Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.Br[CH2:35]/[CH:36]=[CH:37]/[C:38](Cl)=[O:39].[Cl-].[Na+].[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH:20][C:38](=[O:39])[CH:37]=[CH:36][CH2:35][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: C1COCCN1
Reactant: O=C(Cl)/C=C/CBr
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCOCC1
Yield: 47.8 %

Procedure:
To a mixture of 1.2 g (3.5 mmol) of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-amino-quinoline-3-carbonitrile and 2.44 ml (14 mmol) of Hunig's base in 50 ml of dry THF at 0° C., with stirring, was added a THF solution containing 2.57 g (14 mmol) of 4-bromo crotonyl chloride dropwise. The mixture was stirred for an additional hour at 0° C. 50 ml of saturated sodium chloride solution was added to the reaction mixture, then it was extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and then was added to a solution of 4.58 ml (52.5 mmol) morpholine in 5 mL of THF at 0° C. dropwise. The solution was stirred an overnight at 0° C. The mixture was poured into diluted sodium bicarbonate solution . The organic layer dried over sodium sulfate. Chromatography gave 0.83 grams off-white solid: mass spectrum (electrospray, m/e): M+H 496.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[CH:21]=[O:22].CC(=CC)C.C1C[O:31]CC1.[O-]Cl=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[C:21]([OH:31])=[O:22]
Reactant: O=CC1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Reactant: C1CCOC1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound 4a (335 mg, 1.00 mmol) and 2-methyl-2-butene (1.06 ml, 10.01 mmol) were dissolved into 50 ml THF. A freshly prepared solution of 80% NaClO2 (339 mg, 3.00 mmol) and NaH2PO4.H2O (414 mg, 3.00 mmol) in 55 ml of t-BuOH/H2O 5:1 was added. The reaction mixture was stirred in room temperature for 6 hours. The reaction was quenched with water and extracted CH2Cl2. The organic phase was extracted with sat. NaHSO4. The water phase was then made acidic with HCl and extracted with CH2Cl2. the organic layer was washed with brine and dried over Na2SO2. After filtration the solvent was evaporated ant the product recrystallized from ethanol.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH2:5].C(N(CC)CC)C.[CH:19]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[C:23]=2[CH:22]=[CH:21][N:20]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH:5][S:29]([C:24]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:28]=2[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:31]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: NCC(CN)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Reaction time: 4 h
Yield: 61 %

