Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.C([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)(=O)C.[NH2:14][C:15]([NH2:17])=[S:16].Br>O>[NH2:14][C:15]1[S:16][C:9]2[CH2:8][CH:7]([NH2:6])[CH2:12][CH2:11][C:10]=2[N:17]=1
Reactant: CC(=O)NC1CCC(=O)CC1
Reactant: NC(N)=S
Agent: Br
Agent: BrBr
Solvent: O
Product: Nc1nc2c(s1)CC(N)CC2
Temperature: 45 °C

Procedure:
Bromine (112 g) was added dropwise to a solution of 4-acetamidocyclohexanone (100 g) in 500 ml water at room temperature. The mixture was warmed to approximately 45° C. and maintained at this temperature until the bromine colour had been lost. To this, thiourea (125 g) was added, and the mixture was heated to approximately 80° C. To this, aqueous hydrobromic acid (100 ml) was added, and the contents of the reaction vessel were refluxed. The contents were then cooled to approximately 10° C., and neutralized with caustic lye solution. The product, 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole, was isolated by filtration, and washed with chilled water and dried. The product was off-white in colour, and the yield was approximately 60 g in weight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[C:3]=1[F:11].[C-:12]#[N:13].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]#[N:13])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: [C-]#N
Reactant: Fc1c(Br)ccc(CBr)c1F
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1F
Temperature: 10 °C
Reaction time: 12 h

Procedure:
To a solution of 1-bromo-4-(bromomethyl)-2,3-difluorobenzene (330 mg, 1.154 mmol) in ethanol (10 mL) stirred under N2 at 0° C. was added NaCN (73.5 mg, 1.500 mmol) in one charge. The reaction mixture was stirred at 10° C. for 12 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2,3-difluorophenyl)acetonitrile was used in the next step without further purification. TLC (PE/EA=5:1, Rf 0.6): 1H NMR (400 MHz, CDCl3) δ 7.39 (ddd, J=1.8, 6.1, 8.2 Hz, 1H), 7.15 (t, J=6.8 Hz, 1H), 3.78 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1>CC(O)(CC)C.[Cl-].[Zn+2].[Cl-]>[N:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(C)(C)O
Product: c1ccc(-c2cc(N3CCCC3)cc(-c3ccccn3)n2)nc1

Procedure:
28 mg (<5 mol %) of zinc(II) chloride and 4.4 g (61.5 mmol) of pyrrolidine are added in succession to a mixture of 1.1 g (4.1 mmol) of 4′-chloro-[2,2′;6′,2″]terpyridine in 15 ml of 2-methyl-2-butanol. The mixture is heated at reflux for 20 hours, cooled and filtered. After recrystallisation from toluene, pure 4′-pyrrolidin-1-yl-[2,2′;6′,2″]terpyridine is obtained in the form of a white solid. MS (EI, 70 eV): m/z=303 (15); 302 (90, [M+]); 273 (100); 233 (25). 1H-NMR (360 MHz, CDCl3): 1.9-2.0 (m, 4H); 3.39-3.49 (m, 4H); 7.18 (dd, 2H, J=6.7, 5.2 Hz); 7.51 (s, 2H); 7.66-7.76 (tm, 2H); 8.51 (d, 2H, J=7.7 Hz); 8.54-8.60 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])=[CH:3]1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)P(=O)(N(C)C)N(C)C>[Si:19]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])=[CH:3]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(C)CCCCSC1=CC(O)CC1=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)CCCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Reaction time: 20 h
Yield: 57.8 %

