Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([NH2:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].C(O)(=O)C.CO>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)CCc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CC(=O)O
Product: NCCCc1ccc([N+](=O)[O-])cc1
Yield: 64.7 %

Procedure:
10.0 g of the amide compound and 9.5 g of sodium borohydride were suspended in 250 ml of dioxane, followed by the dropwise addition of 15 ml of acetic acid. The resultant mixture was stirred for 10 hours under reflux. The reaction mixture was added with 10 ml of methanol and then concentrated to dryness. The residue was dissolved in chloroform. The solution thus obtained was washed with water and then concentrated to dryness, thereby obtaining 6.0 g of 3-(4-nitrophenyl)propylamine as an oily substance. This compound was provided for the next reaction without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[Br:17]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:17])=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(OC)c1-c1cccnc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc(Br)c(OC)c1-c1cccnc1

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 2 using 1,3-Dimethoxy-2-(Pyrid-3-yl) benzene 29 and N-bromosuccinimide to yield 30.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=3[C:15](O)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:31])[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=3[C:15]([N:28]3[CH2:29][CH2:30][CH:25]([N:24]([CH3:31])[CH3:23])[CH2:26][CH2:27]3)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(I)ccc1Nc1ccnc2cc(Cl)ccc12
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(C(=O)c2cc(I)ccc2Nc2ccnc3cc(Cl)ccc23)CC1

Procedure:
2-(7-Chloro-4-quinolylamino)-5-iodo benzoic acid is converted to the acid chloride which is reacted with 4-dimethylamino piperidine as in Example 1 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C:6]2[C:5]3[C:9](=[CH:10][C:2]([N:35]4[CH:36]=[CH:37][C:32]([O:31][CH2:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:33][C:34]4=[O:38])=[CH:3][CH:4]=3)[N:8]([CH3:11])[C:7]=2[CH2:12]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cn1c2c(c3ccc(Br)cc31)CCCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCCN(C(=O)OC(C)(C)C)C2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
tert-Butyl 8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate (0.13 g, 0.34 mmol), 4-benzyloxy pyridinone (69 mg, 0.34 mmol), and Cs2CO3 (0.12 g, 0.38 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (16 mg, 0.12 mmol) and copper iodide (78 mg, 0.41 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (10 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (80 mL). The solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (4×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 10 column volumes, increased to 50:50 over 20 column volumes and held for 5 column volumes) gave the title compound (56 mg, 32%) as a yellow film: 1H NMR (500 MHz, CDCl3) δ 7.55-7.52 (m, 1H), 7.42-7.36 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.24 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.10-6.09 (m, 1H), 6.04-6.03 (m, 1H), 5.05 (s, 2H), 4.66-4.63 (m, 2H), 3.75-3.67 (m, 5H), 2.92-2.91 (m, 2H), 1.94-1.89 (m, 2H), 1.43-1.42 (m, 9H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([C:28](=[O:30])[NH2:29])=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1>[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[N:18]=2)[CH:20]=1)(=[O:30])[NH2:29]
Reactant: CCOC(=O)C1CCC(Nc2nccc(-n3cc(C(N)=O)c4ccccc43)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cn(-c2ccnc(NC3CCC(C(=O)O)CC3)n2)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.1 %

