Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[C@@H:12]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C@@H:13]3[C@@H:18]([OH:19])[CH2:17][CH2:16][N:14]3[N:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:46](O)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:46]([O:19][C@H:18]1[C@@H:13]2[N:14]([N:15]=[C:11]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@H:12]2[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:16][CH2:17]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C2=NN3CC[C@@H](OC(=O)c4ccccc4)[C@H]3[C@@H]2OC2CCCCO2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile (80 mg, 0.235 mmol) in THF (3 mL) were added PPh3 (123 mg, 0.470 mmol), benzoic acid (58 mg, 0.470 mmol) and DIAD (0.09 mL, 0.470 mmol) and the reaction mixture was stirred at room temperature for 3 h. Then it was diluted with ethyl acetate and washed with saturated NaHCO3 solution, water, and brine, then dried over Na2SO4 and concentrated to get the crude product which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:16]([O-])(O)=O.[Na+]>CO.O1CCOCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C([O-])O
Reactant: Nc1cccc(F)c1C(=O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1c(N)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5 g (31.6 mmol) 2-amino-6-fluorobenzoic acid are dissolved in 50 ml of methanol and combined with 7.9 ml (31.6 mmol) of a 4 M solution of HCL in 1,4-dioxane and stirred for 10 min. at ambient temperature. The reaction mixture is combined dropwise with 3.45 ml (47.4 mmol) thionyl chloride and refluxed for 3 h. Then the reaction mixture is neutralised with 150 ml of a saturated, aqueous NaHCO3 solution and extracted four times with 100 ml of ethyl acetate. The organic phase is dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[O:14]C=CC=3)[N:10]=[C:9]([C:18]3[O:19]C=CC=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:27])(C)(C)C.[O-][Mn](=O)(=O)=O.[K+].[OH2:34]>>[C:1]1([C:7]2[CH:8]=[C:9]([C:18]([OH:19])=[O:34])[N:10]=[C:11]([C:13]([OH:14])=[O:27])[CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: CC(C)(C)O
Reactant: c1ccc(-c2cc(-c3ccco3)nc(-c3ccco3)c2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1cc(-c2ccccc2)cc(C(=O)O)n1

Procedure:
The product of step b is added to the t-butanol. The mixture is heated and stirred then the H2O is added and the KMnO4 is added in portions over about 30 minutes at 75° C. The mixture is refluxed for 90 minutes. The product is worked up to give crystals of the desired 4-phenyl-2,6-pyridinedicarboxylic acid. The dicarboxylic acid which results is useful in its own right in the present invention as a ligand.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:8]([C:6]1[S:7][C:3]([O:2][CH3:1])=[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:10])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: COc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a 50 mL round-bottomed flask was added 5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (148 mg, 0.62 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (242 mg, 0.63 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (356 mg, 0.76 mmol) in Chloroform (6 mL). DIEA (550 μL, 3.15 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (303 mg, 0.51 mmol, 82%): LC-MS (ES) m/z=569 (M+H)+.
Reaction SMILES: [C:1](SC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)(=[O:18])[S:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.O.[NH2:36][NH2:37]>ClCCl>[NH:36]([C:1](=[O:18])[S:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)[NH2:37]
Reactant: CC(C)(C)c1cc(SC(=O)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: NN
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(SC(=O)NN)cc(C(C)(C)C)c1O
Reaction time: 48 h
Yield: 92.7 %

Procedure:
A solution of S,S-bis[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] carbonodithioate (5.0 g, 9.9 mmol) in dichloromethane (50 mL) is added dropwise to a 0° C. solution of hydrazine monohydrate (1.1 g, 22.0 mmol) in dichloromethane (60 mL). The ice bath is removed and the reaction is stirred vigorously for 48 hours. The reaction mixture is diluted with ethyl acetate and washed four times with water and once with brine. The organic phase is dried over magnesium sulfate and the solvents are evaporated in vacuo. The residue is chromatographed on a 100 g silica column with ethyl acetate/hexane (1/9 then 1/1). The hydrazide is crystallized from isopropyl ether to give 2.72 g (92%) of S-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] hydrazinecarbothioate, mp 130.0-131.0° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.[OH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([O:21][CH2:2][C:3]2[N:4]=[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:6][CH:7]=2)=[CH:23][CH:24]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
A solution of tert-butyl 4-(4-chloromethylthiazol-2-yl)piperazine-1-carboxylate (820 mg, 2.58 mmol) and methyl 4-hydroxybenzoate (395 mg, 2.58 mmol) in DMF was treated with potassium carbonate (360 mg, 2.6 mmol). The mixture was stirred at 70° C. for approximately 12 hours and then concentrated under vacuum. The residue was partitioned between ethyl acetate and water and the or organic phase was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was crystallized from a mixture of ethyl acetate/hexanes to provide tert-butyl 4-[4-(4-methoxycarbonyl-phenoxymethyl)thiazol-2-yl]piperazine-1-carboxylate (830 mg, 74% yield). HNMR (dmso-d6): HNMR (dmso-d6): 7.91 (2H, d), 7.13 (2H, d), 6.91 (1H, s), 5.00 (2H, s), 3.81 (3H, s), 3.41 (8H, m), 1.41 (9H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:17]([O:16][C:12](=[O:15])/[CH:13]=[CH:14]/[C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)oc2c1
Yield: 23.2 %