Procedure:
726 mg of 4(RS)-hydroxy-2-(5-methoxycarbonyl-5-methylpentylthio)-2-cyclopentenone and 596 mg (3.96 mmoles) of t-butyldimethylsilyl chloride were dissolved in 10 ml of hexamethylphosphoric triamide, and the reaction was performed at 0° C. for 20 hours. After the reaction, the reaction mixture was extracted with ethyl acetate. The extract was dried and concentrated to give 2.09 g of a crude product. The crude product was chromatographed on a silica gel column using hexane/ethyl acetate (4/1) as an eluent to give 594 mg (1.54 mmoles; yield 58.3%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-methoxycarbonyl-5-methyl-pentylthio)-2-cyclopentenone.
Reaction SMILES: C(OC(=O)[N:7]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:8]1[S:9][C:10]([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])=[CH:11][N:12]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:7][C:8]2[S:9][C:10]([C:13]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])=[CH:11][N:12]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1ncc(C(=O)c2c[nH]c3ncccc23)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1cnc(NCc2ccc(F)cc2)s1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
To a solution of (4-fluoro-benzyl)-[5-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (549, 0.11 g, 0.2 mmol) in dichloromethane (2 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into cold sodium bicarbonate solution, extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After removal of solvents, the residue was washed with ethyl acetate to provide the desired compound as a yellow solid (P-0177, 9 mg, 10%). MS (ESI) [M+H+]+=353.12.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1Br
Reactant: CSc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(-c2ccccc2C=O)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
2-Bromobenzaldehyde (3.7 g, 20 mmol) and 4-(methylthio) benzeneboronic acid (3.36 g, 20 mmol) were dissolved in toluene (80 mL) and sodium carbonate (2M, 10 mL, 20 mmol) was added. To this reaction mixture was added ethanol (5 mL) followed by tetrakis (triphenylphosphine)palladium (240 mg, 0.2 mmol) and the reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (50 mL), stirred well, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (2×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give the crude product. Purification by flash column chromatography using 5% ethyl acetate in hexane gave the title compound as a colorless thick oil (4.4 g, 96% yield). 1H NMR (CDCl3) δ9.98 (s, 1H), 8.01 (dd, J=7.8 Hz and 1.2 Hz, 1H), 7.6 (dt, J=7.5 and 1.4 Hz, 2H), 7.62-7.40 (m, 2H), 7.3-7.25 (m, 3H), 2.53 (s, 3H); LRMS (APIMS) m/z 329 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cccc(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and m-toluidine (52 μl, 0.486 mmol) similar to Example 13 and isolated as a pale yellow oil (132 mg, 99%). 1H NMR (CDCl3): 8.76-8.74 (m, 1H), 8.43-8.40 (m, 1H), 7.78-7.72 (m, 1H), 7.55 (s, 1H), 7.31-7.08 (m, 4H), 6.92 (d, J=7.2 Hz, 1H), 6.55 (s, 1H), 2.41 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C@H:5]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[C:14]([C:16]([CH3:18])=[CH2:17])=[CH:15][C:7]=2[CH2:6]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C@H:5]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:19][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[C:14]([CH:16]([CH3:18])[CH3:17])=[CH:15][C:7]=2[CH2:6]1
Reactant: [H][H]
Reactant: C=C(C)c1cc2c(c3cn[nH]c13)CN(CC(C)(C)C)C(=O)[C@H](CC(=O)OC)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C[C@@H]1Cc2cc(C(C)C)c3[nH]ncc3c2CN(CC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
[(S)-9-(2,2-Dimethyl-propyl)-4-isopropenyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-acetic acid methyl ester (100 mg, 0.26 mmol) was dissolved in a mixture of ethyl acetate (5.0 mL) and methanol (5.0 mL). A catalytic amount of 10% palladium on carbon was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 50 psi of hydrogen gas. Reaction shook at room temperature for 1 hour. Mixture was filtered and the filtrate was concentrated to dryness. Title compound was obtained as brown residue in 90% yield. MS m/e (M+H)+=386.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C1(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]>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][O:17][C:4]1[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=[C:2]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(N3CCOCC3)cn12
Reaction time: 16 h

Procedure:
500 mg of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (1.18 mmol, 1 equivalent), 43 mg of tris(dibenzylideneacetone)dipalladium (0.047 mmol, 4 mol %), 158 mg of sodium tert-butoxide (1.65 mmol, 1.4 equivalents), 67 mg of XPHOS (0.141 mmol, 12 mol %) and 307 μl of morpholine (3.5 mmol, 3 equivalents) were dissolved in 30 ml of dry toluene and reacted in an oil bath preheated to 100° C. After 16 h at this temperature, the reaction mixture was cooled, filtered through kieselguhr, concentrated and chromatographed (Biotage Isolera Four; cyclohexane/ethyl acetate gradient as mobile phase). This gave 352 mg (63% of theory) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:24][C:25]1[N:26]=[CH:27][N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:29]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[N:26]=[CH:27][N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)(F)F)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (85.0 mg, 0.247 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (68.3 mg, 0.247 mmol) and HATU (94 mg, 0.247 mmol) in DMF (5 ml) was added diisopropylethyl amine (0.086 ml, 0.493 mmol) and the reaction mixture was stirred for 30 minutes at rt. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (97 mg, 0.161 mmol, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.43-7.53 (m, 1H), 7.39 (t, 1H), 5.47 (s, 2H), 4.46 (d, 2H), 3.35 (t, 2H), 0.59-0.81 (m, 2H), −0.12 (s, 9H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH:11]1[CH2:14][NH:13][CH2:12]1.Cl.[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2([CH2:31][C:30]3[C:25](=[N:26][CH:27]=[C:28](/[CH:32]=[CH:33]/[C:34](O)=[O:35])[CH:29]=3)[NH:24][C:23]2=[O:37])[CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH:11]1[CH2:12][N:13]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:28]2[CH:29]=[C:30]3[C:25](=[N:26][CH:27]=2)[NH:24][C:23](=[O:37])[C:20]2([CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH2:31]3)[CH2:14]1
Reactant: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Reactant: c1ccc2oc(C3CNC3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC(c4cc5ccccc5o4)C3)cnc1NC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a solution of 3-(benzofuran-2-yl)azetidine hydrochloride (30 mg, 0.086 mmol) and (E)-3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylic acid hydrochloride (20 mg, 0.059 mmol) in dry DMF (4 mL) were added EDCI.HCl (17.02 mg, 0.089 mmol), HOAt (12.09 mg, 0.089 mmol) and DIPEA (51 μL, 0.296 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and H2O, the layers were separated and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organic layers were washed with brine (3×3 mL), dried over Na2SO4 and concentrated. The residue was chromatographic purified (silica gel, eluent dichloromethane/7M NH3 in MeOH 98:2 to 95:5). The residue was further purified by preparative LCMS (Waters X-Bridge 50×19 mm 5 μm ODB in combination with Waters X-Bridge guard 10×19 mm 5 μm, at 25 ml/min flow rate; detection of product by mass and UV signal; eluent 10 mM ammonia in milliQ water to 10 mM ammonia in MeCN 5% to 95% gradient), to yield the title compound (2.6 mg, 9.6%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl)=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].[I-].[K+]>C(O)CCC>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([N:17]2[CH2:21][CH2:22][N:2]([C@H:3]3[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]3)[CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: ClCCN(CCCl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCCCO
Product: COC(=O)[C@@H]1CC[C@H](N2CCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
(1R,3S)-methyl 3-aminocyclopentanecarboxylate hydrochloride (1.5 g, 8.35 mmol), 4-chloro-N,N-bis(2-chloroethyl)aniline (2.32 g, 9.18 mmol), sodium hydrogencarbonate (4.91 g, 58.4 mmol), and potassium iodide (0.14 g, 0.83 mmol) were suspended in n-butanol (50 mL). The reaction mixture was stirred at 110° C. for overnight. Upon completion, the reaction mixture was evaporated under vacuo. The resulting crude residue was purified by column chromatography using ethyl acetate in hexane as eluent to obtain (1R,3S)-methyl 3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentanecarboxylate (1.5 g, 55.6%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>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>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8][N:9]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1ccccc1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
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
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2-c1ccccc1
Yield: 99.1 %

