Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([OH:19])[CH2:15]2)[C:10]1=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([OH:19])[CH2:15]2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CC[C@@H]2CC(O)(c3ccc(F)cc3)CC[C@H]2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CC[C@H]2CN(Cc3ccccc3)CC[C@@H]2C1
Temperature: 25 °C
Reaction time: 23.5 h

Procedure:
A solution of trans-2-benzoyl-6-(4'-fluorophenyl)-6-hydroxydecahydroisoquinolone (76 mg, 2.16 mmol) in anhydrous THF (20 mL) was added dropwise to a stirred suspension of lithium aluminum hydride (95%, 0.49 g, 12.9 mmol) in anhydrous THF (20 mL) under a nitrogen atmosphere. The reaction mixture was then heated to reflux temperature and stirred for 23.5 h. The reaction was cooled to ambient temperature, quenched with an excess amount of ethyl acetate, followed by water (0.5 mL), a 2N NaOH solution (0.5 mL) and water (1.5 mL). The mixture was filtered through Celite. The filtrate was dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography (ethyl acetate or CHCl3 ::MeOH::9:1) gave the product, a solid (382 mg): mp 120°-122° C.; NMR (CDCl3, 300 MHz): 7.45 (2H, dd, J=8, 6), 7.4-7.2 (m, 5H), 7.0 (br t, 2H, J=7), 3.55 (s, 2H), 2.95 (br d, 1H, J=7), 2.85 (br d, 1H, J=7), 2.05 (br t, 1H, J=7), 1.9-1.2 (m, 12H); HRMS: Calcd: 339.1999, Found: 339.2001; Anal. Calcd for C22H26FNO: C, 77.84, H, 7.72, N, 4.13, F, 5.60, Found: C, 77.41, 77.16, H, 7.74, N, 4.19 3.97, F, 5.78.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][C:17]([O:24][CH:25]([CH3:27])[CH3:26])=[C:18]([F:23])[CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[F:42][C:2]([F:1])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:29]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH:25]([CH3:27])[CH3:26])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)Oc1cc2nc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)ccc2cc1F
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-7-isopropoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (700 mg, 1.19 mmol) in DCM was added iodosobenzene acetate (496 mg, 1.54 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 25 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (280 mg, 40.1% yield) as a beige solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(C#N)ccc3[nH]2)C1
Agent: Cl
Solvent: CO
Product: N#Cc1ccc2[nH]c(C3CCNC3)nc2c1
Yield: 130.9 %

Procedure:
The 3-(5-cyano-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (9 g, 28.8 mmol) in a solution of 4M HCl in MeOH (50 mL) was stirred at 60° C. for 1 h, then it was concentrated to give the crude product (8 g, 79%). The crude product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:18][CH:17]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: ClCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(N2CCN(Cc3ccc(CCl)cc3)CC2)cc1
Temperature: 0 °C

