Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].Cl[C:32]([O:34][CH:35]1[CH2:40][CH2:39][CH:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:37][CH2:36]1)=[O:33].CO.ClCCl>O1CCCC1>[CH2:24]([O:23][C@@H:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][C:32]([O:34][CH:35]3[CH2:40][CH2:39][CH:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:37][CH2:36]3)=[O:33])=[CH:8][CH:7]=2)=[CH:13][CH:14]=1)[C:20]([OH:22])=[O:21])[CH3:25]
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Reactant: CC(C)(C)C1CCC(OC(=O)Cl)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)OC3CCC(C(C)(C)C)CC3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (0.2 g, 0.547 mmole) and sodium hydrogen carbonate (0.05 g, 0.595 mmole) were mixed in tetrahydrofurane (5 ml), stirred at room temperature for 20 minutes and then 4-tert-butylcyclohexyl chloroformate (0.131 g, 0.599 mmole) was added. The reaction mixture was stirred at room temperature overnight and then a little more 4-tert-butylcyclohexyl chloroformate was added since the reaction was not complete according to HPLC. The reaction mixture was stirred for 2 more hours and then evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography on silica gel (Isolute, SI ) using dichloromethane:heptane (1:1), followed by dichloromethane, and then methanol: dichloromethane (1:99) as eluants gave 0.28 g (93% yield) (S)-2-ethoxy-3[4-(2-[4-([{4-(tert-butyl)cyclohexyl}oxy]carbonylamino)phenyl]ethoxy)phenyl]propanoic acid.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([CH2:32][CH2:33][CH2:34][OH:35])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1.[H-].[Na+]>CN(C=O)C>[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][O:35][CH2:34][CH2:33][CH2:32][C:15]2[N:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)[N:17]([CH3:18])[C:16]=2[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[CH:39][CH:38]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCCCCc1cccc(-c2nc(CCCO)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCc1cccc(-c2nc(CCCOCc3ccc(F)cc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reaction time: 125 h
Yield: 25.5 %

Procedure:
A solution of 0.200 g (0.42 mmol) of [2-(3-hexyl-phenyl)-5-(3-hydroxy-propyl)-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 33) and 0.107 ml=0.162 g (0.83 mmol) of 4-fluorobenzylbromide in 5.0 ml of DMF was treated with 0.036 g (0.83 mmol) of sodium hydride (55% dispersion in mineral oil) at RT. After stirring for 125 hours, the reaction mixture was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.063 g (26%) of the title compound as light yellow oil. MS: 589.0 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:11][CH3:12])([O:9][CH3:10])=[S:8].[C:14]([C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][C:20]=1[OH:21])#[N:15]>CC(C)=O>[C:14]([C:16]1[S:17][C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][C:20]=1[O:21][P:7]([O:11][CH3:12])([O:9][CH3:10])=[S:8])#[N:15]
Reactant: COP(=S)(Cl)OC
Reactant: N#Cc1sc(-c2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COP(=S)(OC)Oc1cc(-c2ccccc2)sc1C#N
Temperature: 20 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
7 g of potassium carbonate and 8 g of O,O-dimethyl chlorothiophosphate were added to a solution of 10.5 g of 2-cyano-3-hydroxy-5-phenyl-thiophene in 120 ml of acetone and the mixture was stirred at 20° C. for 15 hours and was then filtered. The filtrate was evaporated to dryness and the crystal residue was empasted with petroleum ether. The crystals were then crystallized from isopropyl ether to obtain 12.8 g of 2-cyano-3-(dimethoxythiophosphoryloxy)-5-phenylthiophene melting at 95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH:10]2[C:19]#[N:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:11][CH:10]2[CH2:19][NH2:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)N1CCN(c2ccc(Cl)c(Cl)c2)C(C#N)C1
Agent: [Al+3]
Agent: [H-]
Product: CC(C)(C)N1CCN(c2ccc(Cl)c(Cl)c2)C(CN)C1

Procedure:
In a manner similar to preparation 2, react 1-(3,4-dichlorophenyl)-4-(1,1-dimethylethyl)-2-piperazinecarbonitrile withlithium aluminum hydride to obtain the title compound.
