Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[NH:13][CH:14]=[C:15]([CH3:23])[C:16]=1[CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].[OH-].[Na+]>ClCCl>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C:16]1[C:15]([CH3:23])=[C:14]([CH:3]=[O:4])[NH:13][C:12]=1[CH3:11]
Reactant: Cc1c[nH]c(C)c1CCCN(C)C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
To the ice-cooled solution of N,N-dimethylformamide (6.0 mL, 76 mmol) in dichloromethane (30 mL) was added phosphorus oxychloride (7.0 mL, 76 mmol) dropwise. Upon addition of phosphorus oxychloride, the reaction mixture was stirred at room temperature for 15 minutes and a solution of [3-(2,4-dimethyl-1H-pyrrol-3-yl)-propyl]-dimethyl-amine (6.8 g, 38 mmol) in dichloromethane (20 mL) was added dropwise at 0° C. The final reaction mixture was refluxed at 60° C. for 4 hours and cooled with ice bath. Ice cube was added to the reaction mixture slowly followed by addition of 2 N sodium hydroxide to adjust pH to 12. The reaction mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic-layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude product which was purified on a silica gel column eluting with dichloromethane-methanol-ammonium hydroxide (9:1:0.01) to give 5 g (63%) of 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde as a dark red oil.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:15][C:14](=[O:16])[C@@H:13]2[CH2:17][CH2:18][CH2:19][N:12]2[C:10](=[O:11])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of 3.0 g (11.6 mmol) of N-BOC-glycylproline and 1.93 g (13.9 mmol) of 4-nitrophenol in 82 mL of dry THF was cooled to 0° C. and 3.34 g (16.2 mmol) of DCC was added. The mixture was stirred at 0° C. for 1 hour, the ice bath was removed, and the mixture was stirred for 16 hours at room temperature. HOAc (579 μL) was added to the mixture and it was allowed to stir for 30 minutes. The mixture was kept in the freezer for 30 minutes and filtered under vacuum. The filtrate was concentrated and purified by silica gel chromatography (18×150 mm bed, 2.5% EtOAc/97.5% CH2Cl2/1% HOAc). Traces of acetic acid were removed by concentrating from dioxane several times on the rotary evaporator. The concentrate was triturated with 3/1 hexane Et2O and the resulting white solid was collected by filtration to give 4.1 g (90%) of compound 15 as a white solid; TLC Rf 0.09, 40/60/1 EtOAc/hexane/HOAc; 1H NMR(CDCl3) δ 1.09-2.55 (m, 4H), 1.48 (s, 9H), 3.47-3.77 (m, 2H), 4.05 (m, 2H), 4.74 (m, 1H), 5.45 (bd s, 1H), 7.35 (d, 2H), 8.30 (d, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>ClCCl.C(O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:12](=[O:14])/[CH:11]=[CH:10]/[C:7]3[CH:6]=[CH:5][C:4]([CH:3]([O:2][CH3:1])[O:15][CH3:16])=[CH:9][CH:8]=3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: COC(OC)c1ccc(/C=C/C(=O)O)cc1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: COC(OC)c1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.1.e. from (E)-3-(4-dimethoxymethylphenyl)acrylic acid and 4′-chlorobiphenyl-4-ylamine. Yield: 9.8 g, C24H22ClNO3 (M=407.90); calc.: molecular ion peak (M+H)+: 408/410; found: molecular ion peak (M+H)+: 408/410; Rf value: 0.3 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: C(OC([N:8]1[CH:16]2[CH:11]([CH2:12][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([C:33]5[CH:41]=[C:40]([F:42])[CH:39]=[C:38]6[C:34]=5[CH:35]=[CH:36][NH:37]6)=[N:21][C:20]=4[CH:19]=3)[CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:42][C:40]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][NH:37]2)=[C:33]([C:22]2[N:23]=[C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:25]3[S:26][C:18]([CH2:17][N:13]4[CH2:14][CH2:15][CH:16]5[NH:8][CH2:9][CH2:10][CH:11]5[CH2:12]4)=[CH:19][C:20]=3[N:21]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CN(Cc3cc4nc(-c5cc(F)cc6[nH]ccc56)nc(N5CCOCC5)c4s3)CCC21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCC5NCCC5C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared by BOC-deprotection of 5-[2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-octahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester using TFA:DCM (1:6). The title compound was obtained as a white solid (8.3 mg, 7%).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[N:13][CH:14]=1)=[O:7])([O-])=O.CO>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)=[N:13][CH:14]=1)=[O:7]
Reactant: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Into a 50-mL 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 2-nitro-5-(piperidin-1-yl)-N-(2-(3-(trifluoromethyl)phenyl)pyrimidin-5-yl)benzamide (250 mg, 0.53 mmol, 1.00 equiv), methanol (15 mL), and ethyl acetate (5 mL). The mixture was treated with Pd/C (0.1 g, 0.10 equiv) and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 0.23 g (98%) of product as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].IC.[C:18](=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[CH3:18][O:14][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:6]=1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: COCCOc1nc(C(=O)O)ccc1Br
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1nc(C(=O)OC)ccc1Br
Yield: 66.7 %

