Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nn3c(NCCCCNS(C)(=O)=O)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 99 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (21 mg, 0.04 mmol) in dichloromethane (3 mL) was added triethylamine (0.02 mL, 0.13 mmol) and methanesulfonyl chloride (0.05 mL). The resultant solution was stirred at 0° C. for 1 hour and saturated aqueous sodium bicarbonate was added. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% methanol in dichloromethane) provided N-(4-{[3-[2-(Cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)methanesulfonamide (25 mg, 99%) a yellow solid. 1H NMR (CDCl3): δ 8.01 (d, 1 H), 7.79 (d, 1 H), 7.59 (d, 2 H), 7.32 (m, 1 H), 7.01 (d, 2 H), 6.34 (d, 1 H), 6.13 (m, 1 H), 6.00 (d, 1 H), 5.34 (d, 1 H), 5.02 (m, 1 H), 4.38 (m, 1 H), 3.90 (s, 3 H), 3.38 (m, 2 H), 3.13 (m, 2 H), 2.94 (s, 3 H), 2.14–2.06 (m, 2 H), 1.82–1.54 (m, 10 H); MS m/z 550 (M+1).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[NH:16][C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[CH2:2][CH2:3][CH3:4].[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[N:40]=[C:41]=[O:42]>CCCCCC>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[NH:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:16]=1)[C:41]([NH:40][C:34]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=1[F:32])=[O:42])[CH2:2][CH2:3][CH3:4]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCNCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: CCCCCC
Product: CCCCN(CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Yield: 50.1 %

Procedure:
Part C. To a solution of N-butyl-8-(4,5-diphenyl-1H-imidazol-2-ylthio) octanamine (0.2 g, 0. 00045 mol) in 5 hexane (15 mL) was added, dropwise, a solution of 2,4-difluorophenylisocyanate (0.065 mL, 0.085 g, 0.00055 mol) in hexane (5 mL) and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed with 7:3 hexane-ethyl acetate and the resulting solid was recrystallized from acetonitrile and triturated with hexane to give the title compound (0.138 g, 0.00023 mol) as a white solid, mp 114°-115°. 1H NMR (CDCl3) δ 8.1-7.9(m, 1H), 7.6-7.2(m, 11H), 6.95-6.75 (m, 2H), 6.5-6.4 (m, 1H), 3.4-3.1 (m, 6H), 1.8-1.3 (m, 16H), 1.0 (t, 3H, J=8 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]3[O:13][CH2:14][CH2:15][O:16][C:11]=3[C:10]=2[S:19]([NH2:22])(=[O:21])=[O:20])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[NH:31][CH3:32].Cl>C(O)(C)C>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][C:12]4[O:13][CH2:14][CH2:15][O:16][C:11]=4[C:10]=3[S:19]([NH2:22])(=[O:21])=[O:20])[CH:5]=[CH:4][N:3]=2)=[CH:26][C:25]=1[NH:31][CH3:32]
Reactant: CNc1cc(N)ccc1C
Reactant: NS(=O)(=O)c1c(Nc2ccnc(Cl)n2)ccc2c1OCCO2
Agent: Cl
Solvent: CC(C)O
Product: CNc1cc(Nc2nccc(Nc3ccc4c(c3S(N)(=O)=O)OCCO4)n2)ccc1C

Procedure:
To a suspension of 2.9 g (7.2 mmol) 6-(2-chloro-pyrimidin-4-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-sulfonic acid amide and 2.0 g 4, N3-dimethyl-benzene-1,3-diamine (compound of Example 102f)) in 50 ml isopropanol is added 5 ml conc. HCl and the reaction mixture is heated to reflux for 2 hours. Then the reaction mixture is partitioned between 1 l ethyl acetate and 1 l water. The aqueous layer is adjusted to slightly basic pH by adding NaHCO3. The water layer is extracted a second time with 300 ml ethyl acetate, the combined organic phases are dried with Na2SO4 and evaporated. The crude product is purified by chromatography on silica gel eluting with ethyl acetate to give in the order of elution a mixture of the two starting materials and the title compound. The mixture of starting materials is again subjected to the reaction conditions and workup giving another 1.21 g (37% yield) of desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH2:12][CH2:13][N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1.N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:15]([N:14]([CH:18]([CH3:20])[CH3:19])[CH2:13][CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:22][CH:23]=3)=[O:28])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)([CH3:16])[CH3:17]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)N(CCN1CCCc2ccc(N)cc21)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N(CCN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21)C(C)C

