Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47]I>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:47][C:46]2[CH:49]=[CH:50][CH:51]=[C:44]([O:43][CH3:42])[CH:45]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: COc1cccc(CI)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1cccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c1

Procedure:
In analogy with Example 44c), 1.5 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 2b)] in 3 ml of abs. THF are deprotonated (-75° C.) with 9.62 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and with the addition of 0.998 ml of DMPU and alkylated with 1.22 g of 3-methoxybenzyl iodide. Chromatography on silica gel (eluent E) affords the pure title compound. TLC Rf (hexane/ethyl acetate, 2.5:1)=0.32. FAB-MS (M+H)+ =426.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:8]([CH2:14]Br)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[N:1]12[CH2:6][CH2:5][N:4]([CH2:3][CH2:2]1)[CH2:14][CH:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(Br)CBr
Reactant: C1CNCCN1
Product: CCOC(=O)C1CN2CCN1CC2

Procedure:
reacting piperazine and ethyl 2,3-dibromopropanoate to form ethyl 1,4-diazabicyclo[2.2.2]octane-2-carboxylate;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:22](O)=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)(Cl)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:22]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COc1ccc(-c2c(C(=O)O)ccc3cc(Cl)ccc23)cc1OC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C(=O)N3CCOCC3)ccc3cc(Cl)ccc23)cc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6.9 g of 1-(3,4-dimethoxyphenyl)-6-chloro-2-naphthoic acid are introduced into 50 ml of toluene, and 2.4 g of thionyl chloride are added thereto. The reaction mixture is heated to boiling point and then stirred for 5 hours under reflux. Then, at ~50°, 4.0 g of morpholine are added dropwise, and the mixture is again heated to boiling point and stirred for a further 3 hours under reflux. After cooling to room temperature, the reaction mixture is diluted with 100 ml of toluene, and the organic phase is washed three times with 250 ml of water each time, dried over sodium sulfate and filtered, and the solvent is evaporated off in vacuo. For purification, the oily residue is chromatographed over a column of silica gel using ethyl acetate. The title compound is obtained in the form of beige crystals. M.p. 157°-159°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:21]=1[NH2:22].Cl>C(O)C.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[C:21]([CH:23]=1)[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(Cl)cc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 68.2 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (100 mg, 0.385 mmol), 2-methoxy-5-chloroaniline (90 mg, 0.577 mmol) and 2N HCl (150 μl) in 1:1 ethanol/water (5 ml) was refluxed for 48 h. The resulting yellow solid was collected by filtration, washed with water, ethanol/water (1:4) and then dried under vacuum to give the title compound (100 mg, 67%). 1H NMR (CDCl3): 9.66 (d, J=1.8 Hz, 1H), 8.70-8.76 (m, 2H), 7.68 (dd, J=7.5, 1.0 Hz, 1H), 7.44 (dd, J=7.5, 1.0 Hz, 1H), 7.09 (dd, J=8.7, 2.7 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J=8.7 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([N:26]2[CH2:31][CH2:30][CH:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH2:27]2)[N:19]=1.Cl>O1CCOCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)[N:19]=1
Reactant: COc1cc(-c2c[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(-c2c[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N2CCC(N)CC2)n1
Temperature: 90 °C
Yield: 24.6 %

Procedure:
To solution of tert-butyl (1-(4-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-yl)carbamate (0.1 g, 0.187 mmol) in dioxane (2 mL) was added HCl in dioxane (2 mL) and the mixture was heated at 90° C. for overnight. The reaction was quenched with aq.NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified with basic alumina column chromatography. (eluting in 1% MeOH in CHCl3) to give 1-(4-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)piperidin-4-amine (20 mg, 25%). MS (ESI, pos. ion) m/z: 436.1 (M+1); 1H-NMR (DMSO-d6, 400 MHz): δ ppm 11.84 (brs, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 7.56 (d, 1 H, J=8.4 Hz), 7.47-7.43 (m, 1H), 7.19-7.27 (m, 3H), 6.54 (s, 1H), 4.7 (d, J=12 Hz, 2H), 3.8 (s, 3H), 3.0 (t, J=12 Hz, 2H), 1.85-1.89 (m, 3H), 1.38-1.40 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:29]C)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=1[CH:15]=[N:16][NH:17]3)[C:7]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:6][C:5]2([CH3:28])[CH3:27].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[N:16][NH:17]4)[C:7]([C:23]([F:25])([F:26])[F:24])([OH:22])[CH2:6][C:5]([CH3:27])([CH3:28])[C:4]=2[C:3]=1[OH:29]
Reactant: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2ccc(F)c(O)c21
Temperature: 25 °C
Yield: 92.8 %