Procedure:
A solution of 5-bromo-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid (2.48 g, 9 mmol), iodomethane (2.55 g, 18 mmol) and sodium carbonate (0.106 g, 9 mmol) in DMF (30 mL) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed three times with brine, dried (sodium sulfate) and evaporated. The residue was purified by column chromatography (silica gel, 50 g, 30% ethyl acetate in petroleum ether) to yield the title compound (1.7 g, 6 mmol, 65%) as yellow solid; MS (EI): m/e 290.0 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:16][CH:15]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Nc2c(C)cccc2[N+](=O)[O-])cc1

Procedure:
The product (487 mg) is obtained according to the method of stage 1 of Example 4, by using 1 g of 2-fluoro-3-methyl-nitrobenzene and 1.19 g of 4-methoxyaniline in the presence of 1.16 g of potassium tert-butanolate in 9 mL of DMSO.
Reaction SMILES: Cl.C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18]Cl)[CH2:13][CH2:12]1>C(O)(C)C>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]1
Reactant: CN1CCN(CCCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCN1CCN(C)CC1
Yield: 250.2 %

Procedure:
A solution of 3.75 g of raubasinic acid hydrochloride in 100 ml of anhydrous isopropanol in the presence of 3.20 g of anhydrous sodium carbonate is heated under reflux with agitation and in nitrogen atmosphere with 2.35 g of 1-methyl-4β chlorethylpiperazine dihydrochloride. After 4 hours the mixture is treated as in Example 1. One obtains 3.2 g of 1-methyl-4β ethylpiperazine raubasinate hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.[CH3:12][N:13]1[C:17]([C@@H:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[N:16][C:15]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][N:28]=[C:27]3[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[N:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:18]([C:17]2[N:13]([CH3:12])[N:14]=[C:15]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][N:28]=[C:27]4[C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[N:16]=2)[CH2:19]1
Reactant: Cn1nc(-c2ccc3[nH]nc(-c4ccncc4)c3c2)nc1[C@@H]1CCCNC1
Reactant: COc1cccc(F)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(F)c1CN1CCC[C@@H](c2nc(-c3ccc4[nH]nc(-c5ccncc5)c4c3)nn2C)C1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
Added 2-Fluoro-6-methoxy benzaldehyde (20 mg, 0.129 mmol) to a solution of (R)-5-(1-methyl-5-(piperidin-3-yl)-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole (15 mg, 0.0379 mmol) and sodium triacetoxyborohydride (25 mg, 0.118 mmol) in MeOH (4 ml) at room temperature, then stirred for 2 hours. Reaction was diluted with CH2Cl2 (50 ml) and H2O (25 ml), organic layer was separated, dried over Na2SO4, filtered and solvent evaporated. The residue was chromatographed on silica gel eluting with 5% v/v MeOH/CH2Cl2/NH4OH to yield (R)-5-(5-(1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole as a white solid (12 mg).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH:25]2[CH:34]3[CH:29]([CH:30]=[CH:31][C:32]([NH2:35])=[CH:33]3)[CH2:28][CH2:27][CH2:26]2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.CO>C(O)(C)C.C(OCC)C>[NH:20]1[CH:24]=[C:23]([CH:25]2[CH:34]3[CH:29]([CH:30]=[CH:31][C:32]([NH2:35])=[CH:33]3)[CH2:28][CH2:27][CH2:26]2)[N:22]=[CH:21]1
Reactant: NC1=CC2C(C=C1)CCCC2c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: CCOCC
Product: NC1=CC2C(C=C1)CCCC2c1c[nH]cn1

