Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:10]B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[C:4]([CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CB(O)O
Reactant: N#Cc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ncccc1C#N
Temperature: 25 °C
Yield: 46.1 %

Procedure:
To a mixture of 3-cyano-2-chloro-pyridine (422 mg, 3.05 mmol), methylboronic acid (209 mg, 3.49 mmol) and K2CO3 (1.22 g, 8.83 mmol) in degassed dioxane (5 mL) under argon was added Pd(PPh3)4 (222 mg, 0.19 mmol) and the mixture stirred at reflux over the weekend. The reaction was cooled to room temperature, diluted with CH2Cl2 (20 mL) and filtered through Celite, washing the cake with CH2Cl2 and MeOH. The filtrate was concentrated in vacuo and purified by column chromatography on silica gel (Hexanes/ethyl acetate, 9:1 then 4:1) to afford the desired product (166 mg, 46%) as a white solid. 1H NMR (CDCl3): δ 2.78 (s, 3H), 7.25 (dd, 1H, J=9, 6 Hz), 7.90 (dd, 1H, J=6, 3 Hz), 8.69 (d, 1H, J=3 Hz).
Reaction SMILES: [OH-].[NH4+:2].C(O)C.[CH3:6][Si:7]([CH3:22])([CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:15][O:14]1>O>[NH2:2][CH2:15][CH:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][CH2:8][Si:7]([CH3:22])([CH3:6])[CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: [NH4+]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN
Temperature: 50 °C

Procedure:
Aqueous ammonium hydroxide (25%; 10 g, ˜150 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 50° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 50° C. for an additional 8 hours. Ethanol and water were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>O1CCCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([NH:1][C:20]([CH:17]3[CH2:19][CH2:18]3)=[O:21])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=Cc1cnn2c(NC3CC3)cc(NC(=O)C3CC3)nc12
Temperature: 60 °C

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (step b) (58 mg, 0.266 mmol) in 1.0 mL tetrahydrofuran was added cyclopropane carbonyl chloride (38 ul, 0.419 mmol) and DIPEA (39.0 ul). The reaction mixture was heated at 60° C. for one hour. The reaction was partitioned between ethyl acetate and water, the organic layer was dried under sodium sulfate concentrated on high vac to yield N-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)cyclopropanecarboxamide. The crude product was taken to next step without further purification. LCMS (M+1=286)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:14][C:23](=[O:24])[C:22]4[CH:26]=[CH:27][CH:28]=[N:29][C:21]=4[N:20]=3)=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
5-Trifluoromethyl-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid chloride (example 2, step 3) (800 mg) was added to a mixture of 2-aminonicotinic acid (356 mg) in acetonitrile (20 mL). The mixture was stirred for 10 minutes at room temperature and triethylamine (360 μL) was added and stirred for 15 minutes, before a second portion of triethylamine (720 μL) was added. After the mixture was stirred for further 15 minutes at room temperature, methanesulfonyl chloride (220 μL) was added. After stirring for 1.5 hours at room temperature, the reaction was quenched with water and extracted 2× with ethyl acetate, washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate=1:1, Rf=0.40) to afford 660 mg of the title compound of the formula
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3O)[N:4]=1.[CH2:23]([O:25][C:26]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:27])[CH3:24]>O1CCCC1>[CH2:23]([O:25][C:26]([CH2:28][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1)=[O:27])[CH3:24]
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1OC(=O)c2c(Oc3nc(OC)cc(OC)n3)cccc21

Procedure:
A mixture of 1.5 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy] -3-hydroxy-phthalide (see Example 84) and 2.5 g of (ethoxycarbonylmethylene)-triphenyl-phosphorane is maintained at reflux temperature for 10 hours in approximately 40 ml of tetrahydrofuran. The solvent is then evaporated off and the reaction material which remains is purified on a column of silica gel (eluant: ethyl acetate/n-hexane 1:1) to yield 3-(ethoxycarbonylmethyl)-7[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide, m.p. 150°-152° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][C:30]([CH3:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:42][C:30]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(C)(CCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
0.611 g (1.75 mmol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-yl-amide, 0.5 g (1.75 mmol) of methyl 5-bromo-2-methyl-2-phenyl-pentanecarboxylate and 0.8 g (5.7 mmol) of potassium carbonate are dissolved in 50 ml dimethylformamide and mixed with water. The mixture is stirred for 72 hours at 90° C. Then the reaction mixture is poured onto water, the precipitate is filtered off and dried. After column chromatography on silica gel (eluant: ethyl acetate) colourless crystals are left.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[H-].[Na+]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:18][CH:17]([OH:16])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: c1cncc(CCC2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(Cc2ccc(OCC(O)CCc3cccnc3)cc2)cc1
Yield: 21 %

