Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([I:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]([O:20]CC)=O)[N:8]=2)=[N:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1>C1COCC1>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([I:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[O:20])[N:8]=2)=[N:2]1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccc(I)cc2n1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1nc(Nc2cc[nH]n2)c2ccc(I)cc2n1
Temperature: -40 °C
Reaction time: 5 h
Yield: 35.1 %

Procedure:
To a suspension of ethyl 4-(1H-pyrazol-3-ylamino)-7-iodoquinazoline-2-carboxylate (0.130 g, 0.31 mmol) in THF (5 mL) at −40° C. was added (4-fluorophenyl)magnesium bromide (1.0 M solution in THF, 0.797 mL, 0.79 mmol). The mixture was stirred at −40° C. for 5 h, quenched with 1.0 N HCl (2.0 mL), and concentrated under reduced pressure. The residue wad purified on preparative HPLC (Phenomenex phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O) to afford (4-(1H-pyrazol-3-ylamino)-7-iodoquinazolin-2-yl)(4-fluorophenyl)methanone as a yellow solid (0.050 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ 6.72 (s, 1H), 7.35 (t, 2H), 7.64 (s, 1H), 8.00 (d, 1H), 8.08 (dd, 2H), 8.28 (s, 1H), 8.55 (d, 1H), 10.88 (s, 1H), 12.55 (s, 1H); LC-MS (ESI) m/z 460 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]([NH2:15])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH2:2][CH3:3].[CH3:16][N:17]([CH3:20])C=O>O>[CH2:1]([N:4]1[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:13])([F:14])[F:12])=[CH:7][C:6]=2[N:15]=[C:11]1[C:8]1[CH:9]=[CH:20][N:17]=[CH:16][CH:7]=1)[CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCCNc1ccc(C(F)(F)F)cc1N
Solvent: O
Product: CCCn1c(-c2ccncc2)nc2cc(C(F)(F)F)ccc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 0.44 g of N1-propyl-4-trifluoromethylbenzene-1,2-diamine, 0.51 g of isonicotinealdehyde-bisulfite adduct and 4 ml of N,N-dimethylformamide was stirred for 1 hour at 150° C. The reaction mixture was allowed to cool to room temperature, and water was poured into this, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, then, concentrated under reduced pressure to obtain a solid residue. The residue was washed with hexane, to obtain 0.55 g of 1-propyl-2-(pyridin-4-yl-)-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 218).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]1([C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[O:8]=[C:2]([C:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[S:16][C:15]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: c1ccc(-c2cc3ccccc3s2)cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(-c2ccccc2)sc2ccccc12
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
Ethyl chlorooxoacetate (162 μL, 1.45 mmol) was added at 0° C. to a solution of 2-phenyl-1-benzothiophene (2a) (310 mg, 1.46 mmol) and aluminum chloride (III) (389 mg, 2.92 mmol) in dichloromethane (10 mL). After 30 minutes, the reaction mixture was quenched with a saturated aqueous solution of sodium carbonate. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the organic layer was washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired product (2b) as a pale oil (370 mg, 1.19 mmol, 70%).
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[OH:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[OH:23])[CH2:29]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: COc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc(-c2nc(C(=O)N3CCc4c(ccc(OC)c4O)C3)c3ccccc3n2)cc1
Yield: 16 %

