Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH2:26][CH:27](OC)[O:28]C)[C:8](=[O:25])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CC(C)=O>[CH:1]1([N:7]([CH2:26][CH:27]=[O:28])[C:8](=[O:25])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(-c2cnco2)c1)C1CCCCC1)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCN(C(=O)CCOCCc1cccc(-c2cnco2)c1)C1CCCCC1
Reaction time: 6 h

Procedure:
To a stirred solution of N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(oxazol-5-yl)phenethoxy)propanamide [Example 10, Step iii)] (660 mg) in acetone (30 mL) was added 2M hydrochloric acid (10 mL). The mixture was stirred for 6 h before the solvents were removed followed by the addition of saturated sodium hydrogen carbonate until basic. The mixture was extracted three times with ethyl acetate, and the pooled organic fractions were washed once with brine, dried over sodium sulphate, filtered and evaporated to afford the sub-titled compound (525 mg). This material was used in the next step directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][SiH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[CH:16]=[C:17](Br)Br.C([Li])CCC.[I:25]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][SiH2:9][C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16]#[C:17][I:25]
Reactant: II
Reactant: CCCC(C)(C)[SiH2]Oc1ccc(C=C(Br)Br)c(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C)(C)[SiH2]Oc1ccc(C#CI)c(F)c1
Temperature: -70 °C
Yield: 96.2 %

Procedure:
To a solution of 26 mmol of 1-(2-fluoro-4-dimethylbutylsilyloxyphenyl)-2,2-dibromoethylene in 50 ml of tetrahydrofurane were added dropwise 134 ml of n-butyl lithium (1.6M), while stirring at -70° C. After completion of the addition, the reaction solution was stirred for 3 hours, 10 ml tetrahydrofuran solution of 30 mmol of iodine were added dropwise and the solution was gradually elevated to room temperature. Afer completion of the agitation, the solution was poured into a sodium thiosulfate solution and extracted with heptane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a brown solid. Purification of the solid by a silica gel column chromatography gave 25 mmol of 1-(2-fluoro-4-dimethylbutylsilyloxyphenyl)-2-iodoethyne as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:26][CH:27]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 426 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][C:10]=1[CH3:27])#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][N:42]=[C:41]([CH3:44])[N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[C:10]([CH3:27])[CH:11]=4)=[C:22]([CH2:23][CH2:24][CH3:25])[N:43]4[N:42]=[C:41]([CH3:44])[N:40]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(C)c1)C(=O)OCC
Reactant: Cc1n[nH]c(NC2CCC3(CC2)OCCO3)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-2-methylbiphenyl-4-yl)methyl]-3-oxohexanoate (3.00 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-3-methyl-1H-1,2,4-triazol-5-amine (1.00 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 mL) and N,N-diethylaniline (10 mL) was stirred at 180° C. overnight, allowed to cool and poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a brown oil (1.20 g, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[S:14]1[C:23]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:17]=2[N:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:21][CH2:22][C:23]4[S:14][CH:15]=[N:16][C:17]=4[CH2:18][CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1nc2c(s1)CCNCC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ncsc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 27 mg (35% of theory). ESI-MS: m/z=378 (M+H)+; Rt(HPLC): 1.08 min. (Method B).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[C:13]1([CH:19]([OH:30])[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:23])[CH2:21][CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[OH:23][C:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:21][CH3:22])[C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:30]
Reactant: CCC(O)(c1ccccc1)C(O)c1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(O)(C(=O)c1ccccc1)c1ccccc1
Yield: 99.9 %

Procedure:
o-Iodoxybenzoic acid I (210 mg; 0.75 mmol) was added in one portion to a stirred solution of 1,2-diphenyl-1,2-butanediol (121 mg; 0.5 mmol) in DMSO (1.7 ml). After 1.5 h the reaction was poured in ml of a solution of Na2CO3 (10%) and extracted with diethyl ether (3×10 ml). The combined organic layers were washed with brine and dried over sodium sulfate. The Organic solvent was distilled under vacuum. The residue was triturated with n-pentane to give 120 mg (98%) of 2-hydroxy-1,2-diphenyl-butan-1-one mp 62°-68° C. (lit. 68°-69° C.: MacKenzie A. and Richtie A. Chem. Ber. 1937, 70, 23).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][NH:3][C:2]1=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17]>[N+](C1C=CC=CC=1)([O-])=O>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([C:5]1[NH:1][C:2](=[O:6])[NH:3][CH:4]=1)=[O:17]
Reactant: O=C(Cl)c1ccco1
Reactant: O=c1[nH]cc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1c[nH]c(=O)[nH]1)c1ccco1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 50 ml of nitrobenzene is added 4.2 g of 1,3-dihydro-2H-imidazol-2-one, 13.3 g of aluminum chloride and 7.2 g of furanoyl chloride. The mixture is stirred at 60° C. for 3 hours and poured over ice water. The solids are filtered, washed with ether and recrystallized twice from ethanol-water to afford the title compounds. M.P. 318°-321° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH2:4][N:3]1[CH2:6][C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[CH2:5][CH2:4][N:3]1[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)CN1CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCC1=O
Yield: 80.3 %

