Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])[C:19](Cl)=[O:20]>ClCCl>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([C:19]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:20])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=C1CNCCN1
Reactant: Cc1c(C(=O)Cl)ccc(F)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCNC(=O)C2)ccc(F)c1Cl
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.350 g, 3.5 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (15 mL), and to this was added triethylamine (0.585 mL, 4.20 mmol). The solution was then cooled to 0° C. before 3-chloro-4-fluoro-2-methylbenzoyl chloride (I58) (0.797 g, 3.85 mmol) in Dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then re-dissolved in DCM (50 mL) and washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was then dried over anhydrous sodium sulphate, which was then filtered off and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane (30 mL) at 55° C. for 30 minutes, before being filtered to yield the product in 0.843 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:18]=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C(=O)N([Br:26])C(=O)C1.O>CN(C=O)C>[Br:26][C:18]1[C:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:15][CH:14]=[N:13][C:12]=2[NH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(-c2ncnc3[nH]ccc23)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2ncnc3[nH]cc(Br)c23)c1
Reaction time: 0.5 h

Procedure:
To 4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (12 g, 50 mmol) in DMF (167 mL) was added NBS (10.2 g, 57.4 mmol) and the mixture stirred for 30 minutes. Water (833 mL) was added which led to the precipitation of the desired product. The reaction mixture was allowed to stir for 15 minutes before being filtered and washed with 500 mL of water to give 5-bromo-4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C12H8BrN4O2[M+H]+: 319, found 319.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[C@:5]([NH2:15])([C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:8]=1[F:14])[CH3:6].[CH3:19][NH:20][C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=S>>[C:26]([O:25][C:24](=[O:30])[NH:23][C:21]1[N:20]([CH3:19])[C:3](=[O:18])[C:4]([CH3:16])([CH3:17])[C@:5]([C:7]2[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:8]=2[F:14])([CH3:6])[N:15]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: COC(=O)C(C)(C)[C@](C)(N)c1cc(Br)ccc1F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2,2-dimethyl-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as a white solid. MS (ESI): m/z=442.2 and 444.1 [M+H]+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31](Cl)=[N:30][CH:29]=[CH:28]3)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CC(N(C)C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:30][CH:29]=[CH:28]3)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(Cl)nccc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(OCc4ccccc4)nccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.70 g (6.49 mmol) of benzyl alcohol were dissolved in 10 mL of dimethyl acetamide. 260 mg (6.49 mmol) of sodium hydride (60%) were added and the solution was stirred at room temperature. After 30 min a solution of 1.57 g (4.33 mmol) of 4-(1-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (10) in 10 mL of dimethyl acetamide was added and the resulting mixture was heated at 90° C. (bath temperature). After 8 h and standing at room temperature overnight 1.0 additional equivalents of benzyl alcohol and sodium hydride were added and heating at 90° C. was continued for 8 h. For workup, the solvent was removed i. vac. and the residue was dissolved in dichloromethane. The organic solution was washed twice with water, dried with MgSO4 and evaporated. The resulting crude product was purified by preparative HPLC. Rt=2.13 min (Method C). Detected mass: 435.2 (M+H+).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[N:18]([CH3:20])[CH:17]=[CH:16]2)=[O:10])C1C=CC=CC=1.C(O)=O>CO.[Pd]>[CH3:20][N:18]1[C:19]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[C:9]([OH:10])=[O:8])[CH:16]=[CH:17]1
Reactant: Cn1ccc2cccc(C(=O)OCc3ccccc3)c21
