Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[C@@H:7]([O:28][CH2:29][CH3:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16]/[CH:17]=[C:18](/[CH3:27])\[C:19]#CC2C=CC=CC=2)=[CH:11][CH:10]=1)C.[CH2:32](O)[CH3:33]>>[C:8]1([C:33]2[CH:32]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=[CH:10][C:19](/[C:18](/[CH3:27])=[CH:17]/[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][C@H:7]([O:28][CH2:29][CH3:30])[C:6]([OH:5])=[O:31])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(/C)C#Cc2ccccc2)cc1)OCC
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
Sodium hydroxide (1N, 1.25 mL, 1.25 mmol) was added to a solution of (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-acid ethyl ester (example 3) (0.246 g, 0.627 mmol) in ethanol (20 mL) and the mixture stirred at 70° C. for 2.5 h. After cooling to room temperature the resulting mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase was collected, acidified with 1N hydrochloric acid (5 mL) and extracted into ethyl acetate (100 mL). The organic phase was washed with brine, dried (Na2SO4) and evaporated to give (E)-(S)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionic acid as an oil; 0.150 g (66%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH:40][CH:39]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH:16]([O:22][CH2:23][CH3:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14][CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([NH:44][C:45]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:46])=[CH:42][CH:43]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cc2ccccc2)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)OCC
Yield: 11.7 %

Procedure:
Ethyl 3-(3-benzyl-4-hydroxyphenyl)-2-ethoxypropanoate (2 g, 6 mmol), 2-{4-[(tert-butoxycarbonyl}amino]phenyl}ethyl 4-methylbenzenesulfonate (3.6 g, 9 mmol); was solved in 2-butanone (30 ml). PEG-400 (0.8 g) and potassium carbonate (2.6 g, 19 mmol) was added and the mixture was refluxed for 8 h. Water was added, the organic layer separated and evaporated. The residue was purified on silica gel using isooctane/ethylacetate 2:1 which yielded 0.38 g (0.7 mmol) of the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3B3OC(C)(C)C(C)(C)O3)[CH2:11][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:33]1[O:34][C:35]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:36][C:37](=[O:39])[CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:33]3[O:34][C:35]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[CH:36][C:37](=[O:39])[CH:38]=3)[CH2:11][C:10]=2[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cccc(B3OC(C)(C)C(C)(C)O3)c1S2
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 100 °C

Procedure:
[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-9H-thioxanthen-2-yl]-carbamic acid tert-butyl ester (1.12 g), 2-chloro-6-morpholin-4-yl-pyran-4-one (0.66 g, 3.06 mmol) and grinded K2CO3 (0.71 g, 5.10 mmol) were dissolved in dry 1,4-dioxane (5 ml). The mixture was degassed for 15 mins and Pd(PPh3)4 (0.15 g, 0.13 mmol) was then added The dark brown mixture was heated to 100° C. under an atmosphere of N2 for 24 hour. The reaction mixture was concentrated in vacuo and water (50 ml) was added. The brown solid was filtered, washed with water, dried overnight in a vacuum desiccator and was used without any further purification (1.51 g). m/z (LC-MS, ESP), RT=4.47 min, (M++1)=493
