Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CC([O-])(C)C.[K+].[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>C1COCC1>[CH2:7]([O:6][C:4]([C:3]1[N:1]=[CH:2][O:19][C:15]=1[CH:16]([CH3:18])[CH3:17])=[O:5])[CH3:8]
Reactant: CC(C)C(=O)Cl
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1C(C)C
Reaction time: 0.5 h

Procedure:
Ethyl isocyanoacetate (4.52 g) was added drop-wise to a stirred suspension of KOtBu in THF (35 ml) at 0° C. under nitrogen. After complete addition, the dark brown solution was stirred for 30 minutes and then a solution of isobutyryl chloride (2.1 ml) in THF (15 ml) added drop-wise, keeping the temperature below ˜10° C. The reaction was stirred for 1 hour then evaporated to dryness. The residue was treated with acetic acid (1.14 ml) and water (25 ml), and then extracted with ether (3×30 ml). The combined ether extracts were washed with saturated brine, dried over sodium sulfate, filtered and evaporated to give a brown oil that was purified by column chromatography, eluting with 1% MeOH in dichloromethane. This gave the title compound (1.91 g) as a colourless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:16](I)[CH2:17][CH3:18].C([O-])(=O)C([O-])=O>CCOC(C)=O>[CH2:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)[CH2:17][CH3:18]
Reactant: CC(=O)c1cccc(N2CCNCC2)c1
Reactant: CCCI
Agent: O=C([O-])C(=O)[O-]
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2cccc(C(C)=O)c2)CC1

Procedure:
Beginning with 1-(3-Piperazin-1-yl-phenyl)-ethanone and n-Pr-I: m.p. 119° C. (oxalate), MS m/z (rel. intensity, 70 eV) 246 (M+, 10), 217 (33), 132 (18), 70 (bp), 56 (41); Rf 0.23 (EtOAc).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[S:19][C:12]4[N:13]=[CH:14][N:15]=[C:16](SC)[C:11]=4[CH:10]=3)=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[NH3:26].[NH4+].[Cl-]>O1CCOCC1.C(Cl)Cl.O>[CH:1]1([N:4]2[C:8]([C:9]3[S:19][C:12]4[N:13]=[CH:14][N:15]=[C:16]([NH2:26])[C:11]=4[CH:10]=3)=[C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: N
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C3CC3)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3C3CC3)cc12
Yield: 35 %

Procedure:
6-(1-cyclopropyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 71) (25 mg), NH3 (aq. conc) and NH4Cl (sat. aq.) in dioxane (2 mL) were heated under microwave conditions (CEM explorer, 170° C., 4 hours). The reaction mixture was diluted with DCM and water. The aqueous layer was extracted with DCM and then the combined organics were concentrated. The crude product was purified by flash chromatography on silica eluting with Hex:EtOAc (1:1 to 100% EtOAc, then MeOH:EtOAc 95:5) to afford the title compound as a solid (8 mg, 35%);
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][N:13]3[C:18](=[O:19])[N:17]=[C:16]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[CH2:22][CH2:21]4)[NH:15][C:14]3=[O:33])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:38](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8]2[CH:35]=[CH:34][C:11]([CH2:12][N:13]3[C:14]([O:33][CH3:38])=[N:15][C:16]([N:20]4[CH2:21][CH2:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[CH2:24][CH2:25]4)=[N:17][C:18]3=[O:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)[nH]c(=O)n1Cc1ccc(OCc2ccc(Cl)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nc(N2CCN(c3ccc(F)cc3)CC2)nc(=O)n1Cc1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 7 %

Procedure:
To an N,N-dimethylformamide solution (4 mL) of a crude product (0.69 mmol) of 3-{4-[(4-chlorobenzyl)oxy]benzyl}-6-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazine-2,4(1H,3H)-dione, potassium carbonate (332 mg, 2.40 mmol) and methyl iodide (137 μL, 2.20 mmol) were added at room temperature and the resultant mixture was stirred at room temperature for 1 day. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain the title compound (26 mg, two step yield: 7%).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)sc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 73.6 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(4-bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone (4.05 g, 8.39 mmol) and 1M boron tribromide/CH2Cl2 (26.0 mL) in CHCl2. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 2.90 g (74%) of the title compound. (DMSO-d6) δ1.41-1.48 (m, 2H), 1.59-1.74 (m, 4H), 1.82 (s, 3H), 1.89-1.96 (m, 2H), 2.27 (s, 3H), 3.20 (quintet, 1H), 3.84 (s, 2H), 6.88 (d, 1H), 7.03 (d, 2H), 7.39-7.43 (m, 3H), 7.54 (d, 1H), 10.47 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C(N(CC)CC)C.BrBr.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cccc(F)c1F
Temperature: -78 °C

