Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH2:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([CH2:3][OH:2])[CH2:6][CH2:7]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)N1CCC(C(=O)OC)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCC(CO)CC1
Temperature: -78 °C

Procedure:
The above ester (12.8 g, 59.5 mmol, 1.0 equiv) was dissolved in 50 mL of dry CH2Cl2 under Ar and cooled to −78° C. A 1 Molar solution of DIBAL-H in CH2Cl2 (149 mL, 149 mmol, 2.5 equiv) was added dropwise over a 30 min period. The cold bath was removed and the reaction solution allowed to warm to ambient temperature. At this time EtOAc (10 mL) was added dropwise to quench the excess DIBAL-H. 100 mL of 1H HCl (aq) was added dropwise over a 30 min period with rapid stirring. The resulting mixture was filtered on a pad of diatomaceous earth and the filtrate was dried over Na2SO4, decanted and concentrated to yield 4-hydroxymethyl-piperidine-1-carboxylic acid ethyl ester as a nearly colorless oil that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:16]1[C:21]([S:22](Cl)(=[O:24])=[O:23])=[CH:20][CH:19]=[C:18]([I:26])[CH:17]=1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][CH2:5][NH:6][S:22]([C:21]1[CH:16]=[CH:17][C:18]([I:26])=[CH:19][CH:20]=1)(=[O:24])=[O:23])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CCOCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
2-Ethoxyethylamine (2.14 g, 24 mmol) and diisopropylethylamine (4.2 ml, 24 mmol) were dissolved in DCM (50 ml) and cooled to 0° C. To this was added pipsyl chloride (6.05 g, 20 mmol) in portions and the reaction stirred for 18 hours. Volatiles were evaporated in vacuo. The residue was dissolved in EtOAc (50 ml), extracted 1N citric acid (2×50 ml), brine (50 ml), dried and evaporated in vacuo to yield an oil which solidified on standing to give the title compound as a pale yellow solid (6.97 g, 98%). NMR: 1.01 (t, 3H), 2.89 (q, 2H), 3.30 (m, 4H), 7.53 (d, 2H), 7.75 (t, 1H), 7.97 (d, 2H); m/z 354 (M−H)−.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:34])[N:21]([CH3:33])[C@@H:22]([C:29](=[O:32])[NH:30][CH3:31])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:33][N:21]([C@@H:22]([C:29](=[O:32])[NH:30][CH3:31])[CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[C:20](=[O:34])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl) carbamic acid tert butylester (1.38 g ; 2.71 mmol) was dissolved in methylene chloride (6 ml) and triflouroacetic acid (4 ml) was added. The reaction mixture was stirred for 1 hour at room temperature. Water (30 ml) and solid sodium hydrogencarbonate were added to pH 8. The phases were separated and the aqueous phase was extracted with methylene chloride (4×20 ml). The organic phase was dried over magnesium sulfate and the solvent was removed over vacuo to afford 1.06 g of (2R)-N-methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)-3-(2-naphthyl)propionamide.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH2:21][CH2:20]3)[N:3]=1.Cl.[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>N1C=C(C)C=CC=1C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([N:30]2[CH2:31][CH2:32][CH2:33][CH:28]([OH:27])[CH2:29]2)=[N:3][C:4]=3[NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH2:21][CH2:20]3)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OC1CCCNC1
Reactant: Clc1nc(Nc2ccc3c(c2)CCC3)c2ncn(C3CCCC3)c2n1
Agent: Cc1ccc(C)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: OC1CCCN(c2nc(Nc3ccc4c(c3)CCC4)c3ncn(C4CCCC4)c3n2)C1
Temperature: 180 °C

Procedure:
(2-Chloro-9-cyclopentyl-9H-purin-6-yl)-indan-5-yl-amine (283 mg, 0.8 mmol), 3-hydroxypiperidine hydrochloride (550 mg, 4 mmol) and K2CO3 (829 mg, 6 mmol) were suspended in 2,5-lutidine (10 mL) and the mixture was heated at 180° C. for 4 h. After cooling, CH2Cl2 (50 mL) was added and the solution was extracted with brine (2×15 mL). The organic fraction was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (95:5 CH2Cl2/MeOH) to afford the title compound as a slightly yellow foam (320 mg, 95.6%). Anal. RP-HPLC (Phenomenex Jupiter, 5 μ, C18, 300 Å, 4.6×250 mm; 1 mL/min): tR=19.6 min (10-70% MeCN in 0.1% aq CF3COOH over 20 min); tR=15.4 min (40-50% MeCN in 0.1% aq CF3COOH over 20 min); purity>92% (λ=214 nm). DE-MALDI-TOF MS: [M+H]+=419.5 (C24H30N6O=418.5).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCC(=O)C>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:11][CH2:12][N:13]1[CH2:20][C:21](=[O:24])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Agent: CC(=O)CCl
Product: COc1ccc(N2CCN(CC(C)=O)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Yield: 199.8 %

