Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]1([N:61]=[C:62]=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:62]([NH:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:63])[CH2:49][CH2:48]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and phenyl isocyanate as starting materials in 51% yield. LCMS for C31H32ClN8O2 (M+H)+: m/z=583.2.
Reaction SMILES: CON(C)[C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1COCC1>[C:12]1([CH2:11][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCC(=O)N(C)OC
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC(=O)Cc1ccccc1
Yield: 70.6 %

Procedure:
Part B: To a magnetically stirred solution of pentanoic acid methoxy-methyl-amide (8.6 g, 59.3 mmol) at 0° C. in anhydrous THF (100 ml) was slowly added benzylmagnesium chloride (2 M solution in THF, 45 ml, 90 mmol) and the resulting mixture was reacted for 20 hours in a nitrogen atmosphere at room temperature. The reaction mixture was poured in excess of a cold (0° C.) aqueous hydrochloric acid (4 N solution) and extracted with MTBE. The organic layer was dried over Na2SO4, filtered and concentrated to give crude product. This crude product was further purified using Sepacore equipment: Gradient: (petroleum ether/diethyl ether=98/2 (v/v))=>(petroleum ether/diethyl ether=95/5 (v/v)) to give 1-phenylhexan-2-one (Intermediate II-1) (7.38 gram, 71% yield) as a colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.86 (t, J=7, 3H), 1.21-1.31 (m, 2H), 1.48-1.58 (m, 2H), 2.41-2.47 (m, 2H), 3.68 (s, 2H), 7.18-7.36 (m, 5H).
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[CH:9](=[N:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC1CCOC1=O
Reactant: O=Cc1ccccc1
Agent: Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCCC1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3.84 g of α-amino-γ-butyrolactone hydrogenbromide in 40 ml of dichloromethane is added 2.15 ml of benzaldehyde, followed by5.9 ml of triethylamine and excess magnesium sulfate. After stirring at room temperature for 20 hours, the mixture is filtered and the filtrate concentrated. A 200 ml portion of ether is added and the resulting suspension filtered. The filtrate is washed with 50 ml of saturated aqueous sodium chloride. The aqueous phase is extracted with two 100 ml portions of ether. The combined organic phase is dried (magnesium sulfate), filtered, and then concentrated. The residue is evaporatively distilled at 0.05 mmHg (Krugelrohr oven 200°-250° C.) to give 3.5 g of N-benzylidene-α-amino-γ-butyrolactone as an oil which solidifies on storage in a freezer:
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[N:17]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1Oc1cccc(C(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)O)c(Oc2cccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.7 %

Procedure:
A mixture of methyl 4-tert-butyl-2-(6-(trifluoromethyl)pyridin-2-yloxy)benzoate (0.49 g, 1.4 mmol) and lithium hydroxide hydrate (0.12 g, 2.8 mmol) in THF (5 mL) and water (5 mL) was stirred at room temperature for two days. The reaction was made acidic with 1 M HCl(aq) and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and evaporated to give 4-tert-butyl-2-(6-(trifluoromethyl)pyridin-2-yloxy)benzoic acid (0.45 g, 95% yield). LC/MS: m/z 340.5 (M+H)+ at 1.89 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=8.3 Hz, 1H), 7.85-7.81 (m, 1H), 7.36-7.33 (m, 2H), 7.26-7.24 (m, 1H), 7.09 (d, J=8.4 Hz, 1H) and 1.34 (s, 9H) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Cl.[C:27]1([C:33]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:27]1([C:33]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:38]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g), triethylamine (2.8 cc) and 4,4-diphenylpiperidine hydrochloride (2.7 in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 7 hours at this temperature. After purification by flash-chromatography on a silica 1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (10 cc), 2-[3-(4,4-diphenylpiperidino)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (1.6 g) is obtained, m.p. 168° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH3:12][O:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH2:16]>>[CH3:19][CH:18]([CH3:20])[CH2:17][C@@H:15]([NH:16][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=1)[C:14]([O:13][CH3:12])=[O:21]
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(SC)cc1

