Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.CS(O)(=O)=O>ClC1C=CC=CC=1>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]2[S:30][C:14]3[CH:15]=[C:16]([O:17][CH3:18])[CH:19]=[CH:20][C:13]=3[CH:11]=2)=[CH:2][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Agent: CS(=O)(=O)O
Solvent: Clc1ccccc1
Product: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Temperature: 100 °C
Yield: 10 %

Procedure:
Anisoin (2.87 g), 50 ml of chlorobenzene, and Lawesson's Reagent 4.04 g are placed in a flask under nitrogen. The mixture is heated to 100° C. and a methanesulfonic acid (0.65 mL) is added and the mixture heated at reflux for 92 hours. The reaction is cooled to room temperature before filtering the solids which form. The filter cake is washed with 25 ml of chlorobenzene and dried to give 270 mg of product. The solid is recrystallized from hot chlorobenzene to give 90 mgs of pure product. Analysis calculated for C16H14O4S: C, 71.08; H, 5.22; S, 11.86. Found: C, 71.27; H, 5.43; S, 11.78. MS.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]([OH:37])[CH2:34][NH:35][CH3:36].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:35]([CH2:34][CH:33]([OH:37])[C:29]4[NH:28][CH:32]=[CH:31][N:30]=4)[CH3:36])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ncc[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN(C)CC(O)c2ncc[nH]2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 5 h
Yield: 48.8 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(1H-imidazol-2-yl)-2-(methylamino)ethanol dihydrochloride (Preparation 99)(82 mg, 0.38 mmol) and diisopropylethylamine (230 μL, 1.3 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (61 mg) as a white solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][C@:14]1([C:30]([O:32][CH3:33])=[O:31])[CH2:24][C@@H:23]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])[C@@H:17]2[O:18]C(C)(C)[O:20][C@@H:16]2[CH2:15]1>CO>[OH:13][C@:14]1([C:30]([O:32][CH3:33])=[O:31])[CH2:24][C@@H:23]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])[C@H:17]([OH:18])[C@H:16]([OH:20])[CH2:15]1
Reactant: COC(=O)[C@]1(O)C[C@H]2OC(C)(C)O[C@H]2[C@H](OS(C)(=O)=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](OS(C)(=O)=O)C1
Reaction time: 8 h
Yield: 78 %

Procedure:
Para-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) was added to a room temperature solution of Example 17A in methanol (50 mL). After stirring overnight, the reaction mixture was concentrated and the concentrate was purified by flash column chromatography using ethyl acetate to afford 3.96 g (78%) of the desired product as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:4])=[O:3].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CO>CN(C=O)C>[O:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:5]([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:11]([O:13][CH3:14])=[O:12])[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:20][CH2:21]1
Reactant: COC(=O)c1sccc1NS(C)(=O)=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1sccc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-(methylsulfonamido)thiophene-2-carboxylate (prepared in an analogous manner as described in Example 8, Scheme 8, Step 1, 500 mg, 2.125 mmol), 4-(2-chloroethyl)morpholine hydrochloride (435 mg, 2.338 mmol) and potassium carbonate (646 mg, 4.68 mmol) in dry DMF (13 ml) was heated at 80° C. for 5 h and stirred at RT for 3 days. The solvent was evaporated, the residue was diluted with EtOAc and washed with H2O and brine; the organic layer was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/EtOAc=8/2 to 7/3 and then DCM/MeOH=95/5) to afford methyl 3-(N-(2-morpholinoethyl)-methylsulfonamido)thiophene-2-carboxylate (Int. 50) (655 mg, 1.880 mmol, MS/ESI+ 348.9 [MH]+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[CH2:10][N:11]1[C:16]([CH3:17])=[C:15]([Cl:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29](C(OC(C)(C)C)=O)[CH3:30])[CH:23]=2)[C:12]1=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:15]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH3:30])[CH:23]=2)[C:12](=[O:38])[N:11]([CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:39])[C:16]=1[CH3:17]
Reactant: Cc1c(Cl)nc(NCCc2cccc(CN(C)C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Benzyl-2-[3-[(3-[(tert-butoxycarbonyl)(methyl)amino]methylphenethyl)amino]-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 18) (0.7 g, 1.26 mmol) was dissolved in CH2Cl2 (10 ml) and treated with TFA (1.0 ml). After stirring at room temperature for 3 hr, the reaction mixture was evaporated to dryness then dissolved in ethyl acetate (200 ml) washed with sat. aq NaHCO3, sat aq brine, dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a dark brown oil which was purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 98:2 CH2Cl2:MeOH; 95:5 CH2Cl2:MeOH; 95:5:1 CH2Cl2:MeOH:NH3) to give the desired product (0.38 g, 65%). 1H NMR (CDCl3) δ 2.00 (s, br, 1H), 2.20 (s, 3H), 2.45 (s, 3H), 2.90 (t, 2H), 3.70 (m, 2H), 3.75 (s, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10 (m, 1H), 7.15 (m, 2H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z=455.0, 457.2 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1O[CH2:33][CH2:32]OCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([C:33]2[CH:32]=[CH:5][CH:4]=[CH:3][CH:8]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COc1cccc(N)c1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc(N(c2ccccc2)c2ccccc2)c1

