Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:12])[CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>CN(C=O)C>[CH2:32]([O:31][C:29](=[O:30])[NH:11][CH2:10][C@@H:9]([OH:12])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
A solution of ((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-carbamic acid tert-butyl ester (D102) (25.6 g, 91.4 mmol, 1 equiv) in DMF (250 ml) at 0° C. was treated with NEt3 (15 ml, 108 mmol, 1.2 equiv) and then with benzyl chloroformate (14 ml, 98 mmol, 1.1 equiv) in DMF (50 ml) dropwise. The resulting solution was stirred at 0° C. for 1 h and at room temperature for 16 h and then concentrated in vacuo. The residue was partitioned between AcOEt and saturated aqueous NaHCO3 solution. The resulting precipitate was diluted with H2O and filtered to give ((2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-carbamic acid benzyl ester (D103) (31.5 g, 83%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].N1C=CC=CC=1.[CH3:19][O:20][C:21](=[O:27])[CH2:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:19][O:20][C:21](=[O:27])[CH2:22][S:23](=[O:25])(=[O:24])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
13.02 g (72.70 mmol) of 4-fluoro-3-trifluoromethylaniline and 6.79 ml (84.12 mmol) of pyridine are dissolved in 350 ml of dichloromethane. The mixture is cooled to 0° C. and then, under agitation and exclusion of moisture, 13.2 g (72.70 mmol) of 2-chlorosulfonylacetic acid methyl ester (95.3%), dissolved in 50 ml of dichloromethane, is added dropwise thereto. After agitation overnight, the mixture is washed with 2N hydrochloric acid and water. The dichloromethane solution is dried over sodium sulfate, concentrated to dryness under vacuum, and the residue is crystallized from diethyl ether/hexane. The title compound melts at 111-°113° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([NH:5][C@@H:6]([CH3:33])[C@H:7]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[N:21]=[CH:20]2)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[CH:9]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-]>CC1C=CC=CC=1>[F:34][C:2]([F:1])([F:35])[C:3]([NH:5][C@@H:6]([CH3:33])[C@H:7]([O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[N:21]=[CH:20]2)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)=[O:4]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(F)(F)F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(O)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a stirred solution of 2,2,2-trifluoro-N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)acetamide (Example 6, 10 mg, 20 μmol) in methylbenzene (1 ml) was added dodecanethiole (1 ml), followed with anhydrous aluminium chloride (5.3 mg, 40 μmol). The mixture was stirred at 40° C. for 1 h. Methylbenzene was removed in vacuo, the solution in dodecanethiole was diluted with n-heptane (10 ml). Oily precipitate has formed, which was washed with heptane, dried in vacuo, and dissolved in acetonitrile/water mixture. The crude product was purified by preparative HPLC afforded 4 mg of product as a white solid (42%).
Reaction SMILES: [CH3:1][C:2]12[CH2:11][C:6]3([CH2:12][CH3:13])[CH2:7][CH:8]([CH2:10][C:4]([CH3:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Br:15]Br.S([O-])([O-])=O.[Na+].[Na+]>>[Br:15][C:8]12[CH2:10][C:4]3([CH3:14])[CH2:5][C:6]([CH2:12][CH3:13])([CH2:11][C:2]([CH3:1])([CH2:3]3)[CH2:9]1)[CH2:7]2
Reactant: BrBr
Reactant: CCC12CC3CC(C)(CC(C)(C3)C1)C2
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CCC12CC3(C)CC(C)(CC(Br)(C3)C1)C2
Reaction time: 4 h
Yield: 86 %

Procedure:
Mix 0.4 mol of 1,3-dimethyl-5-ethyl adamantane (III) with a ten times excess of bromine (4 mol). Heat slowly and stir for 4 hrs under reflux. Subsequently allow to cool and pour onto ice water. Decompose the excess bromine with sodium sulfite until discolouration of the aqueous solution. Then extract with ether, wash the combined organic phases with sodium bicarbonate solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 86%).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][C:8]=1[CH3:9])[NH2:2].C(N(CC)CC)C.[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH3:9][C:8]1[C:3]2[N:4]([C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:2][N:1]=2)[N:5]=[C:6]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:7]=1
Reactant: Cc1cc(N2CCOCC2)nnc1NN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(N2CCOCC2)nn2c(-c3ccccc3)nnc12

