Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22](C(OCC)=O)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[BrH:30]>>[BrH:30].[BrH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Product: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Yield: 82 %

Procedure:
A mixture of 3.2 parts of ethyl 4-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-ylamino]-1-piperidinecarboxylate and 300 parts of hydrobromic acid solution 48% was stirred and refluxed for 1 hour. The reaction mixture was evaporated and the residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 3.3 parts (82%) of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide; mp. 290.2° C. (compound 112).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([N:11]=[CH:12][C:13]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:14][C:15]3([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[O:25][CH3:26])[CH2:17][CH2:16]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CCCCCC.C(OCC)(=O)C>CO.O1CCCC1>[N:1]1[C:10]2[C:5](=[C:6]([NH:11][CH2:12][C:13]([C:28]([F:31])([F:29])[F:30])([OH:27])[CH2:14][C:15]3([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[O:25][CH3:26])[CH2:16][CH2:17]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(C=Nc2cccc3ncccc23)C(F)(F)F)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(F)cc1C1(CC(O)(CNc2cccc3ncccc23)C(F)(F)F)CC1

Procedure:
810 mg (1.87 mmol) of 1-(quinolin-5-ylimino)-3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-(trifluoromethyl)propan-2-ol is reacted with 288 mg (7.61 mmol) of sodium borohydride in 6.0 ml of methanol and 3.0 ml of tetrahydrofuran as in Example 1. After chromatography on silica gel with hexane-ethyl acetate (0–100%), 660 mg (81% of theory) of the product is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11](O)=[O:12])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:10][C:11]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=2)=[O:12])=[CH:5][C:4]=1[C:19]([F:20])([F:22])[F:21])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Reactant: Nc1ccc(F)cc1
Product: N#Cc1ccc(N(CC(=O)Nc2ccc(F)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and 4-fluoroaniline: MS (APCI) m/z 420 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:26](O)([CH3:28])[CH3:27]>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:26]([CH3:28])[CH3:27])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CC(C)O
Product: CC(C)Oc1ccc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and isopropanol in analogy to Example 9c): MS (ISP): 404.4 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8](=[CH:11]Cl)[CH:9]=O.[NH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.C(C=C)=O>C(Cl)Cl.CN(C)C=O>[Cl:7][C:8]1[CH:9]=[N:13][C:14]2[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[C:15]=2[CH:11]=1
Reactant: NC1CCCC(=O)C1
Reactant: O=CC(Cl)=CCl
Agent: C=CC=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCc2ncc(Cl)cc21

Procedure:
In reaction 3 of Scheme 1, a solution of oxalyl chloride in methylene chloride is added dropwise to a solution of chloromalondialdehyde III in methyene chloride and a phase transfer catalyst, such as dimethylformamide, under inert reaction conditions. The reaction mixture is stirred at room temperature until conversion to the corresponding 2,3-dichloroacrolein is complete. In reaction 4 of Scheme 1, a solution of 1-amino-cyclohexan-3-one VI in dimethylformamide is added dropwise to the above acrolein to form the corresponding 3-chloro-5,6,7,8-tetrahydroquinolin-5-one VII. The reaction, generally carried out overnight, will be in the temperature range between about 60° C. to about 80° C., preferably about 70° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O1C2C(=CC=CC=2)CCC1.Cl.[CH3:61][O:62][C:63]1[CH:64]=[C:65]2[C:70](=[CH:71][CH:72]=1)[CH2:69][CH:68]([NH2:73])[CH2:67][CH2:66]2.C(N(CC)CC)C>ClCCCl>[CH3:61][O:62][C:63]1[CH:64]=[C:65]2[C:70](=[CH:71][CH:72]=1)[CH2:69][CH:68]([NH:73][C:18]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=1)=[O:19])[CH2:67][CH2:66]2
Reactant: COc1ccc2c(c1)CCC(N)C2
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCc5cc(OC)ccc5C4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
A mixture of 4-(6-cyano-4-(methoxycarbonyl)-chroman-7-yloxy)benzoic acid (Preparation 2) (0.0297 g, 0.0841 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.0177 g, 0.0925 mmol), 1-hydroxybenzotriazole monohydrate (0.0142 g, 0.0925 mmol), and 1,2-dichloroethane (1 ml) was stirred at ambient temperature for 20 minutes. A mixture of chroman-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (0.0197 g, 0.0924 mmol), triethylamine (0.0585 ml, 0.4203 mmol)), and 1,2-dichloroethane (1 ml) was added to the activated acid and the mixture was stirred for 17 hours at ambient temperature. The crude mixture was purified on silica gel (MeOH in dichloromethane gradient) to provide 29.5 mg of the title compound as a foamy film (69%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[N:6][CH:7]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:39]=[CH:40][C:41]=1[CH3:42])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=1)=[O:19])#[CH:14]>>[CH3:42][C:41]1[CH:40]=[CH:39][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:36])([F:38])[F:37])[CH:22]=2)=[O:19])=[CH:16][C:15]=1[C:13]#[C:14][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[N:6][CH:7]=1
Reactant: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Reactant: Brc1ccc(-c2ncc[nH]2)nc1
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(-c2ncc[nH]2)nc1

