Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[C:27]1([CH:33]([O:40][C:41]([C:43]2[N:48]3[C:49](=[O:52])[C@@H:50]([NH2:51])[C@H:47]3[S:46][CH2:45][C:44]=2[CH:53]([S:55][C:56]2[NH:60][N:59]=[N:58][N:57]=2)[CH3:54])=[O:42])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN1CCOCC1>[C:27]1([CH:33]([O:40][C:41]([C:43]2[N:48]3[C:49](=[O:52])[C@@H:50]([NH:51][C:16](=[O:18])[CH2:15][C:13]4[S:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:11][CH:12]=4)[C@H:47]3[S:46][CH2:45][C:44]=2[CH:53]([S:55][C:56]2[NH:60][N:59]=[N:58][N:57]=2)[CH3:54])=[O:42])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)s3)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
5.43 g of 2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetic acid are dissolved in 200 ml of methylene chloride containing 2.20 ml of 4-methyl-morpholine, the solution, from which moisture is kept excluded, is cooled to -20° C. and 2.86 ml of chloroformic acid isobutyl ester are added dropwise. After 30 minutes, a solution of 9.35 g of 7β-amino-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester in 100 ml of methylene chloride is added, after which stirring is continued for one hour at -20° C. and for 16 hours whilst slowly warming to room temperature. The mixture is poured out onto ice-cold water, the organic solution is separated off and the aqueous phase is again extracted with 100 ml of methylene chloride. The organic extracts are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. Crystallisation of the residue from a mixture of methyl acetate and diethyl ether gives 7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(1-methyl-5-tetrazolylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel): Rf= 0.38 (system: chloroform/ethyl acetate/acetic acid, 80:19:1); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): shoulders at 242 mμ (ε=16,400) and 274 mμ (ε=9,200); infrared absorption spectrum (in mineral oil): characteristic bands at 3.03μ, 5.58μ, 5.79μ, 6.12μ and 6.51μ.
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.[H-].[Na+].[CH3:18]I.Cl>CN(C=O)C.C(OCC)C.C(O)C.O>[ClH:1].[CH3:18][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C:3]1[O:2][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: c1ccc2oc(-c3ncc[nH]3)cc2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOCC
Product: Cn1ccnc1-c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the free base (7.0 g) generated from 2-(benzofuran-2-yl)imidazole hydrochloride in DMF (50 ml) at 0° C. was added sodium hydride (1.4 g) 80% in mineral oil in three equal portions. After 30 minutes at room temperature, methyl iodide (2.5 ml) was added dropwise over 15 minutes at 0° C. The mixture was then stirred for 30 minutes at room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with water and the product was extracted with hydrochloric acid (1M). The aqueous layer was basified with sodium hydroxide and the free base was extracted with ethyl acetate, washed with saturated brine and dried. Evaporation of the solvent gave a solid residue which was dissolved in diethyl ether/ethanol. Ethereal HCl was added to solution and the precipitated salt was collected by filtration (8.1 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1Cl)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1Cl)C2
Yield: 199.7 %

