Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([O:30][CH2:31][CH3:32])[N:25]=[C:24]([NH2:33])[CH:23]=1.NC1C(N)=NC=CC=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([O:30][CH2:31][CH3:32])[N:25]=[C:24]([NH:33][C:12](=[O:14])[CH2:11][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])[CH:23]=1
Reactant: CCOc1nc(N)cc(N)c1C#N
Reactant: COc1cccc(CC(=O)O)c1OC
Agent: Nc1cccnc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1nc(NC(=O)Cc2cccc(OC)c2OC)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To 67 mg (0.34 mmol) of (2,3-dimethoxyphenyl)acetic acid in 1 mL of CH2Cl2 was added 32 μL (0.37 mmol) of oxalyl chloride. The solution was stirred at ambient temperature for 20 minutes then added to a solution of 60 mg (0.28 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile in 0.5 mL of pyridine. The mixture was complete within 5 minutes though some diaminopyridine remained. The solvent was removed under reduced pressure, then the residue was taken up in 10 mL of ethyl acetate and extracted with water (2×5 mL), saturated NaHCO3(aq.) (1×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was recrystallized from 8 mL of methanol to provide 35 mg (35%) of white crystals. 1H NMR (300 MHz, d6-DMSO) δ 10.22 (s, 1H), 7.15 (s, 1H), 6.97 (m, 2H), 6.88 (s, 2H), 6.81 (dd, 1H, J=7.1, 2.0 Hz), 4.35 (q, 2H, J=7.1 Hz), 3.79 (s, 3H), 3.71 (s, 2H), 3.68 (s, 3H), 1.31 (t, 3H, J=7.1 Hz); MS (ESI) m/e=327 (M−Et+H)+, 357 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]([CH3:24])[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]([CH3:24])[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(c1cccnc1)c1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cccnc1)c1cnc2[nH]cc(C(=O)NC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
N-tert-butyl-2-(methyl(pyridin-3-yl)amino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (38 mg, 83.6 μmol) was dissolved in dichloromethane (1.5 mL) and treated with trifluoroacetic acid (191 mg, 129 μL, 1.67 mmol). After 16 h, the mixture was concentrated and the residue re-dissolved in dichloromethane (1.5 mL), methanol (0.75 mL) and ammonium hydroxide (0.2 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated then triturated with water and filtered to obtain a solid. This was washed with ether then dried to give N-tert-butyl-2-(methyl(pyridin-3-yl)amino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (16 mg, 49.3 μmol, 59%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.33 (s, 1H), 8.64 (d, J=2.5, 1 H), 8.40 (dd, J=4.7, 1.2, 1 H), 8.05 (d, J=3.1, 1 H), 7.96 (s, 1H), 7.92 (s, 1H), 7.82 (m, 1H), 7.46 (m, 1H), 3.50 (s, 3H), 1.32 (s, 9H); MS (EI/CI) m/z: 325.1 [M+H].
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:43])[C:7](=[CH2:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:32])[CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC>CO>[CH2:1]([NH:5][C:6](=[O:43])[C@H:7]([CH3:42])[CH2:8][C@H:9]([OH:41])[C@@H:10]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:11][C@@H:12]([CH:30]([CH3:31])[CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
3.5 g of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-methoxy-phenyl)-octanoic acid (N-butyl)amide are hydrogenated in 30 ml of absolute methanol in the presence of 20 mg of [Ru2Cl4 ((S)-Binap)2 ].NEt3 at room temperature and 25 bar for 5 hours. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The residue is purified by FC (200 g of silica gel, hexane/ethyl acetate=1:1). Title compound: Rf (hexane/ethyl acetate=1:1)=0.16; FAB-MS (M+H)+ =599.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=1.CS(O[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=O)=O.Cl>CCCCCC.CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH2:18][CH2:19][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)OCCc1cccs1
Reactant: N#CCc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: N#CC(CCc1cccs1)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
To a flask under a nitrogen atmosphere was added, with stirring, 3.3 g. (0.0825 mole) of 60% sodium hydride, washed twice with hexane to remove the original mineral oil, in 75 ml. of a dry 2 to 1 mixture of DMF and toluene. To this slurry at room temperature was added 11.30 g. (0.075 mole) of 4-chlorobenzyl cyanide in 40 ml. of DMF. After 1.5 hours, the mixture was cooled to 10° C. and 13.7 g. (0.0782 mole) of 2-(2-thienyl)ethyl methanesulfonate in 25 ml. of DMF was added dropwise. The reaction was stirred at room temperature for 13 hours. Then aqueous 10% hydrochloric acid, 20 ml., was added followed by 150 ml. of diethyl ether which was washed three times with 50 ml. portions of water. After drying the ether and concentrating, the product was distilled at 130°-150° C. at 1-2 mm of Hg yielding 2-(4-chlorophenyl)-4-(2-thienyl)butyronitrile as an oil.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@@H:13]([NH2:39])[C@@H:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:42](N)(N)(=[O:44])=[O:43]>N1C=CC=CC=1>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]2[NH:39][S:42](=[O:44])(=[O:43])[N:16]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=3[C:28]3[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=3[O:37][CH3:38])[C@H:14]2[CH3:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1[C@@H](C)[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)NS1(=O)=O
Temperature: 120 °C

