Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([N+:13]([O-])=O)=[CH:5][N:4]=1)#[N:2]>CCOC(C)=O.CC(O)=O.[Fe]>[NH2:13][C:6]1[CH:7]=[C:8]([C:9]([F:12])([F:10])[F:11])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ncc(N)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
2-cyano-5-nitro-3-trifluoromethylpyridine (7 mg, 0.032 mmol) is dissolved in 1:1 EtOAc/AcOH (1 mL) and heated to 65° C. Iron powder (9 mg, 0.161 μmol, 5 eq, 325 mesh) is added and the mixture stirred for 2 hours. The mixture is filtered through celite, and the filtrate is concentrated under vacuo. The crude residue is purified by flash chromatography on silica gel (hexane/EtOAc) to afford 4 mg (67%) of the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:21]=2)[CH:16]=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:20]2[CH:21]=[C:22]3[C:17]([CH:16]=[N:15][N:14]3[CH3:13])=[CH:18][CH:19]=2)[S:25]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3cnn(C)c3c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3cnn(C)c3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-indazol-6-yl)methyl)sulfamoyl)benzoate (step-1 of Example 17).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.Cl.[CH:24]([N:27]([CH:33]([CH3:35])[CH3:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O>[CH:33]([N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29][C:30]([O:32][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:31])([CH3:35])[CH3:34]
Reactant: CC(C)N(CCC(=O)O)C(C)C
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)N(CCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)C(C)C
Yield: 27.7 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.9 g) in anhydrous dimethylformamide (70 cc), 3-diisopropylaminopropionic acid hydrochloride (4.4 g) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (7.45 g), and after the residue obtained has been recrystallized successively, first in acetonitrile and then in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 3-diisopropylaminopropionate (2.7 g), m.p. 135° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][C:11]=2[O:19][CH3:20])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][C:11]=1[O:19][CH3:20]
Reactant: COc1cc(C(N)=O)ccc1C(O)c1ccc(Cl)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(N)=O)ccc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 122.3 %

Procedure:
To a solution of 4-((3,4-dichlorophenyl)(hydroxy)methyl)-3-methoxybenzamide (Preparation 156, 142 mg, 0.435 mmol) in DCM (5 mL) was added TFA (0.065 mL, 0.870 mmol) followed by triethylsilane (0.083 mL, 0.522 mmol) and the reaction stirred at room temperature for 72 hours. Further TFA (0.065 mL, 0.870 mmol) and triethylsilane (0.083 mL, 0.522 mmol) were added and the reaction stirred for a further 24 hours. The reaction was partitioned between saturated aq. NH4Cl (20 mL), and EtOAc (20 mL). The layers were separated and the aqueous was extracted with EtOAc (2×20 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and the solvent removed in vacuo to give a white solid (165 mg, 100%). The material was used as crude in the next reaction without further purification.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([NH2:18])=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[Cl-].[Na+].[OH-].[Na+]>ClCCCl>[C:1]1([CH:7]=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[N:18])[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C1CCN(CC=Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1CCN(CC=Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 99.4 g of the 1-(3-phenyl-2-propenyl)-4-piperidinecarboxamide, 25 ml of phosphorus oxychloride and 30 g of sodium chloride are suspended in 750 ml of 1,2-dichloroethane and heated to its reflux temperature with vigorous stirring for a period of 2 hours. After several minutes at the reflux temperature a white precipitate separates. The reaction mixture is cooled, a 10% sodium hydroxide solution is added and the mixture extracted with diethyl ether. The combined extracts are washed with water, followed by a solution of sodium chloride, dried (MgSO4) and concentrated in vacuo. The residual oil is distilled under reduced pressure to yield the desired 1-(3-phenyl-2-propenyl)-4-piperidinecarbonitrile as a viscous, colorless oil, b.p. 169°-76° C./0.35-0.70 mm.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:13]([F:24])=[O:15])[CH:10]([CH3:12])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with (S)-N-BOC-valine (217.2 mg, 1.00 mmol) was added 2.5 mL CH2Cl2, and pyridine (81 μL, 1.00 mmol). The solution was cooled to −15° C., and to the reaction was added cyanuric fluoride (450 μL, 5.0 mmol). The reaction was stirred at −15° C. for 60 minutes, with the gradual formation of a white precipitate. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with ice-cold water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 201.3 mg of 25g as white needles. FTIR (neat) 1847 cm−1.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[OH:18])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N:12]2[CH2:13][CH2:14][N:15]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][CH2:17]2)=[CH:6][C:5]=1[OH:18])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(O)cc1N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)C)c(O)cc1N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a stirring solution of 2-Isopropyl-4-methoxy-5-piperazin-1-yl-phenol (0.47 g, 1.88 mmol) in dichloromethane at 0° C. under nitrogen was added triethylamine (0.26 mL, 1.89 mmol), followed by methanesulfonyl chloride (0.15 mL, 1.89 mmol). The reaction mixture was stirred at 0° C. for five minutes, and then allowed to warm to room temperature. The reaction mixture was partitioned between dichloromethane and water, and the organic layer was separated, washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexanes:EtOAc 3:2) to afford 0.1 g (16% ) of 2-Isopropyl-5-(4-methanesulfonyl-piperazin-1-yl)-4-methoxy-phenol as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[CH3:22][O:23][C:24]1[C:29]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1cncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-Bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 61.1, 90 mg, 0.25 mmol), 2-methoxypyridin-3-ylboronic acid (45.9 mg, 0.300 mmol), K2CO3 (69.1 mg, 0.500 mmol), PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol), water (0.6 mL) and dioxane (3 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 60° C. for 1 h. The RM was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 15 g, EtOAc) to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=1.1 min, m/z=390.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s, 3H) 7.19 (dd, J=7.23, 4.89 Hz, 1H) 7.40 (d, J=8.99 Hz, 2H) 7.89 (m, J=9.00 Hz, 2H) 7.97 (dd, J=7.43, 1.96 Hz, 1H) 8.28 (dd, J=5.08, 1.96 Hz, 1H) 8.46 (t, J=2.15 Hz, 1H) 8.97 (d, J=1.95 Hz, 1H) 9.08 (d, J=2.35 Hz, 1H) 10.64 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH2:26])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:30]=1>>[CH2:1]([O:3][C:4](=[O:27])[C:5]([CH3:7])([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH:26][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:30]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:6])[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3Nc3cccc(-c4ccccc4)n3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 2-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-2-methyl-propionic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: [CH:1]1([Tl])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:7]1([P:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:15]1([P:13]([C:2]2[CH2:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [Tl]C1C=CC=C1
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: C1=CCC(P(c2ccccc2)c2ccccc2)=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 g (0.186 moles) of cyclopentadienylthallium (obtained from Fluka) were placed in a 500 ml flask together with 300 ml of diethyl ether. The suspension was cooled to 0° C. and 34.2 ml (0.186 moles) of diphenylchlorophosphine were added dropwise over 10 minutes. The suspension was then heated to room temperature, stirred for one hour and finally filtered through a frit. The solvent was then stripped off under vacuum to leave 39.5 g (85% of the theoretical yield) of the intermediate diphenylphosphinocyclopentadiene, compound 2. An 18.6 g portion (0.074 moles) of compound 2 was then diluted with toluene and cooled to 0° C. 33.2 ml of a 2.24 molar solution of butyllithium in hexane (0.074 moles) were added to this solution over 10 minutes. After being heated to room temperature and stirred for 2 hours, the yellow solution produced a precipitate, which was filtered off and washed with toluene and then with hexane. After drying under vacuum, 13.2 g of compound 3 (70% of the theoretical yield) were obtained in the form of a brownish powder (cf. J. Am. Chem. Soc. 105, (1983), 3882; Organometallics 1, (1982), 1591). 1H NMR (400 MHz, THF-d8): δ=7.3 (m, 4H); 7.15 (m, 6H); 5.96 (m, 2H); 5.92 (m, 2H); 31P NMR (161.9 MHz, THF-d8): δ=−20.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[N:7]([CH2:10][CH2:11][C:12](Cl)=O)=[N+]=[N-]>>[NH2:7][CH2:10][CH2:11][CH2:12][NH:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1
Reactant: Nc1cc[nH]n1
Reactant: [N-]=[N+]=NCCC(=O)Cl
Product: NCCCNc1cc[nH]n1

Procedure:
Reaction of 3-aminopyrazole with β-azidopropionyl chloride by the procedure of Example 40 gives 3-(3-aminopropylamino)pyrazole.