Procedure:
1.27 g of 3,4,5-trifluorophenol and 870 mg of triethylamine were dissolved in 10 ml of methylene chloride, and the solution was stirred at −78° C. To the solution was added dropwise 5 ml of a methylene chloride solution of 2-(2-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)ethyl)-1,3-dithianilium triflate obtained above (3.8 g), and the to solution was further stirred for one hour. 6.24 ml of Et3N.3HF was then -added, and a methylene chloride solution of bromine (6.24 g) was further added dropwise. After stirring at −70° C. for one hour, the reaction solution was allowed to gradually warm up. It was poured into 100 ml of a cold 3N sodium hydroxide solution at 0° C. and extracted with methylene chloride (30 ml×3). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting yellow oily substance was isolated and purified by a silica gel column chromatography with heptane as a developing solvent to obtain 1.0 g of 1-(3-(trans-4-propylcyclohexyl)cyclohexyl)-1,1-difluoropropyleneoxy)-3,4,5-trifluorobenzene as colorless crystals. A transition point thereof is shown below.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O.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>[Br:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ccccc2Br)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
Sodium carbonate (19.8 g, 186.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.05 g, 0.90 mmol) were added to a solution of 1,2-dibromobenzene (12.8 ml, 105.98 mmol) and 4-chlorophenylboronic acid (14.1 g, 90.08 mmol) in toluene (170 ml) and water (80 ml). The mixture was purged with nitrogen and heated at reflux overnight. The reaction mixture was allowed to cool to room temperature, and partitioned between saturated aq. NH4Cl and ethyl acetate (500 ml). The organic layer was dried over MgSO4, filtered and the volatiles were evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO, 330 g silica gel column, eluting with 100% hexanes) to give the title product (17.0 g, yield: 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[Cl:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[O:32][C:33]([CH3:36])=[N:34][N:35]=3)[CH:29]=2)[N:24]=[CH:23][N:22]=1>>[ClH:20].[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[O:32][C:33]([CH3:36])=[N:34][N:35]=5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: Nc1ccc2c(cnn2Cc2cc(F)cc(F)c2)c1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5cc(F)cc(F)c5)c4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 1-(3,5difluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 12.50(1H,bs), 10.35(1H,s), 9.25(1H,s), 8.61(1H,s), 8.35(1H,m), 8.22(2H,m), 7.88(1H,dd), 7.75(2H,m), 7.16(1H,m), 6.93(1H,m), 5.73(2H,s), 2.67(3H,s); m/z (M+1+) 470.
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].[NH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(Cl)Cl>[C:11]([C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:16])([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:15])[O:10][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)no1
Reactant: NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(NC1CCOCC1)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 60 °C
Yield: 41.6 %

Procedure:
To a solution of 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (prepared according to method B, step 1, 2.0 g, 6.92 mmol) in anhydrous THF (40 mL) are added 4-aminotetrahydropyran (0.70 g, 6.92 mmol) and Cs2CO3. The reaction is heated to 60° C. for 48 h. After cooling the reaction mixture is partitioned between DCM (100 mL) and water (100 mL). The organic layer is separated and dried over Na2SO4. Filtration and concentration of the filtrate gives a yellow oil. The oil is dissolved in DCM and extracted with 1M aqueous HCl solution. The acidic aqueous extract is basified with 5M aqueous NaOH solution and extracted with DCM (3×100 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure to give N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-2-(tetrahydro-pyran-4-ylamino)-propionamide (0.89 g, 42%). m/z 310 [M+H+]. Conversion into its hydrochloride salt is achieved upon treatment with 1M HCl solution in diethyl ether (2.89 mL).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH:29]=1>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2ccc(C(=O)NCCCCc3cccnc3)cc2)ccc(C(C)=O)c1O
Yield: 93 %

