Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[O:17]CC1C=CC=CC=1)=[O:7]>CO.O1CCCC1>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[OH:17])=[O:7]
Reactant: CN(C)CCOC(=O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCOC(=O)c1cc2cccc(O)c2[nH]1
Yield: 56 %

Procedure:
Under the conditions of Example 14(C), 9 g of 7-benzyloxyindole-2-carboxylic acid 2-dimethylaminoethyl ester is hydrogenated in a mixture of 50 ml of methanol and 50 ml of tetrahydrofuran and worked up, yielding 3.7 g of 7-hydroxyindole-2-carboxylic acid 2-dimethylaminoethyl ester, mp 149°-152° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[N:28]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:34]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)(=[O:36])=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)N1CCOCC1

Procedure:
The title compound, white solid (24.6 mg, 60.2%), MS (ISP) m/z=481.2 [(M+H)+], was prepared in accordance with the general method of example 76 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol) and morpholine-4-sulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-fluorophenylboronic acid (230 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Yellow solid. Yield: 160 mg, 0.63 mmol, 75%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.18 (s, 2H), 6.92 (s, 1H), 7.12 (brs, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.48 (dd, J=8.2, 2.2 Hz, 1H), 7.60 (s, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.97 (dd, J=8.8, 5.4 Hz, 2H), 8.57 (d, J=1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 115.7 (d, J=22.1 Hz), 119.0, 120.2, 128.7 (d, J=8.6 Hz), 130.0, 130.4, 134.7 (d, J=3.9 Hz), 135.8, 137.3, 148.6, 156.6, 163.7 (d, J=249.5 Hz); MS (ESI): m/z=254.18 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1/[CH:1]=[CH:12]/[C:13]([OH:15])=[O:14])#[N:6]
Reactant: N#Cc1ccccc1C=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#Cc1ccccc1/C=C/C(=O)O
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A solution of 2-formylbenzonitrile (4.17 g, 31.8 mmol), malonic acid (7.61 g, 73.1 mmol), and piperidine (0.314 mL, 3.18 mmol) in pyridine (40 mL) was heated to reflux for 2 hr. The solution was cooled and poured into crushed ice (150 mL) and 12N HCl (30 mL). The white precipitate was filtered, washed with water, and air dried to give a tan powder (3.85 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 12.81 (br. s., 1H), 8.09 (d, J=7.9 Hz, 1H), 7.93 (dd, J=7.8, 0.9 Hz, 1H), 7.80-7.74 (m, 2H), 7.62 (td, J=7.6, 0.9 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([Br:7])[N:6]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([Br:7])[N:6]=1
Reactant: O=Cc1sc(Br)nc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a 0° C. solution of 2,4-dibromo-1,3-thiazole-5-carbaldehyde (3.38 g, 12.3 mmol) in anhydrous methanol (130 mL) was added sodium borohydride (600 mg, 15.9 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (100 mL) was added, and the mixture was evaporated. The resultant residue was extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with brine (2×100 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (2,4-dibromo-1,3-thiazol-5-yl)methanol (2.64 g, 77%). The product was used without further purification.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH:10]=O)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[NH2:21].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:21]/[C:14]1[C:13]([Cl:12])=[CH:18][C:17]([F:19])=[CH:16][C:15]=1[Cl:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Reactant: Nc1c(Cl)cc(F)cc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(Cl)cc(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Titanium tetrachloride (1M, 4.0 mL, 4.15 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (1.0 g, 6.75 mmol), 2,6-dichloro-4-fluorophenylamine (1.22 g, 6.75 mmol) and triethylamine (2.8 mL, 20.3 mmol) in DCM (24 mL), under nitrogen. The reaction was stirred for 30 minutes at 0° C., warmed to room temperature, stirred for an additional 2 h, and concentrated under reduced pressure. The residue was dissolved in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid (2.09 g, quant.). This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(OCCCBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)cc3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.758 g of 1-(3-bromopropoxy)-4-fluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.13 (1:2 EtOAc-heptane); Rt=5.12.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(COC)OC>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCOCC1