Procedure:
Prepared using the same procedure described in Example 405 from 5-((S)-3-benzyl-piperazin-1-yl)-8-methoxy-2-trifluoromethyl-quinoline (254 mg, 0.63 mmol) and chloroacetone (60 μL), to afford the title compound as yellow solid (288 mg, 98%). LC/MS (Method B) 2.67 min, [M+1]+ 458.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[OH-].[Na+]>[Ni].C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2
Reactant: Nc1cccc2ccc(O)cc12
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c1CC(O)CC2
Temperature: 85 °C
Reaction time: 13 h
Yield: 37.2 %

Procedure:
Ethanol (1 L) was added to 8-amino-2-naphthol (100 g, 610 mmol), Raney nickel (40 g, water wet), and sodium hydroxide (4.00 g, 8 mol % aqueous) in a stirred reactor. The reactor was sealed and sparged with hydrogen. The reaction mixture was stirred for 13 h at 85° C. and then an additional 8 h at 100° C. The mixture was then filtered through a pad of Celite. The resulting solution was treated with Darco G-60 (35 g) and heated to reflux for 1 h, then cooled to ambient temperature and stirred an additional 3 h. This mixture was filtered through Celite (350 g), and the pad washed with EtOAc (1.5 L). The solvent was removed in vacuo and methyl tert-butyl ether (1 L) was added. This was heated for 15 min at 50° C., stirred for 1 h at ambient temperature, filtered, and the solvent removed in vacuo. Approximately half of the resulting crude solid was purified by chromatography on silica gel (gradient elution, 2-30% MeOH/CH2Cl2) to give 37 g of the title compound as a light brown solid. 1H NMR (300 MHz, CDCl3) δ 6.96 (t, J=7.6 Hz, 1H), 6.55 (dd, J=10.7, 7.6 Hz, 2H), 4.44-4.24 (m, 1H), 2.95-2.80 (m, 3H), 2.38 (dd, J=16.1, 7.6 Hz, 1H), 2.09-1.96 (m, 1H), 1.85-1.70 (m, 1H).
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:15])[CH:13]=2)[C:8]([O:16][CH3:17])=[N:7]1)=O)C.BrC1C=CC=C2C=1C(OC)=NN2>>[Br:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([O:16][CH3:17])=[N:7][NH:6]2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)n1nc(OC)c2ccc(Br)cc21
Agent: COc1n[nH]c2cccc(Br)c12
Product: COc1n[nH]c2cc(Br)ccc12

Procedure:
6-Bromo-3-methoxy-1H-indazole CCXXXVII was prepared from 6-bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester using the procedure described for preparation of 4-Bromo-3-methoxy-1H-indazole CLXXXVI (Example 37).
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)C>[OH-].[Na+]>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:25])=[O:3])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)/C=C/C=C(c1cccc(OC)c1)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C(=C/C=C/C(=O)O)c2cccc(OC)c2)c1
Yield: 87.6 %

Procedure:
A mixture of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid ethyl ester (19.8 g) methanol (200 mL) and 2N sodium hydroxide solution (40 mL) was heated at reflux for 30 minutes. After most of the methanol was distilled off in vacuo, the solution was diluted with water (300 ml), acidified with 2N hydrochloric acid (50 mL) and the resulting solid filtered. The dried material (17.8 g) was crystallized from dichloromethane-hexane to afford 15.9 g of (E)-5,5-bis (3-methoxyphenyl)-2,4-pentadienoic acid, mp 179°-180.5° C. Anal. Calculated for C19H18O4 : C, 73.53; H, 5.85 Found: C, 73.80; H, 5.94
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:10][C@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:12]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].Br[C:33]1[N:34]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:35]2[C:40]([C:41]=1[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:39][CH:38]=[CH:37][CH:36]=2.C(=O)(O)[O-].[Na+]>CN(C=O)C.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:27]([O:26][C:25]([NH:24][C@H:11]([C:12]([N:14]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:15])=[O:13])[CH2:10][C:6]1[CH:5]=[C:4]([CH2:1][CH:2]=[CH:3][C:33]2[N:34]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[C:35]3[C:40]([C:41]=2[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:9]=[CH:8][CH:7]=1)=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: C=CCc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccc(OC)cc2)c1
Reactant: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccccc12
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: CN(C)C=O
Product: CCOC(=O)Cc1c(C=CCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)n(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 125 °C
Yield: 48.1 %

