Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>C(Cl)CCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:29]=3)[CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(NC1Cc2ccccc2C1)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 3 h

Procedure:
38.5 g (0.289 mol) of anhydrous aluminium chloride and 12.4 g (0.124 mol) of succinic anhydride are suspended in 250 ml of ethylene chloride and 25.4 g (0.082 mol) of 2-p-chlorobenzenesulphonamido-indane are then added, with vigorous stirring. In the course of this, a clear solution is formed. After 3 hours, the product is decomposed by means of ice and hydrochloric acid, and the reaction product is isolated from the organic phase. It is recrystallised from glacial acetic acid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH3:28][C:29]1([CH3:44])[N:34]([CH3:35])[CH2:33][CH2:32][N:31]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)[CH2:30]1.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl.CO>[CH3:28][C:29]1([CH3:44])[N:34]([CH3:35])[CH2:33][CH2:32][N:31]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:5])=[N:41][CH:42]=2)[CH2:30]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1(C)C
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)C(C)(C)C4)cn3)c3nccnc23)c1F
Reaction time: 0.25 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-(3,3,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 107.1), stirring the reaction mixture for 15 min at reflux, pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 563.1 [M+H]+; tR=3.72 min (System 1); TLC: Rf=0.33 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]#[N:31])=[CH:24][C:23]=2[CH2:32][CH:33]([CH3:35])[CH3:34])[CH:11]=[CH:12][C:13]=1OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([C:40]1[CH:41]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[CH:37]([CH3:39])[CH3:38].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[CH2:1]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]#[N:31])=[CH:24][C:23]=2[CH2:32][CH:33]([CH3:35])[CH3:34])[CH:11]=[CH:12][C:13]=1[C:42]1[CH:43]=[CH:44][C:45]([O:46][CH3:47])=[C:40]([CH2:36][CH:37]([CH3:38])[CH3:39])[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)cc1CC(C)C
Temperature: 80 °C
Yield: 88.9 %

Procedure:
134.6 mg (0.27 mmol) Trifluoro-methanesulfonic acid 3-benzyl-4′-(2-Cyano-ethyl)-2′-isobutyl-biphenyl-4-yl ester (54), 96.9 mg (0.33 mmol, 1.24 eq.) 2-(3-isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (11) and 46.7 mg (40 μmol, 0.15 eq.) Pd(Ph3P)4 were dissolved in 7 ml DME/EtOH (9+1). To this yellow solution 0.27 ml (0.54 mmol, 2.00 eq.) of a 2 M aq. Na2CO3-solution was added and the resulting mixture was heated at 80° C. for 19 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (6+1)) yielded 122.9 mg (0.24 mmol, 88.26%) 3-(3′-Benzyl-2,3″-diisobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (55) as a clear oil. Rf (hexanes/EtOAc (6+1))=0.20. 1H-NMR (500 MHz, CDCl3): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH3), 0.84 (d, 6H, J=6.62 Hz, 2*CH3), 1.63 (m, 1H, CH), 1.83 (m, 1H, CH), 2.42 (d, 2H, J=7.25 Hz, CH2), 2.44 (d, 2H, J=7.25 Hz, CH2), 2.61 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.93 (t, 2H, J=7.41 Hz, CH2CH2CN), 3.81 (s, 3H, OCH3), 3.98 (s, 2H, CH2Ph), 6.81 (d, 1H, J=8.51 Hz), 6.96 (m, 2H), 7.00-7.18 (m, 10H), 7.24-7.26 (d, 1H, J=7.57 Hz). MS (EI): m/z=517 (10), 516 (45), 515 (100), 472 (10), 381 (8), 91 (20). HR-MS (EI): Calcd. for C37H41NO: 515.318814. Found: 515.319235.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO[CH2:6]/[C:7](=[CH:9]\[CH2:10][CH2:11][CH:12]([CH2:14][CH:15]=O)[CH3:13])/[CH3:8]>CO>[CH3:1][O:2][C:7]([CH3:6])([CH3:8])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH2:14][CH:15]=[CH:13][C:12]1[CH:14]=[CH:15][C:9]([CH:7]([CH3:8])[CH3:6])=[CH:10][CH:11]=1
Reactant: C[O-]
Reactant: COC/C(C)=C\CCC(C)CC=O
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)CCCC(C)CC=Cc1ccc(C(C)C)cc1

