Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][Bi:11](Br)[CH3:12].CCCCCC>C(OCC)C.C1COCC1>[CH3:10][Bi:11]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: C[Bi](C)Br
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Bi](C)Cc1ccccc1
Yield: 32.8 %

Procedure:
A 40 ml (40 mmole) of 1.0 M solution of benzyl magnesium chloride in diethyl ether was cooled to 0° C., and thereto was added dropwise a solution of 10.2 g (32.1 mmole) of dimethylbismuthanyl bromide prepared in Preparation Example 2 in 20 ml of THF (45 minutes). The reaction mixture was further stirred at 0° C. for 2 hours qnd hexane was added. The supernatant liquid was extracted, concentrated and distilled in a vacuum, giving 3.5 g (yield 32.8%) of a yellow liquid product. b.p. 67-76° C./0.7 mmHg. 1H-NMR revealed that the product was the desired one.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pd]>[CH3:2][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)o1
Yield: 94 %

Procedure:
A solution of methyl 5-chloromethyl-2-furoate (5.0 g, 28.7 mmol) in ethyl acetate (40 ml) was hydrogenated over 10% palladium on charcoal (50 mg) for 3 h. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to yield the title compound as a colourless oil (3.78 g, 94%); νmax (CH2Cl2) 1725, 1534, 1522, 1437 and 1311 cm-1 ; δH (CDCl3, 90 MHz) 2.38 (3 H, s), 3.86 (3 H, s), 6.12 (1 H, br d, J 4 Hz) and 7.07 (1 H, d, J 4 Hz). [Mass spectrum: M+ (140)].
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][S:7][CH2:6][CH2:5]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:28][C:29]1[CH:48]=[CH:47][C:32]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][C:40](O)=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][N:35]=2)=[C:31]([F:49])[CH:30]=1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:28][C:29]1[CH:48]=[CH:47][C:32]([NH:33][C:34]2[C:43]3[C:38](=[CH:39][C:40]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][S:7][CH2:6][CH2:5]4)=[C:41]([O:44][CH3:45])[CH:42]=3)[N:37]=[CH:36][N:35]=2)=[C:31]([F:49])[CH:30]=1
Reactant: OCCN1CCSCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCSCC1
Reaction time: 3.5 h
Yield: 22.3 %

Procedure:
4-(2-Hydroxyethyl)thiomorpholine (114 mg, 0.78 mmol), (J. Am. Chem. Soc. 1934. 56, 1720), in methylene chloride (1 ml) followed by 1,1′-(azodicarbonyl)dipiperidine (525 mg. 2.08 mmol) were added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 0.70 mmol), (prepared as described for the starting material in Example 2), and tributylphosphine (0.51 ml, 2.08 mmol) in methylene chloride (10 ml) under nitrogen. The mixture was stirred for 3.5 hours and allowed to stand for a further 18 hours. Ether (8 ml) was added, the precipitate removed by filtration and the solvent removed from the filtrate by evaporation. The residue was dissolved in acetone and ethereal hydrogen chloride (2.5 ml of a 1M solution) added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was triturated with ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline (70 mg, 22%) as a pale yellow solid.
Reaction SMILES: N(CCO)CCO.CCOCC.[C:13]([CH2:21][C:22]([OH:24])=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+]([O-])([O-])=O.[Ag+:29]>O>[C:13]([CH2:21][C:22]([O-:24])=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Ag+:29]
Reactant: O=C(O)CC(=O)c1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: OCCNCCO
Solvent: CCOCC
Solvent: O
Product: O=C([O-])CC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Diethanolamine (0.33 g) was dissolved in water (5 mL), and to this was added an ether solution (20 mL) containing benzoylacetic acid (0.54 g). Next, the mixture was stirred at 15° C. while an aqueous solution (5 mL) containing silver nitrate (0.51 g) was added dropwise, and this further was stirred for 15 minutes. The pale yellow precipitate that settled was filtered off, yielding silver benzoylacetate (yield 0.79 g). FIG. 4 shows the infrared absorption spectrum (IR) of the silver benzoylacetate that was obtained. IR:1687 cm−1, 1540 cm−1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2].[I:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1O.N1C=CC=CC=1>O1CCOCC1.CO>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([O:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[I:20])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2oc(=O)c(C(=O)O)cc2c1
Reactant: Oc1ccccc1I
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)OCc1ccc2oc(=O)c(C(=O)Oc3ccccc3I)cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the suspension of the acid chloride of 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid (4 mmol) obtained according to Pochet et al. (Bioorg. Med. Chem. 2000, 8, 1489) in anhydrous dioxane (10 mL) was added 2-iodophenol (5 mmol) and pyridine (0.4 mL). After 12 h stirring at room temperature, the solvent was evapotated under vacuum and the residue was suspended in methanol. The resulting precipitate was collected by filtration, washed with methanol and dried. The solid was crystallyzed in ethyl acetate (45%); mp: 156-158° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][C:10]([CH3:12])=O.Cl[CH2:17][C:18](=O)[CH3:19]>O>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[CH:17]=[C:18]([CH3:19])[C:9]([C:8]([O:14][CH3:15])=[O:13])=[C:10]1[CH3:12])(=[O:3])[CH3:2]