Procedure:
The reaction of 0.635 g of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzoic acid with 0.28 g of 3-pyridine butanamine according to Example 40 gave 0.80 g, mp 133°-134°, (93% yield) of 4-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[CH:7][CH:8]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.[CH3:17][C:18]1(C)[C:22](C)(C)OB(C2C=NNC=2)O1>>[CH3:17][C:18]1([CH3:22])[C@H:4]2[CH2:3][C@@H:8]1[CH2:7][CH2:6][C@H:5]2[CH2:9][N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: CN(C)c1cccc(CO)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC1(C)[C@H]2CC[C@@H](Cn3cccn3)[C@@H]1C2

Procedure:
The title compound was prepared by substituting ((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol for (3-(dimethylamino)phenyl)methanol and pyrazole for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH2:23][NH2:24])[CH:20]=[CH:21][CH:22]=1>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:24]([CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cccc(C(F)(F)F)c1
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cccc(C(F)(F)F)c1

Procedure:
According to the method of Example 160, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with 1-[3-(trifluoromethyl)phenyl]methanamine to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.O>[CH3:18][S:17][C:4]1[N:3]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(Nc2ccccc2)c(C=O)c(-c2ccccc2)n1
Yield: 69.8 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.07 mmol) in dioxane (21 mL) and H2O (7 mL) was added anhyd K2CO3 (443 mg, 3.21 mmol, 3 eq) followed by phenylboronic acid (196 mg, 1.6 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphophine)palladium (61 mg, 0.053 mmol, 0.05 eq) was added. The reaction mixture was then heated under reflux for 24 h and cooled 23°, the layers were separated, EtOAc (50 mL), followed by H2O (10 mL), was added, the organic layer was separated, washed with satd aq NaCl, dried (MgSO4) and filtered. The yellow solution was then evaporated. Product was purified by column chromatography or by crystallization from 10 mL of isopropanol:H2O (2:1) to give 240 mg (70% yield) of pure 2-methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde. 1H-NMR δ 2.60 (s, 3H), 7.22 (m, 1H), 7.35-7.81 (m, 9H), 9.89 (s, 1H), 11.31 (br s, 1H), LC MS (m/e)=322 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8](=[O:20])[CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:4][CH:3]=1.[Br:21]Br>C(O)(=O)C>[BrH:21].[Br:21][CH:9]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:20]
Reactant: Cc1cccc(C(=O)Cc2ccc3ncccc3c2)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Cc1cccc(C(=O)C(Br)c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 189 %

Procedure:
To a stirred solution of 1-(6-methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone (1.0 g, 3.81 mmol) in acetic acid (15 mL) was slowly added a solution of bromine (0.194 ml, 3.81 mmol, 1 equiv) in acetic acid (5 mL) over 5 minutes. After stirring at the ambient temperature for 3 hours the reaction mixture was concentrated in vacuo, and to the residue dichloromethane (10 mL) and ether (60 mL) were added successively. The resulting mixture was stirred during 18 hours. The solid was filtered off and dried in vacuo, which provided 2-Bromo-1-(6-methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone hydrobromide (1.52 g, 95%).
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH:24]4[C:30]5=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=[C:29]5[CH2:28][CH2:27][C:26]5[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:25]4=5)[CH2:20][CH2:19]3)=[O:17])[CH2:11]2)=[NH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:42][N:43]([CH3:48])[S:44](Cl)(=[O:46])=[O:45]>CC#N.C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH:24]4[C:30]5=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=[C:29]5[CH2:28][CH2:27][C:26]5[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:25]4=5)[CH2:20][CH2:19]3)=[O:17])[CH2:11]2)=[N:9][S:44](=[O:46])(=[O:45])[N:43]([CH3:48])[CH3:42])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN(C)S(=O)(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Dissolve the product of Example 9 (1 equivalent) in an inert anhydrous solvent such as CH3CN, benzene or toluene and add Et2N (2 equivalents). Cool the solution to 0° C. and add N,N-dimethylsulfamoyl chloride (1.2 equivalents). Stir the mixture at 0° C. to25° C. for 3 h, extract, filter and evaporate to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]2[CH:12]([CH:13]=1)[C:11]([C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=1)=[CH:10][CH2:9][CH2:8]2)([O-])=O>[Pd].CO.O1CCCC1>[C:19]([N:17]1[CH:18]=[C:14]([CH:11]2[CH:12]3[CH:7]([CH:6]=[CH:5][C:4]([NH2:1])=[CH:13]3)[CH2:8][CH2:9][CH2:10]2)[N:15]=[CH:16]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])C1=CC2C(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)=CCCC2C=C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC1=CC2C(C=C1)CCCC2c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
7.7 g of the product obtained in Step 2 are stirred under a hydrogen atmosphere in the presence of 10% palladium-on-carbon in a methanol/tetrahydrofuran mixture. After filtration and concentration of the solvent, the product is used as it is in the following Step.
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.Cl[C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]([NH:25][C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=2)[N:14]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[OH:10])[CH2:3][NH:2][C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[N:16]=[C:15]([NH:25][C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:28][CH:27]=2)[N:14]=1
Reactant: NCc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.3 %

