Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[N:10]=[C:11]([NH:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][N:35]=2)[C:12]2[N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:16]=[C:15]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:13]=2[N:14]=1.[CH3:40][C@@H:41]1[CH2:46][NH:45][CH2:44][CH2:43][NH:42]1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:40][C@H:41]1[NH:42][CH2:43][CH2:44][N:45]([C:9]2[N:10]=[C:11]([NH:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][N:35]=3)[C:12]3[N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]([F:25])([F:23])[F:24])[N:16]=[C:15]([CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:13]=3[N:14]=2)[CH2:46]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)COCCn1nc(CN2CCOCC2)c2nc(Cl)nc(Nc3ccncn3)c21
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2nc(Nc3ccncn3)c3c(n2)c(CN2CCOCC2)nn3CCOCC(F)(F)F)CCN1
Temperature: 110 °C
Yield: 109.9 %

Procedure:
5-Chloro-3-(morpholin-4-ylmethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate (150 mg, 0.2 mmol), (R)(−)-2-methylpiperazine (86 mg, 0.85 mmol) and N,N-diisopropylethylamine (140 mg, 1.0 mmol) were mixed in methyl sulfoxide (1.0 ml) in a reaction vial. The reaction mixture was heated at 110° C. for 18 hours. The reaction was cooled to room temperature and brought to acidic condition by adding trifluoroacetic acid. The crude reaction mixture was purified on reverse phase HPLC (5-95% acetonitrile in water with 0.05% trifluoroacetic acid) and lyophilized to give 5-[(3R)-3-methylpiperazin-1-yl]-3-(morpholin-4-ylmethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate (143 mg).
Reaction SMILES: [NH:1]1[CH:5]=NC=[N:2]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[H-].[Na+].O.[CH3:20][N:21](C)C=O>>[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12]([N:21]2[CH:20]=[CH:5][N:1]=[N:2]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccnn2)cc1
Reaction time: 0.67 h

Procedure:
To a solution of 1H-1,2,4-triazole (5 g) and 4-toluenesulfonyl chloride (14.5 g) in N,N-dimethylformamide was added sodium hydride (2.9 g) with cooling it on ice, and the reaction mixture was stirred for 40 minutes with cooling it on ice. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with water, and then dried over magnesium sulfate. The residue was purified by a short-column chromatography (eluent: n-hexane/ethyl acetate=4/1) to yield white solids (21.8 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([N:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: N#Cc1ccc(-c2cccc(NCc3cccnc3)c2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1ccc(-c2cccc(N(Cc3cccnc3)S(=O)(=O)CC(F)(F)F)c2)cc1