Procedure:
Prepared in a similar manner to example 4 using 4-(methylthio)benzoic acid and D Leucine methyl ester. MS (M+H, 296).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=O.[C:18]([C:20]1[C:21](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[O:22][C:23]([CH3:27])([CH3:26])[C:24]=1[CH3:25])#[N:19]>C(O)C>[C:18]([C:20]1[C:21](=[C:28]([C:29]#[N:30])[C:31]#[N:32])[O:22][C:23]([CH3:26])([CH3:27])[C:24]=1[CH:25]=[CH:16][C:4]1[CH:5]=[C:6]2[C:15]3[N:10]([CH2:9][CH2:8][CH2:7]2)[CH2:11][CH2:12][CH2:13][C:14]=3[C:3]=1[O:2][CH3:1])#[N:19]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: COc1c(C=O)cc2c3c1CCCN3CCC2
Solvent: CCO
Product: COc1c(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)cc2c3c1CCCN3CCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
In 5 ml of ethanol were dissolved 150 mg (0.65 mmol) of 8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-carboaldehyde and 142 mg (0.71 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at room temperature for 3 hours and further at 50° C. for 3 hours. The precipitate was separated by filtration and washed with methanol. The crystal was purified by silica gel column chromatography and washed with methanol to give 228 mg of a dark blue crystal having amp of 250-252° C. (yield: 85.2%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([Cl:1])[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: Clc1nc2ccccc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 2-chlorobenzothiazole (12.0 g, 70.7 mmol) in concentrated H2SO4 (60 mL) was added HNO3 (69% solution, 6 mL) dropwise at 0° C. for 20 min. The mixture was stirred at 5° C. for 3 h, poured into ice-water (150 mL). The precipitate was collected and washed with 5% sodium bicarbonate and water, dried in vacuo. 1H NMR analysis showed the mixture contained 78% 6-nitro-2-chlorobenzothiazole and 8% 5-nitro-2-chlorobenzothiazole. Recrystallization from ethanol gave 6-nitro-2-chlorobenzothiazole as white crystalline solid (11 g, 72%). 3.5 g of the solid was dissolved in refluxing ethanol-acetic acid (150:15 mL), Iron powder was added in one portion. The mixture was refluxed for 1.5 h, filtered. The filtrate was concentrated in vacuo to half volume and neutralized with 10% NaOH to pH 7.5, extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to give a residue, which was recrystallized from ethanol. Light purple crystals (2.5 g, 83%) were obtained. Mp 160-164° C.; TLC single spot at Rf 0.27 (30% EtOAc/hexane); 1HNMR (270 MHz, DMSO-d6) δ 7.58 (1H, d, J=9.0 Hz, 4-H), 7.03 (1H, d, J=2.0 Hz, 7-H), 6.77 (1H, dd, J=9.0, 2.0 Hz, 5-H), 5.55 (2H, s, NH2). The mother liquor from the recrystallization of nitration product was evaporated and subjected to iron powder reduction as described above. The crude product was purified with flash chromatography (ethyl acetate-DCM gradient elution) to give 2-chlorobenzothiazol-5-yl-amine as yellow solid. Mp 146-149° C.; TLC single spot at Rf 0.52 (10% EtOAc/DCM); 1HNMR (270 MHz, DMSO-d6) δ 7.63 (1H, d, J=8.6 Hz, 7-H), 7.05 (1H, d, J=2.3 Hz, 4-H), 6.78 (1H, dd, J=8.6, 2.3 Hz, 6-H), 5.40 (2H, s, NH2).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][CH:9]=2)[C:5]([NH:16][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])=[CH:4][CH:3]=1
Reactant: CC1(C)CC=C(c2nc(Br)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2nc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-ylamine (as prepared in the previous step, 60 mg, 0.21 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 91.0 mg, 0.290 mmol), PyBroP (157 mg, 0.330 mmol) and DIEA (91.0 μL, 0.520 mmol) according to the procedure in Example 1, step (f) (84 mg, 78%). 1H-NMR (CDCl3; 400 MHz): δ 9.91 (s, 1H), 8.64 (d, 1H, J=8.6 Hz), 7.79 (s, 1H), 7.38 (d, 1H, J=8.6 Hz), 6.00 (m, 1H), 5.92 (s, 2H), 3.67 (m, 2H), 2.46 (m, 2H), 2.14 (m, 2H), 1.62 (t, 2H, J=6.3 Hz), 1.12 (s, 6H), 0.98 (m, 2H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C@H:19]([NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([Cl:40])=[CH:35][CH:34]=2)=[O:30])[C:20](=[O:27])[N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C(OCC)(=O)C>[CH2:12]([C@H:19]([NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([Cl:40])=[CH:35][CH:34]=2)=[O:30])[C:20](=[O:27])[N:21]1[CH2:22][CH2:23][S:24](=[O:6])[CH2:25][CH2:26]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCS(=O)CC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 76 %