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)CCl
Reactant: CC(=O)NCCN
Solvent: O
Product: COC(=O)c1c(C)cn(CCNC(C)=O)c1C

Procedure:
71.5 g (0.70 mol) of (2-acetylaminoethyl)-amine are slowly added to 40.7 g (0.35 mol) of methyl acetoacetate. 32.4 g (0.35 mol) of chloroacetone are then added dropwise and the mixture is heated under reflux for 20 hours. After cooling, water is added, the mixture is extracted with methylene chloride and the extract is concentrated. The residue is recrystallized from ethyl acetate (filtered over active charcoal and silica gel).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:14])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>C(Cl)Cl>[Cl:1][CH2:2][CH:3]([O:14][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1)[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6]
Reactant: CCOC(=O)CNC(=O)CC(O)CCl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CC(CCl)OC1CCCCO1
Reaction time: 7 h

Procedure:
1 g Ethyl 2-(4-chloro-3-hydroxybutanamido)acetate is dissolved in 10 ml CH2Cl2. 100 mg pyridine p-toluenesulphonate and 0.5 ml dihydropyran are added. The mixture is stirred for 7 h. The solvent is evaporated and the residue chromatographed, eluting with ethyl acetate. A colourless oil is obtained, Rf 0.5 (silica gel plates, thickness 0.25 mm, eluent ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=3[F:34])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:35][CH3:36].S(Cl)(Cl)=O.[NH2:41][CH2:42][CH2:43][S:44]([OH:47])(=[O:46])=[O:45].[CH3:48][CH2:49][N:50]([CH2:53][CH3:54])[CH2:51][CH3:52]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:46])=[O:45])=[O:30])=[CH:27][C:26]=3[F:34])=[N:13][CH:12]=2)([CH3:9])[CH3:10])=[CH:4][C:3]=1[O:35][CH3:36].[CH2:49]([NH+:50]([CH2:53][CH3:54])[CH2:51][CH3:52])[CH3:48]
Reactant: NCCS(=O)(=O)O
Reactant: COc1cc(C(C)(C)c2cnc(SCc3ccc(C(=O)O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC[NH+](CC)CC
Product: COc1cc(C(C)(C)c2cnc(SCc3ccc(C(=O)NCCS(=O)(=O)[O-])cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 64.2 %

Procedure:
To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3-fluorobenzoic acid (50 mg, 0.095 mmol) in DCM (3 mL) was added thionyl chloride (14 μL, 0.19 mmol) at 0° C. After reluxing for 13 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was dissolved in DCM (3 mL). To this solution were added taurine (12.4 mg, 0.099 mmol) and Et3N (26 μL, 0.19 mmol). The mixture was stirred for 5 h at room temperature and concentrated in vacuo. The crude residue was triturated with EtOAc (10 mL), and filtered through Celite™. The filtrate was concentrated in vacuo and was purified by chromatography (silica, DCM-MeOH=10:1) to afford triethylammonium 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3-fluorobenzamido)ethanesulfonate (45 mg, 65%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.54-7.47 (m, 2H), 7.27 (s, 1H), 7.15 (d, 1H), 7.06 (t, 1H) 6.81-6.77 (m, 2H), 6.48-6.45 (m, 2H), 6.06-6.03 (m, 2H), 4.04 (s, 2H), 3.85 (t, 2H), 3.69 (s, 3H), 3.24 (q, 6H), 3.13 (t, 2H), 1.50 (s, 6H), 1.33 (t, 9H); MS (EI) m/z 637 (MH+).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1.N1CCCCC1.C(O)(=O)C>C(O)C>[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23](=[CH:1][C:3]3[NH:4][C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=4[C:11]=3[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:24](=[O:28])[NH:25]2)=[CH:21][CH:20]=1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: COc1ccc2c(c1)NC(=O)C2
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A mixture of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.6 g of 6-methoxy-2-oxindole and 2.7 g of piperidine in 25 mL of ethanol was refluxed for 4 hours. Upon slow addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed in 30 mL of refluxing ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and vacuum dried to give 6.4 g (80% yield) of 3-[2-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid, mp 263-266° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O.O>C(Cl)(Cl)Cl>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:25])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