Procedure:
200 mg (0.472 mmol) of the above-described (−)-6-fluoro-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 4.7 ml of a 1 M solution of BBr3 in dichloromethane and stirred for three and three-fourths hours at room temperature. The reaction mixture is mixed drop by drop at −30° C. with saturated sodium bicarbonate solution, specifically until a pH of 8 is reached. After dilution with ethyl acetate, the cold bath is removed, and the batch is stirred vigorously for 15 minutes. After being shaken twice with ethyl acetate, the combined organic extracts are washed with water and saturated brine. After drying on sodium sulfate, and after the solvent is filtered and spun off, the residue is chromatographed on silica gel (mobile solvent:dichloromethane/methanol). 179.4 mg (92.8%) of the desired compound is obtained. The angle of rotation, measured at room temperature, is [α]D=−7.8 (c=1, MeOH).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.CO[C:14]1[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=1.FC(F)(F)C(O)=O>C(O)(=O)C>[C:14]1([C:9]2[C:8]([OH:11])=[CH:7][CH:6]=[C:5]3[C:10]=2[CH2:1][NH:2][CH2:3][CH2:4]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc2c(c1)CNCC2
Reactant: COc1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Oc1ccc2c(c1-c1ccccc1)CNCC2

Procedure:
Scheme 1 (FIG. 1): Protection of the hydroxyl group in vanillin with benzyl bromide yielded aldehyde 1 is shown in Scheme 1. Henry reaction between aldehyde 1 and nitromethane gave nitrostyrene 2. Reduction of compound 2 with lithium aluminum hydride in tetrahydrofuran (THF) afforded amine 3. The reaction of amine 3 with an excess amount of methyl formate provided formamide 4. Cyclization of amide 4 using phosphorus oxychloride (POCl3) via Bischler-Napieralski reaction obtained 3,4-dihydroisoquinoline 5. Alkylation of compound 5 with iodopropane followed by NaBH4 reduction produced tetrahydroisoquinoline 6 in high yield. Catalytic hydrogenation over Pd/C removed the protective groups of 6 to afford 1,2,3,4-tetrahydroisoquinolin-7-ol 7 in quantitative yield. Treatment of compound 7 with Pb(OAc)4 in acetic acid followed by acid-catalyzed aromatic substitution with 1,3-dimethoxybenzene using trifluoroacetic acid (TFA) furnished 8-phenyl-tetrahydroisoquinolin-7-ol 8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][C:20]5[C:21]([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)([CH2:22][CH2:23][C:24](=[O:26])[CH:25]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H][H]>C1COCC1.N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[N:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][C:21]5([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1C=C2CCCc3nc4c(cnn4-c4ccc(F)cc4)cc3C2(Cc2ccccn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1CCC2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4nc3CCCC2C1
Yield: 59.5 %

