Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH:14]=[CH:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CN(C)C(=O)C>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(c1ccccc1)N1C=CC(c2c[nH]c3ccc(F)cc23)C=C1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)N1CCC(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
A mixture of 65 parts of 1-benzoyl-4-(5-fluoro-1H-indol-3-yl)-1,4-dihydropyridine and 270 parts of N,N-dimethylacetamide was hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 5 parts of 1-benzoyl-4-(5-fluoro-1H-indol-3-yl)piperidine as a residue (intermediate 21).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:15]2)[CH2:12][CH2:13]1)(=[O:42])[CH3:41]
Reactant: Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
To N-(2-(3-(4-(2-aminophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (Example #4.149, 0.050 g, 0.10 mmol) in DCM (1 mL) was sequentially added triethylamine (0.044 mL, 0.32 mmol) and acetic anhydride (10.9 μL, 0.116 mmol). The reaction mixture was stirred at room temperature for about 16 h. The solvent was removed in vacuo and the residue purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 5% to 60% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford N-(2-(3-(4-(2-acetamidophenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-3,4-dichlorobenzamide (0.0075 g, 0.014 mmol). RP-HPLC (Table 1, Method a) Rt 1.92 min; nm/z: (M+H)+ 517.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[C:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:18])#[N:9].CI>C1C=CC=CC=1>[C:8]([CH2:10][C:11]1([CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:18])#[N:9]
Reactant: Cc1ccccc1
Reactant: N#CCC1CCCCCC1=O
Solvent: CI
Solvent: c1ccccc1
Product: CC1(CC#N)CCCCCC1=O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A solution of sodium tert.-amylate in toluene (340 ml, 0.297 mole) is added dropwise with stirring under nitrogen to a solution of 2-cyanomethylcycloheptanone (44.6 g, 0.297 mole, obtained as described above) and methyl iodide (42.6 g, 0.3 mole) in dry benzene (200 ml), and the mixture is stirred at 65° C for 4 hrs. and allowed to stand overnight at room temperature. The reaction mixture is washed with 1% aqueous hydrochloric acid, water, saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is evaporated. Distillation of the residue under reduced pressure yields 2-cyanomethyl-2-methylcycloheptanone, bp. 152°-158° C/14 mm, nmr (CDCl3) δ1.27 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)([O-:19])=[O:18]>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-acetylpiperazine (5.0 g; 39.0 mmol) in THF (50 ml) was added triethylamine (5.6 ml; 39.0 mmol) and 3-nitrobenzylbromide (8.4 g; 39.0 mmol). The mixture was stirred at ambient temperature for 1 hour and the solvent was removed by evaporation. The residue was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulphate and evaporated under reduced pressure to leave 6m2, quantitatively.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:23]([F:26])([F:25])[F:24])[C:12]2[C:11](=[O:27])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:28])(=[O:3])[CH3:2].FC(F)(F)S(O[CH2:35][CH3:36])(=O)=O.CO>C1COCC1>[CH2:35]([O:27][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:28])[NH:6]2)[CH3:36]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc([N+](=O)[O-])cc1C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1nccc2c1C(c1ccc([N+](=O)[O-])cc1C(F)(F)F)C(C(C)=O)=C(C)N2
Reaction time: 0.17 h

