Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH:4]([CH3:9])[CH:3]1[CH:10]([OH:13])[CH2:11][CH3:12]>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH:4]([CH3:9])[CH:3]1[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(O)C1C(C)C=C(C)CC1C
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CCC(=O)C1C(C)C=C(C)CC1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
1-(2,4,6-Trimethyl-cyclohex-3-enyl)-propan-1-ol (182 g, 1.0 mol) dissolved in acetone (400 mL) was added dropwise to a solution of chromium trioxide (CrO3, 108 g, 1.08 mol) in aqueous sulfuric acid (H2SO4, 400 mL, 172 g in water) at −10° C. The resulting mixture was aged for 2 hours as the mixture warmed to 0° C. The mixture was then diluted with water and extracted with toluene. The organic layer was concentrated by rotary evaporation and distilled via fractionation to provide 1-(2,4,6-trimethyl-cyclohex-3-enyl)-propan-1-one (113 g, 63% yield) as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Br[CH:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17]([CH:16]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:21][CH3:22])=[O:18]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCC(Br)C(=O)OC
Product: CCC(Oc1ccc(C(=O)OC)cc1[N+](=O)[O-])C(=O)OC

Procedure:
Using methyl 4-hydroxy-3-nitrobenzoate and methyl 2-bromobutyrate, the title compound was synthesized in a similar manner to Reference Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:23]=[N+:24]([CH3:26])[CH3:25].COC1C=C(C=CC=1OC)C=O.CNC>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]([N:24]([CH3:26])[CH3:25])[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: Fc1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(c2c(-c3ccc(F)cc3)[nH]c3ccccc23)N(C)C)cc1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-fluoro-phenyl)-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].[H-].[Na+].Cl.O1CCOCC1>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:17]([C:18](=[O:19])[NH2:20])[C:15]#[N:16])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C#N)C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Starting material 25 (10 g, 50 mmol) and cyanacetamide (26, 8.4 g, 100 mmol) were dissolved in dry THF and NaH (60% ig, 4 g, 100 mmol) was added. The reaction was stirred over night at ambient temperature. Now it was cooled to 0° C. and 4 N HCl/Dioxan was added. The reaction mixture was concentrated in vacuo, the solid residue crystallized with 400 ml isopropyl ethyl ether, resulting crystals were filtered and dried. Then the crystals were washed with water and again filtered and dried. Thereby 8.9 g of the desired product 27 (67%, 34 mmol) were isolated.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[NH:23]=[C:22]1[N:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]2=[N:1][CH:15]=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Nc1nccc2ccccc12
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnc2c3ccccc3ccn2c1=N
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
A mixture of 1-aminoisoquinoline (14.4 g., 0.10 mole) and ethyl ethoxymethylenecyanoacetate (16.9 g., 0.10 mole) was plunged into an oil bath at 105°-110° and kept there for 10 minutes under a nitrogen atmosphere. During this time the mixture melted, evolved ethanol and set solid. The solid was crystallized from toluene to give bright yellow crystals (18 g., 67% yield) of ethyl 4-imino-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate, m.p. 197°-199°. Another recrystallization from toluene provided an analytical sample, m.p. 199°-201°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)cc1OC

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and corresponding 3,4-dimethoxyphenyl boronic acid (182 mg, 1.0 mmol) to afford after chromatographic purification the title compound (92 mg, 42%). 1H NMR (CDCl3, 300 MHz) δ7.15 (s, 1H), 7.11 (s, 1H), 7.01-7.04 (m, 2H), 6.89 (d, 1H, J=8.0 Hz), 4.02-4.10 (m, 1H), 3.92 (d, 6H, J=8.1 Hz), 3.64-3.78 (m, 1H), 2.82-3.52 (m, 8H), 1.82-1.90 (m, 2H), 1.49 (s, 9H) ppm. MS-ApCI: 437 [M+H+].
Reaction SMILES: C(O[CH:4]=[C:5]1[S:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])C.[Na].[CH2:13]([SH:15])[CH3:14].O>C(O)C>[CH2:13]([S:15][CH:4]=[C:5]1[S:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH3:14]
Reactant: CCS
Reactant: CCOC=C1SC(=O)NC1=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCSC=C1SC(=O)NC1=O
Reaction time: 3 h