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:31]([CH3:33])([CH2:32][C@@H:13]12)[C@@H:30]1[C@H:19]([C@H:20]2[C@:27]([CH3:35])([CH2:28][C:29]1=[O:34])[C@@H:23]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3.[Cl-].[NH4+]>CCOCC>[CH2:1]([C@H:13]1[CH2:32][C@@:31]2([CH3:33])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:30]2[C:29](=[O:34])[CH2:28][C@@:27]2([CH3:35])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:24](=[O:26])[CH3:25])[CH2:15][C@@H:14]1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
A 2 molar solution of n-butyl lithium in hexane (30 ml., 60mmole) was added to a stirred suspension of cuprous iodide (5.7 g., 30 mmole) in dry ether (90 ml.) under nitrogen at -20°. A cold solution of 2α,3α-epoxy-5α-pregnane-11,20-dione (1.65 g., 5 mmole) in dry ether (260 ml.) was then added and the mixture was maintained at 0° for 70 hr. The reaction mixture was then poured into aqueous ammonium chloride solution and extracted into ethyl acetate.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C[Al](C)C.C.[NH2:10][C:11]1[C:12]([Cl:27])=[C:13]2[C:18](=[C:19]([CH3:22])[C:20]=1[Cl:21])[CH:17]([C:23](OC)=O)[CH2:16][CH2:15][CH2:14]2>C1(C)C(C)=CC=CC=1.CO.O>[ClH:21].[NH2:10][C:11]1[C:12]([Cl:27])=[C:13]2[C:18](=[C:19]([CH3:22])[C:20]=1[Cl:21])[CH:17]([C:23]1[NH:3][CH2:2][CH2:1][N:4]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: NCCN
Reactant: COC(=O)C1CCCc2c(Cl)c(N)c(Cl)c(C)c21
Agent: C
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1c(Cl)c(N)c(Cl)c2c1C(C1=NCCN1)CCC2
Product: Cl
Yield: 56 %

Procedure:
Ethylenediamine (0.53 ml) was added dropwise to a stirred solution of trimethyl aluminum (4 ml) in 50 ml xylene at 0° C. under an atmosphere of nitrogen. At the end of methane evolution a solution of the product from Example 136 (0.41 g) in xylene (10 ml) was added. The reaction mixture was refluxed for 24 hours. After cooling, the solution was treated with water (10 ml), methanol (20 ml) and the solvent evaporated to one-half volume. The solution was diluted with water, and extracted with methylene chloride. The organic layer was dried and evaporated and the oily residue was purified by column chromatography affording the desired compound in 56% yield. The solid was dissolved in methanol and ethereal hydrochloric acid, affording the desired hydrochloride salt. m.p. 218°-21° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C1COCC1.C(OCC)C>[C:11]([NH:15][S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 23 °C
Yield: 91.7 %

Procedure:
A solution of 5.5 g (27.5 mmol) of 5-chlorothiophenesulfonyl chloride in dry THF at 0° C. was treated with a solution of 5.7 mL (75.5 mmol) of t-butylamine. After warming to 23° C., the reaction mixture was diluted with 125 mL of diethyl ether, filtered, and washed with 1 N HCl, brine, and dried (MgSO4). Concentration in vacuo affords 6.4 g (98%) of the named compound as an oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][OH:53])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2].C(N(CC)CC)C.[CH3:74][S:75](Cl)(=[O:77])=[O:76]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][S:75]([CH3:74])(=[O:77])=[O:76])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:63])([CH3:64])[CH3:65])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCO)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOS(C)(=O)=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (80.8 mg) in methylene chloride (1.0 mL) was added triethylamine (23 μL) followed by methanesulfonyl chloride (7.2 μL) and the mixture stirred at room temperature. After 10 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic portion dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (2:1)+1% methanol) gave the title compound (74 mg).
