Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]1[C:14]([O:16][CH3:17])=[O:15].[CH2:18](O)[CH:19]=C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH2:4][CH:3]1[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15]
Reactant: C=CCO
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Yield: 90 %

Procedure:
A solution of 1-tert-butyl 3-methyl 4-oxopyrrolidine-1,3-dicarboxylate (48.65 g, 0.20 mol), allyl alcohol (300 mL), and dibutyltin oxide (5.0 g, 20 mmol) in anhydrous toluene (800 mL) was refluxed for 20 h under a Dean-Stark trap with portionwise removal of solvent (total of 200 mL) over the first 6 hours, followed by addition of more allyl alcohol (75 mL) at the end of the first 6 hours. The reaction mixture was concentrated, dissolved in minimal methylene chloride, and loaded onto a silica gel column (700 mL volume) and eluted with methylene chloride, 10%, then 15%, then 20% ethyl acetate/methylene chloride to afford 3-allyl 1-tert-butyl 4-oxopyrrolidine-1,3-dicarboxylate (48.6 g, 90%) as a pale pink oil (NMR and MS as above). This compound (48.47 g, 0.18 mol) was dissolved in anhydrous tetrahydrofuran (200 mL) and added to a stirred solution of Pd(PPh3)4 (4.16 g, 3.6 mmol) in anhydrous tetrahydrofuran (400 mL) under nitrogen, stirred for 4 h, and concentrated. The residue was dissolved in heptane and loaded onto a silica gel column (1000 mL volume) and eluted with 60:35:5 heptane/methylene chloride/ethyl acetate to afford tert-butyl 3-allyl-4-oxopyrrolidine-1-carboxylate (27.93, 69%) as a pale yellow oil (NMR and MS as above).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[CH3:22])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25]([N:27]4[CH2:32][CH2:31][S:30][CH2:29][CH2:28]4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[CH3:22])=[CH:19][CH:20]=4)[CH2:12][N:11]([C:25]([N:27]4[CH2:28][CH2:29][S:30](=[O:41])[CH2:31][CH2:32]4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(F)(F)c1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCSCC3)C2)cc1
Product: CC(F)(F)c1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCS(=O)CC3)C2)cc1

Procedure:
34.1 mg (0.074 mmol) of the compound from Example 54A were reacted according to General Method 1 with 22.9 mg (0.066 mmol) of meta-chloroperbenzoic acid. Yield: 39.7 mg (100% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:36]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 39 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.3 mmol) in CH2Cl2 (5 ml) are slowly added triethylamine (0.36 mmol) and 1-butanesulfonyl chloride (0.36 mmol) at 0° C. The reaction mixture is stirred at room temperature for 15 h. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of CH2Cl2. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product. Purification of the residue by silica gel column chromatography affords title compound in 39% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:15])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])=[C:4]([CH3:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CS(C)=O>[CH2:25]([O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:16])[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: Cc1cc(Cl)ccc1-c1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1cccc(F)c1-c1ccc(Cl)cc1C
Yield: 66.6 %