Procedure:
To a suspension of 5.20 g of 5-(ethoxymethylene)thiazolidine-2,4-dione (1:1.71 mixture with thiazolidine-2,4-dione, about 13.9 mmol) in 50 ml of ethanol, 5.0 g (59 mmol) of ethanethiol sodium salt was added at room temperature, followed by stirring under heating conditions for 3 hours. After cooling, the reaction mixture was poured into water and adjusted to a pH level of about 2. The resulting precipitate was collected by filtration, washed with water and then with n-hexane/diethyl ether and dried to yield 1.38 g (52.0%, light yellow powder) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:17]([O-])=O)[C:6]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:7][CH:8]=1)#[N:2]>CO.O1CCOCC1.[Pd]>[NH2:17][C:5]1[C:6]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-cyano-2-(trans-4-hydroxycyclohexylamino)-3-nitropyridine (3.35 g) in methanol (17 mL) and dioxane (17 mL) was added 10% palladium on activated carbon (383 mg) under nitrogen atmosphere. The mixture was shaken at room temperature under hydrogen atmosphere (3 atm) for 3 hours. The reaction mixture was filtered through a celite pad. The filtrate was concentrated in vacuo to give 3-amino-5-cyano-2-(trans-4-hydroxycyclohexylamino)pyridine (3.15 g) as a brown amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[C:18]([Mg]Cl)([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+]>C1COCC1>[CH3:19][C:18]([C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][C:6]3[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:15](=[O:16])[C:10]2=[N:11][CH:12]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cnc2c(c1)CCc1cc(Cl)ccc1C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 20.05 grams (82.28 mmol) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 400 ml of dry THF at -72° C. and under an atmosphere of nitrogen was added dropwise over 40 minutes 66.0 ml of 2.7M t-butyl magnesium chloride in THF. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was then poured into 10% aqueous ammonium chloride and extracted four times with CH2Cl2. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, along with 8-chloro-11-(1,1-dimethyl-1-ethyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol. These compounds were separated via flash chromatography to give the title compound, which was recrystallized from isopropyl ether to give 4.37 grams (18%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C=C(CC(N[C@@H](C2C=CC=CC=2)C(N[C@H]2[C@@H](C3C=CC=CC=3)SCCNC2=O)=O)=O)C=C(F)C=1.[Br:59]C1C=C(C=O)SC=1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[C:21]([Br:59])[CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Agent: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)N[C@@H]1C(=O)NCCS[C@@H]1c1ccccc1)c1ccccc1
Product: COC(=O)/C(=C/c1cc(Br)cs1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that the reaction product was passed through a Dowex ion exchange resin 50×2-200 and 4-bromo-2-thiphenecarboxaldehyde (955 mg) was used as the aldehyde component to afford the desired product (1.52 g). 1H NMR (300 MHz, CDCl3) δ 3.79 (s, 3H), 5.24 (s, 2H), 5.99 (br., 1H), 7.20-7.37 (m, 7H), 7.67 (s, 1H). LC/MS: 2.37 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][C@H:12]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:11]1([C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][C@H:12]12
Reactant: O=C(O)c1ccc(O)cc1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(O)cc1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 25 %

