Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:7]1)=O.B.CO>O1CCCC1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:9]2[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:6]([CH2:4][CH2:3][O:2][CH3:1])[CH2:7][CH:8]2[C:28]([O:30][CH3:31])=[O:29])(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: COCC(=O)N1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A mixture of 1.6 g (3.57 mmol) of methyl 1-(methoxyacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate and 32 ml of borane in tetrahydrofuran (1.0M) was refluxed under nitrogen overnight. Methanol was added and the solvent removed. To the residue was added 25 ml of CH2Cl2 and 25 ml of 2N HCl and the mixture stirred at room temperature for 1 hour. The organic layer was separated and washed with H2O and concentrated to dryness. The residue was triturated with ethyl acetate-hexane, cooled and filtered to give 1.2 g of white crystals, m.p. 86°-90° C.; Mass spectrum (ES) 435.4 (M+H). Anal. for C21H26N2O6S: Calc'd: C,58.1; H,6.0; N,6.5; Found: C.58.5; H,6.0: N,6.5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([OH:20])=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.FC(F)(F)C(O)=O.[CH:44]1([NH:48][C:49]([C@@H:51]2[CH2:55][CH2:54][CH2:53][NH:52]2)=[O:50])[CH2:47][CH2:46][CH2:45]1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([N:52]2[CH2:53][CH2:54][CH2:55][C@H:51]2[C:49](=[O:50])[NH:48][CH:44]2[CH2:45][CH2:46][CH2:47]2)=[O:20])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)O)c2ccccc2n1
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2 g of 4-Carboxymethoxy-quinoline-2-carboxylic acid ethyl ester in 20 ml of DMF, 2.8 g of EDC, 2.7 g of pentafluorophenol was added and the reaction mixture was stirred at RT for 2 h. Then, 3.1 g of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 1.7 g of NEM in 10 ml of DMF was added. After 16 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.4 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:9])[CH2:7][CH3:8].[Al+3].[Cl-].[Cl-].[Cl-].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:4]1[CH:3]=[C:2]([C:6](=[O:9])[CH2:7][CH3:8])[S:1][CH:5]=1
Reactant: BrBr
Reactant: CCC(=O)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCC(=O)c1cc(Br)cs1
Temperature: 0 °C

Procedure:
A 47.3 g (338 mmol) sample of 1-(2-thienyl)-1-propanone (Aldrich) was dissolved in 225 mL of CHCl3 and 101.3 g (760 mmol) of AlCl3 was added with stirring. To this mixture was added a solution of bromine (57.5 g, 360 mmol) in 375 mL of CHCl3. The mixture was stirred at room temperature over night then poured into 500 mL of ice water. The organic layer was separated, washed with water (2×200 mL), dried over MgSO4, filtered and evaporated to yield 81 g of the crude title compound, which was taken directly to the next step. mp 40°-41° C.; MS: 158 (M+H)+, 236 (M+NH4)+ ; NMR (CDCl3) δ: 1.22 (t, 3H, J=7.5 Hz), 2.91 (q, 2H, J=7.5Hz), 7.51 (d, 1H), 7.60 (d, 1H). IR (KBr): 2960, 1670, 1400, 1220 cm-1.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14][Br:15])[NH:8][CH2:7][CH2:6]2.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([CH2:13][CH2:14][Br:15])[NH:8][CH2:7][CH2:6]2.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19]
Reactant: COc1ccc2c(c1)CCN[C@@H]2CCBr
Agent: BrB(Br)Br
Agent: NC(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCN[C@@H]2CCBr
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a solution of 6-methoxy-1-(R)-(2-bromoethyl)-3,4-dihydro-1H-isoquinoline-trifluoroacetamide (390 mg, 1.07 mmol) obtained in step (c) of Example 190 in dichloromethane (5 ml) was added 1M solution of boron tribromide in dichloromethane (2.14 ml, 2.14 mmol) gradually at −78° C. with stirring. The resulting mixture was further stirred at −78° C., and after confirming the disappearance of the starting material by thin layer chromatography, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and after raising the temperature to ambient temperature, the resulting mixture was extracted with ethyl acetate. The extract was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1) as the eluent to afford the title compound (280 mg, yield: 75%) as a colorless oil.
Reaction SMILES: [ClH:1].N[C:3]1[C:4]([C:10]#[N:11])=[N:5][C:6]([I:9])=[CH:7][N:8]=1.N([O-])=O.[Na+]>O>[Cl:1][C:3]1[C:4]([C:10]#[N:11])=[N:5][C:6]([I:9])=[CH:7][N:8]=1
Reactant: N#Cc1nc(I)cnc1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1nc(I)cnc1Cl
Temperature: -50 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
64.3 ml of hydrochloric acid is added at −5° C. to 7.7 g (31.3 mmol) of 3-amino-6-iodopyrazine-2-carbonitrile. At this temperature, a sodium nitrite solution (4.32 g, 62.6 mmol) dissolved in 9 ml of water is added to the reaction mixture and is stirred for 4 hours at −50° C. and then at room temperature overnight. Another equivalent of sodium nitrite is added to the reaction mixture and the precipitate formed is filtered, rinsed with water and dried at 50° C. to yield 3.65 g (44%) of 3-chloro-6-iodopyrazine-2-carbonitrile in the form of a beige solid.
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([CH2:16][NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][CH:19]=3)=[N:13][C:12]=2[CH:27]=1)=[O:7])[CH2:3][CH3:4].[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:1].[CH2:2]([N:5]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([CH2:16][NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[NH:25])[NH2:26])=[CH:20][CH:19]=3)=[N:13][C:12]=2[CH:27]=1)=[O:7])[CH2:3][CH3:4]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCN(CCC(=O)O)C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1
Yield: 75 %

