Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[CH:19]([OH:21])=[O:20].[NH2:22][CH2:23][CH2:24][N:25]([CH3:36])[C:26]1[N:31]=[C:30]([NH2:32])[C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=1>>[CH:19]([OH:21])=[O:20].[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([NH:22][CH2:23][CH2:24][N:25]([CH3:36])[C:26]2[N:31]=[C:30]([NH2:32])[C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: CN(CCN)c1ccc([N+](=O)[O-])c(N)n1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Solvent: O=CO
Product: CN(CCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12)c1ccc([N+](=O)[O-])c(N)n1

Procedure:
In analogy to the procedure for preparing Example 5, the product is obtained by reacting 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) with N6-(2-aminoethyl)-N6-methyl-3-nitropyridine-2,6-diamine formate (preparation analogous to Example 14A).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][C:4]([NH:6][NH:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[C:12]([N:18]([CH2:20][CH:21]2[CH2:23][CH:22]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:19])[CH:11]=[CH:10][N:9]=1)=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CCOC(C)=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:22]2[CH2:23][CH:21]2[CH2:20][N:18]([CH3:19])[C:12]2[CH:11]=[CH:10][N:9]3[C:4]([CH2:3][C:2]([F:32])([F:31])[F:1])=[N:6][N:7]=[C:8]3[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:25][CH:26]=1
Reactant: CN(CC1CC1c1ccc(F)cc1)c1ccnc(NNC(=O)CC(F)(F)F)c1C(F)(F)F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CC1CC1c1ccc(F)cc1)c1ccn2c(CC(F)(F)F)nnc2c1C(F)(F)F
Reaction time: 1.5 h
Yield: 29.1 %

Procedure:
A mixture of 3,3,3-trifluoro-N′-(4-(((2-(4-fluorophenyl)cyclopropyl)methyl)(methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)propanehydrazide (0.5 g, 1.077 mmol) and Burgess reagent (0.513 g, 2.153 mmol) in THF (10 mL) was heated to reflux stirring for 90 min. The reaction mixture was diluted with EtOAc and washed with aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 mL), dried with brine (20 mL), dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-100% EtOAc/hexane as the eluent to give N-((2-(4-fluorophenyl)cyclopropyl)methyl)-N-methyl-3-(2,2,2-trifluoroethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine as a yellow solid (0.14 g, 26.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.91 (d, J=7.8 Hz, 1H), 7.03-6.91 (m, 4H), 6.83 (d, J=7.8 Hz, 1H), 4.02 (q, J=9.8 Hz, 2H), 3.48 (dd, J=14.1, 6.0 Hz, 1H), 3.33 (dd, J=14.1, 7.3 Hz, 1H), 3.16 (s, 3H), 1.77 (dd, J=9.0, 4.8 Hz, 1H), 1.34-1.23 (m, 1H), 1.05 (dt, J=8.5, 5.4 Hz, 1H), 0.91 (dt, J=8.8, 5.5 Hz, 1H). LCMS: M+1=447.12.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][N:11](C(OCC)=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(CN2CCC3CNCC32)cc1

Procedure:
55.6 g (0.2 mol) of ethyl 2-benzyl-2,7-diazabicyclo [3.3.0]octane-7-carboxylate are heated under reflux overnight with 300 ml of concentrated hydrochloric acid. The mixture is then rendered alkaline with potassium carbonate and extracted five times with 100 ml of chloroform each time, the extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.C1COCC1.C([Li])CCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1ccc2cccnc21
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1c(B2OC(C)(C)C(C)(C)O2)cc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To a −78° C. solution of 1-methyl-1H-pyrrolo[2,3-b]pyridine (example Rupp-28) (1.17 g, 8.85 mmol) and THF (12 mL) is added 1.6M n-Bu—Li (6.6 mL, 10.62 mmol). The solution is heated to a reflux for 1 hour, cooled to ambient temperature, and 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.60 mL, 17.70 mmol) is added. After 1 hour, the solution is diluted with CH2Cl2 (100 mL), washed with water (2×100 mL), brine (75 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (5%-15% EtOAc gradient) to furnish the title compound (0.25 g, 0.97 mmol, 11%). 1H NMR (CDCl3), δ 1.38 (s, 12H), 4.07 (s, 3H), 7.02 (dd, J=7.9, 4.7 Hz, 1H), 7.07 (s, 1H), 7.92 (d, J=7.9, 1.8 Hz, 1H), 8.39 (d, J=4.7, 1.8 Hz, 1H) ppm. LC/MS (m/z): calcd. for C14H19BN2O2 (M+H)+: 259.2. found: 258.7.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4]O.B.C1C[O:15][CH2:14]C1>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][CH2:14][OH:15]
Reactant: Cc1ccc(CO)c(C)c1
Reactant: C1CCOC1
Agent: B
Product: Cc1ccc(CCO)c(C)c1
Reaction time: 8 h