Procedure:
4-(2-Nitro-4-trifluoromethylphenyl)morpholine was prepared by reaction of 4-chloro-3-nitrobenzotrifluoride with equimolar amounts of morpholine and triethylamine in monoglyme. The resultant product melts at 37° - 39° C.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[N:12]3[CH:20]=[CH:21][N:22]=[C:11]3[CH:10]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)#[N:24]>>[C:23]([CH2:25][C:26]1([N:17]2[CH:16]=[C:15]([C:13]3[N:12]4[CH:20]=[CH:21][N:22]=[C:11]4[CH:10]=[C:9]([C:7]4[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=4)[N:14]=3)[CH:19]=[N:18]2)[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)#[N:24]
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Yield: 64 %

Procedure:
7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Example 34, Step B) was reacted in the same manner as Example 34, Step C, replacing 3-cyclopropylacrylonitrile with tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (Preparation F, Step A) to obtain tert-butyl 3-(cyanomethyl)-3-(4-(7-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.090 g, 0.1846 mmol, 64% yield). MS (apci) m/z=488.3 (M+H).
Reaction SMILES: Cl[C:2](=O)[CH2:3][C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].O>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]#[CH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: C#CCON=C(CC(=O)Cl)C(=O)OCC
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: C#CCON=C(C(=O)OCC)c1csc(N)n1
Temperature: 40 °C
Reaction time: 1.25 h
Yield: 53.5 %

Procedure:
A mixture of ethyl 4-chloro-4-oxo-2-propargyloxyiminobutyrate (syn isomer, 61 g), thiourea (20 g), sodium acetate 3-hydrate (35.8 g), water (150 ml), and ethanol (180 ml) was stirred at 40° C. for 1.25 hrs. The reaction mixture was treated in a conventional manner to give ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 35.6 g).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[C:13]([N:16]1[C:22]([CH3:24])([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[S:18])(=[O:15])[CH3:14].[OH-].[Na+]>O>[C:13]([N:16]1[C:22]([CH3:23])([CH3:24])[C:20](=[O:21])[N:19]=[C:17]1[S:18][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N:3]([CH3:12])[CH3:2])(=[O:15])[CH3:14]
Reactant: CC(=O)N1C(=S)NC(=O)C1(C)C
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1C(SCc2ccccc2N(C)C)=NC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, 4.18g of 2-dimethylaminobenzylchloride hydrochloride was added to a solution of 3.43 g of 1-N-acetyl-5,5-dimethyl-2-thiohydantoin in 50 mL of N,N-dimethylsulfoxide. The reaction mixture was stirred for one hour at the room temperature and poured into 100 mL of water. The pH of the solution was adjusted to 7-8 with a diluted aqueous solution of NaOH and extracted. The precipitate was extracted with 100 mL of ethyl acetate (AcOEt). The thus obtained AcOET layer was successively washed two times with 100 mL of water and 100 mL of brine, dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The thus obtained residue was purified by column chromatography (using CHCL3 as a developing solvent). Recrystallized from diethyl ether-n-hexane gave the desired compound in the form of needle-like crystal. The yield of this compound was 3.4 g with a yield ratio of 57.6%, and the melting point was 99°-100° C.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15]>C(O)C>[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: COCCOCCN
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: COCCOCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.4 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (2.24 g) in ethanol (20 mL) was added 2-(2-methoxyethoxy)ethanamine (2.5 g), and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (3.1 g).
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C>CO>[CH:23](=[C:19]1[C:20](=[O:21])[C:4]2([CH3:3])[CH:17]([CH:16]3[CH:7]([CH2:6][CH2:5]2)[C:8]2[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=2[CH2:14][CH2:15]3)[CH2:18]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccccc1)C2=O
Reaction time: 4 h

