Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:39]=[C:38]([F:40])[C:11]([CH2:12][S:13][C:14]2[N:15]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:16]([C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([O:29][CH3:30])[CH:23]=3)([CH3:21])[CH3:20])=[CH:17][N:18]=2)=[C:10]([Cl:41])[CH:9]=1)=[N+]=[N-]>CCO.Cl.O=[Pt]=O>[ClH:41].[Cl:41][C:10]1[CH:9]=[C:8]([CH:39]=[C:38]([F:40])[C:11]=1[CH2:12][S:13][C:14]1[N:15]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[C:16]([C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([O:29][CH3:30])[CH:23]=2)([CH3:21])[CH3:20])=[CH:17][N:18]=1)[O:7][CH2:6][CH2:5][CH2:4][NH2:1]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCN=[N+]=[N-])cc3Cl)n2-c2ccc(F)cc2)ccc1F
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCN)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reaction time: 5 h
Yield: 200.6 %

Procedure:
A pressure bottle was charged with a solution of 2-(4-(3-azidopropoxy)-2-chloro-6-fluorobenzylthio)-5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (340 mg, 0.56 mmol) in EtOH (10 mL), conc HCl (1 mL) and PtO2 (170 mg). The bottle was purged with hydrogen (3×40 psi), pressurized with hydrogen (45 psi) and then agitated for 5 h. The reaction mixture was filtered through Celite™ and the filtrate was evaporated. The residue was triturated with ether, and the solids collected by filtration and dried to give the title compound (344 mg, 99% yield). 1H NMR (400 MHz, CD3OD) δ 7.21 (s, 1H), 6.87 (dd, J=10.99, 8.49 Hz, 1H), 6.76 (t, J=8.49 Hz, 2H), 6.67 (s, 1H), 6.58 (dd, J=8.15, 2.15 Hz, 1H), 6.52-6.42 (m, 2H), 6.38-6.29 (m, 2H), 4.16 (t, J=4.34 Hz, 2H), 3.98 (t, J=5.89 Hz, 2H), 3.77 (d, J=5.67 Hz, 3H), 3.50 (t, J=6.51 Hz, 2H), 2.65 (s, 2H), 2.17 (s, 1H), 2.43-2.15 (m, 3H), 1.49 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16]O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc2ccccc2c2c1ncn2CCO
Product: Nc1nc2ccccc2c2c1ncn2CCCl
Temperature: 80 °C
Yield: 86 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (8.46 g, 37.06 mmol), and thionyl chloride (68.99 g, 57.99 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 80° C. to give a heterogeneous reaction mixture that was maintained at 80° C. for 2 hours at which time the starting material was completely consumed. The solution was cooled and quenched by the addition of water (400 mL). To the stirred solution was added solid sodium carbonate until the pH reached 10 at which time a solid precipitated out of solution. The solid was collected by filtration to afford 1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine (7.86 g, 31.86 mmol) as an off-white solid. The material was used without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]1=[O:16]>C(O)(=O)C>[CH:1](=[N:8][N:9]1[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]1=[O:16])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN1CCNC(=O)C1=O
Reactant: O=Cc1ccco1
Solvent: CC(=O)O
Product: O=C1NCCN(N=Cc2ccco2)C1=O
Reaction time: 3 h
Yield: 96.6 %

Procedure:
2.3 pts. by wt. of furfural, 2.6 pts. by wt. of 1-amino-2,3-dioxo-piperazine and 10 pts. by vol. of glacial acetic acid are warmed to 90° for 30 minutes and thereafter left for 3 hrs. at RT, whereupon crystallisation occurs. The precipitate is filtered off, washed first with 5 pts. by vol. of glacial acetic acid and then twice with 10 pts. by vol. of ethyl acetate each time and dried over potassium hydroxide. 4.0 pts. by wt. (96.6%) of 1-furfurylideneamino-2,3-dioxo-piperazine of melting point 193°-7° are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.N1C=CN=C1.[C:17]([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=O>[Pd]>[N:24]1([C:17]2[N:19]=[C:23]3[CH:22]=[N:21][C:20]4[N:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]3[CH:2]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Pd]
Agent: c1c[nH]cn1
Product: c1cnc2ncc3nc(-n4ccnc4)cn3c2c1