Procedure:
The title compound was prepared using 5-bromo-2-(1H-imidazol-2-yl)pyridine and 3-ethynyl-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide as raw materials, according to the method described in Step 4 of Example 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: NCC(F)(F)F
Product: Cc1cc(F)ccc1-c1nc(NCC(F)(F)F)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 84 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 121 (150 mg, 0.35 mmol), 2,2,2-trifluoro-ethylamine (176 mg, 1.77 mmol) were reacted to give the crude material, which was purified as described in Example 198 to give the desired product 130 mg (84%). LC-MS: 443.0 (MH+, m/z), 2.27 (Rt, min).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].[OH:15][C:16]1[C:25]([CH3:26])=[CH:24][C:19]([C:20]([NH:22]O)=[NH:21])=[CH:18][C:17]=1[CH3:27]>>[CH2:1]([C:5]1[C:6]([CH3:14])=[C:7]([C:11]2[O:13][N:22]=[C:20]([C:19]3[CH:24]=[C:25]([CH3:26])[C:16]([OH:15])=[C:17]([CH3:27])[CH:18]=3)[N:21]=2)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1sc(C(=O)O)c(C)c1CC(C)C
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Product: Cc1cc(-c2noc(-c3sc(C)c(CC(C)C)c3C)n2)cc(C)c1O

Procedure:
4-[5-(4-Isobutyl-3,5-dimethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol is prepared from 4-isobutyl-3,5-dimethyl-thiophene-2-carboxylic acid and 4,N-dihydroxy-3,5-dimethyl-benzamidine in analogy to Example 21; LC-MS: tR=1.20 min, [M+1]=357.35; 1H NMR (D6-DMSO): δ 8.91 (s, 1H), 7.60 (s, 2H), 2.53 (s, 3H), 2.44-2.40 (m, 5H), 2.23 (s, 6H), 1.81-1.72 (m, 1H), 0.89 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[C:4]([CH3:34])[N:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:36]/[OH:37])/[CH2:9][C@H:10]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[C:4]([CH3:34])[N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)cc(C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)=N/O)cc(C)n1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-(2,6-dimethyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white semisolid, MS (ESI−): m/z=463.3 ([M−H]−).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.I[CH3:20]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:20])[CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Clc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.8 %