Procedure:
The title compound is prepared from 4-hydroxy-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 25% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=294 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([OH:7])[CH:2]=1.CN(C1CCCCC1)C.[CH3:17][N:18]1[C:23](Cl)=[N:22][C:21]([CH3:25])=[N:20][S:19]1(=[O:27])=[O:26]>C(Cl)Cl>[CH3:17][N:18]1[C:23]([O:7][C:3]2[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=2)=[N:22][C:21]([CH3:25])=[N:20][S:19]1(=[O:27])=[O:26]
Reactant: CC1=NS(=O)(=O)N(C)C(Cl)=N1
Reactant: Oc1cccnc1
Solvent: CN(C)C1CCCCC1
Solvent: ClCCl
Product: CC1=NS(=O)(=O)N(C)C(Oc2cccnc2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
17.1 parts of β-hydroxypyridine in 120 parts of methylene chloride and 19.1 parts of N,N-dimethylcyclohexylamine are introduced simultaneously, via 2 feeds, in the course of 15 minutes and at 15°-20° C., into a stirred solution of 29.3 parts of 2,5-dimethyl-3-chloro-2H-1,2,4,6-thiatriazine 1,1-dioxide in 150 parts of methylene chloride. The mixture is stirred for one hour at 25° C., after which the precipitate is filtered off under suction and the filtrate is washed with water and with dilute sodium carbonate solution, dried over magnesium sulfate, chromatographed over neutral aluminum oxide and then evaporated down under reduced pressure to give 26 parts (68.6% of theory) of 2,5-dimethyl-3-(pyrid-3-yloxy)-2H-1,2,4,6-thiatriazine 1,1-dioxide of melting point 137°-138° C. (compound No. 1).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[C:18]4[N:19]([CH:28]=[CH:29][N:30]=4)[C:20]([C:23]4[CH:24]=[N:25][NH:26][CH:27]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(C)C.Br[CH2:32][C:33]([NH2:35])=[O:34]>>[NH:25]1[CH:24]=[C:23]([C:20]2[N:19]3[CH:28]=[CH:29][N:30]=[C:18]3[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([CH:7]4[CH2:8][CH2:9][N:4]([CH2:32][C:33]([NH2:35])=[O:34])[CH2:5][CH2:6]4)=[CH:15][CH:14]=3)=[N:22][CH:21]=2)[CH:27]=[N:26]1
Reactant: NC(=O)CBr
Reactant: CC(C)N1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)CC1
Product: NC(=O)CN1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)CC1

Procedure:
This compound may be prepared using the methods described for Compound 202, using 2-bromoacetamide in Step 1. LCMS: Rt=0.73 min (100%), m/z (ESI) 417 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2([C:43]3=[CH:44][C:45]4[O:49][CH2:48][O:47][C:46]=4[CH:50]=[C:42]3[O:41][CH2:40]2)[C:32]1=[O:51].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O>>[CH3:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]3([C:43]4=[CH:44][C:45]5[O:49][CH2:48][O:47][C:46]=5[CH:50]=[C:42]4[O:41][CH2:40]3)[C:32]2=[O:51])=[CH:18][CH:17]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C)nc2)cc1
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 10.21, and making non-critical variations using (6-methylpyridin-3-yl)methyl 4-methylbenzenesulfonate to replace 2-bromomethyl-5-(trifloromethyl)furan, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-[(6-methylpyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (56%), which was treated with 2.0 M HCl in diethyl ether to give the title compound: 1H NMR (300 MHz, CD3OD) δ 8.77 (s, 1H), 8.46 (dd, 1H), 7.91 (d, 1H), 7.33 (t, 1H), 7.24-7.09 (m, 3H), 6.52 (s, 1H), 6.14 (s, 1H), 5.86 (s, 2H), 5.18 (s, 2H), 4.93-4.85 (m, 1H), 4.71 (d, 1H), 2.77 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 180.0, 157.6, 155.1, 150.6, 146.6, 143.8, 142.7, 141.2, 135.7, 133.5, 130.3, 129.5, 125.3, 125.2, 120.5, 110.3, 103.8, 103.0, 94.3, 81.5, 59.7, 41.5, 19.5; MS (ES+) m/z 387.4 (M+1).
Reaction SMILES: C(OC([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:14][CH:13]=3)=O)(C)C.C[Li].[Cl-].[NH4+].[O:45]1CC[CH2:47][CH2:46]1>>[CH2:24]([O:23][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:32])=[O:33])[C:10]1[CH:9]=[N:8][C:7]([C:46](=[O:45])[CH3:47])=[C:19]([CH2:20][O:21][CH3:22])[C:18]2=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Product: COCc1c(C(C)=O)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: -60 °C
Reaction time: 4 h