Procedure:
1.48 Grams of 3-hydrazino-4-methyl-6-morpholinopyridazine and 1.8 grams of triethylamine are dissolved in 200 milliliters of dioxane. 3.5 Grams benzoyl chloride are added to the resulting mixture, and the mixture is heated at the boiling temperature under reflux for 3 hours. The mixture is evaporated to dryness, and the 8-methyl-6- -morpholino-3-phenyl-s-triazolo[4,3-b]pyridazine product is obtained as a residue. The product is washed with water, recrystallized from ethanol and found to melt at a temperature of 271°-273° C. 3.6 Grams of the product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg 4-oxazol-5-yl-benzenesulfonyl chloride. Purification by purification by reversed phase HPLC gave pure product. 1H-NMR (400 MHz, CDCl3): δ 7.21 (dd, H, J=1.5, 4.4 Hz), 7.30 (d, 1H, J=2.5 Hz), 7.42 (s, 1H), 7.54 (dd, 1H, J=2.5, 8.8 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.77 (s, 1H), 7.78 (d, 2H, J=8.4 Hz), 7.95 (s, 1H), 8.69 (d, 2H, J=5.8 Hz), 10.06 (br, 1H). MS: m/z 440.9 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]2)[CH2:28][O:27]1>>[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH:37][C:13](=[O:15])[CH:12]([N:8]3[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=4[F:1])[CH:6]=[N:7]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:33]2)[CH2:28][O:27]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (Intermediate 28) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as an off-white solid as a mixture of diastereoisomers (1.21 g, 79%); ES+-HRMS m/e calcd for C25H29N5O5F2 [M+H+] 518.2210 found 518.2214. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.6 Hz, 3H), 1.25 (s, 3H), 1.30, 1.31 (2×s, 3H), 1.38-1.51 (m, 1H), 1.74-1.85 (m, 1H), 2.12-2.24 (m, 1H), 3.74 (dd, J=8.4, 5.9 Hz, 1H), 3.97-4.17 (m, 3H), 4.35 (m, 1H), 5.52 (dd, J=11.2, 4.2 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.35-7.43 (m, 2H), 7.43-7.55 (m, 1H), 7.60 (m, 1H), 8.28 (d, J=2.7 Hz, 1H), 10.85 (s, 1H).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.[Br:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:12]=1N.[ClH:20]>C(O)(=O)C>[Cl:20][C:12]1[C:14]([Cl:19])=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=1[Br:10]
Reactant: Nc1c(Cl)cc(Cl)cc1Br
Reactant: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1cc(Cl)c(Cl)c(Br)c1

Procedure:
Sodium nitrite (3.88 g, 0.056 mole) was added in portions to concentrated sulphuric acid (28.16 ml) stirred below 10° C. A solution of 2-bromo-4,6-dichloroaniline (12 g, 0.05 mole, Lancaster) in glacial acetic acid (126 ml) was added maintaining the temperature below 10° C. The mixture was stirred below 10° C. for 1 hr and then slowly added to a stirred solution of cuprous chloride (10.11 g, 0.10 mole) in concentrated hydrochloric acid (101.05 ml) at room temperature. The mixture was then stirred at room temperature for 17 hrs. The product was filtered, washed with water (3×50 ml), dissolved in chloroform (150 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo to give the desired product. Yield 10 g (77%), M.p. 55-57° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[C:24](B(O)O)=[CH:23][N:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[C:25]([O:27][CH3:28])=[N:26][C:21]([O:20][CH3:19])=[N:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cnc(OC)nc3OC)cccc2c1N
Yield: 27.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.324 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (125 mg, 0.68 mmol) were reacted to afford the title compound (33 mg, 28% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (bm, 1H), 8.33 (s, 1H), 7.91 (dd, J=7.7, 2.0 Hz, 1H), 7.70-7.77 (m, 2H), 4.06 (s, 3H), 3.93 (s, 3H), 3.46 (apparent q, J=6.5 Hz, 2H), 1.67 (apparent sextet, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=369 (M+H) HPLC 1.69 min.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21]O)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C1(C)C=CC(S([Cl:38])(=O)=O)=CC=1>C(#N)C>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21][Cl:38])[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCO)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCCl)c12
Reaction time: 264 h
Yield: 48 %