Procedure:
A solution of carboxylic acid 9 (3.40 g; 17.87 mmol) in THF (100 ml) was cooled to 0° C. and treated with 35 ml of a 1.0M solution of borane in THF. After stirring this mixture overnight it was quenched with 1N HCl and the product was extracted into ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and freed of solvent. The crude product was filtered through a plug of silica gel eluting with 20% ethyl acetate in hexane to obtain 2.75 g (quantitative yield) of the product as a clear light oil. 1H NMR (CDCl3): δ2.25, 2.28 (s, 3H each); 2.88 (t, 2H); 3.78 (t, 2H); 6.97-7.07 (m, 3H). IR (neat): 3340, 2947, 1504, 1448, 1265, 1044 cm-1.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[H][H]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[C:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:8]1)#[N:2]
Reactant: [H][H]
Reactant: CCCCCc1ccc(-c2ccc(C=C[C@H]3CC[C@H](C#N)CC3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C#N)CC3)cc2)cc1
Yield: 90.1 %

Procedure:
3.4 g of 4-[2-(trans-4-cyanocyclohexyl)ethenyl]-4'-pentylbiphenyl were dissolved in 150 ml of toluene/ethanol (volume ratio 4:1), treated with 300 ml of 10% palladium/carbon and hydrogenated at normal pressure and room temperature until the hydrogen uptake came to a standstill. Filtration of the mixture and low-pressure chromatography (0.5 bar) of the concentrated filtrate on silica gel with 5% ethyl acetate/petroleum ether as the eluant gave 3.08 g of 4-[2-(trans-4-cyanocyclohexyl)-ethyl]-4'-pentylbiphenyl as colourless crystals (purity 99.2%; yield 86% based on trans-4-cyanocyclohexanecarboxaldehyde). By additional recrystallization of a sample from ethanol there was obtained pure product of melting point (C-S) 59.7° C., t.p. (S-S) 68.1° C., t.p. (S-N) 89.0° C. and cl.p. (N-I) 134.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:45])=[C:21]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:57]>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([N:37]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH3:57])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:45])=[C:21]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1c(-c2ccc3c(c2)cc2n3CC(NC(=O)OC(C)(C)C)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc3c(c2)cc2n3CC(N(C)C(=O)OC(C)(C)C)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 412, Step 3 (130 mg, 0.18 mmol) was dissolved in DMF (1 mL). Sodium hydride (60% dispersion in mineral oil, 15 mg, 0.36 mmol) was added to the mixture. After 10 min of vigorous stirring at room temperature, iodomethane (35 μL, 0.54 mmol) was added to the mixture. The mixture was stirred an additional 10 min at room temperature, and then was quenched with the addition of aqueous saturated NH4Cl solution (5 mL). The mixture was extracted with CH2Cl2 (5 mL). The organic extracts were concentrated. The residue was 97% pure by UPLC analysis and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[C:11]3[N:15]=[C:16](SC)[N:17]=[C:10]23)=[CH:4][CH:3]=1.[ClH:20]>>[Cl:20][C:16]1[N:17]=[C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:14]=[CH:13][CH:12]=[C:11]2[N:15]=1
Reactant: CSc1nc2cccn(Cc3ccc(Cl)nc3)c-2n1
Reactant: Cl
Product: Clc1ccc(Cn2cccc3nc(Cl)nc2-3)cn1
Temperature: -10 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
A solution of 4-[(6-chloro-3-pyridyl)methyl]-2-methylsulfanyl-imidazo[4,5-b]pyridine (2.22 g, 7.63 mmol) in 25 mL concentrated aqueous hydrochloric acid was cooled to −10° C. and gaseous Cl2 was bubbled through the solution for 1 h. The mixture was stirred at −10° C. for additional 2 h and for 12 h at room temperature. Afterwards the reaction mixture was poured into ice-water, basified to pH 4-5 with NaOH solution (15% in H2O) and extracted three times with CH2Cl2. The combined organic extracts were washed with water, dried with Na2SO4 and the solvent was removed under reduced pressure. Purification by flash column chromatography (SiO2, gradient of MeOH/CH2C12) yielded 1.23 g (4.43 mmol, 58%) of compound E1.8.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[C:13]2[N:14]([CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1.[N:22](OCCCC)=[O:23]>O1CCCC1>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[C:13]2[N:14]([C:18]([N:22]=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCCCON=O
Reactant: Cc1cn2cccc(O[C@@H]3c4ccccc4C[C@H]3O)c2n1
Solvent: C1CCOC1
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1N=O
Yield: 63.4 %