Procedure:
reacting said methanol solution with sodium methoxide, followed by methoxycitronellal to produce 8-methoxy-4,8-dimethyl-1-(4-isopropylphenyl)-1-nonene, and
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=O)=O.[N-:23]=[N+]=[N-].[Na+].C(O)C>CN(C=O)C.[Pd]>[NH2:23][CH2:6][CH:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CN)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)ethyl methanesulfonate (Intermediate 23) (535 mg, 1.53 mmol) in DMF (8 mL) was treated with sodium azide (199 mg, 3.06 mmol) and the mixture was heated at 80° C. for 1 hour. The mixture was cooled and allowed to stir at room temperature overnight. The solution was partitioned between ethyl acetate and water. The organic layer was washed twice with water then dried with magnesium sulfate, filtered and concentrated until the final volume was approximately 5 mL. Ethanol (20 mL) and 10% palladium on carbon (75 mg, 0.07 mmol) were added. The resulting suspension was stirred under an atmosphere of hydrogen at ambient pressure and temperature for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 2-amino-1-(4-chlorophenyl)ethylcarbamate as a gum (410 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([F:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>ClCCl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:12]([O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1ccc(Br)cc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)ethanol (3.01 mmol) in dichloromethane (5 mL) and pyridine (10 mL) was treated with 4-(dimethylamino)pyridine (0.151 mmol) and acetic anhydride (9.04 mmol). The reaction was stirred overnight at room temperature. At this point the reaction was diluted with dichloromethane (100 mL). The organic layer was washed three times with 1N aq HCl, once with saturated aq sodium bicarbonate, and once with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale beige oil (710 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 1.96 (s, 3 H) 2.90 (t, J=6.44 Hz, 2 H) 4.20 (t, J=6.57 Hz, 2 H) 7.26-7.43 (m, 2 H) 7.51 (dd, J=9.73, 1.89 Hz, 1 H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)(Cl)Cl.O.[CH2:22]([OH:24])C>>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][C:12]=1[CH:22]=[O:24]
Reactant: CCO
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1cc(Oc2ccccc2)ccc1O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
4-Phenoxyphenol (20.0 g, 107 mmol) and sodium hydroxide (3.8 g, 845 mmol) are dissolved in a water/ethanol (130 mL/26 mL) mixture and heated at 70° C. To this reaction mixture is added chloroform (24.6 g, 215 mmol) dropwise over 45 minutes, and heating is continued for 3 hours. The mixture is cooled to room temperature, and then evaporated. The aqueous phase is acidified with concentrated hydrochloric acid to pH 1-3, and extracted with ether. The organic phase is dried over magnesium sulfate and evaporated. Purification of the residue by silica-gel flash chromatography gives 2-hydroxy-5-phenoxybenzaldehyde as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=O)[C:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:17])=O>>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:17])[C:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1nc(C)c(CC)c(=O)[nH]1
Product: CCCCc1nc(C)c(CC)c(Cl)n1