Procedure:
NaH (60% dispersion in mineral oil, 0.16 g, 7 mmol) was added at 0° C. to 3-(2-chloro-pyrimidin-4-yl)-1H-indole (0.24 g, 1 mmol) in DMF (8 mL). The resulting mixture was stirred for 10 min, then iodomethane (0.20 mL, 3.2 mmol) was added, and the reaction mixture was warmed to RT and poured onto ice water. The resulting mixture was extracted with EtOAc, the combined organics washed twice with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-(2-chloro-pyrimidin-4-yl)-1-methyl-1H-indole (270 mg) as a yellow solid.
Reaction SMILES: [OH-].[K+].O.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.Br[CH2:15][CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:12]#[N:13])[CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccc(Br)cc2)CCC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
KOH (11.4 g, 204 mmol, 8 eq), water (3.75 mL), 4-bromophenylacetonitrile (5.00 g, 25.5 mmol, 1.0 eq), 1,3-dibromopropane (5.15 g, 25.5 mmol, 1.0 eq), tetrabutylammonium bromide (82 mg, 0.26 mmol, 0.01 eq), and toluene (68 mL) were slowly stirred while heating to 100° C. The biphasic reaction was kept at 100° C. for 30 minutes. The heat was removed, the reaction was slightly cooled, the stirring was then increased to rapid, and then heating continued up to reflux, 115° C. After 1.5 hours at 115° C., the reaction was cooled, diluted with water, and extracted with EtOAc (×3). The combined organics were dried with brine and Na2SO4, and then concentrated in vacuo onto Celite. The resulting material was purified by silica gel chromatography by eluting with a gradient of heptane and EtOAc (0% to 35% EtOAc) to provide Compound [CXXXIV]: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.99-2.15 (m, J=11.52, 9.02, 9.02, 4.40, 4.40 Hz, 1H) 2.34-2.51 (m, 1H) 2.51-2.65 (m, 2H) 2.74-2.89 (m, 2H) 7.21-7.36 (m, 2H) 7.45-7.57 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:12]=2[C:13]#[N:14])[CH:7]=[N:8][CH:9]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:22]3[CH:23]=[C:24]4[N:31]([CH3:32])[CH2:30][CH2:29][N:25]4[C:26](=[O:28])[N:27]=3)=[CH:15][C:12]=2[C:13]#[N:14])[CH:7]=[N:8][CH:9]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cncc(Cl)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (5.52 mg, 0.230 mmol) in THF (5 mL), 2-((5-chloropyridin-3-yl)oxy)-5-(hydroxymethyl)ben-zonitrile (30 mg, 0.115 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidi-n-5(1H)-one (21.4 mg, 0.115 mmol).
Reaction SMILES: [F:1][CH:2]([F:47])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:22]([N:24]([CH:41]([CH3:43])[CH3:42])[C@H:25]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:28]([CH2:38][CH:39]=O)[CH2:27][CH2:26]3)=[O:23])[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=2[O:11][C:10]([CH3:45])([CH3:44])[C:9]1=[O:46])=[O:4].Cl.[F:49][C:50]([F:54])([F:53])[CH2:51][NH2:52].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(O)(=O)C>[F:1][CH:2]([F:47])[C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:22]([N:24]([CH:41]([CH3:43])[CH3:42])[C@H:25]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C@@H:28]([CH2:38][CH2:39][NH:52][CH2:51][C:50]([F:54])([F:53])[F:49])[CH2:27][CH2:26]3)=[O:23])[C:16]([C:18]([F:19])([F:21])[F:20])=[CH:17][C:12]=2[O:11][C:10]([CH3:45])([CH3:44])[C:9]1=[O:46])=[O:4]
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CC=O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CCNCC(F)(F)F)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.4 %

Procedure:
To a solution of tert-butyl (2R,5R)-5-[{[4-{2-[(difluoroacetyl)amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]-2-(2-oxoethyl)piperidine-1-carboxylate (377 mg) in ethanol (3 ml) were added 2,2,2-trifluoroethylamine hydrochloride (227 mg), acetic acid (128 μl), sodium triacetoxyborohydride (367 mg), and the mixture was stirred at room temperature for 19 hours. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution (2 ml), and the mixture was extracted with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=99/1) to give the title compound (425 mg).
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].C(=O)([O-])[O-].[K+].[K+].Br[CH2:58][C:59]([NH2:61])=[O:60]>>[NH2:61][C:59](=[O:60])[CH2:58][O: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][CH: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: 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
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)cc2c(c1OCC(N)=O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(NC1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Yield: 15.9 %