Reaction SMILES: C(O[C:4]([CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:8])=[O:5])C.C[O-].[K+].Cl[CH2:18][C:19]#[N:20]>CO>[C:19]([C:18]1[S:8][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6][C:4]=1[OH:5])#[N:20]
Reactant: CCCCOC(=S)CC(=O)OCC
Reactant: N#CCCl
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: CCCCOc1cc(O)c(C#N)s1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
205 g of O-n-butyl 2-ethoxycarbonylthioacetate were added at 30° C. to a solution of 70 g of potassium methylate in a liter of methanol and the mixture was stirred for 10 minutes at 30° C. 75.5 g of chloroacetonitrile were added all at once to the mixture which was stirred for an hour at 40° C. and then a solution of 70 g of potassium methylate in 300 ml of methanol. The mixture was stirred for 6 hours at room temperature and was evaporated to dryness. The residue was washed with ethyl acetate and ether and was dried. The residue was then dissolved in water and the aqueous solution was acidified with concentrated hydrochloric acid and was vacuum filtered. The recovered precipitate was washed with water, dried and chromatographed over silica gel. Elution with 6-4 cyclohexane-ethyl acetate yielded 81 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene melting at 107° C.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8]C=[CH:6][CH:5]=1.[C:11]([O:15]CC)(=O)[CH:12]=[CH2:13].C(OC)(=O)C=C.C(C(=C)C(OCC)=O)CC>>[CH3:3][NH2:10].[CH3:1][N:2]1[CH2:13][CH2:12][C:11](=[O:15])[CH:5]([CH2:4][CH2:9][CH3:8])[CH2:6]1
Reactant: C=CC(=O)OCC
Reactant: NCc1ccccc1
Agent: C=C(CCC)C(=O)OCC
Agent: CN
Solvent: C=CC(=O)OC
Product: CCCC1CN(C)CCC1=O

Procedure:
In an analogous manner to the procedure described by A. Ziering et al. in J. Org. Chem. 22, 1521-1528 (1957) for the preparation of piperidin-4-ones from the corresponding acrylic acid esters by reaction with methylamine or benzylamine, reaction with ethyl acrylate or methyl acrylate, cyclization and finally decarboxylation, starting from ethyl 2-propyl-acrylate and methylamine there was obtained (3RS)-1-methyl-3-propyl-piperidin-4-one as a colourless oil; Rf : 0.38 (SiO2, methylene chloride:methanol=95:5).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.CN(C=O)C.C(NC(C)C)(C)C.[C:43]([CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)#[CH:44]>CCOC(C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:45]1([C:43]#[C:44][C:2]2[C:7]([F:8])=[CH:6][C:5]([N:9]3[C:18]4[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]5[CH:27]=[CH:26][O:25][N:24]=5)(=[O:20])=[O:21])=[CH:16][CH:17]=4)[N:12]=[CH:11][C:10]3=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: C#CC1CCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C#CC2CCCC2)c(F)cc1-n1c(=O)cnc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 60 °C
Yield: 65 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoxaline-6-sulfonamide (147.0 mg, 0.297 mmol), copper(i) iodide (8.48 mg, 0.045 mmol), and Pd(PPh3)4 (34.3 mg, 0.030 mmol). The vial was flushed with Ar (g), then DMF (1484 μl), N,N-diisopropylamine (423 μl, 2.97 mmol), and ethynylcyclopentane (140 mg, 1.484 mmol) were added in sequence. The vial was sealed and heated to 60° C. for 1 h. The mixture was cooled, diluted with EtOAc, washed with 2N aq. HCl (2×), dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DMSO-MeOH and filtered through a 0.2 micron filter. The filtrate was purified by reverse-phase HPLC (25-75 CH3CN/H2O with 0.1% TFA). Fractions containing desired product were combined and lyophilized to give 1-(4-(cyclopentylethynyl)-5-fluoro-2-methoxyphenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinoxalinesulfonamide (98.2 mg, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=11.74 (s, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.90 (dd, J=2.2, 8.8 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 7.38 (d, J=6.3 Hz, 1H), 6.95 (d, J=8.9 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.67 s, 3H), 2.98 (t, J=7.3 Hz, 1H), 2.09-1.98 (m, 2H), 1.80-1.58 (m, 6H). m/z (ESI) 509.2 (M+H)+.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:30])[C:24]([Cl:31])=[C:23]([Cl:32])[C:22]=1[Cl:33]>C1C=CC=CC=1>[Cl:20][C:21]1[C:26]([C:27]([N:7]2[C:8](=[O:9])[CH:3]3[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]3[C:5]2=[O:6])=[O:28])=[C:25]([Cl:30])[C:24]([Cl:31])=[C:23]([Cl:32])[C:22]=1[Cl:33]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentachlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(pentachlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [Mg].II.[C:4]1([CH3:11])[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[P:12]([O-:19])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:11][C:4]1[CH:9]=[CH:8][C:7]([PH:12](=[O:19])[C:7]2[CH:8]=[CH:9][C:4]([CH3:11])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1
Reactant: CCOP([O-])OCC
Reactant: Cc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc([PH](=O)c2ccc(C)cc2)cc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
Under an argon atmosphere, a solution of magnesium (3.55 g, 1.0 equivalent) and a small amount of iodine in THF (30 mL) was stirred at room temperature for 1 hr. A solution of p-tolyl bromide (25 g, 0.146 moL) in THF (5 mL) was added at 30° C. The mixture was stirred at 45° C. for 30 min. and then at 5° C. for 1 hr. Diethyl phosphite (10.08 g, 0.5 equivalent) was added at 5° C. and the mixture was stirred at 5° C. for 1 hr and at room temperature (25° C.) for 30 min. Water (10 mL) was added at 3° C., and then toluene (40 mL) and 6M-HCl (20 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with water (10 mL), 5% aqueous NaHCO3 solution (10 mL) and 5% aqueous NaCl solution (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-heptane to give the title compound (7.78 g, white crystals). yield 46.3%. melting point: 93.7° C.