Procedure:
A mixture of 7-(2,5-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g), aminoguanidine hydrochloride (0.43 g), concentrated hydrochloric acid (0.82 ml), water (0.82 ml) and ethanol (30 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue recrystallized from water to give 7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 120) (1.3 g) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13])([OH:3])=O.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[O:14]1[CH2:15][CH2:16][C:11]2([S:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:1]2=[O:3])[C:12]1=[O:13]
Reactant: O=C(O)c1ccccc1SC1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C1OCCC12Sc1ccccc1C2=O
Temperature: 140 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
A mixture of 15.5 g of α-[(2-carboxyphenyl)thio]-γ-butyrolactone, 100 ml of acetic anhydride and 20 ml of triethylamine is stirred at 140° C. for 3 hours, at the end of which time the solvent is distilled off. To the residue is added ice-water and the resultant precipitate is recovered by filtration and recrystallized from ethanol. By the above procedure there is obtained 9.4 g of 4',5'-dihydrospiro[benzo[b]thiophene-2(3H), 3'(2'H)-furan]3,2'-dione as pale-yellow platelets melting at 125°-127° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:36])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=3)=[N:18][N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Br>CO.O.ClCCl>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:36])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH:24]=3)=[N:18][N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)nncc2c1
Agent: Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3=CCNCC3)nncc2c1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 4-(6-(5-(cyclopropylcarbamoyl)-2-methylphenyl)phthalazin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 206 μmol) (Method B) in 2 mL methanol was stirred at RT was treated with 1 mL HBr 48% in H2O. The mixture was stirred for 2 h from 0° C. to RT. The mixture was diluted with 20 mL dichloromethane, washed with 1N NaOH to pH11. The mixture was extracted with dichloromethane (3×20 mL). The combined organics were washed with 20 mL brine, dried over anhydrous Na2SO4, concentrated via vacuum and purified by silica gel chromatography eluting with 10% 2M ammonia methanol/dichloromethane to give the title compound as a pale yellow solid. Found MS (ES+): 385(M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1.[CH:22](OCC)(OCC)OCC>C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=4[CH:11]=3)[CH:22]=[N:21][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CSc1nc2ccc(CNc3ccc(Br)cc3N)cc2o1
Solvent: O=CO
Product: CSc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
A mixture of 4-bromo-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (465 mg, 2.40 mmol), triethyl orthoformate (3.8 mL), and HCOOH (0.06 mL) was stirred at 90° C. for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 petroleum ether/ethyl acetate to give 6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole as a light brown solid (327 mg, 68.3%). 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.85 (s, 1H), 7.68 (s, 1H), 7.55-7.60 (m, 2H), 7.30-7.37 (m, 2H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 375 (M+H)+.
Reaction SMILES: [C:1]([CH:4]([CH2:14][C:15]#[C:16][C:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].C(C(CC#C[C@@H](O)CCCCC)CCCCCCC(O)=O)(=O)C>>[C:1]([CH:4]([CH2:14][CH2:15][CH2:16][C:17]1([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)C(CC#CC1(O)CCCCC1)CCCCCCC(=O)O
Agent: CCCCC[C@H](O)C#CCC(CCCCCCC(=O)O)C(C)=O
Product: CC(=O)C(CCCCCCC(=O)O)CCCC1(O)CCCCC1

Procedure:
This compound is prepared essentially by the same hydrogenation procedure described in Example 36, Step C, except that 8 -acetyl-11-(1-hydroxycyclohexyl)-10-undecynoic acid (Example 39) is substituted for 8-acetyl-12-(S)-hydroxy-10-heptadecynoic acid. The product is obtained as a yellowish viscous oil; pmr (CDCl3) δ 2.08 (3H,s CH3CO), δ6.52 (2H,s OH and COOH). Anal. Calcd. for C19H34O4 : C, 69.90; H, 10.50; Found: C, 70.23; H, 10.70.
Reaction SMILES: Cl.C([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)=[CH:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)CCC>>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:22]1[NH:26][CH:25]=[CH:24][N:23]=1)=[CH:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCOc1ccccc1C(=CSc1ccccc1)c1ncc[nH]1
Agent: Cl
Product: Oc1ccccc1C(=CSc1ccccc1)c1ncc[nH]1

