Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:9](=[O:10])[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C=Nc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)Nc2ccccc2Br)CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 103.9 %

Procedure:
2-Bromophenyl isocyanate (10.2 g, 51.5 mmol) was dissolved in N,N-dimethylformamide (40 mL) with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.36 g, 51.5 mmol). The reaction mixture was stirred at 50° C. for 20 hours before being concentrated under reduced pressure. The crude was taken up in dichloromethane (200 mL) and washed with water (2×150 mL) and brine (1×150 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light yellow oil (21.36 g). MS m/z: [M+H+] calcd for C17H23BrN2O4 399-08; found 399.3.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.N1CCCCC1>ClCCl.[OH-].[Na+]>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1
Reactant: Cc1cccc(S)c1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1cccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 1.3 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.4 mmol of 3-methylbenzenethiol, and 1.4 mmol of piperidine in 25 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid which was dissolved in 2N NaOH, washed with ether, acidified to pH 2, and extracted with ethyl acetate. The extract was washed with water, dried over MgSO4, and concentrated to give a solid (m.p. 58°-60° C.). 1H NMR (DMSO-d6) δ2.07 (s, 3H), 3.77 (s, 2H), 6.06 (m, 1H), 6.45 (s, 1H), 6.78 (m, 2H), 7.25-7.47 (m, 10H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][CH:23]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)C(O)=O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1Cl.[CH:34]1N=CN(C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].C[N:53]([CH:55]=[O:56])C>O>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:34])=[CH:2][CH:3]=3)=[CH:10][C:11]([CH2:22][CH:23]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[C:55]([NH2:53])=[O:56])=[N:12]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: COc1ccc(-n2nc(CC(C(N)=O)c3cccc(C)c3)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A mixture of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid (product of Method 2) (0.10 g, 0.23 mmol) and CDI (85 mg, 0.52 mmol) in DMF (2.5 mL) was stirred at rt for 30 min. The solution was then cooled to 0° C., and ammonium carbonate (99 mg, 1.0 mmol) was added in portions. The reaction mixture was allowed to warm to rt and stirred for an additional 18 h. The reaction mixture was then diluted with water (25 mL) and extracted with EtOAc (3×25 mL). Organic layers were combined, washed with water (3×25 mL) and brine (1×25 mL) and dried with Na2SO4, and the solvent removed under reduced pressure giving 70 mg (71%) of the title compound. HPLC: Rt=9.38 (Method A). MS (ES+): mass calculated for C27H27N3O2, 425.21; m/z found 426.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.50 (s, 1H), 7.22 (s, 1H), 7.20 (d, J=5.1 Hz, 2H), 7.14-7.10 (m, 3H), 7.04 (d, J=8.2 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H), 6.82 (s, 1H), 6.27 (s, 1H), 3.89 (dd, J=5.5, 9.6 Hz, 1H), 3.76 (s, 3H), 3.34 (m, 1H), 2.82 (dd, J=5.5, 14.7 Hz, 1H), 2.29 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:29])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])[CH:17]=2)[CH2:10][C@H:9]1[C:30]([N:32]1[CH2:36][CH2:35][S:34][CH2:33]1)=[O:31])=O)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:28][S:25]([NH:24][C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([NH:14][CH2:13][C@H:11]1[CH2:10][C@@H:9]([C:30]([N:32]2[CH2:36][CH2:35][S:34][CH2:33]2)=[O:31])[NH:8][CH2:12]1)=[O:29])=[O:23])(=[O:26])=[O:27]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(C(=O)NS(C)(=O)=O)c2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)NC(=O)c1cccc(C(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of Example 32C (372.1 mg, 0.69 mmol) in methanol (5 mL) was slowly added a solution of 4 M HCl in dioxane (1.6 mL, 6.4 mmol) at 0° C. over 10 minutes via addition funnel. The mixture was allowed to stir for 5 hours at room temperature and then was concentrated under reduced pressure to provide the titled compound. MS (ESI) m/e 441 (M+H)+, 439 (M−H)−; 1H NMR (400 MHz, CD3OD) δ ppm 1.80 (m, 1 H), 2.74 (m, 1 H), 2.84 (m, 1 H), 3.09 (m, 1 H), 3.16 (t, 1 H), 3.24 (m, 1 H), 3.52 (dd, 2 H), 3.55 (m, 1 H), 3.74 (m, 1 H), 3.88 (m, 1 H), 4.51 (m, 1 H), 4.65 (d, 1 H), 4.70 (d, 1 H), 7.63 (m, 1 H) 8.06 (d, 1 H) 8.10 (d, 1 H) 8.39 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH:12]([NH:13][CH2:14]2)[CH2:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1.[C:16]([CH2:24][CH2:25][Cl:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(Cl)(Cl)Cl.O.CN(C)C=O>[ClH:26].[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH:12]([N:13]([CH2:25][CH2:24][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:14]2)[CH2:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C23CCCC(C2)NC3)c1
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: O=C(CCN1CC2(c3cccc(O)c3)CCCC1C2)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 13.7 %