Procedure:
A glass reaction tube was charged with (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine (15.9 mg, 0.0269 mmol), sulfamide (4 mg, 0.0403 mmol), and pyridine (600 μL). The tube was flushed with N2, sealed, and heated at 120° C. for 2 h. The reaction was then cooled to room temperature, diluted with EtOAc (40 mL) and washed with H2O, 1N HCl, and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 25% EtOAc/hexanes afforded (3S,4R)-4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide. Rf=0.27 (25% EtOAc/hexanes). LCMS=655.2 (M+1)+. 1H NMR (C6D6, 500 MHz; atropisomers present) δ 6.51-8.19 (m, 9H), 3.64-4.53 (m, 4H), 3.00-3.18 (m, 4H), 2.73 (m, 1H), 1.13-1.20 (m, 6H), −0.03-0.09 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:27][S:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>>[CH3:27][S:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH:32][CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: CSc1cccc(N)c1
Product: COc1cc(-c2cc(CN3CCC(Nc4cccc(SC)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.40 g) and 3-methylthioaniline (655 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:8][C:4]1[N:3]=[C:2]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: NC1CCC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1cncc(NC2CCC2)n1
Yield: 80 %

Procedure:
A solution of 2,6-dichloropyrazine (4.47 g), cyclobutanamine (3.8 mL) and potassium carbonate (6.20 g) in DMA (30 mL) was stirred at 80° C. for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→15% ethyl acetate/hexane) to give the title compound (4.42 g, 80%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.Cl.[NH2:12][OH:13].O.[OH-].[NH4+]>C(O)C>[CH3:1][C:2]([NH:12][OH:13])=[C:4]1[CH:5]=[CH:6][C:7](=[O:10])[CH:8]=[CH:9]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(NO)=C1C=CC(=O)C=C1
Yield: 99.9 %