Procedure:
A mixture of 7.7 g of the product obtained in Step 3, 4.2 ml of concentrated hydrochloric acid and 100 ml of methanol is heated at reflux for 2 hours. After concentration of the solvent, the residue is taken up in an isopropanol/diethyl ether mixture. The expected product is obtained by filtering off the precipitate.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CC([O-])(C)C.[Na+].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>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:17]1([CH2:16][CH2:15][NH:14][C:2]2[C:10]3[O:9][CH:8]=[CH:7][C:6]=3[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cc(NCCN2CCOCC2)c2occc2c1
Yield: 97 %

Procedure:
7-Iodo-5-nitrobenzofuran (1.00 g, 3.46 mmol), 4-(2-aminoethyl)morpholine (0.54 g, 4.15 mmol), NaOt-Bu (0.47 g, 0.00484 mol), Xantphos (0.20 g, 0.346 mmol) and Pd2 dba3 (80 mg, 0.0865 mol) were heated in xylene (20 mL) at 120° C. for 1.5 hours. The reaction mixture was filtered through Celite and the solvent evaporated. The residue was run through a silica plug using dichloromethane (DCM) and then a 90:9:1 mixture of DCM/MeOH/NH3 (aqueous 25%) as eluents. The product-containing fractions were concentrated to yield 0.978 g (97%) of the title compound as a dark yellow oil. HPLC purity=97%, m/z=292 (M+H)+, 1H NMR (270 MHz, CDCl3) δ ppm 2.44-2.61 (m, 4H) 2.75 (t, J=5.81 Hz, 2H) 3.31-3.43 (m, 2H) 3.69-3.82 (m, 4H) 6.85 (d, J=1.98 Hz, 1H) 7.36 (d, J=1.98 Hz, 1H) 7.70 (d, J=1.98 Hz, 1H) 7.90 (d, J=2.23 Hz, 1H).
Reaction SMILES: CO[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[NH:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11][OH:12]>C1COCC1>[F:7][C:4]([F:5])([F:6])[C:3]([N:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11][OH:12])=[O:8]
Reactant: OCCNCCO
Reactant: COC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(N(CCO)CCO)C(F)(F)F
Temperature: 25 °C

Procedure:
Methyltrifluoroacetate (25 g, 195.3 mmol) was added drop wise to an ice cooled stirred solution of 2,2′-iminodiethanol (20.5 g, 195 mmol) in anhydrous THF (100 mL). The reaction mixture was allowed to warm to ambient temperature naturally and stirred over night at ambient temperature. The solvent was evaporated via rotary evaporation to yield the title compound as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:19][B:18](B2OC(C)(C)C(C)(C)O2)[O:17]1.CC([O-])=O.[K+]>O1CCOCC1.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]>[O:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:5]2[N:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1ccc(N2CCCOCC2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: OB(O)c1ccc(N2CCCOCC2)nc1
Yield: 31.9 %

Procedure:
A solution of 4-(5-bromopyridin-2-yl)-1,4-oxazepane (600 mg, 2.33 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.18 g, 4.67 mmol), Pd(dppf)Cl2 (286 mg, 0.35 mmol) and KOAc (687 mg, 6.99 mmol) in 30 ml of dioxane, under N2, was stirred at 110° C. for 3 hours. The volatiles were removed in vacuo, and the residue was purified by chromatography with EA/MeOH (20:1˜5:1) to give 165 mg of 6-(1,4-oxazepan-4-yl)pyridin-3-ylboronic acid. MS (m/z)=223 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:14][NH2:15]>CCO>[NH:14]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1)[NH2:15]
Reactant: Clc1cnc2cc(Cl)c(Cl)cc2n1
Reactant: NN
Solvent: CCO
Product: NNc1cnc2cc(Cl)c(Cl)cc2n1

Procedure:
To the 2,6,7-trichloroquinoxaline was added anhydrous EtOH (500 ml) to give a brown solution. 5.0 g (156 mmol) anhydrous hydrazine were added dropwise under N2, turning the solution red immediately. The solution was heated at reflux for 1 hour, cooled and the resulting solid was collected. Recrystallization from 1500 ml 95% EtOH yielded 13.0 g of 2-hydrazino-6,7 dichloroquinoxaline
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:18][C:19]([F:28])([F:29])[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:13]2[N:12]=[C:11]([C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)[CH:16]=[N:15][CH:14]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Yield: 20.4 %