Procedure:
9-(4-Fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,5,6,7,9,12b-hexahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3 (2H)-one (116, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (9.28 g, 21.16 mmol) in THF (170 mL) and pyridine (22 mL) with palladium on carbon (10%) (0.690 g, 0.648 mmol) was hydrogenated in a Parr shaker at 50 psi hydrogen and rt for about 8 h. The mixture was filtered through a pad of Celite® and the pad was washed with DCM. The filtrate was concentrated under reduced pressure and the material was purified on silica gel (330 g) using a gradient from 0-100% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(4aR,12bR)-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3(2H)-one (118, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (5.55 g, 59.5%); LC/MS, method 3, Rt=2.46 min, MS m/z 441 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.40-8.37 (m, 2H), 8.31-8.29 (m, 1H), 8.19 (s, 1H), 7.80 (s, 1H), 7.47-7.38 (m, 3H), 7.09-7.05 (m, 1H), 6.61 (d, J=7.8 Hz, 1H), 3.83 (d, J=12.9 Hz, 1H), 3.63-3.56 (m, 1H), 3.40-3.35 (m, 1H), 2.97 (d, J=13.0 Hz, 1H), 2.62-1.81 (m, 9H), 1.75-1.65 (m, 2H).
Reaction SMILES: I[CH2:2][C:3]1([CH3:22])[O:20][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:21])[NH:11][C:10](=[O:16])[C:9]([CH:17]([CH3:19])[CH3:18])=[CH:8]3.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:2][C:3]1([CH3:22])[O:20][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:21])[NH:11][C:10](=[O:16])[C:9]([CH:17]([CH3:19])[CH3:18])=[CH:8]3)=[N+:24]=[N-:25]
Reactant: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CI)C2C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CN=[N+]=[N-])C2C
Temperature: 150 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
2-Iodomethyl-8-isopropyl-2,3,5-trimethyl-6,7-dihydrofuro[2,3-f]quinoline-7-one (2.10 g, 5.11 mmol) was dissolved in dimethylformamide (75 ml). To the solution, sodium azide (4.50 g, 69.2 mmol) was added, and the mixture was stirred at 150° C. for 4 hours. The reaction mixture was condensed under reduced pressure, and the residue was extracted from chloroform-water. The organic phase was washed with saturated aqueous sodium chloride solution, dried, and condensed under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform) to obtain pale yellow crude crystals. The obtained crude was recrystallized from chloroform-ether-hexane to obtain 1.25 g of the title compound (syn:anti=1) as a colorless powder (75.0%).
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13].[NH3:23]>C(Cl)Cl.C(O)C>[NH2:23][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13]
Reactant: CCOc1ccccc1C1(Cl)C(=O)Nc2ccc(OC)cc21
Reactant: N
Solvent: CCO
Solvent: ClCCl
Product: CCOc1ccccc1C1(N)C(=O)Nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.2 g (10 mmol) of the intermediate from step B were suspended in 40 ml CH2Cl2. 50 ml of a 2M solution of NH3 in ethanol were added and the reaction mixture was stirred for 16 h at ambient temperature. The mixture was poured into an ice/water mixture and the precipitate was separated. The precipitate was redissolved in ethyl acetate. This organic phase was washed with 2M aqueous HCl. The aqueous phase was made alkaline (pH=8-9) and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to yield 1.7 g of the intermediate.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29]([CH3:34])=[CH:28]4)=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:35][CH3:36].[CH2:37]([S:39]([CH2:42][CH2:43][CH2:44]O)(=[O:41])=[O:40])[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:37]([S:39]([CH2:42][CH2:43][CH2:44][O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29]([CH3:34])=[CH:28]4)=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:35][CH3:36])(=[O:41])=[O:40])[CH3:38]
Reactant: CCS(=O)(=O)CCCO
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)CCCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
Diethyl azodicarboxylate (117 mg, 0.67 mmol) was added in portions to a solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (120 mg, 0.37 mmol), (prepared as described in Example 49), and 3-(ethylsulphonyl)-1-propanol (74 mg, 0.48 mmol) in methylene chloride (3.5 ml) and triphenylphosphine (176 mg, 0.67 mmol). After stirring for 2 hours at ambient temperature, the residue was poured onto a column of silica and eluted with ethyl acetate/methylene chloride (1/1) followed by methylene chloride/methanol (97/3 followed by 95/5). After removal of the solvent under vacuum, the residue was triturated with ether, filtered and dried under vacuum to give 7-(3-(ethylsulphonyl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (93 mg, 55%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C1COCC1>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)OCc2ccccc2)C1
Temperature: 0 °C

Procedure:
To a stirred solution of 3-(aminomethyl)-1-N-Boc-piperidine (1.64 g, 7.65 mmol) and TEA (1.6 mL, 11 mmol) in THF (5 mL) at 0° C., benzyl chloroformate (1.15 mL, 8.04 mmol) was added dropwise. The reaction was maintained at 0° C. for 1 h, then warmed to RT overnight. The solvent was evaporated in vacuo. The residue was taken up in a saturated solution of NH4Cl (aq) (15 mL) and extracted with EtOAc (10 mL). The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (1:4, EtOAc:hexane) to yield the title compound as a colorless oil. MS m/z: 349.3 (M+H). Calc'd. for C19H28N2O4-348.44.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]([CH3:20])([CH2:18][CH3:19])[C:15](O)=O.C(O)C.CCOCC.[ClH:29]>>[ClH:29].[CH2:18]([C:14]([CH3:20])([C:15]1[NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10]([N:12]=1)=[CH:9][CH:8]=[CH:7]3)[OH:13])[CH3:19]
Reactant: CCC(C)(O)C(=O)O
Reactant: Nc1cccc2cccc(N)c12
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCC(C)(O)C1=Nc2cccc3cccc(c23)N1

Procedure:
1,8-Diaminonaphthalene (44.5 g, 0.282 mole) is suspended in 400 ml of 4N hydrochloric acid. To this suspension is added 2-hydroxy-2-methyl butyric acid (50 g, 0.423 mole) and the whole is stirred and heated under reflux for 96 hours. Then the reaction mixture is allowed to cool and is filtered, yielding a gray-green solid. The solid is heated and stirred with 1 liter of refluxing ethanol, and is filtered while hot to remove unreacted starting materials. The filtrate is concentrated to dryness and the resulting solid is treated with 500 ml of boiling ethanol. After the insoluble material is removed by filtration, the filtrate was treated with charcoal, yielding a yellow solution. Addition of ether, plus cooling, yields a yellow-brown solid. Recrystallization from ethanol (charcoal) yields the desired product, α-ethyl-α-methyl-2-perimidinemethanol, hydrochloride, m.p. 266°-268° dec.).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](OC(F)(F)F)C=2)[N:6]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=1)(=[O:3])[CH3:2].[NH:22]1C2C(=NC=CC=2)C(C(=O)C)=C1>>[C:1]([C:4]1[C:12]2=[N:22][CH:10]=[CH:9][CH:8]=[C:7]2[N:6]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2cccnc12
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: CC(=O)c1cn(CC(=O)O)c2cccnc12

