Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1.FC1C=CC(C=O)=CC=1.C(CC(O)=O)#N.C(#N)C=C.[NH3:45]>N1CCCCC1.[Ni].N1C=CC=CC=1>[N:45]#[N:8].[C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([C:11]([NH:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=1)=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCc1ccc(F)cc1
Reactant: C[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N
Agent: [Ni]
Agent: N#CCC(=O)O
Agent: O=Cc1ccc(F)cc1
Solvent: C=CC#N
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C[C@H](C(=O)NCCCc1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Product: N#N

Procedure:
By the method of part A of Example 3 N-(tert-butyloxycarbonyl)-N-methyl-D-alanine (2.03 g.) was condensed with 3-(4-fluorophenyl)propylamine (prepared by condensing 4-fluorobenzaldehyde with cyanoacetic acid in refluxing pyridine using piperidine as catalyst and hydrogenating the resulting β-4-fluorophenyl)acrylonitrile in ethanolic ammonia under high pressure using Raney nickel catalyst, m.r. of methanesulfonate salt 129°-131° C.; 2.49 g.), affording N2 -(tert-butyloxycarbonyl)-N2 -methyl-N-[3-(4-fluorophenyl)propyl]-D-alaninamide as a syrup (2.77g.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1S(=O)(=O)N.NC1CCN(CC2C=CC=C(C(F)(F)F)C=2)CC1>>[CH2:6]([OH:7])[CH2:5][CH2:4][CH2:3][CH3:2].[O:7]=[C:6]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:12][CH:11]=2)[C:9](=[O:10])[NH:8]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Agent: NC1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Product: CCCCCO
Product: O=C1NC(=O)c2ccccc21

Procedure:
Reaction of 4-chloro-5-sulfamoylphthalimide (10.1 g., 0.0386 mole) and 4-amino-1-(3-trifluoromethylbenzyl)piperidine (10.0 g., 0.0386 mole) in 200 ml. of n-pentanol according to the procedure of Example 1(a) afforded the crude 1,3-dioxoisoindole product purified by chromatography to yield 8.1 g. (42% yield) of 6-chloro-2,3-dihydro-1,3-dioxo-2-[1-[[3-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-1H-isoindole-5-sulfonamide. The NMR spectral data was consistent for the compound used without further purification below.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[N+:18]([C:13]1[C:12](=[O:15])[NH:11][CH:10]=[C:9]([C:4]2[C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:14]=1)([O-:20])=[O:19]
Reactant: O=c1ccc(-c2ncccc2C(F)(F)F)c[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]cc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 92 %

Procedure:
To a solution of 3-trifluoromethyl-1′H-[2,3′]bipyridinyl-6′-one (25 g, 0.1 mol) in concentrated sulfuric acid (100 mL) at 0° C., add dropwise a solution of fuming nitric acid (35 mL) and concentrated sulfuric acid (10 mL). Heat the reaction mixture to 70° C. for 1 hour, cool and pour onto ice (500 mL). Filter the mixture and treat the filtrate with 10 M sodium hydroxide until the solution is at pH 4-5. Collect the precipitate by filtration and air dry to give the title compound (26.2 g, 92%) as a white solid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14]1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14]1)#[CH:5]
Reactant: COC(=O)C1(c2ccccc2C#C[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccccc1C1(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 1-(2-((trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate (I5) (568 mg, 2.09 mmol) in DCM (20.0 mL) at 0° C. was added TBAF (1.0 M in THF, 3.13 mL, 3.13 mmol). The resulting mixture was stirred at 0° C. for 10 minutes then poured into water (50 mL). The aqueous layer was extracted with DCM (2×50 mL), then the combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-25% EtOAc in petroleum benzine 40-60° C.) to give the title compound K2 as an off-white solid (140 mg, 34%); 1H NMR (400 MHz, d6-DMSO) δ 7.46 (dt, J=7.5, 0.8 Hz, 1H), 7.40-7.25 (m, 3H), 4.32 (s, 1H), 3.52 (s, 3H), 1.54 (q, J=4.1 Hz, 2H), 1.25-1.19 (m, 2H). LCMS-A: rt 5.921 min; m/z 201 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[CH3:10][N:11]1[CH:15]=[C:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:13]=[N:12]1
Reactant: O=Cc1ccccc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cn1cc(-c2ccccc2C=O)cn1
Temperature: 150 °C
Yield: 97.2 %

Procedure:
A microwave vial (20 ml) was charged with 2-bromo-benzaldehyde (208 mg, 1.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (222 mg, 1.2 mmol) and 8 ml of acetonitrile. To this mixture was added 2.4 ml of aqueous sodium carbonate (1M), followed by 50 mg of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was evaporated to provide crude material which was purified by ISCO to give 181 mg of 2-(1-methyl-1H-pyrazol-4-yl)-benzaldehyde (96% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH2:9][Br:12])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1noc2cc(Br)ccc12
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1noc2cc(Br)ccc12
Yield: 37.8 %

