Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:24](=[O:31])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: O=C(O)c1cccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)c1cccnc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Temperature: -30 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To solution of 12.7 ml (1 M in THF, 13 mmol) of lithium hexamethyldisilylazide cooled to −78° C. under Ar was added, drop wise, a solution of 3.8 g (12 mmol) of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) in 20 ml of THF. The mixture was brought to −30° C. and stirred for 1 h. Separately, 0.6 g (5 mmol) of nicotinic acid was added to 0.8 g (5 mmol) of 1,1-carbonyl diimidazole in 10 ml of CH2Cl2 and the mixture stirred for 1 h after which time it was concentrated to dryness. The crude residue was re-dissolved in 10 ml of THF under Ar and cooled to −30° C. The enolate solution of intermediate 7B (described above) was then added by cannula to the crude imidazolide solution and the mixture was allowed to reach room temperature. After 2 h the reaction was diluted with EtOAc, washed with saturated ammonium chloride solution, the organic phase dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:1] afforded 1.2 g (58%) of the title compound as an orange oil. MS: 437.2 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]([CH3:18])=[CH:8][C:9]=1OS(C(F)(F)F)(=O)=O)(=[O:3])[CH3:2].[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[C:5](=[O:25])[N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]([CH3:18])=[CH:8][C:9]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:26]([CH3:28])[CH3:27])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c(C(C)=O)c1=O
Reactant: CC(C)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(C(C)=O)c1=O

Procedure:
A mixture of 3-acetyl-4-trifluoromethylsulfonyloxy-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 2 above (2.5 g, 7.2 mmol), 2-isopropylbenzeneboronic acid (1.8 g, 11 mmol), potassium carbonate (1.5 g, 11 mmol), and Pd(PPh3)4 (1.7 g, 1.4 mmol) was heated to reflux under inert atmosphere for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using a gradient elution of 25-75% EtOAc:hexanes to give the title compound (0.72 g; HPLC RT=21.79 min, method B).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[NH:6])(=[O:3])[CH3:2].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)=O>CN(C=O)C>[F:20][C:19]([F:21])([F:22])[O:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[NH:7][CH:9]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 30 %

Procedure:
Acetyl guanidine (2.6 g, 25.7 mmol, 3.0 eq) was dissolved in anhydrous DMF (40 mL) and 2-bromo-1-(4-trifluoromethoxy-phenyl)-ethanone (2.4 g, 8.6 mmol, 1.0 eq) was added; the mixture was stirred at room temperature for 4 days. DMF was removed under reduced pressure, the residue was washed with water, filtered and dried over sodium sulphate; after crystallization from MeOH 0.7 g of the title compound were recovered (yield 30%).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:22]2[CH:21]([CH2:20][CH2:19][CH2:18][C:17]2=[O:23])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CCCC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCC2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl-methoxymethyl-trimethylsilanylmethyl-amine (29.6 g, 0.12 mol) was added to a solution of cyclohex-2-enone (10 g, 0.104 mol) in 500 mL of dichloromethane at 0° C. followed by the dropwise addition of 10 mol % TFA dissolved in 2 mL of dichloromethane. The reaction mixture was stirred at room temperature overnight and was quenched with 50 mL of saturated NaHCO3. The organic layer was washed with 500 mL of brine, dried with MgSO4 and solvent was evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using a 2-45% ethylacetate-hexane gradient to afford the subtitle compound. (13.8 g, 60%). MS calculated for C15H19NO +H: 230, observed: 230.
Reaction SMILES: C(NC1SC=C(/C(=N/OC)/C(O)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.N[C@@H:40]1[C:60](=[O:61])[N:42]2[C:43]([C:57]([OH:59])=[O:58])=[C:44](CSC3N(NC=O)N=NN=3)[CH2:45][S:46][C@H:41]12>ClCCl.CC(N(C)C)=O.C(N(CC)CC)C>[S:46]1[C@@H:41]2[CH2:40][C:60](=[O:61])[N:42]2[C:43]([C:57]([OH:59])=[O:58])=[CH:44][CH2:45]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC=O)CS[C@H]12
Agent: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Reaction time: 0.25 h

