Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:23][O:24][C:25]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2)=[O:26].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:23][O:24][C:25]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:31]2)=[O:26]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: COC(=O)c1cccc2c1CNC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 39.8 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 257 mg of 4-methoxycarbonylisoindoline hydrochloride, 532 mg of DBU, and 2ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 181 mg of the target compound.
Reaction SMILES: CCOP(O[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1)[C:10]#[N:11])(CC)=O.[H-].[Na+].[CH3:20][O:21][C:22](=[O:46])[C@H:23]([CH2:42][CH2:43][S:44][CH3:45])[NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][C:27]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]>COCCOC>[C:10](/[C:9](/[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:32]/[C:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:24][C@H:23]([C:22]([O:21][CH3:20])=[O:46])[CH2:42][CH2:43][S:44][CH3:45])=[O:41])=[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH:28]=1)#[N:11]
Reactant: CCOP(=O)(CC)OC(C#N)c1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(/C=C(/C#N)c2cccnc2)cc1-c1ccccc1C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 3-pyridylcyanomethyl phosphonate (269 mg) in DME (3 mL) was added NaH (39 mg@60%). To the red solution was added N-[4-formyl-2-(2-methylphenyl)benzoyl] methionine methyl ester (example 10756, 340 mg). After 30 min, the reaction was warmed to reflux for 2.5 h. The reaction was cooled, quenched with water (5 mL), and extracted into EtOAc (20 mL). The organic extracts were washed with brine (5 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 50%-100% EtOAc/hexane to afford two products as colorless oils. The more mobile isomer (68 mg, 13%) was assigned the Z configuration based on a ROESY experiment. MS (APCI(+)) m/e 486 (M+H)+. MS (APCI(−)) m/e 485 M−. The less mobile isomer (246 mg, 48%) was assigned the E configuration based on a ROESY experiment. MS (APCI(+)) m/e 486 (M+H)+. MS (APCI(−)) m/e 485 M−.
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH:7]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[C:23]([CH3:29])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].[C:37]([O:41][CH3:42])(=[O:40])[CH2:38]O>C1(C)C=CC=CC=1>[CH3:42][O:41][C:37](=[O:40])[CH2:38][O:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:35])[CH3:36])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:11]([CH3:30])[CH:12]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:22][C:23]=1[CH3:29]
Reactant: CCC(CC)(c1ccc(CO)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Reactant: COC(=O)CO
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(COCC(=O)OC)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Yield: 0 %

Procedure:
To a solution of enantiomer 1 of [4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-methanol, (2.10 g, 4.10 mmol) and PhCH3 (10 mL) is added methyl glycolate (6.5 mL, 81.89 mmol) and MeReO3 (0.02 g, 0.082 mmol). The solution is heated at a reflux for 2 hours with the use of a Dean-Stark trap. The solution is concentrated and chromatographed to give the title compound (0.96 g, 1.64 nmol, 40%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([O:11]C)=O)[CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:18][CH2:19][NH:20][CH3:21].[H-].[Na+].COCCOCCOC>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:18][CH2:19][N:20]([CH3:21])[C:9](=[O:11])/[CH:8]=[CH:7]/[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/c1cccnc1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccc(CCN(C)C(=O)/C=C/c2cccnc2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.6 %

