Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:35]2[CH:47]=[CH:46][C:38]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:35]2[CH:36]=[CH:37][C:38]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:46][CH:47]=2)[CH:3]=1)=[O:15]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide (0.30 g, 0.72 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.26 g, 0.865 mmol) and Pd(PPh3)4 (0.042 g, 0.036 mmol) in 1,4-dioxane (6 mL) was purged with argon for 10 min. 2M Na2CO3 solution (0.27 g, 2.54 mmol) was then added before an additional argon purged for 10 min. The reaction mixture was stirred at 80° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give corresponding N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(4-(morpholinomethyl)phenyl)-1H-indazole-4-carboxamide (0.20 g, 55.7%). LCMS: 514.25 (M+1)+; HPLC: 99.71% (@ 254 nm) (Rt; 5.075); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 8.63 (t, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.81 (d, 2H, J=6.8 Hz), 7.43 (d, 2H, J=7.6 Hz), 5.88 (s, 1H), 5.17-5.14 (m, 1H), 4.38 (d, 2H, J=3.2 Hz), 3.59 (m, 4H), 3.52 (s, 2H), 2.38 (m, 4H), 2.21 (s, 3H), 2.12 (s, 3H), 1.49 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26]>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2([OH:26])[C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(-c2ccccc2)cc1
Product: COc1ccc(-c2ccccc2)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 50 %

Procedure:
With 18.4 g of 4-methoxybiphenyl and 15.1 g of 5-chloroisatin as starting materials, 15.2 g of the title compound (yellow solid) was obtained by a similar method to Step 245-1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=[O:10])[CH:3]=1
Reactant: Cc1nc(Br)cc(CO)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1nc(Br)cc(C=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a cold solution of (6-bromo-2-methylpyrimidin-4-yl)methanol (15 g, 73.9 mmol, Preparation #4) in DCM (300 mL) was added Dess-Martin periodinane (47.0 g, 111 mmol). The resulting suspension was allowed to warm to RT and stirred for about 2 h. The reaction mixture was re-cooled to about 0° C., quenched with sodiumthiosulphate solution (200 mL) and stirred vigorously for about 30 min. The organic layer was separated and washed successively with saturated sodium bicarbonate (2×200 mL), water (1×200 mL) and brine (1×200 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 6-bromo-2-methylpyrimidine-4-carbaldehyde 11 g (74.1%), 1H NMR (400 MHz, DMSO) δ: 9.88 (s, 1H), 7.96 (s, 1H), 2.73 (s, 3H), IR Neat 1720 (C═O) cm−1
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:29][C:30]4[S:31][C:32]5[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=5[N:34]=4)=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1c(C)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (Preparation 1) (200 mg), 2-bromomethylbenzothiazole (147 mg), Cs2CO3 (263 mg) in 3 mL CH3CN and 3 mL DMF was stirred at 60° C. for 4 hours. The mixture was poured onto water, extracted with EtOAc, washed twice with brine, dried (MgSO4), and evaporated. Chromatography of the residue on silica gel eluting with hexane/EtOAc 4:1 provided the title compound as a solid.
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:16]([O:23][CH2:24][C:25]([OH:27])=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:28]([NH:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1COCC1.O>[CH2:28]([N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[C:25](=[O:27])[CH2:24][O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCNCCCC
Reactant: O=C(O)COCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCN(CCCC)C(=O)COCc1ccccc1
Reaction time: 0.17 h