Procedure:
m-Chloroperoxybenzoic acid (80 mg of 50%, 0.23 mmol) was added at 25° C. to a solution of 5chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-amide (100 mg, 0.23 mmol) in dichloromethane (2 mL). After 1 hour, the mixture diluted with ethyl acetate and washed three times with a 50/50 mixture of saturated aqueous sodium bicarbonate and 10% aqueous sodium thiosulfate, once with saturated aqueous sodium bicarbonate, brine, and dried. The crude product was purified by column chromatography on silica gel eluted with 0.5-8% ethanol in dichloromethane to give the title compound. Yield 76%; HPLC (60/40) 3.97 minutes (97%); mp 230-234° C.; TSPMS 444/446 (MH+, 100%);
Reaction SMILES: [F:1][C:2]([F:36])([C:32]([F:35])([F:34])[F:33])[C:3]([F:31])([F:30])[C:4]([F:29])([F:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O.[BrH:37].S(=O)(=O)(O)O>>[Br:37][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:29])([F:28])[C:3]([F:31])([F:30])[C:2]([F:36])([F:1])[C:32]([F:35])([F:34])[F:33]
Reactant: OCCCCCCCCCCCCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Br
Agent: O=S(=O)(O)O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCCCCCCCCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 1.00 g of 22-(nonafluorobutyl)-1-docosanol and 30 mL of 48 weight percent hydrobromic acid was slowly added 3 mL of concentrated sulfuric acid, and the reaction mixture was heated at 100° C. for 24 hr. The mixture was cooled to room temperature, and the solid product was collected by filtration and dissolved in hexanes. The filtrate was extracted once with hexanes, and the combined hexanes solutions were washed with saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. Filtration and concentration yielded 1.03 g of 1-bromo-22-(nonafluorobutyl)docosane as an off-white solid, which was used without further purification.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@H:13]1[CH2:18][CH2:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1.Cl>C(Cl)Cl.CO>[CH3:3][O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@H:13]1[CH2:18][CH2:19][CH:20]([OH:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1
Reactant: COC(=O)COCCCCN1C(=O)CC[C@H]1CCC(=O)Cc1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CC[C@H]1CCC(O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 20.1 %

Procedure:
Sodium borohydride (4.1 mg, 0.11 mmol) was added to a solution of (4{(R)-2-[4-(3-Chlorophenyl)-3-oxo-butyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester (44 mg, 0.11 mmol) in CH2Cl2 (1 mL) at rt. Methanol (3 drops) was added and the reaction was stirred at rt for 4.5 h. Aqueous HCl (0.5 M, 5 mL) was added and the mixture was extracted with CH2Cl2 (2×8 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (0%→3% MeOH/CH2Cl2) to afford 9.1 mg (21%) of (4-{(R)-2-[4-(3-chlorophenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester.
Reaction SMILES: C([N:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([CH3:20])[CH3:19])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:17][C:16]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:20])([CH3:19])[NH:8]1
Reactant: CC1(C)c2ccccc2C(C)(C)N1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)NC(C)(C)c2ccccc21
Yield: 99.8 %

Procedure:
A solution of 2-benzyl-1,1,3,3,-tetramethylisoindoline (5.5 g 20 mmol) in glacial acetic acid (20 ml) was hydrogenated at 60 lb/in2 over 5% palladium/c for 3 h at room temperature. The suspension was filtered and the solvent removed at reduced pressure. The residue was dissolved in water and the solution was made alkaline (PH 9) by the addition of 10% sodium hydroxide and extracted with ether (3×50 ml). The combined organic extracts were dried and evaporated to dryness to give the title compound (3.5 g 96%), which was recrystalized from methanol/water. m.p. 36-38° C. NMR (CDCl3, 400 MHz), 1.46 s, 4 x CH3; 1.9 s, NH, D2O exchanged; 7.1-7.27 m, ArH.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][NH2:20])=[O:18])[CH:15]=2)[C:10]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:9]1[CH:33]([CH3:35])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36](OCC)(OCC)OCC>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][CH:36]=[N:20][N:19]=3)[CH:15]=2)[C:10]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:9]1[CH:33]([CH3:35])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NN)cc2n1Cc1ccccc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(-c3nnco3)cc2n1Cc1ccccc1

