Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:66]([SH:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:66]([S:73][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: SCc1ccccc1
Reactant: COc1cc2c(Cl)ccnc2cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Cl)ccnc2cc1SCc1ccccc1
Temperature: 110 °C
Yield: 115.8 %

Procedure:
To a vial charged with 7-bromo-4-chloro-6-methoxyquinoline (0.240 g, 0.881 mmol) was added Dioxane (3.52 ml), DIEA (0.308 ml, 1.761 mmol), Xantphos (0.102 g, 0.176 mmol), Pd2(dba)3 (0.081 g, 0.088 mmol) and benzyl mercaptan (0.104 ml, 0.881 mmol). The vessel was sealed and heated to 110° C. for 90 mins affording complete conversion according to LC-MS. The mixture was filtered through Celite and dried under reduced pressure and purified with a 25 g Interchim column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording 7-(benzylthio)-4-chloro-6-methoxyquinoline (322 mg, 1.020 mmol, quant. yield) as a yellow solid with minor impurity. m/z (ESI) 316.3 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][O:46][C:47]1[C:52]2[N:53]=[C:54]([NH2:56])[O:55][C:51]=2[C:50]([N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)=[CH:49][CH:48]=1.Cl>C1COCC1.O1CCOCC1.CN(C=O)C.O>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:56][C:54]1[O:55][C:51]2[C:50]([N:57]3[CH2:62][CH2:61][O:60][CH2:59][CH2:58]3)=[CH:49][CH:48]=[C:47]([O:46][CH3:45])[C:52]=2[N:53]=1)=[O:8]
Reactant: O=C(O)c1ccnc(CCl)c1
Reactant: COc1ccc(N2CCOCC2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12
Reaction time: 5 h
Yield: 6.2 %

Procedure:
To a stirred solution of 72 mg (0.42 mmol) 2-choromethyl-isonicotinic acid in 5 ml THF were added 183 mg (0.48 mmol) HATU and 0.08 ml (0.48 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 5 h. A solution of 80 mg (0.32 mmol) 4-methoxy-7-morpholin-4-yl-benzooxazol-2-yl-amine in 5 ml dioxane and 1 ml DMF was then added and stirring continued at 40° C. for 48 h. The reaction mixture was then poured into 50 ml water, acidified with 1 M aq. hydrochloric acid, and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (3/97 methanol/dichloromethane, then 10/90 methanol/dichloromethane) followed by trituration in ether afforded 8 mg (6%) 2-chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzooxazol-2-yl)-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%): 405 (M{37Cl}+H+, 35), 403 (M{35Cl}+H+, 100).
Reaction SMILES: C([O:8][C@H:9]([C:11]1[N:15]2[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:14]2=[N:13][N:12]=1)[CH3:10])C1C=CC=CC=1.CC#N.[Si](I)(C)(C)C>CCOC(C)=O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:14]3[N:15]([C:11]([C@H:9]([OH:8])[CH3:10])=[N:12][N:13]=3)[N:16]([CH2:36][C:37]3[C:38]([CH3:47])=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=3)[C:17](=[O:35])[C:18]=2[C:27]2[CH:28]=[CH:29][C:30]([C:31]#[N:32])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)OCc3ccccc3)n21
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccc(C#N)cc2)c(-c2ccc(Cl)cc2)c2nnc([C@@H](C)O)n21
Temperature: 60 °C
Reaction time: 96 h
Yield: 30.9 %

Procedure:
To a round bottom flask was added (S)-4-(3-(1-(benzyloxy)ethyl)-8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (30 mg, 0.0458 mmol), CH3CN (2 ml) and TMSI (244 mg, 1.22 mmol). The reaction was stirred at 60° C. under argon for 4 days. After this time, the reaction mixture was with EtOAc (50 ml). The resulting organic solution was wash with water (20 ml), 10% NaHSO3(20 ml) and saturated NaCl (20 ml). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (8 g silica gel) eluting with a gradient of 0-80% EtOAc/Hex to give product (R)-4-(8-(4-chlorophenyl)-3-(1-hydroxyethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile as a white solid (8 mg, 31% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[C:19]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: COC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Oc2ccnc(Cl)c2)c1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
Methyl 3-hydroxybenzoate (2.88 g, 18.9 mmol) was added to a mixture of 60% sodium hydride in mineral oil (0.757 g, 18.9 mmol) in DMF (20 mL). The reaction mixture was stirred for 20 minutes and then cooled in an ice bath. 2-Chloro-4-nitropyridine (3.00 g, 18.9 mmol) was added and the reaction mixture was stirred for 1 hour at 0° C., and then overnight at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed twice with water and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 5:1 hexane:ethyl acetate to afford methyl 3-(2-chloropyridin-4-yloxy)benzoate (4.49 g, 90.0% yield) as a thick oil. 1H NMR (CDCl3) δ 8.26 (d, 1H), 7.98 (d, 1H), 7.77 (s, 1H), 7.54 (t, 1H), 7-31 (d, 1H), 6.82 (s, 1H), 6.79 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH3:11])([O-:3])=[O:2].C(N=[C:21]=[O:22])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:12]([N:15]=[C:21]=[O:22])(=[O:13])=[O:14])[CH3:11])([O-:3])=[O:2]
Reactant: CCCCN=C=O
Reactant: CC(c1ccccc1[N+](=O)[O-])S(N)(=O)=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CC(c1ccccc1[N+](=O)[O-])S(=O)(=O)N=C=O

