Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=O)[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH3:33]>N1C=CC=CC=1>[NH2:17][C:16]1[N:18]=[C:19]2[C:12]([N:11]=[CH:10][N:9]2[CH:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[C:13]([NH2:33])[N:15]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: N
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1nc(N)c2ncn(C3C[C@H](O)[C@@H](CO)O3)c2n1
Yield: 34 %

Procedure:
To 2 mmol of deoxyguanosine, dried by evaporation of pyridine and suspended in 20 mL of dry pyridine was added dropwise 2.3 mL (16 mmol) of trifluoroacetic anhydride, with cooling in an ice bath. After ten minutes 20 mL of cold, concentrated aqueous ammonia was added. After a further 11/2 hours the mixture was evaporated to dryness, the residue dissolved in water and the solution filtered through a 100 mL portion of Bio Rad AG 1-X2, hydroxide from resin to remove colored impurities. The resin was washed with 40% methanol in water to elute crude 2,6-diamino-9-(2-deoxy-Beta-D-erythro-pentofuranosyl)purine, which was further purified on the reversed-phase column described above using a gradient of 2-15% acetonitrile in water. Evaporation of appropriate fractions gave 192 mg (34%) of 2,6-diamino-9-(2-deoxy-D-erythro-pentofuranosyl)purine, a sample crystallized from water gave a mp of 148°. UVmax (MeOH) 282 nm, UVmin 256 nm; 1H NMR (DMSO-d6) delta (ppm) 7.91 (s, 1,H8), 6.73 (br s, 2, NH2), 6.17 ("t", 1, Japp =6 Hz, H1'), 5.73 (br s, 2, NH2), 5.25 (m, 2, 3'-OH & 5'-OH), 4.35 (m, 1, H3'), 3.84 (m, 1, H4'), 3.54 (m,2,H5',5"), 2.59 & 2.17 (m & m, 1 & 1, H2' & H2"). Anal. Calcd. for C10H14N6O3.H2O: C, 42.25; H, 5.67; N, 29,56. Found: C, 42.54; H, 5.33; N, 29.56.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH2:11][CH2:12][CH3:13].[H][H]>C(O)C.[Pd]=O>[CH3:15][N:2]([CH3:1])[C:3](=[O:14])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH2:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCCc1[nH]cnc1/C=C/C(=O)N(C)C
Agent: O=[Pd]
Solvent: CCO
Product: CCCc1[nH]cnc1CCC(=O)N(C)C
Yield: 99 %