Procedure:
In 50 ml of a chloroform solution containing 11.55 g of 1,3-diamino-2-phenylpropane and 1.33 g of triethylamine was added dropwise 30 ml of a chloroform solution containing 3.5 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 10° C. to 20° C. for four hours, and the reaction mixture solution was washed with water and dried with anhydrous potassium carbonate. After the chloroform was distilled therefrom, the residue thus obtained was subjected to a silica gel column chromatography (silica gel: 90 g; solvent: 5% methanol/chloroform (volume ratio)) to give 3.20 g of N-(3-amino-2-phenylpropyl)-5-isoquinolinesulfonamide in a yield of 61%.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([OH:8])[CH2:6][CH2:5][O:4]1.[H-].[Na+].[CH2:11]([O:18][CH2:19][CH2:20]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:18][CH2:19][CH2:20][O:8][CH:7]1[CH2:6][CH2:5][O:4][CH:3]1[O:2][CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC1OCCC1O
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1OCCC1OCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-tetrahydro-furan-3-ol in DMF 200 mL was added sodium hydride in small portions with stirring at 0° C. for 2 hrs, then 2-Benzyloxy-ethanol was added from the dropping funnel over a period of 1 hour, the resulting mixture was stirred at 25° C. for 15 hrs, it was poured into 400 mL water, EtOAC (1 L) were added and separated. The organic layer was washed with sat. NaHCO3 (500 mL), dried over Na2SO4, filtered and concentrated, The residue was purified by column chromatography (PE:EA=5:1) to yield 10 g of 3-(2-Benzyloxy-ethoxy)-2-methoxy-tetrahydro-furan (oil).
Reaction SMILES: [CH3:1][C:2]([OH:5])([CH3:4])[CH3:3].Cl[S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8].[Cl:13][C:14]1[C:15]([C:36]([NH:38][CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[O:37])=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([N:24]1[CH2:28][CH2:27][C@H:26]([NH:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25]1)[CH:18]=[CH:17]2.C(N(CC)CC)C>ClCCl.O>[Cl:13][C:14]1[C:15]([C:36]([NH:38][CH2:39][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)=[O:37])=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([N:24]1[CH2:28][CH2:27][C@H:26]([N:29]([S:7]([NH:10][C:11]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:12])(=[O:9])=[O:8])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25]1)[CH:18]=[CH:17]2
Reactant: CCOC(=O)CN[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN([C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-methyl-2-propanol (140 mg) in dichloromethane 2 mL) was added over 15 minutes to a stirred solution of chlorosulfonyl isocyanate (0.17 mL) in dichloromethane (16 mL) under nitrogen at 0° C. The mixture was allowed to warm to room temperature over 2 hours and was then added over 20 minutes to a stirred solution of N-[(3S)-1-[6-chloro-5-[[(cyclohexylmethyl)amino]carbonyl]-2-quinolinyl]-3-pyrrolidinyl]-glycine, ethyl ester (Example 112 (a)) (490 mg) and triethylamine (0.25 mL) in dichloromethane (10 mL) under nitrogen at 0° C. After 3 hours, deionised water (10 mL) was added, the layers were separated and the aqueous fraction was extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. Purification by chromatography (SiO2, dichloromethane:methanol 99:1 as eluant) gave the sub-title compound as a solid (670 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[N:6]=[CH:5][N:4]=1.[H-].[Na+].[Cl:21][C:22]1[C:27]([N:28]=[C:29]=[O:30])=[C:26]([Cl:31])[C:25]([O:32][CH3:33])=[CH:24][C:23]=1[O:34][CH3:35].O>C1COCC1.CCOC(C)=O>[Cl:21][C:22]1[C:23]([O:34][CH3:35])=[CH:24][C:25]([O:32][CH3:33])=[C:26]([Cl:31])[C:27]=1[NH:28][C:29](=[O:30])[N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[N:6]=[CH:5][N:4]=1
Reactant: CNc1cc(Nc2ccccc2[N+](=O)[O-])ncn1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
To a solution of N-methyl-N′-(2-nitro-phenyl)-pyrimidine-4,6-diamine (150 g, 0.61 mmol) in THF (15 mL) was added NaH (60%, 60 g, 1.5 mmol) at 0° C., and the mixture was stirred for 30 minutes at room temperature. A solution of 2,4-dichloro-3-isocyanato-1,5-dimethoxy-benzene (180 g, 0.73 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 2 hours. Water (2 mL) was added to quench the reaction. The mixture was concentrated, and the residue was purified by flash chromatography on silica eluting with DCM:EtOAc=6:1-1:1 to obtain the title compound (54 mg, yield: 18%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.38 (s, 3H), 3.93 (s, 6H), 6.75 (s, 1H), 6.91 (s, 1H), 7.34 (t, 1H), 7.72 (t, 1H), 7.79 (d, 1H), 8.01 (d, 1H), 8.38 (s, 1H), 9.99 (s, 1H), 11.78 (s, 1H); MS (ESI): 493 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][NH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O.O1CCOCC1>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:21]([O:23][CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a stirred solution of N-(3-aminopropyl)-N-methylcarbamic acid tert-butyl ester (2.00 g, 10.6 mmol) and sodium carbonate (2.81 g, 26.6 mmol) in water (7 mL) at 0° C. was added a solution of 9-fluorenylmethyl chloroformate (2.75 g, 10.6 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 2 h and then poured into water (10 mL). This mixture was extracted with diethyl ether (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a clear oil. The oil was purified by silica gel flash chromatography (0-70% EtOAc in hexanes) to give the title compound (4.24 g, 77% yield) as a clear oil (product contained a minor impurity, but was used without further purification).
Reaction SMILES: C1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])C=CC=CC=1.S(Cl)(Cl)=O.[NH3:39]>>[C:12]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH2:39])=[O:33])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: N
Solvent: O=S(Cl)Cl
Product: NC(=O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1