Procedure:
3 g of N-methylmorpholine and 4 g of isobutyl chloroformate were successively added dropwise to 5 g of 2-benzyloxyacetic acid in 50 ml of THF at −10° C. The mixture was stirred for 10 minutes and then 5 ml of di-n-butylamine and a further 3 g of N-methylmorpholine were added. After one hour, the mixture was added to 500 ml of water and extracted several times with ether. The collected organic phases were dried over magnesium sulfate and, after removal of the solvent by distillation, 7 g of an oil were isolated and were immediately employed further.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[N:26][CH:27]=1)=[C:5]([CH3:20])[C:6]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[N:7]2.[NH2:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[NH2:31][C:32]1[N:37]=[C:36]([C:24]2[CH:23]=[C:22]([NH:21][C:4]3[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[N:7]=[C:6]([C:13]4[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=4)[C:5]=3[CH3:20])[CH:27]=[N:26][CH:25]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(B(O)O)c3)c2C)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(-c4ccnc(N)n4)c3)c2C)c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A screw-cap vial was charged with 5-(5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-ylamino)pyridin-3-ylboronic acid (200 mg, 0.49 mmol), 2-amino-4-chloropyrimidine (63.8 mg, 0.49 mmol), bis(triphenylphosphine)palladium (II) chloride (34.6 mg, 0.049 mmol), sodium carbonate (157 mg, 1.48 mmol), 1,4-dioxane (4 mL), and water (1 mL). The solution was stirred at 95° C. for 30 min, and then cooled to rt. The product was extracted with EtOAc and DCM, and the combined organic layer was dried over magnesium sulfate and cond. The crude material was purified by flash-chromatography (basic alumina, 0-10% MeOH in DCM, then recrystallized in MeOH to afford N-(5-(2-aminopyrimidin-4-yl)-pyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=456.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (1H, s), 8.63 (1H, d, J=1.8 Hz), 8.56 (1H, d), 8.31 (1H, d, J=5.3 Hz), 8.13 (1H, d), 7.75 (1H, s), 7.70 (1H, m), 7.60 (1H, m), 7.49 (1H, m), 7.35 (1H, m), 7.09 (1H, s), 6.68 (2H, s), 2.45 (3H, s), 2.20 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH3:17])[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:13]=2[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:34])C=CC=CC=1.C(N(C(C)C)CC)(C)C.[C:53]([OH:57])(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH3:17])[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:13]=2[CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:53]([C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH3:17])[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:13]=2[CH:26]=1)([OH:57])=[O:34]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)O
Agent: Cc1nc2ccc(NC(=O)OC(C)(C)C)cc2n1Cc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl

Procedure:
) 6-t-Butoxycarbonylamino-1-(2-chlorobenzyl)-2-methylbenzimidazole By using the method of example 1, 6-t-butoxycarbonylamino-1-(2-chlorobenzyl)-2-methylbenzimidazole (0.760 g) is obtained from 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (1.01 g), diphenylphosphorylazide (1 ml), diisopropylethylamine (1 ml), and t-butylalcohol (25 ml). 1H-NMR (CDCl3, δ): 1.49 (9H, s), 2.47 (3H, s), 5.37 (2H, s), 6.41(1H, d, J=7.5 Hz), 6.55 (1H, br s), 6.93 (1H, dd, J=1.9 and 8.6 Hz), 7.08 (1H, t, J=7.5 Hz), 7.22 (1H, t), 7.44(1H, d, J=8.0 Hz), 7.62 (2H, d, J=8.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][CH2:32][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=5)=[CH:3][CH:4]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(N)cc1
Reactant: O=Cc1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(NCc2ccccn2)cc1
Reaction time: 24 h
Yield: 40 %

Procedure:
To a stirred mixture of 7-(4-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.150 g, 0.43 mmol), 2-pyridinecarboxaldehyde (81 μl, 0.85 mmol) and acetic acid (18 μl, 0.31 mmol) in anhydrous MeOH (3 ml) under nitrogen was added sodium cyanoborohydride (0.02 g, 0.32 mmol) and the mixture was stirred for 24 h. The mixture was quenched with saturated aqueous K2CO3 (0.5 ml) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to give 0.076 g (39.7%) of the title compound as a yellow solid; 1H NMR (360 MHz, DMSO-d6) δ12.32 (1H, br s), 8.57 (1H, d, J 2.1 Hz), 8.47 (1H, s), 8.14 (2H, d, J 8.7 Hz), 7.77 (1H, t, J 7.5 Hz), 7.43 (3H, m), 7.25 (3H, m), 6.68 (2H, d, J 8.3 Hz), 6.56 (2H, t, J 2.5 Hz), 4.41 (2H, d, J 5.8 Hz), 2.26 (3H, s); MS (ES+) m/z 442/444 [MH]+, 221/222 [(M+2H)/2]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:18]=3)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:12]=2)=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:18]=3)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:12]=2)=[O:10])[CH2:3]1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCNC2)c2nc(C3CC3)cnc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCN(S(C)(=O)=O)C2)c2nc(C3CC3)cnc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
In a 15 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid piperidin-3-ylamide hydrochloride (200 mg, 0.44 mmol) was dissolved in CH2Cl2 (3 mL) and cooled to 0° C. Added triethylamine (0.12 mL, 0.88 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.48 mmol). The reaction mixture was stirred at room temperature for 6 h then diluted with 30 mL of CH2Cl2 and washed with water (5 mL). The aqueous layer was extracted with CH2Cl2 (30 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography over 12 g SiO2 with EtOAc/Hexanes (gradient: 0-100% EtOAc) to provide 174 mg (89%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-yl)-amide as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH2:13][CH2:14][CH2:15][OH:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH3:17])[CH2:13][CH2:14][CH2:15][O:16][C:10]1=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(CCCO)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1(C)CCCOC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.3 %