Procedure:
A solution of (E)-N,N-dimethyl-3-(5-propyl-1H-imidazol-4-yl)-2-propenamide (500 mg) in ethanol (25 ml) was added to a suspension of pre-reduced 10% palladium oxide on carbon catalyst (150 mg, 50% paste with water) in ethanol (15 ml). The mixture was stirred in a hydrogen atmosphere for 2 h, then filtered (Hyflo) and evaporated to give the title compound (500 mg) as a colorless oil, t.l.c. on Et3N impregnated SiO2 (ethyl acetate:methanol 4:1), Rf 0.33.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][C:4]([NH:6][CH2:7][CH2:8][NH2:9])=[O:5].[N+:11]([O-])([OH:13])=[O:12]>C(OCC)C>[O:1]([CH:2]([CH3:10])[CH2:3][C:4]([NH:6][CH2:7][CH2:8][NH2:9])=[O:5])[N+:11]([O-:13])=[O:12]
Reactant: CC(O)CC(=O)NCCN
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: CC(CC(=O)NCCN)O[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
30 g. 2-(3-Hydroxybutanoylamino)-ethylamine are slowly introduced, with stirring at 5° to 10° C., into 100% nitric acid. After stirring for 2 hours at 0° to 5° C., the reaction solution is stirred into 1 liter of ice-cooled anhydrous diethyl ether, the supernatant ethereal layer is decanted off, the separated oil is covered with methylene chloride and the base is liberated with sodium carbonate. After suction filtration and evaporation in a vacuum at a maximum bath temperature of 20° C., there are obtained 33 g. (84% of theory) of base in the form of an oil.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][Cl:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][Cl:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 82.8 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.8 g.), conc. hydrochloric acid (1.6 g.), methanol (27 ml.) and tetrahydrofuran (40 ml.) were treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][CH2:62][OH:63]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:60][CH2:61][CH2:62][OH:63])=[O:26])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a DMF (1 mL) suspension of (R)-5-(2-(5-fluoro-2-methoxy pyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 100 mg, 0.28 mmol) and HATU (128 mg, 0.336 mmol) was added DIEA (0.146 mL, 0.840 mmol) at ambient temperature, followed by a solution of 2-aminoethanol (20.5 mg, 0.336 mmol) in minimal amount of DMF dropwise at 0° C. The reaction was warmed up to ambient temperature and stirred for 30 minutes, then directly purified by reverse-phase column chromatography (0 to 70% acetonitrile/water) to yield the product as white solid (95 mg, 85% yield). MS (apci pos) m/z=401.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>CN(C=O)C.CCOCC.O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([Br:32])=[CH:34][CH:35]=2)[CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: BrCc1ccc(Br)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(Cc3ccc(Br)cc3)CC2C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a solution of 0.30 g (0.820 mmol) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester (Step 1, Example 220) in 10 mL of DMF was added 0.339 g (2.459 mmol) of potassium carbonate followed by 0.205 g (0.820 mmol) of p-bromobenzyl bromide. The reaction was stirred at room temperature for 15 h, then diluted with ether and water. The organics were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1) to provide 0.438 g of 4-(4-bromo-benzyl)-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester as a colorless oil. Electrospray Mass Spec 534.9, 536.8 (M+H)+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:23])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH2:21]O)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[N:10]=1.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[Cl:26][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([CH:14]=1)[O:12][CH2:11][C:9]1[N:10]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][C:8]=1[CH3:23]
Reactant: COc1ccc(CO)cc1OCc1nc(-c2ccco2)oc1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1OCc1nc(-c2ccco2)oc1C
Yield: 98.5 %

Procedure:
To a mixture of (3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-4-methoxyphenyl)methanol (7.0 g) and toluene (150 mL) was added thionyl chloride (3.16 g), and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-(5-chloromethyl-2-methoxyphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole as pale-brown crystals (7.30 g, yield 99%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C@H:15]([C:43]([NH:45][C@@H:46]([C:57]([N:59]2[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)=[O:58])[CH2:47][C:48]2[CH:53]=[CH:52][C:51]([C:54](=[NH:56])[NH2:55])=[CH:50][CH:49]=2)=[O:44])[CH2:16][C:17](=[O:42])[NH:18][C@@H:19]2[O:32][C@H:31]([CH2:33][O:34]C(=O)C)[C@@H:26]([O:27]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@H:20]2[NH:38][C:39](=[O:41])[CH3:40])(=[O:13])=[O:12])=[C:6]([CH3:65])[C:5]=1[CH3:66].[O-2].[Ba+2]>C(Cl)(Cl)Cl.CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C@H:15]([C:43]([NH:45][C@@H:46]([C:57]([N:59]2[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]2)=[O:58])[CH2:47][C:48]2[CH:53]=[CH:52][C:51]([C:54](=[NH:55])[NH2:56])=[CH:50][CH:49]=2)=[O:44])[CH2:16][C:17](=[O:42])[NH:18][C@@H:19]2[O:32][C@H:31]([CH2:33][OH:34])[C@@H:26]([OH:27])[C@H:21]([OH:22])[C@H:20]2[NH:38][C:39](=[O:41])[CH3:40])(=[O:13])=[O:12])=[C:6]([CH3:65])[C:5]=1[CH3:66]
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2NC(C)=O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C
Agent: Cl
Agent: [Ba+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C