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: Cn1ccc2cccc(C(=O)O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.65 g (0.25 mmol) of benzyl-1-methylindole-7-carboxylate (Step B) and 0.035 g of 10% Pd/C in 4 mL of a solution of 4.4% HCO2H in MeOH was stirred for 2 h at rt. The reaction mixture was filtered though a thin pad of celite and concentrated to give the title compound. 1H NMR (CDCl3) δ4.00 (s, 3H), 6.61 (d, 1H, J=3 Hz), 7.11 (d, 1H, J=3 Hz), 7.18 (t, 1H, J=8 Hz), 7.87 (d, 1H, J=8 Hz), 7.91 (d, 1H, J=8 Hz);
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][O:19][CH3:20])[C:13]=3[O:21][CH3:22])[CH2:7][CH2:6]2)[O:4]CC1>C(O)=O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][O:19][CH3:20])[C:13]=2[O:21][CH3:22])[CH2:7][CH2:6]1
Reactant: COCc1nccc(NC2CCC3(CC2)OCCO3)c1OC
Solvent: O=CO
Product: COCc1nccc(NC2CCC(=O)CC2)c1OC
Yield: 89.9 %

Procedure:
4.4 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)amino-3-methoxy-2-methoxymethylpyridine (Example 59) is left to stand in 100 ml of 98% formic acid for 17 hours. The mixture is then concentrated, and the residue is extracted by shaking with 2N NaOH and CH2Cl2. After the organic phase has been concentrated, 3.4 g=89.9% of crystals are obtained.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]1[CH2:27][CH2:28]1
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1ccc2ncccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (80 mg, 0.301 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give a crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg). The crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (35 mg). MS 392.2 (M+H); UV 203.6, 266.4, 299.0, 358.5 nm; t 0.406 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.[C:15](#N)[CH3:16].C(=O)([O-])[O-].[K+].[K+].ICC>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]1
Reactant: OC1(c2cccc(Cl)c2Cl)CCNC1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCN1CCC(O)(c2cccc(Cl)c2Cl)C1
Temperature: 25 °C

Procedure:
In a sealed tube a mixture of 3-(2,3-dichlorophenyl)pyrrolidin-3-ol (0.35 g, 1.51 mmol), acetonitrile (20 mL), potassium carbonate (0.019 g, 3.77 mmol) and iodoethane (0.24 g, 1.51 mmol) was stirred at ambient temperature over night, additional iodoethane (0.02 mL) was added and the resulting mixture was stirred over night. Water (50 mL) was added, the aqueous phase was extracted with tert-butyl methyl ether (2×50 mL) and the combined organic phase was dried (MgSO4) and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.13 g). The amine was converted to the oxalic acid salt and recrystallized from methanol/ethanol/diethyl ether: M.p. 206-207° C.; MS m/z (relative intensity, 70 eV) 259 (M+, 5), 173 (7), 145 (6), 72 (23), 71 (bp).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13].[I-:19].[Na+]>CC(C)=O>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[O:5][C@@H:4]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][CH2:2][I:19]
Reactant: [I-]
Reactant: ClCC[C@@H](Oc1cc(Cl)ccc1Cl)c1cccs1
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccc(Cl)c(O[C@H](CCI)c2cccs2)c1
Yield: 73.3 %

Procedure:
A solution of the product from step (a) (788 mg) and sodium iodide (4.5 g) in acetone (30 ml) was heated under reflux for 18 h. The solvent was removed in vacuo, water added and the mixture was extracted twice with ether. The organic layers were dried (magnesium sulphate), evaporated and purified by chromatography on silica eluting with petrol—diethyl ether (19:1) to give the title compound as a pale yellow oil (742 mg).
Reaction SMILES: [OH:1][C:2]([C:5]1([S:8]([NH:11]C(=O)OCC2C=CC=CC=2)(=[O:10])=[O:9])[CH2:7][CH2:6]1)([CH3:4])[CH3:3]>CO.[Pd]>[OH:1][C:2]([C:5]1([S:8]([NH2:11])(=[O:9])=[O:10])[CH2:6][CH2:7]1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)C1(S(=O)(=O)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)C1(S(N)(=O)=O)CC1
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of the product of Step 2 (995 mg) in methanol (30 mL) under nitrogen was added Pd/C (169 mg). The flask was purged with hydrogen and stirred for 3 hours. Celite was added to the reaction mixture and it was filtered through a pad of Celite. The solvent was removed in vacuo. The resulting residue was purified by flash chromatography (ISCO, 0 to 10% methanol in dichloromethane) to afford the desired product (391 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.88 (br s, 2H), 2.58 (s, 1H), 1.44-1.41 (m, 2H), 1.41 (s, 6H), 1.06-1.03 (m, 2H).