Procedure:
Reaction of 2-(4-methoxylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 22 (16% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.65 and 2.89 (2t, 2H), 3.47 and 4.03 (2t, 2H), 3.74-3.87 (3s, 6H), 4.38 and 4.91 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.09-7.15 (m, 2H), 7.63-7.73 (m, 1H), 7.81-7.93 (2d, 1H), 8.02-8.12 (m, 2H), 8.44-8.51 (m, 2H), 8.68 and 8.73 (2s, 1H); MS (ESI) m/z 442 ([M+H]+).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])C.[OH-].[Na+].Cl>C(O)C.O>[Cl:23][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[C:10]=2[CH:21]=[CH:22][C:7]=1[O:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccc(C)cc3)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2noc3c(Cl)c(OCC(=O)O)ccc23)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 20 g of ethyl{[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetate, Example 12, and 15 ml of 50% sodium hydroxide in 600 ml of ethyl alcohol is refluxed for 1 hour. Thereafter, the hot mixture is diluted with 500 ml of water and acidified with concentrated hydrochloric acid. The acidified suspension is, successively, stirred for 30 minutes and filtered and the filter cake is recrystallized from dimethylformamide to yield the product {[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having a melting point of 257° to 260° C.
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C:10]2([F:18])[F:17])[CH:2]=1.Cl.[CH2:20]([O:32][C:33]([C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](O)=[O:38])=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:20]([O:32][C:33](=[O:34])[C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](=[O:38])[NH:8][C:7]1[CH:1]=[CH:2][N:3]([C@H:9]2[C:10]([F:17])([F:18])[C@H:11]([OH:16])[C@@H:12]([CH2:14][OH:15])[O:13]2)[C:4](=[O:5])[N:6]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: CCCCCCCCCCCCOC(=O)c1ccccc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOC(=O)c1ccccc1C(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
Gemcitabine hydrochloride (0.7 g, 2.34 mmol), 2-(dodecyloxycarbonyl)benzoic acid (1.02 g, 3.04 mmol), (Benzotriazol-1-yl-oxy)tripyrrolidinylphosphonium hexafluorophosphate (1.34 g, 2.57 mmol), and 4-dimethylaminopyridine (428 mg, 3.51 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred overnight at room temperature. The reaction mixture was poured into water, and then extracted three times with ethyl acetate. The isolated organic phase was dried with anhydrous Na2SO4. The solvent was removed by vaporizing under reduced pressure. The residue was purified by silica column chromatography (developing agent: dichloromethane/methanol=30/1) to produce 362.5 mg of Dodecyl-2-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)benzoate. LC purity 98% (UV254). LC-MS m/z 580 [M+H]+ (molecular formula: C29H39F2N3O7, molecule weight: 579). The structure and characterization data of the compound were shown in Table 1.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([NH:21][C:22](=O)OC)=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([NH:21][CH3:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl [2-tert-butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]carbamate (650 mg, 1.89 mmol) was dissolved in 20 mL of THF at 0° C. under nitrogen. 1M HCl/ether (2.65 mL, 2.65 mmol) was added dropwise and the solution was stirred at 0° C. for 15 min. LiAlH4 (360 mg, 9.45 mmol) was then slowly added and the solution was stirred at rt overnight. The reaction mixture was quenched at 0° C. by addition of MeOH (5 mL) followed by water (10 mL). The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The solvent was evaporated and the product was used directly for Step A without further purification. Yield: 544 mg (96%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.08 (s, 2H), 1.17 (m, 3H), 1.54 (s, 9H), 1.64 (m, 2H), 1.67 (m, 2H), 1.72 (m, 2H), 2.02 (m, 1H), 2.87 (s, 3H), 4.06 (d, J=7.62 Hz, 2H), 6.60 (dd, J=8.69, 2.25 Hz, 1H), 7.00 (d, J=1.76 Hz, 1H), 7.12 (d, J=8.59 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O>C1COCC1>[C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][C@H:20]2[CH:21]3[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]3)[CH2:19]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.5 %

Procedure:
To a solution of 2-phenyl-2-(phenylamino)acetic acid (I1) (500 mg, 2.20 mmol), (R)-quinuclidin-3-ol (280 mg, 2.20 mmol) and triphenylphosphine (577 mg, 2.20 mmol) in dry THF (7 mL) cooled at 0° C., is added (E)-diethyl diazene-1,2-dicarboxylate (0.35 mL, 2.20 mmol) and the reaction is stirred for 2 hours at RT. The solvent is removed under vacuum and the residue is taken up with EtOAc, washed with 5% NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The resulting yellow oil is purified by flash chromatography (EtOAc/MeOH/NH4OH=90/10/0.1 to 70/30/0.1) to obtain desired product as a white powder (78.0 mg, 10% yield, mixture of diasteroisomer).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][CH2:14][OH:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>CC(C)=O.O=[Mn]=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][CH:14]=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: OCC#Cc1ccc(-n2cccn2)cc1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: O=CC#Cc1ccc(-n2cccn2)cc1
Yield: 27 %

