Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@H:10]([C:23]([O:25]CC)=O)[CH2:9]1.[OH-].[Na+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.[CH3:48][NH:49][O:50][CH3:51].Cl>C(O)C.CN(C)C=O.O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:51][O:50][N:49]([CH3:48])[C:23]([C@@H:10]1[CH2:9][C@@H:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:12][N:11]1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[O:25]
Reactant: CCOC(=O)[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1
Reactant: CNOC
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCO
Product: CON(C)C(=O)[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
In 127 ml of ethanol is dissolved 12.7 g of 1-benzyl 2-ethyl (2S,4R)-4-(tetrahydro-2H-pyran-2-yloxy)-1,2-pyrrolidinedicarboxylate. After adding 37.0 ml of 1 mol/L sodium hydroxide solution at 5-10° C., the mixture thus obtained is stirred at ambient temperature for 1.5 hours. The solvent is distilled off from the reaction mixture under reduce pressure, the residue thus obtained is dissolved in 90 ml of N,N-dimethylformamide, 10.9 ml of diphenylphosphoryl azide, 14.1 ml of triethylamine and 3.94 g of N,O-dimethylhydroxylamine hydrochloride are successively added at 5-10° C., and the mixture thus obtained is stirred at ambient temperature for one hour. Ethyl acetate and water are added to the reaction mixture, pH is adjusted to 6.5 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1) to obtain 3.75 g of benzyl (2S,4R)-2-{[methoxy(methyl)amino]carbonyl}-4-(tetrahydro-2H-pyran-2-yloxy)-1-pyrrolidinecarboxylate as a light yellow oily product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][NH:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:13][N:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1)[NH2:15]
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(N(C)N)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methylquinazoline (1.0 g, 5.6 mmol), N-methylhydrazine (0.89 mL, 16.8 mmol) and potassium carbonate (1.3 g, 22.4 mmol) in dry THF (20 mL) by a procedure similar to example 1, step 3 yielding 380 mg (36%) of a beige solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:24])[NH:16]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
The mixture of rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (900 mg, 1.89 mmol) in trifluoroacetic acid (10 mL) was stirred at room temperature for 0.5 h. Then the solution was concentrated and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated to give 0.6 g of rac-6-chloro-3-(3-chloro-benzyl)-3-piperazin-1-yl-1,3-dihydro-indol-2-one as a yellow solid. MS m/z 376 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:18]([NH:19][C@@H:20]3[CH2:24][CH2:23][C@@:22]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:25])[C:21]3([CH3:36])[CH3:35])=[C:17]([C:37](=[O:39])[NH2:38])[CH:16]=[N:15][N:14]2[CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.CO.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:37]([C:17]1[CH:16]=[N:15][N:14]2[CH:40]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=[C:13]2[C:18]=1[NH:19][C@H:20]1[CH2:24][CH2:23][C@@:22]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:25])[C:21]1([CH3:36])[CH3:35])(=[O:39])[NH2:38]
Reactant: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1(C)C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1(C)C
Temperature: 100 °C
Yield: 81.8 %

Procedure:
To a vial charged with a solution of phenylboronic acid (215 mg, 1.760 mmol), PdCl2(dppf)-CH2Cl2 adduct (47.9 mg, 0.059 mmol) and tert-butyl (((1S,3R)-3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)methyl)carbamate (290 mg, 0.587 mmol) in 1,4-dioxane (3.91 ml) was added a 2 M aqueous solution of potassium phosphate (880 μl, 1.760 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 2 hrs. The reaction was diluted with methanol (10 ml), filtered, and concentrated, yielding a dark oil. The oil was taken up in ethyl acetate (50 ml). The solution was washed successively with water and brine. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a dark oil. The oil was dissolved in 10% methanol-DCM (5 ml). The crude product mixture was loaded directly on a prepacked silica gel column. The crude product was purified via medium pressure chromatography (0-10% methanol-DCM solvent system over 25 minutes). The desired tert-butyl (((1S,3S)-3-((3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethyl-cyclopentyl)methyl)carbamate (236 mg, 0.480 mmol, 82% yield) was obtained as a white solid. ESI-MS m/z 492.4 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[C:5]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])\[CH3:13])=[C:4]([OH:20])[C:3]=1[CH:21]=[O:22].[H][H]>[Pd].C(O)C>[Cl:8][C:7]1[C:2]([CH3:1])=[C:3]([C:4]([OH:20])=[C:5]([CH2:10][CH2:11][CH:12]([CH3:13])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=1[OH:9])[CH:21]=[O:22]
