Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7]Cl)[CH3:3].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][N:17]1[C:18]2[C:14](=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=2)[C:15](=[O:22])[C:16]1=[O:21])[CH3:3]
Reactant: CCN(CC)CCCCl
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: Cl
Product: CCN(CC)CCCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
This compound was prepared by the same method as that described in reference example 8, using 3-diethylaminopropyl chloride hydrochloride in place of 2-diethylaminoethyl chloride hydrochloride, and using 5-chloroisatin in place of the compound of reference example 1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([C:31]#[N:32])[C:25]=3[F:33])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([C:31]#[N:32])[C:25]=3[F:33])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(C#N)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(C#N)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude rac-{1-[({7-[(3-cyano-2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 126A) in 4 ml of dichloromethane was admixed with 2 ml of trifluoroacetic acid. The resulting solution was stirred at room temperature for 3 h. The solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 4.5 mg (5% of theory over 2 stages) of the target compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([O:34][C:33]([F:32])([F:44])[F:45])=[CH:36][CH:37]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(OC(F)(F)F)cc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 4-trifluoromethoxybenzoyl chloride (0.6 g, 2.8 mmol). The mixture was then stirred at room temperature overnight. The reaction mixture was quenched with MeOH (1 mL), washed with water (40 mL), 1N HCl (2×40 mL), and brine (40 mL), dried over MgSO4, and concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-trifluoromethoxy-benzamide as an off-white solid (0.8 g, 78%): mp, 163-165° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=7.3 min. (99%); 1H NMR (DMSO-d6): δ 2.07-2.10 (m, 1H), 2.51-2.64 (m, 2H), 2.91-2.92 (m, 1H), 4.96 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.74-7.84 (m, 3H), 8.04-8.07 (dd, J=6.8, 1.9 Hz, 2H), 9.28 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.44, 118.23, 120.68, 121.64, 121.90, 127.15, 129.30, 129.67, 131.53, 133.01, 133.07, 134.80, 139.03, 150.39, 150.42, 165.39, 166.94, 167.51, 169.81, 172.74. Anal Calcd for C22H16F3N3O6: C, 55.59; H, 3.39; N, 8.84; F, 11.99. Found: C, 55.43; H, 3.00; N, 8.76; F, 11.77.
Reaction SMILES: C[C:2]1[NH:3][C:4]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[OH-].[Na+]>CO>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([C:4]1[NH:3][CH:2]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1)=[O:18]
Reactant: Cc1ccccc1C(=O)c1cc(C(=O)O)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C(=O)c1cc(C(=O)O)c[nH]1
Yield: 117.9 %

Procedure:
Methyl 5-(2-methylbenzoyl)pyrrole-3-carboxylic acid (3.6 g.) was combined with 40 ml. of methanol and 40 ml. of 1 N sodium hydroxide, reluxed for 2.5 hours, the methanol evaporated, the aqueous residue diluted with approximately one volume of water and extracted with ether. The aqueous phase was cooled and acidified with conc. hydrochloric acid to yield crude product (4.0 g.), recovered by filtration. Recrystallization from methanol afforded purified 5-(2-methylbenzoyl)pyrrole-3-carboxylic acid (2.2 g., m.p. 280°-282° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6](I)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH2:42]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2].[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([CH:42]=[CH:41][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: COC(=O)c1cc(I)cc([N+](=O)[O-])c1
Reactant: C=C[Si](C)(C)C
Agent: [Ag+]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(C=C[Si](C)(C)C)cc([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
A mixture of 3-iodo-5-nitrobenzoic acid methyl ester (307 mg, 1.0 mmol), Pd(OAc)2 (67 mg, 0.30 mmol), triphenylphosphine (0.032 g, 0.60 mmol), AgNO3 (170 mg, 1.0 mmol), triethylamine (0.167 ml, 1.2 mmol) and vinyltrimethylsilane (0.309 ml, 2.0 mmol) was dissolved in acetonitrile (10 ml) and the solution was heated to 60° C. in a closed vessel for 48 h. The precipitated salts were filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate and heptane (1:11) as the eluent. Yield: 210 mg (75%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:15]=[CH:16][C:17]3[S:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[C:18]=3[CH:19]=2)=[N:10][CH:11]=1)=[O:5].C[OH:27]>O>[CH2:2]([O:3][C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:19]=[C:18]3[C:17](=[CH:16][CH:15]=2)[S:23](=[O:27])[CH2:22][CH2:21][C:20]3([CH3:24])[CH3:25])=[N:10][CH:11]=1)[CH3:1]
Reactant: CO
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)nc1
Solvent: O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3=O)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of tazarotene (10.0 g, 28.5 mmol) in methanol (300 mL) was chilled in an ice water bath to <10° C., and then charged with the dropwise addition of a solution of NaIO4 (9.13 g, 42.7 mmol) in water (100 mL) over 30 minutes. The reaction was allowed to warm to room temperature while stirring for 18 hours, and was then concentrated under reduced pressure to remove as much methanol as possible. The reaction was then diluted with DCM (500 mL) and water (150 mL). The two layers were then separated, and the aqueous layer was extracted with DCM (2×100 mL aliquots). The organic fractions were pooled, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude sulfoxide product was then chromatographed using a DCM:EtOAc solvent system. Yield: 9.00 g (86%).
Reaction SMILES: [C:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=O)#[N:2].[BH4-].[Na+].ClCCl.C([OH:24])C>O>[OH:24][C:3]1([C:1]#[N:2])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[C:8]([O:12][CH3:13])[CH:9]=2)[CH2:4]1
Reactant: COc1cc2c(cc1OC)C(=O)C(C#N)C2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1OC)CC(O)(C#N)C2