Procedure:
A mixture of the compound from step A (0.71 g, 3.58 mmol) and MnO2 (3.10 g, 35.66 mmol) in acetone (40 mL) was heated to reflux for 3 h. The cooled reaction mixture was filtered through Celite and the filtrate was concentrated. Purification by chromatography (SiO2, 6:1 hexane/ethyl acetate) yielded 0.19 g (27%) of the title compound as an off-white solid. MS 197 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]=[C:16]1[O:20][C@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[N:18]2[CH2:25][CH2:26][CH2:27][C@@:17]12[CH:28]=[O:29]>ClCCCl.C(Cl)Cl>[OH:29][CH2:28][C@@:17]12[CH2:27][CH2:26][CH2:25][N:18]1[C@@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[O:20][C:16]2=[O:15]
Reactant: O=C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (544 mg, 2.57 mmol) was added to (3R,7aR)-1-oxo-3-trichloromethyl-dihydro-pyrrolo[1,2-c]oxazole-7a-carbaldehyde (obtained as described in J. Org. Chem. 2006, 71(1), 97-102, 500 mg, 1.835 mmol) in DCE (4 mL). The RM was stirred 18 h at rt then taken up in DCM, the organic layer washed with water, dried over Na2SO4 and evaporated. The crude product was purified using a 20 g RediSep® silica gel column (eluent DCM to 10% MeOH in DCM) to give the title compound as a clear pale yellow oil.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:54])[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.33 mmol) in pyridine (2 mL) was added benzoyl chloride (0.046 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave a solid which was isolated by filtration. (0.069 g, 55% yield): 1H NMR (DMSO-d6) δ 14.10 (br s, 1H), 13.44 (br s, 1H), 10.50 (s, 1H), 8.74 (s, 1H), 8.48 (s, 1H), 8.03 (td, 4H), 7.74 (m, 2H), 7.58 (m, 4H); ES-MS (m/z) 381 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][CH2:4]2.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](O)=[O:22])=[N:13]1>>[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]([NH:1][CH2:2][C:3]23[CH2:10][CH2:9][CH2:8][N:7]2[CH2:6][CH2:5][CH2:4]3)=[O:22])=[N:13]1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: NCC12CCCN1CCC2
Product: Cn1nc(C(=O)NCC23CCCN2CCC3)c2ccccc21

Procedure:
Following the procedure of example 1, 7a-Aminomethylhexahydro-1H-pyrrolizine is reacted with N-methylindazole-3-carboxylic acid [J. Medicinal Chemistry (1987) 30: 1535] to afford the title compound.
Reaction SMILES: C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:39]1[CH:43]=[CH:42][CH:41]=[CH:40]1.Br[C:45]1[CH:50]=[C:49]([CH3:51])[C:48]([NH:52][C:53](=[O:60])[CH2:54][CH:55]2[CH2:59][CH2:58][CH2:57][CH2:56]2)=[C:47]([CH3:61])[CH:46]=1>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[CH:55]1([CH2:54][C:53]([NH:52][C:48]2[C:47]([CH3:61])=[CH:46][C:45]([N:39]3[CH:43]=[CH:42][CH:41]=[CH:40]3)=[CH:50][C:49]=2[CH3:51])=[O:60])[CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC1CCCC1
Reactant: c1cc[nH]c1
Agent: [Cu+2]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(-n2cccc2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 110 °C
Yield: 4.5 %

Procedure:
Dibenzylideneacetone (1.1 mg) and 1,10-phenanthroline (17 mg) were mixed in dry toluene (1 mL) under argon for 5 minutes, followed by addition of copper(II) trifluoromethanesulfonate (1.8 mg), cesium carbonate (35 mg), pyrrole (10 mg) and N-(4-bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (1p, 30 mg) and the reaction was heated to 110° C. in a sealed 4 mL vial under argon for 48 hours. The reaction mixture was concentrated in vacuo, sodium hydroxide (2 M, 1.5 mL) was added and the product was extracted with isopropyl acetate (3×1.5 mL). The combined organic phases were dried over magnesium sulfate, concentrated in vacuo and redissolved in dimethyl sulfoxide (0.50 mL) of which 0.25 mL was subjected to preparative LC-MS purification to furnish 1.3 mg (9% yield) of the title compound as an oil. LC-MS-TOF (m/z) 297 (MH+); tR=3.11, (UV, ELSD) 97%, 99%.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9](=[O:50])[CH:10]([C:12]1[CH:49]=[CH:48][CH:47]=[CH:46][C:13]=1[CH2:14][CH2:15][C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[N:17]=1)[CH3:11].C1CCCCC1>C(Cl)Cl.CCOC(C)=O>[NH:36]1[CH2:37][CH2:38][CH:33]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:18]3[N:17]=[C:16]([CH2:15][CH2:14][C:13]4[CH:46]=[CH:47][CH:48]=[CH:49][C:12]=4[CH:10]([CH3:11])[C:9]([NH2:8])=[O:50])[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=3)=[CH:32][CH:31]=2)[CH2:34][CH2:35]1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 46.1 %

