Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Mg].[CH2:11]1[O:27][C:14]2([CH2:19][CH2:18][CH:17]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[O:13][CH2:12]1>C1COCC1>[CH2:12]1[O:13][C:14]2([CH2:15][CH2:16][CH:17]([CH:20]3[CH2:25][CH2:24][C:23]([OH:26])([C:2]4[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=4)[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)[O:27][CH2:11]1
Reactant: Fc1ccc(Br)cc1F
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)c(F)c2)CCC(C2CCC3(CC2)OCCO3)CC1

Procedure:
A Grignard reagent was prepared from 1-bromo-3,4-difluorobenzene and magnesium in THF, and a THF solution of bicyclohexane-4,4'-dione monoethyleneacetal was added thereto dropwise while cooling with ice. After allowing the mixture to react at room temperature for 1 hour, the reaction mixture was worked-up in a conventional manner to obtain crude crystals of 4-[4-hydroxy-4-(3,4-difluorophenyl) cyclohexyl]cyclohexanone ethyleneacetal. The crude crystals were dissolved in toluene, and a small amount of potassium bisulfate was added thereto, followed by refluxing for 10 hours while removing water. After cooling to room temperature, water was added to the reaction mixture, and the product was extracted with toluene. The solvent was removed by distillation to obtain white crystals of 4-[4-(3, 4-difluorophenyl)-3-cyclohexyl]cyclohexanone ethyleneacetal. Triethylamine and a catalytic amount of palladium-on-carbon were added to a toluene solution of the product, and the mixture was allowed to react in an autoclave at a hydrogen pressure of 5 kg/cm2 for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The resulting crude product were recrystallized from ethanol to obtain white crystals of 4-[trans-4-(3,4-difluorophenyl) cyclohexyl]cyclohexanone ethyleneacetal. Formic acid was added to a toluene solution of the product, followed by stirring at room temperature for 4 hours. Water was added thereto, and the organic layer was separated, washed with a sodium bicarbonate aqueous solution, and dried. The solvent was removed by distillation, and the residue was recrystallized from ethanol to obtain white crystals of 4-[trans-4-(3, 4-difluorophenyl)cyclohexyl]cyclohexanone. The resulting product was deuterated in the same manner as in (1-a) to obtain 4-[trans-4-(3,4-difluorophenyl)cyclohexyl]cyclohexanone-2,2,6,6-d4. (16-b) Synthesis of 4-[trans-4-(3,4-difluorophenyl) cyclohexyl]cyclohexane-2,2,6,6-d4 carbaldehyde:
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH2:10][CH2:11]Br.N1(N[C:20](=[O:28])[CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])CCCCC1.S(=O)(=O)(O)O>O1CCCC1>[CH2:23]([O:22][C:21]([O:25][CH2:26][CH3:27])([CH2:11][CH2:10][C:4]1[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:9])[CH:20]=[O:28])[CH3:24]
Reactant: CCOC(OCC)C(=O)NN1CCCCC1
Reactant: Cc1cccc(C)c1CCBr
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(C=O)(CCc1c(C)cccc1C)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9 g of magnesium turnings are covered with 400 ml of dry tetrahydrofuran and the mixture is warmed to boiling. To that mixture is then added 2-(2',6'-dimethylphenyl)-1-bromoethane at such a rate that a gentle boiling is maintained. When the magnesium turnings have reacted the solution containing the Grignard reagent is cooled to room temperature. The reaction mixture is then added dropwise, over a period of 3 hours, to a cooled (0°-5° C.) solution of diethoxyacetic acid piperidinyl amide (80.8 g) in 200 ml of dry tetrahydrofuran. After the addition is complete, the reaction mixture is stirred for two hours at about 5° C. The mixture is then poured into a cold 2% sulfuric acid solution (1000 ml). The solution is extracted with toluene and the combined toluene extracts are washed with water and evaporated to dryness to give a residue of about 95 g. The residue is distilled under reduced pressure. The forefraction distilling below 120° C./0.6 mmHg is discarded and the rest, about 66 g, is crude 2-(2',6'-dimethylphenyl)-ethylglyoxal diethyl acetal, which is used without purification in step (b).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCOc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCCCCCCCCCOc2ccccc2)cc1