Reaction SMILES: CS[C:3](=[S:10])[NH:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1.[NH2:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1>CN(C)C=O>[NH:14]1[CH:15]=[N:16][C:12]([NH:11][C:3]([NH:4][C:5]2[N:9]=[CH:8][NH:7][N:6]=2)=[S:10])=[N:13]1
Reactant: Nc1nc[nH]n1
Reactant: CSC(=S)Nc1nc[nH]n1
Solvent: CN(C)C=O
Product: S=C(Nc1nc[nH]n1)Nc1nc[nH]n1
Yield: 58 %

Procedure:
A 3,000 ml multinecked flask provided with a reflux condenser and placed on a water bath was filled with 156.2 g (0.8964 mole) of N-1,2,4-triazolyl-dithiocarbamic acid methyl ester, prepared as described in U.S. Pat. No. 3,686,201, 1,700 ml of dimethylformamide, 75.37 g (0.8964 mole) of 3-amino-1,2,4-triazole. The reaction mixture was heated for 24 hours thus obtaining first a solution and then the formation of a precipitate. The suspension was filtered, the product thus obtained washed with methanol and then dried thus obtaining 109.3 g of a white product (Yield 57%).
Reaction SMILES: [CH2:1]([CH:4]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])[OH:5])[CH:2]=[CH2:3].[H][H]>C(O)C.[Pt]>[CH2:1]([CH:4]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])[OH:5])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Pt]
Solvent: CCO
Product: CCCC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
30 g (0.135 mol) of 1-allyl sorbitol syrup (produced as in example 1) was dissolved in 300 ml ethanol. 1.0 g of platinum (5% weight on activated carbon) was added and the mixture was hydrogenated at room temperature with hydrogen pressure at 60 psi. The reaction was stopped until no hydrogen pressure drop was observed. The solid was filtered. The allyl group of the solution was completely converted to propyl group based on NMR.
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[O:12][C@H:13]2[C@@H:15]([C@:16]([C:21]3[CH:22]=[C:23]([NH:28][C:29]([C:31]4[CH:36]=[N:35][C:34](Cl)=[CH:33][N:32]=4)=[O:30])[CH:24]=[CH:25][C:26]=3[F:27])([CH:18]([F:20])[F:19])[N:17]=1)[CH2:14]2.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[NH2:10][C:11]1[O:12][C@H:13]2[C@@H:15]([C@:16]([C:21]3[CH:22]=[C:23]([NH:28][C:29]([C:31]4[CH:36]=[N:35][C:34]([O:7][CH2:6][C:5]#[C:4][CH:1]5[CH2:3][CH2:2]5)=[CH:33][N:32]=4)=[O:30])[CH:24]=[CH:25][C:26]=3[F:27])([CH:18]([F:20])[F:19])[N:17]=1)[CH2:14]2
Reactant: OCC#CC1CC1
Reactant: NC1=N[C@@](c2cc(NC(=O)c3cnc(Cl)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=N[C@@](c2cc(NC(=O)c3cnc(OCC#CC4CC4)cn3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 57.5 %

Procedure:
To a solution of 3-cyclopropylprop-2-yn-1-ol (205 mg, 2.137 mmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil; 8.6 mg, 0.214 mmol) at rt. After 15 min N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropyrazine-2-carboxamide (Example 261, 88 mg, 0.214 mmol) was added and the reaction mixture was stirred at 60° C. for 50 min. Water (1.0 mL) and aqueous, saturated NaHCO3 solution (1 mL) were added. The resulting mixture was then extracted with EtOAc (2×10 mL). The combined organic extracts were washed with water and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (0%-20% MeOH/DCM) to give 58 mg of the title compound as an off-white solid. MS m/z=472 [M+H]+
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: COc1cccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-methoxybenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.43 (m, 1 H), 7.27-7.17 (m, 2 H), 7.09-7.04 (m, 1 H), 6.96-6.91 (m, 1 H), 6.89-6.81 (m, 3 H), 6.28 (dd, J=3.5, 10.9 Hz, 1 H), 5.62-5.43 (m, 3 H), 4.33-4.25 (m, 2 H), 3.78 (d, J=1.2 Hz, 3 H), 2.96-2.80 (m, 2 H), 2.78 (s, 3 H), 2.15-2.03 (m, 2 H), 1.02-0.91 (s, 9 H); LC/MS (m/z) ES+=515.38 (M+1).