Procedure:
Trifluoroacetic acid (0.417 mL, 5.46 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I55) (65.2 mg, 0.109 mmol) in dry DCM (8 mL) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 23 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (20 mL) and 2 M NaOH (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a pale yellow solid which was dissolved in EtOAc (2 mL) to which was added cyclohexane (10 mL). The resulting precipitate was collected by filtration to afford the title compound (I2) (25 mg, 47%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 8.67 (s, 1H), 7.68-7.65 (m, 2H), 7.42-7.34 (m, 1H), 7.26-7.12 (m, 6H), 6.87 (s, 1H), 3.86 (q, J=7.0 Hz, 1H), 3.44-3.18 (m, peaks obscured by water peak), 3.14-2.95 (m, 5H), 2.64-2.46 (m, peaks obscured by DMSO), 1.68 (d, J=13.0 Hz, 2H), 1.49 (qd, J=12.1, 2.4 Hz, 2H), 1.31 (d, J=7.0 Hz, 3H). LCMS Method C: rt 4.91 min; m/z 498 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH2:41]([NH:48][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccsc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccsc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
To a stirred mixture of 3-methyl-2-thiophenecarboxylic acid (5.00 g, 35.17 mmol), 1-hydroxybenzotriazole (7.13 g, 52.73 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.11 g, 52.74 mmol) in anhydrous N,N-dimethylformamide (50 mL) was added N,N-diisopropylethylamine (18.4 mL, 105.6 mmol), followed by benzylamine (3.84 mL, 35.19 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h, and partitioned between ethyl acetate (200 mL) and 10% aqueous hydrochloric acid (100 mL). The organic layer was washed with 10% aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (2×100 mL) and water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with 5% ethyl acetate in hexanes to afford the title compound as a colorless solid (6.63 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.25 (m, 6H), 6.90 (d, J=4.9 Hz, 1H), 6.08 (br s, 1H), 4.62 (d, J=5.6 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 232.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9].[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[I:9][C:3]1[C:4]([NH2:8])=[N:5][CH:6]=[CH:7][C:2]=1[O:19][C:12]1[CH:11]=[CH:10][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1
Reactant: Nc1nccc(Cl)c1I
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2)c1I
Yield: 38.5 %

Procedure:
4-Chloro-3-iodo-2-pyridinamine (1.0 g), p-nitrophenol (1.1 g), diisopropylethylamine (1.0 ml) and N-methyl-2-pyrrolidone (2 ml) were stirred at 170° C. for 17 hours. After returning the reaction solution to room temperature, water was added and extraction was performed with ethyl acetate. NH type silica gel was added to the extract, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=3:1). The solvent was distilled off under reduced pressure, and then ethyl acetate and hexane were added to the residue for solidification to obtain 540 mg of light yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][N:21]([CH2:34][C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH2:22]3)[CH2:18]2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:26][CH:27]=1)#[N:2]
Reactant: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CNCC(C1)O2
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(Cc3cccnc3)CC(C1)O2
Reaction time: 1.5 h
Yield: 68 %

Procedure:
N-[2-(4-Cyanophenoxy)ethyl]-N-[2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]methanesulfonamide (79 mg, 0.2 mmol; see Example 3(ii) above) and pyridine-3-carbaldehyde (36 mg, 0.34 mmol) were dissolved in DCM (4 mL) and shaken for 1.5 h. Sodium triacetoxyborohydride (144 mg, 0.68 mmol) was added and the mixture was shaken overnight. The reaction was quenched with 1 M K2CO3 (2 mL) and was then phase-separated. The aqueous layer was washed with DCM (3×3 mL) and the organic layers were combined and evaporated. The residue was purified by chromatography on silica, which gave 66 mg (68%) of the title compound.