Procedure:
A mixture of 16 g of the product from Example 14, 8.0 ml of n-butyl isocyanate, and 0.2 g of 1,4-diazabicyclo[2.2.2]octane (DABCO) in 125 ml dry xylenes was heated to 130°-135° C. for 11/2 hours. To this solution was added 6 ml of phosgene at a rate which maintained the temperature above 130° C. After completion of the addition (ca. one hour), the solution was cooled and filtered under nitrogen. The filtrate was concentrated in vacuo to give the crude 1-(2-nitrophenyl)ethanesulfonyl isocyanate as a viscous orange oil. The IR spectrum of this compound displayed a characteristic isocyanate absorption at 2240 cm-1.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([NH:19][C@H:20]([B:37]2[O:45][CH:44]3[C:39]([CH3:49])([CH:40]4[CH2:46][CH:42]([CH2:43]3)[C:41]4([CH3:48])[CH3:47])[O:38]2)[CH2:21][C:22]2[C:23]([O:35][CH3:36])=[C:24]([CH:32]=[CH:33][CH:34]=2)[C:25]([O:27]C(C)(C)C)=[O:26])=[O:18])[CH2:12][CH2:11]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([NH:19][C@H:20]([B:37]2[O:45][CH:44]3[C:39]([CH3:49])([CH:40]4[CH2:46][CH:42]([CH2:43]3)[C:41]4([CH3:48])[CH3:47])[O:38]2)[CH2:21][C:22]2[C:23]([O:35][CH3:36])=[C:24]([CH:32]=[CH:33][CH:34]=2)[C:25]([OH:27])=[O:26])=[O:18])[CH2:12][CH2:11]1
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](CN)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 3-((2R)-2-(2-(trans-4-((tert-butoxycarbonylamino)methyl)cyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate (422 mg, 0.75 mmol from Example 3, Step 1) in a flask was added 4N HCl in dioxane (3 mL) and the reaction mixture stirred at RT for 1 hr. Removal of the solvents afforded the product as yellow foam.
Reaction SMILES: Cl.[CH2:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1=[O:11])[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[CH3:21][CH:22]([N:24]=[C:25]=[O:26])[CH3:23].O>ClCCl>[CH2:2]([N:5]1[CH2:10][CH2:9][N:8]([C:25](=[O:26])[NH:24][CH:22]([CH3:23])[CH3:21])[CH2:7][C:6]1=[O:11])[CH:3]=[CH2:4]
Reactant: C=CCN1CCNCC1=O
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=CCN1CCN(C(=O)NC(C)C)CC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(2-propenyl)-2-piperazinone hydrochloride (7.9 g, 44 mmol) and diisopropylethylamine (8 mL, 46 mmol) in dichloromethane (100 mL) was added 2-propylisocyanate (5.6 g, 66 mmol). The mixture was stirred at ambient temperature for 18 h. Water (75 mL) was added, and the organic layer was collected, dried (MgSO4), filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography using a gradient elution of 2%, 3%, 4% MeOH in CH2Cl2. Product-containing fractions were combined and concentrated in vacuo to yield 1-(2-propenyl)-4-(N-2-propylcarbamoyl)-2-piperazinone as a solid. HPLC RT=2.17 min (Mehtos A); ES MS (M+H)=226; 1H NMR (400 MHz, CDCl3) δ 5.75 (ddt, 1H), 5.2 (overlapping doublets, 2H), 4.32 (b rd, 1H), 4.04 (d, J=6 Hz, 2H), 3.97 (s, 2H), 3.67 (t, J=7 Hz, 2H), 3.33 (t, J=7 hz, 2H), 1.16 (d, J=7 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1cccc(C2CCc3cc(O)ccc3O2)c1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1