Procedure:
3-methoxytriphenylamine was prepared by a phase transfer variant of the Ullmann coupling procedure (S. Gauthier and J. M. J. Fréchet, Synthesis, 1987, 1331) in which 37.34 g m-Anisidine, 142.47 g iodobenzene, 74.93 g copper powder, 2.20 g 18-crown-6 and 320.8 g anhydrous potassium carbonate in 500 ml phenyl ether were placed into a 1 liter three necked round bottom flask equipped with overhead stirrer, reflux condenser, nitrogen inlet, thermowell, and heating mantle and heated at reflux overnight. The solids were removed by filtration and the solvents by vacuum distillation. The resulting brown oil is used in step 2 below.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc(C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of 4′-hydroxy-3′-methylacetophenone (25.0 g) in N,N-dimethylformamide (120 ml) were added potassium carbonate (69.1 g) and methyl iodide (11.4 ml) under ice-cooling, and the mixture was stirred for 2 hr under ice-cooling and further at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (27.5 g) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([Cl:10])=[CH2:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[C:4]([CH3:15])[N:3]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.O>C(#N)C>[Cl:10][C:8]([C:7]1[C:2]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[N:3][C:4]([CH3:15])=[N:5][C:6]=1[C:11]([F:14])([F:13])[F:12])=[CH2:9]
Reactant: C=C(Cl)c1c(Cl)nc(C)nc1C(F)(F)F
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: C=C(Cl)c1c(-n2ccnc2)nc(C)nc1C(F)(F)F
Temperature: 25 °C
Yield: 65.2 %

Procedure:
4-Chloro-5-(1-chlorovinyl)-2-methyl-6-trifluoromethylpyrimidine (1.83 g) was dissolved in acetonitrile (20 ml) under stirring in room temperature. The mixture was added imidazole (1.45 g) and refluxed 3 hr and then cooled to room temperature and added water. The mixture was extracted with chloroform. The chloroform layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-THF) to give 5-(1-chlorovinyl)-4-imidazol-1-yl-2-methyl-6-trifluoromethyl-pyrimidine (1.34 g) as pale brown oil. 1H-NMR (δ, ppm); 2.82 (s, 3H), 5.78 (d, 1H), 6.03 (d, 1H), 7.21 (br, 1H), 7.87 (br, 1H), 8.55 (br, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.[C:15](=[O:18])([O-])[O-].[K+].[K+].[I-].[K+].[CH3:23][N:24]([CH3:27])C=O>>[ClH:1].[F:14][C:12]1[CH:11]=[CH:10][C:9]2[C:5]([CH2:4][CH2:3][CH2:2][N:24]3[CH2:27][CH2:11][CH2:12][C@@:13]4([CH2:8][C@@H:9]5[CH2:5][CH:4]=[CH:3][CH:2]=[C:15]5[O:18]4)[CH2:23]3)=[N:6][O:7][C:8]=2[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: CN(C)C=O
Agent: [I-]
Agent: [K+]
Product: Cl
Product: Fc1ccc2c(CCCN3CCC[C@@]4(C[C@@H]5CC=CC=C5O4)C3)noc2c1
Temperature: 90 °C
Yield: 38 %