Procedure:
2.66 g of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid and 3 ml of dimethylacetamide were dissolved in 50 ml of dichloromethane, and a solution of 0.78 ml of oxalyl chloride in 2 ml of dichloromethane was added gradually thereto at -17° to -15° C. under stirring. After the mixture was stirred at the same temperature for 10 minutes, a solution of 3.22 g of 7β-amino-3-[(1-formamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid and 3.66 g of triethylamine in dichloromethane (40 ml)-dimethylacetamide (30 ml) was added dropwise thereto at -17° to -13° C. for 15 minutes. Then, the mixture was stirred at -18° for 3 hours. After the reaction, the mixture was evaporated under reduced pressure to remove solvent. Water was added to the residue, and the aqueous solution was washed with ethyl acetate, adjusted to pH 3 with citric acid and then extracted twice with a mixture of 20 ml of ethyl acetate and 5 ml of tetrahydrofuran. The extracts were combined, washed with water, dried and evaporated under reduced pressure to remove solvent. Ether was added to the residue thus obtained, whereby 2.87 g of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-formamido-1H)-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid were obtained as pale brown powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1>[Pd].CO.O1CCCC1>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(N)c([N+](=O)[O-])cc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2nc(N)c(N)cc2c1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
10 mg of palladium on charcoal (10% Pd) are added to a solution of 0.64 g of 2-amino-3-nitro-6-methoxyquinoline (compound B3) in 40 ml of methanol/tetrahydrofurane 1:1. After hydration for 0.5 h, the catalyst is filtered off and the filtrate is concentrated in vacuo. 0.38 g of the title compound are obtained as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][N:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:29][CH:28]=3)[CH3:26])=[CH:16][CH:15]=2)[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][N:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:29][CH:28]=3)[CH3:26])=[CH:18][CH:19]=2)[C:8]([OH:10])=[O:9])=[CH:39][CH:40]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NOCCOc1ccc(CC(Oc2ccc(Cl)cc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 35.6 %

Procedure:
To a solution of ethyl 2-(4-chlorophenoxy)-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate (500 mg) obtained from Reference example 2 in ethanol (8 ml) was added an aqueous sodium hydroxide solution (1N, 1.79 ml), and the resulting solution was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, hydrochloric acid (1N) was added thereto to neutralize the solution, and then ethyl acetate was added thereto to extract the target compound. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by chromatography on a silica gel column (eluant; methylene chloride/methanol=9/1) to afford the target compound (169 mg) as a colorless foam.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@H:23]([N:25]2[C:30](=[O:31])[C:29]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][NH:27][C:26]2=[O:37])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C@H:23]1([N:25]2[C:30](=[O:31])[C:29]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[CH:28][NH:27][C:26]2=[O:37])[O:24][C@H:20]([CH2:19][OH:18])[CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](OC[C@@H]1CC[C@@H](n2c(=O)[nH]cc(-c3cccs3)c2=O)O1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1[nH]cc(-c2cccs2)c(=O)n1[C@@H]1CC[C@@H](CO)O1

Procedure:
1-(2,3-Dideoxy-5- O-tert-butyldiphenylsilyl-α-D-ribofuranosyl-5-(2-thienyl)uracil (0.15 g) was dissolved in tetrahydrofurane, 1M in tetrabutylammonium fluoride (3 ml) and stirred at ambient temperature for 1 hour. The solvent was evaporated and the product was purified by separation on preparative thin layer chromatography (silica-1 mm, ethyl acetate-methanol 9-1) to give 1, (2,3-dideoxy-α-D-ribofuranosyl)-5-(2-thienyl)uracil. TLC (silica, ethyl acetate-methanol 9-1) Rf 0.54.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])/[C:6](/[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:7]/[C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.[NH2:40][CH2:41][C:42]1[CH:53]=[CH:52][C:45]([CH:46]=[CH:47][C:48]([O:50][CH3:51])=[O:49])=[CH:44][CH:43]=1.C(N(CC)CC)C>O>[CH:1]1([NH:4][C:5](=[O:24])/[C:6](/[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:7]/[C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:40][CH2:41][C:42]3[CH:43]=[CH:44][C:45]([CH:46]=[CH:47][C:48]([O:50][CH3:51])=[O:49])=[CH:52][CH:53]=3)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)/C(=C/c1ccc(C(=O)O)cc1)c1ccc(F)cc1
Reactant: COC(=O)C=Cc1ccc(CN)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccc(CNC(=O)c2ccc(/C=C(/C(=O)NC3CC3)c3ccc(F)cc3)cc2)cc1
Reaction time: 8 h
Yield: 87 %