Procedure:
4-[4-(3-Carbamoyl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (1.397 g, 3.44 mmol) was dissolved in THF, and LiOH (3.4 mL, 1M aq) was added, and the mixture stirred at RT for 6 h, and additional aliquot of LiOH (6.8 mL) added, and the mixture stirred overnight. A light yellow solid formed in the flask. The mixture was concentrated in vacuo to remove THF, more was added, and the solid filtered off, washed with DCM and Et2O, and air-dried overnight to provide 4-[4-(3-carbamoyl-indol-1-yl)-pyrimidin-2-ylamino]-cyclo-hexanecarboxylic acid (1.15 g, 89% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[C:16]1([C@H:14]([N:10]2[CH2:11][CH2:12][O:13][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:31])[CH3:30])=[CH:7][CH:6]=3)[CH2:9]2)[CH3:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc([C@H]2CN([C@H](C)c3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (7.9 g, 28 mmol) and triethylamine (8.5 g, 84 mmol) in tetrahydrofuran (180 ml) was added acetyl chloride (4.4 g, 56 mmol). The mixture was stirred at room temperature for 2 hours and partitioned between water and chloroform. The organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the precipitated crystals were collected by filtration, washed with isopropyl ether to give N-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)-acetamide (6.47 g, 71%) as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([NH:14][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)=[O:16])=[CH:12][C:11]([CH:28]([CH3:30])[CH3:29])=[N:10]2)=[CH:5][CH:4]=1.[CH2:31](Cl)Cl>O=[Mn]=O>[C:28]([C:11]1[CH:12]=[C:13]([NH:14][C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:16])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=2)[N:10]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: ClCCl
Reactant: CC(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2ccc(CO)cc2)n1
Agent: O=[Mn]=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2ccc(C=O)cc2)n1
Reaction time: 2 h

Procedure:
To a solution of Example 204 (200 mg) in CH2Cl2 (50 mL) was added MnO2 (450 mg) at RT. The suspension was stirred for 2 h then filtered through celite. The filtrate was concentrated under reduced pressure to afford 150 mg of 1-[5-t-butyl-2-(4-formyl-phenyl)-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea, which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]2[Se:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].[K+].[Br-]>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:4]2[N:3]=[CH:2][C:7]3[Se:8][C:9]4[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=4[C:6]=3[N:5]=2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Clc1ncnc2c3c([se]c12)CCCC3
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Product: Fc1ccc(Nc2ncc3[se]c4c(c3n2)CCCC4)cc1Cl

Procedure:
To a solution of step c compound (700 mg, 2.57 mmol) in isopropanol (15 mL) was added 3-chloro-4-fluoroaniline (1.6 g, 11.56 mmol) at rt and the mixture was refluxed for 1.5 h. Work-up of the mixture as described in example 1, gave the product as an off-white color solid, mp 238-240° C. IR (KBr) νmax cm−1; 1H NMR (400 MHz, CDCl3): δ 8.71 (1H, s), 7.70 (1H, dd, J=6.4, 2.8 Hz), 7.37-7.41 (1H, m), 7.16 (1H, t, J=8.8 Hz), 6.53 (1H, br s, exchangeable with D2O), 2.92 (2H, t, J=6.0 Hz), 2.82 (2H, t, J=6.0 Hz), 1.86-1.99 (4H, m); 13C NMR (100 MHz, DMSO-d6): δ 162.5, 156.2, 153.8, 153.0 (d, J=241 Hz), 148.6, 136.9 (d, J=3.0 Hz), 133.1, 122.7, 121.6 (d, J=7.0 Hz), 118.8 (d, J=19 Hz), 116.5 (d, J=21.0 Hz), 115.6, 27.6, 24.4, 23.5, 21.3; LC-MS (negative ion mode): m/z 378, 380, 382 (M−H)−.
Reaction SMILES: CN(C)C=O.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[N:15][CH:16]=1.[H-].[Na+].F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>O>[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][O:18][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:15][CH:16]=1
Reactant: Fc1ccccn1
Reactant: OCc1ccc(C2OCCO2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(OCc2ccc(C3OCCO3)cn2)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
To an N,N-dimethylformamide (40 mL) solution of (5-[1,3]dioxolan-2-yl-pyridin-2-yl)-methanol (1.37 g, 7.56 mmol) described in Manufacturing Example 154-1-4 was added sodium hydride (333 mg, 8.32 mmol, 60% in oil), which was stirred for 5 minutes at 0° C. Next, 2-fluoropyridine (716 μL, 8.32 mmol) was added to the reaction mixture, which was stirred for 45 minutes at 50° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1 to 1:1) to obtain the title compound (1.51 g, 77%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:17][CH3:18])([CH2:15][CH3:16])[C:4]=2[CH:3]=1.[C:19]1([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([C:5]1([CH2:17][CH3:18])[C:4]2[CH:3]=[C:2]([N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:16]
Reactant: CCC1(CC)c2ccccc2-c2ccc(Br)cc21
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC1(CC)c2ccccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A mixture of 2-bromo-9,9-diethylfluorene (2.44 g, 8.10 mmol), diphenylamine (1.43 g, 8.5 mmol), tris(dibenzylideneacetone)dipalladium (0.018 g, 0.25 mmol %), rac-BINAP (0.037 g, 0.75 mmol %), and sodium t-butoxide (1.08 g, 11.34 mmol) in dry toluene (100 ml) was heated at the refluxing temperature of the solvent for 8–10 h under an atmospheric pressure of nitrogen. After cooling the reaction mixture to room temperature, it was diluted with diethylether (60 ml), washed with brine (40 ml) and water. Organic layer was dried over sodium sulfate and concentrated in vacuuo. The crude product was purified by column chromatography (silica gel, hexane-toluene/9:1 as eluent, Rf=0.6 on thin layer chromatography using hexane-toluene/4:1 as eluent) to give 9,9-diethyl-2-diphenylaminofluorene (3.1 g) as a white amorphous low melting solid in a yield of 98%.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37])[C:8]([O:10]C(C)(C)C)=[O:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:28]1(=[O:37])[N:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:7]([C:6]([OH:38])=[O:5])[C:8]([OH:10])=[O:9])[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]12
Reactant: CC(C)(C)OC(=O)C(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)C(=O)O
Yield: 100 %