Procedure:
A mixture of methyl trans-3-(3-pyridyl)acrylate (326 mg), 3,4-dimethoxy-N-methylphenethylamine (390 mg), 60% sodium hydride (80 mg) and diethylene glycol dimethyl ether (2 ml) was stirred at room temperature for 24 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. After the solvent was distilled out under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=50:1) and recrystallized to yield the titled compound (278 mg, 43%).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].CC1C=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.CI>C(OCC)C>[CH2:3]([C:1]1[CH:2]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)[CH3:4]
Reactant: [Li]C(C)CC
Reactant: Cc1ccc2ccccc2n1
Solvent: CI
Solvent: CCOCC
Product: CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
sec-Butyllithium (1.3 M in cyclohexane, 19.3 mL, 25.1 mmol, 1.2 eq.) was added dropwise to a 0° C. solution of 2-methylquinoline (2.84 mL, 3.0 g, 21.0 mmol, 1.0 eq.) in dry diethyl ether (75 mL). After the addition was complete the cooling bath was removed and the mixture was stirred at r.t. for 1.5 h. The reaction mixture was cooled to 0° C. and methyl iodide (1.96 mL, 4.46 g, 31.4 mmol, 1.5 eq.) was added dropwise. After the addition was complete the cooling bath was removed and the reaction was stirred at r.t. for 3 h. Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (50 mL) and were dried over sodium sulfate and concentrated under reduced pressure which gave the crude product (4.82 g) as an orange oil. The crude product was purified by column chromatography (SiO2, 1:5 ethyl acetate-cyclohexane) which yielded the product (3.03 g, 92% yield) as a clear yellow oil; 1H NMR (500 MHz, CDCl3) δ 1.41 (t, J=7.5 Hz, 3H, CH3), 3.01 (q, J=7.5 Hz, 2H, CH2), 7.31 (d, J=8.5 Hz, 1H, Ar), 7.48 (t, J=7.5 Hz, 1H, Ar), 7.68 (t, J=7.5 Hz, 1H, Ar), 7.77 (d, J=8.0 Hz, 1H, Ar), 8.04 (d, J=8.5 Hz, 1H, Ar), 8.07 (d, J=8.5 Hz, 1H, Ar).
Reaction SMILES: [C:1]1([C@H:7](O)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C([OH:32])CCC2C=CC=CC=2)C=CC=CC=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]1([CH2:7][C:8](=[O:32])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O[C@H](CCc1ccccc1)c1ccccc1
Reactant: OC(CCc1ccccc1)c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
General procedure for conversion of racemic 1-substituted alkanols to optically active 1-substituted alkanols via prochiral ketones. Exemplified for (1 R)-1,3-diphenyl-1-propanol. A solution of racemic 1,3-diphenyl-1-propanol (1.26 g; 5.94 mmol) was dissolved in 10 mL of acetone, and Jones reagent was added until persistence of the orange color. After stirring for 30 min, the reaction was quenched by adding 2 mL of 2-propanol. The solvent was decanted away from the precipitated solids, which were washed with ethyl acetate. The combined organic fractions were washed with 2×20 mL of water, dried and concentrated. The crude product was filtered through a plug of silica gel, eluting with 25% ethyl acetate/hexane, to obtain 1.07 g (86%) of 1,3-diphenylpropanone as a white crystalline solid, 1H NMR (360 Mhz; CDCl3): d 3.09 (t, 2H, 1=8.1); 3.33 (t, 2H, 1=8.1); 7.29 (m, 5H); 7.49 (m, 3H); 7.98 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)[C:3]#[CH:4].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)[C:3]#[C:4][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc[nH]3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(1H-pyrrol-2-yl)-1-propyne (212 mg, 1.75 mmol) (from Example 30 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (125 mg, 0.39 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (42 mg) (Aldrich) and CuI (20 mg) (Aldrich) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(1H-pyrrol-2-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 68 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Cl:22])=[CH:16][CH:15]=2)[C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:23](O)(=O)[CH:24]([CH3:26])[OH:25]>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]2[N:12]=[C:23]([CH:24]([OH:25])[CH3:26])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Cl:22])=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCCl)cc1
Reactant: CC(O)C(=O)O
Product: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCCl)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5 from 4-chloro-N2-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1,2-benzenediamine and lactic acid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33])[C:22]([OH:24])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C[CH2:35][O:36][C:37]([CH3:39])=[O:38]>CN(C=O)C>[CH3:35][O:36][C:37](=[O:38])[CH2:39][N:33]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][CH2:25][C@H:21]([NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:22]1=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reactant: CCOC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reaction time: 18 h
Yield: 71 %

Procedure:
(3S)-2-Oxo-3-tert-Butoxycarbonylamino-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.54 g, 44.5 mmol) was added to a cooled (0° C.) solution of (2S)-2-tert-butoxycarbonylamino-3-(2-aminophenylamino)propionic acid (11.95 g, 40.5 mmol) in 100 ml of DMF and stirred for 18 h. The reaction was poured into 700 ml of EtOAc and washed four times with 100 ml of H2O. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give a brown solid that was purified by flash chromatography eluting with 3:7 EtOAc/hexane to give 8 g (71%) of the title compound: 1H NMR (CDCl3) δ 7.78 (1H, s), 7.02-6.95 (1H, m), 6.88-6.82 (1H, m), 6.82-6.78 (1H, m), 6.75-6.70 (1H, m), 5.8-5.7 (1H, d), 4.55-4.45 (1H, m), 3.95 (1H, s), 3.9-3.82 (1H, m), 3.48-3.40 (1H,m), 1.45 (9H,s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cnn(-c2ccc(C(=O)O)cc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C(=O)Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To a suspension of 4-(4-methylpyrazol-1-yl)benzoic acid (0.75 g) in dichloromethane (15 ml) was added oxalyl chloride (0.50 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo yielded 4-(4-methylpyrazol-1-yl)benzoyl chloride (0.77 g), which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (92% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.97, 7.44, 6.98, 3.99-3.62, 3.55, 1.50, 0.80-0.66, 0.48-0.42, 0.11-0.06. MS (ES+) m/z 380.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][S-:25].[Na+]>O1CCOCC1>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([S:25][CH3:24])[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: C[S-]
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]
Yield: 45.9 %