Procedure:
A mixture of 6-bromo-3-methyl-1,2-benzisoxazole (675 mg), N-bromosuccinimide (642 mg) and 1,1′-azobis(cyclohexanecarbonitrile) (90 mg) in carbon tetrachloride (7 ml) was irradiated using a 300W lamp at reflux under nitrogen for 40 h. On cooling the precipitate was removed by filtration, the solvent was evaporated and the residue was purified by flash chromatography on a silica column (4 cm diam) eluting with a cyclohexane-ethyl acetate gradient (49:1 to 24:1) to give the title compound as a pale yellow solid (350 mg).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.ClCCCl.[N+:13]([O-])([OH:15])=[O:14]>O>[N+:13]([C:5]1[C:6]([OH:7])=[CH:1][CH:2]=[C:3]([CH3:8])[CH:4]=1)([O-:15])=[O:14]
Reactant: Cc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClCCCl
Product: Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A 100 mL reaction flask fitted with reverse dean-stark apparatus was charged with 10.804 g (0.1 mol) p-cresol, 65 mL 1,2 dichloro ethane, and 2.161 g of catalyst as prepared in example 5. The flask was flushed with nitrogen. The reaction mixture was refluxed at 110° C. for 1 h followed by dropwise addition of 8.6 mL (0.133 mol) 70% HNO3. The water formed during the reaction was removed using reverse dean-stark apparatus. The reaction was carried out for 8 h. The reaction was monitored by GC analysis. In this reaction, 98.7% conversion of p-cresol was obtained with 99.1% 2-nitro p-cresol and 0.9% of other products.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:19]#[N:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H][H]>CO.Cl.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:18][CH2:19][NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: N#CC=C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 96.9 %

Procedure:
(c)(d) 3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-phenylacrylonitrile (500 mg; 1.47 mmol) was dissolved in 20 mL MeOH and 4 mL 1 M HCl. 10% Pd on carbon (170 mg) was added and the reaction was hydrogenated in a Parr bottle over an atmosphere of 50 psi hydrogen for 16 h. The catalyst was filtered off and the solvent removed in vacuo to give pure 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropan-1-amine (492 mg, 100%) as a yellow oil. MS found: (M+H)+=376. 28 mg of this product (free base) was coupled to 2,2,2-trifluoroethanesulfonyl chloride using General Coupling Method B to give 20 mg (50%) of 2,2,2-trifluoro-N-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropyl)ethanesulfonamide. MS found: (M+H)+=492.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[C:18]1([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:23](=[O:24])[NH:22][C:21](=[O:25])[NH:20][C:19]1=[O:26].CCCCC=CCCCC.C1(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)F>C(#N)C>[NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:18]3([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:19](=[O:26])[NH:20][C:21](=[O:25])[NH:22][C:23]3=[O:24])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: NCc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Agent: CCCCC=CCCCC
Agent: FC(F)(F)C1(C(F)(F)F)OC(F)(F)C(F)(C2(F)OC(C(F)(F)F)(C(F)(F)F)OC2(F)F)O1
Solvent: CC#N
Product: CCOCCC1(Oc2ccc(Oc3ccc(CN)cc3)cc2)C(=O)NC(=O)NC1=O
Yield: 18.1 %

