Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].[NH:41]1[CH2:46][CH2:45][S:44][CH2:43][CH2:42]1.C(N(CC)CC)C>C(#N)C>[F:38][C:35]([F:37])([F:36])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:40])[F:39])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:41]2[CH2:46][CH2:45][S:44][CH2:43][CH2:42]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: C1CSCCN1
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCN2CCSCC2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 90 °C
Reaction time: 15 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (0.2 g), thiomorpholine (0.042 g) and triethylamine (0.09 ml) in dry acetonitrile (2 ml) was stirred at 90° C. for 15 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) as an eluent to give (2R)-1-(3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-thiomorpholinopropyl)piperazine. The product obtained was dissolved in ethanol and treated with 17.6% hydrogen chloride in ethanol solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-thiomorpholinopropyl)piperazine dihydrochloride (0.19 g) as a powder.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][NH:8][C:11]([NH:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(NCC1CCCCC1)NCC1CCCCC1
Yield: 95 %

Procedure:
A mixture of cyclohexanemethylamine (Aldrich, 68.66 g) and 5 N sodium hydroxide (Fisher, 200 ml) was stirred vigorously with cooling (−10° C.) while a solution of phosgene (30.0 g) in toluene (600 ml) was added rapidly. After stirring for 20 minutes, the resulting mixture was filtered and the precipitated solid was washed with water and dried (0.5 Torr) to give 1,3-bis(cyclohexylmethyl)urea as white powder (72.72 g, 95%), m.p. 150-152° C.; 1H-NMR (DMSO-d6) δ: 5.74 (br t, J=5.8 Hz, 2, 2 NH), 2.81 (t, J=6.3 Hz, 4, 2 NCH2), 1.62, 1.25, and 0.85 (all m, 22, 2 cyclohexyl).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH2:30][CH3:31])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>>[CH2:30]([O:29][CH2:28][C@@:10]12[CH2:9][N:8]([S:38]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)(=[O:40])=[O:39])[CH2:17][CH2:16][C:15]1=[CH:14][C:13]1[N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:19]=[CH:20][C:12]=1[CH2:11]2)[CH3:31]
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: O=S(=O)(Cl)c1cccnc1
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cccnc1)C2

Procedure:
The title compound was prepared by the method of Preparation 1c using (R)-4a-ethoxymethyl-1-(4-fluorophenyl)-1,4,4a,5,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and pyridine-3-sulfonyl chloride. LCMS (Method C): 469 (M+H)+, Retention time 11.1 minutes.
Reaction SMILES: [Li+].[F:2][C:3]1[C:11]([O:12][C:13]2[C:14]3[CH:21]=[C:20]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([O-:28])=O)=[CH:24][CH:23]=4)[NH:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:31])[NH:7]2.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:33].C(OP(C#N)(=O)OCC)C>CN(C=O)C>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:26]([C:25]2[CH:24]=[CH:23][C:22]([C:20]3[NH:19][C:15]4[N:16]=[CH:17][N:18]=[C:13]([O:12][C:11]5[C:3]([F:2])=[C:4]6[C:8](=[CH:9][CH:10]=5)[NH:7][C:6]([CH3:31])=[CH:5]6)[C:14]=4[CH:21]=3)=[CH:30][CH:29]=2)=[O:28])[CH2:36][CH2:35]1)[CH3:33]
Reactant: Cc1cc2c(F)c(Oc3ncnc4[nH]c(-c5ccc(C(=O)[O-])cc5)cc34)ccc2[nH]1
Reactant: CCN1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2ccc(-c3cc4c(Oc5ccc6[nH]c(C)cc6c5F)ncnc4[nH]3)cc2)CC1

Procedure:
To 340 mg (0.83 mMol) 4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid lithium salt in 5 ml of DMF under N2 atmosphere, 0.38 ml (3 mMol) of N-ethylpiperazine and 0.31 ml (95%; 2 mMol) of diethyl-cyanphosphonate are added at 0° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Cl[CH2:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1
Reactant: O=C(CCl)Cc1ccccc1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)Cc1ccccc1