Procedure:
976 mg (2.48 mmol) of 3-acetyl-2-methyl-4-[4-nitro-2-(trifluoromethyl)phenyl]-4,6-dihydro-1,6-naphthyridin-5(1H)-one are suspended in THF (60 ml), and 3 ml (3 mmol) of N′″-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane) are added. Then 389 μl (2.97 mmol) of ethyl trifluoromethanesulfonate are added to the dark red solution. The decolorized solution is stirred for a further 10 min and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 240 mg (23% of theory) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=C)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:16].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=[O:16])=[CH:5][CH:4]=1
Reactant: C=Cc1cccc2ccc(OC)cc12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cccc(C=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step B (13.4 mmol) and osmium tetroxide (0.16 mmol) are dissolved in 70 ml of a mixture of tetrahydrofuran/water (1/1). Sodium periodate (26.9 mmol) is added in small portions and the reaction mixture is stirred for 2 hours at ambient temperature. The reaction mixture is poured into 50 ml of 5% sodium hydrogen carbonate solution, the insoluble material is filtered off and the aqueous phase is extracted twice with 75 ml of ether. The organic phase is washed with water, decolourised and evaporated. The precipitate obtained is recrystallised from cyclohexane and yields the title product in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Temperature: 100 °C
Yield: 23 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 350 mg, 1.544 mmol) was dissolved in DMSO (10 mL). Sodium tert-butoxide (223 mg, 2.316 mmol) was added, followed 5 minutes later by the addition of methyl 4-(bromomethyl)benzoate (531 mg, 2.316 mmol) to give a brown suspension. The reaction mixture was heated to 100° C. in a microwave on high absorbance for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (2×15 mL) and brine (2×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (24 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (133 mg, 23%). ESI-MS m/z [M+H]+ calc'd for C18H19ClN4O3, 375.1. found 375.4.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:26]([NH2:29])(=[O:28])=[O:27])=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:30])[CH:3]=1.CC1(C)[SiH2][SiH]=[N:35][C:34](C)(C)C1(C)C.[Na].BrC#N.CC(O)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:26]([NH:29][C:34]#[N:35])(=[O:27])=[O:28])=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:30])[CH:3]=1
Reactant: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: N#CBr
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2S(=O)(=O)NC#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5,7-dimethyl-2-ethyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine (122 mg, 0.29 mmol) in THF (1.5 mL) at 0° C. was added sodium hexamethyldisilazine (0.35 mL of a 1M solution in THF). After 10 min, a solution of BrCN (37 mg, 0.35 mmol) in THF (1 ml) was added dropwise via a double tipped needle. The reaction was warmed to r.t. and stirred for 3 h at which time 0.3 mL of HOAc was added. Extraction with CH2Cl2 (5×30 mL) from H2O (30 mL), evaporation of the organic extracts and purification (SiO2, 80:19:1 CH2Cl2 /CH3OH/NH4OH) gave 5,7-dimethyl-2-ethyl-3-[2'-(N-cyanoaminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine as a glass.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:46])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][C:42]([O:44]C)=[O:43]>>[C:42]([CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:46])=[O:17])([OH:44])=[O:43]
Reactant: COC(=O)CCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 184, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-(4-methoxy-4-oxobutoxy)-6-[6-(methylsulfonyl)oxyhexyl]benzenepropanoic acid methyl ester from the preceding example, followed by saponification, in 40% overall yield. The product was a colorless solid, mp 116°-117.5° C., recrystallized from acetonitrile.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29](Br)[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)nc1-2
Yield: 77 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho-[1,2-d]thiazol-6-yl)oxy]acetate and bis(4-chlorophenyl)methyl bromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 77%. Amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[N:3]=1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: ClCc1csc(-c2ccccn2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccccn4)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.15 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 51.5 mg (0.61 mmol) of sodium bicarbonate and 58.6 mg (0.23 mmol) of 4-chloromethyl-2-(2-pyridyl)-1,3-thiazole are then added. The suspension is shaken RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 67.4 mg (87.9% of theory) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C>[CH3:34][S:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.40 mmol of methanesulfonyl chloride in 3 ml of DMF were added. The reaction solution was then stirred at room temperature for a further 6 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[Cl:9][CH2:10][CH2:11]O>>[OH:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3]([O:5][CH2:11][CH2:10][Cl:9])=[O:4]
Reactant: OCCCl
Reactant: CCC(C)(O)C(=O)O
Product: CCC(C)(O)C(=O)OCCCl

Procedure:
2-Chloroethyl 2-hydroxy-2-methylbutyrate was prepared from 2-hydroxy-2-methylbutyric acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1: b.p. 108° C./20 mm Hg; 1H NMR δ 0.90 (t, 3H, J=7.4 Hz), δ 1.44 (s, 3H), δ ca. 1.70 (m, 1H), δ ca. 1.83 (m, 1H), δ 3.10 (s, 1H), δ 3.72 (t, 2H, J=5.6 Hz), δ 4.43 (dd, 2H, J=5.6 Hz and 1.5 Hz); HRMS calcd for C6H9ClO3Tms (M--CH3) 237.0714, obsd 237.0750.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH:14]=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[K+].Cl>O1CCCC1.O>[OH:15][CH:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]#[N:17]
Reactant: O=CC1CCCN1C(=O)c1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)C1CCCN1C(=O)c1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3.347 g (16.5 mmoles) of 1-benzoyl-2-formylpyrrolidine in a mixture of 28 ml of tetrahydrofuran and 19 ml of water are added 1.30 g (20 mmoles; 1.23 equivalents) of potassium cyanide and 1.4 ml (16.7 mmoles) of concentrated hydrochloric acid. After 1 hour, the mixture is diluted with water and extracted with chloroform. The organic layer is separated, washed with water, dried over sodium sulfate, and evaporated under reduced pressure to yield 3.8 g of crude crystalline 2-hydroxy-2-(1-benzoylpyrrolidin-2-yl)acetonitrile in quantitative yield.
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[C:22](=[O:34])([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[O:23][CH:24](Cl)[CH3:25]>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH:24]([O:23][C:22]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:34])[CH3:25])=[O:19]
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Product: CC(OC(=O)OC1CCCCC1)OC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)O)[C@@H]21