Procedure:
Following general procedure D, 16.0 mmol (8.45 g) of 5c and 160 mmol (11.9 mL) of trifluoroacetic acid were reacted in 12 mL of dichloromethane at room temperature and the mixture was processed. Yield 100%.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1>C(O)C.[Pd]>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[CH:2][N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)cn2)cc1OC
Reaction time: 0.67 h
Yield: 26.3 %

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (1.5 g) in ethanol (20 ml) was added 10%-palladium on carbon (0.8 g). The mixture was stirred under hydrogen (1 atm) for 40 minutes. After removal of the catalist by filtration, the filtrate was evaporated in vacuo. The residue was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform. The fractions containing the desired compound were combined and evaporated in vacuo to give a residue, which was recrystallized from ethyl acetate to afford 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.36 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1)[CH3:18].Cl.CCCCCCC>ClCCl>[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[O:28])=[CH:22][CH:21]=1)[CH3:18]
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Reactant: CN1CCC(NCc2ccc(F)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCOc1ccc(CC(=O)N(Cc2ccc(F)cc2)C2CCN(C)CC2)cc1
Reaction time: 20 h

Procedure:
50ELH4 (0.11 g, 0.49 mmol, 1.0 eq.) was transferred to a 4 ml vial and dissolved in dichloromethane. 63ELH19 (0.089 mg, 1.0 eq.) was added and the vial was sealed and the reaction shaken for 20 h. The product was extracted in distilled water (made basic with potassium carbonate, pH 10) and dichloromethane. Dried with sodium sulfate and concentrated. Purified by HPLC. The extraction, drying and concentration was repeated and the product dissolved in dichloromethane (1 ml) and HCl (1 eq., 2 M in ether) is added. This mixture was added drop-wise to an excess of heptane whereupon the salt precipitated. Yield 31.1 mg (16%), UV/MS: 94/100 (M+ 385), tr (A, MS) 2.573.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:15]2[N:23]3[C@@H:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:25][O:26][C:21]4=[C:22]3[C:17](=[CH:18][CH:19]=[C:20]4[C:33]3[C:34]([CH3:39])=[N:35][O:36][C:37]=3[CH3:38])[N:16]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.CO>[CH3:39][C:34]1[C:33]([C:20]2[C:21]3[O:26][CH2:25][C@H:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[N:23]4[C:15]([N:8]5[CH2:14][CH2:13][CH2:12][N:11]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:10][CH2:9]5)=[N:16][C:17]([C:22]=34)=[CH:18][CH:19]=2)=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCCNCC3)n3c2c1OC[C@@H]3c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CCCN(S(C)(=O)=O)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
Triethylamine (8.1 μL, 0.058 mmol) was added to a solution of (4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (5.0 mg, 0.012 mmol) in methylene chloride (0.44 mL), and the mixture was cooled to 0° C. Methanesulfonyl chloride (1.8 μL, 0.023 mmol) was then added and the mixture was stirred for 5 min at 0° C. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (3.8 mg, 64%). LCMS calc. for C25H29N6O4S (M+H)+: m/z=509.2. found: 509.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)=[C:4]([F:23])[CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:25]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)=[C:4]([F:23])[CH:3]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCBr
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2F)nc1
Product: CCCCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)cn2)c(F)c1