Procedure:
Prepared according to the method described in Example 5 from bis(4-hydroxyphenyl)methane (1.6 g), (±)-3-(2-oxiranylethyl)pyridine (1.24 g) and sodium hydride (60% dispersion in oil; 0.319 g) in dimethylformamide (25 ml) at 100° C. for 2 hours to give the title compound as a white solid (0.587 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[CH:9]1[C:15]([NH2:16])=[N:14][C:12](=[O:13])[N:11]([C@@H:17]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C:18]2([F:26])[F:25])[CH:10]=1.Cl>>[F:26][C:18]1([F:25])[C@H:19]([OH:24])[C@@H:20]([CH2:22][OH:23])[O:21][C@H:17]1[N:11]1[CH:10]=[CH:9][C:15]([NH:16][C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])=[N:14][C:12]1=[O:13]
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: Cl
Product: CC(C)COC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Yield: 97 %

Procedure:
Using Method A and isobutyl chloroformate, gemcitabine hydrochloride was converted to 22 (white solid, 97% yield): 1H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.25-8.26 (d, 1H), 7.12-7.14 (d, 1H), 6.35 (s, 1H), 6.19-6.22 (t, 1H), 5.33 (s, 1H), 4.22-4.24 (d, 1H), 3.91-3.96 (m, 3H), 3.83-3.85 (d, 1H), 3.68-3.70 (d, 1H), 1.91-1.97 (m, 1H), 0.94-0.95 (d, 6H).
Reaction SMILES: B.C1COCC1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]([CH2:21][C:22](O)=[O:23])([OH:20])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]([OH:20])([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC(=O)O)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CCO)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1M solution of borane in THF (15.8 ml, 15.8 mmol) was added slowly to a solution of 2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)acetic acid (40) (1.02 g, 3.94 mmol) at 0° C. After stirring the mixture at 0° C. for 1 hour and at rt for 16 hours the reaction was quenched by addition of NH4Cl solution and extracted with ethyl acetate. The organic layer was then washed with water and brine, dried over Na2 SO4 and evaporated. The crude product was purified by flash chromatography (silica gel, EtOAc/n-pentane) which furnished the product as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][C:15]3=[O:18])=[CH:11][CH:10]=2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24]>CCOC(C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:23]([NH:24][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:17]=[C:16]4[C:12]([CH2:13][CH2:14][C:15]4=[O:18])=[CH:11][CH:10]=3)[N:3]=2)[CH:22]=[C:21]([O:20][CH3:19])[C:27]=1[O:28][CH3:29]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C1CCc2ccc(Oc3cncc(Cl)n3)cc21
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccc4c(c3)C(=O)CC4)n2)cc(OC)c1OC
Yield: 10 %