Procedure:
A stirred solution of 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one (1.00 g, 4.65 mmol), tert-butyl acrylate (2.7 mL, 18 mmol), palladium(II) acetate (104 mg, 0.465 mmol), tri-o-tolylphosphine (283 mg, 0.930 mmol), and N,N-diisopropylethylamine (1.7 mL, 9.7 mmol) in N,N-dimethylformamide (4 mL) and propionitrile (16 mL) was deoxygenated by bubbling argon through the solution for 20 min. The mixture was heated to reflux for 21 h, then allowed to cool. The mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL). The solution was washed with water (2×200 mL), dried over sodium sulfate, filtered, and the solvent removed in vacuo to give a dark brown oil. Purification by flash column chromatography (silica gel, gradient from 98:2 to 94:6 CHCl3/MeOH) gave the title compound (283 mg, 23%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=1.4 Hz, 1H), 7.64-7.55 (m, 2H), 6.37 (d, J=16.0 Hz, 1H), 1.55 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:32][CH:33]1[CH2:35][O:34]1>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][N:23]([CH2:32][C@@H:33]([OH:34])[CH3:35])[N:24]=4)[N:19]=[CH:20][CH:21]=3)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: CC1CO1
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)c(C)cn2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C[C@H](C)O)nc34)c(C)cn2)n1
Temperature: 120 °C

Procedure:
N-(3′-Fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (374 mg, 1.119 mmol) and Cs2CO3 (364 mg, 1.119 mmol) were stirred in DMF (6 mL) for 10 minutes. 2-Methyloxirane (0.079 mL, 1.119 mmol) was added, the vessel sealed and the mixture was heated in a microwave at 120° C. for 30 minutes. The reaction mixture was cooled and purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 10-25% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to separate the regioisomers which in turn were further purified using a Chiralcel AD-H (5 um, 20×150 mm) column eluting with CO2: 15% EtOH+0.1% DEA at 50 mL/min to give (S)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.21 (d, J=4 Hz, 3H) 2.44 (s, 3H) 2.56 (s, 3H) 4.20-4.33 (m, 1H) 4.37 (dd, J=12, 8 Hz, 1H) 4.49 (dd, J=16, 4 Hz, 1H) 6.99 (d, J=4 Hz, 1H) 7.35 (dd, J=8, 4 Hz, 1H) 7.60 (dd, J=12, 8 Hz, 1H) 7.92 (s, 1H) 8.28 (d, J=4 Hz, 1H) 8.37 (s, 1H) 8.49 (s, 1H), MS [M+H] found 393.4; (R)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.22 (d, J=4 Hz, 3H) 2.46 (s, 3H) 2.57 (s, 3H) 4.21-4.34 (m, 1H) 4.39 (dd, J=12, 8 Hz, 1H) 4.51 (dd, J=12, 4 Hz, 1H) 7.01 (d, J=4 Hz, 1H) 7.36 (dd, J=8, 4 Hz, 1H) 7.61 (dd, J=8, 4 Hz, 1H) 7.93 (s, 1H) 8.29 (d, J=4 Hz, 1H) 8.38 (s, 1H) 8.50 (s, 1H), MS [M+H] found 393.4; (R)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.22 (d, J=8 Hz, 3H) 2.46 (s, 3H) 2.58 (s, 3H) 4.14-4.34 (m, 1H) 4.34-4.43 (m, 1H) 4.51 (m, 1H) 7.01 (d, J=4 Hz, 1H) 7.37 (dd, J=8, 4 Hz, 1H) 7.61 (dd, J=12, 12 Hz, 1H) 7.94 (s, 1H) 8.29 (d, J=4 Hz, 1H) 8.39 (s, 1H) 8.50 (s, 1H), MS [M+H] found 393.4; and (S)-1-(7-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-ol 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.21 (d, J=8 Hz, 3H) 2.46 (s, 3H) 2.57 (s, 3H) 4.19-4.34 (m, 1H) 4.38 (m, 1H) 4.50 (m, 1H) 7.00 (d, J=4 Hz, 1H) 7.36 (dd, J=8, 4 Hz, 1H) 7.61 (dd, J=8, 8 Hz, 1H) 7.93 (s, 1H) 8.29 (d, J=4 Hz, 1H) 8.38 (s, 1H) 8.50 (s, 1H), MS [M+H] found 393.4.
Reaction SMILES: [NH2:1][C@H:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])(OCC)=O>>[C:30]1(=[O:39])[N:1]([C@H:2]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COC(=O)C[C@H](N)c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@@H](c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O