In 10 ml of chloroform was dissolved 2.19 g (10 mmol) of N-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solution were added 0.81 ml (10 mmol) of pyridine and 1.4 ml (15 mmol) of phosphorus oxychloride. The resulting mixture was stirred at room temperature for 24 hours. After the completion of the reaction, thereto was added 10 ml of chloroform and the resulting mixture was poured into 20 ml of iced water to separate an organic layer. The organic layer was washed with 20 ml of water and dried over 3 g of anhydrous magnesium sulfate. Then, the solvent was removed by distillation to obtain 3.18 g of an oily matter. The oily matter was subjected to silica gel column chromatography (stationary phase: 40 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.27 g of N-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[O:23][CH3:24]>O1CCOCC1.[Ag-]=O.[Ag]=O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([CH2:14][C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)=[C:16]([O:23][CH3:24])[CH:17]=1)#[N:20]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: COc1cc(C#N)ccc1CBr
Agent: O=[Ag-]
Agent: O=[Ag]
Solvent: C1COCCO1
Product: COc1cc(C#N)ccc1Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
An efficiently stirred mixture of 5-nitroindole (3.24 g.), bromide (W) (4.57 g.) and silver (I) oxide (4.87 g.) in dry dioxane (90 ml.) was heated at 100° C. for 5 hours. Additional silver oxide (2 g.) was added, and heating continued for 1 hour. The cooled mixture was evaporated, the residue diluted with dichloromethane, filtered, washing the filter cake with dichloromethane until the washings were colorless, and the combined filtrate evaporated. The product was purified by flash chromatography on silica gel, eluting with 3:7 v/v ethyl acetate:hexane, giving a product which was crystallized from a mixture of ethyl acetate and hexane to give 3-(4-cyano-2-methoxybenzyl-5-nitroindole (1.87 g., 30% ) as a yellow powder, m.p. 204°-206° C.; partial NMR (80 MHz, DMSO--d6): 3.92(s,3H, OMe); 4.12(s,2H, ArCH2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][S:14]([CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:29][C@@H:30]([CH2:44][C:45]1[CH:50]=[C:49]([F:51])[CH:48]=[C:47]([F:52])[CH:46]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[CH:36]=1.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:29][C@@H:30]([CH2:44][C:45]1[CH:46]=[C:47]([F:52])[CH:48]=[C:49]([F:51])[CH:50]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH3:42])[CH:36]=1)=[O:26])[CH2:13][S:14]([CH:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])(=[O:15])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(CC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 250 ml round bottom flask equipped with magnetic stir bar and N2 inlet was charged with 4.0 g (10 mmole) N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine and 1.2 g (12 mmole) (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride in 50 ml anhydrous methylene chloride. To the reaction mixture was added 5.6 ml (51 mmole) NMM, 1.7 g (13 mmole) hydroxybenzotriazole, and lastly 3.1 g (16 mmole) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After stirring at room temperature for 3 hours, HPLC analysis indicated complete reaction. The reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate solution, 0.5 M citric acid, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the N2-[(benzyloxy)carbonyl]-N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide. A 50 ml round bottom flask equipped with magnetic stir bar and N2 inlet was charged with the crude residue in anhydrous methylene chloride. The reaction was cooled to 0° C. and added 2.5 g (12 mmole) di-tert-butyl dicarbonate and 1.2 ml (11 mmole) N-methyl morpholine. The reaction was allowed to warm to room temperature and stirred for 18 hours at which point HPLC analysis indicated complete reaction. The reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate solution, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified on silica gel by flash chromatography using a gradient solvent of 5-40% ethyl acetate in hexane to give 3.4 g of N2-[(benzyloxy-)carbonyl]-N1-{(1S,2R)-N-[(t-butyloxy)carbonyl]-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide. M+Na=824.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.[C:18]1(=[O:40])[N:22]([CH2:23][CH2:24][O:25][CH2:26][C:27](=O)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21](=[O:35])[C:20]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:19]12>C(O)(C)C>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:8])[NH:1][C:27]([CH2:26][O:25][CH2:24][CH2:23][N:22]2[C:21](=[O:35])[C:20]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:19]3[C:18]2=[O:40])=[C:28]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CC(=O)COCCN1C(=O)c2ccccc2C1=O
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
Methyl 3-aminocrotonate (72.2 g; 0.627M) and 2-chlorobenzaldehyde (88.1 g; 0.627M) were added to a solution of ethyl 4-(2-phthalimidoethoxy)acetoacetate (200 g; 0.627M) in isopropanol (1 liter) and the mixture was heated under reflux for 20 hours. The isopropanol was evaporated under reduced pressure and replaced by acetic acid (1 liter). After granulation at 10° the solid was collected and slurried in methanol (300 ml). The solid was collected by filtration and dried in vacuo at 50° to afford the title compound, yield 84.4 g, m.p. 146°-147°.