Procedure:
A solution of 4-methoxy-1-phenyl-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (83 mg), tetrakis(triphenylphosphine)palladium(0) (31.0 mg) and 2M aqueous sodium carbonate solution (1.0 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (101 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].[CH:16]([N:19]1[C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:23]2[N:19]([CH:16]([CH3:18])[CH3:17])[N:20]=[CH:21][CH:22]=2)[C:7]([CH:11]([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Reactant: COC(=O)c1cc(I)c(C(C)F)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C(C)C)c(C(C)F)cc1N
Temperature: 90 °C
Reaction time: 24 h
Yield: 16.5 %

Procedure:
To a solution of 2-amino-4-(1-fluoro-ethyl)-5-iodo-benzoic acid methyl ester (0.561 g, 1.74 mmol) in dioxane (5 mL) were added 1-isopropyl-5-tributylstannanyl-1H-pyrazole (0.84 g, 2.08 mmol) and Pd(PPh3)2Cl2 (142 mg, 0.174 mmol) and the resulting mixture was stirred at 90° C. for 24 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:10 to 3:7)) to give 2-amino-4-(1-fluoro-ethyl)-5-(2-isopropyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (90 mg, 0.287 mmol, 16%) ES-MS: m/z 306 [M+H]+, rt 6.47 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12]O.C1(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CCCCCCC=CCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:61]>CN(C=O)C.O.C(OCC)C.C(O)C>[ClH:61].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][NH2:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCCc1ccc2ccccc2c1
Agent: CCCC=CCCCCCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: NCCc1ccc2ccccc2c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution comprising 2-naphth-2-ylethanol (0.5 g, 2.9 mmol) in dry DMF (5 mL) was combined under nitrogen with diphenylphosphoryl azide (0.74 mL, 3.42 mmol) and 1,8-diazaabicyclo[5.4.0]undec-7-ene (0.47 mL. 3.14 mmol). The mixture was heated at 65° C. for 3 hours and then partitioned between water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were washed with 3N hydrochloric acid and then saturated sodium bicarbonate, dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was dissolved in THF (5 mL) and the solution was combined with triphenylphosphine (1 g, 3.81 mmol), stirred for 2 hours at room temperature, diluted with water (0.100 mL), stirred 3 hours, diluted with concentrated hydrochloric acid (0.33 mL) to give a precipitate, treated with ethanol (5 mL) to dissolve the precipitate and treated with diethyl ether, added slowly, to give a white precipitate. The while precipitate was isolated by filtration, washed with diethyl ether and dried under vacuum to provide 2-naphth-2-ylethylamine hydrochloride (0.447 g, 75% yield);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[Cl-].[CH2:38]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:44]=1)[CH3:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:38]([C:40]1[S:41][CH:42]=[C:43](/[CH:45]=[CH:13]\[C:12]2[C:8]([O:7][CH2:6][C:5]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]4[N:27]=[C:28]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)[S:29][CH:30]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:9][N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:44]=1)[CH3:39]
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3csc(N4CCCCC4)n3)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.8 %

Procedure:
A mixture of 3-[(3-methoxy-4-{[2-(piperidin-1-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.76 g), potassium carbonate (0.17 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give 1-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-1,3-thiazol-2-yl]piperidine as colorless crystals (0.13 g, yield 18%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 93-94° C.