Procedure:
3-[6-(5-Nitropyridin-2-yloxy)chroman-2-yl]phenol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b) starting from 2-(3-hydroxyphenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.44 (s, 1H), 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 2.8, 9.1 Hz), 7.21-7.16 (m, 2H), 7.00-6.94 (m, 2H), 6.91-6.84 (m, 3H), 6.73-6.70 (m, 1H), 5.06 (dd, 1H, J 2.1, 9.9 Hz), 2.99-2.92 (m, 1H), 2.75-2.69 (m, 1H), 2.17-2.01 (m, 1H), 2.00-1.93 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19](O)[CH3:20])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19]([N:50]1[C:46](=[O:56])[C:47]3[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:49]1=[O:51])[CH3:20])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2c(Cl)cccc2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(5-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethanol (0.9927 g, 3.290 mmol) in tetrahydrofuran (32.90 mL, 3.290 mmol) were added triphenylphosphine (2.589 g, 9.870 mmol), phthalimide (1.452 g, 9.870 mmol), and diisopropyl azodicarboxylate (1.943 mL, 9.870 mmol). The reaction mixture was stirred at room temperature. After 1.5 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc for 10 min as eluent to give 2-(1-(5-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (1 H, s), 7.98-8.04 (1 H, m), 7.85-7.90 (1 H, m), 7.82 (1 H, s), 7.74-7.81 (2 H, m), 7.65-7.71 (2 H, m), 7.21-7.33 (2 H, m), 7.12-7.19 (2 H, m), 5.76-5.82 (1 H, m), 1.83 (3 H, d, J=6.7 Hz); LC-MS (ESI) m/z 431.0 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:17]#[N:18].[K+].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][C:17]#[N:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: COc1ccc(CCl)cc1OC1CCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC#N)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.2 %

Procedure:
A mixture of 3-cyclopentyloxy-4-methoxybenzyl chloride (119 grams, 0.49 mol), 120 milliliters of methylene chloride, KCN (70.7 grams, 1.09 mol), benzyltriethylammonium chloride (35 grams, 0.015 mol) and water (120 milliliters) was stirred vigorously at room temperature for 48 hours. The reaction mixture was diluted with methylene chloride and the layers were separated. The methylene chloride solution was extracted several times with water and evaporated to yield 3-cyclopentyloxy-4-methoxyphenylacetonitrile (109 grams, 95%) for the subsequent transformation.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41](=[O:43])[CH3:42]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:40][C:41](=[O:43])[CH3:42])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=2)=[CH:31][CH:32]=1
Reactant: CC(=O)CCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 50 °C
Yield: 77.9 %

Procedure:
7-(4-Chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.54 mmol, intermediate 9), potassium carbonate (0.11 g, 0.80 mmol), TBAI (0.10 g) and 1-chloropropan-2-one (0.040 mL, 0.59 mmol) were combined in DMF (3 mL) and heated at 50° C. for 1.5 h. The reaction was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with 1N lithium chloride (2×75 mL) dried with magnesium sulfate, filtered and evaporated under reduced pressure to an off-white solid. The solid was purified using a 25 g silica gel flash column eluted with 1% methanol/DCM to give 7-(4-chlorobenzyl)-3-methyl-1-(2-oxopropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (0.22 g, 79% yield) as a white solid. LCMS retention time 4.433 minutes and 99% purity, LCMS MH+ 523. 1H NMR (DMSO-d6) δ 7.60 (t, 1H, J=8 Hz), 7.50-7.53 (m, 1H), 7.38-7.47 (m, 5H), 7.32 (d, 1H, J=8 Hz), 5.40 (s, 2H), 4.73 (s, 2H) 3.28 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1>[CH:10]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: N#Cc1cc(Br)ccn1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cc(C2CC2)ccn1
Yield: 63.1 %

Procedure:
To a solution of 4-bromopicolinonitrile (0.2 g, 1.1 mmol) in tetrahydrofuran were added cyclopropyl boronic acid (0.093 g, 1.1 mmol), and potassium phosphate tribasic (0.694 g, 3.2 mmol). The resulting reaction mixture was degassed with nitrogen for 10 minutes and then added Pd(OAc)2 and S-phos were added. The reaction mixture was heated at reflux for 16 h, then was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified via flash chromatography (10% ethyl acetate in petroleum ether) to afford 4-cyclopropylpicolinonitrile (0.1 g, 70%). MS (ES+APCI) (M+H) 145.2; LCMS retention time 3.02 min (Method J).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[C:4]([C:18]#[N:19])[CH:3]=1.O1CCCC1.[CH3:25][NH:26][CH3:27].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[N:26]([CH3:27])[CH3:25])=[C:4]([C:18]#[N:19])[CH:3]=1
Reactant: N#Cc1cc(Cl)ccc1NC(=O)Oc1ccccc1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1ccc(Cl)cc1C#N
Reaction time: 8 h