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[C:13]([OH:15])=[O:14].[OH-].[K+].O>CC(C)=O>[CH3:1][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:3])[C:9]([C:13]([OH:15])=[O:14])=[CH:10]1
Reactant: CI
Reactant: Cc1cccc2c(C(=O)O)c[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc2c(C(=O)O)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Methyl iodide (30 g) was added to a stirred mixture of 7-methylindole-3-carboxylic acid (4.3 g) and powdered potassium hydroxide (20 g) in anhydrous acetone at 0° C. The resulting suspension was then stirred at room temperature overnight, then poured into water (500 ml), washed with dichloromethane (3×100 ml) and the aqueous phase acidified to pH 2 with hydrochloric acid. The product was isolated by filtration and dried under vacuum to afford white crystals (4.5 g); m.p. 243° C.; 6 H (360MHz, DMSO-d6) 2.72 (3 H, s, CH3), 4.09 (3 H, s, NCH3), 6.92 (1 H, d, J=6 Hz, H-6), 7.02 (1 H, t, J=6 Hz, H-5), 7.87 (1 H, d, J=6, H-4), 7.92 (1 H, s, H-2); m/z 189 (M+ , 100%), 172 (40), 144 (30), 91 (55).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([O:21][CH3:22])[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>>[CH3:22][O:21][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[O:16][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13]
Reactant: COc1ccccc1O
Reactant: c1ccc(CN2CC3OC3C2)cc1
Product: COc1ccccc1O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Yield: 27 %

Procedure:
A mixture of 40 g. of crude 1-benzyl-3,4-epoxypyrrolidine and 70 g. of guaiacol was heated at 120° C. for 20 hr. Aspirator vacuum was then used to distill off the excess guaiacol. The residue was dissolved in methylene chloride and extracted with dilute sodium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue weighed 54 g., was chromatographed on 1 kg. of silica gel. The product was eluted with 50% ethyl acetate in benzene and crystallized from cyclohexane. The m.p. was 115°-117° C. and the yield was 27%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:40])[CH2:9]2)=[C:4]([C:41]([F:44])([F:43])[F:42])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C@H:10]([CH3:40])[CH2:9]2)=[C:4]([C:41]([F:44])([F:42])[F:43])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCNCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.3 %

Procedure:
To a 50 mL flask containing tert-butyl 4-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)-1-naphthyl]piperazine-1-carboxylate (185.2 mg) and 5 mL of CH2Cl2 was added 3 mL of TFA. This was stirred at room temperature for 4.5 hr. Reaction was complete as determined by TLC. Solvent and TFA was removed under vacuum. The resulting residue was dissolved in CH2Cl2, washed with sat. K2CO3 until pH=8, then washed with saturated brine, dried over Na2SO4 and concentrated down to yield (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(4-piperazin-1-yl-1-naphthyl)sulfonyl]piperazine as a yellow solid (136.3 mg, 87.3% yield). HRMS: calcd for C26H28F4N4O2S+H+, 537.19418. found (ESI-FTMS, [M+H]1+), 537.1968. HPLC Method 1: room temperature, 5.003 min, 94.44%, HPLC Method 2: room temperature, 6.254 min, 93.74%.