Reaction SMILES: Cl.O1CCCCC1[O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1>O1CCCC1.[Cl-].[Na+].O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=c1[nH]c(-c2cccc(COC3CCCCO3)c2)no1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2cccc(CO)c2)no1
Reaction time: 18 h
Yield: 99 %

Procedure:
Add 10% hydrochloric acid (100 ml) to a solution of 3-[3-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-4H-[1,2,4]oxadiazol-5-one (4.50 g, 16.3 mmol) in tetrahydrofuran (0.1M) and stir. After 18 hours, pour reaction into brine and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title product as a white solid (3.10 g, 99%): 1H NMR (DMSO-d6) δ 4.57 (s, 2H), 7.55 (m, 2H), 7.67 (dt, 1H), 7.81 (m, 1H), 12.95 (bs, 1H).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57](Br)=[CH:56][C:55]=2[CH3:61])=[O:50])[CH:45]=[CH:46][CH:47]=1)[CH3:41])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([B:25]([OH:27])[OH:26])=[CH:56][C:55]=2[CH3:61])=[O:50])[CH:45]=[CH:46][CH:47]=1)[CH3:41])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc([C@H](C)NC(=O)OCc2ccccc2)c1
Product: Cc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc([C@H](C)NC(=O)OCc2ccccc2)c1
Yield: 22 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 59C (2.46 g, 4.8 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 59D (560 mg, 22%) as a solid. 1H NMR (400 MHz, MeOD-d4) δ ppm 1.25-1.41 (m, J=4.39 Hz, 3 H) 2.27 (s, 3 H) 2.61 (s, 2 H) 2.92 (s, 2 H) 4.22 (s, 2 H) 4.64 (s, 1 H) 6.84-7.56 (m, 12 H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]2[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:36]1CCOC[CH2:37]1>>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:37][OH:36])[C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1
Reactant: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2NC1=O
Reactant: C1COCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(CO)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
First, 7-(2-chloro-4-trifluoromethylphenoxy)-2-methyl-2H-1,4-benzoxazine-3 (4H)-one (0.4 g) prepared in Example 1 was dissolved in dioxane (5 ml), p-formaldehyde (0.1 g) and p-toluenesulfonic acid (0.1 g) were added to the solution, and the mixture was stirred at 80° C. for 3 hr. After the completion of the reaction, the reaction mixture was concentrated in vacuo, and the resultant residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=1/1) to prepare the title compound (0.2 g) as a colorless crystal (yield: 50%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][CH2:36][N:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=2)[C:38]1=[O:55]>>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:42]3[CH:43]=[C:44]4[C:39](=[CH:40][CH:41]=3)[C:38](=[O:55])[N:37]([CH2:36][CH2:35][CH:31]3[CH2:32][CH2:33][CH2:34][N:30]3[CH3:29])[CH2:45]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN1CCCC1CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(CCC4CCCN4C)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-[2-(1-methylpyrrolidin-2-yl)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=534.3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1.CN(C=O)C>CS(C)=O>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=2)=[CH:6]3)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(Cn4cccn4)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester prepared in Preparation 41 and pyrazole were reacted according to the same procedure as Preparation 92 except that DMF was used as the solvent instead of DMSO to give the title compound.