Procedure:
2-(t-Butyloxycarbonyl)amino-2-methyl-5-hydroxypentanoic acid (3.0 g, 0.012 mol) and EDC (2.56 g, 0.013 mol) were dissolved in DMF (20 mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated to dryness, and the residue was partitioned between EtOAc (30 mL)-H2O (30 mL), the organic layer separated, washed with brine and dried (Na2SO4). Filtration, concentration, and chromatography (SiO2, EtOAc: hexane, 1:3) gave 0.86 g (31%) of the title compound. 1H NMR (CDCl3) δ5.1 (br s, 1H), 4.35-4.55 (m, 2H), 2.49-2.64 (m, 1H), 1.78-2.1 (m, 3H), 1.45 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[C:6]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)[CH:7]=1.Br[CH:22]([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]#[C:16][Si:17]([CH3:19])([CH3:18])[CH3:20])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:22]([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10](=[O:14])[CH:9]=2)[CH:7]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cc1-c1cc[nH]c(=O)c1
Product: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C#C[Si](C)(C)C)cc1=O

Procedure:
125 mg (purity 91%, 0.38 mmol) of 4-{5-chloro-2-[(trimethylsilyl)ethynyl]phenyl}pyridin-2(1H)-one and 1.2 eq. of tert-butyl 2-bromopropanoate (racemate) were reacted at 80° C. according to General Method 4B. Yield: 56 mg (purity 89%, 31% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:6][CH:7]=1)=[O:36]
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Reactant: O=C=Nc1ccccc1Cl
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=O)Nc2ccccc2Cl)c1

Procedure:
The title compound was prepared from ethyl 4-(3-aminophenyl)-8-(trifluoromethyl)quinoline-3-carboxylate and 2-chlorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 511.9.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:5]=12.[BH4-].[Na+].O.ClCCl.CO>CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1ccc2nccn2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: OCc1ccc2nccn2c1
Yield: 57 %