Procedure:
Potassium hydroxide (1.0 g) was added to a solution of estrone (1.350 g, 5.0 mmol) and benzaldehyde (1.0 g, 9.4 mmol) in methanol (50 ml) at room temperature. The resulting orange solution was stirred at this temperature for 4 h. Then glacial acetic acid (ca. 5 ml) was added with stirring. The colour changed to light yellow and a white solid precipitated. The solid was filtered off and washed with water (50 ml), methanol (20 ml), diethyl ether (50 ml) and hexane and dried under high vacuum. Yield 1.578 g (88%). H-NMR (CDCl3, 400 MHz), δ: 1.00 (s, 3H), 1.40-1.77 (m, 5H), 2.04-2.12 (m, 2H), 2.26-2.34 (m, 1H), 2.38-2.45 (m, 1H), 2.50-2.60 (m, 1H) 2.86-3.03 (m, 3H), 4.76 (s, 1H, —OH), 6.60 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.2, 2.3 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 7.34-7.45 (m, 3H), 7.48 (s, 1H), 7.54-7.59 (m, 2H). LRMS (FAB+): 359.2 (100, [M+H]+). LRMS (FAB−): 357.2 (100, [M−H]−). HRMS (FAB+) 359.202332 C25H27O2 requires 359.201105
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[N:5][N:6]=1.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[CH:11]=[O:12].[NH4+].[Cl-].CC(OC)(C)C>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]([C:4]2[O:3][C:2]([CH3:1])=[N:6][N:5]=2)[OH:12])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1nnco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1nnc(C(O)c2cc(Br)cc(C(F)(F)F)c2)o1
Reaction time: 0.5 h

Procedure:
2.79 g (33.2 mmol) of 2-methyl-1,3,4-oxadiazole are dissolved in 45 ml THF at −5° C., 33.2 mmol (25.54 ml) of isopropyl magnesium chloride-lithium chloride complex are added during 20 minutes while the temperature is kept <0° C. The mixture is kept at 0° C. for 30 minutes, then 0.8 Eq (6.7 g) of 3-Bromo-5-trifluoromethyl-benzaldehyde are added and the resulting mixture is allowed to reach RT and stirred for additional 60 minutes. The reaction is then stopped by the addition of 10 ml saturated NH4Cl solution. 50 ml MTBE are added, the organic phase is separated, washed with brine and dried over MgSO4. The solvent is removed in vacuo and the crude material (9 g) is used without further purification in the next step:
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cccc(F)c3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (110 mg, 0.38 mmol, 1.00 equiv), 3-fluorophenylboronic acid (157.4 mg, 1.12 mmol, 3.00 equiv), Pd(PPh3)4 (86.5 mg, 0.07 mmol, 0.20 equiv), K3PO4 (318 mg, 1.51 mmol, 4.00 equiv), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 75 mg (57%) of methyl 2-(3-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:3]=1.P(Br)(Br)([Br:25])=O>O>[Br:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1c2ccccc2c(O)nn1-c1cccc(C(F)(F)F)c1
Solvent: O
Product: O=c1c2ccccc2c(Br)nn1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
4-Hydroxy-2-(3-trifluoromethylphenyl)-2H-phthalazin-1-one (0.50 g, 1.6 mmol) and phosphorus oxybromide (1.9 g, 6.5 mmol) were stirred at 150° C. for 2 h. H2O (100 ml) was added after cooling to room temperature. The precipitated solid was collected by filtration and washed with H2O. Drying of the solid in vacuum gave the title compound (0.4 g, 66% yield). 1H-NMR: (400 MHz, D6-DMSO) 8.39 (1H, d), 7.95–8.12 (5H, m), 7.79–7.99 (2H, m); MS (ESI+)=370.98 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:41][CH:42](Cl)[CH:43]([CH3:45])[CH3:44])(=[O:40])[CH:37]([CH3:39])[CH3:38]>CN(C=O)C>[C:36]([O:41][CH:42]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH:43]([CH3:45])[CH3:44])(=[O:40])[CH:37]([CH3:39])[CH3:38]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)C(=O)OC(Cl)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(OC(=O)C(C)C)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 12.2 %

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL), KOH (69 mg, 1.23 mmol) and a solution of 1-chloro-2-methylpropyl isobutyrate (108 mg, 0.61 mmol) in anhydrous DMF (0.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1), and recrystallized in methanol to afford the title compound as a white solid (47 mg, 13.4%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](Cl)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([C:28]2[NH:32][C:31]([SH:33])=[N:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([S:33][C:31]2[NH:32][C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:29][N:30]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1ncc(-c2ccccc2)[nH]1
Reactant: COC(=O)C(Cl)Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Sc1ncc(-c2ccccc2)[nH]1