Procedure:
1-benzyl-N-(3,4-difluorobenzyl)-6-(hydrazinecarbonyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 88, 21 mg, 0.044 mmol) in triethyl orthoformate (5 ml) was heated to 145° C. for 5 h, then concentrated in vacuo. The residue was purified by chromatography on silica gel (0→55% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][P:14](=[O:21])([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20]
Reactant: CCOP(=O)(CCN1C(=O)c2ccccc2C1=O)OCC
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCN)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of diethyl 2-(1,3-dioxoisoindolin-2-yl)ethylphosphonate (5 g, 16.08 mmol, 1.00 equiv) in ethanol (200 mL) and hydrazine hydrate (8 g, 160.00 mmol, 9.95 equiv). The resulting solution was stirred for 12 h at room temperature. The solids were filtered and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (9:1). This resulted in 1.5 g (51%) of diethyl 2-aminoethylphosphonate as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]O>S(=O)(=O)(O)O.C(OCC)(=O)C>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: O=C(O)C=Cc1ccccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccccc1O
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a 250-mL round bottom flask were added, in turn, 5.57 g (33.9 mmol) of 2-hydroxycinnamic acid, 80 mL of methanol, and 6 drops of concentrated sulfuric acid. The resulting clear solution was heated to reflux for 6 hours and then allowed to cool to room temperature. The solvent was removed in vacuo to give a sticky white solid. The solid was dissolved in 80 mL of ethyl acetate, and washed with: 3 40-mL portions of 10% aqueous sodium bicarbonate; 1 40-mL portion of water; and 2 25 mL portions of brine. The organic layer was concentrated in vacuo to give 5.51 g (91.4%) of methyl 2-hydroxycinnamate as a white solid.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35](OC)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:46]([NH2:48])[CH3:47]>CO>[NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([NH:48][CH2:46][CH3:47])=[O:36])[CH2:31][CH2:32][S:33][CH3:34])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCN
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: CO
Product: CCNC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Yield: 92 %

Procedure:
In a fashion analogous to Step D of Example 1A, 2.15 g of Boc-Tyr-DAla-Phe-Met-OCH3 was treated with 20 ml of ethylamine in 200 ml of methanol to give 2.01 g (92%) of Boc-Tyr-DAla-Phe-Met-NHCH2CH3, m.p. 159°-161° C., [α]D25 =5.04° (c, 0.97 in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([O:21]CC)=[O:20])=[C:11]2[CH3:24])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=[O:20])=[C:11]2[CH3:24])[CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)n(C(C)c2ccc(Cl)cc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccc(Cl)cc1
Yield: 105 %

Procedure:
To a mixture of ethyl 1-(1-(4-chlorophenyl)ethyl)-2-methyl-1H-indole-3-carboxylate (210 mg, 0.61 mmol) in MeOH/H2O (6 mL/2 mL) was added KOH (340 mg, 6.1 mmol) at room temperature. The reaction was refluxed overnight. Then the mixture was adjusted to Ph=4 with 1 N HCl and extracted with EtOAc (3×). The combined organic extract were combined and concentrated in vacuo to afford the title compound as a yellow solid (200 ing, yield 105%) which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[N:5][CH:4]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([SH:25])[CH2:22][CH2:23][SH:24]>C1(C)C=CC=CC=1>[S:24]1[CH2:23][CH2:22][CH2:21][S:25][CH:1]1[C:3]1[N:7]([CH3:8])[CH:6]=[N:5][CH:4]=1
Reactant: Cn1cncc1C=O
Reactant: SCCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1cncc1C1SCCCS1
Yield: 63.9 %

Procedure:
8.3 g (75.4 mmol) of 5-formyl-1-methylimidazole are dissolved in 120 ml of toluene, and 17.1 g (89.9 mmol) of 4-toluenesulfonic acid monohydrate are added. After addition of 8.12 g (75.0 mmol) of 1,3-propanedithiol, the suspension obtained in this way is boiled under reflux with a water trap. It is subsequently washed with 4N sodium hydroxide solution, and the organic phase is dried over sodium sulfate and concentrated in vacuo until crystallization starts. After storage in a refrigerator overnight, 9.6 g (47.9 mmol, 64%) of 5-(1,3-dithian-2-yl)-1-methylimidazole are obtained as a white solid of melting point 111.5°-112.5° C.