Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:33])[CH3:32]
Reactant: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(C)=O)cc12)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A mixture of diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate (3.03 g), pyridine (3.63 g) and dichloromethane (93 ml) was ice-cooled. To the mixture was added acetic anhydride (1.88 g). The reaction mixture was stirred for 30 minutes under ice-cooling and then for 2 hours and 15 minutes at ambient temperature. Ice water was added to the mixture. The resultant mixture was extracted with chloroform. The organic layer was washed three times with water and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a column chromatography on silica gel (developing solvent: chloroform) and recrystallized from chloroform, ethyl acetate and hexane to give crystalline diethyl [(6-acetamido-4-quinazolinylamino)methylene]propanedioate (2.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].C(O[C:14]([SH:16])=[S:15])C.[K]>CN(C=O)C>[SH:16][C:14]1[S:15][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(Cl)c(N)c1
Reactant: CCOC(=S)S
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(S)nc2c1
Yield: 49 %

Procedure:
The title compound was prepared using the method of example 239, starting with 3-amino-4-chloro-benzonitrile (242) (9.0 g, 59.0 mmol), O-ethylxanthic acid, potassium salt (Lancaster, 21.23 g, 132.7 mmol) in DMF (90 mL). 5.6 g (49%) of compound 243 was obtained as a pale brown solid.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]([F:23])([F:22])[C:11]([F:21])([F:20])[C:12]([F:19])([F:18])[C:13](OCC)=[O:14]>>[F:18][C:12]([F:19])([C:11]([F:20])([F:21])[C:10]([F:9])([F:22])[F:23])[C:13](=[O:14])[CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)c1cccs1
Product: O=C(CC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1cccs1

Procedure:
The compound was synthesized according to example 1 using 2-acetylthiophene and ethyl heptafluorobutyrate as starting materials. 1H NMR (CDCl3): 6.49 (s, 1 H); 7.21 (dd, 1H, J=3.8 & 5.1); 7.77 (dd, 1H, J=1.2 & 5.1 Hz); 7.85 (dd, 1H, J=1.2 & 3.8 Hz). IR (film): 1589 (C═O); 1230 (C—F).
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C:10]1([F:16])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1.Br[CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20]>C(Cl)Cl>[F:9][C:10]1([F:16])[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][C:19]([OH:21])=[O:20])[CH2:11]1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: FC1(F)CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CN1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Triethylamine (0.660 mL, 4.76 mmol) was added to a solution of 3,3-difluoropiperidine-HCl (500 mg, 3.17 mmol) and benzyl 2-bromoacetate (763 mg, 3.33 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at ambient temperature for 2 h. The mixture was washed with 1 N aqueous sodium hydroxide and water, successively. The organic layer was concentrated and the residue was purified by flash column chromatography on silica gel (Hexane/EtOAc=25:1) to afford benzyl ester of 2-(3,3-difluoropiperidin-1-yl)acetic acid (486 mg, 56% yield) as a yellow oil.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.P([O-])([O-])([O-])=O.[OH:17][NH3+:18].O[NH3+].O[NH3+]>O>[OH:17][N:18]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: [NH3+]O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1O
Temperature: 130 °C