Procedure:
A stirred solution of 335 mg (0.95 mmol) trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 663 mg (9.46 mmol) sodium methanethiolate in 20 ml dry dioxane under argon was heated at reflux for one hour. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate) followed by recrystallisation from ether/hexane afforded 110 mg (46%) 4-furan-2-yl-6-methylsulfanyl-5-nitro-pyrimidin-2-ylamine as a yellow crystalline solid. EI-MS ni/e (%): 252 (M+, 22), 235 (26), 223 (66), 207 (100), 178 (86), 161 (44), 134 (62), 94 (90).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:5]=1[NH:6][CH2:7][CH:8]=[O:9])[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:6]([CH2:7][CH:8]=[O:9])[C:5]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:4]=1[CH2:1][CH2:2][CH3:3])=[O:30]
Reactant: CCCc1ccc(F)cc1NCC=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCc1ccc(F)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-propyl-5-fluoroanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-propyl-5-fluoroanilino)acetaldehyde.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[N:18]=2)[CH:9]=[CH:8][CH:7]=1.C1COCC1.CO.[Li+].[OH-].Cl>CO>[NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]3[N:18]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(OCCCN)n3)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCCCOc1cccc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)n1
Temperature: 70 °C
Yield: 100 %

Procedure:
To a solution of (R)-ethyl 5-(2-(6-(3-aminopropoxy)pyridin-2-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (70 mg, 0.17 mmol) in 3:1 THF/MeOH (8 mL) was added LiOH (1 N, 1.5 mL, 1.5 mmol) and the reaction mixture was heated at 70° C. for 20 hours. After cooling, the reaction mixture was diluted with MeOH, acidified with 1 N HCl (1.5 mL), and concentrated to afford the desired product (65 mg, 100% yield). MS (apci) m/z=383.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH:12]C(=O)OC(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH2:12]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@H]1Cc2ccccc2[C@H]1N
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
To tert-butyl [(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate (253 mg, 0.961 mmol) was added a 4.00 M solution of hydrochloric acid in 1,4-dioxane (5.00 mL) and the mixture was stirred for 10 min, after which a white solid crashed out. The suspension was concentrated in vacuo and co-evaporated with toluene to afford a white solid, which was dissolved in water. The solution was adjusted to pH 10 via addition of sodium carbonate. The mixture was then extracted with diethyl ether (3×30 mL) and the organic extracts were concentrated in vacuo to afford the title compound (150 mg, 99%). LC/MS: Rt=0.85 min, ES+ 164 (AA standard).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:29][CH2:30][CH:25]([C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:15]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc3ccccc3c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-naphthyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 74% overall yield. mp. 171°-172°FDMS m/e=400 (M+ of free base). α[D]589 =-13.51 (c=1.04, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:9]2[O:10][CH2:13][CH2:14][CH2:15][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: BrCCCBr
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cc(Cl)c2c(c1)OCCCO2
Temperature: 25 °C

Procedure:
A mixture of 3-chloro-4,5-dihydroxy benzaldehyde (4.15 g), of 1,3-dibromopropane (4.71 g, 0.92 eq.) and potassium carbonate (8.28 g, 2.5 eq.) in acetonitrile (160 ml) was heated to 60° C. overnight. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica (20% ethyl acetate in hexanes) to give the product as a white crystal. MS (m+1)=212.1
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.CCN(C(C)C)C(C)C.[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[C:18]([OH:36])(=[O:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Temperature: 0 °C

Procedure:
1.33 gr. of N-hydroxy succinimide (11.56 mmole, 1.5 eq.) and DIEA (1.35 ml), were dissolved in 50.0 ml of anhydrous THF and gently stirred at 0° C. under nitrogen atmosphere. Then, Oleoyl chloride (3.0 ml, 85% tech., 7.8 mmole, 1.0 eq.) dissolved in 50 ml of anhydrous THF was added dropwise during 1 h. The mixture was gently stirred for 2 h at 0° C. and over-night at room temperature. The resulting precipitate were discarded by filtration and the filtrate was evaporated under reduced pressure, redissolved in small amount of DCM and purified over silica-gel column using DCM as eluent. Fractions containing the product were combined and solvent was removed under reduced pressure. The resulting white solid was dried in vacuum over NaOH-pellets.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:46]3[CH2:47][CH2:48][CH:43]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:44][CH2:45]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CCN(C2CCNCC2)C1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-pyrrolidin-1-yl-piperidine (Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C37H47N6O2Cl2 [(M+H)+] 677.3132, observed 677.3132.