Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[CH:11]=[C:10]([C:18](OC)=[O:19])[CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O>[CH3:6][O:7][C:8]1[C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[CH:11]=[C:10]([CH2:18][OH:19])[CH:9]=1
Reactant: COC(=O)c1cc(OC)c2c(c1)OCCO2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 mL of a tetrahydrofuran solution containing 1.06 g of methyl 8-methoxy-2,3-dihydro-1,4-benzodioxin-6-carboxylate, 720 mg of lithium aluminum hydride was added under cooling with ice. The reaction mixture was stirred at room temperature for 1 hour, 5 mL of a 1 mol/L hydrochloric acid and 45 mL of water were added thereto, and the resultant solution was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 940 mg of a brown oily substance, (8-methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)methanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.C(O)(C(F)(F)F)=O>>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]3[C:5]4[NH:6][C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]=4[CH2:3][CH2:2][NH:1]3)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCCO2)NCC3
Yield: 75 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4,92 g, 30.7 mmol), 2,3-dihydrobenzo[1,4]dioxin-6-carboxaldehyde (5.05 g, 1.0 equiv.) and TFA (5.0 mL, 2 equiv.) to give the title compound (7.05 g, 75%) as white crystals after recrystallization from iPr2O.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(#N)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH3:31][S:32]([N:18]1[CH2:17][CH2:16][C:15]2([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14]2)[CH2:20][CH2:19]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCN(S(C)(=O)=O)CC2)C1
Reaction time: 1 h

Procedure:
N,N-Diisopropylethylamine (30.0 μL, 0.000172 mol) was added to tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride (18.5 mg, 0.0000668 mol) in acetonitrile (1.0 mL, 0.019 mol), followed by methanesulfonyl chloride (10.0 μL, 0.000129 mol). After stirring for 1 h the solvent was evaporated, and the residue was dried under high vacuum and was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([N:33]=[C:34]=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:24]=[C:25]([NH:33][C:34]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-bis-(trifluoromethyl)phenyl isocyanate (0.51 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a yellow solid (0.44 g, 51% yield), mp=68–71° C.; MS (−) ESI m/z=434 (M−H)−; [α]D25=+22.8° (c=1, EtOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=3)[C:6](=[CH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[O:20])[C:5]=2[CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:43]1[C:51]2[N:50]=N[NH:48][C:47]=2[CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=3)[C:6](=[CH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:48][C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:51]=3[NH2:50])=[O:28])=[O:20])[C:5]=2[CH:4]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: COc1ccc2c(c1)C(=CC(=O)NCCCCCC(=O)O)c1cc(OC)ccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=CC(=O)NCCCCCC(=O)Nc1ccccc1N)c1cc(OC)ccc1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.8 %

Procedure:
6-(2-(2,7-dimethoxy-9H-fluoren-9-ylidene)acetamido)hexanoic acid (395 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (373 mg, 77% yield) as a brown solid. LC-MS (m/z) 486 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1cnccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 137, 200 mg, 0.61 mmol) in methylene chloride (5 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0° C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.45 mL, 0.91 mmol) and stirred at 0° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminopyrazine (115 mg, 1.21 mmol) and pyridine (0.245 mL, 3.03 mmol) in tetrahydrofuran (10 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combine organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 50/50 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide (172 mg, 70%) as a white foam: [α]23589=−46.8° (c=0.047, chloroform); EI-HRMS m/e calcd for C19H22ClN3O3S (M+) 407.1070, found 407.1068.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].OP(O)(O)=O>[Cl-].[Zn+2].[Cl-].S([O-])([O-])(=O)=O.[Cu+2].CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:4][C@@H:3]([C@H:5]2[O:6][C@@H:11]3[O:12][C:9]([CH3:11])([CH3:7])[O:10][C@@H:9]3[C@H:7]2[OH:8])[CH2:2][O:1]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cu+2]