Procedure:
The pyrimidinone from Example 1 2-butyl-5-ethyl-6-methylpyrimidin-4(3H)-one is converted to the title compound upon treatment with phosphoryl chloride as described by Gabriel and Colman (Ber. 1899, 32, 2921) and by Marshall and Walker (J. Chem. Soc., 1951, 1004).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:52])[CH3:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53](OCCl)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55].[H-].[Na+]>O1CCCC1>[CH3:55][C:54]([CH3:57])([CH3:56])[C:53]([O:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:51])=[O:58]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)C(C)(C)C)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 27.8 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 1m (0.4 g, 0.56 mmol, obtained from the synthetic method described in step 11 of example 1) and chloromethyl pivalate (0.36 mL, 2.5 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (77.8 mg, 1.95 mmol, 60% dispersion in Mineral oil) at 0° C. The mixture was heated to 40° C. and stirred for 48 hours. The resulting mixture was quenched with saturated ammonium chloride (20 mL), and then extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with water (50 mL×2) and then saturated brine (50 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 14a as light yellow oil (125 mg, 27.8%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ (ppm): 7.42-7.30 (m, 10H), 7.28-7.15 (m, 6H), 7.07 (m, 2H), 6.91 (m, 2H), 6.76 (m, 2H), 5.20 (m, 1H), 4.98 (d, 1H), 4.89-4.82 (m, 2H), 4.31 (m, 1H), 4.25 (d, 1H), 4.11-3.80 (m, 7H), 3.86 (d, 1H), 3.70 (m, 2H), 1.41 (t, 3H), 1.27 (d, 3H), 1.20 (s, 9H).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]([NH2:13])=[O:12])[CH2:3]1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O>[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][O:9][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:4]([C:11]([NH2:13])=[O:12])[CH2:3]1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
(2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxa mide (4.10 g) and imidazole (3.27 g) were dissolved in dehydrated N,N-dimethylformamide (100 mL). While the solution was cooled in an ice bath, a solution of tert-butyldimethylsilyl chloride (3.62 g) in dehydrated N,N-dimethylformamide (30 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and dissolved in ethyl acetate (300 mL). The ethyl acetate solution was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-4-fluoro-1-[2-(tert-butyldimethylsilyloxy)acetyl]pyrro lidine-2-carboxamide as a white solid (6.17 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([C:31](O)=[O:32])=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]=[CH:22][CH:23]=[CH:24]3)=[O:32])[CH2:6][CH2:7]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)c1ccc2ncccc2c1
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1ccc2ncccc2c1

Procedure:
Prepared as described in Example from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and quinoline-6-carboxylic acid (0.054 g). Title compound obtained as white solid (0.032 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[C:12]1([CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:11]=[C:10]1[C:4]2[S:3][C:2]([NH:1][C:19](=[O:20])[CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:22][CH3:23])=[N:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C(=O)Nc1nc2c(s1)C(=O)CCC2)c1ccccc1
Reaction time: 16 h

Procedure:
2-Amino-5,6-dihydro-4H-benzothiazol-7-one (34 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (31 mg, 0.099 mmol, 49%). ESI-MS m/z calc. 314.1. found 315.3 (M+1)+ Retention time 2.90 minutes.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.O1CCOCC1.C(Cl)[Cl:31]>Cl>[ClH:31].[ClH:31].[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3([NH2:7])[CH2:10][CH2:9]3)=[N:12][CH:13]=2)[CH:18]=[N:19]1
Reactant: ClCCl
Reactant: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nc2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(C3(N)CC3)nc2)cn1
Reaction time: 8 h

Procedure:
To a solution of {1-[5-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (1.1 g, 3.5 mmol) in CH2Cl2 (15 mL), 4.0M HCl in dioxane (4.35 mL, 17.5 mmol) was added. After stirring overnight, more 4.0M HCl in dioxane (4.35 mL, 17.5 mmol) was added to the solution. After another 12 hours, the solution was concentrated in-vacuo to yield 800 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH2:9].[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:9][CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][NH:6][C:2]5=[O:1])[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCCN1CCNC1=O
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCN5CCNC5=O)n4)cc3)cc12