Procedure:
To a suspension of 4-((1E)-3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)benzoic acid (0.3 g, 0.9 mmol, prepared according to the procedure described in Example 99, step-III) in DMF (5 mL) EDCl (0.35 g, 1.8 mmol), HOBt (0.12 g, 0.9 mmol), methyl 4-aminomethylcinnamate (0.237 g, 1.1 mmol), were added followed by triethylamine (0.4 mL, 3 mmol). The reaction mixture was stirred for 8 hours after which the mixture was poured to cold water (100 mL), the white precipitate formed was filtered, washed with water (1×150 mL), dried under vacuum to afford the title compound as a yellow solid (0.4 g, 87% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH:12]1[C:24]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][NH2:36])[C:31]([OH:33])=[O:32])=[O:28])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH:21]1[C:22]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][NH:36][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:31]([OH:33])=[O:32])=[O:28])[C:24]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCNC(=O)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl chloride (83 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (160 mg, 57%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:21])[CH:3]=1.BrC1C=CC(C(O)=O)=C(C)C=1.N1(C2CCNCC2)CCCC1.BrC1C(C)=C(C(N2CCC(N3CCCC3)CC2)=O)C=CC=1.[F:65][C:66]([F:77])([F:76])[C:67]1[CH:68]=[C:69](B(O)O)[CH:70]=[CH:71][CH:72]=1>>[CH3:21][C:4]1[CH:3]=[C:2]([C:71]2[CH:70]=[CH:69][CH:68]=[C:67]([C:66]([F:77])([F:76])[F:65])[CH:72]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(Br)ccc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: C1CCN(C2CCNCC2)C1
Agent: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)ccc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2-methyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (prepared from 4-bromo-2-methyl-benzoic acid and 4-pyrrolidin-1-yl-piperidine in analogy to the procedure described for the preparation of intermediate 2) was reacted with 3-trifluoromethyl-phenyl boronic acid to give the title compound as off-white amorphous solid. MS: 417.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([NH:20][NH2:21])=[O:19]>C(O)(C)C>[CH3:16][O:17][C:18]([NH:20][N:21]=[C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: COC(=O)NN
Reactant: O=C1CCCCC1=Cc1ccc(Cl)cc1
Solvent: CC(C)O
Product: COC(=O)NN=C1CCCCC1=Cc1ccc(Cl)cc1
Yield: 93.2 %

Procedure:
33.32 g (0.151 moles) of 2-(p-chlorophenylmethylene)-cyclohexan-1-one and 13.5 g (0.151 moles) of N-methoxycarbonyl hydrazine are dissolved in 230 ml of isopropanol. The reaction mixture is boiled for a few hours, then cooled, clarified with activated carbon, filtered, the filtrate is cooled and the separated crystals are filtered off. 41.2 g of the named compound are obtained. Yield: 93.2%. M.p.: 160.5°-162° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:20])([C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15])[CH2:6][CH2:5]2.[O:22]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:22][C:7]([CH3:20])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:21])[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: CCCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: [Ce+4]
Agent: [NH4+]
Product: CCCNC(=O)C(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O

Procedure:
Oxidation as described in protocol B, using 90.6 mg (0.311 mmol) of 6-hydroxy-2,5,7,8-tetramethyl-N-propylchroman-2-carboxamide and 374.9 mg CAN (0.684 mmol) yielded 2-hydroxy-2-methyl-N-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow powder.
Reaction SMILES: [C-:1]#[N:2].C[Mg+].[Br-].[CH2:6]1[CH2:10]O[CH2:8][CH2:7]1>CCOCC>[N:2]1([N:2]2[CH2:1][CH2:10][CH2:6][CH2:7][CH2:8]2)[CH2:1][CH2:10][CH2:6][CH2:7][CH2:8]1
Reactant: C1CCOC1
Reactant: [C-]#N
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: C1CCN(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
The cyanide (4.87 g, 15 mmol) was taken up in THF (75 ml). CH3MgBr (25 ml of a 3.0 M solution in Et2O) was added to the reaction mixture at 0° C. The solution was allowed to warm to 25° C. and was stirred at that temperature for 18 h. The solution was partitioned between 25 wt % aqueous solution of sodium citrate and EtOAc. The aqueous layer was extracted with EtOAc. The combined EtOAc layers were washed with brine and dried (Na2SO4). Filtration and concentration gave a yellow oil. Purification via flash chromatography (95/5 to 90/10 EtOAc/MeOH. SiO2) gave 3.7 g (79%) of the piperidino-piperidine 12 as a yellow gum.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:11]/[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc3ccccc3n2)cc1OC
Yield: 62.7 %