Procedure:
A mixture of 0.4 g of 1-(3-hydroxyphenyl)-6-azabicyclo[3,2,1]octane, 0.4 g of 2-benzoylethyl chloride, 0.4 of potassium carbonate, 0.03 g of potassium iodide and 5 ml of dimethylformamide is stirred at 100°C for 4 hours in a nitrogen atmosphere. After cooling, water is added to the mixture, and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. The residue thus obtained is dissolved in 5 ml of chloroform. The chloroform solution is poured onto a column of 40 g of silica gel. Then, the column is eluted with a mixture of 300 ml of chloroform and 15 ml of methanol, and the effluent is evaporated to remove solvent. Methanolic hydrogen chloride is added to the residue in ether, and the crystalline precipitate is collected by filtration. The precipitate is recrystallized from a mixture of methanol and ether. 0.1 g of 1-(3-hydroxyphenyl)-6-(2-benzoylethyl)-6-azabicyclo[ 3,2,1]octane hydrochloride is obtained. M.p. 187°- 189°C.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2)[CH3:2].[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)#[N:17].C(N(CC)CC)C.C(#N)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C>[C:16]([C:18]1[CH:23]=[C:22]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][C:10]([C:12]([F:14])([F:15])[F:13])=[N:11][C:3]=3[CH2:1][CH3:2])[CH:21]=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCc1nc(C(F)(F)F)nc2nc[nH]c12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1nc(C(F)(F)F)nc2c1ncn2-c1cccc(C#N)c1
Temperature: 52.5 °C
Reaction time: 18 h
Yield: 18.9 %

Procedure:
A mixture of 6-ethyl-2-trifluoromethylpurine (86 mg, 0.40 mmol), 3-cyanophenylboronic acid (103 mg, 0.70 mmol), copper (II) acetate (72 mg, 0.4 mmol), triethylamine (202 mg, 2.0 mmoL), anhydrous acetonitrile (5 ml) and molecular sieves (˜10 pellets) was stirred at 50-55° C. for 18 hours. Ethyl acetate (20 ml) was added and the solid was filtered off. The filtrate was washed with 20 ml of 5% aqueous sodium bicarbonate, concentrated under vacuum, and purified by chromatography over SiO2 (ethyl acetate/hexane 1:3) to give 24 mg of 9-(3-cyanophenyl)-6-ethyl-2-trifluoromethylpurine (yield 19%). 1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 8.11 (m, 2H), 7.82(m, 2H), 3.35 (q, J=7.5 Hz, 2H), 1.50 (t, J=7.5 Hz, 3H). [ESMS m/z (318.4 (M+H)+)]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si:20]([CH2:23][Cl:24])([CH3:22])[CH3:21].CCOCC>O1CCCC1.CCCCCC>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([Si:20]([CH2:23][Cl:24])([CH3:22])[CH3:21])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(Cl)CCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 9.9 g (0.042 mol) of 4-bromobiphenyl in 50 ml of dry tetrahydrofuran was cooled to -78° under nitrogen and stirred while 26.5 ml (0.042 mol) of 1.6 molar n-butyllithium in hexane was added dropwise over 15 minutes. A thick slurry formed, and 35 ml of tetrahydrofuran was added to facilitate stirring. With continued cooling, 5.9 ml (6.7 g, 0.046 mol) of chlorochloromethyldimethylsilane was added over 10 minutes, giving a clear solution that was allowed to warm to room temperature. Addition of 300 ml of ether, filtration to remove precipitated lithium chloride, and evaporation of the filtrate left 13.2 g of semisolid. Redissolution in ether, filtration, and evaporation of the filtrate left 11.0 g (100% crude) of the title compound as a colorless solid, m.p. 30°-40°, suitable for further reaction. Trace impurities could be removed by sublimation at 30°/0.1 mm, leaving the title compound unsublimed in 83% recovery; m.p. 37°-40°; ir (Nujol®) 1585, 1240, 1110, 830, 810, 750, 690 cm-1, nmr (CDCl3) 0.4 (6H, s), 2.9 (2H, s), 7.3-7.7 (9H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([NH:21][C:20]([CH3:23])([CH3:22])[C:19]([O:18][CH3:17])=[O:24])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: COC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
A solution of 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5, 0.2 mmol), 2-methyl-alanine methyl ester (0.2 mmol) and HBTU (CAN 94790-37-1, 114 mg, 0.3 mmol) in DMF (0.5 mL) was stirred for 20 h at room temperature. The crude reaction mixture was concentrated in vacuo by centrifugation and purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in heptane) to give the desired product together with some impurities (73 mg, 116%) as light yellow oil; MS (LC/MS): 333.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]([CH3:15])[CH3:14])[C:7]2=[O:16].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]([CH:13]([CH3:15])[CH3:14])[C:7]2=[O:16]
Reactant: CC(C)(C)N
Reactant: CC(C)n1c(Cl)nc2c(Br)cccc2c1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)n1c(NC(C)(C)C)nc2c(Br)cccc2c1=O
Yield: 86.7 %

