Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][CH3:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:28][CH3:29])([CH3:17])([CH3:18])[CH3:19]
Reactant: Nc1ccc(F)cc1Nc1cccnc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of 4-fluoro-N2-pyridin-3-ylbenzene-1,2-diamine (0.594 g, 2.9 mmol) in DCM (18 mL) at 0° C. were added (S)-2-tertbutoxycarbonylaminobutyric acid (650 mg, 3.2 mmol), HOAt (440 mg, 3.2 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (610 mg, 3.2 mmol) and the reaction mixture stirred at 0° C. for 2 h. The crude mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-60% EtOAc in cyclohexane) to afford {(S)-1-[4-fluoro-2-(pyridin-3-ylamino)phenylcarbamoyl]propyl}carbamic acid tert-butyl ester (839 mg, 75%). LCMS (Method J): RT 0.69 min [M+H]+ 389.2.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15]OS(C)(=O)=O)[CH:12]=[N:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1.[N+:21]([C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+].[I-]>CC(C)=O>[CH3:3][C:4]1([C:9]2[CH:14]=[N:13][CH:12]=[C:11]([CH2:15][N:26]3[CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:28]=[N:27]3)[CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC1(c2cncc(COS(C)(=O)=O)c2)OCCO1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CC1(c2cncc(Cn3cc([N+](=O)[O-])cn3)c2)OCCO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 5-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-3-ylmethyl ester (271 mg, 0.99 mmol) in acetone (6.0 mL) was added, under inert atmosphere (N2) to a solution of 4-nitro-1H-pyrazole (126 mg, 0.99 mmol) in acetone (6.0 mL). K2CO3 (691 mg, 4.95 mmol) followed by TBA iodide (64 mg, 0.20 mmol) were added to the reaction mixture, which was stirred at rt for 5 h. The solvent was removed under reduced pressure. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (50:50 hept-EA)=0.1. LC-MS-conditions 02: tR=0.74 min; [M+H]+=291.11.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH:30]4[CH2:32][CH2:31]4)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[SH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O.C(OCC)(=O)C.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>[CH:30]1([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:13]([C:10]3[NH:9][C:8]([C:5]4[N:6]=[CH:7][C:2]([S:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:3][CH:4]=4)=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH2:32][CH2:31]1
Reactant: CCOC(=O)CS
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a solution of 5-bromo-2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in N,N-dimethylformamide (1 mL) were added ethyl sulfanylacetate (98 μL) and tetrakistriphenylphosphinepalladium(0) (230 mg), and the mixture was stirred using a microwave synthesis apparatus at 120° C. for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (117 mg, yield 54%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 555 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:17]([OH:19])[CH3:18])[C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([NH:28][NH2:29])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1.CN(C=O)C>[C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:17]([OH:19])[CH3:18])[C:14]([NH:29][NH:28][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)O
Reactant: NNC(=O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a mixture of (2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (intermediate 60a) (0.66 g, 2.39 mmol), benzoic hydrazide (330 mg, 2.42 mmol), HOBt (328 mg, 2.42 mmol) in THF:DMF (1:1) (30 mL) was added EDC (698 mg, 3.64 mmol) and Et3N (0.51 mL, 3.66 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min., then at room temperature overnight. The reaction was quenched by adding water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent and purification of the residue gave the title compound N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.72 g, 76%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.94 (m, 2H), 7.82 (d, J=5.7 Hz, 1H), 7.73 (d, J=5.7 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.59 (m, 1H), 7.50 (m, 2H), 6.66 (d, J=8.2 Hz, 1H), 6.20 (d, J=7.4 Hz, 1H), 4.41 (m, 1H), 4.22 (dd, J=3.5, 7.4 Hz, 1H), 1.39 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.S(Cl)(Cl)(=O)=O.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>N1C=CC=CC=1>[F:19][C:3]1[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33]
Reactant: Nc1cccc(C(=O)c2c[nH]c3ncncc23)c1F
Reactant: CCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncncc23)c1F
Temperature: 60 °C
Reaction time: 48 h