Procedure:
To a solution of 3-[3-(phenylsulfonyl)-1H-indol-4-yl]propan-1-ol (1.006 g, 3.19 mmol) in anhydrous acetonitrile (25 mL) at room temperature under nitrogen was added pyridine (0.65 mL, 7.97 mmol) followed by p-toluenesulfonyl chloride, and the reaction mixture stirred for 11 days. The reaction mixture was then concentrated to a small volume in vacuo, and the mixture partitioned between ethyl acetate (100 mL) and 1 N aqueous HCl (100 mL). The organic phase was separated, washed with water (2×100 mL) and brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow syrup. Purification by flash chromatography (0 to 40% ethyl acetate/hexane) afforded 3-phenylsulfonyl-4-(3-chloro-propyl)-1H-indole as a colorless foam (0.51 g, 48%). MS (ES+) m/z 334 (M+H). Further elution afforded 3-[3-(phenylsulfonyl)-1H-indol-4-yl]propyl 4-methylbenzenesulfonate as a white foam (0.48 g, 32%). MS (ES+) m/z 469.7 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:61][C:62]([CH3:75])([CH3:74])[CH2:63][NH:64][S:65]([CH2:68][CH2:69][NH:70][CH:71]([CH3:73])[CH3:72])(=[O:67])=[O:66]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:70]([CH2:69][CH2:68][S:65](=[O:67])(=[O:66])[NH:64][CH2:63][C:62]([CH3:75])([CH3:74])[CH3:61])[CH:71]([CH3:72])[CH3:73])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CC(C)NCCS(=O)(=O)NCC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(CCS(=O)(=O)NCC(C)(C)C)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.030 g) and HATU® (0.058 g) in DMF (0.4 ml) was added DIPEA (0.040 ml) followed by a solution of 2-isopropylamino-ethanesulfonic acid (2,2-dimethyl-propyl)-amide (0.070 g) in DMF (0.6 ml) after 10 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.042 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[CH3:18].C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[CH3:18][C:3]1[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:5][C:6]2[C:11]([CH:2]=1)=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2
Reactant: CCOC(=O)c1nc2ccc(C)cc2c(Cl)c1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2ccc(C)cc2cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 4-chloro-3,6-DIMETHYLQUINOLINE-2-carboxylate (3.0 g), triethylamine (2.4 ml) and 10% palladium on carbon (300 mg) in ethyl acetate (30 ml) was stirred for 4 hours at ambient temperature under hydrogen atmosphere. After filtration the filtrate was concentrated in vacuo and diluted with dichloromethane. The mixture was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (dichloromethane-ethyl acetate) to give ethyl 3,6-dimethylquinoline-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:13]([OH:26])[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].[O:27]1[CH:31]=[CH:30][CH2:29][CH2:28]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1([N:13]([O:26][CH:28]2[CH2:29][CH2:30][CH2:31][O:27]2)[C:14](=[O:25])[CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1(N(OC2CCCO2)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1

Procedure:
To a solution of 4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.3 obtained in analogy to preparation example 11, step 4) (70 g, 192.1 mmol) in dichloromethane (1500 ml) under argon atmosphere was added 2,3-dihydro-furan (29.1 ml, 26.9 g, 384.1 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (1.94 g, 19.2 mmol). The reaction mixture was stirred at reflux for 7 hours, filtered and concentrated. The residue was triturated with hexane, filtered and the solid dried in vacuo. Yield: 70.0 g of 1-methoxy-4-{(tetrahydro-furan-2-yloxy)-[2-(2,4,6-trimethyl-phenyl)acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (compound P3ii.6) as a solid, mp 107-109° C. This material was used without further purification in the next step.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:12](O)(=O)/[C:13](=[C:15](\[CH:17]=[O:18])/[Br:16])/[Br:14].Cl>C(O)C.O>[Br:14][C:13]1[CH:12]=[N:2][N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[C:17](=[O:18])[C:15]=1[Br:16]
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: NNc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-n2ncc(Br)c(Br)c2=O)cc1
Yield: 93.1 %