Procedure:
A slurry of 8-bromo-2-chloro-3-isopropylquinazolin-4(3H)-one (406c, 0.40 g, 1.326 mmol) and tert-butylamine (4.18 mL, 39.8 mmol) was heated in a sealed tube at 80° C. overnight. The reaction was treated with ice, water, and DCM. The cloudy aq. layer was extracted 4×DCM and 1× EtOAc. The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (24 g column) using 0-40% EtOAc/hexanes. The product-containing fractions were concentrated to afford 8-bromo-2-(tert-butylamino)-3-isopropylquinazolin-4(3H)-one (0.39 g, 1.15 mmol, 87% yield) as an oil which slowly solidified. 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, dd, J=7.9, 1.5 Hz), 7.83 (1H, dd, J=7.6, 1.4 Hz), 6.97 (1H, t, J=7.7 Hz), 5.55 (1H, br. s.), 4.68 (1H, br. s.), 1.63 (9H, s), 1.55 (6H, d, J=7.2 Hz). m/z (ESI, +ve) 338.0/340.0 (M+H)+.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])[C:19](Cl)=[O:20]>C1COCC1>[F:15][C:16]1[CH:17]=[C:18]([C:19]2[O:20][CH:2]=[N:1][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1ccc(F)c(F)c1
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a well stirred solution of the methyl isocyanoacetate (2 g, 20.2 mmol) in THF (3 mL), triethyl amine (8.4 mL, 6.06 mmol) was added and the reaction mixture was stirred for 15 minutes. Then 3,4-difluorobenzoylchloride (2.5 mL, 20.20 mmol) was added neat over a period of five minutes and the reaction mixture was allowed to stir at room temperature for 48 hours. It was then concentrated, partitioned between ethyl acetate (50 mL) and water. The organic layer was washed with 10% NaOH solution (20 mL), dried over sodium sulfate, filtered and concentrated to yield 3.8 g (79%) of a brown solid which was recrystallized from hexanes: 1H-NMR (CDCl3) δ3.74(s, 3H), 7.47-7.50 (m, 1 H), 7.92 (s, 2 H), 8.01-8.10 (m, 2 H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][CH2:7][NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCCNN=Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N(CCO)N=Cc1ccccc1

Procedure:
0.78 g (10-2 moles) of acetyl chloride is added dropwise to a solution containing 10-2 moles of benzaldehyde (2-hydroxyethyl)hydrazone and 0.79 g (10-2 moles) of anhydrous pyridine in 20 ml of anhydrous ethyl acetate, with stirring in the cold.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCN(C)CC3)s2)s1
Reaction time: 4 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (280 mg; 0.84 mmol; 1 eq), is dissolved in DCM (10 ml). N-Methyl piperazine (8.4 ml; 8.4 mmol; 10 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After four hours, water (1 ml) is added and the solvents are evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in a mixture of DCM and diethyl ether, affording after filtration, Compound (8) as a white solid (173 mg; 51%).
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[C:11]1([N:8]2[C:7]3[C:2]([C:24]4[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=4)=[CH:3][C:4]([C:17]([F:20])([F:19])[F:18])=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: OCCCO
Product: FC(F)(F)c1cc(-c2ccncc2)c2c(c1)ncn2-c1ccccc1