Procedure:
Prepare by reaction of 2,6-dichloro-3-nitropyridine with excess imidazole followed by hydrogenation with palladium on carbon and cyclization with carbonyldiimidazole to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[N+:18]([O-])=O)[CH2:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[NH2:18])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(N)cc2N)CC1
Yield: 85.7 %

Procedure:
A 2 liter autoclave was charged with 148 g of N1 -methyl-N4 -(2,4-dinitrobenzoyl)piperazine, 1300 ml of methanol and 5 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated under 800 psi hydrogen pressure while maintaining the temperature below 100° C. with cooling. Hydrogen uptake ceased after 30 min. The mixture was cooled, filtered and the methanol removed under reduced pressure to give 101 g of N1 -methyl-N4 -(2,4-diaminobenzoyl)- piperazine, a light tan solid, mp 192° C.
Reaction SMILES: [Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[Br:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:21])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Reaction time: 8 h

Procedure:
4-(2-Bromo-tetrafluoroethoxy)benzoic acid prepared as in Example 1 (26.6 g, 0.083 mol) is transferred to a 250 mL round-bottomed flask along with 150 mL of methylene chloride. Oxalyl chloride (11.64 g, 0.92 mol) is added and the mixture is stirred under nitrogen overnight to form a turbid solution which is concentrated by rotary evaporation and distilled at 80°-90° C./0.1 mmHg to yield 20.88 g of 4-(2-bromotetrafluoroethoxy)benzoyl chloride as a colorless liquid, leaving 6.16 g of unreacted acid (76.8% conversion, 96.5% yield). The benzoyl chloride is added slowly with stirring to 8 mL of cold ammonium hydroxide (0.12 mol). The product amide precipitates as fine white needles which are filtered and dried under vacuum to yield 14.74 g of 4-(2-bromotetrafluoroethoxy)benzamide (75% conversion, 99% yield, m.p. 150.5°-151.5° C.), along with 4.8 g of 4-(2-bromo-tetrafluoroethoxy)benzoic acid which is recovered from the mother liquor (24.3% recovery).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH3:13])[N:3]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.[F-].[K+]>O1CCOCC1.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>[Cl:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)[N:7]=1
Reactant: COC(=O)c1c(C)nc(Cl)nc1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1c(C)nc(Cl)nc1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
A mixture of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (0.79 g, 3.57 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.595 g, 2.86 mmol) and bis(triphenylphosphine)palladium chloride (0.050 g, 0.071 mmol) in dioxane (5 mL) was stirred at RT for 10 min, after which potassium fluoride (1.038 g, 17.87 mmol) was added. The mixture was stirred under a nitrogen atmosphere and heated at 90° C. for 12 h. The reaction mixture was filtered through a bed of Celite 545, rinsed with DCM and a small amount of MeOH. Following solvent removal, the residue was dispersed in DMSO/MeOH (1/1) and purified via reverse phase preparative HPLC to give the title compound (237 mg, 25%). [M+H] calc'd for C11H11ClN4O2, 267. found, 267.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C@@H:37](O)[CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][C@@H:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:29])([F:40])[F:41])[CH3:38])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Reactant: C[C@H](O)c1ccccc1C(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O[C@H](C)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B31, 7.3 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate, 5.0 g of (1S)-1-[2-(trifluoromethyl)phenyl]ethanol, 9.2 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 8.1 g of di-tert-butyl azodicarboxylate in 180 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=4)[C:27]=3[CH3:28])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:28][C:27]1[N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][N:30]=2)[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:22]
Reactant: Cc1c(C(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)Nc2ccc(C3CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.4 %

Procedure:
To N-[6-(1-tert-butyloxycarbonylpiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (4.0 g) were added dichloromethane (75 ml) and trifluoroacetic acid (15 ml), stirred at room temperature for 2.5 hours, and then to the reaction solution was added 4 N aqueous solution of sodium hydroxide under ice-cooling. The precipitated solid was washed with water and ethyl acetate to give the titled compound (2.9 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:13]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10]Cl)=[O:7])=[CH:4][C:3]=1[Br:20].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O-:39])=[O:38].[Na+]>>[NH2:1][C:2]1[C:13]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][O:39][C:37](=[O:38])[CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][C:23]2[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:28])=[O:7])=[CH:4][C:3]=1[Br:20]
Reactant: Nc1c(Br)cc(C(=O)OCCCl)cc1CN1CCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CN1CCCC1

