Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:10]([CH3:16])([CH2:12][CH2:13][C:14]#[CH:15])[CH3:11])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].N1CCCCC1.I[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]([C:10]([CH3:16])([CH2:12][CH2:13][C:14]#[C:15][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH3:11])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: C#CCCC(C)(C)N(C)C(=O)OC(C)(C)C
Reactant: Ic1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)C(C)(C)CCC#Cc1cccs1
Reaction time: 3 h

Procedure:
A mixture of 130 mg of 12f, 100 μl of piperidine, 75 μl of 2-iodothiophene, 10 mg of CuI and 14 mg of PdCl2(PPh3)2 in 2 ml of degassed toluene was stirred under N2 for 3 hr. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with water, dried and concentrated. The crude material was purified by chromatography over a silica column, using a gradient of pentane/diethyl ether as eluent. This provided 130 mg of 12g as colorless oil; Rf 0.60 (heptane/ether 3/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[CH2:5][O:6][C:7]([NH:9][CH:10]1[CH2:16][CH:15]2[N:17](C(OC(C)(C)C)=O)[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=[O:8].Cl>O1CCOCC1>[ClH:1].[CH:15]12[NH:17][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH:10]([NH:9][C:7](=[O:8])[O:6][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:27]=[C:26]([Cl:28])[CH:25]=1)[CH2:16]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(NC(=O)OCc1cc(Cl)cc(Cl)c1)C2
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CC2CCC(C1)N2)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reaction mixture comprising of tert-butyl 3-((((3,5-dichlorobenzyl)oxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (388.3 mg, 0.904 mmol) in dioxane (5 mL) was treated with 4M HCl in dioxane (0.678 mL, 2.71 mmol) and stirred at room temperature for 3 hours. The resulting mixture concentrated under reduced pressure. No further purification was carried out and the material was taken on crude to the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH:14]([F:16])[F:15])=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O>[F:15][CH:14]([F:16])[CH2:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([F:17])=[N:3][CH:4]=1
Reactant: FC(F)COc1cnc(Cl)c2ccccc12
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1ncc(OCC(F)F)c2ccccc12
Temperature: 140 °C

Procedure:
To a solution of 1-chloro-4-(2,2-difluoroethoxy)isoquinoline (630 mg, 2.59 mmol) in DMSO (10 mL) was added CsF (786 mg, 5.17 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 5-50% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give it the desired product 4-(2,2-difluoroethoxy)-1-fluoroisoquinoline (310 mg, 52.8% yield). MS: MS m/z 228.1 (M++1).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:18]=[C:17]([C:19](OCC)=[O:20])[N:16]=[CH:15]3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[BH4-].[Li+]>C1COCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:18]=[C:17]([CH2:19][OH:20])[N:16]=[CH:15]3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25](=[O:26])[O:27][CH:28]([CH3:29])[CH3:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(-n3cnc(CO)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 0 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of ethyl 1-[(cis)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazole-4-carboxylate (for a preparation see Example 90) (857 mg, 2 mmol) in dry THF (10 mL) was cooled to 0° C. and treated with 2M lithium borohydride in THF (2 mL, 4 mmol). The reaction mixture was stirred at room temperature for 8 h then was partitioned between AcOEt (10 mL) and a saturated NH4Cl aqueous solution (10 mL). The layers were separated. The aqueous phase was extracted with AcOEt (2×10 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 10% MeOH in DCM) gave 1-methylethyl {(cis)-1-acetyl-6-[4-(hydroxymethyl)-1H-imidazol-1-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (440 mg, 1.139 mmol, 57%) as a colourless foam.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([N:25]3[CH2:46][CH2:45][C:28]4([NH:32]/[C:31](=[N:33]/[C:34]([C:36]5[C:41]([NH2:42])=[N:40][C:39]([NH2:43])=[C:38]([Cl:44])[N:37]=5)=[O:35])/[NH:30][CH2:29]4)[CH2:27][CH2:26]3)=[O:24])[CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.O1CCOCC1>Cl>[NH2:42][C:41]1[C:36]([C:34](/[N:33]=[C:31]2/[NH:32][C:28]3([CH2:45][CH2:46][N:25]([C:23]([C:19]4[CH:18]=[C:17]([S:14]([NH:13][CH2:12][C:8]5([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11]5)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:26][CH2:27]3)[CH2:29][NH:30]/2)=[O:35])=[N:37][C:38]([Cl:44])=[C:39]([NH2:43])[N:40]=1
Reactant: CC(C)(C)OC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCC5(C(=O)O)CCC5)c4)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 1-[(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-methyl]-cyclobutanecarboxylic acid tert-butyl ester (step 1) (730 mg, 1.080 mmol) in 4N HCl in dioxane (10 ml, 40.0 mmol) was stirred at RT for 1 h. The reaction mixture was partitioned between water and EtOAc and the pH of the aqueous portion was adjusted to 14 by addition of 2N NaOH. The basic aqueous solution was washed with EtOAc and concentrated in vacuo. The dry residue was slurried in water and the pH was adjusted to 6 by dropwise addition of 2N HCl. The resulting solid was filtered and washed with water (20 ml), diethyl ether (20 ml) and dried under vacuum at 50° C. to afford the title product; LC-MS Rt 2.29 mins; 620.3 [M+H]+, Method 10minLC_v003.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:19]1[C:9]2[C:10](=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:7][CH:8]=2)[N:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CNc1cc[nH]c1C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2c(C(=O)OCC)[nH]cc2c1Cl
Temperature: 75 °C