Procedure:
Methyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate (0.45 g, 1.63 mmol), sodium carbonate (0.17 g, 1.63 mmol) and N-carboethoxyphthalimide (0.36 g, 1.63 mmol) were allowed to react according to the procedure of Example 85. Methyl (S)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionate was obtained as a white powder, 0.51 g (85%); 1H NMR (DMSO-d6, 250 MHz) δ 7.87 (br s, 4 H, Ar), 6.80-7.10 (m, 3 H, Ar), 5.65 (dd, 1 H, J1 =7 Hz, J2 =9 Hz), 3.73 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.55 (s, 3 H, OCH3), 3.30-3.67 (m, 2 H); 13C NMR (DMSO-d6) δ 170.8, 167.7, 148.6, 148.4, 134.7, 131.1, 131.0, 123.2, 119.3, 111.7, 111.0, 55.5, 51.6, 49.9, 35.6. Anal.Calcd for C20H19NO6. Theoretical C, 65.03; H, 5.18; N, 3.79. Found C, 64.94; H, 5.29; N, 3.86. HPLC 97%.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cu]I.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>[CH3:7][NH:6][C:5]1[CH:8]=[CH:9][C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:3][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: CNc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CNc1ccc(C#C[Si](C)(C)C)cc1
Yield: 36.4 %

Procedure:
To a suspension of 4-bromo-N-methylaniline (500 mg, 2.7 mmol), trimethylsilyl acetylene (527 mg, 5.4 mmol), CuI (92 mg, 0.5 mmol) and PPh3 (233 mg, 0.9 mmol) in TEA (20 mL) was added PdCl2(PPh3)2 (94 mg, 0.1 mmol) at r.t. under N2. The reaction was stirred at reflux overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE:EtOAc=20:1) to give 200 mg (37%) of the title compound as a yellow oil. [M+H] Calc'd for C12H17NSi, 204. Found, 204.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1.CCN(CC)CC>CC#N>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:35][C:34]4[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=4)[CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Reactant: Fc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCN(Cc2ccc(F)cc2)CC1

Procedure:
A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.50 g, 3.49 mmol), 4-fluorobenzyl bromide (0.478 mL, 3.84 mmol), and Et3N (1.47 mL, 10.5 mmol) in CH3CN (200 mL) was stirred at room temperature for 13 h and concentrated. Column chromatography (SiO2, 10% CH3OH/CH2Cl2) afforded 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1-(4-fluorobenzyl)piperidine.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][CH:11]3O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCc2c(-c3ccccc3)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C1=Cc2cccc(-c3ccccc3)c2C1
Yield: 96.2 %