Procedure:
Using Method K, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 4-(trifluoromethoxy)aniline (51 mg, 0.29 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 80° C. for 12 hours. The same workup as for Method K and a combination of column chromatography and preparative TLC furnished 19 mg of title compound. Yield: 20.4%. 1H NMR (250 MHz, DMSO-d6) δ 2.10 (s, 3 H), 7.34-7.47 (m, 3 H), 7.60 (d, 1 H, 7.9 Hz), 7.74 (d, 1 H, 7.8 Hz), 8.00 (d, 2 H, 9.1 Hz), 8.21 (s, 1 H), 8.51 (bs, 2 H), 9.82 (s, 1 H), 10.10 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.09, 117.01, 119.09, 119.87, 120.94, 121.68, 129.15, 130.40, 133.52, 136.73, 139.92, 141.96, 141.99, 147.66, 151.00, 168.45; m/z 389.3 [(M+H)+, calcd for C19H15F3N4O2 388.1].
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[C:23]([F:25])[N:22]=[C:21]([F:26])[CH:20]=2)[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([CH:33]([NH2:35])[CH3:34])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:20]=[C:21]([F:26])[N:22]=[C:23]([F:25])[CH:24]=2)[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([CH:33]([NH:35][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:34])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2ccccc2)c1-c1cc(F)nc(F)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2ccccc2)c1-c1cc(F)nc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (36 mg, 0.18 mmol), 1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanamine (60 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.058 mL, 0.33 mmol) in isopropyl alcohol (0.6 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C25H20ClF2N6 (M+H)+: m/z=477.1. found: 477.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1cccc(Cl)c1
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2cccc(Cl)c2)N1

Procedure:
The same method as employed in the preparation of intermediate 1 and 2 but starting from racemic tryptophan methyl ester and 3-chlorobenzaldehyde gave the title compound as white solid m.p.:150-160° C.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([OH:12])([CH2:5]3)[CH2:3]1)[CH2:9]2.C(OC(=O)C)(=[O:15])C.OC12CC3CC(CC(C3)C1)C2>>[OH:1][C:2]12[CH2:11][C:6]3([OH:15])[CH2:7][CH:8]([CH2:10][C:4]([OH:12])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: CC(=O)OC(C)=O
Agent: OC12CC3CC(CC(C3)C1)C2
Product: OC12CC3CC(O)(C1)CC(O)(C3)C2

Procedure:
One mol of 1,3-dihydroxyadamantane was stirred in an acetic acid-acetic anhydride solution of CrO3, oxidizing agent, with heating. After carrying out the reaction for 8 hours, the reaction solution was neutralized to obtain a mixture of polyhydroxylated compounds of hydroxyadamantane. This mixture was partitioned by high performance liquid chromatography to obtain 1,3,5-trihydroxyadamantane.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]I)=[CH:37][CH:36]=1.C(OC(C)C)(C)C>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:39][C:38]2[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(CI)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1

Procedure:
2.98 g (9.74 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one dissolved in 40 ml of THF are deprotonated at -75° C. with 19.5 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated with 2.9 g (11.7 mmol) of p-methoxybenzyl iodide in 20 ml of THF (45 min). Column chromatography (SiO2, hexane/ethyl acetate 2:1) and digestion using diisopropyl ether yield the pure title compound; TLC Rf (D)=0.32; tRet (I)=16.7 min.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][N:32]([CH:34]([CH3:36])[CH3:35])[CH:33]=4)[N:21]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37].CO>O1CCOCC1>[ClH:37].[CH:34]([N:32]1[CH:33]=[C:29]([C:22]2[N:21]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)[CH:30]=[N:31]1)([CH3:36])[CH3:35]
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reaction time: 2 h
Yield: 117.3 %

Procedure:
To a suspension of tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.090 g, 0.185 mmol) in 1.5 mL of dioxane was added hydrogen chloride (1.8 mL, 7.20 mmol) in dioxane at ambient temperature with stirring. After 2 hours, 0.5 mL of methanol was added to dissolve all solids and the reaction was concentrated under reduced pressure. The crude was suspended in DCM, sonicated, and concentrated three times and the resulting crude was dried on high vacuum for 3 hours to afford 2-(3-(4-(7-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (0.116 g, 0.217 mmol, 93% yield). MS (apci) m/z=388.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[CH:3]=1.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:23][N:24]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CNc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(c1ccccc1)c1cc(Nc2cccc(NC(=O)OC(C)(C)C)c2)ncn1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl 3-(6-chloropyrimidin-4-ylamino)phenylcarbamate (1.6 g, 5 mmol) and N-methylaniline (1.07 g, 10 mmol) was heated at 120° C. in a sealed tube for 2 hr. The reaction mixture was cooled to RT, mixed with 1 mL of 1N NaOH and 5 mL of DCM, stirred for 30 min, the product was filtered and dried under vacuum to give a solid product. MS (m/z): MH+=392.