Procedure:
7-Amino-1-(2-diisopropylaminoethyl)-1,2,3,4-tetrahydroquinoline (D15) (100 mg, 0.36 mmol), 4-biphenylcarbonyl chloride (258 mg, 1.11 mmol) and pyridine (0.5 ml, 6.2 mmol) in DCM (5 ml) were stirred at room temperatue for 4 hours. 10% Potassium carbonate solution was then added and the mixture extracted with DCM which was dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by flash column chromatography eluting with 0-5% methanol/DCM gave the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.92 (d, 2H), 7.71 (d, 2H), 7.63 (m, 3H), 7.47 (t, 2H), 7.41 (t, 1H), 6.99 (br, 1H), 6.90 (d, 1H), 6.74 (d, 1H), 3.37 (m, 2H), 3.30 (m, 2H), 3.05 (sp, 2H), 2.72 (t, 2H), 2.66 (m, 2H), 1.93 (m, 2H), 1.05 (d, 12H).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][CH:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:18]([NH2:20])=[O:19])=[C:5]([F:26])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:33]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[CH:17]([NH:16][C:6]1[C:5]([F:26])=[CH:4][C:3]([C:1]([NH2:2])=[O:33])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][C:22]([F:23])([F:25])[F:24]
Reactant: Cc1cc(Nc2cc(NC(CC(F)(F)F)C(N)=O)c(F)cc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(NC(CC(F)(F)F)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4,4,4-trifluorobutanamide (98 mg, 0.250 mmol) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL, 1.0 mmol) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (1 mL) was added. The mixture was purified by HPLC to give the titled compound (28 mg). MS 406.1 (M+H); UV 204.7, 287.8 nm.
Reaction SMILES: FC(F)[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][SiH:9](Br)[CH2:8][CH2:7]1.[Mg].Cl[SiH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>C1COCC1>[CH2:5]([CH:6]1[CH2:11][CH2:10][SiH:9]([SiH:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:8][CH2:7]1)[CH2:4][CH3:3]
Reactant: FC(F)CCCC1CC[SiH](Br)CC1
Reactant: FC(F)(F)c1ccc(C2CC[SiH](Cl)CC2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC1CC[SiH]([SiH]2CCC(c3ccc(C(F)(F)F)cc3)CC2)CC1
Yield: 85 %

Procedure:
5.4 g (9.0 mmol) of 4-(4,4-difluorobutyl) silacyclohexyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 5.6 g (20 mmol) of 4-(4-chloro-4-silacyclohexyl)-1-trifluoromethylbenzene to obtain 4-(4-(4-n-propylsilacyclohexyl)-4-silacyclohexyl)-1-trifluoromethylbenzene. This product was a mixture of trans isomers and cis isomers with regard to the silacyclohexane ring. They were separated by means of chromatography to obtain 4 g of the trans isomers (yield 85%).
Reaction SMILES: [C:1]1([O:7][C:8]2[C:13]3[CH:14]=[N:15][C:16]4[NH:20][N:19]=[CH:18][C:17]=4[C:12]=3[N:11]3[N:21]=[CH:22][N:23]=[C:10]3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:24]([N:20]1[C:16]2[N:15]=[CH:14][C:13]3[C:8]([O:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:9][C:10]4[N:11]([N:21]=[CH:22][N:23]=4)[C:12]=3[C:17]=2[CH:18]=[N:19]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(Oc2nc3ncnn3c3c2cnc2[nH]ncc23)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12