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.0 g, 7.5 mmol), pyridine 4-boronic acid (1.38 g, 11.2 mmol), 1,3-propanediol (2.7 ml, 37.3 mmol), potassium carbonate (5.2 g, 37.3 mmol) and bis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in a mixture of dimethoxyethane (30 ml) and water (15 ml) was stirred at reflux for 5 days. The cooled reaction mixture was concentrated under reduced pressure, and the concentrate was partitioned between water and ethyl acetate. The organic phase was dried and concentrated under reduced pressure, and the concentrate was purified by column chromatography on silica gel eluting with a mixture of ligroin and ethyl acetate (1:1 v/v). The product was isolated as a yellowish solid by evaporation of solvent from the eluate (1.55 g, 61%) m/z, 340.1 (M+H)+.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[N:17][CH:18]=[C:19]([CH:21]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[CH3:22])[CH:20]=3)[N:12]=[C:11]([CH3:42])[N:10]=2)=CC=1>FC(F)(F)C(O)=O>[CH3:41][O:40][C:37]1[N:36]=[CH:35][C:34]([NH:33][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:42])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:24]=3)[CH3:22])=[CH:18][N:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(C)c3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (459.4 mg, 0.6277 mmol) was dissolved in trifluoroacetic acid (Aldrich, redistilled, 99+%, 7.5 mL) and the flask was fitted with a reflux condenser and put in a preheated oil bath (75° C.) and stirred overnight. Then, the reaction was cooled to room temperature, concentrated, diluted with DCM, and treated with saturated sodium bicarbonate and 5 N NaOH to raise the pH of the aqueous phase to about 6. The layers were separated, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (25:1 DCM/MeOH to 20:1 DCM/MeOH). The fractions with product were collected, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH, but was still not 95% pure by HPLC. So, the filtrate and solid were combined, concentrated, treated with EtOAc and acetone (which in combination dissolved the compound), concentrated, and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min; total flow rate of 100 mL/min) to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (192.4 mg). 1H NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 8.48 (s, 1H), 8.16 (d, J=1.57 Hz, 1H), 8.07 (d, J=8.02 Hz, 1H), 7.91 (d, J=8.22 Hz, 2H), 7.45 (d, J=8.22 Hz, 2H), 6.93 (d, J=9.00 Hz, 1H), 4.28 (q, J=7.56 Hz, 1H), 4.03 (s, 3H), 3.06 (s, 3H), 2.63 (s, 3H), 1.74 (d, J=7.04 Hz, 3H). m/z (ESI, pos. ion) 492 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][NH:69][CH2:68]1)[CH3:65]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][CH:67]([CH2:66][N:64]([CH3:65])[CH3:63])[CH2:68]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(C)CC1CCCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC(CN(C)C)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-(dimethylamino-methyl)-piperidine.
Reaction SMILES: N1C(CC2N3C=C(F)C=CC3=NC=2C2C=CC(F)=CC=2)=NC=N1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]3[C:39]=2[CH2:40][C:41]2[N:45](C=C)[N:44]=[CH:43][N:42]=2)=[CH:27][CH:26]=1>>[NH:45]1[C:41]([CH2:40][C:39]2[N:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]3=[N:32][C:31]=2[C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[N:42][CH:43]=[N:44]1
Reactant: C=Cn1ncnc1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Fc1ccc(-c2nc3ccc(F)cn3c2Cc2ncn[nH]2)cc1
Product: Clc1ccc(-c2nc3ccccn3c2Cc2ncn[nH]2)cc1

Procedure:
The title compound was prepared according to the experimentals described for compound 210 from 2-(4-chlorophenyl)-3-((1-vinyl-1H-1,2,4-triazol-5-yl)methyl)imidazo[1,2-a]pyridine. m/e+ 310 for C16H13ClN5 (M+H)+.
Reaction SMILES: [CH2:1]([N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[CH:10][N:9]([CH3:15])[C:8]1=[O:16])[CH2:2][CH2:3]CC=C.C[N+]1([O-])CC[O:21]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:33][C:34]([CH3:36])=[O:35]>C(O)(C)(C)C.O.[Os](=O)(=O)(=O)=O>[OH:35][CH:34]([CH2:36][OH:21])[CH2:33][CH2:3][CH2:2][CH2:1][N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[CH:10][N:9]([CH3:15])[C:8]1=[O:16]
Reactant: CC(C)=O
Reactant: C=CCCCCn1c(=O)c(C)cn(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cn(C)c(=O)n(CCCCC(O)CO)c1=O
Yield: 89 %

Procedure:
A solution of 3-(5-hexenyl)-1-methylthymine (2.00 g, 9 mmol), 4-methylmorpholine-N oxide (1.17 mg, 10 mmol), and a 2.5% sol. in t-butanol of osmium tetroxide (0.15 mL ) in acetone (15 mL) and water (10 mL) was stirred for 20 hours. After addition of a saturated solution of sodium hydrosulfite (10 mL) and 15 minutes of stirring, the reaction mixture was extracted with 20% ethanolldichloromethane (4×40 mL). The combined organic layers were dried over sodium sulfate and the solvent evaporated under vacuum to a give white solid residue. The solid was recrystallized in ethanol to yield 2.00 g (89%) of 3-(5,6-dihydroxyhexyl)-1-methylthymine (inventive compound no. 1907).