Procedure:
2-Cyano-5,6-dimethoxy-indan-1-one (18.2 g) was suspended in ethanol (360 ml) under an atmosphere of nitrogen and treated with a solution of sodium borohydride (6.57 g) in water (25 ml) and ethanol (36 ml). After 11/2 hours dichloromethane (200 ml) was added. After a further 30 minutes the excess sodium borohydride was destroyed by the dropwise addition of acetic acid (2 ml) in dichloromethane (10 ml). The inorganic salts were filtered off and the filtrate was concentrated under reduced pressure then extracted into ethyl acetate (3×200 ml). The organic extracts were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to give 2-hydroxy-5,6-dimethoxyindane-2-carbonitrile as a yellow solid (17.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:13][C:14]1[N:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:13][C:14]3[N:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Clc1cc(Br)c2ncccc2c1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(c1ccc(Nc2cc(Cl)cc3cccnc23)nc1)N1CCOCC1
Temperature: 90 °C
Yield: 110.9 %

Procedure:
A mixture of 8-bromo-6-chlorquinoline (140 mg, 0.56 mmol), (6-aminopyrdin-3-yl)(morpholino)methanone (92 mg, 0.44 mmol), xantphos (38.5 mg, 0.067 mmol) and cesium carbonate was taken up in dry dioxane (6.5 ml). The reaction flask is evacuated and back-filled with argon (repeated 5 times). Tris(dibenzylidenacetone)palladium (0) (31 mg, 0.033 mmol) was added and the flask was evacuated and back-filled with argon (repeated 3 times). The material was heated to 90° C. (oil bath) under argon for 14 hours. The reaction mixture was cooled to ambient temperature and filtered through a short plug of celite, rinsing well with dioxane. The solvent was removed and the resulting residue loaded onto 2 preparative thin layer chromatography plates. The plates were eluted with 75% ethyl acetate/hexane and the product band collected. This provided the desired product as a light brown viscous oil (180 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13](=[O:26])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([O:24]C)[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.B(Br)(Br)Br.Cl>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13](=[O:26])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:24])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(C=CC(=O)C=Cc2ccc(OC)c(OC)c2)cc1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C(C=Cc1ccc(O)c(O)c1)C=Cc1ccc(O)c(O)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
1,5-Bis(3,4-dimethoxyphenyl)-1,4-pentadien-3-one (20i, 0.56 g, 1.6 mmol) was dissolved in dichloromethane (10 ml) and stirred under a nitrogen atmosphere at −78° C. for 5 min. Boron tribromide (0.90 ml, 9.5 mmol) was added and stirring continued for 60 min at −78° C., 60 min at 0° C. and 60 min at room temperature. The mixture was poured into hydrochloric acid (30 ml, 1 N) and stirring was continued for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with water and saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to give 0.36 g (76%) of an orange solid: mp>250° C. [expected mp 221-223° C.]; 1H NMR: (DMSO) δ 6.78 (d, 2H, J=8.1 Hz), 6.99 (d, 2H, J=15.9 Hz), 7.06 (d, 2H, J=7.9 Hz), 7.14 (s, 2H), 7.55 (d, 2H, J=15.7 Hz), 9.15 (s, 2H), 9.63 (s, 2H); 13C NMR: (DMSO) δ 114.9, 115.6, 121.5, 122.5, 126.2, 142.5, 145.4, 148.2, 187.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a stirred solution of 4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.5 g, 0.00783 mol) (prepared as described in Reference G above) in ethanol (23.0 mL) was added 10% Pd/C (826 mg, 0.00078 mol) under N2 atmosphere and the mixture was allowed to stir at RT overnight under hydrogen atmosphere. The reaction mixture was filtered through cellite, washing with EtOAc (2×100 mL). The filtrate was concentrated under reduced pressure to obtain 4-(4-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (2 g, 80%).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH3:26])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.N1C=CC=CC=1>[ClH:1].[CH3:26][O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COC(=O)c1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (111 g, 0.5 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and methyl anthranilate (75.6 g, 0.5 mole) are dissolved in a mixture of dimethylformamide and pyridine (1:1, 1250 ml), and thereto is added dicyclohexylcarbodiimide (103 g, 0.5 mole), and the mixture is stirred at room temperature for 40 hours. After the undissolved materials are filtered off, the solvent is evaporated under reduced pressure. To the residue are added methanol (500 ml) and water (80 ml), and the mixture is stirred, and the undissolved materials are again filtered off and the solvent is evaporated under reduced pressure. The resulting residue is washed with acetone (2000 ml) and recrystallized from water to give the title compound (143 g) as white crystals. The physical data of this compound are identical with those of N-(o-methoxycarbonylphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride prepared in Example 2.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]([NH2:31])=[NH:30]>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]1[N:31]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:4]=[CH:3][N:30]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: CN(C)/C=C/C(=O)c1ccncc1
Solvent: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2ccncc2)n1