Reaction SMILES: S(Cl)(Cl)=O.N1C=CC=C([C:11]2[N:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:13]([C:20]([OH:22])=[O:21])[CH:12]=2)C=1>C(Cl)(Cl)Cl.CN(C)C=O>[N:19]1[CH:14]=[CH:15][CH:16]=[C:17]([C:12]2[C:13]([C:20]([OH:22])=[O:21])=[C:14]3[N:19]([CH:11]=2)[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:18]=1
Reactant: O=C(O)c1cc(-c2cccnc2)n2c1CCCC2
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)c1c(-c2cccnc2)cn2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.3 cm3 of thionyl chloride are added dropwise to a suspension 4.8 g of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid in 120 cm3 of chloroform, followed by a few drops of dimethylformamide. The resulting suspension is then stirred at ambient temperature for 16 hours (slow gas release) and is then heated to reflux (75° C.) for 1 hour, at the end of which there is no further gas release. It is then cooled to ambient temperature and then concentrated at reduced pressure (2.7 kPa) and taken up twice in ethanol-free dichloromethane and then concentrated again in the same way. 5.4 g of 3-(3-pyridyl-5,6,7,8-tetrahydroindolizine-1-carboxylic acid are thus obtained in the form of a greenish solid. (Rf=0.44; thin layer chromatography on silica gel; eluent: 10/90 by volume mixture of methanol and of dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[Br-].[C:15]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[CH2:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 7-methoxy-1-tetralone H4.1 (26.9 g, 153 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and triphenylmethylphosphonium bromide (65.4 g, 183 mmol) in THF (550 mL) was added potassium tert-butoxide (1.0 M solution in THF)(183 mL, 183 mmol) via addition funnel over 1 hour. The resulting mixture was stirred at room temperature for 60 minutes after addition. The reaction was then concentrated and resuspended in hexanes (250 mL). The mixture was passed through a silica gel plug (25 g silica) and rinsed with 250 mL of hexanes. Removal of solvent gave H4.2 (24.5 g, 92% yield). MS ESI (pos.) M/E: 175 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[O-:6].[K+].Br[C:14]1[CH:19]=[C:18]([NH:20][C:21]([CH3:23])=[O:22])[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]=1[O:27][CH3:28]>CN(C=O)C.O>[NH:20]([C:18]1[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]([O:27][CH3:28])=[C:14]([O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[CH:19]=1)[C:21]([CH3:23])=[O:22]
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Br
Reactant: [O-]c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Oc1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To the above solid 7 under argon, was added a solution of 3.0 g (10.4 mmol) of bromide 6 in 20 mL of DMF via cannula. The resulting solution was stirred at 120° C. for 1 day. TLC and NMR indicated the presence of a small amount of starting material 6. The reaction solution was cooled to room temperature and 2 mmol of compound 7 was added. The solution was stirred at 120° C. for 12 hour, diluted with 200 mL of ice and water, and the solid was collected by filtration, washed with water, dried under vacuum, and crystallized from ethanol to give 3.04 g (79% yield) of compound 8. 1H NMR (CDCl3) δ 10.4 (s, 1 H, NH), 8.39 (s, 1 H), 7.83 (s, 1 H), 7.5 (m, 2 H), 7.3 (m, 2 H), 3.93 (s, 3 H, OMe), 2.23 (s, 3 H, CH3). 13C NMR (CDCl3) δ 174, 155.7, 153.9, 142.4, 141.6, 130.9, 123.0, 121.7, 121.6, (116.9, 116.8, 116.7, 116.6 q for CF3), 108.7, 106.6, 56.7, 21.8.