Procedure:
0.5 g 8-(2-(trans)-hydroxy-2,3-dihydro-1-indenyloxy)-2-methyl-imidazo[1,2-a]pyridine, dissolved in 50 ml tetrahydrofuran, are mixed with 0.6 g commercial butyl nitrite at 50° C. and left over night at this temperature. After evaporation of the volatile components in vacuo, residue is washed with few cold acetonitrile and, after the solvent is poured off, recrystallized from acetonitrile. 0.35 g yellow title compound of m.p. 178°-179° C. is obtained.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[CH3:15][N:16]1[C:29]2[CH:28]=[C:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:26]=[CH:25][C:24]=2[S:23](=[O:37])(=[O:36])[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2.I[CH2:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O1CCCC1>[CH3:15][N:16]1[C:29]2[CH:28]=[C:27]([CH:30]([CH2:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:26]=[CH:25][C:24]=2[S:23](=[O:36])(=[O:37])[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: ICC1CCOCC1
Reactant: CCOC(=O)Cc1ccc2c(c1)N(C)c1ccccc1S2(=O)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCOCC1)c1ccc2c(c1)N(C)c1ccccc1S2(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.66 ml of 1,1,1,3,3,3-hexamethyldisilazane are dissolved in 20 ml of tetrahydrofuran. With ice cooling, 2.90 ml of n-butyllithium (2.5 M in n-hexane) are added dropwise, and the mixture is stirred at 0° C. for another 30 minutes. At −78° C., this solution is then added dropwise to a stirred solution of 2.0 g of ethyl (10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acetate in 100 ml of tetrahydrofuran. The reaction mixture is stirred at −78° C. for 20 minutes, and 2.0 g of 4-(iodomethyl)tetrahydro-2H-pyran are then added dropwise. The cooling bath is removed and the mixture is allowed to slowly warm to room temperature. The reaction mixture is stirred at room temperature overnight. 10 ml of water are then added, the tetrahydrofuran is removed under reduced pressure and the residue is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate (100%:0%)=>n-heptane:ethyl acetate (0%:100%). This gives 2.0 g of ethyl 2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionate as a colorless solid.
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[CH2:8]([O:10][C:11]([C@@H:13]([NH:30][C@@H:31]1[C:37](=[O:38])[N:36]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:35]2[CH:47]=[CH:48][CH:49]=[CH:50][C:34]=2[O:33][CH2:32]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=[O:12])[CH3:9]>>[ClH:7].[CH2:8]([O:10][C:11]([C@@H:13]([NH:30][C@@H:31]1[C:37](=[O:38])[N:36]([CH2:39][C:40]([OH:42])=[O:41])[C:35]2[CH:47]=[CH:48][CH:49]=[CH:50][C:34]=2[O:33][CH2:32]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:20](=[O:29])[C:21]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]2[C:23]1=[O:24])=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
A mixture of 5N hydrogen chloride-ethyl acetate solution (5 ml) and tert-butyl 3(S)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.1 g) is allowed to stand at room temperature for 3 hours. The mixture is diluted with petroleum ether (80 ml) to precipitate colorless powder, which is collected and dried in vacuo to give 3(S)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride (0.08 g).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33]5[N:34]=[C:35]([O:38][CH3:39])[N:36]=[CH:37][C:32]=5[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:33]5[N:34]=[C:35]([O:38][CH3:39])[N:36]=[CH:37][C:32]=5[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ncc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of 0.54 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)ethyl)piperidin-4-yl)carbamate in 15 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. A 2 mol/L aqueous sodium hydroxide solution was added under cooling with ice to adjust pH at 13, dichloromethane was added thereto, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=10:1 to obtain 0.34 g of 8-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-2-methoxypyrido(2,3-d)pyrimidin-7(8H)-one as a yellow oily substance.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([CH3:17])[C:5](=[O:18])[CH2:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CCO>[CH3:16][O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7]2[N:6]([CH3:17])[C:5](=[O:18])[CH2:4][N:3]=[C:2]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:8]=2[CH:9]=1
Reactant: C1CCNCC1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)N(C)C(=O)CN=C2N1CCCCC1
Temperature: 110 °C
Yield: 59.6 %