Procedure:
Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 75% of theory, C22H25N5O3S (439.54); Rf value: 0.14 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid); EKA mass spectrum: (M+H)+=440; (M+H+Na)++=231.6.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:35]([O:37][CH3:38])=[O:36]>>[CH3:38][O:37][C:35]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:36]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid methyl ester was prepared according to General Procedure E by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with methyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.94-2.06 (m, 4H), 3.09-3.14 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.61 (s, 3H), 4.02-4.10 (m, 2H), 4.98-5.04 (m, 1H), 7.59-7.61 (m, 2H), 8.02-8.04 (m, 2H), 8.35 (s, 1H), 8.54 (s, 1H). Mass spectrum MH+=432.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)=[CH:5][CH:4]=1.C(O)(=O)C.C([O-])(O)=O.[Na+]>Br>[OH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:20]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccc(OC)nc2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccc(O)nc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 11a (240 mg, 0.527 mmol) in hydrobromic acid (5.00 mL of a 33 wt. % acetic acid solution) was heated to 60° C. in a sealed tube. After 20 h, the reaction mixture was cooled to rt and was added to said. aq. NaHCO3. The resulting mixture was extracted with EtOAc, and combined organics were concentrated in vacuo to give a crude residue that was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 11b. m/z (ES) 428 (MH)+.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].Cl>O1CCOCC1>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[C:11](=[O:20])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]2=[O:19])=[CH:7][CH:6]=[N:5][NH:4]1
Reactant: COc1nnccc1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1Cc1ccn[nH]c1=O
Yield: 100.9 %

Procedure:
2-[(3-Methoxypridazin-4-yl)methyl]isoindoline-1,3-dione (1.15 g, 4.27 mmol) in 1,4-dioxane (90 mL) was refluxed with 12 M hydrochloric acid (2 mL) for 1 hour. After completion of the reaction, the solvent was removed by vacuum distillation to give the desired product (1.1 g, 100% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(OCCCCl)cc2)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-hydroxy-4′-methylbiphenyl (194 mg), potassium carbonate (720 mg) and 1-bromo-3-chloropropane (517 μL) in N,N-dimethylformamide (1.5 mL) affords 274 g of 4-(3-chloropropoxy)-4′-methylbiphenyl.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=1[Cl:21])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:21][C:14]1[CH:15]=[C:16]([F:20])[CH:17]=[C:18]([Cl:19])[C:13]=1[N:12]1[CH:11]=[C:5]2[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]2=[N:1]1
Reactant: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc(F)cc1Cl
Solvent: Cc1ccccc1
Product: Fc1cc(Cl)c(-n2cc3cncc(F)c3n2)c(Cl)c1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A suspension of [1-(4-azido-5-fluoropyridin-3-yl)-meth-(E)-ylidene]-(2,6-dichloro-4-fluorophenyl)-amine (14.7 mmol) in toluene (40 mL) was heated under reflux for 16 hours then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in cyclohexane) to afford the title compound as an off-white solid (3.38 g, 77% yield). LCMS (Method D): RT=2.84 min, m/z: 300 [M+H+].
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]12[CH2:11][CH:8]([CH2:9][CH2:10]1)[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]2=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)(O)[O-].[Na+]>C(=S)=S>[C:1]([CH:9]1[CH:8]2[CH2:11][CH:5]([C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=32)[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)C1CCC2C1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)C1CC2CC1c1ccccc12
Temperature: 0 °C