Procedure:
A solution of N-(3-(4-cyanophenyl)phenyl)pyrid-3-ylmethylamine (255 mg, 0.894 mmol) in 8 ml dichloromethane/2 ml pyridine was treated with 2,2,2-trifluoroethylsulfonyl chloride in 3 portions of 171 mg (0.94 mmol) over 1 h at 45° C. The solution was cooled and diluted with 60 ml diethyl ether and washed successively with water and saturated sodium bicarbonate solution. The organics were separated, dried over sodium sulfate, filtered, and concentrated to an oil. The oil was purified by radial chromatography on a 2 micron silica plate eluting with 2 to 4% methanol/dichloromethane to afford the title compound. 1H NMR: 8.65 (bs,1H), 8.42 (bs,1H), 7.85 (m,1H), 7.75 (d,2H,J=8 Hz), 7.58 (d,2H,J=8 Hz), 7.30-7.55 (m,5H), 5.02 (s,2H), 3.78 (q,2H,J=8 Hz). MS calcd. 431.44; MS (M+1) 432.1.
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.[Cl:50]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:50][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=4)[C:24]=3[N:23]=[CH:12]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1scc(-c2cccc(C)c2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: Cc1cccc(-c2csc3c(=O)n(-c4ccc(Cl)cc4)cnc23)c1
Yield: 72.1 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(m -tolyl)thiophene-2-carboxylate (80 mg, 0.32 mmol), triethyl orthoformate (0.7 ml), 4-chloroaniline (76.8 mg, 0.6 mmol), and acetic acid (0.1 ml) were used to give 85.1 mg (0.23 mmol, 72.1% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=2[F:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:17][C:15]1[CH:14]=[CH:13][C:12]([F:20])=[C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To a suspension of iron powder (28.75 g) in 5 % aqueous acetic acid (57.5 ml) heated at 80° C., a solution of 3-chloro-2-(2-fluoro-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole (30.45 g) in acetic acid (103 ml) and ethyl acetate (103 ml) was aded, and the resultant mixture was heated at a temperature of 60° to 80° C. under reflux for 3 hours. After cooling, water and ethyl acetate were added to the reaction mixture. The residue was removed by filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated to give 2-(5-amino-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (22.97 g). m.p., 120.9° C.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[N:5][C:6]([NH+:9]2[C:17]3[CH2:16][C@H:15]([CH3:18])[NH:14][CH2:13][C:12]=3[N:11]=[N:10]2)=[N:7][CH:8]=1.C(N(CC)CC)C.[F:26][C:27]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:17]3[CH2:16][C@H:15]([CH3:18])[N:14]([C:29]([C:28]4[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:27]=4[F:26])=[O:30])[CH2:13][C:12]=3[N:11]=[N:10]2)=[N:7][CH:8]=1
Reactant: C[C@H]1CC2=C(CN1)N=N[NH+]2c1ncc(F)cn1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1Cc2c(nnn2-c2ncc(F)cn2)CN1C(=O)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of (S)-1-(5-fluoropyrimidin-2-yl)-6-methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridinium chloride (0.575 g, 2.12 mmol) in CH2Cl2 (10 mL) was added triethylamine (1.18 mL, 8.50 mmol) followed by 2-fluoro-3-(trifluoromethyl)benzoyl chloride (0.625 g, 2.76 mmol). After stirring for 30 min at rt, sat NaHCO3 (20 mL) was added. The organic layer was separated and the water layer was extracted with CH2Cl2 two times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-100% ethyl acetatehexanes) provided the desired product as a white solid (0.837 g, 93%). MS (ESI) mass calcd. C18H13F5N6O, 424.11. m/z found, 425.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.75 (s, 2H), 7.81-7.49 (m, 2H), 7.46-7.30 (m, 1H), 5.92-5.66 (m, 0.5H), 5.68-5.55 (m, 0.5H), 4.81-4.54 (m, 1H), 4.37 (d, J=16.9 Hz, 0.5H), 4.30-4.18 (m, 0.5H), 3.58-3.40 (m, 0.8H), 3.34-3.12 (m, 1.2H), 1.43-1.12 (m, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]([CH3:17])[CH2:14][CH2:15]O)[CH:10]=[CH:11][CH:12]=1>CCOCC>[Br:2][CH2:15][CH2:14][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=1)[CH3:17]
Reactant: BrP(Br)Br
Reactant: COc1cccc(C(C)CCO)c1
Solvent: CCOCC
Product: COc1cccc(C(C)CCBr)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30 ml.) is added to a solution of 3-(3-methoxyphenyl)-1-butanol (30.0 g., 0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reaction mixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured over ice (200 g.) and the resulting mixture extracted with ether (3×50 ml.). The combined extracts are washed with 5% sodium hydroxide solution (3×50 ml.), saturated sodium chloride solution (1×50 ml.) and dried (Na2SO4). Removal of the ether and vacuum distillation of the residue affords the title product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.[CH3:23][O:24][C:25](OC)(OC)OC.C(O)(=O)CC>>[CH3:23][O:24][C:25]1[N:15]([CH:13]2[CH2:14][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:12]2)[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[N:22]=1
Reactant: COC(OC)(OC)OC
Reactant: Nc1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Solvent: CCC(=O)O
Product: COc1nc2cccnc2n1C1CN(c2ccc3ccccc3n2)C1
Temperature: 90 °C
Yield: 59 %