Procedure:
The (3-amino-2-fluoro-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (39, 20.0 mg, 0.078 mmol) is further reacted, for example, by adding 0.5 mL of tetrahydrofuran, 50 μL of pyridine, and an appropriate sulfonyl chloride (e.g. ethanesulfonyl chloride 40, 0.078 mmol). The reaction vial is allowed to stir at room temperature or in an oil bath at 60° C. After 1-3 days, the solvents are removed under vacuum, the residue dissolved in 0.5 mL dimethyl sulfoxide, and the material purified by C18 reversed phase HPLC, eluting with 20-100% acetonitrile (with 0.1% trifluoroacetic acid) in water (with 0.1% trifluoroacetic acid) at a flow rate of 20 mL/min. Ethanesulfonic acid [2-fluoro-3-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-amide (P-0036) was prepared by this protocol using ethanesulfonyl chloride 40 in step 4. MS (ESI) [M+H+]+=349.1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2ncnc(Nc3ccc(Cl)cc3F)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.7 %

Procedure:
Diethyl azodicarboxylate (2.4 ml, 15 mmol) was added dropwise to a solution of 3-([N-(tert-butylcarbonyl)-N-methyl]amino)-1-propanol (1.77 g, 9.4 mmol), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (2 g, 6.26 mmol), (prepared as described for the starting material in Example 2), and triphenylphosphine (4.1 g, 15 mmol) in methylene chloride (50 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature, and further 3-([N-(tert-butylcarbonyl)-N-methyl]amino)-1-propanol (236 mg, 1.2 mmol), triphenylphosphine (820 mg, 3.1 mmol) and diethyl azodicarboxylate (492 μl, 3.1 mmol) were added. The solution was stirred for 1 hour at ambient temperature and concentrated by evaporation. The residue was purified on column chromatography eluting with acetonitrile. The purified product was triturated with ether, collected by filtration and repurified by column chromatography eluting with methylene chloride/methanol (97/3) to give 7-3-([N-(tert-butylcarbonyl)-N-methyl]amino)propoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (2.2 g, 72%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=1.C(N(CC)CC)C.[NH2:23][C@@H:24]1[CH2:28][C@H:27]([OH:29])[CH:26]=[CH:25]1>O1CCCC1.O1CCCC1.O1CCOCC1>[Cl:11][C:6]1[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=[C:2]([NH:23][C@@H:24]2[CH2:28][C@H:27]([OH:29])[CH:26]=[CH:25]2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: N[C@H]1C=C[C@@H](O)C1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@H]2C=C[C@@H](O)C2)n1
Yield: 64.4 %

Procedure:
To a solution of 4,6-dichloro-5-nitro-2-propylthiopyrimidine (prepared as described in WO 9703084) (4.00 g) and triethylamine (2.00 ml) in dry tetrahydrofuran (THF) (100 ml) was added a solution of [1S-cis]-4-amino-2-cyclopenten-1-ol (prepared as described by S. F. Martin et al., Tetrahedron Lett., 1992, 33, 3583) (1.48 g) in THF/1,4-dioxane 2:1 (150 ml) dropwise over 1 hour. The reaction mixture was filtered, concentrated and purified (SiO2, ethyl acetate:isohexane 1:4 to 1:1 as eluant) to afford the subtitle compound (3.18 g).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][NH:11][CH2:10][CH2:9]2.[BrH:14]>>[BrH:14].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][NH:11][CH2:10][CH2:9]2
Reactant: COc1cccc2c1CNCC2
Agent: Br
Agent: Cl
Product: Oc1cccc2c1CNCC2
Temperature: 120 °C
Yield: 81 %

