Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=1.C(=O)([O-])O.[Na+]>CC(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>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=3)[CH:7]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cn1
Temperature: 90 °C

Procedure:
N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (3.2 g), methyl 6-chloronicotinate (1.73 g), tetrakis(triphenylphosphine)palladium (210 mg) and aqueous sodium hydrogen carbonate (1M, 30 ml) were mixed in propan-2-ol (100 ml) and heated at 90° C. for 18 hours. The reaction was allowed to cool and the propan-2-ol removed under vacuum. The residue was partitioned between ethyl acetate and aqueous sodiumhydrogen carbonate (1M). The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ethyl acetate (×2). The organic extracts were washed with brine, dried (magnesium sulphate) and reduced to dryness under vacuum. The resulting foam was triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acid as a solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:22]2[CH2:27][CH2:26][C:25]([CH2:34][C:35]([CH3:37])=[CH2:36])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:38])([CH3:21])[CH3:20])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:22]2[CH2:27][CH2:26][C:25]([CH2:34][C:35]3([CH3:37])[CH2:36][O:9]3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:24][C:23]2=[O:38])([CH3:21])[CH3:20])=[CH:15][CH:14]=1
Reactant: C=C(C)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(Br)cc2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(CC2(c3ccccc3)CCN(C(C)(C)c3ccc(Br)cc3)C(=O)O2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of m-CPBA (49.2 mg, 285 μmol) in CH2Cl2 (10 mL) was added 3-(2-(4-bromophenyl)propan-2-yl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (61 mg, 142.5 μmol). The reaction mixture was stirred at rt for 1 h. The solution was washed with 30 wt % aqueous sodium thiosulfate (50 mL×3), saturated aqueous sodium bicarbonate and brine successively. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 3-(2-(4-bromophenyl)propan-2-yl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (57 mg, 90%).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CC(C)([O-])C.[Li+].Cl[C:34]([O:36][CH2:37][Cl:38])=[O:35]>C(Cl)Cl.CC#N.O>[Cl:38][CH2:37][O:36][C:34](=[O:35])[N:20]([C:21](=[O:23])[CH3:22])[CH2:19][C@@H:17]1[O:16][C:15](=[O:24])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:4][CH2:3][S:2](=[O:1])(=[O:26])[CH2:7][CH2:6]3)=[C:9]([F:25])[CH:10]=2)[CH2:18]1
Reactant: O=C(Cl)OCCl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCCl
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 74 %