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([O:16]C)=[O:15])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([OH:16])=[O:15])=[N:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1nn(C2CCC2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nn(C2CCC2)c2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
The mixture of methyl 1-cyclobutyl-1H-indazole-3-carboxylate (2.21 g, 9.60 mmol, step 1 of Example 4), 2 N aqueous sodium hydroxide solution (9.6 mL, 1.92 mmol), and ethanol (30 mL) was stirred at 60° C. for 2 h. After cooling to room temperature, 2 N hydrochloric acid (9.6 mL) was added, and the solvent was removed under reduced pressure. The residue was suspended in tetrahydrofuran (100 mL), and the solution was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give 1.90 g (92%) of the title compound as a white solid. This material was used for the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C:8](OCCCC)=[O:9])=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][OH:9])=[CH:2]1
Reactant: CCCCOC(=O)CCc1cc[nH]c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCc1cc[nH]c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of butyl 3-(1H-pyrrol-3-yl)propionate (14.1 g, 72.3 mmol) in ether (400 mL) was added LiAlH4 (4.12 g, 108 mmol, 1.50 equiv.) at 0° C. under N2. The solution was stirred for 2 h at 0° C., and the reaction was cautiously quenched with saturated aqueous NH4Cl. The resulting solution was extracted with ether (3×150 mL). The combined organic layers were dried and concentrated under vacuum to give 3-(1H-pyrrol-3-yl)-1-propanol (8.0 g, 89%) as a light-yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.11 (br, 1H), 6.76 (s, 1H), 6.63 (s, 1H), 6.14 (s, 1H), 3.73 (t, 2H, J=6.6 Hz), 2.62 (t, 2H, J=7.5 Hz), 1.85-1.94 (m, 2H). LC-MS (ESI) m/z 126 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Sn:8]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[N:3]=1.CCN(CC)CC.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Sn:8]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[N:3]=2)[CH2:31][CH2:30]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(Br)n1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCN(C)CC2)n1
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a solution of 2-bromo-6-(tributylstannyl)pyridine (2.0 g, 4.47 mmol) in Et3N (3.12 mL, 22.37 mmol) and was added 1-methyl piperazine (2 ml, 17.89 mmol). The reaction was heated at 100° C. for 24 h then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layer were washed with brine, dried and concentrated. The residue was purified with silica gel chromatography to give 1-methyl-4-(6-(tributylstannyl)pyridin-2-yl)piperazine (1.4 g, 70.3%). MS (ESI, pos. ion) m/z: 466.2 (M+1); 1H-NMR (CDCl3, 300 MHz) δ 7.3 (1H, t), 6.8 (1H, d), 6.5 (1H, d), 3.6 (4H, t), 2.5 (4H, t), 2.4 (3H, s), 1.5-1.7 (6H, m), 1.2-1.5 (6H, m), 1.0-1.2 (6H, q), 0.8-0.9 (9H, q).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15]([Cl:21])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)[C@@H]1CCN1C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
(2S)-1-(benzyloxycarbonyl)azetidine-2-carboxylic acid (729.3 mg, 3.10 mmol, 1.0 eq) was dissolved in dry dichloromethane (15 mL) and cooled to about −5° C. under argon. Oxalyl chloride (380 μL, 4.36 mmol, 1.4 eq) and a drop of DMF were added to the solution. The mixture was warmed to reflux temperature with stirring over about a 3 hour period. After cooling, the mixture was concentrated and used in Reference Example 16.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a 3-neck round-bottomed flask were added zinc powder (1.96 g, 30 mmol) followed by anhydrous THF (40 mL). To the stirred suspension was slowly added, via syringe, TiCl4 (1.6 mL, 2.77 g, 14.6 mmol) at room temperature. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 2 h. To the refluxing reaction mixture was added a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (1.1 g, 3.61 mmol) and cyclohexanone (1.1 mL, 1.04 g, 10.6 mmol) in anhydrous tetrahydrofuran (40 mL). The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 2 h. The oil bath was removed and the reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added water (24 mL) followed by 10% aqueous K2CO3 (24 mL). The reaction mixture was filtered through a pad of Celite and the pad washed with EtOAc. The filtrate was transferred to a separatory funnel with the aid of water and EtOAc and the layers were separated. The organic phase washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 60:40) to give 1.17 g (95%) of compound 6 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (m, 6 H), 2.12 (m, 4 H), 6.65 (d, J=8.4 Hz, 2 H), 6.82 (d, J=8.4 Hz, 2 H), 6.97 (d, J=8.3 Hz, 2 H), 7.44 (d, J=8.3 Hz, 2 H), 9.32 (s, 1 H). HRMS (EI) Calcd for C19H19BrO: 342.0619 (M+). Found: 342.0627.