Reactant: CC(C)=CCC/C(C)=C/Cc1c(O)c(Cl)c(C)c(C=O)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cl)c(O)c(CCC(C)CCCC(C)C)c(O)c1C=O
Yield: 21.9 %

Procedure:
An ethanol solution (24.5 ml) of colletochlorin B (991 mg, 3.07 mmol) described in H. Saimoto et al., Bull. Chem. Soc. Jpn., 67, 1178 (1994) was stirred in the presence of 5% Pd/C (496 mg) at 0° C. in a hydrogen atmosphere for 4.5 hours. After the catalyst was separated by filtration with the use of Celite, the filtrate was concentrated to obtain a crude product (963 mg). This product was purified by silica gel column chromatography (hexane:diethyl ether=30:1) to obtain 3-chloro-4,6-dihydroxy-5-(3,7-dimethyloctyl)-2-methylbenzaldehyde (pale yellow solid 220 mg, yield 22%).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CCCNC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCC(CO)C1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), piperidine-3-methanol (2.9 g), a 1.6M solution of butyllithium in hexane (31 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethyl acetate, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine-3-methanol (1 g), melting at 142° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[CH3:11][C@H:12]([NH2:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:21][C@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: C[C@H](N)CCc1ccccc1
Reactant: N#Cc1c(Br)ccnc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CCc1ccccc1)Nc1ccnc(Br)c1C#N
Yield: 60.2 %

Procedure:
Prepared according to the methods above using 2,4-dibromonicotinonitrile (100 mg, 0.382 mmol), (S)-1-Methyl-3-phenyl-propylamine (58.1 mg, 0.382 mmol) and Hunig's Base (0.080 mL, 0.458 mmol) in DMF (1.5 mL) at 120° C. for 30 min to give the desired product as a clear oil (76 mg). LC/MS (316/318, [M−H]/[M+H]+); 1H NMR (400 MHz, CHLOROFORM-d) δ 8.05 (d, J=5.5 Hz, 1H), 7.33-7.25 (m, 2H), 7.23-7.15 (m, 3H), 6.81 (d, J=5.3 Hz, 1H), 5.06 (br. s., 1H), 4.33 (dt, J=14.0, 6.9 Hz, 1H), 2.71 (t, J=8.0 Hz, 2H), 1.98-1.83 (m, 2H), 1.32-1.25 (m, 3H).
Reaction SMILES: [C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O.[C:43](O)(=O)[C:44]1[C:45](=[CH:47][CH:48]=[CH:49][CH:50]=1)[OH:46].NC(N)=O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([O:8][CH2:43][C:44]1[C:45](=[CH:47][CH:48]=[CH:49][CH:50]=1)[OH:46])=[O:7])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccccc1O
Reactant: C=C(C)C(=O)NC1=CC(C(=O)O)C(O)(C(C)=O)C=C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(N)=O
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: C=C(C)C(=O)NC1=CC(C(=O)OCc2ccccc2O)C(O)(C(C)=O)C=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-acetyl-5-methacrylamidosalicylic acid (1 part by mole), dicyclohexyl carbodiimide (1.1 part by mole) in dry dichloromethane is added N-hydroxysuccinimide. To the solution is further added salicylic acid (1.1 part by mole). The solution is stirred at room temperature overnight. After the reaction, the precipitate including dicyclohexyl carbodiimide urea is removed by filtration. The solution is washed by distilled water three times, by an aqueous solution of 5% by weight of acetic acid three times, and further by distilled water three times. The solution is filtrated again to remove the precipitate. The solvent is removed by evaporation, and the residue is recrystallized to give salicyl 2-acetyl-5-methacrylamidosalicylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Li+].[Cl-].C([Cu])#N.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[C:6]([F:8])[C:7]=1[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O=C(Cl)c1ccccc1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