Procedure:
Using 2-(2-oxo-imidazolidin-1-yl)-ethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 2.96 (bt, 2H); 3.24 (m, 4H); 3.47 (m, 6H); 6.26 (s, 1H); 7.18 (m, 2H); 7.27 (bt, 1H, J=5 Hz); 7.48 (m, 2H); 7.91 (d, 2H, J=9 Hz); 8.19 (m, 3H); 8.36 (bd, 1H); 8.67 (t, 1H, J=5 Hz); 12.10 (bs, 1H). MS (ion spray) m/z 495 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:13]([O:12][C:10]([N:4]1[C@H:3]([CH2:2][O:1][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][O:6][C:5]1([CH3:8])[CH3:9])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](COc2ccccc2)COC1(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a stirred solution of tert-butyl (R)-4-(hydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate (400 mg; CAS 108149-63-9) in THF (20 ml) were added phenol (197 mg), triphenylphosphine (573 mg) and di-tert-butyl azodicarboxylate (488 mg). The resulting yellow solution was stirred at 70° C. for 18 h overnight, then concentrated in vacuo. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0->70:30) to give (R)-2,2-dimethyl-4-phenoxymethyl-oxazolidine-3-carboxylic acid tert-butyl ester (336 mg, 63%) as a colourless viscous oil. MS (ISP): 308.3 ([M+H]+)).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2>C(#N)C.O>[Br:1][C:19]1[CH:18]=[C:17]2[C:13](=[CH:12][C:11]=1[O:10][CH3:9])[CH2:14][CH2:15][CH2:16]2
Reactant: COc1ccc2c(c1)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
N-bromosuccinimide (1.26 g, 7.1 mmol) was added to a solution of 5-methoxyindan 124 (1.0 g, 6.7 mmol) in acetonitrile (34 mL). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-10% ethyl acetate in hexane) provided 125 (1.53 g, 100%) as a liquid.
Reaction SMILES: [CH3:1][OH:2].N1C=CC=CC=1.[Cl:9][C:10]1[N:18]=[C:17]([Cl:19])[CH:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[C:11]=1[C:12](Cl)=[O:13]>ClCCl>[Cl:9][C:10]1[N:18]=[C:17]([Cl:19])[CH:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[C:11]=1[C:12]([O:2][CH3:1])=[O:13]
Reactant: CO
Reactant: O=C(Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Reaction time: 1 h

Procedure:
100 ml of methanol and 4.37 ml (53.9 mmol) of pyridine were cooled in an ice-bath. A solution of 10.0 g (35.9 mmol) of 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride [Y. Tsuzuki et al., J. Med. Chem. 47, 2097-2109 (2004)] in 40 ml of dichloromethane was then added dropwise. The mixture was stirred with ice-cooling for one hour and then at room temperature for one hour. The reaction mixture was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (silica gel: isohexane/ethyl acetate=95/5). This gave 8.98 g (91% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].Cl>N1C=CC=CC=1>[C:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[O:12][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)(=[O:11])[CH3:10]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(OC(=O)c2ccc([N+](=O)[O-])cc2)c(C(C)=O)c1

Procedure:
5′-methoxy-2′-hydroxyacetophenone (1.5 g, 9.03 mmol) was added to a pyridine solution (20 ml) that contained 4-nitrobenzoyl chloride (1.72 g, 9.26 mmol) in an ice bath. The obtained mixture was reacted at room temperature for 30 minutes, and the reaction solution was then poured into 1 N hydrochloric acid under cooling on ice. The obtained mixture was intensively stirred. The obtained precipitate was collected by filtration, and the filtrate was then washed with purified water, so as to obtain a product of interest, 4-nitrobenzoic acid 2-acetyl-4-methoxyphenyl ester (compound 21). Yield: 2.49 g (yield constant: 87.4%)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I-:25].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][C:34]#[C:35][CH2:36]O>ClCCl>[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][C:34]#[C:35][CH2:36][I:25]
Reactant: [I-]
Reactant: OCC#CCOC1CCCCO1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICC#CCOC1CCCCO1
Reaction time: 0.05 h
Yield: 56.1 %

Procedure:
To a stirred solution of triphenylphosphine (1.4154 g, 5.34 mmol) in anhydrous dichlormethane (20 mL) at room temperature under nitrogen was added imidazole (360 mg, 5.24 mmol), followed by iodide (1.2688 g, 4.95 mmol). The mixture was stirred for three minutes, a solution of 4-(tetrahydro-pyran-2-yloxy)-but-2-yn-1-ol (708.6 mg, 4.16 mmol) in dichloromethane was added dropwise via spring. The resulting mixture was continued to be stirred for 1.5 hours. The mixture was filtered through a pad of Celite. And the solid was washed with dichloromethane. The combined organic filtration was concentrated under reduced pressure. The residue was separated with flash column chromatography on silica using 0-20% EtOAc/hexane to afford 654 mg of product in 56% yield. 1H-NMR (CDCl3): δ 4.77 (t, J=3.0 Hz, 1H), 4.33-4.18 (m, 2 H), 3.85-3.77 (m, 1 H), 3.70 (t, J=2.1 Hz, 2 H), 3.56-3.49 (m, 1 H), 1.85-1.62 (m, 6 H).