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 1.35 g) and 1-chloroethyl cyclohexyl carbonate (2.06 mL) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-10, 113 mg) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][NH:7][C@H:6]([C:13]([OH:15])=[O:14])[CH2:5]2.Cl.[CH3:17]O>>[CH3:17][O:14][C:13]([C@@H:6]1[CH2:5][C:4]2[C:9](=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=2)[CH2:8][NH:7]1)=[O:15]
Reactant: O=C(O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Reaction time: 18 h

Procedure:
(S)-6,7-Dihydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (62 g), 200 mL anhydrous MeOH, and 26 mL concentrated hydrochloric acid were stirred together overnight at 70° C. The mixture was then evaporated and the residue resuspended in 500 mL acetonitrile with vigorous stirring to wash all the solid material. Stirring continued for 18 h at r.t., after which the solid product was collected by filtration, washed with 100 mL acetonitrile, and dried under vacuum overnight. Yield 77 g (quantitative). 1H NMR (400 MHz, MeOH-d4): 6.64(s, 1H), 6.61(s, 1H), 4.42-4.36(m, 1H), 4.29-4.24(m, 2H), 3.89(s, 3H), 3.29-3.22(m, 1H), 3.11-3.02(m, 1H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,4-dichlorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=279.9 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 6.72 (d, J=8.7 Hz, 1H), 7.57 (dd, J1=8.5 Hz, J2=2.2 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 8.34 (s, 1H).
Reaction SMILES: O1C2=CC3C=[C:9]([C:13]([OH:15])=[O:14])[NH:10]C=3C=C2OC1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[C:26]([CH3:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1C2C=CC(C=O)=CC=2OC1>>[CH2:16]([O:23][C:24]1[CH:31]=[C:30]2[C:27]([CH:28]=[C:9]([C:13]([OH:15])=[O:14])[NH:10]2)=[C:26]([CH3:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2cc3c(cc2[nH]1)OCO3
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Agent: O=Cc1ccc2c(c1)OCO2
Product: Cc1cc(OCc2ccccc2)cc2[nH]c(C(=O)O)cc12

Procedure:
Intermediate I-5a was prepared using procedures analogous to those described above for the synthesis of 5H-[1,3]dioxolo[4,5-f]indole-6-carboxylic acid (I-4c) using 4-(benzyloxy)-2-methylbenzaldehyde (I-4c) as the starting material instead of benzo[d][1,3]dioxole-5-carbaldehyde. ESI MS: m/z 282.24 (M+H).
Reaction SMILES: [C:1]1([C:9]([O-:11])=[O:10])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46]>C1COCC1>[C:4]([C:1]1([C:9]([O:11][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:10])[CH:2]=[CH:3]1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1(C(=O)[O-])C=C1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)OC(=O)C1(C(=O)OCC)C=C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 250 milliliter round-bottom flask was equipped with a magnetic stirrer and an addition funnel with N2 inlet. The flask was charged with 1.30 grams (0.008 mole) of monoethyl cyclopropene-1,1-dicarboxylate, 50 millilaters of dry THF, 2.3 grams (0.02 mole) of potassium carbonate (anhydrous), and 450 milligrams of dicyclohexano-18-crown-6 ether. The stirred reaction mixture was cooled to 0° C., and 0.90 gram (0.008 mole) of ethyl chloroformate in 10 millilaters of THF was added dropwise. The mixture was stirred for 21/2 hours at O° C. At this time an aliquot from the reaction mixture showed a very strong anhydride carbonyl stretch at 1820 cm-1 in the infrared indicating the formation of the mixed anhydride 1-carboethoxy-1-ethoxycarbonyloxycarbonyl-2-cyclopropene. The balance of the reaction mixture containing the mixed anhydride was carried on to Part E.
Reaction SMILES: [CH2:1]([CH:11]([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40](O)=[O:41].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>ClCCl>[CH3:35][N:36]([CH3:43])[CH2:37][CH2:38][CH2:39][C:40]([O:23][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:41]
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCC=CCCCC(CCC/C=C\CCCCC)C(CCCC=CCCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 (0.4 g, 0.9 mmol), 4-(dimethylamino)butanoic acid hydrochloride (0.2 g, 1.3 mmol), EDCI hydrochloride (0.25 g, 1.3 mmol), diisopropylethylamine (0.4 mL, 2.6 mmol) in anhydrous dichloromethane (10 mL) was added dimethylaminopyridine (5 mg). The solution was refluxed for 2 hours then stirred at room temperature for 2 hours. The mixture is concentrated in vacuo to dryness and purified by column chromatography (100% ethyl acetate) to afford 6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 4-(dimethylamino)butanoate 9 as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.36 (m, 6H), 4.93 (m, 1H), 2.30 (m, 4H), 2.22 (s, 6H), 2.03 (m, 12H), 1.88 (m, 2H), 1.66-1.18 (m, 31H), 0.90 (m, 9H). Rf 0.3 (10% MeOH—CH2Cl2).