Procedure:
8-(1,4,5-Triphenylimidazol-2-yloxy)octanoic acid was treated with thionyl chloride followed by ammonia to give the title compound, m.p. 152.5°-153.5° C., Found: C, 76.6; H, 7.0; N, 9.1%: C29H31N3O2 requires: C, 76.8; H, 6:9; N, 9.3%
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 54.3 %

Procedure:
4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 3.3 g.), 10% palladium-carbon (1.7 g.), methanol (65 ml.) and tetrahydrofuran (65 ml.) were treated in similar manner to that of Example 11-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.45 g.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][CH2:23][C:24](O)=O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O1CCCC1.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH:10][CH2:24][CH2:23][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH:2]=1
Reactant: NCCCc1cccnc1
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CCCCNCCCc2cccnc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 3-(3-pyridyl)propylamine (517.8 mg, 1.679 mmoles), 4-(3,4-dimethoxyphenyl)butanoic acid (376.5 mg, 1 equiv.) and N-hydroxysuccinimide (193.2 mg, 1.1 equiv.) in methylene chloride (15 mL) at 0° C. was treated with EDC hydrochloride (353.1 mg, 1.1 equiv.). The mixture was allowed to warm to room temperature after 10 minutes. Stirring was continued for 16 hours and then the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was re-extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and evaporated to give a colorless oil. This crude amide was dissolved in dry tetrahydrofuran (5 mL) under argon. The solution was cooled to 0° C. and then treated with 1 M borane-tetrahydrofuran complex (7.0 mL, 4 equiv.). The mixture was heated at reflux for 16 hours and then cooled to room temperature. Dry methanol (10 mL) was added carefully to the stirred mixture to avoid foaming. The resulting solution was evaporated under reduced pressure and the residue dissolved in dry methanol (20 mL). The mixture was heated at reflux for 4 hours and then evaporated. The crude amine was carried on without purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH3:10])=[O:4].CCN(C(C)C)C(C)C.[CH2:22]([O:29][C:30](N1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30](=[O:31])[N:8]([CH2:9][CH3:10])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:11])([F:12])[F:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: CCNCCNC(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
A solution of compound M (24.6 g, 82.4 mmol) and DIEA (14.3 ml, 82.4 mmol) in THF (100 ml) was cooled to ˜5° C., followed by the addition of a solution of N-(benzyloxycarbonyl)succinimide (20.3 g, 81.6 mmol) in THF (75 ml) dropwise over 20 min The temperature of the reaction mixture was raised to room temperature and stirring was continued for an additional 30 min. Solvents were evaporated and the residue was dissolved in EtOAc (500 ml). The organic layer was extracted with 5% aqueous NaHCO3 (2×100 ml) and brine (100 ml). The organic layer was evaporated to provide compound N (24.9 g, 78.2 mmol) as yellowish oil. LC-MS [M+H] 319.0 (C14H17F3N2O3+H, calc: 319.2). Compound N was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][C:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@:9]1([C:14](=[O:16])[NH:36][S:33]([C:30]2([CH3:29])[CH2:32][CH2:31]2)(=[O:35])=[O:34])[CH2:11][C@H:10]1[CH:12]=[CH2:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(S(N)(=O)=O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(C)CC1
Temperature: 85 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
To a solution of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85° C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH˜2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58%) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS: MS m/z 343 (M++1).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([CH2:25][N:26]([CH:28]4[CH2:30][CH2:29]4)[CH3:27])[CH:24]=2)[O:21][C:20]([CH3:32])([CH3:31])[CH2:19][C:18]3([CH3:34])[CH3:33])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>CO.O1CCCC1>[CH:28]1([N:26]([CH2:25][C:23]2[CH:24]=[C:15]([C:14]#[C:13][C:10]3[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:35])=[O:2])=[CH:8][CH:9]=3)[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([CH3:32])([CH3:31])[CH2:19][C:18]3([CH3:33])[CH3:34])[CH3:27])[CH2:30][CH2:29]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cc(C#Cc2ccc(C(C)(C)C(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C)C1CC1
Yield: 20.7 %