Reaction SMILES: [CH:1]([Li])=[CH2:2].[O:4]1[CH2:9][CH2:8][CH:7]=[CH:6][C:5]1=[O:10]>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]([CH:7]1[CH2:8][CH2:9][O:4][C:5](=[O:10])[CH2:6]1)=[CH2:2]
Reactant: [Li]C=C
Reactant: O=C1C=CCCO1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC1CCOC(=O)C1
Reaction time: 0.25 h

Procedure:
A stream of nitrogen gas is passed through a mixture of 19.6 mL (41.2 mmol) of 2.1M vinyllithium in tetra-hydrofuran and 21 mL toluene to evaporate tetrahydrofuran. The resulting pale yellow suspension is diluted with 21 mL ether and cooled to -78°. To this solution is added 1.87 g (20.9 mmol) cuprous cyanide and the reaction mixture is then warmed to 0° for 2 minutes. The resulting gray suspension is cooled to -78° and 0.9 mL (10.4 mmol) of 5,6-dihydro-2H-pyran-2-one is added. The reaction mixture is stirred at -78° for 30 minutes and at -20° for 15 minutes. The reaction is quenched by the addition of saturated aqueous ammonium chloride and stirred for 1 hour at room temperature. The insoluble salts are filtered off and washed with water (1×20 mL) and ether (2×20 mL). The layers are separated and the aqueous phase is extracted with ether (2×30 mL). Combined organic extracts are dried (MgSO4), filtered and evaporated to give yellow oil which is purified by flash chromatography to obtain 4-ethenyltetrahydro-2H-pyran-2-one as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:29].[Cl-].[Na+]>C(O)CO>[CH:15]1([NH:14][C:12]2[CH:13]=[C:4]3[C:3](=[O:2])[NH:29][C:6](=[O:7])[C:5]3=[CH:10][C:11]=2[NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1cc(NC2CCCCC2)c(NC2CCCCC2)cc1C(=O)OC
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Product: O=C1NC(=O)c2cc(NC3CCCCC3)c(NC3CCCCC3)cc21
Reaction time: 12 h

Procedure:
Analogously to Example 1, 194 mg (0.5 mmol) of 4,5-bis(cyclohexylamino)phthalic acid dimethyl ester in 15 ml of ethylene glycol are heated at 120°, ammonia gas being passed through the mixture, with stirring, for 12 hours. The reaction mixture is cooled, saturated with sodium chloride and extracted with ethyl acetate. The ethylacetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed onsilica gel with hexane/ethyl acetate 3:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of orange crystals, m.p. 170°-175° C., FAB-MS: 342 [M+ +H].
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH2:18][CH2:19][C@@H:20]1[O:24][C:23]([CH3:26])([CH3:25])[O:22][C:21]1=[O:27]>CCOCC.O1CCCC1>[CH2:19]([C@@H:20]1[O:24][C:23]([CH3:26])([CH3:25])[O:22][C:21]1=[O:27])[CH2:18][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC1(C)OC(=O)[C@H](CCO)O1
Reactant: [Li]CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC[C@@H]1OC(C)(C)OC1=O
Temperature: -10 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a flame-dried 500 mL three-necked round bottom flask under nitrogen containing a suspension of 4.85 g (25.48 mmol) of cuprous iodide in 200 mL of anhydrous ether and held at -30° C. was added dropwise 31.85 mL of 1.6M n-BuLi (50.96 mmol) in hexanes. The dark red-brown solution was stirred at -30° C. to -40° C. for 2 hours and cooled to -78° C. (S)-5-(2-hydroxyethyl)-2,2-dimethyl-l,3-dioxolan-4-one p-toluenesulfonate (4.0 g, 12.74 mmol), dissolved in 30 mL of anhydrous ether and 10 mL of anhydrous tetrahydrofuran, was added dropwise while maintaining the temperature below -70° C. The reaction mixture was stirred for 18 hours at -78° C. Following completion (TLC monitoring), the reaction was warmed to -10° C. and quenched by the addition of 125 mL of precooled saturated ammonium chloride solution. Ether (100 mL) was added and the mixture filtered over Celite. The aqueous phase was extracted with 3×175 mL ether. The combined ether extract was washed with 2×125 mL of saturated ammonium chloride solution, 1×75 mL of water and 2×100 mL of brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified (silica gel) using ethyl acetate:hexanes (1:5) as eluant to give 2.44 g (95%) of the title compound as a colorless oil: [α]D25 0.6°(c=1.9, CH3OH); IR (Kbr, cm-1) 2958, 2933, 2861, 1797; 1H NMR (CDCl3) δ 4.39 (dd, J=4.4, 7.1 Hz, 1H), 1.95-1.81 (m, 1H), 1.81-1.62 (m, 1H), 1.61 (s, 3H), 1.54 (s, 3H), 1.49-1.38 (m, 2H), 1.35-1.29 (m, 6H), 0.89 (t, J=6.6 13C NMR (CDCl3) δ 173.3, 110.2, 74.2, 31.7, 31.6, 28.8, 25.8, 24.8, 22.5, 13.9; HRMS calculated for C11H20O3 (M+), 200.1412, found 200.1422.