Procedure:
A mixture of 8-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride [Tetrahedron Letters, 1991, 32(17), 1965.] (3.0 g 15.0 mmol) and 45 mL of 48% aqueous HBr was heated for 18 h at 120° C. The resulting brown suspension was filtered and dried to provide 8-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (2.8 g, 81% yield). LRMS (ESI) m/z 150.1 [(M+H)+; calcd for C9H1NO: 150.2].
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH3:13][O:14][C:15](=[O:21])[C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:13][O:14][C:15]([C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)=[O:21]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (6.00 g, 17.3 mmol) and L-proline methyl ester hydrochloride (2.88 g, 17.4 mmol) in DMF (125 mL) was treated with a solution of triethylamine (7.8 mL, 55.5 mmol) in DMF (75 mL). After stirring at room temperature under N2 for 3 h, the cloudy mixture was diluted with H2O (300 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with H2O (2×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1 to 98:2) gave the title compound (3.66 g, 67%) as a pale yellow oil: MS (ESI) m/e 314 (M+H)+.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:7][C:6](=[O:8])[CH2:5][N:4]1[CH2:9][C:10]([OH:12])=O.[NH2:13][C@@H:14]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:33]([O:32][CH2:31][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:4]1[CH2:5][C:6](=[O:8])[NH:7][C:3]1=[O:2])[C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:23]=1)=[O:16])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)CN1CC(=O)NC1=O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: O=C1CN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccccc3)cc2)C(=O)N1
Yield: 45 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,4-dioxoimidazolidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-phenoxyphenyl)propanamide, gave Compound 201, (S)-3-(benzyloxy)-2-(2-(2,4-dioxoimidazolidin-1-yl)acetamido)-N-(4-phenoxyphenyl)propanamide (54.1 mg, 45%). 1H-NMR (400 MHz, DMSO-D6): σ 10.62 (d, 1H), 10.15 (d, 1H), 8.47-8.41 (m, 1H), 7.83 (d, 1H), 7.65-7.61 (m, 2H), 7.39-7.26 (m, 6H), 7.10 (t, 1H), 7.02-6.96 (m, 4H), 4.73-4.66 (m, 1H), 4.53 (s, 2H), 4.25-4.20 (m, 1H), 3.71-3.63 (m, 2H), 2.73-2.63 (m, 1H). MS (EI) for C27H26N4O6. found 503.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([N:33](C)[C:34](=O)OC(C)(C)C)[C:10](=[O:32])[NH:11][C:12]2[CH:13]=[C:14]3[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:16]4=[C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[NH:18][C:19]([CH:20]=2)=[C:15]34)=[CH:4][CH:3]=1.[ClH:42].C(N(CC)CC)C>O1CCOCC1>[ClH:42].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][CH3:34])[C:10]([NH:11][C:12]2[CH:13]=[C:14]3[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:16]4=[C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[NH:18][C:19]([CH:20]=2)=[C:15]34)=[O:32])=[CH:4][CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN[C@H](Cc1ccc(O)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 48 %

Procedure:
Preparation of example 167 from the title compound of Example 151 (47 mg, 0.085 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner, included freebasing with triethylamine and subsequent silica gel chromatography eluting with 3:1:1 hexane:ethyl acetate:ethanol. With ice bath cooling, the purified freebase in CH2Cl2 (10 mL) was treated with 4M HCl in dioxane (0.1 mL). After removal of the volatile components, the title compound (20 mg, 0.041 mmol) was obtained as an orange/yellow powder in 48% yield.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]1N.Cl.[NH:13]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>CCO>[CH:8]1[C:9]2[C:17]3[CH2:18][CH2:19][NH:13][CH2:14][CH2:15][C:16]=3[N:1]3[C:10]=2[C:5]([CH2:4][CH2:3][CH2:2]3)=[CH:6][CH:7]=1
Reactant: NC1C=Cc2ccccc2N1
Reactant: O=C1CCCNCC1
Agent: Cl
Solvent: CCO
Product: c1cc2c3c(c1)c1c(n3CCC2)CCNCC1
Temperature: 20 °C
Yield: 25.2 %

Procedure:
To a solution of 3,4-dihydro-[(2H)-quinolinamine (1.0 g, 14 mmol) and hexahydro-4H-azepin-4-one hydrochloride (1.0 g, 14 mmol) in EtOH (13 mL) was added concentrated HCl (1.2 mL). The reaction was stirred at reflux for 14 h, then cooled to 20° C. A brown precipitate was filtered from the reaction mixture, affording the title compound (800 mg, 45%) as a brown solid. 1H NMR (CD3OD, 300 MHz) δ 2.14–2.23 (m, 2H), 2.91 (t, 2H, J=6.0 Hz), 3.16–3.21 (m, 2H), 3.27–3.33 (m, 2H), 3.39–3.50 (m, 4H), 4.04 (t, 2H, J=5.7 Hz), 6.70 (d, 1H, J=6.9 Hz), 6.87–6.93 (m, 1H), 7.22 (d, 1H, J=8.0 Hz) ppm. MS (ESI): 227.2 (base, M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N:16]3[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]3)[CH:10]=2)[CH2:6][N:5]([CH2:23][CH3:24])[S:4]1(=[O:26])=[O:25])[CH3:2].[K+].[CH3:28][C:29]1[N:33](COCC[Si](C)(C)C)[C:32]([C:42]([O-])=[O:43])=[N:31][CH:30]=1>>[CH2:23]([N:5]1[CH2:6][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:42]([C:32]3[NH:31][CH:30]=[C:29]([CH3:28])[N:33]=3)=[O:43])=[C:11]([N:16]3[CH2:17][CH2:18][CH:19]([CH3:22])[CH2:20][CH2:21]3)[CH:10]=2)[CH2:8][N:3]([CH2:1][CH3:2])[S:4]1(=[O:26])=[O:25])[CH3:24]
Reactant: CCN1CC(c2ccc(N)c(N3CCC(C)CC3)c2)CN(CC)S1(=O)=O
Reactant: Cc1cnc(C(=O)[O-])n1COCC[Si](C)(C)C
Agent: [K+]
Product: CCN1CC(c2ccc(NC(=O)c3nc(C)c[nH]3)c(N3CCC(C)CC3)c2)CN(CC)S1(=O)=O