Procedure:
Following General Procedure: Method A using (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 (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and bromoacetamide (21 mg, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) and preparative HPLC (45:55 acetonitrile/water with 0.05% TFA) to afford (6R,6aS,14aR)-methyl 1-(2-amino-2-oxoethoxy)-6,8,14a-trihydroxy-11-((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 (6 mg, 15%) as an orange-red solid and as a mixture of diastereomers: 1H NMR (500 MHz, CDCl3) δ 14.27 (s, 0.3H), 14.21 (s, 0.7H), 8.12 (s, 0.3H), 8.11 (s, 0.7H), 6.90 (br s, 1H), 6.22 (br s, 1H), 5.94 (br s, 1H), 5.91 (s, 0.7H), 5.90 (s, 0.3H), 5.14 (d, J=4.5 Hz, 0.3H), 4.97 (d, J=6.7 Hz, 0.7H), 4.75 (d, J=14.7 Hz, 0.3H), 4.48 (d, J=14.7 Hz, 0.7H), 4.70 (br s, 1H), 4.21 (d, J=14.7 Hz, 1H), 3.81-3.80 (m, 1H), 3.81 (s, 3H), 3.78 (br s, 2H), 3.74-3.70 (m, 2H), 3.65-3.56 (m, 1H), 3.61 (s, 3H), 3.40 (s, 3H), 3.36 (s, 3H), 3.13 (t, J=9.2 Hz, 1H), 2.21 (s, 3H), 1.36 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 755 (M+H); HPLC >99% (AUC), tR 13.72 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]([N+:15]([O-:17])=[O:16])=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]([N+:15]([O-:17])=[O:16])=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 80 g (0.33 mol) of 3,4-dimethoxy-6-nitrobenzoic acid, methyl ester in 1700 ml of methanol was added 500 ml of 2N sodium hydroxide, and the mixture was warmed to 50° C. for 45 minutes. After 30 minutes, a clear solution was obtained. The methanol was evaporated in vacuo and the aqueous solution was acidified with 3N hydrochloric acid to pH 1. The resulting crystals were filtered off by suction, washed with water and dried in vacuo; yield: 72.5 g; melting point 194.9° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)([OH:20])[C:16]([F:18])([F:19])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:12]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:30])[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:30])[CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)C(C)c1ccccc1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)C(C)c2ccccc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyl-2-phenylpropionamide. It is used in crude form in the following reaction.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[OH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)[N:3]=[CH:4][N:5]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: Oc1ccc2[nH]ccc2c1
Product: O=Cc1c(Cl)ncnc1Oc1ccc2[nH]ccc2c1

Procedure:
Using the procedure of Example 1, 4,6-dichloro-pyrimidine-5-carbaldehyde Compound 2a (0.10 g) and 5-hydroxy-indole Compound 3a (75 mg) were reacted to provide 4-chloro-6-(1H-indol-5-yloxy)-pyrimidine-5-carbaldehyde Compound 3b (15 mg, 10%). 1H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 8.60 (s, 1H), 8.30 (s, 1H), 7.45 (d, 1H), 7.40 (d, 1H), 7.30 (d, 1H), 6.95 (dd, 1H), 6.55 (d, 1H). MS (ESI) m/z: 306 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:11]O)[CH3:10])[CH:6]=[CH:5][CH:4]=1>CO.[C].[Pd]>[NH2:11][CH:9]([C:7]1[N:8]=[C:3]([CH2:2][OH:1])[CH:4]=[CH:5][CH:6]=1)[CH3:10]
Reactant: CC(=NO)c1cccc(CO)n1
Agent: [Pd]
Solvent: CO
Product: CC(N)c1cccc(CO)n1
Reaction time: 7 h
Yield: 91 %

Procedure:
To a solution of 1.8 g of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone oxime in 36 ml of methanol was added 500 mg of 10% palladium-carbon (50% wet) under an argon atmosphere, followed by stirring for 7 hours under a hydrogen atmosphere. After filtration through Celite, the filtrate was evaporated under reduced pressure to obtain 1.5 g of [6-(1-aminoethyl)pyridin-2-yl]methanol.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:35])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.CCOC(C)=O>CO>[F:35][C:11]1[C:12]([C:16]2[CH:17]=[N:18][C:19]([CH:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[N:20][CH:21]=2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cccc(-c2cnc(C3CCNCC3)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
tert-Butyl 4-{5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}piperidin e-1-carboxylate (170 mg) was mixed with MeOH (1.7 ml), and a 4 M hydrogen chloride/EtOAc (0.17 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 10% MeOH/CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added to the residue. Then, the reaction mixture was concentrated under reduced pressure. 10% MeOH/CHCl3 was added to the obtained residue, followed by stirring for 30 minutes. The filtrate was concentrated under reduced pressure to obtain {2-fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (96 mg).