2,4-Difluoro-1-nitrobenzene 15 (159 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. CuCN.2LiCl (1.0 M solution in THF, 1.1 mL, 1.1 mmol) was slowly added at −40 ° C. and the reaction mixture was stirred at the same temperature for 30 min. Then, benzoyl chloride (281 mg, 2.0 mmol) was added dropwise at −40° C. and the resulting mixture was allowed to warm up slowly to 25° C. overnight. The reaction mixture was then quenchend with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:2) furnished compound 17b (221 mg, 84%) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([F:23])=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 4-fluorobenzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 452.0 (M)+
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]3[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:15]([NH:24][S:25]([C:28]3[S:29][C:30]([Cl:33])=[CH:31][CH:32]=3)(=[O:27])=[O:26])=[N:14]2)=[CH:8][CH:7]=1.[C:34](O)(=[O:36])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.C(Cl)Cl.O>[Cl:33][C:30]1[S:29][C:28]([S:25]([NH:24][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[N:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:5][NH:4][C:34](=[O:36])[CH3:35])=[CH:11][CH:10]=3)[N:14]=2)(=[O:27])=[O:26])=[CH:32][CH:31]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(CN)cc1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: O=CO
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(CNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A solution of N-[1-{[4-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide formate salt for a preparation see Intermediate 30) (15 mg, 0.03 mmol) and acetic acid (0.001 mL, 0.03 mmol) in acetonitrile (2 mL) and DIPEA (0.046 mL, 0.26 mmol) was treated with HATU (37.0 mg, 0.097 mmol) and the resulting mixture was stirred for 2 h and 15 min at ambient temperature. The reaction mixture was diluted with DCM (2 mL) and water (3 mL). The organic was separated and the aqueous layer was further extracted with DCM (2 mL). The combined organic solutions were dried through an hydrophobic frit and concentrated under reduced pressure. The residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus to give the title compound (13 mg, 87%) as a gum. LCMS (System A) RT=1.11 min, ES+ve m/z 505/507 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10]CC)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.O.[NH2:14][NH2:15]>C(O)C.C(OCC)C>[CH3:1][C:2]1[C:3]([C:8]([NH:14][NH2:15])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1ncccc1C
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: Cc1cccnc1C(=O)NN
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 3-methylpyridine-2-carboxylate (2 g, 12.11 mmol, CAS [58997-10-7], commercially available e.g. from Beta Pharma) was dissolved in ethanol (40 mL) and treated with hydrazine monohydrate (0.706 mL, 14.53 mmol). The reaction mixture was stirred at room temperature for 15 mins before heating at reflux for 18 hours. The reaction mixture was cooled to room temperature, more hydrazine monohydrate (0.5 ml) was added, and the reaction mixture was heated at reflux for a further 24 hours. The reaction mixture was cooled to room temperature. The solvent was evaporated to near dryness, and the residue was azeotroped with ethanol (3×35 ml). The mixture was evaporated to dryness after the third time to afford a pale yellow solid. This solid was slurried in diethyl ether, filtered off and dried to afford the title compound as a white solid (0.575 g, 3.80 mmol).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:13]=1)=O>CO>[O:3]=[C:2]1[NH:4][C:5](=[O:6])[C:7](=[CH:10][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=3)[CH:13]=2)[C:8](=[O:9])[NH:1]1
Reactant: N#Cc1ccc(Cn2cc(C=O)c3ccccc32)cc1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CO