Procedure:
The title compound is prepared from 4-(2,6-diethyl-1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine (as prepared in the previous step) and 5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid potassium salt (as prepared above in this example, step (c)) following the procedure of Example 11, steps (d)-(e).
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23].BrCCC1CC1.Br[CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1>>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1)[C:17](=[O:22])[C:16]2=[O:23]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccc(F)cc21

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 5-fluoroisatin, and (2-bromoethyl)cyclopropane with 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (59%) as a red solid: 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.50 (m, 1H), 7.47-7.44 (m, 1H), 7.20 (dd, 1H), 7.14-7.13 (m, 1H), 6.75 (d, 1H), 4.99 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 182.4 (d), 160.7, 158.5 (d), 157.5, 153.0 (d), 146.5 (d), 139.9 (q), 124.3, 119.3 (d), 114.5 (d), 112.7 (d), 112.0 (d), 110.5, 36.8.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>Cl.C(O)C.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1
Reactant: c1ccc(COc2ccc3c(c2)OC[C@@H](c2ccccc2)[C@H]3c2ccc(OCCCCCCN3CCOCC3)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCCCCCN2CCOCC2)cc1

Procedure:
(+,−) cis 7-Benzyloxy-4-[4-(6-morpholinohexyloxy)-phenyl]-3-phenyl-chroman (150 mg, 0.26 mmol) was dissolved in a solution of 1% Hydrochloride in ethanol (5 ml). The solution was added to a 10% palladium on carbon catalyst, and hydrogenated (1 atm.) overnight. The reaction mixture was filtered and evaporated to give an oil which solidified.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:39])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH3:26])=[N:21][CH:22]=[N:23][C:24]=2[CH3:25])=[C:15]([C:27]#[C:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[N:14]=1)=[O:11])C)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:25][C:24]1[C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[CH:9]([NH:7][CH3:6])[CH3:39])=[N:14][C:15]=2[C:27]#[C:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[C:20]([CH3:26])[N:21]=[CH:22][N:23]=1
Reactant: Cc1ncnc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CNC(C)C(=O)Nc1ccc(-c2c(C)ncnc2C)c(C#Cc2ccc3ccccc3c2)n1

Procedure:
A mixture of tert-butyl-N-[1-[[5-(4,6-dimethylpyrimidin-5-yl)-6-(2-naphthalen-2-yl-ethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate E2g (12 mg, 0.02 mmol) and DCM:TFA (9:1, 5 ml) is stirred at RT for 60 minutes. The mixture is diluted with toluene (10 ml) and concentrated in vacuo. The product is purified by RP HPLC. Yield: 6 mg (61%). HPLC-MS: M+H=436; tR=1.38 min (*Method—1).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]3[N:25]([CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:24]([CH2:33][CH2:34][CH2:35][CH3:36])=[N:23][C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[NH2:38][C:19]1[C:18]2[N:23]=[C:24]([CH2:33][CH2:34][CH2:35][CH3:36])[N:25]([CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([Br:12])=[CH:22][C:21]=2[N:20]=1
Reactant: CCCCc1nc2cnc3cc(Br)ccc3c2n1CCNS(C)(=O)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (1.0 equivalent of 50% pure material) was added to a solution of N-[2-(7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide (44 g, 103.4 mmol) in 1000 mL dichloromethane. After 2 hours, concentrated ammonium hydroxide solution (600 mL) was added. The reaction was stirred for 15 minutes before p-toluenesulfonyl chloride (1.1 equivalents) was slowly added in small portions. The reaction was stirred overnight at room temperature and then water and potassium carbonate were added with vigorous stirring. A precipitate formed and was isolated by filtration to provide N-[2-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-ethyl]methanesulfonamide.