Procedure:
To an aqueous solution (100 ml) of 1-(4-fluorophenyl)piperazine dihydrochloride was added an aqueous solution (50 ml) of sodium hydroxide (10 g) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a white solid (ca. 20 g). A solution of this solid (1-(4-fluorophenyl)piperazine), α,α′-dichloro-p-xylene (20.0 g) and potassium carbonate in dimethylformamide (150 ml) was stirred at 75° C. for 2 hr and poured into ice water (500 ml). The mixture was extracted with ethyl acetate (400 ml×2). The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:3) and recrystallized from ethyl acetate-hexane to give the title compound (10.66 g) as white crystals.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][C:8](=[O:17])[C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:3])=O.Cl.[CH3:25][O:26][NH2:27].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O1CCCC1.O.C(N(CC)CC)C>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([O:5][CH2:4][C:1]([NH:27][O:26][CH3:25])=[O:3])=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8](=[O:17])[NH:9]2)=[CH:14][CH:13]=1
Reactant: CON
Reactant: O=C(O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CONC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
To a solution of 4-carboxymethoxy-7-chloro-3-phenyl-2(1H)-quinolone (Example 15, 1.83 g) in tetrahydrofuran (150 ml) under nitrogen at room temperature, was added triethylamine (3.65 ml), O-methyl hydroxylamine hydrochloride (0.96 g), 1-hydroxybenzotriazole (1.15 g) and 1-(3 dimethylaminopropyl)-3-ethyl carbodiimide (1.73 g). The reaction mixture was stirred at room temperature for 16 h, then poured into water (150 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (1×100 ml), 1N citric acid (1×100 ml), brine (1×100 ml) and a saturated sodium hydrogen carbonate solution (1×50 ml), dried (MgSO4), filtered and the solvent was removed in vacuo to leave a solid residue. Recrystallisation from ethyl acetate gave the title compound (0.12 g). Mp 205°-207° C. m/z (CI+), 359, (m+1). 1H NMR (360 MHz, DMSO-d6) δ 3.32 (3H, s, NHOCH3), 3.93 (2H, s, OCH2CONHOCH3), 7.23 (1H, dd, J=8.63 Hz, J=1.83 Hz, 6-H), 7.36-7.45 (6H, m, Ph+8-H), 8.00 (1H, d, J=8.63 Hz, 5-H), 11.26 (1H, bs, OCH2CONHOCH3), 11.94 (1H, bs, NH). Found: C, 60.57; H, 4.26; N, 7.82; C18H15N2O4Cl requires C, 60.26; H, 4.21; N, 7.81%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][CH2:35][CH2:36][OH:37])(=[O:33])=[O:32].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C(OC(=O)C)C.O.O1CCOCC1>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][CH2:35][CH2:36][OH:37])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(NCCO)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)NCCO)cc2F)cn1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
5-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine (40 mg, 0.13 mmol) and 2-bromo-N-(2-hydroxyethyl)benzenesulfonamide (53 mg, 0.19 mmol) were added to a 5 mL sealable vial equipped with a stir bar. 1,4-Dioxane (0.7 mL) and Na2CO3 (0.3 mL, 2 M) were added. Argon was bubbled through the solvent while it was rapidly stirred for 10 min before adding Pd(dppf)Cl2.CH2Cl2 (5 mg, 0.006 mmol) and heating the mixture heated 15 hours at 80° Celsius. The reaction was cooled to rt, diluted with 2 mL of ethylacetate, 2 mL of water and extracted with of ethyl acetate (3×10 mL). The combined organic extracts were then dried with Na2SO4 and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C18H17FN4O3S, 388.10; m/z found, 389.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.43-8.37 (dd, J=2.2, 1.5, 1H), 8.11-8.06 (m, 2H), 7.93-7.86 (m, 1H), 7.70-7.64 (m, 1H), 7.62-7.56 (m, 1H), 7.44-7.38 (dd, J=7.6, 1.3, 1H), 7.35-7.27 (m, 2H), 3.49-3.44 (t, J=5.9, 2H), 2.90-2.84 (t, J=5.9, 2H).
Reaction SMILES: [OH-].[K+].F[C:4]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:5]=1[NH:6][C@@H:7]([CH3:10])[CH2:8][OH:9].C(O[CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.O>[Cl-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC.CN(C=O)C>[F:16][C:13]1[CH:12]=[CH:11][C:5]2[N:6]([CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:14]=1[F:15]
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
At room temperature, KOH (330 mg) and tetrahexylammonium chloride (190.1 mg) were dissolved in DMF (15 ml). After adding a solution (5 ml) of (2S)-2-(2,3,4-trifluoroanilino)propanol (1 g, 99.8% ee) and diethyl ethoxymethylenemalonate (2.09 g) in DMF, the mixture was stirred for 1 hour. Next, it was heated to 60° C. and a solution (5 ml) of KOH (330 mg) and diethyl ethoxymethylenemalonate (120 mg) in DMF was added thereto. The resultant mixture was stirred at the same temperature for 5 hours. After adding water, the liquid reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography. Thus, 1.37 g (99.8% ee) of the title compound was obtained as a yellow oily substance. Various spectral data was identical with those described in Japanese Patent No. 2,769,174.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])([O-:17])=[O:16]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:23](=[O:24])[CH:22]([O:21][C:20]1[CH:28]=[CH:29][CH:30]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=1)[CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Oc1cccc([N+](=O)[O-])c1)C(=O)Cl
Reactant: NCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(Oc1cccc([N+](=O)[O-])c1)C(=O)NCc1ccccc1
Yield: 58.7 %

Procedure:
In 30 ml of toluene were dissolved 1.6 g (0.015 mole) of benzylamine and 1.2 g (0.015 mole) of pyridine, and thereto was added dropwise a solution of 3.1 g (0.013 mole) of 2-(3-nitrophenoxy)-butyroyl chloride in 30 ml of toluene at room temperature with stirring. Subsequently, after the same procedure as in Synthesis Example 7 was followed, the resultant crude crystals were recrystallized from ethanol to give 2.4 g of N-benzyl-2-(3-nitrophenoxy)-butyramide melting at 114°~116° C. as pale yellow needles.
Reaction SMILES: Br[C:2]1[C:11]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:10][C:9]([C:17]([OH:19])=[O:18])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.[NH3:20]>[Cu]>[NH2:20][C:2]1[C:11]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:10][C:9]([C:17]([OH:19])=[O:18])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2
Reactant: CCS(=O)(=O)c1cc(C(=O)O)c2c(c1Br)CCCO2
Reactant: N
Agent: [Cu]
Product: CCS(=O)(=O)c1cc(C(=O)O)c2c(c1N)CCCO2