Procedure:
4-Hydrazinobenzoic acid (2.00 g, 13.1 mmol) in ethanol-water (1:1, 20 mL) was stirred with mucobromic acid (2.26 g, 8.76 mmol) and concentrated hydrochloric acid (10 mL) at 70° C. for 2 days. After cooling, the resulting crystals were collected by filtration, washed with ethanol and water and dried under reduced pressure to give the desired product (3.05 g, 62% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C([Li])CCC.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH:5][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1Nc1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
A solution of 3,4-difluoroaniline (10.0 mL, 1.0 mol) in tetrahydrofuran (200 mL) was cooled to −78° C., treated with n-butyllithium solution (44 mL of a 2.5 M hexanes solution, 1.1 mol), stirred at −78° C. for 1 h and then warmed to 0° C. for 30 min. The reaction mixture was cooled to −78° C. and 1-fluoro-2-nitrobenzene (9.5 mL, 0.9 mol) in tetrahydrofuran (10 mL) was slowly added and the reaction, after which the reaction was warmed to room temperature. The reaction mixture was evaporated to provide 3,4-difluoro-N-(2-nitrophenyl)aniline (22.76 g, 91%) as a brown solid. The crude product was taken on to the next step.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)#[N:39].Cl>CN(C)C=O>[CH2:1]([N:8]([C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([C:38]#[N:39])=[CH:41][CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1cccc(OC[C@@H](CC(=O)OCc2ccccc2)NCc2ccccc2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N(Cc2ccccc2)[C@@H](COc2cccc(C#N)c2)CC(=O)OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
190 mg (0.47 mmol) of benzyl 3-(3R)-benzylamino-4-(3-cyanophenoxy)butyrate and 153 mg of triethylamine were stirred in 5 ml of dimethylformamide, and 70 mg (0.47 mmol) of 4-cyanobenzoyl chloride was added thereto under cooling with ice and stirred for 3 hours. 1 N hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The extract was washed with 1 N sodium hydroxide and saturated saline and dried over magnesium sulfate anhydride, and the solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.[BH4-].[Na+].[OH-].[Na+]>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[CH2:9][OH:10])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Crude 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (26.4 g) in absolute ethanol (200 mL) was treated with sodium borohydride (8.23 g, 217 mmol) under an argon atmosphere at room temperature for 0.33 h. Ten percent aqueous sodium hydroxide (150 mL) was added, the ethanol was removed in vacuo and the aqueous residue was extracted three times with ether. The organic extract was washed twice with brine, was dried (sodium sulfate), was filtered and was evaporated to a pale yellow oil (24.4 g).
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]([O:23][CH2:24][CH2:25][CH3:26])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:15][CH2:16][C:17]([O:19]CCC)=[O:18].C(O)(=O)C>C(O)CC>[O:3]=[C:4]([O:23][CH2:24][CH2:25][CH3:26])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCOC(=O)CCc1[nH]c2ccccc2c1CC(=O)OCCC
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Solvent: CC(=O)O
Product: CCCOC(=O)Cc1c(CCC(=O)O)[nH]c2ccccc12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Aqueous 8 N KOH (1.05 equiv.) was added to a stirred solution of propyl 3-[3-(2-oxo-2-propoxyethyl)-1H-indol-2-yl]propanoate from Step 1 in n-propanol (0.5 M). The mixture was stirred at 50° C. for 4 h. The reaction mixture was cooled to rt, quenched with acetic acid (1.2 equiv.) and concentrated. The residue was purified on a pad of silica gel using CH2Cl2, then CH2Cl2/EtOAc (9:1) and finally CH2Cl2/EtOAc/MeOH (88:10:2) to afford after evaporation of the volatiles, the desired material (68%) as yellow oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([F:23])[C:20](B(O)O)=[C:19]([F:27])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:23][C:21]1[CH:22]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=2)[CH:18]=[C:19]([F:27])[C:20]=1[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(Br)s1
Reactant: CCCc1ccc(-c2cc(F)c(B(O)O)c(F)c2)cc1
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: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(-c2cc(F)c(-c3ccc(C)s3)c(F)c2)cc1

Procedure:
A mixture of 5.50 g (31.0 mmol) of 2-bromo-5-methylthiophene, 9.0 g (32.6 mmol) of 4′-propyl-3,5-difluoro-4-biphenylboronic acid, 1.83 g (1.58 mmol) of tetrakis(triphenylphosphine)palladium(0) and 36 ml of 2 N sodium carbonate soln. in 90 ml of toluene/ethanol (1:2) is heated under reflux for 16 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with toluene. The combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to completion. The residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). Further purification is carried out by recrystallisation from ethanol and n-heptane; 2-(3,5-difluoro-4′-propylbiphenyl-4-yl)-5-methylthiophene (PUS-3-1) is obtained as a colourless solid (m.p. 75° C.).