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[NH:17]2.BrCCC1CC1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][N:17]1[C:18]2[C:14](=[C:13]([Br:12])[CH:21]=[CH:20][CH:19]=2)[C:15](=[O:23])[C:16]1=[O:22])[CH3:36]
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: CCOC(=O)CBr
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 4-bromoisatin and (2-bromoethyl)cyclopropane with ethyl bromoacetate, the title compound was obtained as a yellow solid (68%): 1H NMR (300 MHz, CDCl3) δ 7.39 (t, 1H), 7.27(dd, 1H), 6.71 (dd, 1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES+) m/z 312 (M+1), 314 (M+1), 334 (M+23), 336 (M+23).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)[C:47]([O-])=[O:48].Cl.[CH2:53]([O:60][C:61](=[O:64])[CH2:62][NH2:63])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:47]([NH:63][CH2:62][C:61]([O:60][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:64])=[O:48])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: Cl
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)NCC(=O)OCc3ccccc3)cc2)C1=O

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and glycine benzyl ester hydrochloride according to the procedure described in Example 46, Step A. 1H NMR (200 MHz, CD3OD): δ 1.38 (s, 6H), 1.82 (m, 1H), 2.18-2.60 (m, 3H), 3.86 (s, 2H), 4.13 (s, 2H), 4.32 (m, 1H), 4.84 (d, 15 Hz, 1H)i 4.99 (s, 2H), 5.11 (s, 2H), 5.30 (d, 15 Hz, 1H), 7.05-7.41 (m, 22H). FAB-MS: calculated for C46 H47N5O7 781; found 782 (M+H, 90%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Na].[CH:17](=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C(O)C>[C:1]([N:4]1[CH:17]([OH:26])[CH2:18][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=CC=Cc1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)C(c2ccccc2)CC(O)N1C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of diethyl acetamidomalonate (75.0 g, 345 mmol) in ethanol (375 ml) at 0° C. was added sodium metal (6.9 g, 36 mmol). Cinnamaldehyde (50.0 g, 378 mmol) was added dropwise to the resulting solution. The reaction was warmed to rt and allowed to stir for 2 h. Acetic acid (7 ml) was added, and the solution was concentrated. The residue was dissolved in EtOAc, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was triturated with hexanes/EtOAc to yield diethyl 1-acetyl-5-hydroxy-3-phenylpyrrolidine-2,2-dicarboxylate as a white solid (96%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[Si:18]([O:25][CH2:26][C:27]1[S:31][CH:30]=[N:29][C:28]=1[C:32](OCC)=[O:33])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:18]([O:25][CH2:26][C:27]1[S:31][CH:30]=[N:29][C:28]=1[CH:32]=[O:33])([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1ncsc1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1scnc1C=O
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A 1.0 M diisobutylaluminum hydride/toluene solution (2.4 ml) was added dropwise to a solution of 578 mg of 5-t-butyldimethylsilyloxymethyl-4-ethoxycarbonylthiazole in 10 ml of toluene under an argon atmosphere at −60° C. The mixture was stirred at the same temperature for 2 hr, water and ethyl acetate were added thereto and the mixture was adjusted to pH 5.5 by the addition of 1 N aqueous hydrochloric acid. The insolubles were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to ethyl acetate only) to give 308 mg of 5-t-butyldimethylsilyloxymethyl-4-formylthiazole.