Reaction SMILES: [CH3:1][N:2]([CH2:22][CH2:23][OH:24])[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>>[CH3:1][N:2]([CH2:22][CH2:23][O:24][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(C)CCO
Reactant: CC(C)(C)C(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(C)CCOC(=O)C(C)(C)C

Procedure:
N-methyl-N-(2-trimethylacetoxyethyl)oleamide was prepared by the procedure of example 1 from 34 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)oleamide and 12 gms. (0.1 mole) trimethylacetyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:19]1([NH:25][C:16]([C@H:10]2[O:11][CH2:12][C@@H:13]([CH2:14][CH3:15])[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Reactant: NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@@H]1CO[C@H](C(=O)NC2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.250 g, 0.964 mmol) in CH2Cl2 (10 mL) were added cyclohexylamine (0.096 g, 0.964 mmol), HOAt (0.131 g, 0.964 mmol) and EDC (0.222 g, 1.157 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was washed with H2O (2×) and the organics were dried over Na2SO4 and concentrated to afford the title compound (0.296 g) as a brown oil. LC-MS (ES) m/z=241 [M+H-Boc]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[NH:14][C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]=[C:15]([CH3:17])[N:14]=1
Reactant: COc1ccc(-c2cc(=O)[nH]c(C)n2)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc(Cl)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-methylpyrimidin-4-one (2.4 g) in phosphorus oxychloride (20 ml) was refluxed for 2 hours, and evaporated. To the residue were added aqueous sodium bicarbonate solution and chloroform, and stirred at ambient temperature for 2 hours. The organic layer was obtained and washed with water. After evaporated, the residue was dissolved in ethyl acetate-diisopropyl ether mixture (1:6 v/v). The precipitates were filtered off, and the filtrate was evaporated to give 4-chloro-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (2.09 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[C:4]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:3]=1.O.NN.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][O:22][CH:12]2[C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C2OCCc3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17.6 g (55 mM) of 4-chloro-2-(4-nitrobenzoyl)-phenylacetic acid and 8 ml of 85% hydrazine hydrate were refluxed in 340 ml of ethanol for 4 hours. The reaction mixture was cooled, acidified with 115 ml of 1 M hydrochloric acid and evaporated. The residue was mixed with 50 ml of water, the crystals were filtered and dried. The resulting hydrazone derivative was dissolved in 300 ml of anhydrous dichloromethane and treated with a solution of 13.4 g (65 mM) of dicyclohexylcarbodiimide in 210 ml of anhydrous dichloromethane. The reaction mixture was stirred at room temperature overnight, then the precipitated crystals were filtered and washed with dichloromethane.
Reaction SMILES: O.[OH-].[Li+].[OH:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:10]=1[C:11]([O:13]CC)=[O:12]>O.O1CCOCC1>[OH:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:53][CH2:54][CH3:55])[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=2)[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of 0.66 g of lithium hydroxide monohydrate in 20 ml of water was added to a solution of 1.22 g of ethyl 4-hydroxymethyl-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 35(b)] in 5 ml of dioxane, and the resulting mixture was stirred at 80° C. for 5 hours. At the end of this time, the reaction mixture was freed from dioxane by distillation under reduced pressure, and the aqueous residue was mixed with ice and with ethyl acetate: 15.7 ml of 1N aqueous hydrochloric acid were then added. The title compound precipitated, and was collected by filtration and washed with water. The ethyl acetate layer was then separated from the filtrate and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was washed with diethyl ether, to give more of the title compound as a powder. The two portions of the title compound were combined and together weighed 0.98 g, and this was immediately used in the subsequent esterification reaction without further purification or characterisation.