Procedure:
In 28 ml of methanol was dissolved 1.44 g of ethyl α-(2-oxo-1-azetidinyl)acetate (19) and 10 ml of a 1N sodium hydroxide aqueous solution was dropwise added to the solution under ice cooling. The mixture was reacted at 10° to 15° C. for 1 hour. The reaction solution was ice-cooled and 10 ml of 1N-hydrochloric acid was added thereto. Methanol was removed by distillation under reduced pressure. After the remaining aqueous solution was saturated with sodium chloride, the mixture was extracted 3 times with 140 ml of ethyl acetate. The ethyl acetate extracts were combined and dried over anhydrous sodium sulfate and then concentrated to obtain 950 mg of α-(2-oxo-1-azetidinyl)acetic acid (20).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[NH:17]([C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C@H:18]([C:44](O)=[O:45])[CH2:19][C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]([C:44](=[O:45])[C@@H:18]([NH:17][C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[CH2:19][C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=1)[CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)CNCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
The product from Step 1 (0.67 g, 2.5 mmol) was dissolved in methylene chloride (10 mL) and Cbz-His(Trt)-OH (1.46 g, 2.75 mmol) was then added, followed by diisopropylethylamine (1.3 mL, 7.5 mmol), HATU (1.05 g, 2.76 mmol), HOAt (0.374 g, 2.75 mmol), and dimethylformamide (10 mL). The reaction was stirred overnight at room temperature. The solution was concentrated, the residue taken up in ethyl acetate and washed three times with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to give a white solid; 1.8 g (97% yield). MS-APCI: M+1=747.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][C:3]=1[S:11][CH3:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([NH2:25])[CH3:24])=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([NH:25][CH2:7][CH:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([S:11][CH3:12])[CH:4]=2)[OH:8])[CH3:24])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCC(C)N)cc1
Reactant: CSc1cc(C2CO2)ccc1C
Solvent: c1ccccc1
Product: COc1ccc(CCC(C)NCC(O)c2ccc(C)c(SC)c2)cc1
Temperature: 115 °C
Yield: 29.2 %

Procedure:
A mixture of 6 g of 4-methyl-3-methylthiostyrene oxide and 7 g of 3-(4-methoxyphenyl)-1-methylpropylamine was heated to 115° C. for 3 hours. After the reaction was over, the reaction mixture was dissolved in 100 ml of benzene and after washing twice each time with 200 ml of water, the benzene layer was purified by a silica gel column chromatography (eluate: a mixture of benzene, ethyl acetate, and methanol (4:3:1 by volume ratio) to provide 3.5 g of amorphous α-{[3-(4-methoxyphenyl)-1-methylpropylamino]methyl}-4-methyl-3-methylthiobenzenemethanol.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:26]=[N:27][N:28]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)[CH:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[N:26]=[N:27][N:28]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)[CH:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4cn(Cc5ccc(Cl)cc5)nn4)ccc3C)csc12
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4cn(Cc5ccc(Cl)cc5)nn4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.33 g, 0.60 mmol) (from Example 35 supra) in 2-propanol (30 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.23 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([F:35])[CH:37]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2cccc(F)c2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 3-fluoro-benzylbromide (135 μL). The reaction mixture is allowed to stir at room temperature for 18 h. The resulting suspension is poured into water (10 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 425 mg (81%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O>O1CCCC1>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O
Reaction time: 18 h
Yield: 20.7 %

Procedure:
To 3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone (1.0 g), prepared as described in Scheme 4, and 7-chloro-5-methoxyindoline hydrochloride (0.92 g), prepared as described in U.S. Pat. No. 6,245,769, stirring in anhydrous tetrahydrofuran (25 mL, 0° C.) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 11.9 mL, dropwise). The reaction mixture was allowed to come to ambient temperature and stirred 18 hours. Water was added, and the mixture was extracted with three portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford the title compound (329 mg). mp 131-133° C. 1H-NMR (CDCl3) δ: 0.93 (3H, t, J=7.3 Hz), 1.83 (2H, m), 3.09 (2H, t, J=7.6 Hz), 3.35 (3H, s), 3.56 (1H, dd), 3.67 (1H, dd), 3.78 (3H, s), 4.34 (2H, t, J=7.7 Hz), 4.94 (1H, m), 6.74 (2H, s), 6.99 (1H, s). MS (APCI+) m/z 398 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C)C=O>[Si:16]([O:14][CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Yield: 84.7 %

Procedure:
A procedure similar to that described in Preparation 8 was repeated, except that 12.54 g of (5)-2-benzyloxycarbonylaminopropanol (prepared as described in Preparation 23), 9.97 g of t-butyldimethylsilyl chloride, 4.90 g of imidazole and 150 ml of anhydrous dimethylformamide were used, to give 16.43 g of the title compound having an Rf value of 0.54 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:6]=1)[OH:4])#[CH:2].[OH:28][C:29]1[CH:38]=[C:37](I)[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32]>>[OH:28][C:29]1[CH:38]=[C:37]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:6]=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c1
Product: COC(=O)c1ccc(C#CC(O)c2cc(C(C)(C)C)c(OCOCC[Si](C)(C)C)c(C(C)(C)C)c2)cc1O