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18](=[SiH2:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:14]([C:25]([CH3:28])([CH3:27])[CH3:26])([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:29])[N:3]=1.[CH3:30]N(C=O)C.[H-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([C:18](=[SiH2:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C@@:14]([C:25]([CH3:28])([CH3:27])[CH3:26])([OH:15])[C@H:12]2[O:13][CH3:30])=[C:4]([NH2:29])[N:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=[SiH2])[C@H]1O[C@@H](n2cnc3c(N)nc(N)nc32)[C@H](O)[C@@]1(O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CO[C@H]1[C@H](n2cnc3c(N)nc(N)nc32)O[C@H](C(=[SiH2])OC(C)(C)C)[C@]1(O)C(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
To a stirred −20° C. solution of (62) (2.11 g, 5 mmol) in anhydrous DMF (40 ml) methyl iodide (0.93 ml, 15 mmol) was added followed by sodium hydride as a 60% mineral oil suspension (0.3 g, 7.5 mmol). The reaction mixture was stirred for 1.5 h at −20° C. and quenched with ammonium chloride (1.5 g). The resulting suspension was partitioned between chloroform (75 ml) and water (50 ml). The aqueous layer was washed with additional chloroform. The combined chloroform extracts were washed with 50 ml of water and the aqueous layer was extract back with chloroform. The resulting organic solution was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. Crystallization from dichloromethane-hexane mixture (1:1) afforded (63) as colorless crystals. Yield 1.92 g (88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:15][CH2:14][C:13]2([CH3:19])[C:16]([OH:18])=O)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:42][NH:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1>CN(C=O)C.C1COCC1.C(Cl)Cl>[CH3:42][N:43]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1)[C:16]([C:13]1([CH3:19])[CH2:14][CH2:15][N:12]1[C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:18]
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)O)c1
Reactant: CNCc1ccc(C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(CN(C)C(=O)C2(C)CCN2C(=O)Cc2cc(C)cc(C)c2)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of Intermediate 119 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (1 eq.) in either DCM, THF or DMF was added HOBt (1.1 eq.), EDC.HCl (1.5 eq.), TEA (3 eq.) and methyl-(4-methyl benzyl)-amine (1.5 eq.). The reaction was stirred at 20° C. for 15 h, then the crude was concentrated under reduced pressure and partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The aqueous layer was extracted three times with EtOAc. The organic layers were combined, washed with water then with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 100/0 to 99/1) to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid methyl-(4-methyl-benzyl)-amide.
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[N:9][CH:10]=1.[BrH:14].C(O)C.BrBr>C(O)(=O)C>[BrH:14].[Br:14][CH2:12][C:11]([C:7]1[CH:8]=[N:9][CH:10]=[C:5]([F:4])[CH:6]=1)=[O:13]
Reactant: CC(=O)c1cncc(F)c1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(CBr)c1cncc(F)c1
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To an ethanol (5.0 mL) solution of 1-(5-fluoropyridin-3-yl)ethanone (0.50 g), acetic acid (6.0 mL) was added, then a 20 to 30% hydrobromic acid/ethanol solution (1.0 mL) and bromine (0.30 mL) were added under ice cooling, and the resultant was stirred at 70° C. for 45 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound (1.30 g) as a faint orange solid.