Agent: O=P(O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1

Procedure:
Anhydrous D-glucose (600w), dry acetone (4000v), anhydrous pulverized zinc chloride (480w) and 89% O-phosphoric acid (30v) and anhydrous copper sulphate (100w) were mechanically stirred for 30 hours at room temperature. Undissolved glucose was filtered and washed with acetone. The filtrate was cooled to 0°-5° C., made alkaline with sodium hydroxide (340w in 340w water) and filtered. The filtrate was evaporated under reduced pressure to remove solvent, the residue diluted with water and extracted with chloroform. The combined chloroform extract was washed with water, concentrated, dried and evaporated to give crude product (462w, 91% on recovered glucose), white crystals, mp 95°-101° C. Recrystallization from hexane/chloroform (2;1) afforded 1,2: 5,6-di-O-isopropylidene-α-D-glucofuranose, mp 105°-109° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1)CCC.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.FC(F)(F)S(O[C:41]1[CH:54]=[C:53]2[C:44]([O:45][C:46]3[CH:47]=[CH:48][C:49]([C:60]4[CH2:61][CH2:62][O:63][CH2:64][CH:65]=4)=[CH:50][C:51]=3[C@@:52]32[CH2:58][O:57][C:56]([NH2:59])=[N:55]3)=[CH:43][C:42]=1[F:66])(=O)=O>CN(C=O)C>[O:63]1[CH2:64][CH:65]=[C:60]([C:49]2[CH:50]=[C:51]3[C:46]([O:45][C:44]4[CH:43]=[C:42]([F:66])[C:41]([C:6]5[CH:11]=[N:10][CH:9]=[N:8][CH:7]=5)=[CH:54][C:53]=4[C@:52]43[CH2:58][O:57][C:56]([NH2:59])=[N:55]4)=[CH:47][CH:48]=2)[CH2:61][CH2:62]1
Reactant: NC1=N[C@]2(CO1)c1cc(C3=CCOCC3)ccc1Oc1cc(F)c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Product: NC1=N[C@]2(CO1)c1cc(C3=CCOCC3)ccc1Oc1cc(F)c(-c3cncnc3)cc12
Temperature: 130 °C

Procedure:
A mixture of 5-(tributylstannyl)pyrimidine (73.8 mg, 0.200 mmol), AmPhos (4.24 mg, 5.99 μmol) and (R)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-6′-fluoro-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (50 mg, 0.100 mmol) in 0.3 mL of DMF was heated at 130° C. for 1 hour. After cooling and evaporation of the solvent under high vacuum, the mixture was purified by silica gel chromatography (DCM to DCM/EA=1:1 to 1:2 to pure EA to EA/MeOH=100:5 to 100:10) to provide (R)-7′-(3,6-dihydro-2H-pyran-4-yl)-3′-fluoro-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [Li]CCCC.BrC1C=CC=CC=1[C:13]1[C:14]2[C:19]([C:20](C3C=CC=CC=3Br)=[C:21]3[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]3)=[CH:18][CH:17]=[CH:16][CH:15]=2.B(OC)(OC)OC.OC(C(O)(C)C)(C)C>C(OCC)C.O.C1(C)C=CC=CC=1.C(OCC)(=O)C.C(O)(=O)C>[CH:15]1[C:14]2[C:19](=[CH:20][C:21]3[C:26]([CH:13]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccccc1-c1c2ccccc2c(-c2ccccc2Br)c2ccccc12
Agent: CC(C)(O)C(C)(C)O
Agent: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
40.0 ml of n-BuLi (2.5M in hexane) are added to a suspension of 19.5 g (40 mmol) of 9,10-bis(2-bromophenyl)anthracene in 1000 ml of diethyl ether, and the mixture is stirred at room temperature for 6 h. The reaction mixture is subsequently cooled to −78° C., and 26.8 ml (240 mmol) of trimethyl borate are added rapidly with vigorous stirring. After slow warming to room temperature, a mixture of 8 ml of acetic acid and 300 ml of water and then 500 ml of ethyl acetate are added, the mixture is stirred at room temperature for a further 1 h, and the organic phase is separated off, washed twice with 500 ml of water and evaporated under reduced pressure. 300 ml of toluene and 10.6 g (90 mmol) of pinacol are added to the residue, and the mixture is heated on a water separator. When the separation of water is complete, 250 ml of toluene are distilled off, and 300 ml of ethanol are added. After cooling, the colourless solid is filtered off with suction, recrystallised three times from toluene and dried under reduced pressure. Sublimation, p=1×10−5 mbar, T=260° C. Yield: 10.6 g (18 mmol), 45.5% of theory; purity: 99.9% according to 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][CH:11]=[N:12][OH:13].[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]([Cl:14])=[N:12][OH:13]