Reaction SMILES: [CH:1]1([C:6]([OH:18])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]12[CH2:24][CH:23]1[CH2:22][N:21]([CH2:25][C:26]#[C:27][CH2:28]O)[CH2:20]2>>[C@@H:19]12[CH2:24][C@@H:23]1[CH2:22][N:21]([CH2:25][C:26]#[C:27][CH2:28][O:8][C:7](=[O:9])[C:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[OH:18])[CH2:20]2
Reactant: OCC#CCN1CC2CC2C1
Reactant: COc1ccc(C(O)(C(=O)O)C2CCCC2)cc1
Product: COc1ccc(C(O)(C(=O)OCC#CCN2C[C@H]3C[C@H]3C2)C2CCCC2)cc1

Procedure:
The title compound was prepared by following the procedure described in Step-b of Example-3, using 2-cyclopentyl-2-hydroxy-2-(4-methoxyphenyl)acetic acid instead of 2-cyclopentyl-2-hydroxy-2-phenyl acetic acid and 4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynol instead of 4-(1,5-dimethyl-3-azabicyclo[3.1.0]hex-3-yl)-2-butynol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:13]Br.OS([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:13][C:11]1[CH:10]=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]=1
Reactant: BrBr
Reactant: Clc1ccc(-n2cccn2)cc1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(-n2cc(Br)cn2)cc1
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A solution of 1-(4-chlorophenyl)pyrazole (834 mg, 4.67 mmol) in acetic acid (10 mL) is treated with bromine (0.26 mL, 5.08 mmol). After stirring for 18 h, the solution is diluted with 40 mL water, and satd. aq. NaHSO3 solution is added until the bromine color had dissipated. Then, solid sodium bicarbonate is added until a neutral pH is obtained. This mixture is extracted with ethyl acetate (2×50 mL), and the extracts are washed with brine, combined, dried over MgSO4, filtered and evaporated. The solid residue is recrystallized from cyclohexane to afford pure product, 4-bromo-1-(4-chlorophenyl)-pyrazole (797 mg, 3.10 mmol, 66%). m.p. 75-76° C. (cyclohexane), 1H NMR (300 MHz, CDCl3): δ 7.89 (1H, s), 7.66 (1H, s), 7.57 (2H, d, J=9.0 Hz), 7.41 (2H, d, J=9.0 Hz). MS (ES+): m/e 261 (26), 259 (100), 257 (77).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH3:3][C:4]([C:20]1[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([Cl:15])[CH:21]=1)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(Cl)c1
Reaction time: 7 h

Procedure:
The starting material can also be prepared as follows: 4.8 g 50% sodium hydride in mineral oil are added to 100 ml hexamethylphosphoramide while stirring under nitrogen. Hereupon 17.1 g diethyl α-methylmalonate are added and the mixture slowly heated to 100°. The solution of 19.2 g 2,4-dichloro-nitrobenzene in 20 ml hexamethylphosphoramide is added dropwise during 1/2 hour and the temperature kept at 100° for seven hours. After cooling, the mixture is diluted with water, concentrated in vacuo, the residue taken up in water and extracted with benzene. The extract is washed with water, dried, filtered, evaporated, the residue distilled and the fraction boiling at 147°-148°/0.25 mm Hg collected, to yield the diethyl α-methyl-α-(3-chloro-4-nitrophenyl)-malonate. (The analogously prepared diethyl α-ethyl-α-(3-chloro-4-nitrophenyl)-malonate boils at 170°-174°/1 mm Hg.)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][O:25][C:26]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:24][O:25][C:26]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1cccc(C(=O)O)c1OC
Product: COc1cccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1OC

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-Dimethoxy-benzoic acid.