Procedure:
2-(4-Hydroxy-2-fluorophenyl)-5-octyloxypyridine, which is alkylated with 1-bromodecane to produce 2-(4-n-decyloxy-2-fluorophenyl)-5-octyloxypyridine, is obtained analogously by reacting 4-benzyloxy-2-fluoroacetophenone with 2-octyloxytrimethinium perchlorate, ammonium acetate 5. and hydrogenating cleavage of the benzyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C:6](=[O:20])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]=1[CH3:9])#[N:2].Cl.[NH2:36][OH:37].CC([O-])=O.[Na+].C(O)C>O>[CH3:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21]([C:5]2[C:6](=[O:20])[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[C:8]([CH3:9])=[C:3]([C:1](=[NH:2])[NH:36][OH:37])[CH:4]=2)=[O:22])=[CH:30][CH:29]=1)(=[O:33])=[O:32]
Reactant: Cc1c(C#N)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=N)NO)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 28 %

Procedure:
5-Cyano-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (0.040 g, 0.082 mmol), hydroxylamine hydrochloride (0.015 g, 0.209 mmol), NaOAc (0.017 g, 0.209 mmol), ethanol (3 ml), water (0.1 ml) and a magnetic stirrer bar were placed in a vial. The mixture was heated (90° C.) overnight. LC-MS showed a 50:50 mixture of two components, one of which had the expected MW. The product was isolated by preparative HPLC giving 0.012 g (28%) of the intermediate N-hydroxyamidine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]=[CH:20][N:21]([CH3:23])[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(C)c2c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: COc1ccc2nc(Cl)cc(C=CN(C)C)c2c1
Temperature: 120 °C
Yield: 92.6 %

Procedure:
2-Chloro-6-methoxy-4-methylquinoline (25 g, 0.12 mol) and tert-butoxybis(dimethylamino)methane (Bredereck's reagent) (30 g, 0.17 mol) was stirred under heating at 120° C. for 1.5 hours. After cooling the reaction mixture, the precipitated crystals were washed with diisopropyl ether to obtain the title compound (29.2 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:21][CH2:20][CH2:19][NH2:22])=[N:13][CH:12]=1
Reactant: NCCN
Reactant: Nc1cc(Cl)ccc1NC(=O)c1ccc(Cl)nc1
Product: NCCNc1ccc(C(=O)Nc2ccc(Cl)cc2N)cn1
Yield: 59 %

Procedure:
N-(2-Amino-4-chlorophenyl)-6-chloronicotinamide (282 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (180 mg, 59% yield) as a brown solid. LC-MS (m/z) 306 (M+1).
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:16]CC)=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1>>[CH2:1]([C:8]1[C:21]2[CH2:20][O:19][CH2:23][C:22]=2[C:10]([OH:16])=[C:11]([CH:13]([CH3:14])[CH3:15])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1oc(Cc2ccccc2)nc1C(C)C
Reactant: C1=CCOC1
Product: CC(C)c1nc(Cc2ccccc2)c2c(c1O)COC2

Procedure:
36.8 g of 2-benzyl-4-isopropyl-5-ethoxyoxazole (150 millimoles) and 210 g (3 moles) of 2,5-dihydrofuran are heated in an autoclave at 190° C. for 5 hours. Unconverted 2,5-dihydrofuran is distilled off. The residue is taken up in methylene chloride and the solution is extracted with 10% strength sodium hydroxide solution. On neutralizing the alkaline solution, crude 4-benzyl-6-isopropyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol is obtained and is extracted with methylene chloride (20.4 g). The product is converted to the hydrochloride by means of dilute hydrochloric acid and the hydrochloride is recrystallized from ethanol; melting point 232°-233° C.