Procedure:
The title compound was prepared by condensation reaction between (2E)-3-(dimethylamino)-1-pyridin-4-ylprop-2-en-1-one and N-(2-methyl-5-nitrophenyl)guanidine nitrate, according to the procedure described in Step C of EXAMPLE 8. MS (M+1)=308.11.
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34](OCC)=O)[CH2:29]C2)[CH:9]=1.C[Si](C)(C)CCOC[N:55](COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC#N)C2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:46][Si:43]([CH3:44])([CH3:45])[CH2:42][CH2:41][O:40][CH2:39][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:48])([CH3:1])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]#[N:55])[CH2:29]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)C2)nc2c(I)cnn12
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)C2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
2-(3-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.[CH3:26][O:27][C:28]1[C:33]([NH2:34])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:25][C@H:20]1[O:21][C@@H:22]([CH3:24])[CH2:23][N:18]([CH2:17][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([C:31]4[CH:32]=[C:33]([NH2:34])[C:28]([O:27][CH3:26])=[N:29][CH:30]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[CH3:11])=[N:16][N:15]=2)[CH2:19]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: C[C@@H]1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)C[C@H](C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(C)c3c2)cc1N
Temperature: 100 °C
Yield: 58.8 %

Procedure:
6-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-methyl-1H-indazole (200 mg, 0.492 mmol), 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (123 mg, 0.492 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (72.0 mg, 0.098 mmol) and tripotassium phosphate (313 mg, 1.477 mmol) were added to 1,4-dioxane (4 ml) and water (1 ml) then heated under microwave irradiation for 20 mins at 100° C. The solvent was removed under nitrogen and the crude residue purified by chromatography (20 g Si cartridge, gradient: 0-100% EtOAc/DCM +0-20% MeOH). The appropriate fractions were combined and the solvent was removed to give the title compound as a brown solid (130 mg).
Reaction SMILES: Br[CH2:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)([CH3:6])[CH3:5].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)([CH3:6])[CH3:5])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C(=O)CBr)c1ccc(S(N)(=O)=O)c(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C(=O)CN=[N+]=[N-])c1ccc(S(N)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 4-(4-bromo-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide (11.3 g, 31.8 mmol) in DMF (50 mL) was added NaN3 (3.1 g, 47.8 mmol, 1.5 eq) at 0° C. After stirring 2 h, the residue was diluted with water and extracted with EtOAc. The combined extracts were washed with 1M HCl and water successively, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography (Hex/EtOAc=4:1 to 2:1) to give 4-(4-azido-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide (8.0 g, 79% yield) as yellow sticky oil. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.29 (d, J=2.2 Hz, 1H), 5.12 (s, 2H), 4.11 (s, 2H), 1.58 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH:17]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])([CH3:19])[CH3:18]>C(O)C>[CH:17]([C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:24]=[CH:25][CH:26]=1)([CH3:19])[CH3:18]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: CC(C)c1cccc(N)c1
Solvent: CCO
Product: CC(C)c1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.48 g (25.8 mmol) 3-isopropylaniline was heated to reflux under N2. At 4 hours, removed heat and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected solids. Dissolved in ethyl acetate, stirred with Darco, filtered through celite, stripped solvent and dried in vacuo, giving 5.289 g of yellow solid: mass spectrum (electrospray m/e): M+H=333.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH3:24]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([CH3:24])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CB(O)O
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
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: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (0.49 g, 1.5 mmol), methylboronic acid (1.8 g, 29 mmol), and tetrakis(triphenylphosphine)palladium (0.086 g, 0.074 mmol) in toluene (30 mL) is stirred for 10 minutes under N2 atmosphere. A solution of sodium carbonate (6.3 g, 59 mmol) in water (20 mL) is added and the mixture is heated at 100° C. for 48 hours. After cooling to room temperature, the reaction mixture is diluted with water (20 mL) and extracted with EtOAc. The combined extracts are washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. The residue is purified by flash chromatography (elution with hexane/EtOAc 20/1) to give 6-(2,6-diethyl-phenyl)-2,4-dimethyl-nicitinic acid ethyl ester as a colorless oil: 1H NMR (CDCl3) 7.27 (dd, 1H), 7.12 (d, 2H), 6.96 (s, 1H), 4.47 (q, 2H), 2.60 (s, 3H), 2.38 (s, 3H), 2.36-2.28 (m, 4H), 1.45 (t, 3H), 1.05 (t, 6H).