Yield: 40.5 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.45 g, 6.5 mmoles) and 1-chloro-3-phenyl-2-propanone (1.1 g, 6.5 mmoles) in acetonitrile was stirred for 18 hours at 20°. After removal of the acetonitrile at reduced pressure, the residue was treated with water and extracted with methylene chloride. The residue, after concentration of the extracts, was chromatographed on alumina (grade III) using ethyl acetate from elution. Combination of the appropriate fractions gave 1.1 g of product which was recrystallized from ethyl acetate to give the title compound, mp. 138°-139°.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:13](=[O:23])[N:14]([CH2:21][CH3:22])[C:15]3[C:20]([C:11]=2[C:10]2[CH:9]=[C:8]([Cl:24])[CH:7]=[CH:6][C:5]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)#[N:2].CN(C)C=O.O1CCCC1>[Ni].C(O)C>[NH2:2][CH2:1][CH2:3][N:4]1[C:12]2[C:13](=[O:23])[N:14]([CH2:21][CH3:22])[C:15]3[C:20]([C:11]=2[C:10]2[CH:9]=[C:8]([Cl:24])[CH:7]=[CH:6][C:5]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CCn1c(=O)c2c(c3ccccc31)c1cc(Cl)ccc1n2CC#N
Agent: [Ni]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1c(=O)c2c(c3ccccc31)c1cc(Cl)ccc1n2CCN

Procedure:
5 g. of 7-cyanomethyl-10-chloro-5-ethyl-7H-indolo[2,3-c]-quinolin-6(5H)-one was dissolved in 200 ml. of boiling dimethylformamide. After cooling, 200 ml. of tetrahydrofuran, 100 ml. of ethanol and Raney nickel were added. The mixture was hydrogenated for 21/2 hours at atmospheric pressure. The catalyst was separated by filtration and the filtrate was evaporated. Crystallization of the residue from ethanol yielded 2.9 g. (57 percent) of 7-(2-aminoethyl)-10-chloro-5-ethyl-7H-indolo[2,3-c]quinolin-6(5H)-one, which after recrystallization from ethanol had a melting point of 166°-169°.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[Cl:31][C:32]1[CH:33]=[C:34]([O:43][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:35]=[CH:36][C:37]=1[O:38][CH2:39][C@@H:40]1[CH2:42][O:41]1>C(Cl)(Cl)Cl.CO>[Cl:31][C:32]1[CH:33]=[C:34]([OH:43])[CH:35]=[CH:36][C:37]=1[O:38][CH2:39][C@@H:40]([OH:41])[CH2:42][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:29][CH:30]=1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)c(Cl)c1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3Cl)cc2)CC1
Yield: 17 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.57 g, 1.35 mmol) was reacted with tert-butyl(diphenyl)silyl 3-chloro-4-[(2S)oxiranyl-methoxy]phenyl ether (0.59 g, 1.35 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.185 g, 0.23 mmol).
Reaction SMILES: CCCCCC.CCOC(C)=O.[CH3:13][O:14][C:15](=[O:25])[C:16]([CH3:24])([CH3:23])[CH2:17][CH2:18][C:19]([O:21]C)=[O:20].[OH-].[K+]>CO>[CH3:13][O:14][C:15](=[O:25])[C:16]([CH3:23])([CH3:24])[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)CCC(C)(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
To a solution of 2,2-dimethyl-pentanedioic acid (3.0 g, 19 mmol) is added K2CO3 (6.49 g, 47 mmol) and iodomethane (2.5 ml, 39 mmol) at room temperature. The mixture is stirred at room temperature for 18 hours. To the mixture, H2O is added and the solution is extracted with AcOEt. The organic layer is washed with H2O, saturated aqueous NaHCO3 and brine, and dried over MgSO4. Solvent is removed under reduced pressure to give 2,2-dimethyl-pentanedioic acid dimethyl ester (2.49 g, 70%); TLC (hexane/AcOEt, 3:1) Rf 0.50, 1H NMR (400 MHz, chloroform-d) δ ppm 1.19 (s, 6H), 1.88 (m, 2H), 2.29 (m, 2H), 3.67 (s, 6H). To a solution of 2,2-dimethyl-pentanedioic acid dimethyl ester (2.40 g, 12.8 mmol) in MeOH (15 ml) is added potassium hydroxide (0.788 g, 14.0 mmol). The mixture is stirred at room temperature for 16 hours and refluxed for 2 hours. The mixture is cooled to room temperature and concentrated under reduced pressure. To the obtained residue, 1M aqueous HCl (14 ml) is added and the solution is extracted with ether. The organic