Procedure:
Heat at 110° C. in a sealed tube a mixture of 100 mg (0.37 mmol) of 5-chloro-7,8-dimethoxy-1-methyl-1,3-dihydro-1,4-benzodiazepin-2-one XVIIIaa and 300 μl (3 mmol) of piperidine in 10 ml of EtOH for 48 hours. Evaporate to dryness and purify by silica chromatography (CH2Cl2 50/AcOEt 40/EtOH 10). Triturate in hexane, filter, dry. One obtains 70 mg of a beige powder. Yield: 60%. M=125–127° C. 1H-NMR (200 MHz, DMSO): δ 1.63–1.70 (m, 6H, 3×CH2), 3.20–3.23 (m, 4H, 2×CH2), 3.37 (s, 3H, NCH3), 3.91 (AB system, Δδ=0.71, JAB=11.5, 2H, 3-CH2), 3.94 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 6.73 (s, 1H Ar), 6.99 (s, 1H Ar).
Reaction SMILES: C(=O)(O[C@H:4]1[C:17]2[CH:16]=[C:15]3[C:10]([N:11]([CH3:27])[C:12](=[O:26])[CH:13](CCC4C=CC=CC=4)[O:14]3)=[C:9](C(C)(C)C)[C:8]=2[O:7][C:6]([CH3:33])([CH3:32])[C@@H:5]1[OH:34])N.C(=O)([O-])O.[Na+].CCO[CH2:44][CH3:45]>Cl.O1CCOCC1>[OH:34][C@@H:5]1[C@@H:4]([NH:11][CH2:10][CH2:9][C:45]2[CH:44]=[CH:6][CH:5]=[CH:4][CH:17]=2)[C:17]2[CH:16]=[C:15]3[C:10]([N:11]([CH3:27])[C:12](=[O:26])[CH2:13][O:14]3)=[CH:9][C:8]=2[O:7][C:6]1([CH3:32])[CH3:33]
Reactant: CN1C(=O)C(CCc2ccccc2)Oc2cc3c(c(C(C)(C)C)c21)OC(C)(C)[C@H](O)[C@H]3OC(N)=O
Reactant: CCOCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1C(=O)COc2cc3c(cc21)OC(C)(C)[C@H](O)[C@H]3NCCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of t-butyl(2-phenylethyl)(7R*,8S*)-[7-hydroxy-4,6,6-trimethyl-3-oxo-4,6,7,8-tetrahydro-1,5-dioxa-4-aza-anthracene-8-yl] carbamate (115 mg, 0.24 mmol) in ether (2.2 mL), 4 mol/L hydrogen chloride-dioxane (500 μL) was added at room temperature, and the resulting mixture was stirred at room temperature for 5 hours and then at 50° C. for 30 minutes. Upon the completion of the reaction, saturated aqueous sodium hydrogencarbonate solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/2) and the aimed product was obtained (yield: 76%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:34]1[CH2:33][CH2:32][CH:31]([C:27]2[O:26][CH:30]=[CH:29][N:28]=2)[CH2:36][CH2:35]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Reactant: c1coc(C2CCNCC2)n1
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ncco4)CC3)cnc12
Yield: 72.7 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.20 g, 0.58 mmol) obtained in Example 21, step 4 and 4-(oxazol-2-yl)piperidine (WO2001/036980, 0.11 g, 0.70 mmol), the title compound (0.20 g, 72%) was obtained.
Reaction SMILES: [N:1]1([C@H:10]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([OH:14])[CH2:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:31]1C=CC=C[CH:32]=1>C(OCC)(=O)C.CN>[N:1]1([C@H:10]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C@H:11]([OH:14])[CH2:12][NH:31][CH3:32])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccncc1
Reactant: OC[C@@H](O)[C@@H](c1cccs1)n1ccc2ccccc21
Agent: CN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CNC[C@@H](O)[C@@H](c1cccs1)n1ccc2ccccc21
Reaction time: 2 h