Procedure:
118 g of 5-bromo-6-ethylsulphonylchroman-8-carboxylic acid, 460 ml of 34% ammonia, 5 g of powdered copper and 4 g of cuprous chloride were introduced into a 1-liter autoclave and the contents were then heated between 115° and 120° C., for 10 to 12 hours, with stirring.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[NH:7][C:6]2=[O:24].N[C@H](C(O)=O)CCSC.C([O-])(O)=O.[Na+]>CS(O)(=O)=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[NH:7][C:6]2=[O:24]
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1OC
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1O
Temperature: 100 °C

Procedure:
A mixture of 6,7-dimethoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (5.72 g, 17.5 mmol) and L-methionine (3.1 g, 20.7 mmol) in methanesulfonic acid (40 mL) was heated at 100° C. for 4.5 h. An additional aliquot of L-methionine (0.45 g, 1.36 mmol) and methanesulfonic acid (10 mL) were added and the mixture was heated for a further 2 h. The mixture was allowed to cool to RT, poured into ice water (ca. 500 mL) and was neutralized with sat. NaHCO3 solution. A solid separated out which was collected by filtration and dried under vacuum to give the desired 6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one. (7.3 g). HPLC retention time 5.486 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:14]1([CH3:21])[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][CH:15]=1.OS(O)(=O)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([OH:20])=[C:14]([CH3:21])[CH:15]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(CC)(c1ccc(Br)cc1)c1ccc(O)c(C)c1
Temperature: 0 °C
Yield: 63 %

Procedure:
To a stirred suspension of 3-(4-bromophenyl)-pentan-3-ol (2.45 g, 10 mmol) and o-cresol 1.05 mL, 10.2 mmol) in H2O (1.0 mL) chilled to 0° C. was added conc H2SO4 (4.0 g) dropwise. After 1.5 h the reaction mixture was diluted with H2O (50 mL) and extracted with Et2O (2×50 mL). The combined extracts were washed with water, satd NaHCO3, and brine, then dried (anhyd Na2SO4) and concentrated under reduced pressure. The resulting crude product was chromatographed (silica, EtOAC/Hex, 0:100 to 10:90) to afford the title compound (2.1 g, 64% non-optimized) as a colorless liquid: 1H-NMR (CDCl3) δ 7.36 (2H, d, J=8.6), 7.05 (2H, d, J=8.6), 6.83-6.88 (2H, m), 6.67 (1H, d, J=8.1), 4.52 (1H, br s), 2.20 (3H, s), 2.04 (4H, q, J=7.3), 0.61 (6H, t, J=7.3).
Reaction SMILES: [Cl:1][C:2]1[CH:61]=[CH:60][C:5]([O:6][CH2:7][C:8]2[N:9]([CH2:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:36]3)[C:10]3[C:15]([C:16]=2[C:17](=[O:31])[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]([CH2:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]3)[C:10]3[C:15]([C:16]=2[C:17](=[O:31])[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:21][CH2:20]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:60][CH:61]=1
Reactant: O=C(CN1CCC(N2CCCCC2)CC1)c1c(COc2ccc(Cl)cc2)n(CCCC2CCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c2ccccc12
Solvent: ClCCl
Solvent: O=CO
Product: O=C(CN1CCC(N2CCCCC2)CC1)c1c(COc2ccc(Cl)cc2)n(CCCC2CCCNC2)c2ccccc12
Reaction time: 1 h