Product: N#Cc1ccc(Cn2cc(C=C3C(=O)NC(=O)NC3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of barbituric acid (1.28 g; 0.01 mol) and 4-((3-formyl-1H-indol-1-yl)methyl)benzonitrile (2.60 g; 0.01 mol) in methanol (50 ml) were stirred at room temperature. After 10 min the reaction mixture became a solid suspension and the color of reaction mixture changed to yellow color solid suspension. The suspension continued to stir at room temperature for 5 hrs. Solid product was separated by filtration and washed several times with cold methanol (3×5 ml). The isolated yellow solid recrystallized from methanol gave (1) as a yellow crystalline product; m.p. >300° C.; 1H NMR (DMSO-d6): δ 5.81 (s, 2H), 7.33-7.36 (m, 2H), 7.43-7.45 (d, 2H), 7.61-7.64 (m, 1H), 7.82-7.84 (d, 2H), 7.90-7.93 (m, 1H), 8.68 (s, 1H), 9.63 (s, 1H), 11.07 (bs, 1H), 11.15 (bs, 1H); 13C NMR (DMSO-d6): δ 49.7, 109.4, 110.5, 110.8, 111.8, 117.9, 118.4, 123.0, 123.8, 128.0, 129.6, 132.6, 136.1, 141.7, 141.8, 142.6, 159.2, 162.9, 164.1.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([CH2:28][N:29]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]4=[O:39])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([CH2:28][N:29]4[C:37](=[O:38])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[C:30]4=[O:39])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4cc(CN5C(=O)c6ccccc6C5=O)ccn34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Reaction time: 0.33 h

Procedure:
To a solution of 2-((3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione (1.012 g, 1.889 mmol) and silica gel (3 g) in THF (20 mL) was added TBAF (2.267 mL, 2.267 mmol) (1M in THF). The reaction was stirred for 20 minutes, then filtered and washed with DCM/MeOH (10:1). The combined organics were concentrated in vacuo to afford the desired crude product.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13]O)[O:10][N:9]=1)=[O:7])[CH3:4].CCN(CC)CC.S([Cl:26])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][Cl:26])[O:10][N:9]=1)=[O:7])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(CO)on1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CCl)on1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-hydroxymethyl-isoxazole-3-carboxylic acid ethyl ester (3.00 g, 17.53 mmol) in dry CH2Cl2 (30.0 mL) was treated at 0° C. with Et3N (3.17 mL, 22.79 mmol) followed by DMAP (214 mg, 1.75 mmol) and Ms-Cl (2.04 mL, 26.29 mmol). The reaction mixture was stirred at rt for 4 h before being quenched with water (50 mL), extracted with CH2Cl2 (50 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 5-chloromethyl-isoxazole-3-carboxylic acid ethyl ester as an orange oil. A solution of 1.01 g of this crude material in acetone (8.0 mL) was treated, under inert atmosphere (N2) with K2CO3 (1.260 g, 9.12 mmol) followed by 4-nitro-1H-pyrazole (343 mg, 3.04 mmol) and TBA bromide (195 mg, 0.61 mmol). The resulting mixture was stirred at rt overnight. Water (50 mL) and EA (50 mL) were added. The aq. layer was extracted with EA (50 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC: rf (50:50 hept-EA)=0.31. LC-MS-conditions 02: tR=0.86 min.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19]C)[C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:34][CH:33]=[CH:32][CH2:31]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].B>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([OH:19])[C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:31][CH:32]=[CH:33][CH2:34]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:36][CH:37]=1
Reactant: COc1cccc2c1N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Agent: B
Agent: [Br-]
Solvent: ClCCl
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3cccc(O)c32)cc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7 mg (0.014 mmol) of 4-(4-chlorobenzoyl)-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-9-methoxy-1,3,4,5-tetrahydrobenzo[e][1,4]-diazepin-2-on was dissolved in 10 ml of dichloromethane. 1.0 ml of borane tribromide was added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:25].Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.C(OC([N:51]([CH:65]([CH3:67])[CH3:66])[CH2:52][C:53]([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=1)([OH:57])[C:54](O)=[O:55])=O)(C)(C)C>C(Cl)Cl>[Cl:64][C:61]1[CH:60]=[CH:59][C:58]([C:53]([OH:57])([CH2:52][NH:51][CH:65]([CH3:66])[CH3:67])[C:54]([N:40]2[CH2:39][CH2:38][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:42][CH2:41]2)=[O:55])=[CH:63][CH:62]=1.[ClH:25]
Reactant: CC(C)N(CC(O)(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)NCC(O)(C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid (35 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was subject to column chromatography, eluted by DCM/MeOH (40:1). The resulting product was treated with HCl (4M, 2 mL) to afford 2-(4-chlorophenyl)-2-hydroxy-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one as HCl salt (22 mg, 48%).