Procedure:
In a similar manner to Example 1(d), by reaction of 6.7 g (17.3 mmol) of α-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)benzenemethanol with 4.8 g (17.3 mmol) of methyl 2-hydroxy-4-iodobenzoate, 8.5 g (91%) of the expected ester are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:23]1([CH2:22][N:16]2[CH2:17][CH:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:2]([C:1]([O:11][CH3:12])=[O:10])[CH2:15]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)/C=C\c1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccccc2)CC1c1ccccc1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of 1.98 g (12.2 mmol) of methyl (Z)-cinnamate and 5.80 g (24.4 mmol) N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine in 30 mL of CH2Cl2 at 0° C. was treated with 20 drops of trifluoroacetic acid and stirred cold for 1 h. The reaction mixture was partitioned between 200 mL of ether and 100 mL of sat'd NaHCO3 and the layers were separated. The organic layer was washed with 100 mL of sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 150 g of silica gel using 20:1 v/v CH2Cl2/ether as the eluant afforded 2.61 g (72%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ2.83 (t, J=8.7, 1H), 3.09-3.19 (m, 6H), 3.16 (s, 3H), 3.46-3.51 (m, 1H), 3.73-3.79 (m, 3H), 7.19-7.42 (1OH). Mass Spectrum (NH3 -CI): m/z 296 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([NH:15][C@H:16]([C:18]([OH:20])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C(OC(C(N[C@H](C(O)=O)C)CCC1CCCCC1)=O)C.C(C(N[C@H](C(O)=O)C)CCC1C=CC=CC=1)(O)=O>>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([OH:20])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Agent: CCOC(=O)C(CCC1CCCCC1)N[C@@H](C)C(=O)O
Agent: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Yield: 85 %

Procedure:
According to the same manner as that described in Example 1, the catalytic reduction was carried out to give a reaction solution containing 10% (w/w) of N-(1(R)-ethoxycarbonyl-3-phenylpropyl)-L-alanine, 0.1% (w/w) of N-(1-ethoxycarbonyl-3-cyclohexylpropyl)-L-alanine and 7% (w/w) of N-(1-carboxy-3-phenylpropyl)-L-alanine, based on N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine, respectively. The reaction yield was 85%. According to the same manner as that described in Example 1, the crystallization from the reaction solution was carried out to give N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (6.3 g, 23 mmoles). The yield from N-(1(S)-ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-alanine: 75%, HPLC purity: 99.0% (w/w), the content of N-(1(R)-ethoxycarbonyl-3-phenylpropyl)-L-alanine: not detected, the content of N-(1-ethoxycarbonyl-3-cyclohexylpropyl)-L-alanine: 0.1% (w/w), the content of N-(1-carboxy-3-phenylpropyl)-L-alanine: 0.1% (w/w), residue on ignition: 0.1% (w/w).
Reaction SMILES: [Ca].N.C([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][S:20]([N:23](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:17]=2)[C:12]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])=[CH:11]1)C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.O>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([CH2:19][S:20]([NH:23][CH3:24])(=[O:21])=[O:22])[CH:14]=2)[NH:10][CH:11]=1
Reactant: CN(C)CCc1cn(Cc2ccccc2)c2ccc(CS(=O)(=O)N(C)C(c3ccccc3)c3ccccc3)cc12
Agent: N
Agent: [Ca]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
To a stirred slurry of calcium turnings (243 mg, 6 mmol) in tetrahydrofuran (4 ml) at −40° C. was condensed liquid ammonia (4 ml). The blue bronze was stirred at −50 to −40° C. for a further 15 min, before a solution of 1-[1-benzyl-3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-N-diphenylmethyl-N-methylmethanesulfonamide (from step (e), 836 mg, 1.5 mmol) in tetrahydrofuran (2 ml) was added dropwise, maintaining the temperature below −40° C. The dark blue solution was stirred at −40° C. for a further 30 minutes, before saturated ammonium chloride solution (10 ml) was added dropwise and the grey solution warmed to ambient temperature. Water (10 ml) was then added and the white slurry stirred for 15 min, before being filtered in vacuo. The solid was then dissolved in 5N HCl (12 ml) and the resulting orange solution extracted with ethyl acetate (10 ml). The pH of the aqueous phase was then adjusted (pH=10) with 10N NaOH which resulted in precipitation. The solid was filtered and dried in vacuo at 50° C. overnight to yield the title compound (250 mg, 56%) as a white solid. m.p. 159-163° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:24])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:23])=[CH:17]/[CH2:18][O:19]C(C)=O.CCOC1C=C2C(C)=CC(C)(C)NC2=CC=1>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:24])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:23])=[CH:17]/[CH2:18][OH:19]
Reactant: CC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Agent: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1

Procedure:
mixture of vitamin A acetate, 2.8 million IU/G unstab. (80% by weight) (BASF AG) and ethoxyquin (20% by weight) (Raluquin, Raschig AG) were run in at 60° C. via a heated pump unit.