Procedure:
(2S,3S)-3-(1H-indol-1-yl)-3-thien-2-ylpropane-1,2-diol (250 mg, 0.91 mmol) was dissolved in pyridine (3 mL), para-toluenesulfonyl chloride (216 mg, 1.13 mmol) was added and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate and washed with water, a saturated aqueous solution of copper sulfate, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0%-100% ethyl acetate in hexane) to afford 360 mg that was immediately dissolved in methylamine (8M solution in ethanol, 15 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via flash column chromatography (silica, gradient 2%-10% methanol saturated with ammonia in chloroform) to give 180 mg of (1S,2R)-1-(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol as a colorless oil. The freebase was dissolved in ether (5 mL) and treated with a 1N ethereal solution of hydrochloric acid (0.63 mL, 0.63 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 193 mg (60%) of (1S,2R)-1(1H-indol-1-yl)-3-(methylamino)-1-(2-thienyl)propan-2-ol hydrochloride. HRMS: calcd for C16H18N2OS+H+, 287.12126; found (ESI, [M+H]+), 287.1204
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:7]([CH3:26])=[N:6][C:5]=1[CH3:27])(=[O:3])[NH2:2].CCN=C=NCCCN(C)C.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][C:5]1[C:4]([C:1]([NH2:2])=[O:3])=[N:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C@H:16]3[CH2:17][CH2:18][C@H:19]([CH2:22][C:23]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:24])[CH2:20][CH2:21]3)=[CH:14][CH:15]=2)=[C:7]([CH3:26])[N:6]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1nc(C)c(-c2ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc2)nc1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C)c(-c2ccc([C@H]3CC[C@H](CC(=O)NS(C)(=O)=O)CC3)cc2)nc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1 (30 mg, 0.082 mmol) in DCM was added DMAP (2 mg, 0.02 mmol), TEA (16 μL, 0.122 mmol), EDCI (20 mg, 0.11 mmol) and finally methanesulfonamide (11 mg, 0.11 mmol, CAS 3144-09-0). The solution was stirred at RT overnight. The crude was concentrated and purified by HPLC (acidic). Evaporation and co-evaporation with toluene gave title compound (22 mg, 60%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:9]=2)=[C:4]([CH3:16])[N:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH:13]1([C:10]2[N:9]=[C:8]([C:5]3[N:6]([CH3:7])[C:2]([C:24]#[C:23][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:3][C:4]=3[CH3:16])[O:12][N:11]=2)[CH2:15][CH2:14]1
Reactant: C#Cc1ccccc1
Reactant: Cc1nc(Br)n(C)c1-c1nc(C2CC2)no1
Product: Cc1nc(C#Cc2ccccc2)n(C)c1-c1nc(C2CC2)no1

Procedure:
The title compound, white solid, m.p. 120° C. and MS: m/e=305.2 (M+H+), was prepared from 5-(2-bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-cyclopropyl-[1,2,4]oxadiazole and phenylacetylene in accordance with the general procedure of example 12c.