Procedure:
In 50 ml dry dimethylformamide (DMF) were combined 5.00 g (22.2 mmol) 2,3-dihydro-spiro[benzofuran-2(3H),3'-piperidine]hydrochloride of Example 1c, 7.41 g (1.25 equivalents) 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole of Example 1d, 18.4 g (6 equivalents) milled anhydrous potassium carbonate, and a catalytic amount (0.5 g) potassium iodide. The mixture was stirred under nitrogen at 90° C. for three and one-half hours, then cooled and filtered. The DMF was evaporated in vacuo to an oil which was partitioned between 10% K2CO3 and ether. The ether was separated, washed with water, saturated aqueous alt solution, dried over MgSO4, filtered, and passed through a column of 40 g alumina in ether. The product-containing fractions were combined and adjusted to pH 1 with ethereal-HCl. The resultant precipitate was collected and recrystallized from 1:1 dichloromethane/ethyl acetate to yield 3.36 g (38%) of (R,S)-dihydro-1'-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-spiro[benzofuran-2(3H),3'-piperidine]hydrochloride, m.p. 257°-259° C.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]([NH2:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(O)C>[CH:10]([NH:13][CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: CCOC(=O)/C=C/CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)/C=C/CNC(C)C
Yield: 65.8 %

Procedure:
Ethyl 4-bromocrotonate (25.0 g) was added dropwise to a solution of isopropylamine (7.7 g) and triethylamine (13.2 g) in ethanol (200 ml) at room temperature under stirring and taking an hour. The mixture was stirred for 5.5 hours at room temperature. After removing the solvent, to the residue was added ethyl acetate, and the mixture was extracted with 1N hydrochloric acid. Ethyl acetate was added to the hydrochloric acid layer, and alkalified by addition of potassium carbonate powder. After removing the separated oily substance, the ethyl acetate layer was taken out, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and distilled to remove the solvent to give the title compound (14.6 g) as pale yellow oily substance.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)O1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:37]=[C:36]([OH:38])[C:30]3[CH2:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[CH:28]=2)=[O:26])=[N:20]1.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:37]=[C:36]([O:38][C:9]3[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)[C:30]3[CH2:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[CH:28]=2)=[O:26])=[N:20]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)nc3)c3c(c2)OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.5 %

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (634 mg, 2.76 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (396 mg, 1.33 mmol), Et3N (0.96 mL, 6.89 mmol), and Cu(OAc)2 (501 mg, 2.76 mmol) in CH2Cl2 (15 mL) was stirred at room temperature with 4 A molecular sieves for 4 days, then filtered through celite, washed with CHCl3, concentrated, and purified by column chromatography with 30-60% EtOAc in hexanes to give a white foam (246 mg, 46% yield). 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1 H) 8.45 (d, J=2.53 Hz, 1 H) 7.65 (d, J=8.59 Hz, 1 H) 7.21-7.35 (m, 2H) 7.10 (d, J=11.37 Hz, 2 H) 6.78 (d, J=2.02 Hz, 1 H) 3.73 (s, 3 H) 2.89 (s, 2 H)) 1.48 (s, 6 H); LCMS for C21H19N5O3 m/z 390.00 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:7]=1
Reactant: CC(C)(O)c1cc(Br)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of 2-(5-bromo-2-chlorophenyl)-propan-2-ol (500 mg, 2 mmol, 1 eq) in toluene (5 ml) was added a catalytic amount of p-toluenesulfonic acid (38 mg, 0.2 mmol, 0.1 eq) and the solution was refluxed under a Dean-Stark H2O separator overnight. The reaction mixture was allowed to cool to RT and was diluted with ether. The mixture was washed with sat. NaHCO3-solution and brine, dried (MgSO4), filtered and concentrated in vacuo to give the desired product (357 mg, 77%) as a colorless oil which did not require further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([F:15])([F:14])[CH2:12][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:21][CH3:22])CC)C.[C:23]1(C)[C:24]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:26]=C[CH:28]=1>ClCCl.CCOCC>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:15])[CH2:12][NH:13][S:29]([C:24]1[CH:25]=[CH:26][C:21]([CH3:22])=[CH:28][CH:23]=1)(=[O:31])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: NCC(F)(F)CCOCc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NCC(F)(F)CCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-benzyloxy-2,2-difluorobutylamine (5.16 g, 20.5 mM) and triethylamine (4.4 g, 43.4 mM) in dry dichloromethane is added toluenesulfonyl chloride (4.14 g, 21.7 moles). The mixture is stirred at room temperature overnight. Additional dichloromethane is added, and the organic phase is washed with 1N HCl followed by a water wash. Drying (Na2SO4) and evaporation of the solvent yields a white solid which is dissolved in a small volume of ether. Addition of petroleum ether yields the compound, N-(4-benzyloxy-2,2-difluorobutyl)-p-toluenesulfonamide as white crystals: 7.0 g (92%).
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[OH:55][C:48]1[C:47]([CH2:46][NH:45][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH2:4][CH2:3][OH:2])[CH3:6])=[CH:15][CH:14]=2)=[C:52]([CH3:53])[CH:51]=[C:50]([CH3:54])[N:49]=1
Reactant: COCCC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
A mixture of 4-(4-methoxybutan-2-yl)benzoic acid (177 mg, 0.85 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (245 mg, 1.3 mmol), N-hydroxybenzotriazole (176 mg, 1.3 mmol) and triethylamine (258 mg, 2.55 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (130 mg, 0.85 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (47 mg, 17%). LRMS (M+H+) m/z: calcd 324.19 found 324. 1H. NMR (300 MHz, CD3OD): δ 12.96 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 5.95 (s, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.20-3.14 (m, 5H), 2.93 (q, J=7.2 Hz, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.23 (d, J=6.9 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:20][CH3:21].[Cl:22]Cl.O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][C:14]([CH3:18])([CH3:19])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:20][CH3:21])[Cl:22]
Reactant: ClCl
Reactant: CCC1Cc2cc(OC(C)(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: CC(=O)O
Solvent: O
Product: CCC1(Cl)Cc2cc(OC(C)(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 1 h