Procedure:
N2-(1-Quinolin-2-yl-azetidin-3-yl)-pyridine-2,3-diamine (150 mg, 0.51 mmol) was combined with tetramethylorthocarbonate (1 mL) and propionic acid (8 mg) and heated at 90° C. for 2 hours. After that, the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give 2-(3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)azetidin-1-yl)quinoline (100 mg, 0.30 mmol, 59% yield). M+1: 332. 1H NMR (CDCl3, 400 MHz): δ(ppm) 8.06-8.05 (m, 1 H); 7.87-7.85 (m, 1 H); 7.72-7.68 (m, 2 H); 7.58-7.47 (m, 2 H); 7.20-7.17 (m, 1 H); 7.06-7.03 (m, 1 H); 6.62-6.60 (m, 1 H); 5.62-5.55 (m, 1 H); 4.84-4.80 (m, 2 H); 4.61-4.57 (m, 2 H); 4.10 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]([O:16]C)=O)=[N:4][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:6][C:7]=1[OH:8].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.Cl>CN(C=O)C>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:14]([C:3]2[C:2]([OH:1])=[C:7]([OH:8])[N:6]=[C:5]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[N:4]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: COC(=O)c1nc(-c2cccs2)nc(O)c1O
Reactant: NCc1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1nc(-c2cccs2)nc(O)c1O
Reaction time: 8 h

Procedure:
Methyl 5,6-dihydroxy-2-thien-2-ylpyrimidine-4-carboxylate (A-2) was dissolved in DMF and 2.0 eq. of 4-fluorobenzylamine were added to the stirred solution. Reaction mixture was left overnight at 90° C. After cooling to room temperature 1 N HCl was added and a solid precipitated from the mixture. This solid was collected by filtration, washed with ethyl ether and dried under vacuum to afford the compound (A-3). 1H NMR (DMSO-d6, 300 MHz) δ 13.0 (s, 1 H), 12.5 (s, 1H), 9.18 (bs, 1 H), 8.03 (d, J=3.0 Hz, 1 H), 7.81 (d, J=4.8 Hz, 1 H), 7.39 (dd, J=5.7 Hz, J=8.4 Hz, 2 H), 7.19-7.2 (m, 3 H), 4.51 (d, J=6.3 Hz, 2 H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[N:10]([CH3:17])[C:9]=2[CH:18]=1.[CH2:19](I)[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:14]1[C:13](=[O:15])[CH2:12][C:11](=[O:16])[N:10]([CH3:17])[C:9]2[CH:18]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]1=2)[CH3:20]
Reactant: CCI
Reactant: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
Sodium hydride (60% in oil, 44 mg, 1.1 mmol) was suspended in dimethylformamide (DMF) (8 ml), and cooled in an ice water bath to 0° C. 8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg, 1.0 mmol) was added to the suspension at the same temperature, and stirred at 0° C. for 1 hour. Ethyl iodide (187 mg, 1.2 mmol) was added to the mixture and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 190.2 mg (yield: 77%) of 1-ethyl-7-methoxy-5-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[N:16][CH:17]=1>>[F:9][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:22])([F:10])[F:21])=[CH:17][N:16]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(Br)cc1F
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1F

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (3-fluoro-4-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 299.3 [M+H]+) was prepared from 4-bromo-2-fluorotoluene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=4[F:30])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)cc4F)c3O2)cc1
Yield: 81.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-difluorophenylboronic acid (3.09 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.651 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 afforded 4.43 g (82%) of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 116-118° C.; Anal. calcd. for C22H18F2O4S: C, 63.45; H, 4.36. Found: C, 63.3; H, 4.11.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[N+:28]([O-:30])=[O:29].C(Br)(Br)[Br:32]>C(#N)C>[Br:32][C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[N+:28]([O-:30])=[O:29]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[N+](=O)[O-]
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1[N+](=O)[O-]
Temperature: 55 °C

Procedure:
Tertiary butyl nitrite (6.6 ml) was added at room temperature to a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitropyrazole (3.7 g), bromoform (13.3 ml) and acetonitrile (10 ml). The mixture was heated at 50-60° C. for 4.5 hours and the solvents were evaporated to give an orange oil. This was purified by medium pressure liquid chromatography (eluant hexane/ether 2:1) to give 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitropyrazole (3.4 g) as a solid, m.p. 147-150° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[CH2:35]([O:37][C:38](=[O:43])[C:39](O)([CH3:41])[CH3:40])[CH3:36].CO>C(OCC)(=O)C>[CH2:35]([O:37][C:38](=[O:43])[C:39]([CH3:41])([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:40])[CH3:36]
Reactant: CCOC(=O)C(C)(C)O
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Agent: COC(=O)C(O)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2