Procedure:
Compound 26 (1.0 g) was deacetylated as described above with barium oxide (210 mg) in chloroform and methanol (90 mL). Yield: 0.65 g. [α]D =+15.6° (c 1.013 in methanol)
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[O:21][N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([S:30]([NH:33][CH2:34][C:35]([OH:37])=[O:36])(=[O:32])=[O:31])=[CH:28][CH:29]=3)[O:21][N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(S(=O)(=O)NCC(=O)OC(C)(C)C)cc3)n2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(S(=O)(=O)NCC(=O)O)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
TFA (2.0 ml, 26.0 mmol) was added dropwise to a stirred mixture of tert-butyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonamido)acetate (0.121 g, 0.238 mmol), DCM (5.0 ml) under N2. The mixture was stirred at ambient temperature for 3 hrs then concentrated in vacuo. The resulting solid was triturated in ether, filtered and dried to yield 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonamido)acetic acid (46 mg, 0.102 mmol) as a white solid. LCMS (Table 1, Method c) Rt=2.14 min, m/z 450.34 (M−H)−
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH:15]=[CH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[CH3:14]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C=O)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccc(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 6-methyl-pyridine-2-carbaldehyde (3.0 g, 24.8 mmol) and carbethoxymethylene triphenylphosphorane (9.5 g, 27.2 mmol) in toluene (20 ml) was stirred at room temperature overnight. The precipitate was filtered and washed with toluene. The filtrate was concentrated, and the residue was purified via flash chromatography (DCM/MeOH) affording 3-(6-Methyl-pyridin-2-yl)-acrylic acid ethyl ester CCLII in 63% yield (2.95 g).
Reaction SMILES: [OH:1][C:2]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:37](I)[CH2:38][CH:39]([CH3:41])[CH3:40].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:27]([O:26][C:24]1[CH:23]=[CH:22][C:3]([C:4]([C:6]2[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)=[O:5])=[C:2]([O:1][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH:25]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CCI
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2O)ccc1OCC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(C(=O)c2ccc(OCC(C)C)cc2OCCC(C)C)ccc1OCC(C)C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In 3 ml of N,N-dimethylformamide are suspended 0.28 g of methyl 2-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isobutoxyphenyl]acetate, 0.32 g of potassium carbonate and 0.23 ml of isopentyl iodide. The suspension is stirred at 120° C. for 2 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.17 g of methyl 2-[5-(4-isobutoxy-2-isopentyloxybenzoyl)-2-isobutoxyphenyl]-acetate as a colorless oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7]2)([O-:3])=[O:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7]2)([O-:3])=[O:2]
Reactant: NCc1ccccc1
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CC(NCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 14 h