Procedure:
Treatment of 4′-chloro-6-fluoro-2′-methylbiphenyl-2-ol (2.7 g, 11.4 mmol) with potassium carbonate (2.4 g, 17.1 mmol) and allyl bromide (1.5 mL, 17.1 mmol) in DMSO (100 mL) according to the procedure described for Example 69, Step 3 provided 2.1 g (66%) of 2′-allyloxy-4-chloro-6′-fluoro-2-methylbiphenyl as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO.[CH3:20][NH2:21]>>[CH3:20][NH:21][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:16]
Reactant: COC(=O)C1CCN(c2ccc(Br)cc2)CC1
Reactant: CN
Solvent: CO
Product: CNC(=O)C1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 1-(4-bromophenyl)piperidine-4-carboxylate (950 mg) was added methylamine methanol solution (25%, 20 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, and concentrated under reduced pressure. To a solution of the residue in acetonitrile (15 mL) were successively added tetraethylammonium bromide (1.05 g), isoamyl nitrite (1.05 g) and copper(I) bromide (0.09 g) at room temperature. The reaction mixture was stirred at room temperature for 40 min, and then at 60° C. for 2 hr. The reaction mixture was added to water, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (800 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:30])[C:11]([CH:28]=[O:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4].CSC>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[N:9]2[C:10](=[O:30])[C:11]([CH2:28][OH:29])=[C:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:13]([CH:14]3[CH2:16][CH2:15]3)=[C:8]2[S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(C=O)c(=O)n21
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CSc2c(C3CC3)c(Cc3cccc4ccccc34)c(CO)c(=O)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
The formylated 2-pyridone 2 (100 mg, 0.239 mmol) was dissolved in tetrahydrofuran (3.30 mL) at 0° C. Then 2M BH3.DMS.THF (0.131 mL, 0.262 mmol) was added dropwise during 15 min. The mixture was then stirred in room temperature during 1 h, quenched with methanol and concentrated twice from methanol. The residue was purified through flash column chromatography (CH2Cl2:MeOH, 9:1). Co-concentration from CH2Cl2 (×2) resulted in 4 as white foam (80.6 mg, yield: 80%). 1H-NMR (400 Mhz, CDCl3) δ 8.16 (d, J=8.23 Hz, 1H, ArH), 7.87 (d, J=7.96 Hz, 1H, ArH), 7.71 (d, J=8.14 Hz 1H, ArH), 7.64-7.48 (m, 2H, ArH) 7+(m, 1H, ArH) 6.83 (d, J=6.95 Hz, 1H, ArH), 5.68 (d, J=7.04 Hz, 1H, CHCO2Me), 4.72 (d, J=16∞Hz, 1H, Nph-CH2), 4.61 (d, J=16.28 Hz, 1H, Nph-CH2) 4.58-4∓(m, 2H, CH2OH) 3.84 (s, 3H, CH3) 3.76-3.62 (m, 2H, SCH2, OH) 3.60-3.50 (m, 1H, SCH2) 1.46-1.34 (m, 1H, CH-cyclopropyl) 0.65 (ss, 2H, CH2-cyklopropyl) 0.51 (ss, 2H, CH2-cyklopropyl) 13C-NMR (100 Mhz, CDCl3) δ 168.61, 161.87, 152.08, 146.62, 134.11, 133.76, 131.77, 128.94, 127.17, 126.37, 125.92, 125.66, 125.63, 124.26, 122.98, 114.93, 63.27, 58.78, 53.40, 31.77, 31.58, 11.81, 7.53, 7.20.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Cl.Cl[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[C:4]([F:9])[CH:3]=1
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc(Br)cc1F