Procedure:
2-Quinolinecarboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (225 mg) through Method A (production step 2), to thereby yield the target product (yield: 252 mg, 63%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][C:16]#[C:17][CH3:18])[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:30][N:31]=[C:32]=[O:33]>C(Cl)Cl>[CH3:30][NH:31][C:32](=[O:33])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][C:16]#[C:17][CH3:18])[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: CC#CN=C1CCc2c1n(C)c1ccc(O)cc21
Reactant: CN=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC#CN=C1CCc2c1n(C)c1ccc(OC(=O)NC)cc21
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-ol (3.4 g) in CH2Cl2 (15.0 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (326 mg) followed by the dropwise addition of methyl isocyanate (0.8 g) in CH2Cl2 (5.0 ml). The reaction was monitored via TLC and after 1.0 hour, the solution was concentrated and the crude product was purified via flash chromatography eluting with hexane/acetone (2:1). The product which precipitated out of the pure fractions was collected to give 4-methyl-3-propynylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-yl methylcarbamate (1.2 grams) and the fractions were concentrated to give an additional 0.9 gram.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:38][C:39]1[S:40][C:41]2[CH:47]=[C:46]([O:48][S:49]([C:52]3[CH:57]=[CH:56][C:55]([NH:58][CH2:59][CH2:60][N:61]([CH:65]([CH3:67])[CH3:66])[CH:62]([CH3:64])[CH3:63])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[CH:45]=[CH:44][C:42]=2[N:43]=1>CN(C)C=O.O>[C:1]([NH:38][C:39]1[S:40][C:41]2[CH:47]=[C:46]([O:48][S:49]([C:52]3[CH:57]=[CH:56][C:55]([NH:58][CH2:59][CH2:60][N:61]([CH:65]([CH3:67])[CH3:66])[CH:62]([CH3:63])[CH3:64])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[CH:45]=[CH:44][C:42]=2[N:43]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCN(C(C)C)C(C)C)cc3)cc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.6 %

Procedure:
28 mg of acetic acid, 177.5 mg of HBTU and 163 μl of DIEA are added to a solution of 4-(2-diisopropylaminoethylamino)benzenesulfonic acid 2-amino-benzothiazol-6-yl ester (intermediate 34) (70 mg, 0.156 mmol) in 4 ml of dimethylformamide. The solution obtained is stirred for 20 hours at room temperature. After addition of 50 ml of water, the reaction mixture is extracted with 3 times 25 ml of ethyl acetate. The extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 130 mg of crude oil. This oil is purified by LC/MS to give 15 mg of 4-(2-diisopropylamino-ethylamino)benzenesulfonic acid 2-acetylaminobenzothiazol-6-yl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]#[N:38]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:36][C:37]#[N:38])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:3]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#CCBr
Reactant: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC#N)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1-methyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenol (0.173 g, 0.472 mmol) was reacted with K2CO3 (0.078 g, 0.566 mmol) and bromoacetonitrile (0.068 g, 0.566 mmol) in acetone (10 ml) to give the product (0.160 g, 0.392 mmol, 83%) as a white solid, mp 101-102° C. 1H NMR (DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.14-1.22 (m, 4H), 1.52-1.98 (m, 2H), 2.66 (t, J=7.5 Hz, 2H), 3.56 (s, 3H), 5.21 (s, 2H), 7.16 (d, J=8.9 Hz, 2H), 7.43-7.51 (m, 5H), 7.55 (t, J=7.2 Hz, 2H), 7.69 (d, J=8.9 Hz, 2H), 7.76 (d, J=1.1 Hz, 1H); [ESI(+)], m/z 409 (M+H)+.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[C:24]([F:39])[C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[CH:37][C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].O>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[C:24]([F:39])[C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[C:37]([I:8])[C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2occ(-c3ccc4c(c3F)CCN4C(=O)Cc3cc(F)ccc3F)c12
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2occ(-c3ccc4c(c3F)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of NIS (130 mg, 0.578 mmol) in DMF (2 mL) was added dropwise to a solution of 3-{1-[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (190 mg, 0.449 mmol) in DMF (2.5 mL) at −40° C., and the mixture was stirred and allowed to slowly warm to room temperature. It was stirred for 25 hours then poured into water (25 mL) and stirred for a few minutes. The precipitate was collected by vacuum filtration. The damp solid was then rinsed into another filter flask using DCM (50 mL), and the filtrate was dried (Na2SO4), filtered, and concentrated in vacuo to give 3-{1[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-amine (252 mg) as a dark solid. LC/MS (ES) m/z=550 [M+H]+.