Procedure:
Diethyl 2-((2-(ethoxycarbonyl)-1H-pyrrol-3-ylamino)methylene)malonate was dissolved in phosphoryl chloride (0.2 M) and heated at 75° C. for 18 hours. Reaction mixture was concentrated to dryness and water and ethyl acetate were added. The aqueous layer was extracted with ethylacetate, the combined organic fractions were washed with brine and dried over magnesium sulfate before concentrating in vacuo to afford the crude compound 10a as an orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][C:15]=2[F:27])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:29](F)(F)[C:30]([OH:32])=O>C(Cl)Cl>[CH:22]1([C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([CH:29]([C:19]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:30]([N:8]([CH2:13][CH3:12])[CH2:9][CH3:10])=[O:32])[CH2:9][CH2:10]3)=[C:15]([F:27])[CH:16]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C3CCCC3)cc2F)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(C(=O)C3CCCC3)cc2F)CC1

Procedure:
A solution of 4-(4-cyclopentanecarbonyl-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.29 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (1.5 mL). After 3 h the solvent was removed and water (5 mL) and 1 M NaOH were added (˜pH 10). The mixture was extracted with DCM and the solvent removed. The residue was then taken up in DMF (2 mL) and K2CO3 was added (0.13 g, 0.91 mmol). This mixture was then treated with 2-bromo-N,N-diethyl-2-phenyl-acetamide (0.11 g) as described in previous examples to provide 0.072 g of the title compound. MS: 466.6. 1H NMR (CDCl3): 7.69-7.66 (m, 1H), 7.63-7.59 (m, 1H), 7.47-7.43 (m, 2H), 7.38-7.30 (m, 3H), 6.90-6.86 (m, 1H), 4.26 (s, 1H), 3.63-3.56 (m, 1H), 3.51-3.35 (m, 2H), 3.31-3.14 (m, 6H), 2.76-2.67 (m, 4H), 1.92-1.85 (m, 4H), 1.75-1.57 (m, 4H), 1.09 (t, J=7.1, 3H) 1.04 (t, J=7.1, 3H).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C1COCC1.CCN(CC)CC>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of the compound (28.8 mg) obtained in Example 26 in THF (2.0 ml), Et3N (25.1 μl) was added, methylsulfonyl chloride (9.3 μl) was added at 0° C., and the reaction mixture was reacted at room temperature 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:19][C:20]([C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:22]12([C:20](=[O:21])[CH2:19][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=4)[CH2:6][CH2:5]3)[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCN(CC(=O)C34CC5CC(CC(C5)C3)C4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(piperazin-1-yl)benzoate (100 mg), 1-admantyl bromomethyl ketone (110 mg) and sodium carbonate (46 mg) were suspended in anhydrous acetonitrile (2 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 aqueous solution, and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated to afford the title compound
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH:11]1([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:18][CH:19]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(C2CCCCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C2CCCCC2)cc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
6-Chloronicotinoyl chloride (0.24 g) was dissolved in toluene (5 mL), and the solution was cooled to 0° C. 4-Cyclohexylaniline (0.47 g) was added thereto at 0° C., and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added thereto, and the organic layer was washed with a 1 N aqueous sodium hydroxide solution and water and dried over sodium sulfate. After concentration under reduced pressure, the obtained solid was collected by filtration and washed with diethyl ether. The solid was dried under reduced pressure to obtain the title compound (0.40 g) as a white solid (yield: 95%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:17]=[CH:16][C:9]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:8]([O:18][CH3:19])[C:7]=2[CH3:20])[CH2:2]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34](OCC)=[O:35])=[N:31][N:30]=2)=[CH:25][CH:24]=1>>[CH3:19][O:18][C:8]1[C:7]([CH3:20])=[C:6]([CH:17]=[CH:16][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[O:5][CH:3]1[CH2:4][N:1]([C:34]([C:32]2[O:33][C:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[N:30][N:31]=2)=[O:35])[CH2:2]1
Reactant: COc1c(CN2CCCC2)ccc(OC2CNC2)c1C
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCCC5)c(OC)c4C)C3)o2)cc1
Yield: 37.2 %