Procedure:
4-Bromo-2-fluorophenol (1.0 g, 5.24 mmol), 2-chloro-N,N-diethylethanamine HCL (0.90 mg, 5.24 mmol) and Cs2CO3 (8 g, 25 mmol) were combined in DMF (20 mL) and the mixture was heated at reflux over night. H2O was added and the mixture was extracted with EtOAc, then washed with 2N NaOH and brine. The organic layers were combined, dried over Na2SO4 and concentrated to a brown oil. Flash chromatography (gradient eluent: 10-50% EtOAc in hexanes) of the crude concentrate afforded title compound 56.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(Br)nc1C(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (100 mg, 0.43 mmol) in MeOH (5 mL) was added 2 mL of NaOH aqueous solution (5 N). After being stirred at 50° C. for 4 h, the mixture was cooled and acidified with 1 M HCl to a pH of 2. The precipitate was collected by filtration and washed with water to afford the product of 3-amino-6-bromopyrazine-2-carboxylic acid (90 mg, yield: 96%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.38 (s, 1H), 7.51˜7.56 (m, 2H). MS (M+H)+: 218/220.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:16]=[CH:17][C:18]3[N:23]=[N:22][N:21]([CH2:24][C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[C:19]=3[N:20]=2)[CH:12]=[N:11]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([CH2:24][N:21]3[C:19]4[N:20]=[C:15]([C:13]5[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=5)[N:16]=[CH:17][C:18]=4[N:23]=[N:22]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: c1cnc2ccc(Cn3nnc4cnc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: OCCn1cc(-c2ncc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-((5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)quinoline (237 mg, 0.520 mmol) and TsOH.H2O (119 mg, 0.624 mmol) in MeOH (15 mL) was stirred for 3 h at room temperature. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (CH3CN, H2O gradient plus 0.1% AcOH) to afford the title compound, after lyophilization, as a white powder (116 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ 3.72 (dd, 2H, J=10.8, 5.4 Hz), 4.18 (t, 2H, J=5.4 Hz), 4.90 (t, 1H, J=5.3 Hz), 6.06 (s, 2H), 7.47 (m, 1H), 7.76 (m, 1H), 7.93-7.97 (m, 2H), 8.12 (m, 1H), 8.31 (m, 1H), 8.45 (s, 1H), 8.90 (m, 1H), 9.64 (s, 1H); LCMS (APCI) m/z 373.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.CO[C:18](=[O:38])[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([O:30][CH2:31]C2C=CC=CC=2)[CH:22]=1)[CH3:20]>>[NH:14]([C:31]1[O:30][C:23]2[CH:22]=[C:21]([CH:19]([C:18]([NH:14][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:15])[CH:13]=3)=[O:38])[CH3:20])[CH:26]=[CH:25][C:24]=2[N:27]=1)[C:12]1[CH:13]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CCCOc1cccc(N)c1
Reactant: COC(=O)C(C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Product: CC(C(=O)Nc1cccc(OCCCC(=O)O)c1)c1ccc2nc(Nc3ccccc3)oc2c1

Procedure:
Methyl4-(5-aminophenoxy)butyrate was made as described in example 7 above and coupled with methyl-2-(3-benzyloxy-4-nitrophenyl)propionate according to the method described in example 7 to produce the methyl ester of 2-anilino-6-(1-(3-[3-carboxypropoxy]anilino carbonyl)ethyl)benzoxazole.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19](=S)(OCC)[S-:20].[K+]>N1C=CC=CC=1.C(OCC)(=O)C>[SH:20][C:19]1[O:12][C:11]2[C:10]3[CH:9]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=1
Reactant: CCOC(=S)[S-]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc3nc(S)oc3c21
Yield: 63.5 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) and potassium O-ethyl dithiocarbonate (65.1 mg, 0.406 mmol) were heated under reflux in pyridine (1 mL) for 2 hr. The reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (64.8 mg, yield 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[N:9]([CH2:21][CH3:22])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:26]([CH:25]=[CH2:24])(=[O:28])=[O:27])=[CH:7][CH:6]=1)#[N:18]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Solvent: c1ccncc1
Product: C=CS(=O)(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1
Reaction time: 4 h

Procedure:
A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, prepared by example 1Ga step B, (0.82 mg, 2.82 mmol), in pyridine (10 mL) is treated dropwise with chloroethyl sulfonylchloride (0.38 mL, 3.66 mmol) at room temperature. After stirring for 4 h, the reaction mixture is quenched with ice-water and enough 6N HCl is added until the pH is lowered to 2. The suspension is extracted with hot EtOAc (3×). The organic phases are then washed sequentially with 1N HCl, H2O and saturated NaCl and dried and concentrated to give ethenesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a pale orange solid which is used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:21][NH2:22])[N:14](CC3C=CC(OC)=CC=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:21][NH2:22])[NH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2CC3(CCN(Cc4ccccc4)C3)c3c(CN)cccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc2c1C1(CCN(Cc3ccccc3)C1)CN2
Yield: 72 %