Procedure:
A suspension of (5)-tert-butyl 3-(3-allylphenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (220 mg, 0.52 mmol), tert-butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (297 mg, 0.78 mmol), sodium bicarbonate (435 mg, 5.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) in 4 ml of DMF was heated to 125° C. overnight. The reaction was cooled to room temperature and then filtered through celite. The filtrate was concentrated and the crude product was introduced to a silica gel loading column and purified by column chromatography (30-60% EtOAc/Hexans) to provide the desired product (178 mg, 0.25 mmol), 47%. MS (m/z) 726 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:14][CH:15]([OH:19])[CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]1[C:8]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]1[CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: OC(CBr)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: OC1CCN(c2cccc(C(F)(F)F)c2F)C1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2-Fluoro-3-(trifluoromethyl)aniline (5.0 g) and 1,4-dibromobutan-2-ol (6.7 g) were stirred at 100° C. for 3 hr. After cooling to room temperature, to the reaction mixture was added saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10-50:50) to give the title compound (1.9 g, yield 27%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[CH3:6].CCN(CC)CC.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.O>[CH3:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)([CH3:7])[CH3:6]
Reactant: CCCNC(C)(C)Cc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCNC(C)(C)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of compound D-3-6 (195.0 g, 799 mmol) in THF (1.0 L) and H2O (1.0 L) is added Et3N (242.0 g, 2.4 mol) and Boc2O (174.0 g, 799 mmol). The resulting mixture is stirred at room temperature overnight, then extracted with EtOAc. The combined organic phases are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by silica gel chromatography (using 10:1 petroleum ether:EtOAc) to provide compound D-3-7 (100.0 g, 56% yield over 4 steps).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:4][CH2:5][CH3:6].[CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH2:26].O>O1CCCC1.[Cl-].[Na+].O>[CH2:3]([C:7]1[N:8]([CH2:20][C:21]([CH3:24])([O:23][CH2:26][CH2:25][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:22])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Reactant: C=CS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 55 mg, 1.38 mmol) was added to a stirred solution of 1-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (4.10 g, 13.8 mmol) in tetrahydrofuran (55 mL). After 5 minutes, methyl vinyl sulfone (2.90 g, 27.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) and a small amount of brine were added and the mixture was extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a solid that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 2.7 g of 2-butyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2].S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>O>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([N+:21]([O-:23])=[O:22])=[C:9]([CH:8]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1cccc(C(=O)O)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Yield: 76.9 %

Procedure:
Finely ground 3-ethoxycarbonyloxybenzoic acid (10.5 g) was added with stirring to concentrated sulphuric acid at 2°. A mixture of concentrated sulphuric acid (10 ml) and 70% nitric acid (4.5 g) was then added dropwise with stirring, keeping the temperature at 5° or below. When addition was complete, the solution was stirred for another 30 minutes and then poured into ice and water (200 ml). The white solid which separated was washed with water and taken up in chloroform. The solution was dried (MgSO4) and concentrated to yield 5-ethoxycarbonyloxy-2-nitrobenzoic acid (9.8 g) with a melting point of 126°-130°.
Reaction SMILES: [C:1]([C:3]1C=C(C=CC=1)N)#N.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12]1=[O:38].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH2:10]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[N:18]=2)[CH:13]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:12]1=[O:38])[CH:1]=[CH2:3]
Reactant: CN1CCN(c2ccnc(Nc3cccc(C#N)c3)n2)C(c2ccccc2)C1=O
Reactant: N#Cc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCN1CCN(c2ccnc(Nc3cccc(C#N)c3)n2)C(c2ccccc2)C1=O
Yield: 57 %

Procedure:
Intermediate 6, (0.10 g, 0.30 mmol) and 3-cyanoaniline (0.05 g, 0.45 mmol) were reacted together following the procedure detailed for the compound of Example 2, with the addition of an equivalent of tosic acid which eventually gave the title compound as a white solid (0.07 g, 57%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:20][N:21]=[C:22]2[N:27]=1
Reactant: Brc1cccc(-c2cccnc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4cccnc4)n3)cnc2n1
Yield: 23.8 %