Procedure:
0.90 g of the 6-imidazo[1,2-a]pyridinecarbaldehyde prepared in the Preparative Example 5 was dissolved in 20 ml of methanol. The obtained solution was stirred under cooling with ice, followed by the addition of 90 mg of sodium borohydride. The obtained mixture was stirred for 50 minutes, followed by the addition of water. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1 to 10:1) to give 0.52 g of the title compound as a faintly orange-yellow solid (yield: 57%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.[N+:52]([O-])([OH:54])=[O:53]>C(#N)C>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[C:5]([N+:52]([O-:54])=[O:53])=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(C)c([N+](=O)[O-])c2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 70 °C
Yield: 32.7 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in acetonitrile (1 mL) was added zirconyl(IV) nitrate hydrate (36 mg, 0.16 mmol). The reaction mixture was heated to 70° C. for 1 h. After cooled to room temperature, the reaction mixture was filtered through a micro filter and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative TLC (silica gel, 96:4 chloroform/methanol) and semi-preparative HPLC to afford (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-4-nitro-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (34 mg, 33%) as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.23 (s, 1H), 12.27 (br s, 1H), 8.19 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.89 (s, 1H), 5.31 (s, 1H), 5.19 (s, 1H), 4.69 (d, J=8.5 Hz, 1H), 4.61 (s, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.76-3.65 (m, 2H), 3.61 (s, 3H), 3.49 (dd, J=19.5, 6.5 Hz, 1H), 3.40 (s, 3H), 3.39-3.35 (m, 1H), 3.28 (d, J=19.5 Hz, 1H), 3.13 (t, J=9.5 Hz, 1H), 2.47 (d, J=4.5 Hz, 1H), 2.40 (s, 3H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 743 (M+H); HPLC 98.0% (AUC), tR 13.79 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[CH3:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[NH:8][C:4]1[CH:3]=[C:2]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([CH3:16])[CH:18]=2)[N:7]=[CH:6][N:5]=1
Reactant: Cc1cccc(N)c1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Product: Cc1cccc(Nc2cc(Nc3cccc(C)c3)ncn2)c1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 2, 6-chloro-4-(3'-methylanilino)pyrimidine was reacted with 3-methylaniline to give 4,6-di-(3'-methylanilino)pyrimidine in 25% yield, m.p. 242°-244° C.;
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[NH:18][C:19](=[O:25])[C:20]([O:22]CC)=[O:21])=[O:15])[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+:31]>C(O)C>[CH:2]1([N:8]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[NH:18][C:19](=[O:25])[C:20]([O-:22])=[O:21])=[O:15])[CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1.[Na+:31]
Reactant: CCOC(=O)C(=O)Nc1ccccc1C(=O)NC1CCN(C2CCCCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C(=O)Nc1ccccc1C(=O)NC1CCN(C2CCCCC2)C1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A stirred solution of 4.2 g. of ethyl 2-(1-cyclohexyl-3-pyrrolidinylaminocarbonyl)oxanilate hydrochloride in 20 ml. of 50% aqueous ethanol was treated dropwise with 19.5 ml. of 1.03 N sodium hydroxide. After thirty minutes the solution was heated to 50° C. and poured into 130 ml. of boiling ethanol. After the mixture cooled to room temperature it was kept at 4° C. for two days and the amorphous sodium salt was collected by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.CN([CH:29]=[O:30])C>>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([N:12]2[CH2:11][CH2:10][C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[NH:1][C:29]2=[O:30])[CH2:14][CH2:15]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(N)c(CCNC2CCN(Cc3ccccc3)CC2)c1
Product: COc1ccc2c(c1)CCN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
35.0 g (216 mmol) N,N′-carbonyldiimidazole were added to 23.9 g (70.3 mmol) [2-(2-amino-5-methoxyphenyl)-ethyl]-(1-benzylpiperidin-4-yl)-amine in 175 mL DMF and the mixture was stirred for 2 h at 100° C. The reaction mixture was poured onto approx. 1 kg ice water and stirred overnight. The precipitated product was suction filtered, washed with 100 mL water and dried. The residue was stirred with 150 mL DIPE and suction filtered. The solid product was washed with 50 mL DIPE and dried.
Reaction SMILES: [CH3:1]O.C[Si](C=[N+]=[N-])(C)C.[Br:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:12]([OH:14])=[O:13]>C1(C)C=CC=CC=1>[CH3:1][O:13][C:12](=[O:14])[CH:11]([Br:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: CO
Reactant: O=C(O)C(Br)c1ccccc1Cl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)C(Br)c1ccccc1Cl
Yield: 86 %

Procedure:
Methanol (1 mL) was added to toluene (10 mL) under an argon atmosphere at room temperature. The flask was cooled in a water bath and 2M (trimethylsilyl)diazomethane (5 mL, 10 mmol) was added, followed by α-bromo-2-chlorophenyl acetic acid (2.2 g, 8.81 mmol) in portions over 5 minutes. After 10 additional minutes, the toluene/methanol was removed under reduced pressure. The crude oil was purified by MPLC (companion) on a silica cartridge (40 g) with a gradient of ethyl acetate in heptane (10% to 50%) over 20 minutes. The product containing fractions were combined, concentrated, and dried under high vacuum for 1 hour at room temperature to provide bromo-(2-chlorophenyl)-acetic acid methyl ester (2.0 g, 86% yield) as a clear liquid that solidified at low temperatures (−10° C.). 1H NMR (300 MHz, CDCl3/TMS): δ=7.75 (d, 1H, J=6.9 Hz), 7.39-7.26 (m, 3H), 5.91 (s, 1H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ=168.29, 133.82, 133.30, 130.93, 130.47, 129.83, 127.66, 53, 80, 43.08.