Procedure:
1.48 g (10.0 mmol) of phthalic anhydride and 0.723 g (3.67 mmol) of hydroxylammonium phosphate were pulverized, mixed and, following the addition of 2 ml of water, heated at a bath temperature of 130° C. for about 1½ hours. The cooled lemon-yellow reaction mixture was diluted with water, and the solid was filtered off with suction, washed with water and dried at 50° C. The yield was 1.39 g (86%).
Reaction SMILES: [CH2:1]([C@H:5]1[C@@H:10]([NH2:11])[CH2:9][CH2:8][C@@H:7]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([NH:48][C@@H:49]([C:51](O)=[O:52])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:1]([C@@H:5]1[CH2:6][C@H:7]([N:12]([CH:14]([CH3:15])[CH3:16])[CH3:13])[CH2:8][CH2:9][C@@H:10]1[NH:11][C:51](=[O:52])[C@H:49]([NH:48][C:41](=[O:42])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH3:50])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (1R,3R,4S)-3-butyl-N1-isopropyl-N1-methylcyclohexane-1,4-diamine (81 mg, 0.35 mmol; see Example 3a, Step 4) in 1:1 DMF/methylene chloride (5 mL) was charged successively with HATU (162 mg, 0.43 mmol), N-Boc D-Alanine (67 mg, 0.35 mmol), and N,N-diisopropylethylamine (0.31 mL, 1.77 mmol). The reaction was stirred for 16 h at RT, concentrated in vacuo, and diluted with EtOAc. The organic phase was washed successively with sat. NaHCO3, water, 1N HCl, water, and brine before being dried (sodium sulfate), filtered, and concentrated in vacuo to afford tert-butyl (R)-1-((1S,2R,4R)-2-butyl-4-(isopropyl(methyl)amino)cyclohexylamino)-1-oxopropan-2-ylcarbamate. MS found: (M+H)+=398.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Mg].II.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=1)#N.S(=O)(=O)(O)[OH:25]>C1COCC1>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[O:25])=[N:18][CH:19]=1
Reactant: O=S(=O)(O)O
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: N#Cc1ccc(O)cn1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)cc1)c1ccc(O)cn1
Temperature: 10 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 23.4 g (104 mM) of 1-bromo-4-trifluoromethylbenzene in 100 ml of THF is added dropwise to 2.53 g (104 mM) of magnesium metal and one crystal of iodine covered with 100 ml of THF. The mixture is stirred at the reflux temperature of the solvent for 2 hours and then cooled to 10° C. A solution of 5 g (42 mM) of 2-cyano-5-pyridinol in 80 ml of THF is then added dropwise. The mixture is refluxed for 2 hours and then stirred for 18 h at room temperature. It is treated with 120 ml of 0.5 N sulfuric acid and the solvents are evaporated off under reduced pressure. The medium is brought to neutral pH by washing with saturated sodium bicarbonate solution, extraction is carried out with ethyl acetate and the extract is dried over magnesium sulfate. After purification by chromatography on silica gel (eluent: toluene/ethyl acetate 8/2, then pure ethyl acetate and finally ethyl acetate/aqueous ammonia 95/5; v/v), the expected product is obtained in the form of a pale pink solid with a yield of 66%.
Reaction SMILES: [O-:1][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:17]([O:16][C:14]([N:8]([CH2:9][CH2:10][CH2:11][OH:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N+:2]=1[O-:1])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [O-][n+]1ccccc1NCCCO
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(OCc1ccccc1)N(CCCO)c1cccc[n+]1[O-]

Procedure:
3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino] propanol was prepared by reaction of 3-[N-(1-oxido-2-pyridinyl)amino] propanol (obtained as described in MILLER, W. H. et al. Bioorg. Med. Chem. Lett. 1999, 9 1807–1812) with benzyl chloroformate according to the standard procedure.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[S:18]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:20])(=[O:19])[CH3:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OCCOS(C)(=O)=O
Reaction time: 2 h

Procedure:
Combine 2-isopropoxyethanol (1.0 g, 9.6 mmol), N,N-diisopropylethylamine (2.73 g, 21.12 mmol), and dichloromethane (20 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (1.43 g, 9.6 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with 1 M hydrochloric acid solution, a saturated solution of sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give 2-(isopropoxy)ethyl mesylate: bp; 84° C. at 0.1 mm Hg.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[CH:14]=[CH:13][CH:12]=[N:11][C:5]=1[NH:6]2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:15]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2[CH:14]=[CH:13][CH:12]=[N:11][C:5]=2[NH:6]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cccc2[nH]c3ncccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(-c2cccc3[nH]c4ncccc4c23)cc1
Temperature: 150 °C
Yield: 20.2 %