Procedure:
Following the procedure outlined for the preparation of Example 1, 4-(4-aminomethyl-phenoxy)-phenol (0.70 g, 3.32 mmol) was reacted with 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (0.95 g, 2.4 mmol), 1,5,7-trazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 2.22 9) and 11 mL of acetonitrile, affording 5-[4-(4-aminomethyl-phenoxy)-phenoxy]-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (0.180 g) as a colorless solid after purification by reverse phase HPLC.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].I[CH3:19]>CN(C=O)C>[CH3:19][O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
A solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.300 g, 1.395 mmol) in DMF (2.5 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.067 g, 1.674 mmol) in anhydrous DMF (2.5 mL) at 0 C. The reaction mixture was stirred at 0 C for 10 min followed by dropwise addition of iodomethane (86 μL, 1.395 mmol). The mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was re-treated with sodium hydride (60% dispersion in mineral oil, 0.067 g, 1.674 mmol) and iodomethane (86 μL, 1.395 mmol) and was stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure, dissolved in DCM and washed with a saturated aqueous solution of sodium bicarbonate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by FCC (EtOAc: heptane, 1:1) to afford the title compound (0.074 g, 23%). Method B HPLC-MS: MH+ requires m/z=229 Found: m/z=174 (MH+-tBu) Rt=1.98 min (99%).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][N:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:24][O:23][CH2:22][CH2:21][O:20]3)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=2[N:14]=1)=[O:8].[CH3:30][O:31][CH2:32][CH2:33][OH:34].C(Cl)(Cl)Cl>O1CCOCC1.CN(C=O)C>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:27]=[CH:28][N:29]=[C:4]([O:34][CH2:33][CH2:32][O:31][CH3:30])[CH:5]=3)=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COCCO
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide sodium hydride and 2-methoxyethanol in dioxane and DMF. [α]D20=+17.6° (c=0.15, CHCl3), ES-MS m/e (%): 446 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22]>ClCCl>[F:19][C:20]([F:26])([F:25])[S:21]([O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COC(=O)c1ncccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-hydroxypyridine-2-carboxylate (80 g, 523 mmol) in anhydrous dichloromethane (250 ml) was added triethylamine (58.2 g, 575 mmol). The solution was cooled to 0° C., and trifluoromethanesulfonyl chloride (97 g, 575 mmol) was added dropwise. The reaction suspension was allowed to stir at 0° C. for 1 h, and it was then warmed to rt to stir for 4 h. The solid triethylammonium chloride was removed via filtration, and the filtrate was concentrated in vacuo to yield methyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyridine-2-carboxylate as an oily residue (148.6 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH3:19])=[CH:14][CH:13]=2)[CH2:7]1>N1C=CC=CC=1.C(O)C>[OH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[N:2][OH:3])[CH3:19])=[CH:14][CH:13]=2)[CH2:7]1
Reactant: NO
Reactant: CC(=O)c1ccc(N2CC(CO)OC2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc(N2CC(CO)OC2=O)cc1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Hydroxylamine hydrochloride (5 g) was added to a solution of 5 g 5-hydroxymethyl-3-(4-acetylphenyl)-2-oxazolidinone in 40 ml of 1:1 pyridine/ethanol. The mixture was stirred at reflux under nitrogen for 4 hours. After cooling to room temperature, the mixture was evaporated and the residue was triturated with water and dilute aqueous hydrochloric acid and collected. Recrystallization from aqueous ethanol gave 4.61 g pure 5-hydroxymethyl-3-[4-(1-hydroxyiminoethyl)phenyl]-2-oxazolidinone, m.p. 189.5°-190° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[C:51](Cl)(=[O:53])[CH3:52]>C1COCC1>[C:17]1([C@H:15]([NH:14][C:12](=[O:13])[NH:11][C:9]2[N:8]=[CH:7][C:6]3[C:2]([NH:1][C:51](=[O:53])[CH3:52])=[N:3][N:4]([C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:5]=3[CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (900 mg, 1.671 mmol) and DIEA (0.584 mL, 3.34 mmol) in THF (16 mL) at 0° C. was treated drop-wise with a solution of acetyl chloride (0.131 mL, 1.838 mmol) in THF (0.5 mL). The reaction was stirred at 0° C. for 10 min, then allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated in vacuo and purified by flash chromatography (0-30% EtOAc/DCM) to afford (R)—N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. For C36H32N6O2 [M+1]+ 581. found 581.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[OH:30])[C:12]3=[O:31])=[CH:4][CH:3]=1.[CH3:32][S-:33].[Na+]>CS(C)=O.C(OCC)(=O)C>[OH:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[N:13]1[C:12](=[O:31])[C:11]2[C:16](=[C:17]3[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[C:6]([S:33][CH3:32])=[N:7][CH:2]=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: CN1CC=Cc2c(Cc3ccc(Cl)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSc1ncccc1Cc1cc2c(=O)n([C@H]3CCCC[C@@H]3O)cnc2c2c1C=CCN2C
Temperature: 100 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (Example 1, 0.050 g, 0.11 mmol) in 2 mL of DMSO was added sodium thiomethoxide (0.024 g, 0.34 mol). The mixture was heated in a sealed tube at 100° C. for 15 h, cooled to room temperature, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, and again via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 448.9 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.05 (br s, 1H), 8.86 (br s, 1H), 8.41 (br s, 1H), 8.02 (s, 1H), 7.86 (br s, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 4.22 (br s, 1H), 3.13 (s, 3H), 2.61 (s, 3H), 2.11 (br s, 1H), 1.87-1.72 (m, 5H), 1.48-1.39 (m, 3H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:9]C)([CH2:7]C)[C:4]#[C:5][CH3:6])C.[Li]CCCC.CCCCCC.Br[CH2:23][C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>C1COCC1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]#[C:24][CH2:23][CH2:6][C:5]#[C:4][Si:3]([CH3:1])([CH3:7])[CH3:9])=[CH:27][CH:28]=1
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CC#C[Si](CC)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C#CCCC#Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of triethyl(prop-1-ynyl)silane (2.19 g, 19.50 mmol) in 22 mL of THF at −78° C., was added dropwise n-BuLi 2.5M in hexane (7.8 mL, 20 mmol). After stirring 2 hours at −78° C., 1-(3-bromoprop-1-ynyl)-4-fluorobenzene (1.40 g, 6.5 mmol) in 6 mL of THF was slowly added and the resulting mixture was stirred for 1 h at −78° C. and warmed to room temperature for an additional 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.57 g of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (99%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH:3]=[CH2:4].[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]([C:15]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])=[O:16])=[CH:10][N:9]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([N:5]([C:12]1[C:11]([C:15]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])=[O:16])=[CH:10][N:9]=[C:8]([Cl:7])[N:13]=1)[NH2:6])[CH2:2][CH:3]=[CH2:4]
Reactant: Cc1cccc(C)c1NC(=O)c1cnc(Cl)nc1Cl
Reactant: C=CCCNN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCN(N)c1nc(Cl)ncc1C(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of 1.3 g (14.9 mmol) of 3-butenylhydrazine in 60 mL of THF was cooled to 0° C. and treated sequentially with 4.0 g (13.5 mmol) of 2,4-dichloro-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide 30 (Example 1, Step B) and 2.1 mL (14.9 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 23 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (75 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (eluens CH2Cl2:MeOH, 17:3) to give the title compound. 1H-NMR (DMSO-d6) δ 2.24 (s, 6H), 2.40-2.48 (m, 2H), 3.32 (s, 2H), 3.80 (t, J=7.3 Hz, 2H), 5.03 (dd, J=10.3 Hz, 1.1 Hz, 1H), 5.13 (dd, J=17.2 Hz, 1.5 Hz, 1H), 5.75-5.86 (m, 1H), 7.07 (s, 3H), 8.15 (s, 1H), 9.61 (s, 1H). Mass Spectrum (ESI) m/e=346.1 (M+1).
Reaction SMILES: C([O:4][CH:5]([C:10]1[N:11]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:22])[C:13]=2[N:23]=1)[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:3])C.C(Cl)Cl>C[O-].[Na+].CO>[OH2:3].[NH2:22][C:14]1[C:13]2[N:23]=[C:10]([CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[OH:4])[N:11]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:12]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1.[NH2:22][C:14]1[C:13]2[N:23]=[C:10]([CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[OH:4])[N:11]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:12]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCCCC(OC(C)=O)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCC(O)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Product: O
Yield: 24.2 %