Procedure:
0.01 mol. of 5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine and 0.02 mol. of benzoyl chloride are stirred overnight in 50 ml. of dry pyridine at room temperature. On addition of 50 ml. of water, 8-benzoyl-5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is filtered off.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3](=[O:27])[CH2:4][O:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[NH:8][N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:42](O)(=[O:44])[CH3:43]>C1(C)C=CC=CC=1>[C:42]([N:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([O:5][CH2:4][C:3](=[O:27])[C:2]([CH3:29])([CH3:28])[CH3:1])=[N:7]1)(=[O:44])[CH3:43]
Reactant: CC(C)(C)C(=O)COc1n[nH]c(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccccc1
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)n1nc(OCC(=O)C(C)(C)C)c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 19 %

Procedure:
A mixture of 3,3-dimethyl-1-[(5-(4-(methylsulphonyl)phenyl)-4-phenyl-1H-pyrazol-3-yl)oxy]butan-2-one (145 mg, 0.35 mmol), prepared according to the method of Example 32B, p-toluene-sulfonic acid hydrate (15 mg), and molecular sieves (4 g) in toluene (35 mL) and acetic acid (5 mL) was refluxed for 24 hours. The mixture was concentrated in vacuo, and the residue was purified by chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product (yield: 30 mg; 19%). MP 189-191° C.; MS (APCI+) m/z 455 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ1.22 (s, 9H), 2.48 (s, 3H), 3.28 (s, 3H), 5.37 (s, 2H), 7.23 (m, 5H), 7.60 (d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 2H); Anal. calc. for C24H26N2O5S.0.5 H2O: C, 62.18; H, 5.87; N, 6.04. Found: C, 62.38; H, 5.81; N, 5.83.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:23]1(C(OC(C)(C)C)=O)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:15]=[CH:14][C:13]=2[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Nc1cc(F)ccc1S(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Yield: 49 %

Procedure:
N-(1-(3,5-Dichlorophenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (600 mg, 1.62 mmol), t-butyl piperazine-1-carboxylate (0.29 mmol), N,N-diisopropylethylamine (0.58 mmol) were stirred at 60° C. in dry acetonitrile (20 mL) for 3 days. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (49% yield). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.22 (s, 2H), 6.18 (d, 1H), 5.53 (s, 1H), 4.48 (m, 1H), 3.48 (m, 4H), 3.25 (m, 4H), 1.60 (d, 3H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C19H23Cl2N3O2S: 428.3; Observed: 429.4 (M++1).
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[CH3:6][C:7]([CH3:15])=[CH:8][CH2:9][CH2:10][C:11]([CH:13]=[CH2:14])=[CH2:12].[CH3:16][C:17](=[CH:20][CH3:21])[CH:18]=[O:19].O>C1C=CC=CC=1.[Cl-].[Cl-].C([Al+2])C>[CH3:16][C:17]1([CH:18]=[O:19])[CH:20]([CH3:21])[CH2:12][C:11]([CH2:10][CH2:9][CH:8]=[C:7]([CH3:15])[CH3:6])=[CH:13][CH2:14]1
Reactant: C=CC(=C)CCC=C(C)C
Reactant: CC=C(C)C=O
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)=CCCC1=CCC(C)(C=O)C(C)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A 3-neck reaction vessel is charged with 100 ml benzene and 50 grams of 25% ethyl aluminum dichloride in benzene. A solution containing 320 grams myrcene (85% pure), 170 grams 2-methyl-2-butenal, and 200 ml benzene is fed in at 40°-50° C. over a 1 hour period. The temperature is then raised to 60° C. and held there for 1/2 hour. An additional 10 grams ethyl aluminum dichloride solution mixed with 20 ml benzene is added and heating is continued for an additional 1/2 hour. The mixture is then cooled, water is added and the layers are separated. The organic layer is washed with water and distilled without fractionation to free the material of residue. Redistillation through an 18" Goodlow packed column provides 199 grams of 1,6-dimethyl-4-(4-methyl-3-pentenyl)-3-cyclohexene-1-carboxaldehyde (b.p. 105° C., 0.9 mm).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48](O)=O)=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:48][C:45]1[CH:44]=[CH:43][C:42]([CH:39]2[CH2:38][CH2:37][N:36]([CH3:34])[CH2:41][CH2:40]2)=[CH:47][CH:46]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 25.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (250 mg) according to an analogous synthetic method to Example 337 described below and purified by LC-MS, the title compound (32 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]([C:16]#[N:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].O.C([O-])([O-])=[O:23].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]([C:16]([NH2:17])=[O:23])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(3,4-difluorophenyl)methyl]-3-nitro-2-pyridinecarbonitrile (3.39 g, 12.32 mmol) in acetone (60 ml), was added water (23 ml), urea-hydrogen peroxide complex (19.69 g, 209 mmol), and K2CO3 (2.04 g, 14.78 mmol). The reaction mixture was stirred at room temperature for 30 minutes and the acetone was evaporated without using heat. The resulting precipitate was collected by filtration and thoroughly washed with water to afford a yellow solid. 1H NMR (d6-DMSO) δ 8.79 (1H, s), 8.33 (1H, s), 8.21 (1H, br s), 7.87 (1H, s), 7.49-7.40 (1H, m), 7.38-7.33 (1H, m), 7.19-7.16 (1H, m), 4.12 (2H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1>>[Br:22][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1OC(F)(F)F
Product: N#Cc1ccc(CBr)c(OC(F)(F)F)c1