Procedure:
After adding an equivalent amount of hydrogen chloride to 100 mg of an oily substance which was Isomer B (Compound 66) of 1-(2-n-butyloxyphenyl)-1-imidazolyl-2-phenylthioethylene obtained from Compound 62 in the same manner as in Example 10, the resultant precipitate was recrystallized from ethyl acetate/acetone to obtain 75 mg of Isomer B (Compound 95) of 1-(2-n-butyloxyphenyl)-1-imidazolyl-2-phenylthioethylene hydrochloride as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH2:22][N:30]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:27])=[O:28]
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Reactant: C1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCCCC5)c4)cc23)CCS1(=O)=O
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 25.1 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.093 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and acetic acid (0.056 mg, 0.929 μmol) was added, hexahydro-1H-azepine (0.453 mL, 4.02 mmol) was added. The mixture was left stirring 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (399 mg, 0.929 mmol). The vial was sealed and the mixture heated in a microwave 10 minutes at 100° C. The sodium triacetoxyborohydride polymer bound was removed by filtration, and the mixture was run through prep HPLC from 10% acetonitrile containing 0.1% TFA to 50% acetonitrile containing 0.1% TFA in 25 minutes. The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([N:24]=[CH:25][N:26]=3)[C:10](=[O:23])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1.O1CCCC1.Cl.C(=O)(O)[O-].[Na+]>O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[C:12]3[N:13]=[C:4]([CH:3]=[O:2])[CH:5]=[CH:6][C:7]=3[C:8]3=[N:26][CH:25]=[N:24][N:9]3[C:10]2=[O:23])=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3ccc(C(OC)OC)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3ccc(C=O)nc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
8-(Dimethoxymethyl)-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (682 mg, 1.79 mmol), tetrahydrofuran (20 ml), water (5 ml) and 12 N hydrochloric acid (3 ml) were combined and stirred at room temperature for 20 hours. The mixture was neutralized slowly with powdered sodium bicarbonate to pH 8. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried (MgSO4) and concentrated to afford 516 mg (77%) of the aldehyde as a yellow foam, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.73-3.81 (m, 3H), 5.83, (s, 2H), 6.85 (d, J=8.66 Hz, 2H), 7.64 (d, J=8.53 Hz, 2H), 8.03 (d, J=7.78 Hz, 1H), 8.42 (s, 1H), 8.83 (d, J=7.91 Hz, 1H), 10.22 (s, 1H). LCMS (MH+, 336.1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][N:11]([CH:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[C:10](=[O:26])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C.Cl>[CH2:1]([CH:8]1[CH2:12][N:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:10](=[O:26])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(Cc2ccccc2)CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1NC(Cc2ccccc2)CN1C1CCNCC1
Reaction time: 16 h
Yield: 89.7 %

Procedure:
10% palladium on carbon (10 mg) was added to a solution of 4-benzyl-1-(1-benzylpiperidin-4-yl)imidazolidin-2-one (30 mg, 0.086 mmol) in ethanol (15 mL) and concentrated hydrochloric acid (0.05 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (40 psi). After 16 h, the mixture was filtered and concentrated to give the title compound (20 mg). MS 260.3 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:44][CH2:45][CH2:46][NH2:47]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:47][CH2:46][CH2:45][F:44])=[O:21])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: NCCF
Agent: Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NCCF)(CC1)CC2
Yield: 77.5 %

Procedure:
In a similar manner to Example 13, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-fluoroethylamine hydrochloride (11.2 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-2-fluoroethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (33.9 mg).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]([NH:17][C:18]([CH:20]1[N:24]2[C:25](=[O:44])[CH:26]([NH:31][C:32]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)=[O:33])[CH2:27][CH:28]=[CH:29][CH2:30][CH:23]2[CH2:22][CH2:21]1)=[O:19])[CH2:9][C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11])(C)(C)C.P([O-])([O-])([O-])=O>C1COCC1.N1C=CC=CC=1>[OH:6][CH2:7][CH:8]([NH:17][C:18]([CH:20]1[N:24]2[C:25](=[O:44])[CH:26]([NH:31][C:32]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=3)=[O:33])[CH2:27][CH:28]=[CH:29][CH2:30][CH:23]2[CH2:22][CH2:21]1)=[O:19])[CH2:9][C:10]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])=[O:11]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C(CC(=O)NS(C)(=O)=O)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)CC(CO)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 6-[(Naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid [1-(tert-butyl-dimethyl-silanyloxymethyl)-3-methanesulfonylamino-3-oxo-propyl]-amide (160 mg, 0.24 mmol) in THF (6 mL) at 0 C. is added HF in pyridine (0.3 mL). The solution is stirred at 0 C. for 1 h, poured into pH=7 phosphate buffer, and extracted with CH2Cl2. The combined organic extracts are washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue obtained is purified by flash chromatography on silica gel (CH2Cl2/MeOH) to yield 86 mg of desired product. 1H NMR (CDCl3) δ 8.34 (s, 1H), 7.91–7.79 (m, 4H), 7.49 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 5.88 (m, 2H, 5.45 (m, 1H), 4.43 (m, 1H), 4.20 (m, 2H), 3.04 (s, 3H), 3.80–1.80 (series of m, 12H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Li+].CC([N-]C(C)C)C.BrC1C=CN=CC=1[Li].CN([CH:28]=[O:29])C>>[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: Brc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Product: O=Cc1cnccc1Br

Procedure:
Following the procedure of Gribble and Saulnier, Tetrahedron Lett., 21:4137-4140 (1980)) reacting 4-bromopyridine HCl (Aldrich) with 2 eq of LDA, and reacting the 4-bromo-3-lithiopyridine with DMF provided 4-bromo-3-pyridinecarboxaldehyde, which was converted to the title compound by DIBAL reduction. MS: 188 & 190 (M+H)+ ; 1H NMR (CDCl3) δ: 8.66 (s, 1H), 8.36 (d, J=6 Hz, 1H), 7.52 (d, J=6 Hz, 1H), 4.82 (d, J=6 Hz, 2H), 2.12 (t, J=6 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+].CO.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 27.3 %

Procedure:
5.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-mannopyranosylurea are dissolved in 20 ml of formic acid, and 3.5 g of sodium nitrite are added gradually thereto for 2 hours under ice-cooling and stirring. 40 ml of methanol and 30 g of potassium carbonate anhydrate are added to said mixture. Then, said mixture is further stirred for 10 minutes under ice-cooling. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.6 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-mannopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1>C(O)C.[Fe]>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3cc(N)ccc3s2)cc1
Temperature: 80 °C

Procedure:
Iron powder (45.9 g, 0.822 mol), water (70 ml) and 37% hydrochloric acid (1.6 ml, 0.019 mol) are added to 2-(4-methoxyphenyl)-5-nitrobenzothiazole (10.95 g, 0.038 mol) in ethanol (300 ml). The mixture is heated at 80° C. for one hour. The resulting mixture is filtered and evaporated, and the residue is taken up in ethyl acetate and basified with NaOH (pH=11). The organic phase is filtered and washed with water. The resulting solution is evaporated and the product obtained is recrystallized from isopropyl ether. Yield: (61%); Rf (9/1 chloroform/methanol): 0.60; Elem. anal. C14H12N2OS; theory C, 65.60; H, 4.72; N, 10.93. found C, 65.44; H, 4.87; N, 10.37. IR (KBr): 3440, 3320, 1600, 1465, 1245, 1170 cm−1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[N:37][CH:38]=2)[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:39][C:35]1[CH:36]=[N:37][CH:38]=[C:33]([N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH:34]=1)=[C:3]([CH3:26])[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCC[C@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCC[C@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using (S)-tert-butyl 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidine-2-carboxylate (260 mg, 0.68 mmol) and 5-morpholinopyridin-3-amine in toluene to give (S)-tert-butyl 1-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)pyrrolidine-2-carboxylate. 1H NMR (CDCl3) δ ppm 7.80 (1H, d, J=2.2 Hz), 7.65-7.75 (2H, m), 7.07-7.17 (1H, m), 6.90 (1H, br. s.), 6.60 (1H, ddd, J=13.1, 8.8, 2.5 Hz), 4.71 (1H, t, J=7.0 Hz), 3.83-3.94 (1H, m), 3.77-3.83 (4H, m), 3.67-3.77 (1H, m), 3.15-3.26 (4H, m), 2.28-2.43 (1H, m), 2.21 (3H, s), 2.08-2.19 (1H, m), 1.90-2.06 (2H, m), 1.45 (9H, s). Mass Spectrum (ESI) m/e=526.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:21][SH:22])[NH:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9].C(N(CC)CC)C.[C:31](Cl)(=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:21][SH:22])[NH:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])[CH3:14])[CH3:9].[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:21][SH:22])[N:5]([C:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])[CH3:14])[CH3:9]
Reactant: O=C(Cl)CCc1ccccc1
Agent: COC(=O)[C@H](CS)NCC=C(C)CCC=C(C)CCC=C(C)C
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CS)N(CC=C(C)CCC=C(C)CCC=C(C)C)C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Farnesyl-L-Cysteine methyl ester (FCM) was synthesized as described in Ma et al., Methods Enzymol. 250, 226-34 (1995). The FCM (1 g) was dissolved in approximately 100 ml of acetone followed by the addition of triethylamine (TEA, 1 ml) and 1 g of hydrocinnamoyl chloride. This was stirred for 2 h at room temperature. The solvent was removed under reduced pressure, the residue dissolved in 150 ml of ethylacetate and washed three times with water. The ethylacetate layer was dried with anhydrous sodium sulfate, filtered and the ethylacetate removed under reduced pressure. The residue was purified by silica gel chromatography to obtain hydrocinnamoyl-farnesyl-L-Cysteine methyl ester (HCFCM). The purified HCFCM was then analyzed by Electron Spray Ionization Mass Spectrometry (ESI-MS).