Procedure:
Following the procedures of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol, 2-hydroxy-3-methyl-butyric acid methyl ester and 2-hydroxy-2-methyl-propionic acid ethyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give 2-methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid ethyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=3.68 min, [M+H]+=466
Reaction SMILES: [CH2:1]([C:15]([O:17][CH3:18])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-])=[O:13].O=S(Cl)[Cl:21]>C(Cl)Cl>[CH3:18][O:17][C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:21])=[O:13])=[O:16]
Reactant: COC(=O)CCCCCCCCCCCC(=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold solution of 4.8 gms monomethyl 1,11-undecanedicarboxylate in 10 ml CH2Cl2 was added 5 ml SOCl2 dropwise over 5 minutes; then it was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give 4.8 gms of an oily residue which was used without further purification.
Reaction SMILES: OC1C=C(O)C=CC=1C([C:16]([CH:18]([C:25]1C=CC(O)=CC=1O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])C1C=CC=CC=1.N1[CH2:38][CH2:37][O:36]CC1>C([O-])([O-])OCC.CN(C)C=O>[OH:17][C:16]1[CH:38]=[C:37]2[C:20]([C:16](=[O:17])[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:25][O:36]2)=[CH:19][CH:18]=1
Reactant: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Reactant: C1COCCN1
Agent: CCOC([O-])[O-]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)coc2cc(O)ccc12

Procedure:
reacting 2,4-dihydroxy-phenyl-benzyl-ketone of formula (II) ##STR7## with ethyl orthoformate in dimethylformamide as solvent and in the presence of a catalyst consisting of morpholine, to yield 7-hydroxyisoflavone of formula (III) ##STR8## b) separating of product (III) from the reaction residue, c) alkylating of product (III) from step b) with isopropyl halide to obtain ipriflavone, wherein:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:5])[CH3:2]>C1COCC1.[Pd].ClCCl>[CH2:1]([O:3][C:4]([CH:6]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(C(=O)O)cc1)C(=O)C(C)C
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)O)cc1)C(=O)C(C)C
Yield: 89.4 %

Procedure:
50 g of 4-(2-ethoxycarbonyl-4-methyl-3-oxo-pent-1-enyl)benzoic acid are dissolved in 300 ml of THF, 1.00 g of palladium on carbon (10%) is added, and the mixture is hydrogenated under a hydrogen pressure of 4 bar in an autoclave for 24 h. The mixture is diluted with dichloromethane and filtered with suction through Celite, the residue is washed with dichloromethane and concentrated in vacuo. The residue is purified by chromatography on silica gel (ethyl acetate/n-heptane=3/1). 45 g of compound 45 are obtained as an oil. C16H20O5 (292.3) MS (ESI+): 293.1 (M+H)+, tR=1.37 min (Gradient 2).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[C:27]1([C@H:33]([OH:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:35][C@@H:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: C[C@@H](O)c1ccccc1
Product: C[C@@H](Oc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1)c1ccccc1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (110 mg; 0.289 mmol), intermediate 42.1, and (R)-(+)-1-phenylethanol (143 mg; 1.157 mmol), example 79 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[NH:35][C:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[CH:33][C:32]2=O.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN1CCCC1.O>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: COc1cc2[nH]c(-c3ccccc3)cc(=O)c2cc1Br
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 15 h
Yield: 92.1 %

Procedure:
To a solution of the product from Step 4 (19.4 g, 41.7 mmol) and 6-bromo-7-methoxy-2-phenylquinolin-4(1H)-one (Step 3, 13.5 g, 40.9 mmol) in N-methylpyrrolidine (200 mL) was added cesium carbonate (20.0 g, 61.3 mmol). The reaction mixture was then heated at 45° C. with stirring for 15 hours and cooled to RT. The reaction mixture was poured into EtOAc and water, and the white solids removed by filtration. The layers were separated, and the organic phase washed with saturated aqueous NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica (gradient elution 10% to 50% EtOAc in hexanes) to give the title compound (21.0 g) as a pale yellow solid. LRMS (M+H)+ Calcd.: 557.1; found 557.3.