Procedure:
This compound was prepared from 2-(4-amino-3-bromo-5-pyrrolidinomethyl-benzoyloxy)-ethylchloride and sodium 2-[(2,6-dichlorophenyl)-amino]phenylacetate analogous to Example 8.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][C:21]([CH2:26][C:27]#[N:28])([CH2:23][C:24]#[N:25])[CH2:20]1>O1CCCC1>[C:21]1([CH2:26][C:27]#[N:28])([CH2:23][C:24]#[N:25])[CH2:22][C:19](=[CH:9][C:7]#[N:8])[CH2:20]1
Reactant: N#CCC1(CC#N)CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=C1CC(CC#N)(CC#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (5.1 mL) was added dropwise at 0° C. diethyl cyanomethylphosphonate (0.82 mL, 0.0051 mol). The reaction was warmed to rt and 30 min later cooled to 0° C. again. To the reaction mixture was added a solution of 2,2′-(3-oxocyclobutane-1,1-diyl)diacetonitrile (0.5 g, 0.003 mol) in THF (5 mL). The reaction was allowed to warm up to rt gradually and stirred at rt for 2 h. The reaction was quenched with saturated aq. NH4Cl, then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give a brown oily crude product, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([OH:12])[CH3:11].Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1>>[Br:20][C:18]1[N:19]=[C:14]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Product: CC(Oc1nc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
5-Bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine was prepared following procedure 2 from 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol and 3,5-dibromo-pyrazin-2-ylamine.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#N)=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.[NH4+].[Cl-].[BH4-].[Na+].C[OH:35]>ClCCl.C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]([C:12]3[CH:19]=[CH:18][C:15]([CH2:16][OH:35])=[CH:14][CH:13]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: N#Cc1ccc(-n2ccnc2-c2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCc1ccc(-n2ccnc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
To a solution of 4-(2-phenylimidazol-1-yl)benzonitrile (3.2 g, 13 mmol) in dichloromethane (30 ml) and toluene (20 ml) cooled to -78° C. was added dropwise diisobutylaluminum hydride (13 ml, 13 mmol: 1.02M solution in toluene) under a nitrogen atmosphere and the whole stirred at this temperature for 1.5 h. Saturated aqueous NH4Cl solution (20 ml) was then added carefully to the reaction mixture, and the whole allowed to warm to room temperature. The resulting gelatinous mixture was filtered through a pad of celite, washing with ethyl acetate (200 ml). The filtrate was washed with 0.3N HCl solution (100 ml), water (200 ml) and brine (100 ml), and the organic layer dried over MgSO4. Removal of solvent under reduced pressure provided crude product (2.5 g) which was dissolved in methanol (30 ml) and cooled to 0° C. NaBH4 (0.3 g, 8 mmol) was added in portions and the reaction mixture stirred for 30 min. Saturated aqueous NH4Cl solution (30 ml) was added to the reaction mixture and the whole extracted with ethyl acetate (20 ml×3). The organic layer was washed with water (10 ml), brine (10 ml), dried over MgSO4 and solvent removed under reduced pressure. The resultant crude product was washed with ethyl acetate (35 ml) to give the title compound (0.81 g, 25%) as a white powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH3:25][S:26]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](CO)=[CH:32][CH:31]=1)(=[O:28])=[O:27]>O1CCCC1>[Cl:24][CH2:20][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)Cc1ccc(CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
Triphenylphosphine (5.71 g, 21.8 mmol), carbon tetrachloride (8.4 mL, 87 mmol), and tetrahydrofuran (12 mL) were combined in a round bottom flask under argon and stirred at room temperature for 10 minutes. A heterogeneous mixture of (4-methanesulfonylmethyl-phenyl)-methanol (2.18 g, 10.9 mmol) and tetrahydrofuran (37 mL) were added to the reaction mixture, and then the mixture was heated at 75° C. for 3 hours. The reaction mixture was cooled to room temperature, and then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was concentrated over silica gel, and the resulting silica gel supported crude product was loaded onto a RediSep® Flash column. Flash chromatography (25%-40% ethyl acetate in hexanes) afforded 1.59 g (67%) of 1-chloromethyl-4-methanesulfonylmethyl benzene as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.47 (d, J=8.2 Hz, 2 H), 7.41 (d, J=8.2 Hz, 2 H), 4.78 (s, 2 H), 4.50 (s, 2 H), 2.91 (s, 3 H).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16](O)=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2].S(Cl)(Cl)=O.[CH3:34][NH2:35]>C(Cl)(Cl)(Cl)Cl>[CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([NH:35][CH3:34])=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)O)c(=O)oc12
Reactant: CN
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)NC)c(=O)oc12
Reaction time: 0.67 h

