CC(C)OS(=O)(=O)c1ccccc1

Procedure:
Benzenesulfonyl chloride (50 g, 283 mmol) was added to a solution of 4-methylmorpholine (57 g, 2 equiv.) and isopropyl alcohol (66 g, 3.9 equiv.). After reaction completion (ca. 3 hours), 250 mL of methyl tert-butyl ether (MTBE) and 60 mL of 3M sulfuric acid were added. The rich MTBE layer was washed with aqueous sodium chloride solution. The rich MTBE solution was solvent exchanged into tetrahydrofuran solution. The rich tetrahydrofuran solution containing 56 g (96 M %, HPLC area % 97) of the title compound was used as is in the next step (Example 5).
Reaction SMILES: C(OC(=O)[N:7]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[C:10]([O:25][CH3:26])[N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[C:10]([O:25][CH3:26])[N:9]=2)=[CH:33][CH:32]=1
Reactant: COc1nc(N(Cc2ccc(Cl)cc2)C(=O)OC(C)(C)C)ccc1C(O)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(NCc2ccc(Cl)cc2)ccc1Cc1c[nH]c2ncccc12

Procedure:
To (4-Chloro-benzyl)-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methoxy-pyridin-2-yl-carbamic acid tert-butyl ester (68, 40.0 mg, 0.081 mmol) in acetonitrile (10.0 mL) were added trifluoroacetic acid (0.30 mL, 0.0039 mol) and triethylsilane (0.60 mL, 0.0038 mol). The reaction was heated to reflux for 3 hours. The reaction was concentrated to remove the solvents, then purified with silica gel column chromatography eluting with 40% ethyl acetate in hexane to give compound (P-0081, 10 mg, 32.7%). MS (ESI) [M+H+]+=379.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:5]([OH:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:5]2[O:12][C:9](=[O:10])[CH2:8][C:6]=2[CH:7]=1
Reactant: O=C(O)Cc1cc(Cl)c(C2CCCCC2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Cc2cc(Cl)c(C3CCCCC3)cc2O1

Procedure:
5 g of 5-chloro-4-cyclohexyl-2-hydroxyphenylacetic acid are dissolved in toluene with heating, 50 mg of p-toluenesulphonic acid are added, and the mixture is boiled in a water separator for 3 hours. The oil obtained after evaporation is purified on a 100-fold quantity of silica gel Merck. The desired product is eluted with chloroform and recrystallized from methylene chloride/petroleum ether. The crystals have an M.P. of 100°-102°.
Reaction SMILES: [H-].[Na+].[CH:3]1([C@@H:6]2[O:16][CH2:15][C:9]3=[N:10][O:11][C@@H:12]([CH2:13][OH:14])[C@@H:8]3[CH2:7]2)[CH2:5][CH2:4]1.I[CH3:18].O>CN(C)C=O>[CH:3]1([C@@H:6]2[O:16][CH2:15][C:9]3=[N:10][O:11][C@@H:12]([CH2:13][O:14][CH3:18])[C@@H:8]3[CH2:7]2)[CH2:4][CH2:5]1
Reactant: CI
Reactant: OC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 395 mg, 9.88 mmol) was slurried in N,N-dimethylformamide (30 mL) and cooled in an ice bath. A solution of rel-[(3R,3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazol-3-yl]methanol (C37) (1.30 g, 6.59 mmol) in minimal N,N-dimethylformamide was added drop-wise, and the reaction mixture was stirred at 0° C. for 30 minutes. Iodomethane (0.45 mL, 7.2 mmol) was then added in a drop-wise manner, and the reaction was allowed to proceed for an additional 30 minutes at 0° C. Water was added, and the mixture was warmed to room temperature and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 60% ethyl acetate in heptane) provided the product as an oil. Yield: 1.0 g, 4.7 mmol, 71%. LCMS m/z 212.1 [M+H+].
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9](/[C:11](/[CH3:16])=[CH:12]\[C:13]([OH:15])=O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22]>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9](/[C:11](/[CH3:16])=[CH:12]\[C:13]([N:19]2[CH2:26][CH2:25][CH2:24][C@H:20]2[C:21]([OH:23])=[O:22])=[O:15])=[O:10])=[CH:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)/C(C)=C\C(=O)O)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Product: CC(=O)Nc1ccc(C(=O)/C(C)=C\C(=O)N2CCC[C@H]2C(=O)O)cc1

Procedure:
As for Example 8, 3-(4-acetamidobenzoyl)crotonic acid is coupled to L-proline to give 1-[3-(4-acetamidobenzoyl)crotonyl]-L-proline. Reaction of the preceding compound with thiolacetic acid in carbontetrachloride as for Example 8 gives the product of the example as a glass.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17])[CH3:2].[H-].[Na+].[CH:22]([O:24][CH2:25]C)=O.IC>COCCOC>[CH2:1]([O:3][C:4](=[O:19])[C:5]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17])=[CH:22][O:24][CH3:25])[CH3:2]
Reactant: CCOC=O
Reactant: CCOC(=O)COc1cc(C)c(OC)cc1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: COCCOC
Product: CCOC(=O)C(=COC)Oc1cc(C)c(OC)cc1C(C)C
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
To a solution of (2-isopropyl-4-methoxy-5-methyl-phenoxy)-acetic acid ethyl ester (4.42 g, 16.6 mmol) in anhydrous 1,2-dimethoxy ethane (60 ml) was added sodium hydride (60% in mineral oil, 3.5 g, 87.5 mmol) at room temperature. After 5 minutes of stirring, ethyl formate (40 ml, 495 mmol) was added. The mixture was heated at 85° C. for 7 hours. After cooling to room temperature, iodomethane was added and stirring was continued overnight. Solvent was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified with silica gel chromatography (10% to 30% ethyl acetate in hexane) to yield 2-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3-methoxy-acrylic acid ethyl ester as a pale yellow oil (1.19 g, 23%).
Reaction SMILES: [CH2:1]([N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])CCC(OC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:36]O>C(O)(C)C>[CH2:1]([N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[OH:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)CCC(=O)OC
Reactant: OO
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCC
Yield: 43.5 %

Procedure:
Using the general procedure of Example 2, 57.5 grams (0.116 mol) of the product of Example 7 in 450 ml of isopropanol is oxidized using 5.6 ml (0.15 mol) of 70% aqueous hydrogen peroxide solution to give 21.5 grams (44% yield) of the above-named product as a white solid melting at 94°-96° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[C:27]([CH3:34])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:31]([C:28]3[C:27]([CH3:34])=[N:26][N:25]([CH3:24])[C:29]=3[CH3:30])=[O:32])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1nn(C)c(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.71 min; [M+H]+=469.2.