Procedure:
Compound 4 (20 mg, 0.081 mmol) was mixed with phenylboronic acid (20 mg, 0.16 mmol) and Tetrakis Pd(0) catalyst (19 mg, 0.016 mmol) in a solution comprising dioxane (3 ml) and a saturated K2CO3 solution (1 ml). The mixture was heated in a microwave reactor at 150° C. for 20 minutes. Purification by HPLC afforded the title compound as a tan solid (4 mg, 22%). 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1 H) 8.10 (d, J=7.84 Hz, 1 H) 7.67 (m, 2 H), 7.60 (m, 5 H) 7.27 (m, 2 H). [M+H] calc'd for C17H12N2, 245; found 245.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19]C(NC1SC=CN=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:28]([CH2:19][CH2:18][CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:29]=[N-:30]
Reactant: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1nccs1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCC1c2ccccc2C(=O)N1Cc1ccccc1

Procedure:
The product from Example 1, Part B (2.0 g, 7.5 mmol), sodium azide (731 mg, 11.25 mmol), and K2CO3 (3.1 g, 225 mmol) were stirred in 20 mL DMF at 50° C. for 16 h. The mixture was poured into water and washed with EtOAc. The organic phase was washed with water and brine, then dried (Na2SO4), filtered and evaporated. The title compound was purified by silica gel chromatography (2.04 g, 93%).
Reaction SMILES: C([O:8][C:9](=[O:44])[CH2:10][C@@H:11]([C:25]1[CH:29]=[CH:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[CH:26]=1)[C:12]([NH:14][C@H:15]([C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])C1C=CC=CC=1>CCO.C1COCC1>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH:28]=[CH:29][C:25]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20]4[NH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH2:10][C:9]([OH:44])=[O:8])=[CH:26]3)=[CH:35][CH:34]=2)=[CH:37][CH:38]=1)#[N:43]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)c1ncc[nH]1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)c1ncc[nH]1
Yield: 54 %

Procedure:
According to the procedure described in Example 1(a), 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid benzyl ester was hydrogenolyzed in EtOH/THF for 3 h to give a 54% yield of 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid: mp 206-210° C. (dec); 1HNMR (DMSO-d6): δ 12.0 (bs, 1H), 8.31 (d, 1H, J=8.45 Hz), 7.93 (s, 4H), 7.86 (d, 2H, J=8.5 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.33-7.30 (m, 2H), 6.81 (s, 2H), 6.18 (s, 1H), 5.02 (dd, 1H, J=15.8, 8.8 Hz), 3.86 (dd, 1H, J=9.6, 4.8 Hz), 2.87 (dd, 1H, J=16.9, 10.3 Hz), 2.60 (dd, 1H, J=16.5, 4.8 Hz), 1.7-1.5 (m, 3H), 0.87 (d, 3H, J=6.6 Hz), 0.84 (d, 3H, J=5.9 Hz); HRFABMS Calculated for C29H29N5O3Cs (M+Cs): 628.1325 Found: 628.1335
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][CH3:14])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5]CN.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17].[CH2:20]([N:22](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][CH3:14])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:22]([CH3:20])[C:15](=[O:18])[CH:16]=[CH2:17]
Reactant: C=CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCCOc1c(Cl)cccc1CCN
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cccc(Cl)c1OCCC
Reaction time: 0.08 h
Yield: 87.9 %

Procedure:
To a solution of (3-chloro-2-propoxybenzyl)methylamine (0.435 g, 2.04 mmol) in CH2Cl2 (18 mL) was added acryloyl chloride (0.18 mL, 2.24 mmol) drop-wise. After stirring for five minutes, triethylamine (0.531 mL, 2.24 mmol) was added. The solution was stirred under N2 for 18 h. The solution was diluted with CH2Cl2 (30 mL) and then washed with H2O (3×50 mL) and brine (2×100 mL), dried over Na2SO4, filtered and concentrated to yield the title compound (0.48 g, 89%) as a light yellow oil and as a mixture of amide rotamers: 1H NMR (500 MHz, CDCl3) δ 7.31-7.26 (m, 1H), 7.10-6.98 (m, 2H), 6.63-6.37 (m, 2H), 5.77-5.73 (m, 1H), 4.76-4.65 (m, 2H), 3.94-3.89 (m, 2H), 3.01 (s, 3H), 1.89-1.82 (m, 2H), 1.11-1.05 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:11][C:3]=12.[C:19]([Zn]C#N)#[N:20].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CN(C=O)C>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].O>[CH3:8][C:6]1[CH:7]=[C:2]([C:19]#[N:20])[C:3]2[CH:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:5]=1
Reactant: N#C[Zn]C#N
Reactant: Cc1cc(Br)c2cnn(Cc3ccccc3)c2n1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C#N)c2cnn(Cc3ccccc3)c2n1
Temperature: 120 °C

Procedure:
A mixture of 4-bromo-6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine (3.45 g, 11.42 mmol), dicyanozinc (1.542 g, 13.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.523 g, 0.571 mmol), SPhos (0.562 g, 1.370 mmol), DMF(49 mL), and water (0.5 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was heated at 120° C. for 2 hours, and then cooled to room temperature. The contents were concentrated to 50% volume and then 50 mL of 1N NaOH and 50 mL of EtOAc were added. The solids were filtered off. The phases were separated and the aqueous phase extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with water (3×50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product containing SPhos reagent (˜30-40%) was collected as 3.69 g and used without further purification. LCMS E-S (M+H)=249.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.77 (s, 3 H), 5.73 (s, 2 H), 7.08-7.44 (m, 6 H), 8.16 (s, 1 H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C(N1CCN([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)CC1)(=O)C.Cl.O1[CH2:55][CH2:54]OCC1>CC(O)C>[CH3:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:48][C:45]3[CH:44]=[CH:43][CH:42]=[C:47]([CH2:2][N:3]4[CH2:55][CH2:54][CH2:5][CH2:4]4)[CH:46]=3)[N:7]=2)[CH:16]=1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)Cc4cccs4)c3)nn2c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2c(-c3ccnc(Nc4cccc(CN5CCCC5)c4)n3)c(-c3cccc(NC(=O)Cc4cccs4)c3)nn2c1
Yield: 50 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (60 mg, 0.13 mmol), [4-(4-acetyl-1-piperazinyl)phenyl]amine (35 mg, 0.16 mmol), and 4N HCl in dioxane (0.04 mL) were combined in i-PrOH (3 mL) and microwaved for 10 min. at 180° C. to afford the title compound as a yellow solid (42 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.27 (s, 1H), 8.63 (s, 1H), 8.15 (d, J=5.1 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.40-7.35 (m, 2H), 7.30 (d, J=9.8 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 6.95-6.93 (m, 2H), 6.84 (d, J=8.7 Hz, 2H), 6.41 (d, J=5.0 Hz, 2H), 3.84 (s, 2H), 3.56-3.52 (m, 4H), 3.03 (t, J=4.6 Hz, 2H), 2.96 (t, J=4.7 Hz, 2H), 2.34 (s, 3H), 2.01 (s, 3H). ES-LC/MS m/z=643 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20].C(=O)(O)[O-].[Na+]>CC#N>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[C:19](=[O:20])[CH2:18][N:14]1[CH2:15][CH2:16][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:12][CH2:13]1
Reactant: O=C(CBr)N1CCc2ccccc2C1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CN1CCC(c2n[nH]c3cc(F)ccc23)CC1)N1CCc2ccccc2C1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.8 g, 18.9 mmol) in CH3CN (200 ml) was added 2-bromo-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethanone (4.8 g, 18.9 mmol) and sodium bicarbonate (1.9 g, 22.7 mmol) at room temperature. The reaction mixture was warmed to reflux (4 hours), cooled to room temperature and filtered through a pad of celite. The solids were washed with DCM and the combined filtrates were concentrated. The remaining residue was purified via preparative HPLC (silica gel, 5-10% MeOH/DCM) to give 4.1 g of 1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethanone which was used without further purification. To a suspension of the latter (3.7 g, 9.4 mmol) in THF (100 ml) was added (dropwise) lithium aluminum hydride (11.3 ml of 1.0M solution in THF, 11.3 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux (5 hours), cooled to room temperature and carefully quenched with water (10 ml). The precipitated salts were removed via filtration and washed with 1:1 EtOAc/DCM. The combined filtrates were concentrated, and the remaining oil was purified via flash column chromatography (silica gel, 10% MeOH/DCM) to give 2.2 g of the product. The dimaleate salt was prepared in methanol (30 ml) with maleic acid (3.0 eq.), m.p. 185°-187° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34](O)=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:70][CH:71]1[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]1>CN(C=O)C.C(OCC)(=O)C>[C:80]([O:79][C:77]([N:74]1[CH2:73][CH2:72][CH:71]([NH:70][C:34]([C:10]2[CH:11]=[C:12]([C:23]3[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:32][CH3:33])[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:35])[CH2:76][CH2:75]1)=[O:78])([CH3:83])([CH3:82])[CH3:81]
Reactant: COc1ccc(C(C)C)cc1-c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid (4.4 g, 9.2 mmol), diisopropylethylamine (3.2 ml, 18.3 mmol) and HBTU (5.2 g, 13.7 mmol) in anhydrous DMF (44 ml) was charged 4-amino-1-N-Boc-piperidine (2.3 g, 11.4 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with water. The organics were then dried (Na2SO4), filtered and evaporated to yield 4-[(4,6-bis-benzyloxy-5′isopropyl-2′methoxy-biphenyl-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a brown solid (6.1 g, quant.), carried forward without further purification. M.p.: 168-170° C.; 400 MHz 1H NMR (CDCl3) δ: 8.16 (s, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.42 (s, 4H), 7.34-7.26 (m, 6H), 7.18 (dd, J=8.4, 2.0 Hz, 1H), 7.14 (s, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.64 (s, 1H), 5.12 (s, 2H), 5.05 (s, 2H), 4.07 (m, 1H), 3.73 (s, 3H), 3.56 (br s, 2H), 2.90 (m, 2H), 1.78 (d, J=7.2 Hz, 2H), 1.57 (s, 1H), 1.47 (s, 9H), 1.24 (d, J=7.2 Hz, 6H), 1.08 (m, 2H); LCMS: 576 [M+H].
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.Cl.N1CC[O:11][CH2:10][CH2:9]1.O.[Cl:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](CC=O)=[CH:22][CH:21]=1>O1CCOCC1>[Cl:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:3]2[CH:2]([OH:6])[O:5][C:10](=[O:11])[CH:9]=2)=[CH:22][CH:21]=1
Reactant: C1COCCN1
Reactant: O=CC(=O)O
Reactant: O=CCc1ccc(OCCCCl)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1C=C(c2ccc(OCCCCl)cc2)C(O)O1

Procedure:
A suspension of glyoxalic acid hydrate (3.04 g, 33.1 mmol) and morpholine hydrochloride (4.09 g, 33.1 mmol) in dioxane (48 mL) was stirred as 4.5 mL of water was added. To the homogeneous solution [4-(3-chloropropoxy)phenyl]acetaldehyde (6.70 g, 31.5 mmol) was then added and the solution was stirred at reflux for 24 h. The solvent was evaporated and 50 mL of water was added. The solid was collected and washed with water to give 8.3 g (98%): MS m/z 251 (M−17+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3](=[CH:7][CH:8]=1)[C:4]([Cl:21])=[C:17]1[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]1)=[N:1]2
Reactant: O=C1CCCCC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: Clc1ccc2c(Cl)c3c(nc2c1)CCCC3
Yield: 98.2 %

Procedure:
To a mixture of 2-amino-4-chlorobenzoic acid (4.5 g, 26.23 mmol) and cyclohexanone (2.72 mL, 26.23 mmoL) was added 22 mL phosphorus oxychloride. The mixture was heated to reflux for 3 hours. The excess phosphorus oxychloride was distilled off and the resulting mixture was treated with saturated sodium bicarbonate. The light brown precipitate was filtered, rinsed with water and dried under vacuum to give the desired product 6.50 g (25.77 mmoL, 98.2%).