Procedure:
Using Method EE with 2-chloro-6-(indanone-6-oxy)-pyrazine (200 mg, 0.77 mmol) and 3,4,5-trimethoxyaniline (169 mg, 0.92 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (30 mg). Yield: 10%. 1H NMR (250 MHz, DMSO-d6) δ 2.73 (t, 2H, H3, J=5.4 Hz), 3.13 (t, 2H, H2, J=5.8 Hz), 3.37 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.72 (s, 2H, Harom2′+6′), 7.37 (d, 1H, Harom 7, J=2.2 Hz), 7.52 (dd, 1H, Harom 5, Jm=2.3 Hz, Jo=7.2 Hz), 7.64 (d, 1H, Harom 4, J=8.3 Hz), 7.81 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.57 (s, 1H, NH). m/z: 408.1 [(M+H)+, calcd for C22H21N3O5 407.1].
Reaction SMILES: NN.O=[C:4]1[C:12]2C(=CC=CC=2)C(=O)[N:5]1[O:14][CH2:15][C:16]1[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]3[N:26]=[N:27][N:28]=[C:20]3[C:19]=2[N:29]=1.[CH2:43](O)C>>[CH3:25][C:22]1[N:21]2[N:26]=[N:27][N:28]=[C:20]2[C:19]2[N:29]=[C:16]([CH2:15][O:14][N:5]=[C:4]([CH3:43])[CH3:12])[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:18]=2[C:23]=1[CH3:24]
Reactant: CCO
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)c3ccccc3)c12
Agent: NN
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Anhydrous hydrazine (0.47 mL, 15 mmol) was added to a stirred suspension of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]benzamide (2.8 g, 5.0 mmol) in ethanol (50 mL). After two hours, a solid was isolated by filtration and the filter cake was washed with ethanol. Acetone (25 mL) and methanol (25 mL) were added to the solid and the mixture was stirred overnight. The volatiles were removed under reduced pressure to afford a solid that was triturated with 1 M aqueous sodium hydroxide (10 mL) and 1:1 methanol/acetone (4 mL). The solid was isolated by filtration, washed with water, and dissolved in chloroform (100 mL). The solution was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to afford 1.9 g of a N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}benzamide as a white solid.
Reaction SMILES: Cl.CN.[CH3:4][C:5]1[CH:6]=[C:7]([O:23][C:24]2[CH:25]=[N:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20]([OH:22])=O)[CH2:17][N:18]=1)=[CH:10]2.O[N:35]1[C:39]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.C(N(CC)CC)C>[CH3:4][C:5]1[CH:6]=[C:7]([O:23][C:24]2[CH:25]=[N:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20]([NH:35][CH3:39])=[O:22])[CH2:17][N:18]=1)=[CH:10]2
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(C)c3[nH]2)S1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a mixed solution of methylamine hydrochloride (120 mg), triethylamine (0.24 mL) and N,N-dimethylformamide (20 mL) were added [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-hydroxybenzotriazole (230 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 85:15, volume ratio), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (436 mg, yield 85%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C@@H:5]([C:6]2[N:10]3[C:11]4[CH:17]=[CH:16][N:15]([S:18]([C:21]5[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=5)(=[O:20])=[O:19])[C:12]=4[N:13]=[CH:14][C:9]3=[N:8][N:7]=2)[CH2:4][C@H:3]1[NH:28]C(=O)C.C(N[C@@H]1C[C@H](C(O)=O)C1(C)C)(=O)C.CCN(C(C)C)C(C)C.Cl>O1CCOCC1.C(Cl)CCl>[CH3:1][C:2]1([CH3:32])[C@@H:5]([C:6]2[N:10]3[C:11]4[CH:17]=[CH:16][N:15]([S:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=5)(=[O:20])=[O:19])[C:12]=4[N:13]=[CH:14][C:9]3=[N:8][N:7]=2)[CH2:4][C@H:3]1[NH2:28]
Reactant: CC(=O)N[C@@H]1C[C@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1(C)C
Agent: CC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@H]4C[C@@H](N)C4(C)C)n23)cc1
Temperature: 100 °C
Yield: 78 %

Procedure:
To a solution of N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)acetamide (2.20 g, 4.86 mmol, prepared using A from Preparation #9 and (1S,3R)-3-acetamido-2,2-dimethylcyclobutanecarboxylic acid [prepared as described in Tetrahedron: Asymmetry 2008, 19, 302-308] with EDC, C with DIEA) in 1,4-dioxane (30 mL) was added 6 N aqueous HCl (32.4 mL, 194 mmol). The reaction was heated at about 100° C. for about 16 h. The reaction was allowed to cool to ambient temperature and was partitioned between EtOAc (500 mL) and aqueous NaHCO3 (500 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutanamine (1.56 g, 78%) as a tan solid: LC/MS (Table 2, Method a) Rt=1.60 min; MS m/z: 411 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(N(C)C)cc2)cnc1N
Temperature: 25 °C