Procedure:
A solution was prepared by adding 13.6 g (0.1 mol) of 4-hydroxyacetophenone, 7.6 g (0.11 mol) of hydroxylamine hydrochloride, and 10 g of water to 40 mL of ethanol. To the solution was added 5.0 g of 30% ammonium hydroxide which was then heated at reflux for 2 h. The ethanol was removed on a rotary evaporator to yield a yellow oil. An extractive work-up afforded 15.1 g (99%) of 4-hydroxyacetophenone oxime.
Reaction SMILES: [Cl: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][CH:14]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.Cl>CCO>[ClH:1].[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][CH:14]=[C:4]3[N:3]=[C:2]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:7]=2)[CH2:11][CH2:10]1
Reactant: Clc1cc(NC2CC2)n2nccc2n1
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(Nc2cc(NC3CC3)n3nccc3n2)cc1
Temperature: 23 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
5-chloro-N-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (208 mg, 1 mmol) was suspended in EtOH (1 mL). 4-aminobenzonitrile (236 mg, 2 mmol) and then conc. HCl (125 μL, 1.5 mmol) were added and the reaction was placed in a 95° C. oil bath. After 24 h, additional conc. HCl was added (62 μL). After an additional 24 h, the reaction was cooled to 23° C. and the filter cake was washed with EtOH (2 mL) to afford 4-(7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile hydrochloride (205 mg, 63%) as a light brown solid. LCMS (ES): >90% pure, m/z 291 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([OH:13])=O)[O:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.O[NH:25][C:26](=[NH:28])[CH3:27]>O1CCCC1>[O:4]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]2[O:13][N:28]=[C:26]([CH3:27])[N:25]=2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)C1CCCCC12OCCO2
Reactant: CC(=N)NO
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1noc(C2CCCCC23OCCO3)n1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 60.2 %

Procedure:
A mixture of 1,4-dioxa-spiro[4.5]decane-6-carboxylic acid (3.72 g, 20 mmol), N,N-dicyclohexyl-carbodiimid (2.06 g, 22 mmol) and 1-hydroxy-benzotriazole (3.03 g, 22 mmol) in tetrahydrofuran (40 mL) was stirred at 0° C. for 3.5 h. N-Hydroxy-acetamidine (1.48 g, 20 mmol) was added to the mixture and stirring was continued at 20° C. for 18 h. The reaction mixture was cooled to 0° C. and insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure. Toluene (250 mL) was added to the remaining oil and the mixture was heated at reflux for 5 h, water being removed using a Dean-Stark trap. The solution was cooled, solvents were evaporated under reduced pressure, and the residual material was purified by column chromatography on silica gel (100 g) using heptane/20-80% ethyl acetate as eluent to give the title compound (2.70 g, 60%). Obtained as light-yellow oil. MS ISP (m/e): 225.1 [(M+H)+].
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.O>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Clc1cc2c(Cl)cccc2c(N2CCSCC2)n1
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 97 %

Procedure:
1-Thiomorpholino-3-piperazino-5-chloro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3,5-dichloro-isoquinoline and piperazine by heating in diphenyl ether at 200°C. M.p. of its hydrochloride: 273°-275°C (from water); yield: 97% of theory.
Reaction SMILES: Br[C:2]1[S:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[Br:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Br:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:10][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1sc2cnccc2c1Br
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: COCCOC
Product: Brc1c(-c2ccccc2)sc2cnccc12
Temperature: 100 °C
Yield: 34.7 %