Procedure:
6-Bromo-2,3′-bipyridine (0.37 g, 1.6 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.6 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane on a gradient of methanol (0-5%) and trituration with isohexane gave 6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,3′-bipyridine (130 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.40 (1H, d, J 7), 7.50 (1H, dd, J 8 and 8), 7.72 (1H, d, J 8), 7.85 (1H, d, J 8), 7.97 (1H, dd, J 8 and 8), 8.30 (1H, m), 8.59 (1H, s), 8.75 (1H, m), 9.29 (1H, s), 10.51 (1H, d, J 7); m/z (ES+) 341 (M++H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14]>CO.C(OCC)(=O)C>[CH3:12][N:13]([CH3:14])[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)c1nccc(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 0.67 %

Procedure:
2-Chloro-4-trifluoromethylpyrimidine (600 μL, 5.0 mmol) was dissolved with 2.0M dimethylamine in methanol (10 mL), and stirred for 2 hours in a sealed tube at 60° C. The reaction mixture was diluted with ethyl acetate (50 mL), and the whole was washed with water (50 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 640 mg of the title Reference Compound as a colorless oil (Yield: 0.67%).
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]#[C:18][Si](C)(C)C)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[K+]>CO.O.C(Cl)(Cl)Cl>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]#[CH:18])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:24][CH3:25]
Reactant: CCCN(CCC)C(=O)c1cc(C#C[Si](C)(C)C)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: C#Cc1cc(C(=O)O)cc(C(=O)N(CCC)CCC)c1
Reaction time: 4 h
Yield: 105.9 %

Procedure:
To a stirred solution of methyl 3-[(dipropylamino)carbonyl]-5-[(trimethylsilyl)ethynyl]benzoate 26 (185.3 mg, 0.49 mmol) in MeOH (2.5 mL) was added a solution of KOH (2.9 mL of a 1 M solution in H2O, 2.9 mmol). The resulting homogeneous brown solution turned to a white/brown suspension, then to a clear brown solution. The reaction mixture was stirred for 4 h, diluted with CHCl3 (40 mL), separated and the organic layer was concentrated under reduced pressure to provide 3-[(dipropylamino)carbonyl]-5-ethynylbenzoic acid 27 (141.8 mg): 1H NMR (300 MHz, CDCl3): δ 8.22 (d, J=1 Hz, 1H), 8.05 (d, J=1 Hz, 1H), 7.71 (d, J=1 Hz, 1H), 3.48 (br s, 2H), 3.17 (s, 1H), 3.16 (br s, 2H), 1.71 (d, J=7 Hz, 2H), 1.55 (d, J=7 Hz, 2H), 1.00 (d, J=7 Hz, 3H), 0.78 (d, J=7.Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH2:18][CH3:19])[CH3:17]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH:7]([CH2:8][CH3:9])[CH2:6][NH:5][CH2:4][C:3]1([CH2:18][CH3:19])[CH3:17]
Reactant: CCC1CN(Cc2ccccc2)CC(C)(CC)C1N
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCC(C)(CC)C1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 4-amino-1-benzyl-3,5-diethyl-3-methylpiperidine (2.1 g, 8.07 mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (4 atm.) at 45° C. for 4 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,5-diethyl-3-methyl-piperidine as an oil. Yield 1.2 g (88%), C10H22N2, m/z 171 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[N:9]=[C:8]([C:11]3[C:12]([CH3:21])=[CH:13][C:14]([CH3:20])=[C:15]([CH:19]=3)[C:16](O)=[O:17])[NH:7][C:6]=2[CH2:5][O:4][CH2:3]1.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:22])[C:10]2[N:9]=[C:8]([C:11]3[C:12]([CH3:21])=[CH:13][C:14]([CH3:20])=[C:15]([CH:19]=3)[C:16]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:17])[NH:7][C:6]=2[CH2:5][O:4][CH2:3]1
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)COCC3(C)C)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2nc3c([nH]2)COCC3(C)C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 16 h

Procedure:
Crude 5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoic acid (compound 449.4, 0.086 mmol) was dissolved in DMF (1 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 19 mg, 0.086 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (HBTU) (65 mg, 0.17 mmol) and DIEA (45 μl, 0.26 mmol) were added and the mixture was stiffed at room temperature for 16 hrs. The mixture was then diluted with ethyl acetate (10 mL) and washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound as a solid foam (15 mg, 30%). m/z (ES+) 469 (M+H)+.