layer is washed with H2O, dried over Na2SO4, and concentrated under reduced pressure to give 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.97 g, 88%); 1H NMR (400 MHz, chloroform-d) ppm 1.20 (s, 6H), 1.87-1.91 (m, 2H), 2.32-2.36 (m, 2H), 3.67 (s, 3H). To a suspension of 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.00 g, 5.75 mmol) in THF (3 mL), 1M LiBHEt3 in THF (38.0 ml, 38.0 mmol) is added dropwise maintaining the temperature below 10° C. under nitrogen. The mixture is stirred at 10° C. for 1 hour. To the mixture, 50% AcOH (4.6 mL) and H2O are added. The solution is extracted with AcOEt, and the organic layer is washed with H2O, dried over MgSO4, and concentrated under reduced pressure to give 5-hydroxy-4,4-dimethyl-pentanoic acid (850 mg, quant.); 1H NMR (400 MHz, chloroform-d) ppm 1.06 (s, 6H), 1.70 (t, 2H), 2.56 (t, 2H), 3.98 (s, 2H). To a solution of 5-hydroxy-4,4-dimethyl-pentanoic acid (300 mg, 2.05 mmol) in DMF (5 ml), K2CO3 (369 mg, 2.87 mmol) and iodomethane (154 ul, 2.47 mmol) are added at room temperature. The mixture is stirred at room temperature for 15 hours. To the mixture, H2O is added and the solution is extracted with AcOEt. The organic layer is washed with H2O, and brine, and dried over MgSO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 5,5-dimethyl-tetrahydro-pyran-2-one (150 mg, 47%); TLC (hexane/AcOEt, 2:1) Rf 0.40, 1H NMR (400 MHz, chloroform-d) δ ppm 1.06 (s, 6H), 1.70 (t, 2H), 2.56 (t, 2H), 3.97 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:31]([NH:35][CH2:36][CH2:37]O)([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH2:37][CH2:36][NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)NCCO
Reactant: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)NCCOC(=O)c1cccc2cc(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
1.43 g of 2-phenylbenzofuran-7-carboxylic acid are dissolved in 10 ml of tetrahydrofuran, and 1.08 g of carbonyldiimidazole are added to the solution. The mixture is stirred at room temperature for 2 hours and a solution of 0.76 g of 2-(t-butylamino)ethanol in 4 ml of tetrahydrofuran is added thereto. The mixture is stirred at room temperature for 15 hours and evaporated to remove solvent. Water is added to the residue and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried, and evaporated to remove solvent to give 1.72 g of 2-(t-butylamino)ethyl 2-phenylbenzofuran-7-carboxylate as pale yellow oil.
Reaction SMILES: [C:1]([S:5]([CH2:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:12]CC)=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ca+2].[Cl-]>[OH-].[Na+]>[C:1]([S:5]([CH2:8][CH:9]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Temperature: 38 °C

Procedure:
1.60 g (5.12 mmol) of ethyl (RS)-α-[(tert-butylsulfonyl)methyl]hydrocinnamate were treated with 50 ml of aqueous 5 mM calcium chloride solution and the reaction mixture was warmed to 38° C. while stirring. The pH value was adjusted to 7.5 with 1N sodium hydroxide solution. The hydrolysis was started by the addition of 150 mg of Savinase 6.0 T (NOVO, 2880 Bagsvaerd, Denmark). The pH value was held constant at 7.5 using automatic titration by dosing-in 1N sodium hydroxide solution while stirring vigorously at 38° C. After a consumption of 2.39 ml of 1N sodium hydroxide solution (after 21.3 hours), the reaction mixture was washed twice with 50 ml of ethyl acetate. The aqueous phase was acidified to pH 2.2 with 25% hydrochloric acid and extracted twice with 50 ml of ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated at 1200 Pa/40° C., whereby there were obtained 690 mg (2.42 mmol, 47%, 94% of theory) of (S)-α-[(tert-butylsulfonyl)methylhydrocinnamic acid in the form of white crystals, which had an enantomeric excess of >99%. In order to determine the purity by gas chromatography, the compound obtained was silylated and likewise had a purity of >99%.
Reaction SMILES: C(O[C:6](=[O:35])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH2:26][CH:27]=[CH2:28])=[C:20]([Cl:29])[CH:19]=2)[CH2:12][CH2:11][C:10](=[O:31])[N:9]1[CH2:32][CH2:33][CH3:34])(C)(C)C.[CH2:36]([N:43]1[C:49](=[O:50])[CH2:48][CH2:47][CH:46]([NH:51][C:52]([C:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:57]=[CH:56][N:55]=2)=[O:53])[C:45](=[O:64])[N:44]1[CH2:65][C:66](=[O:82])[NH:67][CH:68]1[CH2:72][C:71](=[O:73])[O:70][CH:69]1[O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:26]([O:25][C:21]1[C:22]([Cl:24])=[CH:23][C:18]([C:17]([NH:16][CH:13]2[CH2:12][CH2:11][C:10](=[O:31])[N:9]([CH2:32][CH2:33][CH3:34])[N:8]([CH2:7][C:6](=[O:35])[NH:67][CH:68]3[CH2:72][C:71](=[O:73])[O:70][CH:69]3[O:74][CH2:75][C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)[C:14]2=[O:15])=[O:30])=[CH:19][C:20]=1[Cl:29])[CH:27]=[CH2:28].[CH2:36]([N:43]1[C:49](=[O:50])[CH2:48][CH2:47][CH:46]([NH:51][C:52]([C:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH:57]=[CH:56][N:55]=2)=[O:53])[C:45](=[O:64])[N:44]1[CH2:65][C:66](=[O:82])[NH:67][CH:68]1[CH2:72][C:71](=[O:73])[O:70][CH:69]1[O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: C=CCOc1c(Cl)cc(C(=O)NC2CCC(=O)N(CCC)N(CC(=O)OC(C)(C)C)C2=O)cc1Cl
Agent: O=C(CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1)NC1CC(=O)OC1OCc1ccccc1
Product: C=CCOc1c(Cl)cc(C(=O)NC2CCC(=O)N(CCC)N(CC(=O)NC3CC(=O)OC3OCc3ccccc3)C2=O)cc1Cl

Procedure:
4-Allyloxy-N-{2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-3,7-dioxo-1-propyl-[1,2]diazepan-4-yl}-3,5-dichloro-benzamide (10c) was synthesized from 7c and the diastereomers of 9 by the method and chromatography used to prepare 10a to afford both anti diastereomer (78 mg, 31% yield, lower Rf) and syn diastereomer (129 mg, 52% yield, higher Rf) of the title compound. 1H-NMR (500Hz, CDCl3) for the anti diastereomer: δ 1.00-1.05 (t, 3H), 1.60-1.80 (m, 2H), 2.03-2.18 (m, 1H), 2.23-2.30 (d, 1H), 2.40-2.48 (m, 1H), 2.62-2.78 (m, 1H), 2.90-3.12 (m, 2H), 3.50-3.60 (m, 1H), 4.05-4.25 (m, 3H), 4.48-4.52 (m, 1H), 4.60-4.68 (m, 3H), 4.80-44.85 (d, 1H), 5.08-5.20 (m, 1H), 5.30-5.39 (m, 2H), 5.40-5.45 (d, 1H), 6.08-6.20 (m, 1H), 6.82-6.85 (d, 1H), 7.30-7.45 (m, 6H), 7.85 (s, 2H); for the syn diastereomer: δ 0.94-1.04 (t, 3H), 1.60-1.72 (m, 2H), 1.85-1.93 (m, 1H), 2.31-2.40 (m, 1H), 2.41-2.51 (m, 1H), 2.72-2.82 (m, 1H), 2.83-2.95 (m, 1H), 3.00-3.09 (m, 1H), 3.17-3.30 (m, 1H), 3.99-4.10 (m, 1H), 4.10-4.18 (d, 1H), 4.21-4.30 (d, 1H), 4.58-4.65 (m, 3H), 4.70-4.78 (m, 1H), 4.85-4.90 (d, 1H), 5.05-5.15 (m, 1H), 5.28-5.35 (d, 1H), 5.40-5.45 (d, 1H), 5.53 (d, 1H), 6.08-6.17 (m, 1H), 6.55-6.60 (d, 1H), 6.75-6.80 (d, 1H), 7.27-7.40 (m, 3H), 7.40-7.55 (m, 1H), 7.60-7.70 (m, 1H), 7.73 (s, 2H). Analytical HPLC for diastereomers of the title compound: 10.26 min. LC-MS (ES+) for the mixture of the product: m/e=661, 663 (M+H+).