Procedure:
A mixture of 7.0 g of ethyl p-[(11-phenoxyundecyl)amino]benzoate, 7.0 g of potassium hydroxide and 150 ml of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is made acidic while hot with concentrated hydrochloric acid, diluted with water, cooled and filtered to give white crystals, mp 117°-119° C. Recrystallization from ethanol gives white crystals, mp 118°-119.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]12[CH2:33][C:29]([CH2:34]O)([CH2:30][CH2:31][CH2:32]1)[CH2:28][CH2:27][CH2:26]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:25]12[CH2:33][C:29]([CH2:34][O:11][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])([CH2:30][CH2:31][CH2:32]1)[CH2:28][CH2:27][CH2:26]2
Reactant: OCC12CCCN(CCC1)C2
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(OCC12CCCN(CCC1)C2)c1c[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of indole-3-carboxylic acid (1.62 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.70 g, 10.5 mmol),stirred for one hour, and degassed with a stream of nitrogen for 10 minutes giving a suspension. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.3.1]nonane-5-methanol (1.71 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5 N n-butyllithium/hexane (10.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The 1,1'-carbonyldiimidazole adduct suspension was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated m vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little isopropanol and saturated sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 7% methanol/methylene chloride). The filtrated was concentrated in vacuo and the residue was triturated from cold ether and recrystallized from acetonitrile (2 crops) to afford 1.79 g (60% ) of colorless crystals; m.p. 207°-209° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-])=O)=[C:13]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:19][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]=1[S:15]([NH2:18])(=[O:16])=[O:17]
Reactant: NS(=O)(=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O

Procedure:
The product of Example 304C (3.85 g, 0.0125 mol) was treated with iron powder (4.3 g, 0.077 mol, 6.15 equivalent) and ammonium chloride (4.4 g, 0.082 mol) in methanol (100 mL) and water (50 mL), and stirred at reflux for 1 hour. The hot reaction mixture was filtered through fluted filter paper and washed with hot methanol. The filtrate was concentrated under reduced pressure to a white semi-solid that was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound as a off white solid (2.5 g). 1H NMR (300 MHz, DMSO-d6) δ ppm 4.98 (s, 2 H) 5.46 (s, 2 H) 6.76 (d, J=8.82 Hz, 1 H) 7.01 (dd, J=8.82, 2.94 Hz, 1 H) 7.21 (d, J=2.94 Hz, 1 H) 7.23 (s, 2 H) 7.37 (m, 5 H). ESI m/z (M+H)+279. ESI m/z (M−H)−277.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][O:39][CH:40]=2)O1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[CH:37]=[N:38][O:39][CH:40]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnoc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole to afford a white solid. LC-MS (Condition 2) tR=1.80 min, m/z=435.2-436.2 [M+H]+, m/z=433 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.82 (m, 1H) 1.84-1.94 (m, 1H) 3.01 (d, J=11.25 Hz, 1H) 3.29-3.53 (m, 3H) 4.22-4.28 (m, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.86 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.20 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 8.85 (s, 1H) 9.12 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[CH2:16][CH3:17]>CO>[CH2:15]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1)[CH2:16][CH3:17]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: CCCOc1ccccc1N
Solvent: CO
Product: CCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A mixture of ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (4.2 g) and 2-propoxyaniline (3.5 g) is heated with stirring without a solvent at 120° C. for 1 hour. After cooling, methanol is added to the reaction mixture in order to pulverize the solid, and then the product is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(2-propoxyanilino)-6-oxo-5-pyrimidinecarboxylate (4.5 g). M.p. 198°-200° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([OH:23])=O)=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[CH2:48]([CH2:50][NH2:51])[OH:49]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([NH:51][CH2:50][CH2:48][OH:49])=[O:23])=[CH:6][N:5]2[C:24]=1[CH3:25]
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(=O)NCCO)cn2c(C)c(C)nc12
Reaction time: 0.08 h

Procedure:
2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.3 g, 0.88 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.29 g, 0.90 mmol) were added to methylene chloride (15 ml) and the mixture was stirred for 5 min. Ethanolamin (0.11 g, 1.8 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. Crystallization from diethyl ether gave 0.2 (59%) of the desired product.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A suspension of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (8.16 g, 24.2 mmol), (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (5.00 g, 26.8 mmol), and diisopropylethylamine (5.14 ml, 29.5 mmol) in propan-2-ol (150 ml) was heated at 80° C. for 13 h. The mixture was then cooled to 25° C. and stirred for 4 h. The resulting yellow solid was collected by vacuum filtration, washed with heptanes (1×20 ml), and was air-dried to afford (R)-3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.90 g, 88%). LCMS (Method G, ESI): RT=1.19 min, m+H=488.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14].S(Cl)(O[CH2:20][Cl:21])(=O)=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][CH2:20][Cl:21])=[O:14]
Reactant: COCCOCCOCCOCC(=O)O
Reactant: O=S(=O)(Cl)OCCl
Product: COCCOCCOCCOCC(=O)OCCl