Reactant: ON=CCCc1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)CCc1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 3-(2,6-dichlorophenyl)propanal oxime (1.05 g, 4.82 mmol) in dimethylformamide (3.8 mL) was stirred as N-chlorosuccinimide (0.64 g, 4.82 mmol) was added. The resulting solution was allowed to stir for one hour. The solution was poured into water and extracted with ether. The organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the title compound (1.05 g, 86%). 1H NMR (DMSO-d6): δ 11.67 (s, 1H), 7.45 (d, J=8 Hz, 2H), 7.28 (t, J=8 Hz, 1H), 3.17-3.13 (m, 2H), 2.68-2.64 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.Cl.N[C@H](C([C:20]1([NH2:35])[C:26](=[O:27])[N:25]([CH3:28])[C:24]2[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=2[N:22]([CH3:33])[C:21]1=[O:34])=O)C>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:35][C@H:20]([C:26]([NH:35][CH:20]2[C:21](=[O:34])[N:22]([CH3:33])[C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[N:25]([CH3:28])[C:26]2=[O:27])=[O:27])[CH3:21])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(C)c2ccccc2N(C)C1=O
Agent: Cl
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluoromandelic acid (Lancaster) and the product from Example 8-R, the title compound was prepared as an amorphous white solid. Purification was by L.C. 2000 eluting with straight EtOAc then flash chromatography eluting with CH2Cl2/Acetone (4:1 gradient to 3: 1). Rf=0.39 and 0.34 (EtOAc).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.Cl.[CH3:17][O:18][C:19](=[O:31])[C@@H:20]([NH2:30])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:17][O:18][C:19](=[O:31])[C@@H:20]([NH:30][C:13]([C:4]1[CH:3]=[C:2]([OH:1])[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1)=[O:15])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8 g of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid and 10 g of (S)-2-Amino-pentanedioic acid 5-tert-butyl ester 1-methyl ester hydrochloride in 300 ml of DCM, 16 g of triethylamine and 15 g of HATU was added and stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 11 g.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([CH3:13])[N:5]=1.[Br:15]Br.O.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:15][C:8]1[C:4]([O:3][CH:2]([F:1])[F:14])=[N:5][N:6]([CH3:13])[C:7]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(OC(F)F)nn1C
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(Br)c(OC(F)F)nn1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
A solution of 700 mg (3.39 mmol) of methyl 3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate in 20 ml of chloroform is admixed dropwise with a solution of 570 mg (3.56 mmol) of bromine in 10 ml of chloroform and then stirred for three days at room temperature. The reaction mixture is added to 80 ml of water with some sodium bisulfite and shaken. The organic phase is separated off, dried over magnesium sulphate, filtered and concentrated by evaporation in vacuo: 792 mg of methyl 4-bromo-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate (82%) are produced as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)[CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1cn(C)c2ccccc12)C(=O)OCC
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CC(=O)O)(Cc1cn(C)c2ccccc12)C(=O)OCC
Yield: 63.5 %

Procedure:
Produced analogously to Example A1b) from tert.-butyl β,β-bis-(ethoxycarbonyl)-1-methyl-1H-indol-3-butanoate through the action of trifluoroacetic acid in dichloromethane in a yield of 63.5% of theory. Colourless crystals of Mp. 127-130° C. (diisopropylether).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.[F:31]C1C=C(C(=O)CC2C=CN=CC=2)C=CC=1OCC1C=CC2C(=CC=CC=2)N=1>>[F:31][C:29]1[CH:30]=[C:13]([C:4]2[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)=[CH:6][N:2]([CH3:1])[N:3]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)c(F)c2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-[3-Fluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6.2 Hz, 2H), 8.21 (d, J=8.3 Hz, 1H), 8.05 (d, J=8.7 Hz, 1 H), 7.83 (d, J=7.9 Hz, 2H), 7.72 (m, 2H), 7.55 (m, 2H), 7.16 (m, 2 H), 7.07 (m, 1H), 6.99 (m, 2H), 5.45 (s, 2 H), 3.95 (s, 3H); MS: (M+H m/z=411.0).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[C:9]=2[CH:10]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].Cl.C(OCC)(=O)C>CN(C)C=O>[CH2:17]([O:13][C:12](=[O:14])[CH2:11][C:8]1[C:9]2[CH:10]=[C:2]([CH3:1])[NH:3][C:4]=2[CH:5]=[CH:6][CH:7]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Cc1cc2c(CC(=O)O)cccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1cccc2[nH]c(C)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methylindole-4-acetic acid (53 g) in N,N-dimethylformamide (500 ml) was added dropwise allyl bromide (31 ml), and added anhydrous potassium carbonate (59 g). The mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into a mixture of 2N hydrochloric acid-ethyl acetate and then extracted with ethyl acetate. The extraction was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give the title compound (43.5 g) having the following physical data.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([OH:15])=O)=[N:3]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:4]2[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:2]([CH3:1])[N:3]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: Cn1nc(C(=O)O)cc1-c1ccccc1
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
1-Methyl-5-phenylpyrazole-3-carboxylic acid (2.1 g), 5-amino-2-neopentyloxybenzonitrile (2.2 g), triethylamine (3.4 g) and diethyl cyanophosphate (2.7 g) were added to dimethylformamide (25 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (3.1 g), melting point: 156–157° C.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@H:10]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)([CH3:4])[CH3:3].C1COCC1.[CH3:36][C:37]([CH3:41])([CH3:40])[CH:38]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:36][C:37]([CH3:41])([CH3:40])[CH2:38][NH:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@H:10]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)([CH3:3])[CH3:4]
Reactant: CC(C)(N)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)CNC(C)(C)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of N-[(S)-6-(1-amino-1-methylethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (30 mg), THF (1 ml), methanol (0.5 ml), trimethylacetaldehyde (10 mg) and acetic acid (9 mg) was added polymer-bound sodium cyanoborohydride (0.15 mmol), and the suspension was agitated at room temperature for 12 hours. The polymer was filtered off with suction and the filtrate was concentrated. The residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 478.68 (C30H42N2O3); MS (ESI): 479 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:12])[C:5]2[O:9][C:8](=O)[NH:7][C:6]=2[CH:11]=1.[Cl:13]C1C=CC2NC(=O)OC=2C=1>C1(C)C=CC=CC=1>[Cl:13][C:8]1[O:9][C:5]2[C:4]([Cl:12])=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[N:7]=1
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2o1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)c2oc(Cl)nc2c1
Yield: 68 %

Procedure:
In analogy to Example 1, 204 g of 5,7-dichlorobenzoxazolin-2-one, in place of 6-Chlorobenzoxazolin-2-one, are reacted. 2,5,7-Trichlorobenzoxazole of melting point 140° -142° C. is obtained in a yield of 68% of theory by recrystallisation, from toluene or ligroin, of the residue remaining after distilling out the o-dichlorobenzene.