Procedure:
2-(1-Oxo-2-ethyl-6,7-dichloro-5-indanyloxy)-2-methylpropionic acid (4.7 g., 0.0014 mole) is dissolved in warm acetic acid (170 ml.) and treated with a solution of chlorine (1.06 g., 0.015 mole) in acetic acid (20 ml.) at 20° C. with stirring. The reaction mixture is kept at 20° C. for one hour and then at 80°0 C. for one hour. The reaction mixture is cooled and added to water (1 1.) with stirring. The white powder that separates is recrystallized from acetic acid-water (4:3) to obtain 3.0 g. of 2-(1-oxo-2-ethyl-2,67-trichloro-5-indanyloxy)-2-methylpropionic acid, m.p. 164.5°-165° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl.[NH:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:16]([C:23](O)=[O:24])[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:16]([C:23]([NH:1][C@H:2]([C:10]([NH2:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1)=[O:24])[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: NC(=O)[C@@H](N)Cc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H](Cc1cccnc1)C(N)=O)C1CCCCC1
Yield: 81.2 %

Procedure:
Stir overnight H-(L)-Pal-NH2.2HCl (432 mg, 1.82 mmol), Boc-(L)-Chg-OH (609 mg, 2.37 mmol, 1.3 equivalent), dicyclohexylcarbodiimide (494 mg, 2.4 mmol), hydroxybenzotriazole (324 mg, 2.4 mmol) and diisopropylethylamine (4 mmol) in dimethyl formamide (15 mL). Evaporate dimethyl formamide, add ethyl acetate and store the mixture at room temperature for 1 h. Filter off the diisopropylcarbodiimidecyclohexylurea formed, extract the solution by a saturated solution of sodium bicarbonate (3×), dry over magnesium sulfate, and evaporate. Crystallize by addition of hexanes to give Boc-(L)-Chg-(L)-Pal-NH2 (598 mg, 81%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[CH3:12][CH:13]([C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](OCC)=[O:15].C(O)(C(F)(F)F)=O.O>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14](=[O:15])[CH:13]([CH3:12])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:11]1
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2Cl)C(=O)C1C
Temperature: 75 °C

Procedure:
2,4-dichlorophenylhydrazine hydrochloride(12.6 g) is dissolved in 100 ml of toluene and this solution is placed under nitrogen; after stirring, 10 g of diethyl 2-methyl-3-oxosuccinate are added and the mixture is then heated and 5 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 30 ml of water. The mixture is separated by settling out, the aqueous phase is discarded and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 10 ml of toluene and the expected product then crystallizes, m=10.2 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([O:19]S(C)(=O)=O)=[C:14]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([OH:19])=[C:14]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1c(-c2ccc(F)cc2)ccc2cc(OCc3ccccc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1c(-c2ccc(F)cc2)ccc2cc(OCc3ccccc3)ccc12
Temperature: 50 °C
Yield: 80.3 %

Procedure:
Dissolve methanesulfonic acid 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yl ester (5.2 g, 12.3 mmol) in 5M sodium hydroxide (12 mL, 60 mmol), THF (86 mL) and MeOH (86 mL). Heat to 50° C. for 1 hour. Cool and add ethyl acetate (100 mL). Wash the organic layer with 1N HCl, saturated sodium bicarbonate solution and brine. Dry with magnesium sulfate and concentrate in vacuo to obtain 3.4 g (89%) of 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-ol.