Procedure:
A solution of 5-bromo-3-methylpyridin-2-amine (120a, 1.87 g, 10.0 mmol) in toluene (60 mL) was treated with 4-(dimethylamino)phenylboronic acid (2.48 g, 15.0 mmol), Pd(PPh3)4 (345 mg, 0.30 mmol), and 2M Na2CO3(aq) (10 mL). The reaction mixture was heated to reflux for 18 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-(4-(dimethylamino)phenyl)-3-methylpyridin-2-amine (120b).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[C:28]3[N:36]([CH2:37][CH2:38][CH2:39][CH:40]([OH:42])[CH3:41])[C:35]([CH2:43][CH2:44][CH3:45])=[N:34][C:29]=3[CH:30]=[N:31][C:32]=2[CH:33]=1>ClCCl.S([O-])([O-])=S.[Na+].[Na+]>[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[C:28]3[N:36]([CH2:37][CH2:38][CH2:39][C:40](=[O:42])[CH3:41])[C:35]([CH2:43][CH2:44][CH3:45])=[N:34][C:29]=3[CH:30]=[N:31][C:32]=2[CH:33]=1
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [O-]S([O-])=S
Solvent: ClCCl
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
Dess-Martin periodinan (3.51 g, 8.29 mmol) was added to a solution of 5-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol (2.6 g, 6.9 mmol) in dichloromethane and stirred overnight at ambient temperature. The reaction mixture was diluted with sodium thiosulfite (2×50 mL) and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate (twice) and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 2.50 g of 5-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[C:7]([NH:15][NH:16][C:17](=O)[CH2:18][CH2:19][CH3:20])=[N:6]2.C1(O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[C:7]3[N:6]2[C:17]([CH2:18][CH2:19][CH3:20])=[N:16][N:15]=3)=[CH:11][CH:12]=1
Reactant: CCCC(=O)NNc1nc2cc(OC)ccc2n(C)c1=O
Solvent: Oc1ccccc1
Product: CCCc1nnc2c(=O)n(C)c3ccc(OC)cc3n12
Temperature: 25 °C

Procedure:
A mixture of 6-methoxy-1-methyl-3-(2'-butanoyldiazanyl)-1H-quinoxalin-2-one (10.9 g., 27.5 mmol) and phenol (27.3 g.) was heated at 180° for 3.5 hours and allowed to cool to room temperature. The mixture was diluted with 50 ml. of ether and the resulting solid collected by filtration and washed with ether. The material was recrystallized from acetonitrile, collected by filtration, and dried under high vacuum overnight to give 7.6 g. of 8-methoxy-5-methyl-1-propyl-4H-1,2,4-triazolo(4,3-a)quinoxalin-2-one, m.p. 219°-220°.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:55]=[C:49]3[CH2:50][N:51]([CH3:54])[CH2:52][CH2:53][N:48]3[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:55]=[C:49]3[CH2:50][N:51]([CH3:54])[CH2:52][CH2:53][N:48]3[N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 65.2 %

Procedure:
A 25 mL sealed tube was charged with 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (210d) (500 mg, 1.0 mmol), 5-bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one (146a) (350 mg, 1.0 mmol), CH3COONa (170 mg, 2.0 mmol), K3PO4 (552 mg, 2.0 mmol), PdCl2(dppf) (85 mg, 0.1 mmol) suspended in CH3CN (25 mL) and H2O (1 mL). The mixture was heated at 110° C. for 2 hours. It was then evaporated and the residue was purified by silical-gel column eluting with 20:1 methylene chloride/methanol to give 234a as a brown solid (400 mg, 63%). MS: (M+H)+ 614.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.Br[CH2:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:19]>>[N:7]1([CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:19])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(Cn1cnc2ccccc21)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
A solution of potassium tert-butoxide (1.7 mL of 1 M solution in THF, 1.7 mmol,) was added to a solution of 1H-benzoimidazole (165 mg, 1.4 mmol) in anhydrous TBF (3 mL). The reaction mixture was stirred for 20 min at ambient temperature. 2-Bromo-N-(3-trifluoromethyl-phenyl)-acetamide (Example 92 part A) was added (261 mg, 0.93 mmol) and the mixture was stirred at 55° C. for subsequent 24 h. The crude product was purified on a preparative HPLC (XTerra C8 column 19×300 mm, 0.1 M aqueous NH4Ac/CH3CN). The pooled fractions were lyophilized to afford 81 mg (27%) of the title compound. Calculated for C16H12F3N3O m/z: 319.29, found 320.0 [M+H]+. 1H NMR (400 MeOH) δ ppm 5.2 (s, 2H), 7.3 (m, 2H), 7.4 (d, J=7.6 Hz, 1H), 7.5 (m, 2H), 7.7 (d,J=7.1 Hz, 1H), 7.8 (d, J=8.6 Hz, 1H), 8.0 (s, 1H), 8.2 (s, 1H).