Procedure:
A solution of (1′-benzyl-1-(4-methoxybenzyl)spiro[indoline-3,3′-pyrrolidine]-4-yl)methanamine (0.500 g, 1.21 mmol) in TFA (7.00 mL) was heated at 85° C. for 24 hours. The solvent was evaporated to give (1′-benzylspiro[indoline-3,3′-pyrrolidine]-4-yl)methanamine trifluoroacetic acid salt (0.355 g, 0.872 mmol, 72%). LCMS (APCI+) M+H+ 294 (100%); Rt=2.06 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[CH2:18]([OH:21])[C:19]#[CH:20]>C(NCC)C.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>[OH:21][CH2:18][C:19]#[C:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1I
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1C#CCO
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 0.37 g (0.5 mmole) of dichlorobis(triphenylphosphine)palladium II, 70 mg (0.35 mmole) of cuprous iodide, 36.1 g (0.1 mole) of 5-chloro-2'-fluoro-2-iodobenzophenone and 12 ml (0.2 mole) of propargyl alcohol in 200 ml of diethylamine was stirred at room temperature for 4 days. The mixture was concentrated at reduced pressure and the residue was partitioned between ether and water. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give the product as an amber oil.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9](C2C=CC=C(C(F)(F)F)C=2)=[CH:10][CH:11]=1)=[O:5].[O:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:33]=[CH:34][C:35]([CH3:41])=[C:36](B(O)O)[CH:37]=1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:36]2[CH:37]=[C:32]([C:28]3[O:27][CH:31]=[CH:30][N:29]=3)[CH:33]=[CH:34][C:35]=2[CH3:41])=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1ccc(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Reactant: Cc1ccc(-c2ncco2)cc1B(O)O
Product: Cc1ccc(-c2ncco2)cc1-c1ccc(NC(=O)c2c(F)cccc2F)s1

Procedure:
Compound 119 was synthesized in an analogous fashion as described for Compound 117 except that 5-(oxazol-2-yl)-2-methylbenzeneboronic acid was used instead of 3-trifluoromethylbenzeneboronic acid in the final step.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])[OH:3].[C:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:21]1[CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]1)[OH:3]
Reactant: CC(O)c1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)c1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-2-aminophenyl carbinol from Step 1 above (0.86 g, 6.3 mmol), N-Boc-4-piperidone (2.5 g, 12.6 mmol), and acetic acid (1.08 mL, 1.13 g, 18.9 mmol) were combined in methanol (10 mL). Sodium cyanoborohydride (0.79 g, 12.5 mmol) was added in portions, and the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo. Ethyl acetate (100 mL) was added to the residue and the resulting mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel eluted with 1:9 then 15:85 EtOAc:hexane. The combined product fractions were evaporated to dryness in vacuo to give methyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(F)ccc1O
Yield: 33.3 %

Procedure:
Using 5-fluorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Yield: 20.8 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (29 g, 0.135 mol), benzaldehyde (14.3 g, 0.135 mol) and borax (51.5 g, 0.135 mol) in ethanol (180 mL) and H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-phenyl-chroman-4-one (8.5 g, 21%). 1H-NMR (CDCl3): 2.89 (dd, 1H), 3.06 (dd, 1H), 5.46 (dd, 1H), 6.95 (d, 1H), 7.37-7.46 (m, 5H), 7.58 (d, 1H), 8.02 (d, 1H).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C[C:15]([CH3:18])([O-:17])C.[K+]>C1COCC1>[CH2:11]([OH:12])[CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:13][CH2:18][CH2:15][OH:17]
Reactant: OCCOCCOCCOCCO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCCO
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a solution of non-polydispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1 L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over ˜30 min). The reaction mixture was then stirred for 1 h and then 24 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, ˜200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 24. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 24. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the 25 has been removed from the aqueous phase. The first extraction will contain 24, 25, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H2O (50 mL volumes) until 25 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2×500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford a the non-polydispersed title compound as an oil (16.9 g, 41% yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH:19]=2)[CH2:14]1)(=[O:11])=[O:10].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:19]=2)[CH2:14]1)(=[O:10])=[O:11]
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1OC)C2
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1S(=O)(=O)NC1Cc2ccc(C(=O)CCC(=O)O)cc2C1

Procedure:
Prepared analogously to Example 2 from methyl 4-(2-o-methoxybenzenesulphonamido-indan-5-yl)-4-oxobuty rate by hydrolysis with sodium hydroxide.