Procedure:
was prepared in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid from 1-(1H-pyrrolo[3,2-b]pyridin-3-yl)-ethanone (prepared according to J. Org. Chem. 2002, 67, 6226). MS (UPLC/MS): 219.2 [M+H]+, 217.3 [M−H]−, 435.3 [2M−H]−; tR (HPLC conditions f): 1.16 min. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.79 (bs, 1H), 8.64 (m, 2H), 7.64 (m, 1H), 5.33 (s, 2H), 2.67 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH3:13].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:12]([O:14][C:15](=[O:20])[CH:16]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1)[C:17](=[O:19])[CH3:18])[CH3:13]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (4.5 g) in anhydrous tetrahydrofuran (70 mL) at 0° C. was treated with a mixture of tert-butanol (0.2 mL) and 3-oxobutyric acid ethyl ester (5.2 g). After stirring at 15° C. for 15 minutes a solution of 1-bromomethyl-4-methanesulfonylbenzene (10 g) in tetrahydrofuran (30 mL) was added and the resulting mixture heated at 70° C. for 17 hours. The mixture was diluted with saturated aqueous citric acid solution (20 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (2:1 to 0:1 by volume) to afford title compound as a gum, 3.5 g.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH3:14][CH:15]1[CH:19]=[CH:18][CH:17]([CH3:20])[NH:16]1>>[CH3:14][CH:15]1[CH:19]=[CH:18][CH:17]([CH3:20])[N:16]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: CC1C=CC(C)N1
Product: CC1C=CC(C)N1c1ccc(C#N)c2ccccc12
Yield: 3.4 %

Procedure:
The title compound (1 mg, 3% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 2,5-dimethyl-2,5-dihydro-1H-pyrrole (45 mg, 0.468 mmol).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C>[CH2:30]([N:20]1[C:18]2[N:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=[CH:16][C:17]=2[C:23](=[O:24])[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21]1)[CH3:31]
Reactant: CCOC(=O)c1cn(CC)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc(N3CCNCC3)ncc2c1=O
Yield: 106 %

Procedure:
A solution of 3.0 g of ethyl 2-(4-benzyl-1-piperazinyl)-5,8-dihydro-8-ethyl-5-oxopyrido[2,3-d]-pyrimidine-6-carboxylate in 100 ml of ethanol was allowed to consume an equivalent amount of hydrogen over 1.5 g of 10% palladium-on-carbon under hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated to give a solid which was collected and recrystallized from acetone. There is obtained 2.5 g of the product, m.p. 156° - 158°C.
Reaction SMILES: [Br:1][C:2]([I:8])=[C:3]([I:7])[C:4]([OH:6])=[O:5].[N+](=[CH2:11])=[N-]>C(OCC)C>[Br:1][C:2]([I:8])=[C:3]([I:7])[C:4]([O:6][CH3:11])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(I)=C(Br)I
Solvent: CCOCC
Product: COC(=O)C(I)=C(Br)I
Reaction time: 0.25 h

Procedure:
0.5 g of 3-bromo-2,3-diiodoacrylic acid was dissolved in 20 ml of diethyl ether. A solution of diazomethane in diethyl ether was then added until nitrogen gas was no longer produced, whereupon the mixture was left to stand for 15 minutes. The diethyl ether was distilled off, giving 0.50 g of the desired compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH:34]([CH3:36])[CH3:35])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][C:20]=1[Br:33])[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH:34]([CH3:36])[CH3:35])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:53][N:52]=[N:51][N:32]=2)=[CH:21][C:20]=1[Br:33])[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1Br)[C@H](C(=O)OCc1ccccc1)C(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1Br)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
A solution of 4.5 g (8 mmol) of N-[(3-bromo-2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester and 3.4 g (10.4 mmol) of tributyltin azide in 50 ml of xylene is heated to boiling under reflux for 20 hours. Working-up analogously to Example 54 and "flash"-chromatographic purification (toluene-methanol 4:1) gives the title compound as a colourless foam (Rf 0.57, system A2).