Procedure:
This compound was prepared from 2-(2-(2-methoxyethoxy)-ethoxy)-ethoxy-acetic acid and chloromethyl chlorosulfate as described in the general procedure given in Synthetic Communications 14, 857-864 (1984). The resulting oil was purified by distillation in vacuo, b.p.: 130-132° C. at 0.06 mbar.
Reaction SMILES: [C:1]([C:4]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:15])[CH3:14])[CH2:8][C:7]=2[S:6][C:5]=1[CH2:16][CH2:17]Cl)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1>>[C:1]([C:4]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:15])[CH3:14])[CH2:8][C:7]=2[S:6][C:5]=1[CH2:16][CH2:17][N:31]1[CH2:30][CH2:29][CH:28]([C:25]2[C:24]3[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=3[O:27][N:26]=2)[CH2:33][CH2:32]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(CCCl)sc2c1CCN(C(C)=O)C2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Product: CC(=O)c1c(CCN2CCC(c3noc4cc(F)ccc34)CC2)sc2c1CCN(C(C)=O)C2

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.5 g of 3,6-diacetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 1.3 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 3,6-diacetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([C:20]1[N:21]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:22]([CH2:25][CH2:26]O)=[CH:23][N:24]=1)[CH2:17][CH2:18][CH3:19].C(N(C(C)C)CC)(C)C.[CH3:45][O:46][C:47](=[O:57])[C@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH2:49]>C(Cl)Cl>[CH3:45][O:46][C:47](=[O:57])[C@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH:49][CH2:26][CH2:25][C:22]1[N:21]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:20]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:24][CH:23]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCCc1ncc(CCO)n1Cc1ccccc1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ncc(CCN[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
A solution of trifluoromethanesulfonic anhydride (0.954 g, 3.38 mmol) in methylene chloride (5 ml) was cooled to -78° C. under nitrogen, and a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(2-hydroxyethyl)-1H-imidazole (0.9 g, 3.07 mmol), diisopropylethylamine (0.44 g. 3.38 mmol) and methylene chloride (10 ml) was added dropwise. The mixture was stirred at -78° C. for an additional 15 minutes, then a solution of the free base of phenylalanine methyl ester (prepared from 1.33 q (6.15 mmol) of the hydrochloride salt) in methylene chloride (10 ml) was added. This mixture was stirred for 2 hours at -78° C. and an additional 18 hours at ambient temperature. The reaction mixture was washed with water, dried and concentrated and the crude product was flash chromatographed with 5% methanol in ethyl acetate to yield 0.9 g (65%) of N-[2-{1-[(2 chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}ethyl ]phenylalanine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[NH:31][CH2:30][CH2:28][OH:29]
Reactant: NCCO
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: O=C(Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12)NCCO

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with ethanolamine at 22° C. to give the title compound as a white solid. MS: 421.0 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[H-].[Na+]>C1(C)C=CC=CC=1>[O:19]=[C:13]([CH2:11][C:10](=[O:12])[C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1c(C)cc(C)cc1C
Yield: 66.7 %