Procedure:
A mixture of 2,3-dibromothieno[2,3-c]pyridine (500 mg, 1.71 mmol), phenylboronic acid (197 mg, 1.61 mmol), Pd(PPh3)4 (187 mg, 0.16 mmol), 2.0 M aqueous sodium carbonate (4 mL, 8 mmol) in DME (25 mL) was evacuated and refilled with nitrogen 3× and then heated in a microwave at 100° C. for 30 min. The reaction was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate and purified by ISCO chromatography (0 to 25% EtOAc:heptane) to afford 162 mg (35%) of the title compound as a white solid. 1H NMR (acetone-d6): δ 9.24 (s, 1 H), 8.65 (d, J=5.5 Hz, 1 H), 7.82 (dd, J=7.9, 1.5 Hz, 2 H), 7.76 (d, J=5.5 Hz, 1 H), 7.55-7.61 (m, 3 H); MS (ESI): 290.36, 292.34 [M+H]+; HPLC tR=1.25 min (HPLC: Analytical—2 min).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17]3)[CH:10]=2)[CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[N:16]1([CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:4]3[CH:3]=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])[N:7]=[CH:6][N:5]=3)[CH:14]=[CH:13][CH:12]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Nc2cccc(Cn3ccc4ccccc43)c2)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Nc2cccc(Cn3ccc4ccccc43)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
234 mg (6-Chloro-pyrimidin-4-yl)-(3-indol-1-ylmethyl-phenyl)-amine (pre-pared in Example 90) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water were added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (90 mg, 32% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: CS(O[CH:6]([C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH2:7][N:8]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])(=O)=O.[N-:52]=[N+:53]=[N-:54].[Na+]>CN1C(=O)N(C)CCC1.CCOC(C)=O>[C:34]([O:33][C:31](=[O:32])[N:8]([CH2:7][CH:6]([N:52]=[N+:53]=[N-:54])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:49])([F:50])[F:51])[CH:39]=1)[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:27])[CH3:28])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])([CH3:36])([CH3:37])[CH3:35]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The 1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl methanesulfonate from the previous reaction was dissolved in DMPU (15 mL) and treated with NaN3 (140 mg, 2.15 mmol). The reaction was stirred at room temperature for 15 hours and then diluted with EtOAc (75 ml). The solution was washed with H2O (5×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified with 20% EtOAc/hexanes to afford tert-butyl{2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.52 (15% EtOAc/hexanes). LCMS=605.3 (M+1−BOC)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.80 (s, 1H), 7.67 (s, 1H), 7.48 (s, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.01-7.11 (m, 2H), 6.89 (m, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.22-4.69 (m, 3H), 3.28 (s, 3H), 2.61-3.16 (m, 3H), 1.34 (s, 9H), 1.13-1.18 (m, 6H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]3[CH:2]=2)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1ccccn1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Solvent: CCO
Product: COc1cc(-c2cn3ccccc3n2)ccc1-c1ccccn1

Procedure:
To a solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (130 mg, 0.42 mmol) in ethanol (5 mL) was added 2-aminopyridine (40 mg, 0.42 mmol). The resulting reaction mixture was heated to reflux for 2 h and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and washed with a solution of saturated aqueous NaHCO3 (3×10 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:1 to 1:0) to afford 2-(3-methoxy-4-pyridin-2-ylphenyl)imidazo[1,2-a]pyridine as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.72 (d, 1H), 8.13 (d, 1H), 7.75 (s, 1H), 7.91 (d, 1H), 7.87 (d, 1H), 7.75 (s, 1H), 7.70 (dd, 1H), 7.66 (d, 1H), 7.57 (dd, 1H), 7.20 (m, 2H), 6.79 (dd, 1H), 4.00 (s, 3H) ppm. MS (ESI) 302 (M)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])=[CH:5][CH:4]=[N:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]=1[CH3:32].C(N(CC)CC)C>C1COCC1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[CH3:20])=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:28])=[CH:25][C:24]=1[CH3:32]
Reactant: CN1CCCC1COc1ccc(N)cc1-c1ccnn1C
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(OC[C@@H]3CCCN3C)c(-c3ccnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
A mixture of 3-(2-Methyl-2H-pyrazol-3-yl)-4-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine (64 mg, 0.23 mmole), 4-fluoro-3-methyl-benzoyl chloride (60 mg, 0.35 mmole), and triethylamine (63.4 μL, 0.46 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 92 mg, 95% yield). Exact mass calculated for C24H27FN4O2 422.2, found 423.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1.Cl[CH2:19][C:20](=[O:22])[CH3:21].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:19][C:20](=[O:22])[CH3:21])[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1
Reactant: CC(=O)CCl
Reactant: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(C)cc23)C1
Yield: 63.4 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (30 g, 0.13 mole), 1-chloro-2-propanone (23.6 g, 0.25 moles), and triethylamine (27.3 g, 0.27 moles) in 550 ml of absolute ethanol is stirred at reflux for 21 hours. The reaction mixture is evaporated, and the residue is partitioned between dichloromethane (700 ml) and water (500 ml). The two-phase mixture is made basic with conc. ammonium hydroxide, the layers are separated, and the aqueous phase is extracted with fresh dichloromethane. The combined organic layers are backwashed with water, dried over sodium sulfate, and evaporated. Recrystallization of the residue from absolute ethanol yielded the product (23.5 g), mp 136°-138° C.