Procedure:
5-Nitro-2-indanone (1.48 g, 8.36 mmol), benzylamine (4.40 ml, 41.8 mmol), acetic acid (15.0 ml), 4 Å molecular sieves (20 ml), THF (15 ml), and MeOH (15 ml) were introduced into a flask and cooled to 0° C. Sodium cyanoborohydride (1.05 g, 16.7 mmol) was then added portionwise over a 5-minute period. The mixture was stirred for 14 hr, filtered through celite, and concentrated to a syrup. The mixture was made basic with 2N NaOH and extracted with ether (3×50 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographed over silica gel (3% methanol/methylene chloride) to yield 5-nitro-2-(phenylmethyl)aminoindane: (1.18 g, 53%); M.S. (M+H)+ =269.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][C:25]([OH:27])=O)[CH:6]=[CH:7][C:8]=1[O: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][CH3:23].CN(C)C=O.C(Cl)(=O)C([Cl:36])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][C:25]([Cl:36])=[O:27])[CH:6]=[CH:7][C:8]=1[O: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][CH3:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 10 g of product from Example 67, 0.0965 g of dimethylformamide and 150 ml of methylene chloride is added dropwise 3.46 ml of oxalyl chloride. The reaction is stirred at room temperature for 20 hours and the solvent concentrated in vacuo. The residue is dissolved in diethyl ether, filtered and concentrated in vacuo to give 10.5 g of the desired product as colorless needles.
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:27](=[O:28])[NH:26][C:21]1[CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]([Cl:18])[CH:20]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
Et3N (1.7 mL) was added to an ice-cold solution of (S)proline methyl ester hydrochloride (1.31 g) and 3,5-dichlorophenylisocyanate (1,97 g) in CH2Cl2 (40 mL). The mixture was stirred for 3 hours. It was washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/3) afforded (S)-N-[N-(3,5-dichlorophenyl)carbamoyl]proline methyl ester (2.27 g). mp. 110-112° C.; MS (m/z) 339 (M++Na).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[CH:13]=2)=[CH:8][CH:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][N:32]=1>N1C=CC=CC=1>[F:40][C:30]([F:29])([F:41])[C:31]1[N:32]=[CH:33][C:34]([C:35]([N:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[NH:20][C:19]4[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=4[CH:13]=3)=[CH:10][N:11]=2)[CH2:4][CH2:3][O:2][CH3:1])=[O:36])=[CH:38][CH:39]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)cc2n(CCC)c1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Solvent: c1ccncc1
Product: CCCn1c(=O)c2[nH]c(-c3ccc(N(CCOC)C(=O)c4ccc(C(F)(F)F)nc4)nc3)cc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
9a (40 mg) was dissolved in pyridine (5 mL) at room temperature. 6-(Trifluoromethyl)nicotinoyl chloride (218 mg) was added. The mixture was stirred at room temperature for 24 h. After quenching with ice, the crude product was purified by column (26 g silica gel, RT Scientific) (CH2Cl2:MeOH=100:0 to 98:2) to give the 10a (43 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][O:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.ClCl>CN(C)C=O.ClCCl.CO>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][O:59][CH3:60])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 95 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine in dimethylformamide. Yield: 95%; Rf value: 0.49 (silica gel; dichloromethane/methanol=95:5); C23H25ClN4O3 (440.93); mass spectrum: (M+H)+=441/443 (chlorine isotope).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[N:66][C:67]([C:70]#[N:71])=[CH:68][CH:69]=1>>[C:70]([C:67]1[N:66]=[CH:65][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:69][CH:68]=1)#[N:71]
Reactant: N#Cc1ccc(N)cn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 37.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol), was reacted with diisopropylethylamine (0.37 g, 2.9 mmol), diphenylphosphinic chloride (0.27 g, 1.1 mmol), then reacted with 3-amino-6-cyanopyridine (Aldrich) (0.1 g, 0.9 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (6-cyano-pyridin-3-yl)-amide as a yellow solid (Yield 0.12 g, 38%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH3:15][C:16]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][C:3]=2[CH3:14])=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)c(C)c2)o1

Procedure:
Example 23 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 27).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1.[CH:13]1[C:14](/[CH:29]=[N:30]/[OH:31])=[CH:15][CH:16]=[N+:17]([CH2:19][N+:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[N:27]/[OH:28])=[CH:22][CH:21]=2)[CH:18]=1.[Br-:32].[Br-].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>N1C=CC=CC=1>[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[CH:15]1[C:14](/[CH:29]=[N:30]/[OH:31])=[CH:13][CH:18]=[N+:17]([CH2:19][N+:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[N:27]/[OH:28])=[CH:24][CH:25]=2)[CH:16]=1.[Br-:32].[Br-:32]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC=C1CCCCCO
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCC2=CCCC2=O)cc1

Procedure:
Treatment of 2-(5-hydroxypentyl)-2-cyclopentenone methoxime (Example 25) with p-toluenesulfonyl chloride in pyridine in the manner described in Example 18 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885 cm-1.