Procedure:
A solution of 2-(4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-2-methyl-propionic acid methyl ester (Intermediate 15, 0.040 g, 0.084 mmol) in methanol (2.5 mL) and tetrahydrofuran (2.5 mL) was treated with a 2M solution of sodium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was refluxed overnight. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Preparative reverse phase HPLC on a partisil 10 ODS-3 column using 10% water in acetonitrile as the mobile phase afforded the title compound (0.008 g, 27%).
Reaction SMILES: C(=O)C1C=CC=C(OC)C=1.[CH3:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[N:31](CC3C=CC(OC)=CC=3)[CH:32]=[CH:33][N:34]=2)=[N:24][N:23]=1.C1(OC)C=CC=CC=1.Br>C(O)(=O)C>[CH3:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[NH:34][CH:33]=[CH:32][N:31]=2)=[N:24][N:23]=1
Reactant: COc1ccc(Cn2ccnc2Cc2nnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cc1
Agent: Br
Agent: COc1cccc(C=O)c1
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: Cc1[nH]cnc1CSCCNc1nnc(Cc2ncc[nH]2)c(=O)[nH]1

Procedure:
Substitution of 1-(4-methoxybenzyl)-2-imidazole carboxaldehyde for m-anisaldehyde in the general procedure of Example 1 leads to the production of 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(1-(4-methyoxybenzyl)-2-imidazolylmethyl)-1,2,4-triazin-5-one, which when treated with anisole and hydrogen bromide in acetic acid gives 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(2-imidazolylmethyl)-1,2,4-triazin-5-one
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH:15]=[C:16]([O:21]C)[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@:5]2([C:24]#[CH:25])[OH:23])[CH2:2][CH3:3].Cl.O.CO>CCOCC>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C@@H:13]4[C:18]([CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@:5]2([C:24]#[CH:25])[OH:23])=[CH:17][C:16](=[O:21])[CH2:15][CH2:14]4)[CH2:2][CH3:3]
Reactant: C#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@@]21CCC
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CCC
Yield: 33.6 %

Procedure:
Shake 13β-n-propyl-3-methoxy-17β-ethynyl-gona-2,5(10)-dien-17 -ol (0.31 g.) with a solution prepared by mixing concentrated hydrochloric acid (0.81 cc.), water (0.54 cc.) and methanol (12.15 cc.), until the solid dissolves. After addition of water, work up with ether, purify by recrystallization from cyclohexane to obtain the title compound (0.1 g.), m.p. 149°-50.5°; ultraviolet absorption peak at 240 mμ (ε15,700); infrared absorption peaks at 2.99, 3.06, 6.04, 6.16 μ.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH:27]=[CH2:28])[C:14]=2[CH3:29])=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[C:19]([C:17]1[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH:27]=[CH2:28])[C:14]([CH3:29])=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:10][CH:9]=2)[CH:18]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: C=Cc1c(C)c(C#Cc2ccc(CC(=O)OC)cc2)cc(C(C)(C)C)c1OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=Cc1c(C)c(C#Cc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 104.5 %

Procedure:
A solution of [4-(5-tert-butyl-4-isopropoxy-2-methyl-3-vinyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 146, 0.02 g, 0.049 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was treated with 1M lithium hydroxide (0.5 mL, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 45 minutes. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.020 g, 100%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:22]=3)[CH:17]=[CH:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C1COCC1>[Br:1][C:17]1[C:18]2[C:23](=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[N:15]([C:12]2[CH:11]=[CH:10][N:9]=[CH:14][CH:13]=2)[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ccn(-c4ccncc4)c3c2)CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(Br)cn(-c4ccncc4)c3c2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
N-Bromosuccinimide (64.4 mg, 0.36 mmol) was added to a mixture solution of tert-butyl 4-(1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (137 mg, 0.36 mmol) in THF (12 mL) at −78° C. After stirring at −78° C. for 2 hours, the mixture was further stirred at 0° C. for 1 hour and then pyridine (88 μL, 1.09 mmol) was added. After filtering using a diatomite pad, the solution was adsorbed by adding silica gel. Purification by chromatography (silica gel, EA:Hx=4:1) yielded the target compound (49.1 mg, 30%) as white solid.