Procedure:
Several drops of 25% sodium methoxide in methanol were added to a solution of 2-(1-acetoxypentyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (12 g; 32 mmol, Example 59) in methanol and the resulting mixture was heated at reflux for about one hour. The reaction was concentrated under vacuum to provide a solid. A portion of this solid was taken up in a large volume of methylene chloride, washed with water, dried over magnesium sulfate and reduced to a volume of about 50 mL. The resulting precipitate was collected and dried to provide 2.6 g of a white crystalline solid, m.p. 208°-211° C. Analysis: Calculated: C, 68.0; H, 8.1; N, 16.7; Found: C, 67.8; H, 7.7; N, 16.6.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][CH:3]=1.[I:16]N1C(=O)CCC1=O>CS(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][C:3]=1[I:16]
Reactant: Clc1cncc(NCC2CCOCC2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CS(C)=O
Solvent: O
Product: Clc1nc(NCC2CCOCC2)cnc1I
Temperature: 0 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.250 g, 1.098 mmol) was dissolved in a mixture of DMSO (4.30 ml) and H2O (0.105 ml). It was cooled to 0° C. in an ice bath and was then treated with N-iodosuccinimide (0.247 g, 1.098 mmol) by portion-wise addition. Once the addition was complete the reaction mixture was stirred at ambient temperature for 24 hr. Additional NIS (0.025 g, 0.111 mmol) was added. Stirring at ambient temperature was continued for 24 hr. The reaction mixture was diluted with H2O (50 ml). This was extracted with EtOAc (3×50 ml). The organic layers were combined and washed with brine (1×50 ml). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo to give 0.410 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 30 EtOAc/70 heptane to 100 EtOAc gave 0.2144 g (55%) of 6-chloro-5-iodo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine. LCMS (m/z): 353.9 (MH+), retention time=0.92 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.37 (qd, 2H) 1.59 (s, 2H) 1.67 (d, J=12.91 Hz, 2H) 1.77-1.94 (m, J=14.87, 7.63, 7.63, 3.52 Hz, 1H) 3.25 (t, J=6.46 Hz, 2H) 3.39 (td, J=11.74, 1.96 Hz, 2H) 4.00 (dd, J=11.15, 3.72 Hz, 2H) 4.80 (br. s., 1H) 7.62 (s, 1H).