Procedure:
(S)-N-{3-[4-(1,1-Dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1) (2.0 g, 5.2 mmol) in 13 mL of CH2Cl2 and 13 mL of CH3CN is cooled to 0° C. Lithium t-butoxide (1.0 M in hexanes, 5.7 mL, 5.7 mmol) is added and the mixture is stirred at 0° C. for 25 min and then at RT for 10 min. The mixture is re-cooled to 0° C. and chloromethyl chloroformate (0.6 mL, 6.2 mmol) is added dropwise. The mixture is stirred for 10 min at 0° C. and then allowed to stir at RT overnight. The solution is diluted with CH2Cl2 and water and the layers are separated. The organic layer is washed with water, brine, dried over Na2SO4, and conc in vacuo. Purification by silica gel chromatography afforded the title compound in 74% yield (1.8 g). 1H NMR (400 MHz, CDCl3): δ 7.47 (dd, 1H), 7.22 (t, 1H), 7.13 (dd, 1H), 5.91 (d, 1H), 5.76 (d, 1H), 4.82 (m, 1H), 4.16 (m, 1H), 4.07 (m, 2H), 3.69 (dd, 1H), 3.10 (m, 5H), 2.58 (s, 3H), 2.38 (m, 2H), 2.17 (m, 2H). MS-APCI (m/z+): 341, 385, 477.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:19][C:20](Br)([F:22])[F:21]>C(OCC)(=O)C.O.C(#N)C>[Br:19][C:20]([F:22])([F:21])[CH2:3][CH2:2][C:1]([OH:5])=[O:4]
Reactant: C=CC(=O)O
Reactant: FC(F)(Br)Br
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CCC(F)(F)Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of acrylic acid (1.44 g) and acetonitrile (80 cm3) was added sodium dithionite (4.18 g), sodium bicarbonate (2.01 g), water (20 cm3) and finally dibromodifluoromethane (5 cm3). The biphasic mixture was stirred at the ambient temperature with the inorganic salts gradually dissolving. GC analysis after 4 hours indicated complete consumption of acrylic acid. The aqueous phase was saturated with solid sodium chloride. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a pale yellow oil with a small amount of a white solid. This mixture was taken up in ethyl acetate, filtered and solvent evaporated under reduced pressure to give a pale yellow oil (2.54 g). 1H NMR (DMSO-d6): δ 2.45(2H,t); 2.65(2H,m).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][S:10][C:11]2[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([OH:3])=[O:2].Cl[C:23]1[C:32]2[C:27](=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>>[CH2:37]([C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[C:13]1[CH:12]=[C:11]([S:10][CH2:9][C:8]3[CH:20]=[CH:21][C:5]([CH2:4][C:1]([OH:3])=[O:2])=[CH:6][CH:7]=3)[CH:16]=[CH:15][CH:14]=1)=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(O)Cc1ccc(CSc2cccc(B(O)O)c2)cc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: O=C(O)Cc1ccc(CSc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-(4-carboxymethyl-benzylsulfanyl)phenylboronic acid and [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone according to the procedure of Example 1. MS (ES) m/z 541.9.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:36][OH:37].C(N(CC)CC)C.[O:45]1CCC[CH2:46]1>CO>[CH3:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)=[N:14][C:13]=2[CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH:7]=[CH:6][C:3]=1[C:4]1[NH:5][C:46](=[O:45])[O:37][N:36]=1
Reactant: Cc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)ccc1C#N
Reactant: C1CCOC1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)ccc1-c1noc(=O)[nH]1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
1.5 g 2-Methyl-4-[4-(tetrahydro-pyran-2-yloxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile were dissolved in a mixture of 10 ml tetrahydrofuran and 10 ml methanol. 2.12 g hydroxylamine hydrochloride were added followed by the addition of 5.08 ml triethylamine. The reaction mixture was stirred at 65° C. overnight. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with ethylacetate. The combined organic extracts were washed with brine, dried over MgSO4 and the solvent was evaporated in vacuo. The residue was dissolved in 10 ml dichloromethane. 0.32 ml pyridine and 0.49 ml phenylchloroformate were added and the mixture stirred at room temperature for fifteen minutes. The mixture was diluted by the addition of 50 ml acetonitrile and 2.28 ml 1,8-diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at room temperature for thirty minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by silica gel chromatography with the eluent n-heptane: ethyl acetate=4:1=>ethyl acetate=>ethyl acetate:methanol=4:1 to obtain 1.05 g 3-{2-methyl-4-[4-(tetrahydro-pyran-2-yloxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one as pale yellow solid.
Reaction SMILES: O.C(N(CC)CC)C.P(=O)(O)(O)O.C[N+:15]1[CH:16]=[C:17]2[C:22]3OCO[C:21]=3[CH:20]=[CH:19][C:18]2=[C:26]2[CH:35]=[CH:34][C:33]3[CH:32]=[C:31]4OCO[C:30]4=[CH:29][C:28]=3[C:27]=12>CO>[CH:32]1[C:33]2[CH:34]=[CH:35][C:26]3[C:27]([C:28]=2[CH:29]=[CH:30][CH:31]=1)=[N:15][CH:16]=[C:17]1[C:18]=3[CH:19]=[CH:20][CH:21]=[CH:22]1
Reactant: C[n+]1cc2c3c(ccc2c2ccc4cc5c(cc4c21)OCO5)OCO3
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: c1ccc2c(c1)cnc1c3ccccc3ccc21