Procedure:
To a solution of 2′,4′,6′-trimethylacetophenone (15 g, 92.6 mmol) and diethyl oxalate (20 g, 139 mmol) in 500 mL of anhydrous toluene was cautiously added 7.4 g of NaH (60% dispersion in mineral oil). The reaction mixture was slowly heated to reflux under N2. It was refluxed for about 20 minutes, then cooled, poured into ice-cold aqueous HCl solution, and extracted with ether. The extracts were washed with brine, dried over Na2SO4, filtered through a short silica gel pad and concentrated to give 16.2 g of a red oil which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[CH:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[Si]([N:26]=[N+:27]=[N-:28])(C)(C)C.CN(C=O)C>CO.[Cu]I>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[N:26]=[N:27][NH:28][CH:12]=3)=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ncnc(N)c12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1c[nH]nn1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 100 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
An argon purged mixture of 7-ethynyltubericidine 2o {compound from example 15} (200 mg, 0.69 mmol), CuI (6.5 mg, 0.03 mmol) and TMSN3 (150 μl, 1.15 mmol) in MeOH (0.2 ml)/DMF (1.8 ml) was stirred 100° C. for 24 h. Volatiles were evaporated under reduced pressure, the residue was twice co-evaporated with MeOH and rest was suspended in MeOH and filtered through celite. Filtrate was co-evaporated with silica and column chromatography on silica afforded title compound 2p as yellowish solid (55 mg, 24%). Compound was recrystallized from water. Mp 286-288° C. [α]D −70 (c 0.217, DMSO). 1H NMR (499.8 MHz, DMSO-d6, t=60° C.): 3.58 (dd, 1H, Jgem=11.9, J5′b,4′=4.2, H-5′b); 3.68 (dd, 1H, Jgem 11.9, J5′a,4′=3.9, H-5′a); 3.93 (ddd, 1H, J4′,5′=4.2, 3.9, J4′,3′=3.6, H-4′); 4.15 (dd, 1H, J3′,2′=5.3, J3′,4′=3.6, H-3′); 4.45 (dd, 1H, J2′,1′=6.0, J2′,3′=5.3, H-2′); 4.93, 5.04 and 5.17 (3×bs, 3×1H, OH-2′,3′,5′); 6.08 (d, 1H, J1′,2′=6.0, H-1′); 7.85 (bs, 2H, NH2); 7.91 (s, 1H, H-6); 8.09 (s, 1H, H-2); 8.23 (s, 1H, H-5-triazole). 13C NMR (125.7 MHz, DMSO-d6, t=60° C.): 61.83 (CH2-5′); 70.54 (CH-3′); 73.72 (CH-2′); 85.15 (CH-4′); 87.41 (CH-1′); 100.16 (C-4a); 105.83 (C-5); 120.80 (CH-6); 126.16 (CH-5-triazole); 141.51 (C-4-triazole); 151.04 (C-7a); 152.35 (CH-2); 158.04 (C-4). MS (ESI) m/z 334 (M+H), 356 (M+Na). HRMS (ESI) for C13H16N7O4 [M+H] calcd: 334.1258. found: 334.1258. Anal. Calcd for C13H15N7O4: C, 46.85; H, 4.54; N, 29.42. Found: C, 47.12; H, 4.82; N, 27.96.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH2:21]([O:24][C:25]([C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:30]=2[N:31]=1)=[O:26])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[CH2:21]([O:24][C:25]([C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]3[CH:20]=[CH:19][CH:18]=[C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:4]=3)=[CH:32][C:30]=2[N:31]=1)=[O:26])[CH2:22][CH3:23]
Reactant: CCCOC(=O)c1nc2cc(O)ccc2o1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1nc2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1

Procedure:
A mixture of 3.47 g of 2-((3-chloromethylphenoxy)methyl)quinoline, 2.7 g of n-propyl-5-hydroxybenzoxazole-2carboxylate, 1.69 g of potassium carbonate and 1 ml of dimethylformamide is refluxed in 50 ml of acetone for 41 hours. The mixture is concentrated in vacuo and the residue is dissolved in water. This solution is neutralized with diluted hydrochloric acid and the resulting solid is filtered off and purified by flash silica gel chromatography in propanol-dimethylformamide to give n-propyl-5-(3-(quinolin-2-ylmethyloxy)benzyloxy)-benzoxazole-2-carboxylate
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[N:7][CH:8]=1.C1COCC1.Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(N(CC)CC)C>[O:15]=[C:10]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=2)[CH2:14][CH2:13][N:12]([CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:11]1
Reactant: O=C1CNCCN1c1ccc(C(F)(F)F)cn1
Reactant: O=C(CBr)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(c2ccc(C(F)(F)F)cn2)C(=O)C1)OCc1ccccc1

Procedure:
1.12 g of 1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one, 40 ml of THF and 0.87 ml of benzyl bromoacetate are placed in 1.5 ml of triethylamine in a round-bottomed flask equipped with a magnetic stirrer. The mixture is reacted under a stream of nitrogen overnight at room temperature. The solvent is evaporated off and the residue is purified by flash chromatography on a Biotage® column, using 1/1 hexane/ethyl acetate as eluent. 2.9 g of title product are isolated in the form of a white solid.