Procedure:
The solution of 0.3 g (0.001 mol) of methyl 3-[4-(benzyloxy)phenyl]-2-chloropropionate in methanol (2 ml) was added dropwise to the solution of 0.18 g (0.001 mol) 5-phenyl-1H-imidazol-2-thiol and 0.04 g (0.001 mol) of NaOH in methanol (3 ml). The solution then was heated at reflux for 5 h. The crude product obtained after removing the solvent was used without purification in the next step of the synthesis.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30]C5C(C)=NC=CC=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[C:39]1[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=1>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:39]5[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nccc1O
Reactant: Cc1ncccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1
Product: Cn1nccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1

Procedure:
Prepared as for 6-fluoro-3-(4-{4-[(2-methylpyridin-3-yl)oxy]phenyl}-1H-1,2,3-triazol-1-yl)-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 5-hydroxy-1-methyl-1H-pyrazole.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([CH3:12])[N:5]=1.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=O>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:13]=[CH:10][C:9]3[CH:8]=[N:7][C:6]([CH3:12])=[N:5][C:4]=3[N:3]=2)=[CH:17][CH:18]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Cc1ncc(C=O)c(N)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc2ccc(-c3ccc(F)cc3)nc2n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
15 ml of 40% strength by weight aqueous potassium hydroxide solution were slowly added to a suspension of 30.1 g (0.22 mol) of 4-amino-5-formyl-2-methylpyrimidine and 31.7 g (0.23 mol) of 4-fluoroacetophenone in 395 ml of methanol at 20°-25° C., a homogeneous solution being formed. After the mixture had been stirred for 20 hours at about 20° C., the solid formed was isolated and was recrystallized from ethanol. Yield: 50%; mp.>200° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=1.Cl[CH2:13][C:14]1[O:15][C:16]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([CH3:24])[C:17]=2[N:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:24][C:19]1[C:17]2[N:18]=[C:14]([CH2:13][NH:1][C:2]3[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=3)[O:15][C:16]=2[C:22]([CH3:23])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C)c2oc(CCl)nc12
Reactant: CCc1cc(N)c(=O)[nH]c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1cc(NCc2nc3c(C)ccc(C)c3o2)c(=O)[nH]c1C

Procedure:
A mixture of 3-amino-5-ethyl-6-methyl-2-(1H)-pyridinone (0.23 g, 1.5 mmol), 2-chloromethyl-4,7-dimethylbenzoxazole (0.29 g, 1.5 mmol), diisopropylethylamine (0.39 g, 3 mmol) in acetonitrile (50 mL) was refluxed under an atomosphere of nitrogen for 12 hours. The resultant mixture was concentrated under reduced pressure (15 torr). The residue was then subjected to column chromatography on silica gel (100 g, elution with 4% methanol in chloroform). Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [F:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]=[CH2:5].B.[O:13]1CCCC1.OO>>[F:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][CH2:5][OH:13]
Reactant: C=CCC(F)CCCCCC
Reactant: C1CCOC1
Agent: B
Agent: OO
Product: CCCCCCC(F)CCCO

Procedure:
The title compound was prepared essentially as described in Example 1. R-4-fluoro-1-methanesulfonoxydecane was prepared by copper catalyzed addition of vinyl magnesium bromide to epichlorohydrin to yield 5-chloro-4-hydroxypent-1-ene which was treated with base to give the corresponding epoxide. The epoxide is then ring opened by the addition of propyl magnesium bromide to yield 4-hydroxy-dec-1-ene. This hydroxy compound is converted to 4-fluoro-dec-1-ene as described in Example 1, followed by treatment with borane/tetrahydrofuran and hydrogen peroxide to give 4-fluoro-decanol. This alcohol was treated with methane sulfonyl chloride in the presence of triethylamine to yield the desired intermediate R-4-fluoro-1-methylsulfonoxy decane.