Procedure:
A 5CN 10u radial pack column (5 mm. ID×100 mm.; from Water Associates) was run at 0.5 ml./min. with a mobile phase containing 84/16 (u/v) methanol: water with 0.005 M. triethylamine and phosphoric acid (pH 4.8). Detection of the benzophenanthridine alkaloid was monitored at 280 nm. using sanguinarine in methanol as a standard. After removal of the 5 ml. samples, the fluid was replaced with 5 ml. of isotonic saline. A 20 μl. sample was injected into the HPLC and analyzed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[CH:8][C:7]2=[O:22].[S:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[N:25]=[CH:24]1.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>CN(C=O)C.O>[O:22]=[C:7]1[C:6]2[C:11](=[C:2]([NH:1][C:28]([C:26]3[N:25]=[CH:24][S:23][CH:27]=3)=[O:29])[CH:3]=[CH:4][CH:5]=2)[O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)=[CH:8]1
Reactant: Nc1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Reactant: O=C(O)c1cscn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12)c1cscn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.2 %

Procedure:
8-amino-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one (178) (70 mg, 0.23 mmol) was taken up in 2 mL of DMF along with thiazole-4-carboxylic acid 3 (30 mg, 0.23 mmol), HATU (175 mg, 0.46 mmol) and DIEA (80 μL, 0.46 mmol). The reaction mixture was stirred at room temperature for 18 h. It was then diluted with 5 mL of H2O. The resulting solids were collected by filtration, washed successively with a solution of dilute NaHCO3/MeOH (1:1), aqueous MeOH, dilute 1 N HCl/MeOH (1:1), aqueous MeOH, and then pure MeOH. After drying under high vacuum, 28 mg of Compound 204 was obtained as an off-white solid. MS (ESI) calcd for C20H11F3N2O3S: 416.04. found: 417 [M+H].
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:9][C:8]2[CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:12]=[N:13][C:7]=2[NH:6][C:5](=[O:19])[CH2:4]1.[CH3:20][NH:21][CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[CH2:33][CH2:34][CH3:35].C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[ClH:1].[CH3:20][N:21]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[CH2:33][CH2:34][CH3:35])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:11]1[CH:12]=[N:13][C:7]2[NH:6][C:5](=[O:19])[CH2:4][N:3]([CH3:2])[CH2:9][C:8]=2[CH:10]=1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CCCc1c(CNC)ccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C)CC(=O)N3)ccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.2 %

Procedure:
(E)-3-(4-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride (1.40 g, 1.25 mmol) was added to a solution of methyl-(1-propyl-naphthalen-2-ylmethyl)amine (0.292 g, 1.37 mmol) and diisopropylethylamine (0.65 mL, 3.75 mmol) in DMF (25 mL) followed by the addition of 1-hydroxybenzotriazole hydrate (0.185 g, 1.37 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.263 g, 1.37 mmol). The reaction was allowed to stir at room temperature for 18 h. The reaction was quenched with H2O (70 mL) then concentrated to a yellow oil. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 99:1 to 95:5) gave the title compound (0.229 g, 41%) as a glassy orange solid and as a mixture of amide rotamers: 1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.55-8.54 (m, 1H), 8.24-8.14 (m, 1H), 7.98-7.86 (m, 5H), 7.72-7.24 (m, 3), 3.75 (s, 2H), 3.42 (s, 2H), 3.86 (s, 2H), 2.54-2.36 (m, 6H), 2.11-2.02 (m, 2H), 1.40-1.34 (m, 2H), 1.01-0.98 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]3[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[C:14]=3[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.CCOCC.[NH4+].[Cl-]>O.O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:16]2([OH:20])[C:14]3[N:15]=[C:11]([C:10]4[C:2]([CH3:1])=[N:3][N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=45)[S:12][C:13]=3[CH2:19][CH2:18][CH2:17]2)=[CH:24][CH:23]=1
Reactant: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2=O
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn2ccccc2c1-c1nc2c(s1)CCCC2(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 250 mL round bottomed flask was placed 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-6,7-dihydro-1,3-benzothiazol-4(5H)-one (505.1 mg, 1.783 mmol) and tetrahydrofuran (50 mL). To the mixture was added a solution of 4-chlorophenylmagnesium bromide in ether (1M, 3.0 mL, 3.0 mmol) and the mixture was stirred for 4 hr at rt. To the mixture were added a saturated aqueous solution of NH4Cl (50 mL) and water (50 mL) and the resulting mixture was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain crude 4-(4-chlorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4,5,6,7-tetrahydro-1,3-benzothiazol-4-ol as a yellowish off-white crystalline solid which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34](O)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:34]([C:29]1[C:30]2[C:25](=[C:24]([Cl:23])[CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:27][CH:28]=1)=[O:35])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(tert-butyl)phenyl]-1-(3-chlorophenyl)-1-propanol (0.313 g, 0.985 mmol) in N,N-dimethylformamide (5 ml) were added 5-chloronaphthalene-1-carboxylic acid (0.214 g, 1.04 mmol) and 1-hydroxybenzotriazole monohydrate (0.160 g, 1.04 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.04 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide (0.307 g, 62%) as colorless crystals.
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][C@H:60]([OH:63])[C@@H:59]([CH3:64])[CH2:58]2)CC1>>[ClH:1].[ClH:1].[OH:63][C@H:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][C@@H:59]1[CH3:64]
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc12
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc12