Procedure:
30 cm3 of acetyl chloride are added to a solution of 30 g of benzonorbornene in 400 cm3 of carbon disulphide and then 10.5 g of anhydrous aluminum chloride are added gradually in small quantities over approximately 2 hours. At this stage, the complete conversion of the starting product is checked by thin-layer chromatography. The reaction mixture is then poured into two litres of ice water and then neutralized with sodium bicarbonate. After three extractions with ether, the ether phase is dried over sodium sulphate and then concentrated. 38 g of an orange oil which corresponds to the expected product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:21][NH:22][C:23]2=[O:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CN)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)NCc3ccccc32)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
The obtained 1-(tert-butoxycarbonyl)-4-[(2-aminomethylphenyl)amino]-piperidine (219 mg) was dissolved in toluene (5 ml), added with 1,1′-carbonyldiimidazole (128 mg) and stirred at 100° C. for 1.5 hours. The reaction mixture was added with water (10 ml) and extracted twice with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:2→1:3) to obtain 130 mg of the title compound. Yield: 17% (for the three steps).
Reaction SMILES: [CH:1]1([CH:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:18]([O:21][CH3:22])[O:19][CH3:20])[NH:10][C:9]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=[C:8]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CC(C)=O.O>[CH:1]1([C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:18]([O:19][CH3:20])[O:21][CH3:22])[N:10]=[C:9]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:8]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1=C(C(OC)OC)NC(C(OC)OC)=C(C(=O)OCC)C1C1CCCCC1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1c(C(OC)OC)nc(C(OC)OC)c(C(=O)OCC)c1C1CCCCC1
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
To a solution of diethyl 4-cyclohexyl-2,6-bis(dimethoxymethyl)-1,4-dihydropyridine-3,5-dicarboxylate (30.7 g, 67.54 mmol) in acetone (450 mL) was added a solution of ceric ammonium nitrate (75.05 g, 135.08 mmol) in water (125 mL) fairly rapidly at room temperature. After stirring for 10 minutes, the resulting solution was concentrated to remove the acetone. Water (300 mL) was added and the mixture was extracted with CH2Cl2 (3×500 mL). The organic phase was washed with brine (600 mL), dried (MgSO4), and evaporated to afford 29.23 g of diethyl 4-cyclohexyl-2,6-bis(dimethoxymethyl)pyridine-3,5-dicarboxylate as an oil. The oil was chromatographed on silica gel using hexane/ethyl acetate mixtures to give single spot material: 1H NMR (CDCl3) δ 5.37 (s, 2H) 4.32 (q, J=7.2 Hz, 4H) 3.33 (s, 12H) 2.4-2.6 (m, 1H) 1.0-1.8 (m, 16H); 13C NMR (CDCl3) δ 167.79, 153.25, 151.44, 128.68, 104.01, 61.51, 54.41, 52.18, 44.41, 31.10, 27.19, 25.85, 14.04; MS (HR-ESI) m/z 460.2534 [M+Li]+ (460.2523 calcd for C23H35NO8Li).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH3:3].CN(CCC1CC=CC=1)C.[Cl-:26].[Cl-].[Cl-].[CH:29]1([Zr+3:34])[CH:33]=[CH:32][CH:31]=[CH:30]1.[Cl-].[Cl-].[Cl-].C[Zr](C)(C)(C)(C)C1C=CC=C1>>[Cl-:26].[Cl-:26].[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[Zr+2:34][CH:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1)[CH3:3]
Reactant: [Zr+3]C1C=CC=C1
Reactant: CN(C)CCCC1C=Cc2ccccc21
Agent: C[Zr](C)(C)(C)(C)C1C=CC=C1
Agent: CN(C)CCC1=CC=CC1
Agent: [Cl-]
Product: CN(C)CCCC1C([Zr+2]C2C=CC=C2)=Cc2ccccc21
Yield: 40 %

Procedure:
Example 1 was repeated in the same manner as described except that 1-(N,N-dimethylaminopropyl)indene was substituted for (N,N-dimethylaminoethyl)cyclopentadiene and that cyclopentadienylzirconium trichloride was substituted for pentamethylcyclopentadienylzirconium trichloride. The yield was 40.0%. The physical properties of the product are as follows:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[NH:13][C:12]1=[O:29])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:30]([C:33]1[S:34][CH:35]=[CH:36][C:37]=1[CH2:38]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:30]([C:33]1[S:34][CH:35]=[CH:36][C:37]=1[CH2:38][N:13]1[C:14]2[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:17][CH:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:12]1=[O:29])(=[O:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: CC(=O)c1sccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1sccc1CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21
Reaction time: 1.5 h
Yield: 57.9 %