Procedure:
Using a similar protocol as described in Example 16 employing 52B (0.25 g, 0.90 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.34 g, 1.36 mmol) as starting materials afforded 160 mg (37%) of 52 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.77 (s, 4H), 2.19 (s, 3H), 2.52 (s, 4H), 3.60 (s, 2H), 3.76 (s, 3H), 3.89 (s, 3H), 4.35 (dd, 1H), 4.66 (dd, 1H), 4.75 (dd, 1H), 5.07 (m, 1H), 5.13 (dd, 1H), 6.29 (d, 1H), 7.02 (d, 2H), 7.17 (d, 1H), 8.10 (d, 2H), MS (APCI+) m/z 479 [M+H]+, LC purity: 95%.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C(OC([N:34]1[CH2:38][CH2:37][C@H:36]([OH:39])[C@H:35]1[C:40](O)=[O:41])=O)(C)(C)C>CS(C)=O>[OH:39][C@H:36]1[CH2:37][CH2:38][NH:34][C@@H:35]1[C:40]([N:23]1[CH2:24][CH2:25][CH:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:26])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)=[O:41]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(C(=O)[C@H]5NCC[C@@H]5O)CC4)n3)ccc21

Procedure:
The preparation was carried out analogously starting from 150 mg (0.36 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 94 mg (0.40 mmol) of (2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in DMSO. The product was purified by means of flash chromatography on silica gel. The protecting group was cleaved off analogously using HCl in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[C:28]([S:30][C:31]#[N:32])[CH:27]=[C:26]([CH:33]([CH3:35])[CH3:34])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:29]=[C:28]([S:30][C:31]#[N:32])[CH:27]=[C:26]([CH:33]([CH3:35])[CH3:34])[C:24]=1[NH:25][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])([CH3:22])[CH3:21]
Reactant: CC(C)c1cc(SC#N)cc(C(C)C)c1N
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cc(SC#N)cc1C(C)C)c1ccccc1CO2
Yield: 78.6 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.12 g of Compound A and 1.24 g of 2,6-diisopropyl-4-thiocyanatoaniline in place of aniline to obtain 1.63 g of Compound 31.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[CH2:18](I)[CH3:19]>>[CH2:18]([O:17][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)[CH3:19]
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: CCI
Product: CCOc1ccc2c(N3CCCC3)cc(C)nc2c1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with ethyl iodide, whereby the product was isolated as free base, 7-ethoxy-2-methyl-4-pyrrolidin-1-yl-quinoline as a brown solid. ISP mass spectrum, m/e: 257.1 (M+1 calculated for C16H20N2O: 257).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])[N:11](O)[C:12]=2[C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[CH:4][CH:3]=1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=3[F:27])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2c(-c3ccc(Br)cc3)nc(-c3c(F)cccc3F)n2O)cc[nH]1
Solvent: CO
Product: O=c1cc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccc(Br)cc2)cc[nH]1