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CO>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH3:2])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2cccc(C)c2c1Sc1ccc(Cl)cc1
Yield: 81 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.19 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with MeOH (3 mL) provided 52 mg (81%) of product 9 as a white solid, mp 192-193° C. 1H NMR (300 MHz, DMSO-d6) δ 2.57 (s, 3H), 3.84 (s, 3H), 6.88 (d, J=7 Hz, 1H), 6.95-6.98 (m, 2H), 7.24 (t, J=8 Hz, 1H), 7.26-7.29 (m, 2H), 7.41 (d, J=9 Hz, 1H), 12.52 (s, 1H). LC-MS (CI): m/z 332.1 [(M+H)+ C17H14ClNO2S requires 331.04]. Purity (100%). Calcd for C17H14ClNO2S: C, 61.53; H, 4.25; N, 4.22; S, 9.66; Cl, 10.68. Found: C, 61.25; H, 4.24; N, 4.14; S, 9.56; Cl, 10.64.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH3:23])=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[CH:32])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:2]2[CH:3]=[C:4]([C:20]([NH:22][CH3:23])=[O:21])[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:7]=2[CH3:8])=[CH:27][CH:26]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CNC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNC(=O)c1cc(C#Cc2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 70 °C
Yield: 78 %

Procedure:
A mixture of 5-iodo-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (139 mg, 0.32 mmol), tetrakis(triphenylphosphine) palladium(0) (1.8 mg, 1.6 μmol), copper(I) iodide (0.6 mg 3.2 μmol), 1-chloro-4-ethynylbenzene (87 mg, 0.638 mmol) and DIEA (64 mg, 0.5 mmol) in acetonitrile (1.5 ml) was heated in a microwave oven to 70° C. for 0.5 h. After cooling, the reaction mixture was purified by flash chromatography to give 5-[(4-chlorophenyl)ethynyl]-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (111 mg, 78%).
Reaction SMILES: [Na].C(O)C.[NH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[CH3:17][CH:18]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])CCO>C1CCCCC1>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH2:14][CH:18]([CH3:17])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:11])=[CH:15][CH:16]=1
Reactant: CC(CCO)CC(C)(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Na]
Solvent: C1CCCCC1
Solvent: CCO
Product: CC(CCOC(=O)c1ccc(N)cc1)CC(C)(C)C

Procedure:
Sodium metal (1 g cat.) was added to ethanol (30 mL) to give a solution which was added to a suspension of ethyl 4-aminobenzoate (175 g, 1.06 mol) and 3,5,5 trimethyl hexanol (200 g, 1.4 mol) in cyclohexane (300 mL). The suspension was heated under reflux for 24 hours with the azeotropic removal of ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][N:25]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH2:24][CH2:23][CH2:22][C:21]=4[CH:35]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>CCOCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:26][N:25]([CH2:27][C:28]([OH:30])=[O:29])[CH2:24][CH2:23][CH2:22][C:21]=4[CH:35]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CC(=O)OC(C)(C)C)C4)no2)cc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CC(=O)O)C4)no2)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
1,1-Dimethylethyl [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]acetate (Preparation 8) (65 mg, 0.131 mmol) was treated with HCl (1305 μl, 5.22 mmol) (4N in dioxan) and left standing for 2 hours. The reaction mixture was then warmed at 50° C. for 1 hour then heated at 60° C. for a further 1.25 hours before solvent removal by evaporation. Trituration with ether/EtOAc failed and the material obtained was purified by MDAP. A white solid (20 mg) was obtained freeze drying appropriate MDAP fractions. Further drying under vacuum at 70° C. for 16 hours yielded the title compound (16 mg) as a solid. δH (400 MHz, d6DMSO) 1.36 (6H, d), 1.51-1.53 (2H, m), 2.98-3.00 (2H, m), 3.4 (2H, br.s), 4.10 (2H, s), 4.86-4.92 (1H, m), 7.32 (1H, d), 7.44 (1H, d), 7.83-7.88 (2H, m), 8.11 (1H, dd), 8.18 (1H, d); MS (ES) C23H2435ClN3O4 requires 441; found 442 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]=1[CH3:22])(=[O:25])[CH3:24]
Reactant: CC1=C(CCCCCCCCCCCCO)C(C)(C)CCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCCCCCCCC1=C(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 1-(12-hydroxydodecyl)-2,6,6-trimethyl-1-cyclohexene (316 mg, 1.026 mmol) were added acetic anhydride (7 ml) and pyridine (7 ml). The mixture was stirred at room temperature for 1 hour, then quenched with HCl 5%, extracted with ether, washed with water, dried with MgSO4 and concentrated in vacuo to obtain 1-(12-acetoxydodecyl)-2,6,6-trimethyl-1-cyclohexene as a colorless oil (353 mg, 98%).