Procedure:
To a suspension of sodium hydride (0.119 g of a 60% dispersion in mineral oil) in dry N,N-dimethylformamide (8 ml) was added dropwise a solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5- (2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.005 g) in dry N,N-dimethylformamide (5 ml) under stirring at cooling in an ice-bath. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1.5 hours. To the mixture was added a solution of 2-acetyl-3-bromomethylthiophen (0.82 g) in N,N-dimethylformamide (3 ml) under cooling in an ice-bath. The mixture was stirred under the same condition for 30 minutes and then at ambient temperature overnignt. The reaction mixture was concentrated in vacuo. The residue was treated with ethyl acetate and water. The organic layer seas washed with water and a brine, and dried over sodium sulfate. Removal of the solvent at reduced pressure gave a crude product. The crude product was purified by column chromatography on silica gel with chloroform as an eluent to give (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.80 g).
Reaction SMILES: [O:1]([CH2:19][C:20]1([CH2:28][CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[N+:35]([O-:37])=[O:36])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:26][C:23]1([CH3:27])[O:24][CH2:25][C:20]([CH2:19][OH:1])([CH2:28][CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[N+:35]([O-:37])=[O:36])[CH2:21][O:22]1
Reactant: CC1(C)OCC(CCn2ccnc2[N+](=O)[O-])(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)OCC(CO)(CCn2ccnc2[N+](=O)[O-])CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
46 mg (0.088 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-1,3-dioxane was dissolved in 1 mL of tetrahydrofuran, 0.11 mL (1 mol/L solution, 0.11 mmol equivalents) of a solution of tetrabutylammonium fluoride in tetrahydrofuran was added thereto, and the mixture was stirred at room temperature (25° C.) for 1 hour. After completion of the reaction, the solvent was removed by distillation, and the obtained crude product was purified by silica gel column chromatography (eluent: chloroform/methanol (v/v)=10/1) to give 25 mg (0.086 mmol equivalents) of 2,2-dimethyl-5-hydroxymethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-1,3-dioxane.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][C:16]([O:18]C)=[O:17])(=[O:4])=[O:3].O.[OH-].[Li+]>C1COCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][C:16]([OH:18])=[O:17])(=[O:3])=[O:4]
Reactant: COC(=O)Cn1ccc2c(NS(C)(=O)=O)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cccc2c1ccn2CC(=O)O
Yield: 89.9 %

Procedure:
To a solution of methyl 2-(4-(methylsulfonamido)-1H-indol-1-yl)acetate (620 mg, 2.196 mmol) in a 1:1 mixture of H2O and THF (10 ml), lithium hydroxide (526 mg, 21.96 mmol) was added, and the mixture was reacted for 1 hour at room temperature. The organic solvent was evaporated and 1N HCl was added to the aqueous residue (pH=2); the aqueous phase was extracted with ethyl acetate (3×20 ml), and the combined organic layers were dried over sodium sulfate. The crude was purified by flash chromatography on silica gel column (DCM:MeOH=95:5) affording 2-(4-(methylsulfonamido)-1H-indol-1-yl)acetic acid (530 mg, 1.975 mmol, 90% yield). MS/ESI+ 269.1 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([C@H:6]([CH3:17])[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[CH:8]=1)[NH2:5].[C:19]([O:23][C:24]([NH:26][C@@H:27]([C:35](O)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([CH:6]([CH3:17])[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:16])[CH:8]=1)[NH:5][C:35](=[O:36])[C@@H:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25]
Reactant: COC(=O)[C@H](N)[C@H](C)c1cn(C)c2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)[C@@H](Cc1ccccn1)NC(=O)OC(C)(C)C)C(C)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
To a solution of (αR,βR)-1,β-dimethyltryptophan methyl ester (6.36 g) and Nα -t-butoxycarbonyl-3-(2-pyridyl)-D-alanine (6.65 g) in dry methylene chloride (250 ml) was added dicyclohexylcarbodiimide (5.15 g), and resulting mixture was stirred for 1.5 hours at room temperature. After evaporation of the solvent, crude residue was taken up with ethyl acetate (200 ml), filtered, washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate, treated with active charcoal, and evaporated. Nα -[N-t-Butoxycarbonyl-3-(2-pyridyl)-D-alanyl]-1,β-dimethyl-D-tryptophan methyl ester (10.54 g) was obtained as an oil.