Procedure:
Using the general procedure in Example 1 Step D, the intermediate of Example 9 Step A was treated with TiCl3 in methanol to provide the title compound: [M+1]+ 428.
Reaction SMILES: Br[C:2]1[CH2:8][NH:7][C:6](=[O:9])[C@H:5]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].S(C1C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=C(S([O-])(=O)=O)C=CC=2)C=CC=1)([O-])(=O)=O.[Na+].[Na+].[Na+]>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH2:8][NH:7][C:6](=[O:9])[C@H:5]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C(N[C@@H]1CC=C(Br)CNC1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CC=C(c2ccc(O)cc2)CNC1=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
Palladium acetate (1 mg, 0.003 mmol) was added to a solution of benzyl (3R)-6-bromo-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (18 mg, 0.053 mmol), 4-hydroxyphenylboronic acid (9 mg, 0.064 mmol), sodium carbonate (2M in water; 0.066 mL, 0.133 mmol) and trisodium 3-[bis(3-sulfonatophenyl)phosphino]benzenesulfonate (5 mg, 0.088 mmol) in N,N-dimethylformamide (0.45 mL) and water (0.15 mL) and heated to 80° C. After 1.5 h, the mixture was allowed to cool to ambient temperature and filtered. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (15 mg). MS 353 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:24]([CH:20]3[C:21]([CH3:23])([CH3:22])[C:19]3([CH3:27])[CH3:18])=[O:25])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C(=O)C3C(C)(C)C3(C)C)c[nH]c2c1
Yield: 39.5 %

Procedure:
A mixture of methyl-indole-6-carboxylate (2.0 g, 11.4 mmol), ethylmagnesium bromide (1.0 M solution in THF, 14 mL, 14 mmol), zinc chloride (1.0 M solution in Et2O, 14 mL, 14 mmol) and the product of Example 1A (17 mmol) in 30 mL of dichloromethane was processed as described in Example 1B to provide the title compound (1.35 g, 4.5 mmol, 40% yield). MS (DCI/NH3) m/z 300 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[C:11](=[C:22]3[N:26]([CH3:27])[C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[S:23]3)[S:10]2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[CH2:14]([N:13]1[C:12](=[O:21])[C:11](=[C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2)[S:10][C:9]1=[N:8][C:4]1[CH:3]=[C:2]([NH:1][S:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1C(=C2SC(=Nc3cccc(N)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Solvent: ClC(Cl)Cl
Product: CN1C(=C2SC(=Nc3cccc(NS(=O)(=O)c4ccccc4)c3)N(Cc3ccccc3)C2=O)Sc2ccccc21
Temperature: 50 °C
Reaction time: 20 h
Yield: 20.9 %

Procedure:
To a 25 mL flask was added 2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one (0.18 g, 0.40 mmol), anhydrous CHCl3 (7 mL), benzenesulfonyl chloride (56 μL, 0.44 mmol), and TEA (0.10 mL, 0.80 mmol). The solution was stirred at 50° C. for 20 h. The yellow precipitates were collected by filtration under reduced pressure, washed with hexanes (30 mL), and dried under vacuum to give the title compound (49 mg, 21%) as a yellow solid. 1H-NMR (DMSO-d6): δ 7.97 (1H, s), 7.76 (2H, d), 7.53 (2H, m), 7.45 (2H, t), 7.37 (2H, d), 7.09-7.31 (8H, m), 6.81 (1H, d), 6.74 (1H, s), 6.57 (1H, d), 4.99 (2H, s), 3.72 (3H, s); MS(ESI): 585 (MH+).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([O:9][CH2:10][C:11]1[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])=[N:13][O:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[CH2:2]2.CC(N(C)C)=O.[F:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1F)[C:40]([O:42][CH3:43])=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O>[CH:16]1([C:15]2[O:14][N:13]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:28])([F:27])[F:29])[C:11]=2[CH2:10][O:9][CH:3]2[CH2:2][CH:1]3[N:8]([C:46]4[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][C:37]=4[F:36])[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)(F)F)noc2C2CC2)C3)c(F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The amine, 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (41.5 mg, 0.102 mmol), dimethylacetamide (0.6 mL), methyl 3,4 difluorobenzoate (510 mg, 3.0 mmol), and cesium carbonate (108 mg, 0.33 mmol) were combined sequentially and heated to 100° C. for about 20 minutes and then 120° C. for approximately 1 hour. The mixture was diluted with ethyl acetate 20 mL and water washed (2×3 mL). The organics were dried under vacuum to a residue, the resulting residue was diluted with 3 mL of MeOH, and the liquid was directly purified using mass directed reverse phase HPLC under a gradient of 30 to 90% acetonitrile/water that was TFA modified (0.05%). The resulting product was cold vacuum concentrated and free based using an SPE polymer support cartridge and MeOH (5 mL) mobilizing solvent (product SPE PLHCO3 MP part no PL3540-C603). All resulting methanol effluent was concentrated to give the free based intermediate ester as a dense oil.