Procedure:
Under an argon atmosphere (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(1-tritylpiperidin-3-yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-1H-indole (0.0162 g, 0.0194 mmol) was dissolved in 0.2 ml methylene chloride. The reaction vessel was then placed in an ice bath and formic acid (0.073 ml, 0.194 mmol) was slowly added. The resulting mixture was stirred for about one hour over ice. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then stirred at room temperature for two additional hours and then an additional 5.0 equivalents of formic acid were added, followed by stirring at room temperature.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)=[CH:17]1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1c[nH]c2ccccc12
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3c[nH]c4ccccc34)nn2)c[nH]1
Yield: 58.3 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.073 g, 0.429 mmol) was reacted with 3-azidomethyl-indole (0.089 g, 0.515 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(1H-Indol-3-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1Himidazol-2-ylamine hydrochloride (0.086 g, 58%) as a yellow oil. 1H NMR (300 MHz, CD3OD) δ 8.11 (s, 1H), δ 7.84 (m, 2H), δ 7.41 (m, 2H), δ 7.06 (d, 1H), δ 5.66 (s, 2H), δ 3.04 (t, 2H), δ 2.85 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 147.5, 144.9, 144.8, 134.7, 131.9, 127.2, 127.1, 127.1, 125.8, 125.3, 124.4, 109.5, 49.9, 23.6, 23.2 ppm; HRMS (ESI) calcd for C17H19N7 (M+) 321.1701. found 321.1704.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[F:14][C:15]1[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=1>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:21][C:18]2[N:19]=[CH:20][C:15]([F:14])=[CH:16][N:17]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Nc1ncc(F)cn1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ncc(F)cn1)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
A suspension of 5-chloro-2,4-difluorobenzenesulfonyl chloride (1.99 g, 8.05 mmol) in dichloromethane (15 mL) was added portion-wise to a solution of 5-fluoro-pyrimidin-2-ylamine (1.00 g, 8.84 mmol) in pyridine (15 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature gradually and stirred for 16 hours. The reaction mixture was diluted with dichloromethane and partitioned with 1 N aqueous hydrogen chloride solution. The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with water, diluted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by automated silica gel column chromatography (100% chloroform to 10% methanol in chloroform gradient elution) to afford the title compound as a light yellow solid (0.32 g).
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29](CC5C=C(C=CC=5)C(OC)=O)[C:28](=O)[CH2:27]4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1.[Cl:44][C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[C:47]([Cl:52])[C:46]=1[S:53](Cl)(=[O:55])=[O:54]>>[N:4]1([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([S:53]([C:46]5[C:47]([Cl:52])=[CH:48][C:49]([Cl:51])=[CH:50][C:45]=5[Cl:44])(=[O:55])=[O:54])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[O:18])=[C:11]([C:13]([F:14])([F:16])[F:15])[N:12]=2)[CH2:3][CH2:2][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1cccc(CN2CCN(c3ccc(NC(=O)c4oc(N5CCCC(C)C5)nc4C(F)(F)F)cn3)CC2=O)c1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: O=C(Nc1ccc(N2CCN(S(=O)(=O)c3c(Cl)cc(Cl)cc3Cl)CC2)nc1)c1oc(N2CCCCC2)nc1C(F)(F)F

Procedure:
Compound 152 was prepared by the general procedure for compound 8, by using compound C-3 and 2,4,6-trichlorophenylsulfonyl chloride as the starting materials. LCMS (ESI) Rt=4.56 min, [M+1]+ 669.4.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([N+:21]([O-])=O)=[C:16]([CH3:24])[N:15]=2)=[N:6]1.[H][H]>N1C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([CH3:24])[N:15]=2)=[N:6]1
Reactant: [H][H]
Reactant: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: c1ccncc1
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N

Procedure:
592 mg (1.56 mmol) of the compound from example 53A were initially charged in pyridine (25 ml) and then 133 mg (0.125 mmol) of palladium (10% on charcoal) were added. The mixture was stirred at standard hydrogen pressure overnight. The suspension was then filtered through Celite and the filtercake was washed with methanol. The filtrate was concentrated, methanol was added and the mixture was filtered and concentrated again. The residue was dried under high vacuum. This gave 396 mg of the title compound (80% purity, 45% of theory), which were converted without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2].[C:22](#[N:24])[CH3:23]>C(N(CC)CC)C>[NH2:24][CH:22]1[CH2:11][CH2:12][CH2:13][N:14]([C:11]2[CH:12]=[CH:13][N:14]3[C:9]([C:10]=2[O:18][CH3:19])=[C:8]([CH2:20][CH3:21])[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:15]3=[O:16])[CH2:23]1
Reactant: CCOC(=O)c1cc(CC)c2c(OC)c(Cl)ccn2c1=O
Reactant: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CC)c2c(OC)c(N3CCCC(N)C3)ccn2c1=O
Temperature: 40 °C
Reaction time: 120 h

Procedure:
Ethyl-8-chloro-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (Precursor A) (0.05 g) is dissolved in acetonitrile (3 ml) and triethylamine (0.3 ml). To this solution is added 3-S-aminopiperidine dihydrochloride (Precursor E) (0.055 g) and the mixture is stirred at 40° C. for five days. The reaction mixture is evaporated and the desired product obtained by recrystallization in isopropyl alcohol.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18](Br)=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9].[CH3:36]B(O)O.[F-].[Cs+]>O1CCOCC1>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18]([CH3:36])=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(Br)cc(C(F)(F)F)cc21
Reactant: CB(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(C)cc(C(F)(F)F)cc21
Temperature: 80 °C
Yield: 62.3 %

Procedure:
A mixture of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-bromo-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.0830 g, 0.144 mmol), methyl boronic acid (0.0260 g, 0.432 mmol) and cesium fluoride (0.0770 mg, 0.504 mmol) in dioxane (2.00 ml) was purged with nitrogen for 10 minutes. To it was added PdCl2(dppf) (0.0170 g) in one portion. The mixture was heated at 80° C. overnight. The solid was removed by filtration, washed with ethyl acetate (30.0 ml) and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (gradient eluent, 0-40% ethyl acetate in hexane) provided the titled compound (0.0460 g, 63%) as white solid. MS (ES+): 513 (M+H).