Procedure:
A stirred solution of 16.7 g (0.08 mole) of 4-phenyl-1-indanol and 0.1 g of p-toluenesulfonic acid in 180 ml of benzene was heated under reflux for one hour as by-product water was collected in a Dean-Stark trap. The reaction mixture was washed with two portions of 50 ml of a 5% aqueous solution of sodium bicarbonate, then with one portion of 50 ml of water. The organic phase was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure, keeping the temperature under 50° C., to give 14.8 g of 7-phenyl-1H-indene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.[CH3:11][NH:12][NH2:13].[CH3:14]N(C=O)C>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[N:13]([CH3:14])[N:12]=[CH:11][CH:1]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CNN
Reactant: CN(C)C=O
Product: Cn1nccc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A N,N′-dimethylformamide (15 mL) solution of 4-bromoacetophenone (10.60 g, 53.25 mmols) and N,N′-dimethylformamide dimethyl acetal (2.5 equivalents) was heated at 125 degrees Celcius for 3 hours. The dark red solution was cooled to room temperature. The volatiles were removed by rotary evaporation providing a red viscous oil. To this substance was added anhydrous N,N′-dimethylformamide (15 mL) and methyl hydrazine (7.6 g, 160 mmols, 3 equivalents). The mixture was stirred at room temperature for 1 hour and then heated at 75 degrees Celcius for 4 hours. The volatiles were removed by rotary evaporation and the crude residue was taken up in a small volume of methylene chloride. This red solution was applied to a cartridge of silica gel. The cartridge was eluted with a 20:80 mixture of ethyl acetate and hexanes, respectively. The appropriate fractions were combined and concentrated to produce 12.5 g of a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH:6]1([NH:9][C:10](=[O:32])[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](OC)=[O:22])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1>CO.C(Cl)Cl.O>[CH:6]1([NH:9][C:10](=[O:32])[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([NH:2][OH:3])=[O:22])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)/C=C/c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(/C=C/c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Hydroxylamine hydrochloride (0.86 g, 12.3 mmol) in methanol (3 mL) was mixed with KOH (0.69 g, 12.3 mmol) in methanol (3 mL) at 0° C., and sonicated for 2 minutes, the white precipitate formed was filtered. The filtrate was added to methyl 3-(E)(4-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)phenyl)acrylate (0.25 g, 0.68 mmol) in DCM (1.5 mL) and the mixture was stirred at room temperature, for 30 minutes. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×150 mL). The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated to obtain a sticky compound, which was triturated with DCM (15 mL). The pale brown solid obtained was filtered and washed with DCM (3×5 mL) to afford the title compound (0.07 g, 28% yield). 1H NMR (DMSO-d6) δ (ppm): 0.49-0.53 (2H, dd, —CH2), 0.61-0.66 (2H, m, —CH2), 2.72-2.77 (1H, m, —CH), 6.38-6.42 (1H, d, ═CH), 7.00-7.02 (2H, d, Ar—H), 7.16-7.27 (5H, m, Ar—H and ═CH), 7.33-7.43 (3H, m, Ar—H and ═CH), 7.81-7.82 (1H, d, —NH), 9.04 (1H, s, —OH), 10.73 (1H, s, —NH). MS m/z: 367.1 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][CH2:12][C@@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:14])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A solution of (S)-benzyl(1-hydroxypropan-2-yl)carbamate (400 g, 1.91 mol) and triethylamine (270 g, 2.67 mol) in methylene chloride (2.4 L) was cooled to 0° C. To this mixture was added methanesulfonyl chloride (263 g, 2.30 mol) at an internal temperature of 5° C. or below. Subsequently, the resulting reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, to the reaction mixture was added purified water. The resulting organic layer was partitioned, washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the target product as a yellow solid (519 g, yield 94.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1
Yield: 17 %

Procedure:
A mixture composed of 500 mg of N-(4-bromophenyl)methane-sulfonamide, 334 mg of 4-methoxyphenyl boronic acid, 55.5 mg of tetrakis-triphenylphosphinepalladium, 2 ml of a 2 M aqueous solution of sodium carbonate, 4 ml of toluene, and 1 ml of ethanol was heated under. reflux for 5 hours in an atmosphere of nitrogen. After the reaction mixture was poured into a saturated aqueous solution of sodium chloride, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (using a 7:1 mixture of chloroform and tetrahydrofuran as the eluent) to obtain 94 mg of N-(4′-methoxybiphenyl-4-yl)methanesulfonamide.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>C(OCCO)C>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccccc1N
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCCO
Product: Cc1ccccc1Nc1cc(C(=O)O)ccc1C(=O)O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
Bromoterephthalic acid (12.2 g), ortho-toluidine (10.7 ml), anhydrous K2CO3 (13.8 g), catalytic Cu powder (0.2 g) in 2-ethoxy-ethanol (17.5 ml) were stirred together while heating under reflux conditions in an oil bath at 150° C. After 6 hours, water (200 ml) was added and, when all salts had dissolved, the solution was clarified and crude product precipitated by acidification to pH 2. The collected diacid was well washed with boiling water then recrystallised from 50% ethanol, pure product being obtained as yellow needles of mp 318° C. (dec).