Procedure:
4-Methyl-3-Trifluoromethoxybenzonitrile is brominated with NBS according to Example 1A to give 4-bromomethyl-3-trifluoromethoxybenzonitrile. 1H NMR (400 MHz, CDCl3) δ (ppm) 4.51 (s, 2H), 7.55 (br s, 1H), 7.59 (d, J=8.0z, 1H), 7.64 (d, J=8.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH:13]3[CH2:17][CH2:16][C:15](=[O:18])[NH:14]3)C(=O)[NH:10][C:5]2=[N:4][CH:3]=1.BrC1C(N)=NC=C(Br)N=1.Cl.NCC1NC(=O)CC1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:10][C:5]1[C:6]([NH:8][CH2:12][CH:13]2[NH:14][C:15](=[O:18])[CH2:16][CH2:17]2)=[N:7][C:2]([Br:1])=[CH:3][N:4]=1
Reactant: O=C1CCC(Cn2c(=O)[nH]c3ncc(Br)nc32)N1
Agent: Cl
Agent: NCC1CCC(=O)N1
Agent: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1ncc(Br)nc1NCC1CCC(=O)N1

Procedure:
6-Bromo-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 3,5-Dibromopyrazin-2-amine (253 mg, 1 mmol), 5-(aminomethyl)pyrrolidin-2-one hydrochloride (150 mg, 1 mmol), diisopropylethylamine (0.5 mL), and dimethylsulfoxide (2 mL) were heated in a Biotage Emrys Optimizer microwave reactor at 150° C. for 2 h to afford crude 5-((3-amino-6-bromopyrazin-2-ylamino)methyl)pyrrolidin-2-one. MS (ESI) m/z 286.0 [M]+, 288.0 [M+2] +. 1,1′-Carbonyldiimidazole (243 mg, 1.5 mmol) was added to the reaction mixture and the solution was heated again in a Biotage Emrys Optimizer microwave reactor at 150° C. for 10 min. The product was purified by reverse-phase semi-preparatory HPLC (10-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The product fractions were concentrated and then triturated with ether to give a white solid. MS (ESI) m/z 312.0 [M]+, 314.0 [M+2]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[CH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>CCN(CC)CC.[Cu]I.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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(I)cc1
Reactant: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(C#Cc2ccc(F)cc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a suspension of CuI (4 mg, 0.02 mmol) in Et3N (1 ml) was added 3-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.38 mmol) followed by PdCl2(PPh3)2 (13 mg, 0.02 mmol) and 1-Iodo-4-fluoro-benzene (85 mg, 0.38 mmol). The mixture was stirred 1 h at R.T then heated to 60° C. for 12 h. Et3N was removed by evaporation. The product was purified by flash chromatography (DCM 100%) to give 0.1 g (89%) of 3-(4-Fluoro-phenylethynyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil.