Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)CC(NC2C=CC(F)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:8][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]
Reactant: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccncc2[N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
To 4-amino-2-fluorophenol (see Step A of Example 19, 127 mg, 1.0 mmol) in DMF (5 mL) at rt under nitrogen was added sodium hydride (80 mg, 2 mmol, 60%). After stirring at rt for 10 min, 4-chloro-3-nitropyridine hydrochloride (Lancaster, 195 mg, 1.0 mmol) was added. The mixture was stirred at rt for 1 h and was then diluted with EtOAc (50 mL) and washed with water, 10% aqueous lithium chloride solution, and then brine (1×30 mL each). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc to give the title compound (150 mg, 60%) as a yellow-orange solid. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.63 (d, 1H, J=6 Hz), 7.09 (t, 1H, J=9.2 Hz), 6.92 (d, 1H, J=6 Hz), 6.55 (dd, 1H, J=13.2, 2.4 Hz), 6.45 (dd, 1H, J=9.2, 2.4 Hz), 5.61 (s, 2H); MS (ESI+) m/z 250.18 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][CH:16]([F:32])[C:17]1[CH:18]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:21][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>COCCOC.O.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]>[F:15][CH:16]([F:32])[C:17]1[CH:22]=[C:21]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cccc(C(F)F)c2)OC1(C)C
Reactant: O=C(O)c1cccc2ccc(Cl)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccc2ccc(-c3cccc(C(F)F)c3)nc12
Temperature: 85 °C
Reaction time: 12 h
Yield: 80.2 %

Procedure:
To a solution of 2-chloroquinoline-8-carboxylic acid (3.1 g, 15.0 mmol) in DME (20 mL) and water (2 mL) was added 2-(3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.5 g, 17.7 mmol), K3PO4 (5.2 g, 22.6 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.50 g, 0.63 mmol). The reaction mixture was stirred under nitrogen at 85° C. for 12 hours, then the reaction was cooled to room temperature and water (20 mL) was added. The mixture was filtered and the filter cake was washed with water, and the solid was dried in vacuo to give 2-(3-(difluoromethyl)phenyl)quinoline-8-carboxylic acid (3.6 g, 80% yield).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C>CCO>[NH2:19][C:18]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[N:10]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1cnn(-c2ccc(F)cc2)c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A flask was charged with (4-fluorophenyl)hydrazine hydrochloride (50.9 g, 313 mmol), EtOH (320 mL) and 2-(ethoxymethylene)malononitrile (40.1 g, 329 mmol). The stirred suspension was treated with TEA (45.8 mL, 329 mmol). After about 10 min the mixture was warmed in an oil bath heated to about 80° C. for about 1.5 h. The mixture was allowed to cool and stir overnight at rt. The solvent was removed under reduced pressure then the material was stirred with water (300 mL). After about 30 min the solids were collected by filtration, washed with water (3×100 mL) and dried under vacuum at about 65° C. to yield 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (110, R1=4-Fluorophenyl) (56.2 g, 89%); LC/MS, method 3, Rt=1.64 min, MS m/z 201 (M−H)—. 1H NMR (400 MHz, DMSO) δ 7.77 (s, 1H), 7.59-7.45 (m, 2H), 7.43-7.27 (m, 2H), 6.68 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH:7]([OH:26])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[CH:16]([OH:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:9]=1.[OH-].[Na+]>CO>[OH:26][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[CH:16]([OH:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:9]=1)[CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2]
Reactant: CCCCCCCCC(O)/C=C/c1cccc(C(O)CCCC(=O)OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(C(O)CCCC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
A solution of 140 mg of (5RS)-5-hydroxy-5-{6-[(1E)-(3RS)-3-hydroxy-1-undecenyl]-2-pyridyl)-pentanoic acid methyl ester in 6 ml of methanol is mixed with 6 ml of 0.5 n sodium hydroxide solution and stirred for 2 hours at room temperature. The methanol is removed in a vacuum, the residue is acidified to pH 4 with 0.5 n sulfuric acid, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. 125 mg of the title compound is thus obtained as colorless oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].Br[CH2:8][C:9]1[C:13]2[CH:14]=[C:15]([N:18]3[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]3=[O:30])[CH:16]=[CH:17][C:12]=2[S:11][N:10]=1.C(OCC)C>O1CCCC1.C(Cl)Cl.O>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH2:8][C:9]1[C:13]2[CH:14]=[C:15]([N:18]3[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]3=[O:30])[CH:16]=[CH:17][C:12]=2[S:11][N:10]=1
Reactant: COC(=O)CS
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COC(=O)CSCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12

Procedure:
A mixture of hexanes washed sodium hydride (0.0360 g of a 60% dispersion in oil, 0.900 mmol) in tetrahydrofuran is treated with methyl thioglycolate (90.0 mL, 1.00 mmol), stirred until gas evolution stops, treated dropwise with a solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.300 g, 0.710 mmol) in tetrahydrofuran, stirred for 10 minutes, and concentrated in vacuo to obtain a residue. The residue is diluted with methylene chloride and water. The organic phase is separated, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and a 5% diethyl ether in methylene chloride solution gives the title product as a clear oil which is identified by 1H NMR spectral analysis.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[C:21]=1[O:22]C)[C:6]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].B(Br)(Br)Br.C(O)C>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[C:21]=1[OH:22])[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.1 g of diethyl (3,4-dimethoxy-5-nitrobenzoyl)-malonate are dissolved in 200 ml of methylene chloride, whereupon the solution is cooled to -20° and at this temperature there is added dropwise while stirring within 15 minutes a solution of 68.1 g of boron tribromide in 120 ml of methylene chloride. The mixture is subsequently stirred at room temperature overnight. After cooling to -20° , the mixture is treated with 300 ml of ethanol and stirred at room temperature for 30 minutes. The solvent is distilled in a water-jet vacuum at 40° . The residue is treated with 300 ml of ice-water and methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product obtained is chromatographed on a 10-fold amount of silica gel with toluene. After crystallization from methylene chloride/hexane there is obtained ethyl (3,4-dihydroxy-5-nitrobenzoyl)acetate in the form of yellow crystals of m.p. 136°-137°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCCC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCCC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 23.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.3 g) and 5-amino-2-pyrrolidinobenzonitrile (0.8 g), the title compound (0.4 g) was obtained, melting point: 205° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C([O:19][C:20](=O)[C:21]([F:24])([F:23])[F:22])C>C1COCC1>[F:22][C:21]([F:24])([F:23])[C:20]([C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:19]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1nc2c(Br)cccc2[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc2c(C(=O)C(F)(F)F)cccc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-methyl-1H-benzimidazole (500 mg, 2.37 mmol) was dissolved in THF (8 mL) and cooled to −78° C. n-Butyllithium (2.3 mL, 2.5 M in hexanes, 5.7 mmol) was added dropwise and the reaction was stirred at −78° C. for 30 min. Trifluoroacetic acid ethyl ester (339 μL, 2.8 mmol) was added and the reaction was stirred at 0° C. for 1 h. The reaction was quenched with HCl (2 N, 4 mL), then extracted with water and EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (CH2Cl2/MeOH/NH4OH) provided 2,2,2-trifluoro-1-(2-methyl-1H-benzoimidazol-4-yl)-ethanone.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]([CH2:20][C:21]1([CH2:27][C:28]([O:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[C:18]=[O:19]>C1(C)C=CC=CC=1>[C:7]([CH:9]([O:10][C:18]([NH:17][CH2:20][C:21]1([CH2:27][C:28]([O:30][CH2:31][CH2:32][C:33]#[N:34])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: N#CCCOC(=O)CC1(CN=C=O)CCCCC1
Solvent: Cc1ccccc1
Product: N#CCCOC(=O)CC1(CNC(=O)OC(C(=O)c2ccccc2)c2ccccc2)CCCCC1
Yield: 83 %

Procedure:
A solution of benzoin (0.599 mmol) and 2-cyanoethyl 1-isocyanatomethyl-1-cyclohexane acetate (7) (0.599 mmol) in 10 mL of anhydrous toluene was refluxed overnight. The reaction mixture was concentrated and the residue purified on silica gel (40% ethyl acetate in hexane) to afford 230 mg (83%) of the title compound. 1H NMR (CDCl3): δ 7.95 (2H, dd, J=8.2, 1.4 Hz); 7.50-7.46 (3H, m); 7.41 (5H, m); 6.84 (1H, s); 5.40 (1H, t, J=6.8 Hz); 4.26 (2H, m); 3.24 (2H, d, J=6.8 Hz); 2.68 (2H, dt, J=2.4, 6.4 Hz); 2.36 (2H, d, J=1.2 Hz); 1.52-1.37 (10H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](I)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(O)cc2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(SC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 95.2 %

Procedure:
A mixture of 1-tert-Butoxycarbonyl-4-[(4-hydroxyphenyl)sulfanyl]piperidine (3.09 g, 10.0 mmol), ethyl iodide (1.04 mL, 13.0 mmol), and potassium carbonate (1.80 g, 13.0 mmol) in DMF (15 mL) was stirred at 60° C. for 20 hours. The reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate (40 mL), washed with water (10 mL), 0.5 N sodium hydroxide solution (10 mL×3), brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using ethyl acetate/hexane (1/19 to 1/9) as eluent to afford the title compound (3.21 g, 9.52 mmol, 95%) as a colorless oil.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:18]/[C:19](O)=[O:20]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:19](=[O:20])/[CH:18]=[CH:17]/[C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1cccs1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1cccs1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-thienyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 263 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:21]=1[C:22](Cl)=[O:23].N1C=CC=CC=1>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([C:29]([F:30])([F:31])[F:32])[CH:27]=[CH:28][C:20]=2[F:19])[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(Cc2ccc(F)cc2)n1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)n(Cc2ccc(F)cc2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
To a solution of Example 30A (0.7 g, 2.6 mmol) in tetrahydrofuran (20 mL) were added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.46 mL, 3.1 mmol, Aldrich) and pyridine (0.62 mL, 7.6 mmol). After stirring at 60° C. for 16 h, the reaction mixture was cooled and quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, O-25% ethyl acetate in methylene chloride) to afford 0.75 g (67%) of the title compound. MS (ESI+) m/z 438 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]([NH2:21])=[S:20].[OH-].[Na+].C>>[SH:20][C:19]1[N:21]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)[CH:4]=[CH:3][N:18]=1
Reactant: NC(N)=S
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cccc(-c2ccnc(S)n2)c1

Procedure:
A mixture of 12.2 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone and 15.2 g. of thiourea is heated at 180°-190° C. for 2 hours. The cooled crude reaction mixture is dissolved in 200 ml. of 1 N sodium hydroxide solution and is treated with activated charcoal and filtered. The filtered solution is acidified with 1 N hydrochloric acid and the desired compound is collected by filtration, m.p. 200°-205° C.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[CH:36]1[CH:37]=[CH:38][C:39]2[N:44](O)N=[N:42][C:40]=2[CH:41]=1.O>CN(C=O)C>[NH2:42][C:40]1[CH:41]=[CH:36][CH:37]=[CH:38][C:39]=1[NH:44][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:5][NH:4][CH:1]2[CH2:2][CH2:3]2)=[CH:9][CH:10]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(C=C(CNC2CC2)c2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NC(=O)c1ccc(C=C(CNC2CC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
To a solution of 4-(3-(cyclopropylamino)-2-(4-fluorophenyl)prop-1-en-1-yl)benzoic acid (0.4 g, 1.3 mmol) in DMF (5 mL), EDCl (0.49 g, 2.6 mmol), HOBt (0.175 g. 1.3 mmol) and TEA (0.54 mL, 3.9 mmol), were added, followed by n-phenylenediamine (0.280 g, 2.6 mmol). The reaction mixture was stirred at room temperature for 2 hours, subsequently the residue was poured into water and extracted with ethyl acetate (300 mL) and washed with water (3×50 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the crude compound. The obtained compound was purified with flash chromatography using 15% ethyl acetate/hexane as the eluent, pure fraction evaporated to afford title compound (0.040 g, 9% yield). 1H NMR (DMSO-d6) δ (ppm): 0.24-0.25 (2H, m, —CH2), 0.37-0.39 (2H, m, —CH2), 2.13-2.14 (1H, m, —CH), 3.57 (2H, s, —CH2), 4.86 (2H, s, —NH2), 6.55-6.59 (1H, t, Ar—H), 6.70 (1H, s, ═CH), 6.74-6.76 (1H, d, Ar—H), 6.93-6.95 (1H, t, Ar—H), 7.02-7.04 (2H, m, Ar—H), 7.10-7.12 (1H, d, Ar—H), 7.16-7.26 (4H, m, Ar—H), 7.74-7.76 (2H, d, Ar—H), 9.52 (1H, s, —NH), MS m/z: 402.2 (M++1).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].[OH:32][CH:33]1[C@H:38]2[CH2:39][NH:40][CH2:41][C@@H:34]1[CH2:35][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:40]5[CH2:39][C@H:38]6[CH:33]([OH:32])[C@H:34]([CH2:35][N:36]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]6)[CH2:41]5)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@@H](C1)C2O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Agent: [Cl-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5CN(C(=O)OC(C)(C)C)C[C@@H](C4)C5O)cn3)nc2n1C1CCCC1
Yield: 77 %

Procedure:
Following general amide formation method 1, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid with 5 equiv LiCl was combined with (1R,5S)-tert-butyl 9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate which gave (1R,5S)-tert-butyl 7-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (158 mg) in 77% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.76 (s, 1H), 8.56 (d, J=8.59 Hz, 1H), 8.41 (s, 1H), 8.28 (br s, 1H), 7.92 (d, J=7.07 Hz, 1H), 6.47 (s, 1H), 4.80 (m, 1H), 4.67-4.29 (m, 2H), 4.14-3.68 (m, 3H), 3.48 (m, 1H), 3.24-2.99 (m, 7H), 2.60 (m, 2H), 2.26-1.54 (m, 10H), 1.49 (s, 9H); LCMS m/z 619.0 (M+H)+.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH:22]([F:24])[F:23])[C:17]=1[C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][CH:31]([CH:39]([CH3:41])[CH3:40])[C:32]2([CH3:38])[CH3:37])=O>O1CCOCC1>[Cl:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH:22]([F:24])[F:23])[C:17]=1[C:25](=[S:2])[NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][CH:31]([CH:39]([CH3:41])[CH3:40])[C:32]2([CH3:38])[CH3:37]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)C1Cc2c(NC(=O)c3c(C(F)F)nn(C)c3Cl)cccc2C1(C)C
Solvent: C1COCCO1
Product: CC(C)C1Cc2c(NC(=S)c3c(C(F)F)nn(C)c3Cl)cccc2C1(C)C
Yield: 89 %

Procedure:
In a microwave sealable tube, P2S5 (29 mg, 0.132 mmol, 0.5 eq) is added to a solution of 5-chloro-3-(difluoromethyl)-N-(2-isopropyl-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)-1-methyl-1H-pyrazole-4-carboxamide (104 mg, 0.264 mmol, 1 eq) in 2 ml of dioxane. The tube is sealed and the reaction is microwaved 20 min at 130° C. The resulting solution is filtered through alumina and washed with dioxane. The solvent is evaporated and the residue purified by chromatography on silica gel to give pure material (89%)
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[CH:34][C:35](Br)=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[F-].[K+]>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(-c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Add a solution of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.080 g, 0.134 mmol) in tetrahydrofuran (1 mL) to phenylboronic acid (0.024 g, 0.202 mmol), palladium acetate (0.0015 g, 0.0067 mmol), 2-(dicyclohexylphosphino)biphenyl (0.0047 g, 0.013 mmol) and potassium fluoride (0.023 g, 0.403 mmol) and purge with nitrogen and stir for 2 h at room temperature, then at 50° C. for 12 h. After this initial period, additional phenylboronic acid (0.024 g, 0.202 mol), palladium acetate (0.0015 g, 0.0067 mmol), 2-(dicyclohexylphosphino)biphenyl (0.0047 g, 0.013 mmol) and potassium fluoride (0.023 g, 0.403 mmol) is added and the reaction is heated at 50° C. for 1 h. Cool the reaction to room temperature and dilute with ethyl acetate (30 mL) and wash with 2 N sodium hydroxide and brine (10 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a white solid (0.058 g, 72%): ESI MS 593 (M+H).