Procedure:
To a 100 mL round-bottom flask equipped with a stir bar was added 4-(aminomethyl)-2-chlorophenol hydrobromide (1.34 g, 5.63 mmol), tert-butyl 4-((4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (3.00 g, 5.63 mmol) and THF (28 mL). To the solution was added N,N-diisopropylethylamine (2.95 ml, 16.9 mmol). The mixture was stirred at room temperature for 3 days. The mixture was concentrated in vacuo and the resulting residue was subjected to C18 chromatography (water:methanol 1:1 to methanol) to afford tert-butyl 4-((4-((3-chloro-4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate as a colorless solid (2.88 g, 90%). MS m/z=526.3 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[NH2:2][CH2:1][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: N#CCCc1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCCc1ccccn1

Procedure:
2(2-Cyanoethyl)pyridine is reduced with lithium aluminium hydride in ether, in the normal way, yielding 2-(3-aminopropyl) pyridine, b.p. 77° C/0.4 mm. (Dihydrochloride, m.p. 175°-177° C).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19].O1CCCC1.[H][H]>[Rh].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1cc(Cl)ccc1OCCCCCBr
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(Cl)ccc1OCCCCCBr
Yield: 100.8 %

Procedure:
A mixture of 2.02 g (5.59 mmol) of 3-[2-[(5-bromopentyl)oxy]-5-chlorophenyl]-2-propenoic acid methyl ester (mixture of E/Z-isomers), 90 mL of tetrahydrofuran, 190 mL of toluene, and 1.26 g of 5% rhodium on alumina was stirred at room temperature, in an atmosphere of hydrogen, until reduction was complete. The catalyst was removed by suction filtration and the filtrate was concentrated in vacuo giving 2.05 g (ca. 100%) of 2-[(5-bromopentyl)oxy]-5-chlorobenzenepropanoic acid methyl ester as a pale-yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[NH:24][C:23]4[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[C:16]2=[O:33])[C@H:11]([CH2:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:10]1.[CH:44](=O)[CH3:45].[C:47](O)(=O)[CH3:48].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:47]([N:8]([CH2:44][CH3:45])[C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[NH:24][C:23]4[C:25]([C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[C:16]2=[O:33])[C@H:11]([CH2:34][S:35]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)(=[O:36])=[O:37])[CH2:10]1)[CH3:48]
Reactant: CC(=O)O
Reactant: N[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCN(CC)[C@@H]1CC[C@H](N2CCC(c3nc4cccc(C(F)(F)F)c4[nH]3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.33 h
Yield: 28 %

Procedure:
To a solution of Example 47 (25 mg, 44 μmol) in 1,2-dichloroethane (2.7 mL) was added acetaldehyde (28 μL, 492 μmol) and acetic acid (8 μL, 96 μmol). The resulting mixture was stirred for 20 min, then sodium triacetoxyborohydride (31 mg, 144 μmol) was added. After stirring for 2 h, the mixture was diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by preparative TLC (90:10:1 CHCl3/MeOH/NH4OH). After concentrating the material in vacuo, the resulting oil was dissolved in CH3CN/H2O/TFA and lyophilized to provide the title compound (8.5 mg, 26%) as a white solid and mixture of diastereomers: ESI MS m/z 577 [C29H35F3N4O3S+H]+.