Procedure:
(Step 2) To a solution of phenyl (4-chloro-2-cyanophenyl)carbamate obtained in Step 1 (3.0 g) in tetrahydrofuran (30 ml) was added 2N dimethylamine tetrahydrofuran solution at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→2:3) to give 3-(4-chloro-2-cyanophenyl)-1,1-dimethylurea (2.33 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[N:8]=2)=[C:5]([CH3:14])[O:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:14])=[N:8][C:9]1=[O:13]
Reactant: Cc1noc(C)c1-c1cc[nH]c(=O)n1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccn(CCCCCl)c(=O)n1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a solution of 4-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrimidin-2-one (156 mg, 0.82 mmol) in dry DMF (20 ml), 60% NaH (40 mg, 1.06 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (123 μl, 1.06 mmol) was added at room temperature and the mixture was heated at 100° C. for 2 hours. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate phase was dried (Na2SO4) and evaporated to afford 81 mg of the title compound that was used in the next step without further purification (35% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:3].[ClH:15]>O>[ClH:15].[CH3:3][NH+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1]
Reactant: CCCCCCCCCCCN(C)C
Agent: Cl
Solvent: O
Product: CCCCCCCCCCC[NH+](C)C
Reaction time: 2 h

Procedure:
20 g (0.1 mol) of N,N-dimethylundecylamine were added in portions with stirring to 14.8 g (0.15 mol) of concentrated hydrochloric acid (37 wt. %). After the exothermic reaction (up to approx. 35° C.), the highly viscous mixture was diluted with 5 ml of concentrated hydrochloric acid and 5 ml of water, stirred for a further 2 hours and finally left to stand overnight. The aqueous phase was then extracted with 80 ml of methylene chloride, the organic phase dried with sodium sulfate and the solvent removed under a vacuum. In order to remove any traces of water, the residue was resuspended in 80 ml of toluene and concentrated under a vacuum and the operation was then repeated in 100 ml of hexane. Once the solvent had again been removed by distillation under a vacuum, N,N-dimethylundecylammonium hydrochloride was obtained as a colourless solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8](/[N:10]=C/N(C)C)[N:7]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].NN.C(O)(=O)C>O1CCOCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)/C=N/c1cc(C(C)(C)C)nn1CC1CCCCO1
Agent: NN
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(N)n(CC2CCCCO2)n1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of Example 63B (0.9 g, 3.1 mmol) in dioxane (10 mL) were added hydrazine (0.12 mL, 3.7 mmol, Aldrich) and acetic acid (0.35 mL, 6.2 mmol). After stirring at 85° C. for 16 hours, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. MS (APCI+) m/z 238 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[CH3:15]C1C=CC2C(=CC(C)=C(O)C=2)N=1>>[Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2
Reactant: Cc1ccc2cc(O)c(C)cc2n1
Reactant: Cc1ccc2c(Br)c(O)c(Cl)cc2n1
Product: Cc1ccc2c(Br)c(O)c(C)cc2n1

Procedure:
Compound 2C was prepared following the procedure used to prepare compound 1D of Example 1, except that 2,7-dimethylquinolin-6-ol (2B) was used instead of compound 1C. LCMS-ESI+ (m/z): 252.2, 254.2 (M+H)+.
Reaction SMILES: OC1C(C)=CC(N)=CC=1C.[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[O:23].[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>O>[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[O:23].[OH:11][C:12]1[C:13]([CH3:24])=[C:14]2[C:18](=[CH:19][C:20]=1[CH3:21])[NH:17][C:16](=[O:22])[C:15]2=[N:32][NH:31][C:30]1[CH:29]=[CH:28][C:27]([S:33]([NH2:36])(=[O:34])=[O:35])=[CH:26][CH:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cc1cc(N)cc(C)c1O
Agent: Cc1cc2c(c(C)c1O)C(=O)C(=O)N2
Agent: Cl
Solvent: O
Product: Cc1cc2c(c(C)c1O)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione was prepared from 4-hydroxy-3,5-dimethylaniline according to Procedure A. The title compound was prepared from 5-hydroxy-4,6-dimethyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 2.18 (s, 3H), 2.47 (s, 3H), 6.50 (s, 1H), 7.22 (s, 2), 7.44 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.99 (s, 1H), 10.78(s, 1H), 12.98 (s, 1H); APCI−MS: m/z 359 (M−H)−. Anal. Calcd for C16H16N4O4S.0.25 H2O: C, 52.67; H, 4.56; N, 15.35; S, 8.79. Found: C, 52.69; H, 4.47; N, 15.33; S, 8.87.