Procedure:
To a suspension of (E)-8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of the formula (V) (0.5 g, 1.28 mmol) in CCl4 (15 mL), added thionyl chloride (1.0 mL), was refluxed for 2.5 h. The resulting solution was evaporated to dryness under reduced pressure, and the residue was dispersed in CCl4 (10 mL). The solvent was eliminated under reduced pressure. Dispersion in CCl4 and solvent elimination was repeated twice. The residue was dissolved in CCl4(10 mL) and added with stirring to a solution of the methyl amine (0.04 g, 1.28 mmol). After 40 min at room temperature, the solvent was removed by evaporation under reduced pressure and extracted 3-fold with CHCl3 (25 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-8-sec-butyl-N-methyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxamide (General Formula VI). (0.33 g, 65% yield). White solid, m. p. 215-216° C.; 1H NMR (CDCl3 300 MHz): δ 8.93 (s, 1H), 8.72, (brd, J=4.6 Hz, 1H) 7.96 (d, J=8.1 Hz, 2H), 7.83-7.77 (m, 3H), 7.55 (d, J=15.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 3.49-3.37 (m, 1H), 3.04 (d, J=4.9 Hz, 3H), 2.45 (s, 3H), 1.80-1.71 (m, 2H), 1.35 (d, J=6.9 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.5, 1610, 161.2, 153.1, 148.5, 144.1, 142.2, 136.5, 135.4, 132.2, 131.4, 129.5, 128.8, 127.1, 123.2, 119.0, 118.8, 33.6, 29.8, 26.7, 21.8, 20.6, 12.1; ESI-MS (m/z): 404 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][N:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]1=[O:20].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:21]1([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: CCCC1CC(=O)N(Cn2cnc3c(Cl)ncnc32)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(Cn2cnc3c(NC4CC4)ncnc32)C1
Yield: 54 %

Procedure:
A mixture of 1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one x166 (250 mg, 0.85 mmol, 1 eq) and cyclopropylamine (1 ml) is heated at 50° C. during 24 hours in THF. After cooling, a saturated aqueous solution of NaHCO3 is added and the aqueous phase is extracted with AcOEt. The combined organic layers are dried on anhydrous MgSO4, filtered of and evaporated under reduced pressure. The crude mixture is purified by preparative HPLC to yield 1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one 285.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:10])([F:9])[F:8])[C@@H:3]1[C:12](O)=[O:13].S(Cl)([Cl:18])=O>>[CH3:1][C:2]1([CH3:15])[C@H:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:10])([F:9])[F:8])[C@@H:3]1[C:12]([Cl:18])=[O:13]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
10 g of cis-2,2-dimethyl-3-(2'-chloro-3',3',3'-trifluoropropenyl)-cyclopropanecarboxylic acid were dissolved in 50 ml of thionyl chloride and the solution was heated to the boil for one hour. After distilling off the excess thionyl chloride, the residue was distilled under a high vacuum. Cis-2,2-dimethyl-3-(2'-chloro-3',3',3'-trifluoropropenyl)-cyclopropanecarboxylic acid chloride of boiling point 52°-54° C./0.9 mm Hg and nD20 : 1.4520 was obtained.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:10])[CH2:7]1)=[O:4].C[Si]([C:48]#[N:49])(C)C.O>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:48]([C:8]1([OH:10])[CH2:9][C:6]([NH:5][C:3](=[O:4])[C:2]([F:42])([F:1])[F:43])([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:7]1)#[N:49]
Reactant: O=C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: N#CC1(O)CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,2,2-trifluoro-N-(3-oxo-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) (25 mg, 0.043 mmol), trimethylsilyl cyanide (0.012 mL, 0.086 mmol), and zinc iodide (1.4 mg, 0.0043 mmol) in CH2Cl2 (1.0 mL) was stirred at room temperature for 1 hour. To the mixture was added water, extracted with CHCl3, washed with brine, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC, eluting with 10% MeOH in CHCl3 to give N-(3-cyano-3-hydroxy-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)-2,2,2-trifluoroacetamide (4-10) as a yellow solid. MS (M+H)+: observed=607, calculated=607.