Procedure:
This compound is synthesized from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119, see example 80) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH2:4][CH2:3]1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[NH4+]>C(O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](=[N:18][OH:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH2:4][CH2:3]1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1CCC(C(=NO)c2ccccc2F)CC1
Yield: 54 %

Procedure:
A mixture of 5.2 g of 1-methyl-4-(2-fluorobenzoyl)piperidine, 2.5 g of hydroxylamine hydrochloride, 5.4 g of ammonium acetate and 50+15 ml of ethanol-water was heated under reflux for 22 hrs. Most of the ethanol was removed under reduced pressure. The aqueous mixture was made basic with aqueous sodium hydroxide and the mixture was extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the chloroform was evaporated in vacuo to give a solid. The solid was triturated with ether. Recrystallization from ethanol-water gave 3.0 g (52.6%) of product, mp, 136°-139°.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].[CH3:17][Li]>C(OCC)C>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:17])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2]
Reactant: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Reactant: [Li]C
Solvent: CCOCC
Product: CCc1sc(C(C)=O)c2c1CC(C)(C)CC2
Reaction time: 0.25 h

Procedure:
To a solution of 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.10 g, 8.81 mmol) in diethyl ether (100 mL), a solution of methyllithium (11 mL, 1.6 M solution in diethyl ether) is added at rt. The pale yellow solution is stirred at rt for 15 min before another portion of methyllithium (2 mL) is added. Stirring is continued for 15 min, a further portion of methyllithium (1 mL) is added, and the mixture is again stirred for 15 min at rt. The reaction is quenched with water. The organic layer is separated, washed once more with water, dried over MgSO4 and evaporate. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (1.65 g) as a pale yellow solid; LC-MS: tR=1.00 min, [M+1]=237.15; 1H NMR (CDCl3): δ 3.03 (t, J=7.0 Hz, 2H), 2.73 (q, J=7.6 Hz, 2H), 2.47 (s, 3H), 2.31 (s, 2H), 1.55 (t, J=7.0 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H), 0.97 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[C:32]([C:36]1[O:37][CH:38]=[C:39](/[CH:41]=[CH:42]/[C:43]2[C:44]([OH:54])=[N:45][N:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:47]=2)[N:40]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([C:36]1[O:37][CH:38]=[C:39](/[CH:41]=[CH:42]/[C:43]2[C:44]([O:54][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:45][N:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:47]=2)[N:40]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CC(C)(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(C(C)(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 20.4 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.29 g), 4-[(E)-2-(2-tert-butyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (1.24 g), potassium carbonate (0.995 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to aminopropyl silica gel column chromatography and eluted with ethyl acetate-hexane (1:5-1:4-1:3, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (430 mg, yield 20%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-129° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=[C:22]([Cl:30])[N:21]=1>CN(C)C=O>[ClH:30].[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:22]1[N:21]=[C:20]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]2[CH3:9])[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1
Reactant: CNc1ccccc1
Reactant: CC1c2ccccc2CCN1c1nc(Cl)nc2c1CCCC2
Solvent: CN(C)C=O
Product: CC1c2ccccc2CCN1c1nc(N(C)c2ccccc2)nc2c1CCCC2
Product: Cl
Yield: 25.7 %

Procedure:
After N-methylaniline(0.50 ml, 4.8 mmol) was added to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloro-5,6,7,8-tetrahydroquinazoline(0.75 g, 2.40 mmol) and dimethylformamide(5 ml), 0.26 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.