Procedure:
8.4 g of 6-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid isopropyl ester is dissolved in 500 ml absolute tetrahydrofuran and cooled to -60° C. 15 ml of a 1.5 molar ethereal methyllithium solution is added drop by drop to this solution under argon atmosphere and then stirred for another 4 hours at -60° C. After heating to room temperature the reaction solution is mixed with saturated ammonium chloride solution, extracted with methylene chloride, dried and concentrated by evaporation. The resulting crude product is chromatographed on silica gel with cyclohexane: ethyl acetate=8:2. 4.1 g of 6-benzyloxy-4-methoxymethyl-3-acetyl-9-tosyl-β-carboline with a melting point of 173-175° C. is obtained.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:9])(=[NH:8])[CH2:6][CH3:7].[C:10](OC)(=[O:16])[CH2:11][C:12](OC)=[O:13]>CO>[OH:13][C:12]1[CH:11]=[C:10]([OH:16])[N:9]=[C:5]([CH2:6][CH3:7])[N:8]=1
Reactant: CCC(=N)N
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1nc(O)cc(O)n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a cooled, stirred solution of 25% sodium methoxide (1200 ml, 5.55 mole) was added a slurry of 200 g (1.85 mole) of propionamidine hydrochloride in 300 ml of methanol. Next, 244 g (1.85 mole) of dimethyl malonate was added and the mixture was permitted to warm to about 20° C., after which it was stirred for 16 hours. The mixture was evaporated in vacuo and water (about 2 l) was added. This mixture was neutralized with concentrated hydrochloric acid to provide a white precipitate which was separated by filtration to provide 230 g (96%) of 4,6-dihydroxy-2-ethylpyrimidine, m.p. 312°-215° C. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:26]([NH:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH3:37][CH:38]([CH2:40][C@H:41]([NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C:42](OC1C=CC([N+]([O-])=O)=CC=1)=[O:43])[CH3:39]>CN(C)C=O>[NH:54]([C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C@H:41]([C:42]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:26]([NH:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:43])[CH2:40][CH:38]([CH3:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
26.5 g of H-Asn-Asn-Phe-NHNH-BOC are dissolved in 58 ml of warm dimethylformamide, a solution of 24.2 g of Z-Leu-ONP in 16 ml of dimethylformamide is added at room temperature, and the mixture is stirred until it solidifies. After standing overnight the mixture is triturated with ether, filtered off, dissolved in 190 ml of dimethylformamide, and the product reprecipitated by adding dropwise to 1.5 liters of ether. The product is filtered off and washed with ether until free of nitrophenol. Rf = 0.45 in the system chloroform-methanol (7:3) on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([F:14])[CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[CH3:26][S:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[NH:36][CH:35]=[CH:34]2>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[C:33]3[C:37](=[C:29]([CH2:28][S:27][CH3:26])[CH:30]=[CH:31][CH:32]=3)[NH:36][CH:35]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([F:14])[CH:3]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CCC(O)(CC)c1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(Cl)cc1F)c1c[nH]c2c(CSC)cccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
600 mg (2.77 mmol) of the compound from Example 146A, 585 mg (2.64 mmol) of indium(III) chloride and 301 mg (2.64 mmol) of trifluoroacetic acid were added to 446 mg (2.52 mmol) of the compound from Example 8A in 15 ml of dichloromethane. The reaction mixture was stirred at 80° C. for 1 h. After cooling to RT, the reaction solution was mixed with dichloromethane and silica gel, and the solvent was removed in a rotary evaporator. The residue was purified twice by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) and twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 208 mg (22% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH:17]=[CH2:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29](Br)[CH:30]=[CH2:31]>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:16][CH:17]=[CH2:18])[CH2:9][CH:10]([CH2:31][CH:30]=[CH2:29])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: C=CCN(CCC(=O)OCC)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(CN(CC=C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Yield: 48.4 %

Procedure:
To a solution of ethyl N-(tert-butoxycarbonyl)-3-(2-propenylamino)propionate (1.12 g, 4.86 mmol) was added 1N solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (THF) (5.8 mL) and allyl bromide (1.46 mL, 17.0 mmol) successively at −78° C. The mixture was stirred at 0° C. for an hour, then quenched by a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of ethyl acetate and n-hexane (1:20) to give ethyl N-(tert-butoxycarbonyl)-2-(2-propenyl)-3-(2-propenylamino)propionate (0.7 g, 2.35 mmol, 48.4%) as a colourless oil.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(OCC)(=O)C>[C:25]([O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OC(C)=O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate [synthesized by the method described in Tetrahedron Lett., 46(3), 447-450 (2005)] (10 g, 38.3 mmol), pyridine (100 mL) and acetic anhydride (18.1 mL, 192 mmol) was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with 1 N hydrochloric acid and brine, and dried over magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Elution solvent: hexane/ethyl acetate=4/1) to obtain 9.65 g of the title compound as a colorless oil (83%).